Saturday Abstracts

www.sobp.org/journal

Saturday Abstracts BIOL PSYCHIATRY 2013;73:1S-326S 221S

saTurday, May 18

Plenary SeSSionLeveraging Plasticity in Therapeutics and Recovery

Saturday, May 18, 2013, 8:00 AM - 11:30 AMContinental 4-6 - Ballroom Level

Chair: Kerry Ressler

691. The Next Generation of Therapeutics: Where? When? How?Thomas R. Insel

National Institute of Mental Health, National Institutes of Health, Bethesda, MD

Although psychiatric medications have been among the most widely prescribed of all drugs in medicine for the past decade, the continuing high morbidity and mortality from mental disorders demonstrates the urgent need for better treatments. The challenges to developing new medications are formidable, but recent research, mostly from the public sector, suggests several avenues for hope. This presentation will review three areas for treatment development: new molecular targets, new clinical targets, and new uses of existing treatments. (Insel, 2012) How will we identify new molecular targets? The genetics of schizophrenia, bipolar disorder, and autism are beginning to cluster around common biological pathways. While it is too early to know how the genetics of mental illness will translate to the pathophysiology of mental illness, as the genetic architecture begins to point to specific biological pathways, there is good reason to expect that novel druggable targets will emerge. (Hyman, 2012) What will be the new clinical targets? Rapid acting antidepressants, treatments for cognition in schizophrenia, and pro-social compounds are new areas with enormous potential for improving public health. Neuroplasticity, whether activated by medication, electrical stimulation, or cognitive training is a new frontier for therapeutics. In an era of “precision medicine”, current clinical targets like “depression” and “psychosis” may need to be replaced. What about current interventions? The combination of medications and psychosocial treatments is clearly an opportunity for enhancing public health impact. Medications from other fields may also reveal great promise. While we often disparage serendipity, “repurposing” has been the best way to discover new medications for mental disorders and can now be systematized.Progress will depend on not only translating this new biology to new treatments but also creating a new culture for accelerating this translation based on standardization, integration, and sharing of data through new partnerships.References:Insel TR (2012) Next Generation Treatments for Mental Disorders, Science Translational Medicine, 4: 155ps19.Hyman SE (2012) Revolution Stalled, Science Translational Medicine, 4: 155cm11.

692. Neurogenesis and Generalization: A New Approach to Stratify and Treat Anxiety DisordersRene Hen

Psychiatric Institute, Columbia University, New York, NY

Although an influence of adult neurogenesis in mediating some of the effects of antidepressants has received considerable attention in recent years, much less is known about how alterations in this form of plasticity may contribute to psychiatric disorders such as anxiety and depression. One way to begin to address this question is to link the functions of adult-born hippocampal neurons with specific endophenotypes of these disorders. Recent studies have implicated adult-born hippocampal neurons in pattern separation, a process

by which similar experiences or events are transformed into discrete, non-overlapping representations (Sahay et al., 2011a; 2011b). Here we propose that impaired pattern separation underlies the overgeneralization often seen in anxiety disorders, specifically post-traumatic stress disorder and panic disorder, and therefore represents an endophenotype for these disorders (Kheirbek et al., 2012). The development of new, pro-neurogenic compounds may therefore have therapeutic potential for patients who display pattern separation deficits.References:Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R.(2011a). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 472(7344):466-70. Sahay A, Wilson DA, Hen R. (2011b). Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron. 70 (4):582-8. Review. Kheirbek MA, Klemenhagen KC, Sahay A, Hen R. (2012) Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat Neurosci. 15(12):1613-20.

693. Translational Neuroscience: Early Detection and Improving Cognition in Neuropsychiatric DisordersBarbara J. Sahakian

Department of Psychiatry and MRC, Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom

Psychiatric disorders are disorders of neurocognition. Many psychiatric disorders are of neurodevelopmental origin with an onset or prodromal stage in childhood or adolescence. Cognitive manifestations include: attentional biases, aberrant learning, memory impairments, dysfunctional reward systems; and lack of top down cognitive control by prefrontal cortex. Recent neuroscience and mental health policy has emphasized the importance of successful and resilient neurodevelopment. (Beddington et al 2008; Sahakian et al 2010; Collins et al 2011). Therefore biomarkers, including cognitive, genetic and neuroimaging ones, are needed for prevention, early detection and for assessing the efficacy of treatments. Policy has also emphasized the importance of novel approaches to drug development for psychiatric disorders (Insel, Sahakian et al 2012). For example, targets for treatment may become closely related to genetics and neurobiology (eg impulsivity, episodic memory) rather than diagnostic categories (eg ADHD, schizophrenia) (Sahakian et al 2010; Insel and Cuthbert 2010). A treatment which reduces impulsive behaviour might do so whether an individual has a diagnosis of mania, ADHD or substance abuse, and treatment of episodic memory problems might prove useful for improving cognition and functional outcome in both mild Alzheimer’s disease and first-episode schizophrenia (Sahakian et al 2010). Forward and back translation is key to developing effective neurobiological models of neuropsychiatric disorders and for novel treatment development. It is now recognised that cognitive problems impair the everyday functioning of patients with mental health disorders and prove the biggest barrier to rehabilitation and return to paid employment (Beddington et al 2008). Therefore cognitive enhancing drugs are needed to treat cognitive impairment thereby improving the quality of life and wellbeing for patients and their families and reducing the financial burden on society (Beddington et al 2008). Pharmacological treatments may prove most effective when used in combination with cognitive ones, such as cognitive behavioural therapy or cognitive training.References:Beddington J, Cooper CL, Field J, Goswami U, Huppert FA, Jenkins R, Jones HS,Kirkwood TBL, SahakianBJ, & Thomas SM (2008). The mental wealth of nations. Nature, 455, 1057-1060Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS, Bordin IA, Costello EJ,Durkin M., Fairburn C., Glass RI, Hall W, Huang Y, Hyman SE, Jamison K KaayaS, Kapur S, Kleinman A, Ogunniyi A, Otero-Ojeda A, Poo M-M, Ravindranath V,Sahakian BJ, Saxena S, Singer PA, Stein DJ, Anderson W, Dhansay MA, EwartW, Phillips A, Shurin S, & Walport M (2011) Grand challenges in global mental


Saturday Abstracts222S BIOL PSYCHIATRY 2013;73:1S-326S

health. Nature, 475, 27-30.Insel T and Cuthbert B (2010) Research Domain Criteria (RDoC): Toward a New Classification Framework for Research on Mental Disorders. Am J Psychiatry 167:7Insel TR, Sahakian BJ et al. (2012) A plan for mental illness. Nature 483, 269Sahakian BJ, Malloch G, Kennard C (2010) A UK strategy for mental health and wellbeing. Lancet, 375, 1854-1855

694. The Science of Neuronal and Synaptic Reconnection Therapies for Neurodegenerative DiseasesOle Isacson

Neuroregeneration Research Institute, McLean Hospital / Harvard Medical School, Belmont, MA

Cell therapy for the Parkinson’s disease (PD) has advanced significantly in recent years (Tsui and Isacson, 2011). Open-label clinical trials have provided proof of principle that transplantation of fetal dopamine (DA) neurons can improve patients’ motor symptoms. It is likely that technical improvements, including standardization in cell preparation and delivery, will provide more reliable clinical outcome and reduce the risk of side effects (Mendez et al., 2008). However, cell therapy is only an experimental procedure and depends on complex issues for access to rare donor cells. Stem cell derived neurons may provide a more practical source of neurons for future cell therapy and transplantation. Early work demonstrated that embryonic stem (ES) cell derived DA neurons restored striatal DA storage capacity and cortical motor activation as measured by PET and functional magnetic resonance imaging in animal models of PD (Bjorklund et al., 2002). A gradual recovery of motor function reflected the differentiation and maturation of synaptic connections of the transplanted DA neurons. Alternatives to human ES cells as sources of donor cells have emerged through manipulation of adult cells, including fibroblasts, with various transcription factors. A very promising approach involves controlled de-differentiation (reprogramming) adult cells to become ES-like, also known as induced pluripotent stem (iPS) cells (Hargus et al., 2010). In addition, our data from diverse populations of human iPS-derived neural cells indicate that mitochondrion-associated PD disease phenotypes can be analyzed and treated pharmacologically (Cooper et al., 2012). Human neurons mature too slowly for extensive functional studies in vitro, and therefore in vivo rodent transplantation bioassays including physiology can be used to test pathobiologic and therapeutic hypotheses for human iPS-derived neurons.References:1. Cooper O, Seo H, Andrabi S, Sundberg M, McLean J, Carrillo-Reid L, Xie Z, Osborn T, Hargus G,Deleidi M, Lawson T, Bogetofte-Thomasen H, Perez-Torres E, Clark L, Moskowitz C, Guardia-Laguarta C, Mazzulli J, Chen L, Volpicelli-Daley L, Romero N, Jiang H, Uitti RJ, Huang Z, Opala G, Feng J, Ross OA, Trojanowski JQ, Lee VM-Y, Krainc D, Marder K, Przedborski S, Surmeier DJ, Wszolek ZK, Dawson TM, Isacson O. (2012) Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson’s Disease. Sci. Transl. Med. 4(141): 52-64.2. Tsui A and Isacson O. (2011) Functions of the Nigrostriatal Dopaminergic Synapse and the Use of Neurotransplantation in Parkinson’s Disease. J. Neurol. Aug;258(8):1393-405.3. Hargus G, Cooper O, Deleidi M, Levy A, Lee K, Marlow E, Yow A, Soldner F, Hockemeyer D, Hallett PJ, Osborn T, Jaenisch R, Isacson O. (2010) Differentiated Parkinson patient-derived iPS cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc Natl Acad Sci USA 107(36):15921-6.4. Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O. (2008) Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med;14:507-9. 5. Bjorklund, L., Pernaute, R.S., Chung, S., Andersson, T., Chen, I.Y.C., McNaught, K.S.P., Brownell, A.-L., Jenkins, B.G., Wahlestedt, C., Kim, K.-S., Isacson, O. (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl. Acad. Sci. 99, 2344-9.

SymPoSiumBrainCloud: Weathering the Deluge of High-

Throughput Gene Expression AnalysisSaturday, May 18, 2013, 12:30 PM - 2:30 PM

Yosemite A - Ballroom LevelChair: Daniel R. Weinberger

Supported By: Lieber Institute Intramural Research Fund

695. Transcriptional Patterns of Brain Development Andrew Ellis Jaffe1, Elana Fertig2, Michael Ochs2, Luigi Marchionni2, Barbara K. Lipska3, Daniel R. Weinberger1, Joel E. Kleinman3, Thomas M. Hyde1, Carlo Colantuoni1

1Lieber Institute for Brain Development, Baltimore, MD, 2Division of Biostatistics & Bioinformatics, Johns Hopkins University, Baltimore, MD, 3Clinical Brain Disorders Branch, NIMH, Bethesda, MD

Background: Recent work identified temporal patterns of gene expression in the prefrontal cortex across human brain development [Colantuoni 2011]. Here we further explore processing of this data to better identify global trajectories of gene expression in the developing and aging human brain.Methods: The data from BrainCloud was re-normalized using surrogate variable analysis and an approach more biologically focused on finding gene expression trajectories. We then used Bayesian data-driven methods [Fertig 2010] to decompose genome-wide expression data into a pre-specified number of patterns, and identified distinct temporal trajectories of gene expression in the developing brain. More traditional approaches to decomposing global transcription patterns of principle component analysis and multidimensional scaling were contrasted with the Bayesian approach. For each global approach, we performed gene-set analysis on these global patterns to determine enrichment for predefined gene sets and pathways.Results: More rigorous statistical normalization greatly improved our ability to identify global transcription patterns across all three statistical approaches. However, the Bayesian approach identified important patterns of development that other approaches were unable to identify.Specifically, we observe several distinct waves peaking during fetal development, one during the first year of life, another during early adolescence, then a wave that plateaus in early adulthood, and another that rises far into aging.Conclusions: These fundamental patterns can potentially be used to inform the association of genetic variation with multi-genic expression phenotypes throughout life. Additionally, the re-normalized data will be available on Brain(Cloud)2, the new cross-platform cloud-based version of our BrainCloud research tool (www.libd.org/braincloud)Keywords: genomics, post-mortem human brain, gene expression, development, data processingSupported By: Lieber Institute Intramural Research Fund

696. Temporal Expression of Genes in the WNT Pathway Associated with CognitionAnna S. Karlsen1, Joey W. Trampush2, Dwight Dickinson2, Daniel R. Weinberger2, 3, Tianzhang Ye3, Joel E. Kleinman2, Niels Plath4, Thomas M. Hyde3

1Res.Lab. for Stereology and Neuroscience, Bispebjerg University Hospital, Copenhagen, Denmark, 2Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, IRP, NIMH, NIH, Bethesda, MD, 3Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, 4Synaptic Transmission 1, H. Lundbeck A/S, Valby, Denmark

Background: The Wnt signaling pathway is critical for the development and maintenance of the nervous system, involved in functions ranging from



neuroplasticity and neurogenesis to cell survival. Recent studies show that the Wnt pathway may contribute to the etiology of psychiatric disorders such as schizophrenia (SZ).Methods: In this study, we identify genes in the pathway that are associated with an array of cognitive scores in a clinical data set of controls (n = 630) and patients with SZ (n = 433) and combine the results with postmortem gene expression data (n = 785). Using the BrainCloud application, where the temporal expression of genes in the prefrontal cortex can be analyzed and filtered based on genotype, sex, age, and race, we identify potential SNPs that affect expression in the Wnt genes that showed the best association across the cognitive scores and diagnosis.Results: Having identified candidate SNPs and genes from clinical data sets, including cognitive phenotypes, the relationship between risk-associated SNPs and gene expression is checked in BrainCloud.Conclusions: BrainCloud has been useful in assessing the association between individual SNPs and transcript expression in fetal and postnatal brain development, and can also be applied to ages of highest risk for the onset of particular disorders.Keywords: schizophrenia, Wnt pathway, cognition, BrainCloud, gene expressionSupported By: Danish Research Council

697. Understanding the Complex Dynamic Expression of Risk-Associated Genes and Developmental Neuropsychiatric Disorders: GABA Signaling and Risk for IllnessThomas M. Hyde1, Kasey Davis2, 3, 4, Ran Tao3, Barbara K. Lipska3, Tianzhang Ye2, Mary M. Herman3, Daniel R. Weinberger3, 5, Joel E. Kleinman3

1Lieber Institute for Brain Development, Baltimore, MD, 2Neuropathology, Lieber Institute for Brain Development, Baltimore, MD, 3Clinical Brains Disorders Branch, NIMH, Bethesda, MD, 4Anatomy, Howard University, Washington, DC, 5Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD

Background: Abnormalities in prefrontal GABA signaling are among the most reproducible findings in studies of post-mortem human brain. Using BrainCloud, an online web tool and database, our team was able to investigate GABA-related transcript expression across the lifespan and its relationship to risk-associated allelic variations.Methods: Using high throughput cDNA microarrays and SNP chip technology, the expression of particular transcripts was assessed across the lifespan. After identifying potential alternative transcripts using information from RNA-Seq, they were confirmed using end-to-end PCR. qPCR was then used to measure the pattern of expression of these transcripts across the lifespan, and any changes associated with allelic variation in a well-established GAD1-risk associated genotype.Results: The cation-chloride co-transporters NKCC1 and KCC2 each have multiple alternative transcripts, and the expression of some of these transcripts is associated with a particular genetic variation in GAD1 (a gene that produces a vital GABA synthetic enzyme). The genes GAD1 and GAD2, which produce almost identical proteins for GABA synthesis, also yield multiple alternative transcripts.Conclusions: BrainCloud can be used to interrogate the expression of multiple genes associated with neurodevelopmental disorders such as schizophrenia. The results from BrainCloud can then guide additional explorations into the role of full-length and alternative transcripts in the etiology of neuropsychiatric disorders.Keywords: Neuropsychiatric Disorders, GABA Signaling, Schizophrenia, Gene expression, Alternative transcriptionSupported By: Lieber Institute Intramural Research Fund

698. Using Braincloud to Understand the Mechanism of Action of Potential Drug TargetsKristin L. Bigos

Lieber Institute for Brain Development, Baltimore, MD

Background: BrainCloud, a database that includes gene expression in the human brain, along with genetic SNP data and DNA methylation data, can be used to explore clinical research questions, from discovering mechanisms of genetic risk to understanding the mechanisms of potential drug targets and pathways. This presentation will demonstrate the application of BrainCloud to clinical research, with a focus on its use in clinical pharmacology.Methods: BrainCloud can be used to evaluate the mechanism of action of potential drug targets, to explore patterns of brain expression of candidate genes, or to understand a gene’s role in brain development.Results: BrainCloud was used to identify an mRNA transcript in human prefrontal cortex that was associated with increased expression in normal brains that carried the CACNA1C risk genotype associated with bipolar disorder and schizophrenia. This supported testing calcium channel blockers as a treatment for schizophrenia and/or bipolar disorder in individuals with the CACNA1C risk genotype. Similarly, using BrainCloud, we found genetic variation in GRM7 associated with schizophrenia is also associated with a GRM7 transcript that is preferentially expressed in fetal human brain. Many CYP450 genes, which are drug metabolizing enzymes, are highly expressed in brain. BrainCloud provides evidence for how these isoforms are differentially expressed in human prefrontal cortex across the lifespan, which gives us insight into their potential roles in brain development and brain function.Conclusions: BrainCloud is a valuable tool to explore how differences in brain expression related to genetic variation can be exploited as novel potential drug pathways.Keywords: BrainCloud, GRM7, CACNA1C, mRNA, CYP450Supported By: Private funding from the Lieber Institute for Brain Development

SymPoSiumProgress in Functional Genomic and Epigenomic

Approaches to Investigate Mental IllnessSaturday, May 18, 2013, 12:30 PM - 2:30 PM

Yosemite B - Ballroom LevelChair: Gustavo Turecki*

Co-Chair: David Goldman***Supported By: CIHR; AFSP**Supported By: AA000301

699. Epigenetic Mechanisms of Synaptic Remodeling in DepressionScott Russo

Mount Sinai School of Medicine, New York, NY

Background: Depression is thought to involve lasting changes in synaptic structure of brain reward neurons, although the mechanisms and behavioral relevance are unknown.Methods: We utilized RNA transcriptional profiling and chromatin immunoprecipitation assays to probe expression of the synaptic remodeling gene, Rac1, following chronic social defeat stress and in humans with major depressive disorder (MDD). We also utilized viral vectors and Rac1 knockout mice to determine its role in regulating synapse formation and depression-like behavioral responses.Results: Our data reveals a selective and long-term reduction in Rac1 transcription. This was marked by a repressive chromatin state surrounding its



proximal promoter region. Inhibition of class 1 HDACs with MS-275 rescued both decreased Rac1 transcription and social avoidance behavior. A similar repressive chromatin state was found surrounding the Rac1 promoter in human postmortem NAc from MDD subjects, which corresponded with reduced Rac1 transcription. Using targeted viral gene transfer and Rac1 conditional mice we show this adaptation is necessary and sufficient for social avoidance and anhdeonia and the formation of immature stubby excitatory spines by redistributing synaptic cofilin, an actin severing protein downstream of Rac1.Conclusions: Our data identifies epigenetic regulation of Rac1 in NAc as a bona fide disease mechanism in depression and reveals a functional role in regulating stress-related behaviors.Keywords: depression, synapse, spines, reward circuit, nucleus accumbensSupported By: NIH R01 MH090264

700. Discovery of Functional Loci in Old Animal Models by Exome Sequencing: A Grm2 Stop Codon in the Alcohol-Preferring RatDavid Goldman

NIAAA, Rockville, MD

Background: QTLs for alcohol preference have been identified in preferring (P) and non-preferring (NP) rats, an alcoholism model created by artificial selection. However, functional variants and genes in which they reside, remain elusive.Methods: Effects of variants identified by exome sequencing were confirmed by QTL analysis in F2 rats from the iP x iNP intercross. Global gene expression effects were profiled by RNA-Seq. Function of the Grm2 stop codon was evaluated via Western blots, by field potential recordings in presence of a mGluR2 agonist and via behavioral studies in Grm2 -/- mice.Results: From 6 P and 6 NP rats, we identified 25,715 SNVs that segregated between the strains. Two were stop codons and 36 were missense variants predicted to affect protein functions. P rats were homozygous for a stop codon in the mGluR2 gene (Grm2 *407). Loss of the receptor protein was complete, and as shown by the field potential recordings, loss of function was uncompensated. QTL analysis in iPxiNP F2’s revealed that loss of mGluR2 resulted in 32% increase in alcohol consumption and 28% increase in alcohol preference. The Grm2 stop codon is abundant in Wistar rats (allele frequency: 0.086). P rats were also homozygous for a stop codon in lipocalin 2 (Lcn2 *137). Lcn2 *137 was also linked to increased alcohol preference. In hippocampus of P and NP rats there was significant over-representation of differentially expressed genes (FDR < 0.05) involved in glutamate transmission. Conclusions: Exome sequencing in selected lines can detect loci altering complex behavioral traits.Keywords: alcoholism, exome sequencing, linkage, metabotropic glutamate receptorSupported By: AA000301

701. A Primate-Specific and Brain-Enriched miRNA is Involved in Depression and Regulates the Expression of GRM4Juan Pablo Lopez1, Raymond Lim2, Carl Ernst1, Mechawar Naguib1, Paul Pavlidis2, Gustavo Turecki3

1Psychiatry, McGill University, Montreal, QC, Canada, 2Psychiatry, University of British Columbia, Vancouver, BC, Canada, 3McGill University, Montreal, QC, Canada

Background: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by means of RNA degradation or translational repression. In this study, we identified a miRNA specific to primates and enriched in the brain as differentially expressed in depression.Methods/Results: We initially conducted a genome-wide expression study of miRNAs in the prefrontal cortex of depressed individuals (N=28) and

psychiatrically healthy controls (N=11) using miRNA microarrays. Significantly differentially expressed miRNAs were validated using alternative techniques. MiRNA-1202 was validated and subsequently replicated in a larger, independent sample (N=90). As this was a previously uncharacterized miRNA, we investigated its expression in different tissues and animal species. This miRNA is specific to primates and is significantly enriched in brain tissue. Target genes of miRNA-1202 were identified using several complementary bioinformatic tools, all of which suggested that it targets the metabotropic glutamate receptor 4 (GRM4) gene. The PFC expression of this gene correlated inversely with the expression of miRNA-1202, and in addition, functional experiments using miRNA mimics and target protectors were conducted to confirm the interaction between this miRNA and GRM4. We subsequently investigated the effects that antidepressants have on this miRNAs, using human neural progenitor cells (NPCs), and showed that antidepressants have a significant impact on miRNA-1202 levels in NPCs.Conclusions: In summary, our results suggest that miRNA-1202, a miRNA that is specific to primates, and more highly expressed in the human CNS, is differentially expressed in the depressed brain. This miRNA interacts with GRM4 and seems to be regulated by antidepressant treatment.Keywords: microRNA, depression, glutamatergic receptors, prefrontal cortex, epigeneticsSupported By: CIHR; AFSP

702. Epigenomics of Major Psychiatric DiseaseArturas Petronis

Centre for Addiction and Mental Health and University of Toronto, Toronto, ON, Canada

Background: Psychiatric diseases exhibit numerous non-Mendelian features, which are consistent with putative epigenetic misregulation. Identification of causal and disease-specific epigenetic differences, however, is a challenging task.Methods: We interrogated differentially modified DNA fractions in schizophrenia, bipolar disorder, and major depression using genomic microarrays and various bioinformatics tools.Results: Our studies show that detection of epimutations can be confounded by epigenetic heterogeneity, large but uncommon epimutations, tissue- and cell- specific effects, DNA sequence impact on epigenetic variation, age effects (heteroscedasticity), and the presence of small epigenetic differences over extended genomics regions. We explored new analytical avenues by employing tools that have not been previously applied to psychiatric epigenetic and epigenomic studies, including methylome networks, which may uncover systemic epigenomic changes in the diseased cell. We also performed a study differentiating the two main types of DNA modification, i.e. 5-methylcytosine and 5-hydroxymethylcytosine, and detected that such differentiation may be critical for the discovery of the molecular mechanisms of synaptogenesis and alternative splicing and their role in psychiatric disease.Conclusions: Epigenetic and epigenomic studies exhibit a significant potential in psychiatric research, however, the structure of disease epimutations is not completely clear.Keywords: epigenomics, schizophrenia, epimutation, DNA methylation, 5-hydroxymethylcytosineSupported By: NIH, CIHR, OMHF



SymPoSiumGlutamate/NMDA Redux: From the Gene to

Function in SchizophreniaSaturday, May 18, 2013, 12:30 PM - 2:30 PM

Continental 7-9 - Ballroom LevelChair: David L. Braff

Supported By: MH042228, MH065571, MH093533, MH084071, MH085265, MH079777

703. NRG1-IV Impacts Cortical Glutamatergic and Gabaergic Development and Cognition in a Mouse Model of SchizophreniaAmanda J. Law

University of Colorado School of Medicine, Denver, CO

Background: Neuregulin 1(NRG1), a trophic factor critical for synaptic development is associated with schizophrenia and normal adult brain function. A molecular mechanism behind the association involves transcriptional regulation of a family of NRG1 isoforms of unknown function. rs6994992, a functional risk variant in the NRG1 promoter predicts differential transcription of NRG1-type IV in human brain with the risk-allele associated with elevated expression. To characterize the neurological, developmental and behavioral consequences of elevated NRG1-type IV in-vivo, we created transgenic mice (NRG1IV-tg) engineered to express human NRG1-type IV.Methods: We created a mouse that expresses human NRG1-IV under the tetracycline responsive promoter. Mice were crossbred with (NSE)-tetracycline transactivator(tTA) transgenic mice to achieve neuronal-specific expression. Mice were tested using an extensive battery of neurocognitive tests, including PPI, temporal order recognition memory, fear conditioning and social interaction. Electrophysiology using acute cortical slices and whole cell clamp was used to study intrinsic properties and synaptic transmission in layer V prefrontal (PFC) cortical neurons.Results: NRG1IV-tg mice exhibit impaired temporal order recognition memory (p≤0.007;n=12-15/ group), dependent on PFC function; attenuated sensorimotor gating (F1,29=5.33,P<0.03) and deficits in sociability and social novelty preference (F1,31=10.51,P<0.005). Electrophysiologically, NRG1-IV-tg mice exhibit significant and selective deficits in mEPSC frequency (P=0.0029) in layer V pyramidal neurons and altered interneuron excitability and density.Conclusions: These data provide novel insight into the biology of NRG1-IV and its association with schizophrenia. Genetic modification of NRG1-IV, modeling the molecular risk association, results in impaired prefrontal cortical function in mice and malformation of cortical glutamatergic and GABAergic circuits.Keywords: NRG1, schizophrenia, erbb4, cognitionSupported By: NIMH, NIH intramural program

704. The Role of D-Serine in the Synaptic Pathology of SchizophreniaJoseph T. Coyle1, Darrick Balu2, Yang Li3, Matthew Puhl2, Michael A. Benneyworth2, Vadim Y. Bolshakov2

1Harvard Medical School?McLean Hospital, Belmont, MA, 2Psychiatry, Harvard Medical School/McLean Hospital, Belmont, MA, 3Psychiatry, Harvard Medical School/McLean, Belmont, MA

Background: Three of the top fifty risk genes for schizophrenia - D-amino acid oxidase (DAO; #40), G72 (#12) and serine racemase (SR: #45) - all affect the availability of D-serine, the NMDA receptor co-agonist in the cortical-limbic regions of the brain. To understand better the contribution of low D-serine to the synaptic pathology of schizophrenia, we have manipulated the expression of SR in mice.Methods: The first coding exon (exon 3) of SR was flanked by loxP sites,

which results in excision of the intervening sequence upon exposure to Cre recombinase. These mice were crossed with mice with constitutive Cre or with CaMKIICre2834 driven Cre. Hippocampal slices were prepared from 14- to 18-week-old mice; recordings were made from the CA1 pyramidal neurons while stimulating the Schaffer collaterals. Proteins were quantified by Western blots.Results: The hippocampus of SR-/-male mice exhibit reduced spine density of dentate granule cells, reduced hippocampal volume (-4%), reduced perforant pathway-granule cell long-term potentiation (LTP), reduced BDNF, P-TrkB, P-mTor, and P-Akt (all significant, p<0.05). Furthermore, synaptic deficits, albeit milder, were caused by inactivating SR in forebrain glutamatergic neurons in adolescence. Treatment of SR-/- mice with daily injections of D-serine (300mg/Kg) for 3 weeks normalized the D-serine levels of the hippocampus and restored markers of synaptic plasticity including LTP, BDNF, P-TrkB, P-mTor and P-Akt.Conclusions: The hippocampus of SR-/- mice exhibit many parallels to the synaptic pathology of schizophrenia. The reversal by D-serine treatment suggest that these deficits might be also be amenable to treatment in schizophrenia.Keywords: D-Serine, NMDA Receptor, Glutamate, Synaptic Plasticity, SchizophreniaSupported By: R01MH05190 and P50MH0G0450 to JTC;National Research Service Award F32 MH090697 and an Andrew P. Merrill Research Fellowship awarded to DTB.

705. Glutamate Signaling in Medial Temporal Cortex in SchizophreniaCarol A. Tamminga

University of Texas Southwestern Medical Center, Dallas, TX

Background: Although molecular changes throughout the cerebrum can be found in schizophrenic psychosis, there are several areas whose dysfunction can be associated with symptom manifestations, one of which is the medial temporal cortex (MTC), an area largely identified by the hippocampal formation (HF). Decades of research have identified perfusion increases, task-activation reductions and molecular changes in humans with the illness.Methods: Our laboratory has focused on HF subfield function during psychosis and declarative memory dysfunction, showing increased regional perfusion, especially in CA3 and CA1 and evidence of decreased synaptic glutamate in dentate gyrus (DG).Results: Curiously, CA3 shows evidence of (1) increased NMDA, but not AMPA receptor signaling, (2) increased BDNF mRNA in the st. oriens, the insertion of the recurrent collaterals, and (3) increased spines and dendritic length in CA3. Our recent subfield specific analyses show increased GluN2B- and GluN2A-containing receptors and an increase in PSD95 in CA3 but not in CA1.Conclusions: These outcomes suggest that the primary glutamate signaling changes in DG could sensitize CA3 toward overactivity resulting in increased positive memory-associated, feed-forward signaling mechanisms, ones that could be associated with psychotic thought. We are combining DG and CA3 molecular outcomes found in human cases with schizophrenia, as stringent tests for the development of glutamate-based animal models of schizophrenic psychosis.Keywords: schizophrenia, glutamate, hippocampus, CA3, dentate gyrusSupported By: NIMH; NARSAD

706. Glutamate-Related Treatment Strategies in Schizophrenia PatientsStephen R. Marder

VA Greater LA Health Care System/University of California Los Angeles, Los Angeles, CA

Background: Clinical researchers have taken a number of approaches to addressing the hypothesized hypofunction of NMDA receptors in schizophrenia. Early studies suggested that agents acting at the glycine modulatory site were effective for improving negative symptoms and cognition. However, a multisite trial comparing glycine and d-cycloserine (DCS) to placebo failed to find an



effect. This talk will critically evaluate the clinical studies that have evaluated these strategies and othersResults: Recent attention has focused on DCS’s ability to foster memory consolidation in schizophrenia. Trials by Goff and colleagues suggest that weekly administration of DCS may facilitate learning in patients who are receiving cognitive remediation and cognitive behavioral treatment for schizophrenia. Other studies have evaluated d-serine, another co-agonist at the modulatory site. There is emerging evidence that adding d-serine to an antipsychotic may improve symptoms and neurocognition. Another strategy proposes increasing synaptic levels of glycine by blocking the glycine transporter-1 (GlyT-1) in glia cells. Clinical studies have found that the administration of GlyT-1 inhibitors to subjects results in increased levels of glycine in CSF. Recent studies of a GlyT-1 inhibitor, bitopertin, found that administering this agent to patients receiving an antipsychotic medication resulted in improvements in negative symptoms. This agent is currently being evaluated in Phase 3 trials.Conclusions: The glycine modulatory site of NMDA receptors continues to be an attractive site for drug development.Keywords: Glutamate, Neurocognition, Negative Symptoms

SymPoSiumLimbic-Cortical Interactions in Health and Disease

Saturday, May 18, 2013, 12:30 PM - 2:30 PMContinental 6 - Ballroom Level

Chair: Joshua A. Gordon*Co-Chair: Patricio O’Donnell**

*Supported By: R01MH081968; R01MH096274; R21 MH088103; HDRF; IMHRO**Supported By: R01MH060131

707. Functional Organization of Excitatory Synaptic Inputs to the Prefrontal CortexMichael J. Higley

Yale University, New Haven, CT

Background: The prefrontal cortex (PFC) regulates cognitive processes including short-term “working” memory, vigilance, and attention. Additionally, perturbed prefrontal function is linked to psychiatric illnesses including schizophrenia and anxiety disorders. PFC activity is determined by the integration of synaptic inputs and regulated by neuromodulators such as norepinephrine.Methods and Results: Here, we use a combination of approaches to determine the functional organization of synaptic inputs to pyramidal neurons in the mouse PFC. First, transgenic fluorescent labeling of presynaptic terminals along axons originating from the hippocampus, medial thalamus, and amygdala reveals distinct but partially overlapping laminar distributions of synaptic contacts. Second, using selective expression of Channelrhodopsin2, we find that both hippocampal and thalamic excitation is capable of driving action potentials in single pyramidal neurons, indicating that these inputs can “drive” PFC activity. Subcellular ChR2-assisted mapping of afferent inputs further demonstrates synaptic clustering of afferent inputs within dendritic subregions. Third, we 2-photon calcium imaging and focal glutamate uncaging reveal that activation of alpha2-type adrenergic receptors selectively inhibits glutamatergic transmission in the basal and apical tuft dendrites of intracortically-projecting Layer 5 pyramidal neurons.Conclusions: Our results demonstrate that excitatory inputs to the PFC are organized into laminar projection patterns that correspond to the specific dendritic subregions of PFC pyramidal neurons. This subcellular organization provides a mechanism for selective neuromodulation of prefrontal subnetworks that may be critical for normal cognitive processes that are disrupted in neuropsychiatric disease.Keywords: prefrontal, synaptic, dendrite, modulationSupported By: R01MH099045, Smith Family Foundation

708. Basolateral Amygdala Stimulation Elicits Heterosynaptic Suppression of Hippocampal Inputs to Medial Prefrontal Cortical Pyramidal NeuronsPatricio O’Donnell1, Hugo A. Tejeda2

1University of Maryland School of Medicine, Baltimore, MD, 2Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD

Background: Amygdala inputs to the prefrontal cortex (PFC) likely provide information related to emotional states, and may adjust PFC function accordingly. Here we tested whether strong amygdala activation reduces synaptic responses the ventral hippocampus (VH) in PFC pyramidal neurons using in vivo intracellular recordings.Methods: Medial PFC pyramidal neurons were recorded intracellularly in anesthetized rats, and synaptic responses were generated by electrical or optogenetic stimulation of the BLA and VH inputs. To determine whether BLA train stimulation attenuated VH-evoked responses, a baseline test pulse (S1) was applied to the fimbria followed by conditioning burst stimulation of the BLA (10 pulses; 10-50 Hz). A test synaptic response (S2) was evoked 50-500 ms after the last BLA pulse. In a separate group of rats, viral-mediated expression of channelrhodopsin-2 (ChR2) in hippocampal projection neurons was utilized to determine whether BLA burst stimulation also suppressed optically-evoked VH responses in the PFC.Results: BLA burst stimulation attenuated VH-evoked EPSPs, with S2 responses at short delays being suppressed more robustly than those at longer delays. These effects were also observed using optical stimulation in rats expressing ChR2 in VH neurons. VH train stimulation did not alter BLA-evoked responses, suggesting that heterosynaptic suppression of temporal cortical inputs is unidirectional and only produced by activation of the BLA-PFC pathway.Conclusions: The interaction reported here may be relevant to BLA overriding other influences onto PFC function in cases of strong emotional activation.Keywords: prefrontal cortex, amygdala, electrophysiology, hippocampusSupported By: R01MH057683

709. Hippocampal-Prefrontal Connectivity in Psychiatric Disease ModelsJoshua A. Gordon

Columbia University, New York, NY

Background: Deficits in limbic-cortical interactions have been proposed to play a role in the susceptibility to psychiatric disorders, including schizophrenia. To examine the relationship between deficits in limbic-cortical connectivity and schizophrenia, and to explore the neural mechanisms underlying these deficits, we characterized these interactions in mouse models of the 22q11 microdeletion, a copy number variant with relatively high (~30%) penetrance for the disorder.Methods: Mice carrying a deletion homologous to the 1.5 Mb core region of the 22q11 microdeletion, as well as mice carrying a heterozygous deletion of a Dgcr8, one of the genes in the core region, were implanted with microelectrodes in the hippocampus and medial prefrontal cortex. Multiple single unit and local field potential recordings were obtained during performance of a spatial working memory task. Additional experiments were carried out using virally-expressed optogenetic and pharmacogenetic probes to disrupt activity in the circuit, also during behavior. Interactions across brain regions were assessed using standard measures of synchrony, including phase-locking, power correlations, and coherence across recording sites.Results: In wild-type mice, synchrony between the hippocampus and prefrontal cortex is enhanced during spatial working memory performance; this synchrony is dramatically decreased in both 22q11 microdeletion and Dgcr8 heterozygote mice. Opto- and pharmacogenetic studies confirm the requirement for limbic-cortical connections during working memory.Conclusions: These findings demonstrate a key role for hippocampal-prefrontal interactions in spatial working memory. They also provide evidence in support of the hypothesis that deficits in limbic-cortical interactions underlie the cognitive



deficits seen in patients with schizophrenia.Keywords: Connectivity, Hippocampus, Prefrontal Cortex, Working MemorySupported By: R01MH081968; R01MH096274; R21MH093887; IMHRO; HDRF

710. Surfing on Slow Waves: Sleep-Dependent Limbic-Cortical Interactions in Rodents and PatientsMatt W. Jones

University of Bristol, Bristol, United Kingdom

Background: Limbic-cortical interactions extend beyond waking behavior and into sleep, when orchestrated network activity during cortical slow-wave activity (SWA), thalamocortical spindles and hippocampal ripples underpins distinct aspects of memory consolidation. Disrupted sleep architecture and neurophysiology are therefore likely contributors to impaired information processing in psychiatric disease.Methods: EEG, local field potential and multiple single unit recordings from hippocampus and prelimbic cortex of adult male rats were used to detail sleep structure and network activity in the MAM-E17 neurodevelopmental model of schizophrenia (13 MAM-exposed, 14 SHAM controls). Spectral analyses alongside SWA (0.3-3Hz), spindle (10-15Hz) and ripple (120-250Hz) detection allowed quantification of oscillatory patterns characteristic of non-REM sleep. Data from the MAM-E17 model were compared with sleep EEG recordings taken from a cohort of 12 chronic, medicated schizophrenia outpatients and 11 healthy volunteers.Results: During non-REM sleep in MAM-E17 exposed rats, coherence between anterior and posterior cortical EEG was significantly and selectively attenuated in the SWA frequency range (p<0.01, Bonferroni-corrected t-test) and the relative timing of posterior delta-waves and spindles was severely disrupted. Hippocampal ripples and prelimbic spindles were also desynchronized in MAM-E17 animals. A similar reduction in SWA coherence between anterior/central and posterior EEG was evident in patients (p<0.05, Wilcoxon rank sum) and was also associated with decoupling of spindles from delta waves.Conclusions: The mis-timing of thalamocortical spindles relative to SWA may constitute a translational biomarker of circuit dysfunction that reflects and/or contributes to aberrant non-REM dependent limbic-cortical interactions and memory consolidation in schizophrenia.Keywords: sleep, slow-wave, spindle, ripple, memorySupported By: Medical Research Council (UK)

SymPoSiumBalancing Plasticity and Stability Across Cortical Development: Implications for

Psychiatric IllnessSaturday, May 18, 2013, 12:30 PM - 2:30 PM

Imperial B - Ballroom LevelChair: Takao K. Hensch*Co-Chair: Kim Q. Do**

*Supported By: NIMH 1P50MH094271**Supported By: Swis National Science Foundation, NCCR Synapsy

711. Shaping Neural Circuits by Early ExperienceTakao K. Hensch

Harvard University, Cambridge, MA

Background: Neural circuits are shaped by genes and environment during early windows of brain development. Classic sensory deprivation models have

begun to unravel the cellular/molecular constraints that establish such ‘critical periods’ of plasticity. This talk will summarize mechanistic insight into the opening, execution and closure of circuit rewiring in the developing neocortex of mice. We aim to establish key principles across systems and the implications for neurodevelopmental origins of psychiatric illness.Methods: Gene-targeting or pharmacological manipulation in mouse brain paired with sensory input early in postnatal life followed by physiological or behavioral assessment.Results: Postnatal development of excitatory-inhibitory (E/I) circuit balance initiates critical period plasticity. Specifically, loss- / gain- of parvalbumin (PV)-positive GABA circuit function delays / accelerates onset timing, respectively. Once induced, synaptic rewiring in response to experience is manifest by pruning and regrowth of connections. Plasticity gradually winds down as a consequence of late-emerging molecular “brakes.” Effects of early experience or deprivation are thus actively consolidated throughout life by two classes of factors: those limiting structural change (myelin signaling, perineuronal nets enwrapping PV-cells) and those modulating E/I balance. Lifting any of these reactivates cortical plasticity enabling recovery of function in adulthood.Conclusions: The biology of the brain is heavily invested in the optimal timing and duration of plasticity, having evolved numerous molecular checks and balances. Notably, their frequent impairment in mental disorders suggests a mis-timing or failure to close developmental plasticity may contribute to the etiology.Keywords: Parvalbumin, Critical Period, GABA, MyelinSupported By: NIMH (1P50MH094271)

712. NMDA Receptor Regulation Prevents Regression of Visual Cortical Function in Rett SyndromeMichela Fagiolini

Boston Children’s Hospital, Boston, MA

Background: Neuronal circuits are sculpted by experience in infancy and early childhood. There is growing evidence that dysfunction of this activity-dependent circuit refinement may underlie neurodevelopmental disorders such as Rett Syndrome(RTT), the most common form of mental retardation in girls caused by mutations in the methyl-CpG-binding protein 2 gene(MeCP2). How sensory experience affect the maturation and maintenance of a particular cortical function through MeCP2 regulation remains largely unknown.Methods: By applaying multilevel analysis of development and plasticity of visual cortex in RTT mouse models, we are gaining the most rapid insight into underlying neuronal circuit disfuction and importantly how and when to treat it.Results: we have identified a clear visual cortical phenotype and demonstrated its rescue by enviromental and genetic manipulation. we revealed an apparently normal onset of visual function followed by regression of visual acuity that directly correlates with the onset of RTT phenotype. Remarkably, cortical function and inhibitory hyper-connectivity could be rescued independent of MeCP2 by early visual deprivation or genetic disruption of NMDA receptor subunit NR2A.Conclusions: The identification of a receptor pathway within a specific cortical circuit offers an accessible new target for drug intervention strategies that does not rely on the re-expression of intracellular molecules. Furthermore, vision is a sensitive biomarker of pregressive cortical dysfunction and may guide novel, circuit based therapies for MeCP2 deficiencyKeywords: Rett Syndrome, vision, circuit-based therapy, parvalbuminSupported By: Simons Foundation

713. The Perineuronal Net Protects Fast-Spiking Parvalbumine Interneurons Against Oxidative StressKim Q. Do

Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly-Lausanne, Switzerland

Background: Redox dysregulation during development is involved in schizophrenia. Parvalbumine expressing inhibitory interneurons (PVI) are



deficient in patients prefrontal cortex. Due to their fast-spiking properties which require high metabolic activities, PVI are susceptible to oxidative-stress. As most mature PVI are surrounded by an extracellular matrix called perineuronal net (PNN), its potential protective role against oxidative-stress was explored.Methods: In model of glutathione deficiency (Gclm-/-mice), effects of oxidative-stress (induced by dopamine uptake blocker GBR12909, assessed by 8-oxo-dG) were investigated on PNN (stained by Wisteria floribunda agglutinin-WFA), PVI, and local neuronal synchronization in anterior-cingulate cortex.Results: In 180-day-old Gclm-/-, oxidative-stress decreased PVI and β/γ oscillations power. The proportion of PVI surrounded by PNN was higher compared to WT mice (81 % vs. 66%), suggesting that PVI with well-formed PNN were better protected against oxidative-stress than those lacking PNN. Consistently, oxidative-stress led to decreased number of PVI in 20-day-old (PNN still immature), but not in 90-day-old (PNN more mature). In the latter, PVI surrounded by well-formed PNN displayed less 8-oxo-dG labeling than PVI with none or less PNN. Moreover, direct removal of PNN by chondroitinase ABC in 90-day-old Gclm-/- led to reduced number of PVI and decreased β/γ oscillations after GBR-induced oxidative-stress.Conclusions: Immature PNN leaves PVI highly susceptible to oxidative-stress, while mature PNN acts as protective shield, preventing PVI functional impairment. Excessive reactive-oxygen-species production, generated by environmental insults particularly in at-risk individuals, should have deleterious impact on PVI bearing immature PNNs, which are key players in timing critical periods of brain plasticity.Keywords: Oxidative stress, Perineuronal net, Parvalbumine interneurons, Glutathione, Extracellular matrixSupported By: Swiss National Science Foundation; Loterie Romande; Damm-Etienne Foundation; Alamaya Foundation; NCCR Synapsy; NIH

714. Unexpected Role for MHCI and PirB in Developmental Synapse Elimination- A Link to Schizophrenia?Carla J. Shatz

Stanford University, Stanford, CA

Background: During development, neural circuits are turned up as synaptic connections are either or eliminated or strengthened in a process requiring neural activity. Activity also regulates neuronal gene expression. The objective here is to learn more about molecular mechanisms of activity-dependent synapse remodeling.Methods: Major Histocompatibility Class I (MHCI) genes were unexpectedly discovered in neurons and regulated by activity and visual experience (Corriveau et al, 1998; Goddard et al, 2007) in an unbiased PCR-based screenResults: Mutant mice lacking specific MHCI genes were examined. Synapse regression in developing visual system fails, and ocular dominance (OD) plasticity in visual cortex is greater than WT (Huh et al, 2000; Datwani et al, 2009). PirB, an innate immune receptor known to bind MHCI, was found expressed in neurons throughout mouse CNS. In PirB KO mice, OD plasticity is increased (Syken et al., 2006), as is LTP in hippocampus.Conclusions: PirB may bind and transduce signals from MHCI ligands in neurons, acting to “brake” synaptic plasticity (Shatz, 2009). These molecules may be crucial for controlling circuit excitability and stability in developing as well as adult brain. Changes in their function could contribute to developmental disorders such as Autism and Schizophrenia.Keywords: Major Histocompatibility Class I, synapse elimination, critical periodSupported By: NIH Grants EY02858, MH071666, Mathers Charitable Foundation and Ellison Foundation

SymPoSiumTargeting Protein Toxicity Therapeutics for

Mental Illness: Taking Lessons from Viral and Neurodegenerative Disorders


Chair: Nick BrandonCo-Chair: Akira Sawa*

*Supported By: NIH, NARSAD, Stanley,

715. Role of DISC1 Protein Aggregates as a Homeostatic Regulator of Dopamine at the SynapseCarsten Korth

Department Neuropathology University of Duesseldorf Medical School, Duesseldorf, Germany

Background: Disrupted-in-schizophrenia 1 (DISC1) has been identified as a rare gene in a Scottish pedigree prone to mental illness, and has been genetically associated to a variety of mental illness phenotypes establishing it is a vulnerability factor for behavioral control. This notion is supported by a dozen animal models expressing mutant DISC1 protein.We previously demonstrated the aggregation propensity of non-mutant DISC1, aberrant molecular interactions of these DISC1 aggregates and their presence in post mortem brains of patients with severe mental illness. Here, we investigated how DISC1 aggregates regulate dopamine homeostasis.Methods: Cell lines with inducible full length DISC1 expression were generated and dopamine measured by HPLC. Biochemical interaction assays were performed. A transgenic rat line overexpressing full length human DISC1 (tgDISC1 rat) was generated and characterized in terms of biochemistry, imunohistochemistry, neurochemistry and behavior.Results: DISC1 aggregate formation led to a decreased clearance of extracellular dopamine in vitro, mediated by a modulation of the dopamine transporter. Cytosolic dopamine, in turn, increased DISC1 aggregation suggesting an autoregulatory loop for dopamine homeostasis. A tgDISC1 rat displayed abundant DISC1 aggregates and exhibited aberrant whole dopamine concentrations. The tgDISC1 rat displayed behavioral phenotypes like amphetamine hypersensitivity, spontaneous hyperlocomotion consistent with changes in dopamine homeostasis.Conclusions: We could mechanistically link DISC1, a major vulnerability factor for adaptive behavior, in vitro and in vivo to aberrant dopamine homeostasis in an unexpected manner, through the generation of functional, reversible protein aggregates. We thereby offer a novel mechanism for dopamine regulation and potentially novel pharmacological target.Keywords: dopamine, schizophrenia, DISC1, aggregates, transgenic rat modelSupported By: DFG 1679/3-1, 4-1; NEURON-ERANET DISCover BMBF 01EW1003

716. Dynamics and Clearance of DISC1 Aggregates in NeuronsJosef Kittler

University College London, London, United Kingdom

Background: Disrupted in Schizophrenia 1 (DISC1) is a key susceptibility gene implicated in major mental illnesses, such as schizophrenia, depression, bipolar disorder and autism, but the link between this protein and the pathology of these diseases remains unclear. Recently, DISC1 has been demonstrated to form insoluble protein aggregates in vitro and in human post-mortem brain tissue but the cellular dynamics of these DISC1 aggregates and their effects on neuronal function are unknown. DISC1 is also associated with mitochondrial function



and distribution but the mechanisms remain unclear.Methods: To characterize the stability of DISC1 aggregates we have used biochemical approaches including protein stability and degradation assays. This has been complemented with state of the art imaging with confocal and wide-field microscopy in addition to fluorescent recovery after photobleaching (FRAP) of GFP labeled DISC1 aggregates. Lice cell confocal imaging approaches have also been used to explore the impact of DISC1 aggregates on mitochondrial quality control.Results: Confocal and FRAP analysis provide a detailed description of the dynamics of DISC1 aggregates in cells and the impact of DISC1 post translational modification and DISC1 disease associated mutations on DISC1 dynamics. The impact of DISC1 aggregates on neuronal function and mitochondrial quality control is also addressed. We also demonstrate that cross-talk with mitochondrial quality control pathways is important for the clearance of DISC1 aggregates, and the impact played by disease related mutations in this regulation.Conclusions: Pathological alterations in DISC1 aggregate dynamics is a determinant of DISC1 dependent signaling pathways important for neuronal function.Keywords: DISC1, Schizophrenia, aggregate, mitochondrion, SignallingSupported By: MRC, Brain research trust

717. Small-Molecule Enhancement of the Degradation of Toxic Proteins in NeuronsDaniel Finley

Harvard Medical School, Boston, MA

Background: Many devastating neurodegenerative diseases reflect cytotoxic effects of misfolded and amyloidogenic proteins. Thus, one possible therapeutic approach would be to enhance the degradation of such proteins. The ubiquitin-proteasome pathway is designed in part to specifically break down misfolded proteins. Therefore, we sought to enhance the activity of this pathway using small molecules.Methods: The proteasome, which degrades ubiquitinated proteins, is antagonized by deubiquitinating enzymes (DUBs). We found that the DUB Usp14 is activated 800-fold by binding the proteasome and is a key antagonist of proteasomes. Therefore we performed a high-throughput screen for Usp14 inhibitors.Results: Our screen of 63,000 compounds yielded 300 Usp14 inhibitors, three being highly selective for Usp14. One inhibitor, IU1, was characterized in detail. Our results show that, upon delivery of ubiquitinated proteins to the proteasome, ubiquitin chains are rapidly trimmed, largely by Usp14. IU1 blocks this reaction. Since ubiquitin chains target the substrate to the proteasome, the failure of chain trimming stabilizes the substrate-proteasome interaction and promotes substrate degradation. IU1 promotes the elimination of critical proteins such as tau and TDP43. IU1 promotes tau degradation in primary neurons and crosses the blood-brain barrier. These effects can be achieved at nontoxic doses, but whether this approach can be sufficiently safe to employ in humans remains to be determined.Conclusions: Enhancement of protein degradation pathways is in principle a promising approach for the treatment of neurodegenerative diseases. There are potentially several avenues to enhance degradation. One, described here, is to release these pathways from tonic inhibition.Keywords: proteasome, neurodegeneration, tau, ubiquitinSupported By: Tau Consortium

718. Developing Small Molecule Inhibitors of Proteinopathies for Mental Illness - Taking Lessons from Host-Targeted Antiviral Drug DiscoveryVishwanath R. Lingappa1, Carsten Korth2, Clarence Ray Hurt3

1Prosetta Antiviral Inc, San Francisco, CA, 2University of Dusseldorf, University of Dusseldorf, Dusseldorf, Germany, 3Chemistry, Prosetta Antiviral, Inc, San Francisco, CA

Background: In the course of exploring new concepts in antiviral disease therapeutics, namely the identification of small molecules that block aberrant host assembly machines catalytic for viral capsid formation, we have made observations with important implications for brain diseases. Our working hypothesis is that much of what is generally viewed as protein aggregation in CNS disease may be assembly events, or the end products of events whose pathophysiologically relevant stages are assembly intermediates, perhaps involved in the formation of signaling complexes that govern neuronal survival.Methods: Cell-free translation of various proteins of interest with products analyzed by a variety of tools that distinguish putative assembly intermediates and score the effects of compounds blocking assembly.Results: Small molecules targeting aberrant host assembly machines and validated against infectious virus in cell culture, were found active in blockade of A beta peptide oligomerization and DISC1 aggregation in cellular models. Structure-activity relationship optimization improved compound potency and therapeutic index. Affinity chromatography with advanced analog resins and gradient analysis reveal the compounds bind to allosteric sites on labile cellular multiprotein complexes hypothesized to be host subcellular assembly machines whose aberrant forms may be a molecular basis for brain disease.Conclusions: Aberrant host machines are involved not only in assembly of viral capsids but also may be the basis for a significant burden of non-infectious brain diseases including Alzheimer’s Disease and schizoaffective disorders. Small molecules active in correlated cellular model systems have been identified and are being advanced for therapeutic trials in appropriate small animal models.Keywords: CNS proteinopathy, therapeutics, cellular assembly machinesSupported By: Prosetta Antiviral inc

SymPoSiumGateway for Inflammation’s Impact

on the Brain and Behavior: The Tryptophan/Kynurenine Pathway


Chair: Angelos Halaris*Co-Chair: Andrew Miller

*Supported By: AstraZeneca

719. Neuroprotective Action of Escitalopram in the Treatment of Major DepressionAngelos Halaris

Loyola University Chicago Stritch School of Medicine, Maywood, IL

Background: Inflammatory biomarkers are elevated in patients with major depressive disorder (MDD). There is an interaction between pro-inflammatory cytokines and serotonergic transmission involving the metabolism of tryptophan and modulation by the NMDA receptor in part through the enzyme, indoleamine 2,3-dioxygenase (IDO), that catabolizes tryptophan to kynurenine. A toxic end product is quinolinic acid (QUIN) and 3-hydroxykynurenine (3-OHK); they impair neuronal function via NMDA agonism, excitotoxicity and apoptosis.



Methods: MDD patients (N=24) were treated with escitalopram (ESC) for 12 weeks. Patients were evaluated at baseline (BL), and weeks 2, 4, 6, 8 and 12 using the HAM-D, HAM-A, BDI and BAI scales. The dose ranged were 10-40 mg daily. Blood samples were collected at BL, W8 and W12. We measured tryptophan, kynurenine, kynurenic acid (KYNA), K/T ratio, 3-OHK, QUIN and ESC blood levels. Statistical analyses were performed with SPSS software.Results: A 65% response rate was obtained. No significant differences were found between healthy controls and depressed patients at BL The analyses revealed: 1) Tryptophan increased (p<0.001); 2) Kynurenine declined (p<0.015); 3) K/T ratio declined from (p<0.001); 4) QUIN was reduced (p<0.0005); 5) 3-OHK was reduced p<0.001). Blood levels of ESC corresponded to the doses the patients were receiving.Conclusions: Our data confirm that the tryptophan/kynurenine pathway is abnormally regulated in depression. ESC exerts neuroprotective action by reducing toxic metabolites, notably 3-OHK and QUIN.. This apparent neuroprotective effect may have significant beneficial implications for the long-term management of depressive disorders.Keywords: Depression, Kynurenine pathway, Neuroprotection, EscitalopramSupported By: Intramural grant Loyola University Stritch School of Medicine

720. Interferon-Alpha-Induced Behavioral Changes Correlate with Increased Basal Ganglia Glutamate Which is in Turn Associated with Activation of the Kynurenine PathwayAndrew Miller

Emory University, Atlanta, GA

Background: Peripheral inflammatory states and their behavioral consequences including depression and fatigue have been well-documented. One mechanism that may contribute to inflammation-induced behavioral changes is alterations in central nervous system (CNS) glutamate metabolism secondary to activation of the kynurenine (KYN) pathway. Indeed, end products of KYN pathway activation including quinolinic acid (QUIN) have been shown to activate NMDA receptors which can stimulate glutamate release.Methods: To examine the role of CNS glutamate and the KYN pathway in inflammation-induced depression and fatigue, proton magnetic resonance spectroscopy (MRS) was conducted in 12 patients with hepatitis C virus (HCV) before and after 4 weeks of treatment with interferon (IFN)-alpha compared to 12 HCV patients awaiting IFN-alpha therapy. IFN-alpha is an inflammatory cytokine well-known to induce symptoms of depression and fatigue in association with increases in plasma KYN and cerebrospinal concentrations of KYN and QUIN.Results: Compared to controls, the glutamate/creatine ratio in the left basal ganglia significantly increased following 4 weeks of IFN-alpha administration (p<0.05), which in turn significantly correlated with increases in fatigue (r=0.44, p<0.05). Interestingly, increases in the left basal ganglia glutamate/creatine ratio was also correlated with plasma concentrations of the KYN pathway metabolite, 3-OH anthranilic acid, which is the metabolite immediately upstream of QUIN (r=0.61, p<0.005).Conclusions: These data are consistent with previously reported alterations in basal ganglia function following IFN-alpha administration and suggest that IFN-alpha activation of the KYN pathway may lead to changes in CNS glutamate metabolism which in turn are associated with IFN-alpha-induced behavioral changes including fatigue.Keywords: Kynurenine, Depression, Fatigue, Cytokine, NeuroimagingSupported By: K23MH091254

721. Interactions Between Cytokines and Kynurenines in Depressed Patients: Of Blood and BehaviourAye-Mu Myint1, Elif Weidinger2, Markus Schwarz2, Mueller Norbert2

1Ludwig-Maximilian University of Munich, Munich, Germany, 2Psychiatry, LMU, Munich, Germany

Background: Pro-inflammatory cytokines are increased in the blood of patients diagnosed with major depressive disorder (MDD). Certain cytokines activate the enzyme indoleamine 2,3-dioxygenase (IDO) which in turn activates the tryptophan degradation pathway that enhances the formation of downstream metabolites, some of which are neuroactive. Factors influencing the activities of enzymes involved in the tryptophan/kynurenine pathway include cofactors, such as vitamin B6, and gene polymorphisms controlling the expression of enzymes involved in this metabolism.Methods: Fifty MDD patients receiving antidepressant therapy and age and sex matched control subjects were recruited. Clinical data were collected using the MINI, HAMD rating scale, Childhood Trauma Questionnaire (CTQ) and Perceived Stress Scale (PSS). Early morning blood samples were collected to measure vitamin B6, cytokines and tryptophan pathway metabolites using HPLC and enzyme-linked immunosorbent assays.Results: Levels of the pro-inflammatory cytokine interleukin (IL)-6 were significantly increased in the patients. Unlike drug-naive patients, all tryptophan metabolites were found to be increased in these medicated patients. The ratio between 3-hydroxykynurenine to kynurenine was significantly increased. The vitamin B6 levels were significantly decreased in the patients. High IL6 and low IL10 (anti-inflammatory) showed an association with the development of depression among those who had a history of childhood trauma. Vitamin B6 levels were inversely correlated with PSS.Conclusions: Although the treatment seems to partially correct the kynurenines changes, decreases in vitamin B6 which could be due to either inflammatory state or antidepressants could disturb the kynurenine metabolism. Supported By: EU Collaborative Research Project (Grant No. 22963) Moodinflame

722. Suicidality, Cytokines and the Kynurenine PathwayLena Brundin

Michigan State University, Grand Rapids, MI

Background: The NMDA-receptor antagonist ketamine is efficient in reducing suicidality, but the mechanisms explaining this are not completely understood. Several recent studies show evidence of central inflammation in suicidal patients. Inflammation leads to production of quinolinic acid (QUIN) and kynurenic acid (KYNA), an agonist and antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, respectively.Methods: We measured QUIN and KYNA in the cerebrospinal fluid (CSF) of 64 medication-free suicide attempters and 36 controls, using gas chromatography mass spectrometry and high-performance liquid chromatography. The patients were assessed using the Suicide Intent Scale and the Montgomery-Åsberg Depression Rating Scale (MADRS).Results: We found that QUIN, but not KYNA, was elevated in the CSF of suicide attempters (p<0.001). The increase in QUIN was associated with higher levels of the pro-inflammatory cytokine interleukin-6. CSF QUIN also correlated with the total scores on Suicide Intent Scale.Conclusions: We present clinical evidence of increased QUIN in the CSF of suicide attempters. An increased QUIN/KYNA quotient speaks in favor of an overall NMDA-receptor stimulation. The correlation between QUIN and the Suicide Intent Scale indicates that changes in glutamatergic neurotransmission might be specifically linked to suicidality.Keywords: Suicide, Inflammation, Quinolinic acid, depressionSupported By: Swedish Research Council grants no 2009-4284 and 2011-4787



SymPoSiumDeep Brain Stimulation Modulation of Mood in

Treatment Resistant Depression - Distinct Targets, Differential Mechanisms?


Chair: Susannah Tye*Co-Chair: Helen Mayberg**

*Supported By: NARSAD YI Award; Zarrow Foundation**Supported By: Dana Foundation, Hope for Depression Research Foundation, Stanley Medical Research Institute, Woodruff Fund, devices donated by St. Jude Medical, Inc

723. Deep Brain Stimulation of the Nucleus Accumbens and Medial Forebrain Bundle in Treatment Resistant DepressionThomas E. Schlaepfer

University of Bonn / The Johns Hopkins University, Bonn, Germany

Background: The Nucleus accumbens (NAcc) is a key center in the depression network, converging animal, pharmacological and neu-roimaging evidence point toward NAcc dysfunction in depression.The supero-lateral branch of the medial forebrain bundle (slMFB) has also been proposed as a potential target within the human reward system. The slMFB is linked to reward seeking and appetitive motivation (reward seeking).Methods: NAcc: Ten patients with treatment resistant de-pression (TRD) were implanted with bilateral DBS electrodes in the NA. Mean (+/-SD) length of the current episode was 10.8 (+/- 7.5) years, number of past treatment courses was 20.8 (+/- 8.4), mean Hamilton Rating Scale of Depression (HRSD28) was 32.5 (+/- 5.3) . slMFB: Seven patients suf-fering from TRD with mean baseline MADRS of 29.9 (SD=8.0) underwent bilateral DBS electrode implantation in the supero-lateral medial forebrain bundle after Diffusion Tensor Imaging based personalized target site def-inition.Results: NAcc: Twelve months after initiation of DBS treatment five patients reached 50% reduction of the Hamilton Rating Scale of Depression (Responders, HDRS =15.4 (+/- 2.8).slMFB: Five patients reached the response criterion (reduction of 50% in MADRS score) within 7 days of slMFB-DBS, 6 responded rapidly. Stimulation intensity ranged from 1.5 to 2.5V.Conclusions: These pilot data support the notion that DBS to structures within the human reward system (NAcc and slMFB) are associated with antidepressant effects in patients with TRD, in the case of slMFB-DBS these effects are more robust and develop rapidly within days after stimulation onset.Keywords: deep brain stimulation, nucleus accubens, medial forebrain bundleSupported By: Medtronic Inc., German Research Foundation

724. Deep Brain Stimulation of the Lateral Habenula in Treatment Resistant DepressionFritz A. Henn

Mt. Sinai Medical School; Cold Spring Harbor Laboratory, New York, NY

Background: Understanding the circuits involved in depression suggests that the reward pathway and mPFC are both clearly involved. Recent animal model data suggests that both the reward pathway and PFC cortex may act through altrations in l. habenula output to control mood. We will examine some of this evidence and present preliminary data on trials looking at l. habenular inhibition as a target for effective DBS in treatment resistant depression.Methods: Using the learned helplessness model of depression and congenital

lines bred to be helpless or resistant to helplessness a circuit was defined, electrophysiologically and anatomically which suggested the l.habenula is a major control pointin animals.Results: Initial studies in man using tryptophan depletion to trigger depressive symptoms activates the l. habenula. Using learned helplessness, DBS inhibiting the output of the l. habenula proved to be effective in reversing helplessness and led to an initial case in Germany which showed complete remission over 4 years leading to a new trial at Mt. Sinai Medical Center. The initial results of this trial will be reported.Conclusions: It appears activation of the lateral habenula leads to decreased 5HT, DA, and NE release leading to a depressed state, this appears to be reversed via inhibition of the l. habenula via DBS.Keywords: l. habenula, DBSSupported By: Simon’s Foundation; Dept. of Energy

725. Optimizing Subcallosal Cingulate DBS for Treatment Resistant DepressionHelen Mayberg

Emory University, Atlanta, GA

Background: Ongoing studies of high frequency stimulation of the subcallosal cingulate (SCC) demonstrate sustained long-term antidepressant effects (Kennedy et al, 2011; Holtzheimer et al, 2012). Currently, electrodeplacement is based on local SCC anatomy with clinical effects assessed using standardized symptom severity scales. Clinical response may be improved by more precise targeting along specific white matter tracts and refined assessment of the subtleties and time course of behavioral effects.Methods: Refinement of the optimal DBS target was first evaluated using probabilistic tractography, with locations evoking maximal acute intraoperative effects compared to contact locations mediating long-term antidepressant response in a previous TRD DBS cohort (n=15). Causal relationships between contact-specific stimulation and changes in local field potentials, EEG and behavior were then tested in a new cohort of patients receiving SCC DBS (n=10) during electrode implantation surgery using blinded, randomized active/sham testing.Results: Tractography maps seeded at contacts evoking acute behavioral changes identified common involvement of white matter projections linking SCC to medial frontal cortex, midline thalamus and ventral pallidum, a pattern matching the long-term responder maps. Acute behavioral effects were further correlated with changes in SCC LFP/frontal EEG in the new TRD cohort, occurring at brainlocations defined preoperatively using individualized tractography maps.Conclusions: Stimulation induced changes in regional oscillations and concurrent behavioral effects can be potentially predicted using probabilistic tractography providing a new strategy for optimizing electrode implantation for SCC DBS. These findings may further delineate critical pathways and mechanisms mediating the antidepressant effects of chronic stimulation.Keywords: depression, deep brain stimulation, cingulate, imaging, tractographySupported By: Dana Foundation, Hope for Depression Research Foundation, Woodruff Fund, Stanley Medical Research Institute

726. Behavioral and Neurobiological Effects of Deep Brain Stimulation in an Animal Model of Antidepressant ResistanceSusannah J. Tye

Mayo Clinic, Rochester, MN

Background: Deep brain stimulation (DBS) of the mesoaccumbens dopamine system and associated circuitry effectively reduces symptoms of depression in severely treatment-resistant individuals. A mechanism of therapeutic action may



involve modulation of mesoaccumbens dopamine system function.Methods: We investigated the effects of DBS (130 Hz) for treatment resistant depression (TRD) on mesoaccumbens dopamine neurotransmission, neurotrophic factor expression and behavior in control and adrenocorticotropic hormone (ACTH)-treated (100µg/day; 14 days) antidepressant-resistant rats. Three neural targets for TRD were assessed: the infralimbic cortex, nucleus accumbens and lateral habenula.Results: ACTH pre-treatment blocked imipramine (10 mg/kg)-mediated reductions of immobility in the forced swim test (FST) (n=10; p<0.05). In contrast, high frequency DBS effectively reduced immobility in ACTH-treated animals (n=8; p<0.05). ACTH-mediated dysregulation of mesoaccumbens dopamine function was evidenced by attenuated transient dopamine efflux and potentiated D1 and D2 receptor expression. Attenuated transient dopamine efflux was restored with DBS of each target (n=5; p<0.05). Brain derived neurotrophic factor was upregulated in the dorsal and ventral hippocampus following DBS (n=8; p<0.05). Similar increases in BDNF were also detected following sham DBS treatment (electrode implantation, no stimulation; n=8; p<0.05), suggesting electrode placement, rather than high frequency DBS, mediates upregulation of BDNF in this model.Conclusions: DBS of the infralimbic cortex, nucleus accumbens and lateral habenula all have antidepressant actions in the ACTH-induced model of antidepressant resistance and effectively reverse attenuated transient mesoaccumbens dopamine signalling. Interaction between dopamine dysregulation and the inflammatory response, and its role in mediating neurobiological and behavioral effects of DBS in TRD, warrants further investigation.Keywords: depression, deep brain stimulation, dopamine, BDNFSupported By: NARSAD Young Investigator Award; Zarrow Foundation

SymPoSiumDepression and the Aging Brain

Saturday, May 18, 2013, 12:30 PM - 2:30 PMYosemite C - Ballroom LevelChair: Mirjam I. Geerlings*Co-Chair: Lotte Gerritsen**

*Supported By: Netherlands Organisation of Scientific Research (NWO: project no. 917-66-311)**Supported By: PIEF-GA-2011-300355

727. Long-Term Cumulative Depressive Symptom Burden and Risk of Cognitive Decline and Dementia among Very Old WomenKristine Yaffe1, Adina Zeki Al Hazzouri2, Eric Vittinghoff2, Amy Byers3, Ken Covinsky4, Dan Blazer5, Susan Diem6, Kristine E. Ensrud6

1University of California, San Francisco, San Francisco, CA, 2Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 3Psychiatry, University of California, San Francisco, San Francisco, CA, 4Medicine, University of California, San Francisco, San Francisco, CA, 5Psychiatry and Behavioral Sciences, Duke University, Durham, NC, 6Medicine, University of Minnesota, Minneapolis, MN

Background: Depressive symptoms, which fluctuate during late-life, and cognitive outcomes are strongly inter-related, but little is known about the impact of long-term cumulative depressive symptom burden on cognitive decline and dementia.Methods: We assessed depressive symptoms in 7,240 women ≥ 65 years old using the Geriatric Depression Scale (GDS) at serial visits. Cognitive outcomes included repeated measures of the Mini-Mental State Exam (MMSE) and Trails

B score over 20 years, Year 20 neuropsychological test battery and adjudicated dementia and Mild Cognitive Impairment (MCI) status. We used a Poisson model with random slopes to estimate GDS trajectories and characterize depressive symptom burden by quartile of the area under the curve, from baseline to three years before the outcome.Results: After adjusting for age, education, living status, smoking, alcohol, BMI, exercise, history of hypertension, heart attack, stroke, diabetes, and anti-depressants use, compared to women with the lowest quartile of cumulative depressive symptoms burden, women in the highest quartile had 19% more MMSE errors over time (95%CI=14%, 23%) and 19% worse Trails B score (95%CI=16%, 22%). Similarly, those with the highest quartile of cumulative depressive symptom burden had worse scores on most cognitive tests at Year 20 and a two-fold greater likelihood of developing dementia or MCI (OR=2.0; 95%CI=1.38, 2.90).Conclusions: Long-term cumulative depressive symptom burden was associated with cognitive decline, worse cognitive scores and greater risk of developing dementia or MCI. Older adults with a history of depression should be monitored for recurrent or unresolved depressive symptoms as well as cognitive deficits.Keywords: depressive symptoms, cognition, dementiaSupported By: NIMH R01 MH086498

728. Hypothalamic-Pituitary-Adrenal Axis Activity and Regional Brain Volumes in Community-Dwelling Older Persons: The AGES-Reykjavik StudyMirjam I. Geerlings1, Sigurdur Sigurdsson2, Gudny Eiriksdottir2, Melissa E. Garcia3, Binbing Yu3, Tamara B. Harris3, Vilmundur Gudnason4, Lenore J. Launer3

1National Institute on Aging, NIH / University Medical Center Utrecht, Bethesda / Utrecht, MD, 2Icelandic Heart Association, Icelandic Heart Association, Kopavogur, Iceland, 3Laboratory for Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, 4Icelandic Heart Association and University of Iceland, Icelandic Heart Association and University of Iceland, Kopavogur and Reykjavik, Iceland

Background: Major depressive disorders is associated with brain volume reductions and may increase risk for dementia. One of the hypothesized underlying mechanisms is HPA-axis hyperactivity. However, few studies examined the relation between HPA-axis dysregulation and brain volumes. We investigated whether HPA-axis activity was associated with total and regional brain volumes in community-dwelling older persons.Methods: Within the AGES-Reykjavik Study 4,244 persons (76±5 years) without dementia answered questionnaires and underwent clinical examinations. Saliva was collected at home 45 minutes after awakening and at night for cortisol measures. From 1.5Tesla brain MRI total and regional brain volumes were calculated using automated brain segmentation.Results: Higher evening cortisol was associated with smaller total brain volume (highest vs. lowest tertile -16.0 ml; 95%CI -19.7 to -12.2 ml, adjusted for age, sex, education, intracranial volume, smoking, steroid use, white matter lesions and brain infarcts). The volume reduction was observed in all brain regions, but was significantly greater in gray matter (similarly across the four lobes) than in white matter regions. Morning cortisol was not associated with total brain volume.Conclusions: In this large-scale study, higher levels of evening cortisol were associated with widespread brain volume reductions, particularly in the gray matter. Prospective studies should examine whether hypersecretion of evening cortisol results from or contributes to brain volume loss and whether this is an underlying mechanism linking depression and development of dementia.



Keywords: cortisol, brain, MRI, cohort, HPA-axisSupported By: N01-AG-12100, Icelandic Heart Association, Netherlands Organization for Scientific Research (NWO: project no. 917-66-311)

729. The Role of Psychosocial Stress and Genetic Factors in Depression and the Aging BrainLotte Gerritsen1, Hui-Xin Wang2, Grégoria Kalpouzos2, Chandra Reynolds3, Nancy Pedersen4, 5, Laura Fratiglioni2

1Karolinska Institutet, Stockholm, Sweden, 2Department of Neurobiology, Care Sciences and Society, Division of Aging Research Center, Karolinska Institute, Stockholm, Sweden, 3Dept of Psychology, University of California, Riverside, Riverside, CA, 4Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, 5University of Southern California, Los Angeles, CA

Background: Stress and depression have frequently been associated with cognitive impairment and brain atrophy. Our aim was to investigate the combined effect of stress and depression and interaction with genetic factors in relation to cognitive decline and structural brain volumes in elderly subjects.Methods: We will present results from two large cohort studies, the Swedish National study on Aging and Care in Kungsholmen (SNAC-K:N=485;aged 60-90 years;58% female) and data from Swedish Twin Registry (STR:N=1002;aged 57-101 years;69% female). In both studies data were available on diagnosis of depression and depressive symptoms, stressful life events and APOE genotype. In SNAC-K structural MRI data were available for hippocampal and amygdala volume, global cognitive functioning was assessed by MMSE. In STR longitudinal data on memory functioning and perceptual speed was available and telomere length was assessed by terminal restriction fragment analysis.Results: So far we found no effect of depression on cognitive decline and brain atrophy. In SNAC-K childhood life events were associated with smaller hippocampal volume and larger amygdala volume in men, but not in women. In STR we found interactions of stress with APOE4 and shorter telomere length on memory decline, but not on perceptual speed.Conclusions: These findings will be discussed in light of stress by gene interactions as underlying mechanism for late-life depression, cognitive decline and brain atrophy. Possibly, the experience of stressful experience isa more important risk factor for cognitive decline and brain atrophy than depression in old age.Keywords: psychosocial stress, Depression, genetics, cognitive decline, brain atrophySupported By: PIEF-GA-2011-300355

730. APOE Genotype and the Temporal Relation between Depression and DementiaIda Mattsson

Karolinska Institutet, Stockholm, Sweden

Background: Late-onset depression may be a prodromal stage of dementia rather than a risk factor, but the cause of this association remains unknown. W e aimed to investigate the temporal relationship between depression and dementia, by also looking into a possible mediating effect of apolipoprotein E (APOE) ε4.Methods: This was investigated in a case-control study with longitudinal depression and dementia evaluations, among 3007 Swedish twins.Results: A significant interaction was found between APOE ε4 status and depression for both total dementia and AD. In ε4 carriers, history of depression was significantly associated with dementia and AD (OR 1.90, 95%CI 1.33-2.73 for dementia, OR 1.88, 95%CI 1.25-2.82 for AD). After categorizing depression into time of first onset (early depression occurring more than ten years before dementia onset, recent depression within ten years),no association was found between early depression and dementia or AD, while ε4 carriers with recent depression had highly increased odds of disease development (OR 2.38, 95%CI 1.53-3.69 for dementia, OR 2.45, 95%CI 1.51-3.99 for AD).Conclusions: APOE ε4- modifies the association between depression and dementia. Our results suggest that only depression with onset close in time to possible dementia or AD development increases the odds of dementia, and that carriers of APOE ε4 are more likely to proceed from depression to dementia and AD than non-carriers.

Keywords: Dementia, Depression, APOE



SymPoSiumBiological Markers for PTSD

Saturday, May 18, 2013, 12:30 PM - 2:30 PMImperial A - Ballroom Level

Chair: Roger K. PitmanSupported By: U.S. Government grants

731. Psychophysiological Markers for PTSDScott P. Orr

Massachusetts General Hospital/Harvard Medical School, Charlestown, MA

Background: Heart rate (HR), skin conductance (SC), facial electromyogram (EMG), and cortical electroencephalographic event-related potential (ERP) measures have been applied to the study of PTSD for more than 25 years. PTSD diagnosis largely relies on self-report. New research is described here that examined convergent and predictive validity and stability of psychophysiological reactivity during script-driven imagery (SDI) as a diagnostic measure of PTSD.Methods: Thirty-six individuals completed the SDI procedure, the Clinician-Administered PTSD Scale (CAPS), and self-report measures of depression, anxiety and mental and physical health initially and 6 months later. Subjects engaged in script-driven imagery of their traumatic event(s) while HR, SC and facial EMG were recorded. A composite measure of psychophysiological reactivity was obtained by applying an a priori discriminant function to each individual’s responses, yielding a single score reflecting overall psychophysiological reactivity.Results: Psychophysiological reactivity during SDI showed moderately strong convergent validity with the CAPS, which remained even after adjusting for self-reported depressive symptoms. Psychophysiological reactivity and CAPS demonstrated excellent, and comparable, stability across measurement occasions (r’s=.75, p<.001). After adjusting for depressive symptoms, predictive validity for the CAPS with regard to health sequelae was reduced, whereas it remained mostly unchanged for psychophysiological reactivity.Conclusions: Findings support psychophysiological responses during SDI as a reliable and valid measure that captures a pathophysiologic process in PTSD. The fact that psychophysiological measures may be less subject to reporting and diagnostic bias than standard measures lends support for psychophysiological reactivity to SDI as a standardized PTSD assessment strategy.Keywords: PTSD, Psychophysiology, DiagnosisSupported By: Department of Veterans Affairs

732. Neuroimaging Markers for PTSDIsrael Liberzon

University of Michigan, Ann Arbor, MI

Background: Neuroimaging research demonstrated hyperactivation in amygdala and insula, and hypoactivation in mPFC, in PTSD, it is not clear however whether these can serve as effective biomarkers of PTSD diagnosis or treatment. Only, few studies examined the patterns of connectivity in large-scale networks i.e. the salience network (SN), and default mode network (DMN) in PTSD. These, might be both linked to PTSD pathophysiology, and serve as useful biomarkers for diagnosis and treatment.Methods: Resting state brain connectivity was examined in returning OIF/OEF veterans with and without PTSD and community controls. Correlation coefficients were calculated between the time course of seed regions in key SN and DMN regions and the rest of the brain.Results: PTSD participants showed reduced functional connectivity within DMN (between DMN seeds and DMN regions), and increased connectivity within SN (between insula seeds and SN regions including amygdala, as well as amygdala seeds and insula). Furthermore, reduced negative coupling between

amygdala and dorsal and rostral ACC was observed. PTSD participants also demonstrated increased cross-network connectivity - increased connectivity of DMN seeds with SN regions (insula, putamen, and SMA), and of SN seeds with DMN regions including hippocampus.Conclusions: Reduced resting state connectivity in PTSD within DMN, greater coupling within SN (insula and ACC) and with amygdala, and increased coupling between DMN and SN, suggest larger network desegregation and potential shift toward salience/threat detection in PTSD, even in task-free conditions. These findings might both help to elucidate PTSD pathophysiology and serve as useful biomarkers for diagnosis and treatment.Keywords: network, connectivity, fMRI, resting state, PTSDSupported By: R24 MH075999

733. Integration of Neuroendocrinological Markers for PTSD with Relevance to PTSD Risk, Recovery, and TreatmentAnn M. Rasmusson

VA Boston Healthcare System and Boston University School of Medicine, Boston, MA

Background: Pre-stress and stress-induced changes in several neuroendocrinological factors are associated with acute changes in mood state, cognition, behavior and propensity for fear conditioning and development or maintenance of PTSD. Many of these neurobiological factors are influenced by gender; in women, they are also influenced by menstrual cycle phase and reproductive status. Relevant neurobiological factors include: adrenal steroids such as dehydroepiandrosterone (DHEA) and its sulfated derivative, DHEAS, as well as cortisol; other neuroactive steroids such as allopregnanolone and androsterorone, derivatives of progesterone and testosterone, respectively, which potently and positively modulate brain gamma amino butryic acid (GABA) receptor function; peptides such as neuropeptide Y; and classical neurotransmitters such as serotonin, norepinephrine, GABA, and excitatory amino acids. Gonadal hormones, including estrogen, progesterone, and testosterone influence the neurophysiology of these stress hormone systems and are also influenced by stress.Methods: This presentation will review and integrate clinical and basic research findings regarding the neuroendocrinology of PTSD with relevance to fear conditioning and extinction.Results: Integration of neuroendocrine systems findings, as well as potential genetic and epigenetic regulation of these systems, as relevant to PTSD.Conclusions: A translational systems approach to integrating neuroendocrinological findings with regard to stress exposure, PTSD, and specific population and individual characteristics can lead to new strategies for intervening in PTSD development and selection of best individualized treatments for PTSD.Keywords: PTSD, Neuroendocrinology, Neuroactive Steroids, Biomarkers, Fear ConditioningSupported By: VA National Center for PTSD, VA CSR&D Merit Reviews, Center for Naval Analysis, ORWH & NIDA: 1K12DA14038-01, NIMH MH49486 & MH56890, NIMH R21MH31113, NARSAD Young Investigator Award, VA/DOD INTRuST Clinical Consortium, VA HSR&D TRACTS Program

734. Novel Genetic Markers for PTSDKarestan C. Koenen1, Guia Guffanti2, 3

1Mailman School of Public Health, Columbia University, New York, NY, 2Psychiatry, New York State Psychiatric Institute, New York, NY, 3New York State Psychiatric Institute, New York, NY

Background: Genetic variants associated with PTSD have been proposed as promising, potential biomarkers because DNA can be obtained non-invasively and genotype is established at conception and reliably assayed. However, to date, robust genetic risk factors for PTSD have not been established; only one genome-



wide association study (GWAS) has been published.Methods: We conducted a GWAS of PTSD in a cohort of trauma exposed African Americans women from the Detroit Neighborhood Health Study (N=449). Genotyping was performed using the HumanOmniExpress BeadChips. GWAS was conducted using logistic regressions for genotypes coded log additively (0,1,2 copies of the minor allele) and PTSD case status. All analyses were performed using PLINK software package (v 1.07, October 2009).Results: The strongest signal was at SNP rs10170218 with a p-value at genome-wide significance threshold (p=5.09 x 10-8; OR=2.88). We replicated the association with PTSD in a large and independent sample set of trauma exposed Caucasian women (p=0.027). SNP rs10170218 maps in AC068718.1, a novel long intergenic non-coding RNA (lincRNA) located at 2q32.1 onchromosome 2. In silico analysis of the current genome annotations available at UCSC Genome Browser (hg19) revealed that SNP rs10170218 overlaps with LTR8, a LTR (long terminal repeat) repetitive element (Family ERV1).Conclusions: Our data provide the novel evidence for the role of a linc RNA in the genetic architecture of a common mental disorder. An emerging literature that suggests a regulatory role of lincRNA on other genes in terms of protein expression, DNA binding, and transcriptional function.Keywords: posttraumatic stress disorder, genetics, linc RNA, genome-wide association study, traumaSupported By: MH 088283, DA 022720, DA 022720-S2, MH078928, MH093612

oral SeSSionTreatment and Pathophysiology in Depression


Chair: Darin D. Dougherty

735. Effects of Pharmacologically Induced Sex-Hormone Fluctuations on Depressive Symptoms and Serotonin Transporter Binding in Healthy WomenVibe G. Frokjaer1, Anja Pinborg2, Maria Heede1, Susanne Henningsson3, Jacob Madsen4, Claus Svarer1, Gitte M. Knudsen1

1Neurobiology Research Unit, Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital, Copenhagen, Denmark, 2The Fertility Clinic, Copenhagen University Hospital, Copenhagen, Denmark, 3Hvidovre Hospital, Danish Research Centre for Magnetic Resonance, Hvidovre, Denmark, 4PET and Cyclotron Unit, Copenhagen University Hospital, Copenhagen, Denmark

Background: Mood disorders are twice as frequent in women relative to men. Sex-hormone fluctuations may increase risk for depressive symptoms as supported by observations in menopausal transition or post-partum. Serotonergic signalling is critical in the pathophysiology of mood disorders and may be sensitive to sex-hormone fluctuations. We investigated whether sex-hormone downregulation provoked depressive symptoms, and if such symptoms were correlated to changes in brain serotonin-transporter (SERT)-binding as compared to placebo.Methods: Sixty-one healthy women (24.3±5.0 years) participated in this randomised placebo-controlled double-blind study. At day 21 in their natural cycle they underwent intervention with a gonadotropin releasing hormone agonist (GnRHa) or placebo. Regional SERT-binding, assessed with [11C]DASB-PET, and Hamilton scores of depressive symptoms were acquired at baseline and 16.2±2.6 days after intervention.Results: Relative to placebo, GnRHa initially increased estradiol (p=0.03) and subsequently downregulated estradiol to postmenopausal levels (p<0.0001). GnRHa increased depressive symptoms from baseline (p=0.001), and relative to

effect of placebo (p=0.025). Change in Hamilton score was significantly predicted by a group-by- change in SERT-binding interaction for neocortex (p=0.003) and prefrontal cortex (p=0.03), but not subcortically (midbrain: p=0.12, pallidostriatum: p=0.21). Within the GnRHa group, changes in Hamilton scores were positively correlated to changes in neocortical SERT-binding (p=0.01).Conclusions: Relative to placebo, sex-hormone downregulation with GnRHa provoked subclinical depressive reactions, which were coupled to increases in neocortical SERT-binding. Our data are consistent with the hypothesis that effects of sex-hormone fluctuations on cortical SERT-binding influence the development of depressive symptoms.Keywords: sex-hormone, serotonin transporter, depression, PET, DASBSupported By: FSS, Region Hovedstaden

736. Long Term Sertraline Treatment Decreases Volumes of Hippocampus and Anterior Cingulate Cortex in an Adult Female Primate Model of DepressionStephanie Willard1, Warwick D. Johnston2, Ashlee Clark1, Beth Uberseder3, David Neely3, Adreanna Massey3, James Daunais4, Jeff Williamson5, Thomas C. Register3, J. Daniel Bourland6, Carol Shively3

1Integrative Neuroscience Graduate Program, Wake Forest, Winston-Salem, NC, 2Integrative Physiology and Pharmacology PH D Program, Wake Forest, Winston-Salem, NC, 3Pathology, Wake Forest, Winston-Salem, NC, 4Physiology & Pharmacology, Wake Forest, Winston-Salem, NC, 5Internal Medicine, Wake Forest, Winston-Salem, NC, 6Radiation Oncology, Wake Forest, Winston-Salem, NC

Background: Effects of long term SSRI treatment are difficult to assess in patients due to intermittent and varied drug regimens. Effects of 18 months treatment with sertraline on hippocampus (HC), anterior cingulate cortex (ACC) and amygdala volumes were examined in a cynomolgus macaque (Macaca fascicularis) model of social stress-associated depressive behavior.Methods: 42 adult female monkeys were housed in long term stable social groups (n=4 each) and consumed a Western diet. Depressive behavior was recorded in 42 adults for 18 months. Stratified randomization was used to assign subjects to treatment or placebo balanced on pretreatment depression scores and BW. Monkeys were trained to comply with oral dosing and administered 20 mg/kg sertraline HCl daily for 18 months. Structural MRI scans were performed using a 3T instrument. Volumes of left and right whole, anterior, and posterior HC, amygdala, whole ACC, area 32, 25 and 24 were measured, corrected for total brain volume, and analyzed with a 2 (left, right) X 2 (depressed, nondepressed) X 2 (sertraline, placebo) ANOVA.Results: The left amygdala was larger than the right (p=0.04). Females treated with sertraline had smaller HC than placebo (p=0.05). Sertraline treatment also resulted in smaller right but not left ACC (side X treatment interaction p=0.01). Sertraline effects tended to be larger on average in nondepressed than depressed monkeys, however, these tendencies were not significant (all p’s>0.05).Conclusions: Long term sertraline treatment appears to result in smaller volumes of neural areas critical to mood in an adult female primate model of depression.Keywords: nonhuman primate, depression, hippocampus, anterior cingulate cortex, imagingSupported By: RO1HL087103;TSI of Wake Forest School of Medicine



737. Habenula Responses in Major Depression: A High-Resolution FMRI StudyRebecca P. Lawson1, Camilla L. Nord1, Ben Seymour2, Raymond J. Dolan3, Peter Dayan4, Nikolaus Weiskopf3, Jonathan P. Roiser1

1Institute of Cognitive Neuroscience, University College London, London, United Kingdom, 2Center for Information and Neural Networks, Osaka University, Osaka, Japan, 3Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom, 4Gatsby Centre for Computational Neuroscience, University College London, London, United Kingdom

Background: The lateral habenula (LHb) has been shown to respond to cues that predict aversive stimuli in non-human primates and has been implicated in reinforcement processing and the pathophysiology of major depression (MDD), possibly via reciprocal connections with monoaminergic nuclei. We report the first high-resolution fMRI investigation of hemodynamic responses during appetitive and aversive conditioning in the LHb in MDD.Methods: Unmediated MDD patients (n=10) and matched controls (n=10) performed a Pavlovian conditioning task where they were exposed to conditioned stimuli (CSs) that preceded reinforcing outcomes (win £1; lose £1; and painful electric shock) in a probabilistic manner. Neural responses were monitored using high-resolution T2* echo-planar imaging (1.5mm isotropic), and T1-weighted (0.77mm isotropic) images were obtained to accurately identify the LHb (Lawson et al, 2012). Using a temporal difference learning algorithm, trial-by-trial values for win, loss and shock predicting CSs were derived for each subject and used as parametric modulators in the fMRI analysis.Results: We replicated our previous result that LHb responses were positive to shock-predicting CSs and negative to reward-predicting CSs in healthy volunteers (Lawson et al, in prep). We found no significant group differences in habenula responses to win and loss CSs (Ps>0.7), but habenula responses to shock CSs were negative in MDD subjects (trend difference to controls: t(18)=1.857, p=0.080).Conclusions: These surprising results may reflect a difference in how depressed patients process aversive stimuli, with important implications for understanding the constructs of anhedonia and learned helplessness.Keywords: habenula, major depression, high-resolution fMRI, aversive, punishmentSupported By: Medical Research Council (MRC)

738. Hippocampal Choline Level Predicts Symptomatic Improvement with Agomelatine in Major Depressive Disorder: A 3 Tesla Single Voxel Spectroscopy StudyNajib Allaïli1, 2, Romain Valabregue1, 3, 4, 5, Malgorzata Marjanska6,

7, Pauline Delaveau2, Eric Bardinet1, 3, 4, 5, Maritza Jabourian8, Judith Laredo8, Stéphane Lehéricy1, 3, 4, 5, Philippe Fossati2

1Centre de Neuro-Imagerie de Recherche - CENIR, Institut du Cerveau et de la Moelle Epinière - ICM, Paris, France, 2Usr 3246, CNRS, Paris, France, 3U975, INSERM, Paris, France, 4Cricm, UPMC, Paris, France, 5Umr 7225, CNRS, Paris, France, 6Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, 7Department of Radiology, University of Minnesota, Minneapolis, MN, 8IRIS, SERVIER, Paris, France

Background: There is growing evidence for the implication of the hippocampus in the neurobiology of depression and in the mechanism of action of antidepressants. We used magnetic resonance spectroscopy to identify hippocampal spectroscopic correlates of depressive state and of response to Agomelatine, a new antidepressant with melatonin agonist and 5-HT2C antagonist properties.Methods: 21 MDD patients and 15 matched healthy controls were scanned before treatment (W0) with Agomelatine (6weeks, 25mg/day), using a 2.4-mL spectroscopic volume in the left posterior hippocampus to minimize partial volume

effects. Patients’ symptoms were assessed with HAM-D scale at W0 and W7.Results: HAM-D score decreased significantly between W0 and W7 in the patient group. Glutamate+Glutamine (Glx) was significantly lower (p<0.005, Cohen d=1.07) in the patient group (6.0±1.7mM vs 8.0±2.0mM) at W0 and choline-related compounds (tCho) showed a trend to decrease (p=0.12). We observed a strong positive correlation (N=15, r=0.69, p<0.005) between tCho and ΔHAMD (=HAMDW0−HAMDW7).Conclusions: Our results extend to the hippocampus the existing pattern of decreased Glx found in other brain regions during depression. They indicate for the first time that hippocampal tCho level before Agomelatine treatment predicts clinical improvement. tCho has been proposed to reflect cell membranes turnover and may therefore be a marker of the hippocampal dendritic remodeling observed in animal studies. Further studies are needed to delineate the biological significance of hippocampal tCho signal in MDD.Keywords: Proton Magnetic Resonance Spectroscopy, Choline, Neuroplasticity, Hippocampus, Major Depressive DisorderSupported By: SERVIER Pharmaceuticals

739. Resting State Functional Connectivity in Adolescents with Major Depression Before and After TreatmentKathryn R. Cullen1, Bonnie Klimes-Dougan2, Melinda Westlund1, Bryon A. Mueller1, Kelvin O. Lim1

1Psychiatry, University of Minnesota Medical School, Minneapolis, MN, 2Psychology, University of Minnesota, Minneapolis, MN

Background: Major depressive disorder (MDD) commonly emerges during the adolescent period, a developmental window associated with ongoing maturational changes in neural systems including the fronto-limbic circuitry that has been implicated in MDD. The deficient connectivity within fronto-limbic circuitry that has been found in adult depression may have arisen due to a developmental abnormality. However, despite the high prevalence, less is known about neural circuitry in adolescents with MDD. Previous work in adults with MDD has shown that treatment with anti-depressants can increase resting-state functional connectivity between frontal and limbic regions. However, no previous studies have examined the effects of medication on neural circuitry in adolescents with MDD.Methods: 44 adolescents with MDD (29 depressed, 27 healthy) underwent a resting state fMRI scan for six minutes and a structural scan. Five of the depressed adolescents were scanned a second time after they had received treatment with fluoxetine for 8 weeks. Rigorous methods were applied to remove physiological noise signals and motion effects.Results: At baseline, MDD patients showed lower functional connectivity between bilateral amygdala and several cortical regulatory regions in comparison to controls. For the subset of adolescents that were scanned post-treatment, connectivity between left amygdala and left orbitofrontal cortex increased significantly.Conclusions: The impaired connectivity within fronto-limbic neural circuitry that been found in adults is already present in adolescents with MDD. Further, treatment with medication may restore fronto-limbic connectivity in adolescents. These results suggest that the adolescent period may be an opportune window for intervention to restore healthy developmental trajectories.Keywords: depression, resting-state, functional connectivity, adolescents, treatmentSupported By: 5K23MH090421-04



740. Six-Month Stability in FMRI Markers of Emotion Processing in Depressed and Healthy Control ParticipantsJay C. Fournier, Henry W. Chase, Jorge Almeida, Mary L. Phillips

Psychiatry, University of Pittsburgh Scool of Medicine, Pittsburgh, PA

Background: Neuroimaging holds tremendous promise for understanding trait-like markers of psychiatric illness; however, little prior work has examined the stability of fMRI markers over time in patient samples. The current study examined 6-month test-retest reliability during emotion processing in a sample of unipolar depressed (UPD, N=17), bipolar depressed (BPD, N=15), and healthy control (HC, N=16) adults.Methods: On two occasions, separated by 6 months, subjects performed an emotional-faces paradigm in which neutral faces dynamically morphed into one of four emotional expressions. Median voxelwise intraclass correlation coefficients (mvICCs) were calculated to examine stability over time in regions showing significant activity at Time 1. Prior work has demonstrated group differences in amygdala activity to emotional stimuli, thus test-retest stability of amygdala function in each group was also examined.Results: At Time 1, whole brain analyses (p<0.05, FWE-corrected) revealed four clusters of activation (k range: 129-786 voxels) in bilateral visual (BA 17 & 18) and fusiform face regions during the emotional stimuli. Six-month test-retest reliability of activity across these regions was fair for all groups (mvICC=0.42(UPD), 0.50(BDP), 0.50(HC)), whereas test-retest reliability of amygdala activity was poor in all groups (mvICC=0.24(UPD), 0.30(BPD), 0.03(HC)).Conclusions: Despite substantial changes in symptoms among the patient groups, the test-retest stability of activity in visual/facial processing regions was adequate and fell within the range typically observed for fMRI studies of healthy participants. Stability of amygdala activity was substantially lower in all groups, and near zero in the HC group, suggesting a possible habituation effect in this region.Keywords: fMRI, Emotion Processing, Test-retest Reliability, Bipolar Disorder, Major Depressive DisorderSupported By: RO1MH076971

741. Morning Blue Wavelength Light Therapy Improves Sleep, Cognition, Emotion and Brain Function Following Mild Traumatic Brain InjuryMareen Weber1, David M. Penetar2, George H. Trksak2, Sophie R. DelDonno1, Maia Kipman1, Zachary J. Schwab1, Scott L. Rauch1, William D. S. Killgore1

1Center for Depression, Anxiety, and Stress Research, McLean Hospital, Belmont, MA, 2Neuroimaging Center, McLean Hospital, Belmont, MA

Background: Mild traumatic brain injury (mTBI) may offset the circadian rhythm of alertness, resulting in irregular sleep-wake patterns, delayed sleep onset, and degraded cognitive-emotional functioning. Given that sleep plays a pivotal role in neuroplasticity and recovery from TBI, effective treatments that improve sleep following TBI, but exert no adverse side effects need to be identified and evaluated. Because blue wavelength light affects melatonin rhythm, it may be particularly effective to re-entrain the circadian rhythm following TBI, and to improve sleep and subsequently cognition, emotion and brain function.Methods: We present preliminary data (N=18; mean age=24.3±8.6, 50% female) on the effect of a 6-week morning exposure to blue light on sleep, cognition, emotion and brain function in individuals with mTBI compared to placebo amber light. Participants underwent comprehensive psychiatric and neuropsychological assessment, Multiple Sleep Latency Tests, actigraphy, and magnetic resonance imaging before and after the intervention.b: Compared to placebo, the blue light intervention yielded a marked increase in

mean sleep minutes per sleep interval and improvements in neuropsychological measures of attention and speed of information processing, memory and executive functioning. In addition, subjective symptoms and daytime sleepiness decreased, while mood improved (all p<.05).Conclusions: These data offer promising support to the potential efficacy of blue light therapy in the treatment of sleep disturbance following mTBI, but need to be confirmed using the full data set (N=30). Future analyses will also determine whether and how these objectively and subjectively assessed cognitive and emotional improvements relate to brain functional and structural changes.Keywords: Sleep, Circadian rhythm, Blue light, mTBI, fMRISupported By: W81XWH-11-1-0056

742. Comparing Mindfulness-Training to Cognitive-Behavior Therapy for Smoking Cessation: Evidence for Distinct Neural Mechanisms?Hedy Kober

Yale Univeristy, New Haven, CT

Background: Cigarette smoking is the leading preventable cause of disease and death in the US. Stress is a major trigger for smoking relapse and treatment failure. Here we compared whether mindfulness-based vs. a cognitive-behavioral treatment are associated with distinct neural responses to stress, and whether these neural responses were related to treatment outcomes.Methods: We used Functional Magnetic Resonance Imaging (fMRI) to probe neural activity in 23 participants following a clinical trial in which they were randomized to receive Mindfulness Training (MT) or Freedom-From-Smoking (FFS), a form of cognitive-behavioral therapy. Participants were scanned during individualized script-driven guided imagery of two stress and two neutral-relaxing scenarios. Neural activity was compared between groups using t-tests, and correlated with % reduction in smoking. Results were familywise error corrected for multiple comparisons.Results: Both treatments were effective in reducing smoking behaviors. However, neural activity during stress revealed several significant between-group differences, including greater activity in dorsolateral prefrontal cortex in the FFS group, but lower amygdala and insula activity in the MT group. Importantly - across both groups - lower amygdala and insula activity was significantly correlated with greater reduction in smoking both immediately after treatment, as well as at 17-week follow-up.Conclusions: These findings suggest that MT vs FFS may contribute to stress reduction and smoking cessation via different mechanisms. Specifically, mindfulness treatment may be effective in part via reduction in neural responsivity to stress in amygdala and insula, which is related to improved smoking outcomes. Conversely, FFS may increase cognitive control of emotion.Keywords: fMRI, mindfulness, smoking cessation, stress, treatment mechanismSupported By: K12-DA00167, P50-DA09241, UL-DE019586, PL1-DA024859



oral SeSSionMedical, Neurological,and Hormonal Mechanisms

of Psychiatric DisordersSaturday, May 18, 2013, 12:30 PM - 2:30 PM

Continental 2 - Ballroom LevelChair: Trey Sunderland

743. Structural Characteristics of the Prefrontal Cortex Over Development in Bulimia NervosaRachel Marsh, Mihaela Stefan, Ravi Bansal, Bradley Peterson

Psychiatry, Columbia University, New York, NY

Background: Our fMRI findings suggest that adults and adolescents with BN fail to engage frontostriatal systems appropriately, likely contributing to their inability to regulate feeding behaviors. Our objective herein was to determine whether anatomical abnormalities account for deficient frontostriatal functioning in BN.Methods: Anatomical MRI scans were collected and surface based analyses were used to map and compare features of the cortical surface in 34 individuals with BN (mean age: 22.9 years) and 34 control participants (23.5 years).Results: In the BN group, local reductions were detected bilaterally in medial frontal gyri and in superior and inferior frontal gyri (IFG) of the left hemisphere (Fig.1). The number of objective binge-eating episodes in the patients correlated inversely with local volumes of inferior frontal cortices. Diagnosis-by-age interactions were detected in lateral IFG and scatterplots suggested that local volumes increased with age at a faster rate in the BN group. Surface measures in left IFG also correlated inversely with Stroop Interference scores in the BN group.Conclusions: Individuals with BN had regional reductions of the cerebral surface located in inferior frontal cortices, with the greatest reductions in those with the most severe symptoms. Reductions in inferior frontal cortices may be a marker for illness persistence, and functional deficits in self-regulation may be due to the abnormal maturation of these cortices in BN.

Keywords: Bulimia Nervosa, Surface Morphometry, Prefrontal Cortex, Self-regulation, MRISupported By: R01MH090062

744. Increased Lactate Levels During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Subjects with Bipolar DisorderRodrigo Machado-Vieira1, Marcus V. Zanetti1, Maria C. G. Otaduy2, Rafael T. de Sousa1, Alana C. Costa1, Tiffany M. Chaim3, Claudia C. Leite2, Geraldo F. Busatto3, Wagner F. Gattaz1

1Mood Disorders Program, LIM27, Department of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil, 2Department of Radiology, University of Sao Paulo, Sao Paulo, Brazil, 3LIM21, Department of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil

Background: Altered energy metabolism has been widely described in Bipolar Disorder (BD). However, brain lactate levels have been only evaluated in few

studies with heterogeneous samples using magnetic resonance spectroscopy (MRS). These findings support the presence of dysfunctional brain energy production as a central component in the pathophysiology of BD. However, no study to date has evaluated brain lactate levels specifically in bipolar depression or even the effects of lithium treatment in brain lactate levels in subjects with BD.Methods: Twenty-four BD individuals (up to 5 years of illness duration) presenting with an acute depressive episode underwent MRS at baseline and after 6 weeks of lithium therapy at therapeutic doses. Lactate levels were measures in the cingulated cortex (CC). Clinical assessment was performed weekly using the 21-item Hamilton Depression Rating Scale (HDRS) and the Young Mania Rating Scale (YMRS). A group of age and gender-matched healthy controls (n=18) was also studied.Results: BD patients exhibited increased brain lactate in the CC relative to healthy controls at baseline. A significant decrease in brain lactate levels was observed after 6 weeks of lithium treatment, and correlated with clinical response (reduction ≥ 50% in HDRS scores).Conclusions: Lithium treatment produces a significant decrease in brain lactate levels of acutely depressed BD patients. This suggests that the clinical efficacy of lithium is also associated with reduction in the shift from aerobic to anaerobic metabolism observed in BD.Keywords: bipolar disorder, depression, lithium, treatment, lactateSupported By: Fapesp, Sao Paulo

745. Interaction Between Catechol-O-Methyl Transferase (COMT) and Gonadal Steroid Hormones Affects Dorsolateral Prefrontal (DLPFC)-Dependent Working Memory Function -- A Positron Emission Tomography (PET) StudyShau-Ming Wei1, Peter J. Schmidt1, Erica B. Baller1, Philip D. Kohn1, Jonathan S. Kippenhan1, Bhaskar Kolachana1, David R. Rubinow2, Daniel R. Weinberger3, Karen F. Berman1

1National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 2Psychiatry, University of North Carolina, Bethesda, MD, 3Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD

Background: Molecular interactions between ovarian steroids and the dopamine catabolizing enzyme COMT are well documented. While both affect prefrontal cortex (PFC) physiology and PFC-related cognition, there is little data about their interactions in modulating PFC function. We used PET and an incisive pharmacologically-controlled hormonal manipulation protocol to investigate the interaction between COMT Val158Met genotype and ovarian steroids on working memory-related regional cerebral blood flow (rCBF).Methods: Thirty-four healthy, regularly menstruating women (11 Val homozygotes; 13 heterozygotes; 11 Met homozygotes) underwent PET scanning during each of three hormone conditions: (1) ovarian suppression induced by the GnRH agonist leuprolide acetate (Lupron), (2) Lupron plus estradiol replacement, and (3) Lupron plus progesterone replacement. rCBF was measured with oxygen-15 water PET (10mCi H215O/scan) during a series of fourteen 60-second scans that alternated between a 0-back sensorimotor control task and a 2-back working-memory task. Differences in working memory activation were assessed at p<0.001, uncorrected.Results: A significant COMT-genotype-by-ovarian-steroids interaction was observed in the right DLPFC. Post-hoc analyses revealed that 1) in the Val homozygotes and heterozygotes, DLPFC activation was increased during estradiol replacement compared to Lupron alone, whereas, Met homozygotes showed the opposite pattern; 2) during estradiol replacement, a genotype-related step-wise DLPFC activation pattern was observed where Met homozygotes had the highest activation, followed by the heterozygotes and then the Val homozygotes.Conclusions: These data demonstrate that COMT genotype and ovarian steroids interactively affect PFC-dependent neural activity in women. These results warrant further investigation in patient groups with sexually dimorphic or hormonally-dependent clinical expression.



Keywords: catechol-O-methyl transferase (COMT), estradiol and progesterone, working memory, dorsolateral prefrontal cortex (DLPFC), Positron Emission Tomography (PET)Supported By: NIMH

746. Higher Salivary Alpha Amylase Levels are Associated with Smaller Hippocampal VolumesLaura E. M. Wisse1, Geert Jan Biessels2, Lotte Gerritsen3, Arnoud J. G. Knoops4, Yolanda Van der Graaf5, Mirjam I. Geerlings5

1Julius Center/Department of Neurology, University Medical Centre Utrecht, Utrecht, Netherlands, 2Department of Neurology, University Medical Centre Utrecht, Utrecht, Netherlands, 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, 4Department of Radiology, University Medical Centre Utrecht, Utrecht, Netherlands, 5Julius Center, University Medical Centre Utrecht, Utrecht, Netherlands

Background: Hippocampal volume reduction has often been found in stress-related disorders. The role of the hypothalamic-pituitary-adrenal axis herein has frequently been affirmed, but the sympathetic nervous system (SNS) has received little attention. We investigated the relation between salivary alpha amylase, a proxy for SNS activity, and hippocampal volume.Methods: In 581 patients (age 62±9 years) from the SMART-Medea study, diurnal alpha amylase was assessed with saliva samples at awakening, 30, 45, and 60 minutes thereafter; at 10 and 11PM; and at awakening after 0.5 mg of dexamethasone administered at 11 PM. Hippocampal volumes were manually segmented on a 1mm3 T1-weighted 1.5Tesla MRI scan and dichotomized into the lowest versus the upper four quintile.Results: Logistic regression analyses, adjusted for age, sex, education, and total brain volume showed greater odds of having hippocampal atrophy (lowest quintile) in patients with higher amylase levels (log-transformed per unit increase) at 45 and 60 minutes after awakening (OR=1.23, 95%CI 0.97-1.56; OR=1.25, 95%CI 0.98-1.60, respectively); at 10PM (OR=1.29, 95%CI 1.01-1.66); at 11PM (OR=1.37, 95%CI 1.03-1.74); and after dexamethasone (OR=1.35, 95%CI 1.05-1.73).Conclusions: Higher alpha amylase levels were associated with smaller hippocampal volumes, suggesting that the SNS might play a role in hippocampal volume reduction. Future studies need to examine the importance of alpha amylase, as potential biomarker, in disentangling the relation between stress-related disorders and hippocampal volume loss.

Keywords: alpha amylase, hippocampus, stress, sympathetic nervous systemSupported By: VIDI grant from NWO

747. Recurrent Depression is Associated with Earlier Ocurrence of Metabolic Syndrome and Aggravates the Effect of Vascular Risk Factors on Cerebral Microangiopathy Determined By MRIPhilipp Sämann1, Derek Spieler2, Tanja Brückl3, Susanne Lucae4, Michael Czisch1, Florian Holsboer5, Stefan Kloiber4

1Neuroimaging, Max-Planck-Institute of Psychiatry, Munich, Germany, 2Institute of Human Genetics, Helmholtz Zentrum, Munich, Germany, 3Molecular Psychology, Max-Planck-Institute of Psychiatry, Munich, Germany, 4Pharmacogenetics of Depression, Max-Planck-Institute of Psychiatry, Munich, Germany, 5Director, Max-Planck-Institute of Psychiatry, Munich, Germany

Background: Major depressive disorder (MDD) and metabolic syndrome (MetS) show a high comorbidity and are possibly linked by common pathophysiological factors. Recently, MDD is discussed as independent risk factor for the occurrence of MetS and vascular morbidity.Methods: In a cross-sectional study (988 patients with recurrent unipolar depression (RUD) and 1023 controls) we investigated age-dependent frequency of MetS. In the MRI surrogate marker subgroup (n=392) we analyzed to which degree metabolic risk factors and history of RUD are associated with the formation of brain white matter lesions (WML) as summative surrogate marker of neurovascular pathology.Results: We observed an increased occurrence of MetS in RUD patients. Cumulative age group analysis showed a significant shift of MetS frequency towards younger age groups in RUD patients. MRI data revealed an overrepresentation of RUD patients in the low lesion count class, whereas in controls predominantly radiologically intact white matter was detected. Age, gender, and hypertension could be confirmed as substantial neurovascular risk factors. Further factorial analysis revealed a significant interaction effect of a history of RUD with hypertension (p=0.001) and with hypertension-by-age (p=0.003) on the degree of neurovascular microangiopathy. Diabetes directly interacted with RUD (p=0.020) with the effect being carried by interaction with hypertension-by-age (p=0.024) in higher order models.Conclusions: RUD conceivably leads to earlier occurrence of metabolic disorders and MetS and may aggravate the sequelae of known vascular risk factors on end organ damage. Following our findings we recommend increased attention on screening and prevention of vascular risk factors in MDD patients.Keywords: Depression, Magnetic Resonance Imaging, Neurovascular Microangiopathy, Metabolic Syndrome, Risk Factor

748. HIV-1 and Morphine Combined Induce Behavioral Changes and Synaptodendritic Injury via Disruption of Ion HomeostasisSylvia Fitting1, ShiPing Zou2, Elizabeth M. Podhaizer1, Pamela E. Knapp2, Kurt F. Hauser1

1Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 2Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA

Background: HIV-associated neurocognitive disorders (HAND) continue to be a major clinical manifestation of HIV infection in the combination antiretroviral therapy era, which is specifically enhanced with drugs of abuse. The viral protein Tat and its interaction with opiate drugs are thought to trigger synaptodendritic injury and thereby contribute to HAND.Methods: In vivo studies were conducted using GFAP-driven, doxycycline-inducible HIV-1 Tat transgenic mice to examine striatal morphology (pathology, spine density) and behavior (rotarod, gait, grip strength) with conducting parallel in vitro studies to study the mechanisms underlying opioid-Tat-induced synaptodendritic injury.Results: Tat induction disrupted synaptodendritic organization in vivo with



combined opioid exposure causing synergistic dendritic pathology. In vitro studies (primary striatal neurons) showed nearly identical dendritic swellings as seen in vivo. Tat caused significant increases in [Na+]i and [Ca2+]i that coincided with dendritic swelling, which was attenuated by NMDA and AMPA receptor antagonists. Tat + morphine exacerbated responses were negated in mu-opioid receptor knockout mice. Importantly, Tat + morphine-induced initial losses in ion homeostasis and increased [Ca2+]i production were attenuated by blockade of ryanodine receptors (RYR), IP3 inhibitors, and pyruvate, indicating the importance of [Ca2+]i stores and ATP.Conclusions: Tat-driven increases of [Ca2+]i production appears to be accompanied by increases in [Na+]i and ATP depletion, which is enhanced by morphine exposure likely via RyR and/or IP3 and is a critical determinant in the disruption of synaptic connectivity and striatal function that might underlie deficits in HAND-associated motor skill behaviors.Keywords: neuroAIDS, neurodegeneration, behavior, morphology, ion homeostasisSupported By: NIDA R01 DA018633; K02 DA027374; K99 DA033878; F31 DA033203

749. Molecular Imaging of Glial Cell Activation in Normal Aging: Implications for Aging with Neuropsychiatric IllnessCrystal C. Watkins

Johns Hopkins University School of Medicine, Baltimore, MD

Background: Cytokines in the peripheral and central nervous system have been implicated in mood disorders and cognitive dysfunction. Microglia modulate cytokines in the CNS and are important in regulating neuronal plasticity and neurotransmitter synthesis in the context of neuroinflammation. Translocator protein (TSPO) is up regulated in activated microglia and has been evaluated as a potential biomarker for neuroinflammation in a variety of imaging studies. We recently completed a phase I study of [11C]DPA-713, a TSPO PET ligand with higher affinity and brain uptake and lower nonspecific binding than the first generation TSPO-ligand [11C](R)-PK11195. It has been hypothesized that with aging, there is a heightened sensitivity to CNS immune activation, recapitulating the idea of increased neuroinflammation.Methods: We examined 14, young, healthy controls (age 22-47) and 12 cognitively healthy older adults (age 51-82) to determine whether healthy aging is accompanied by increased neuroinflammation using in vivo PET imaging with [11C]DPA-713.Results: We observed a trend of increased total distribution volume in the thalamus of older subjects , however,P >0.05. Voxel-wise analysis demonstrated greater [11C]DPA-713 binding in older subjects in the anterior (BA 24) and posterior (BA 31) cingulate bilaterally and right thalamus with P <0.05, even after accounting for TSPO binding gene polymorphisms.Conclusions: These data suggests increased [11C]DPA-713 binding in normal aging in areas traditionally implicated in geriatric depression and cognitive disorders. An understanding of DPA binding in normal aging is critical for the interpretation of ongoing studies in aging with mood disorders, HIV and Alzheimer’s disease.Keywords: aging, glia, PET imaging, HIV, TSPOSupported By: Johns Hopkins Mosaic Initative; R21082277;K0802915

750. Discovery of New Therapeutic Agents for Neurodegenerative DiseaseAndrew A. Pieper

University of Iowa Carver College of Medicine, Iowa City, IA

Background: We discovered a novel series of proneurogenic / neuroprotective molecules, the ‘P7C3 series,’ through a target-agnostic in vivo screen for agents that enhance hippocampal neurogenesis. P7C3 is an aminopropyl carbazole that

augments neurogenesis by blocking death of newborn neural precursors. P7C3 restored hippocampal structure and function to mice suffering from pathologically high apoptosis, and also impeded hippocampal cell death and enhanced cognitive ability in aged rats. To determine whether P7C3 might protect mature neurons in other CNS regions, we examined efficacy in two neurodegeneration models: G93A SOD1 transgenic mice (model of amyotrophic lateral sclerosis (ALS) exhibiting death of spinal cord motor neurons) and the MPTP model of Parkinson’s disease (PD) (dopaminergic neuron death in the substantia nigra).Methods: Efficacy of administration of P7C3 and analogs after disease onset was assessed in a dose response manner.Results: P7C3A20, a more highly active P7C3 analog, protects spinal motor neurons from death in the ALS model, correlating with improved motor function. P7C3 and P7C3A20 also block MPTP-killing of dopaminergic neurons in the substantia nigra of mice and MPP+-killing of dopaminergic neurons in C elegans. In C elegans, this correlates with preservation of mobility. Additional proneurogenic P7C3 analogs also protect in the mouse PD model, whereas non-proneurogenic P7C3 analogs show no protection.Conclusions: Evaluation of P7C3 analogs in the in vivo neurogenesis assay predicts neuroprotective efficacy for mature CNS neurons. The chemical scaffold represented by P7C3 may provide a basis to discover and optimize future pharmacologic agents for neurodegenerative diseases.Keywords: neuroprotection, P7C3, neurogenesis, Parkinson disease, ALSSupported By: NIMH RO1MH087986

SymPoSiumEpigenetic Profiling of the Human Brain:

Advances and ChallengesSaturday, May 18, 2013, 3:00 PM - 5:00 PM

Continental 5 - Ballroom LevelChair: Barbara K. Lipska

Co-Chair: Joel E. Kleinman**Supported By: NIMH/IRP

751. Epigenetic Signatures of Developing Human Prefrontal CortexBarbara K. Lipska

NIMH, Bethesda, MD

Background: The human prefrontal cortex (PFC) plays a critical role in complex cognitive behavior, shows a prolonged period of postnatal maturation and has been implicated in schizophrenia. Global transcriptome analyses of the developing human PFC implicated involvement of DNA methylation.Methods: We examined DNA methylation in ~14,500 genes at ~27,000 CpG loci in 5’ promoter regions (Illumina Infinium) in PFC of 109 normal control subjects from fetal period to old age. Samples were genotyped using 1M Illumina BeadArrays. We used ComBat and SVA to account for known and unknown factors, including batch effects, and GLM to analyze the effects of age. Associations of SNPs with methylation were analyzed on residuals using PLINK. We conducted co-methylation network analysis to find clusters of highly correlated CpG sites and DAVID for functional clustering analysis.Results: The highest rates of methylation change with age were observed during fetal life. Methylation changes slowed with aging. Hundreds of highly significant SNP-methylation associations were observed (top loci <E-39 LCLAT1 and HLA-DQB1), including genes implicated in schizophrenia, such as 5HTR2A. Moreover, strong negative and positive correlations were found between expression of genes and DNA methylation (for NNAT, neuronatin, r>0.9). Co-methylation network analysis shows that transcription factors, genes related to signaling, glycolysation and inflammation were overrepresented among the differentially methylated genes.



Conclusions: These data show that DNA methylation is dynamically regulated throughout life, and suggest that changes in DNA methylation may contribute to altered gene expression in schizophrenia.Keywords: development, prefrontal cortex, DNA methylation, epigenetics, human brainSupported By: IRP NMIH

752. DNA Methylation Signatures of Prefrontal Cortex and Peripheral Leukocytes in SchizophreniaShusuke Numata

The University of Tokushima Graduate School, Tokushima, Japan

Background: DNA methylation is a major epigenetic mechanism affecting transcription, and attention to its role in schizophrenia (SCZ) has recently increased.Methods: A genome-wide DNA methylation profiling (25,156 CpG sites) of the human dorsolateral prefrontal cortex (DLPFC) was conducted using Infinium® HumanMethylation27BeadChips in a large cohort (109 patients with SCZ and 114 non-psychiatric controls), combined with an analysis of genetic variance at ~880,000 SNPs. Surrogate variable analysis followed by multiple regression was used to identify CpG loci associated with SCZ. FDR correction was applied at the 0.05 level for multiple testing. To examine whether or not the CpG loci showing aberrant DNA methylation in SCZ identified in brain are also seen in the human peripheral leukocytes, the DNA methylation status of the same 23,431 CpG sites analyzed in the DLPFC was assessed using Infinium® HumanMethylation450BeadChips in an independent cohort (24 medication-free patients with SCZ and 23 non-psychiatric controls).Results: Altered DNA methylation in SCZ was detected at 649 CpG sites in the DLPFC, and a large number of cis- and trans- methylation quantitative trait loci were identified, providing potential roles in DNA methylation for the risk SNPs associated with SCZ. Altered DNA methylation in SCZ was detected at 394 CpG sites in the leukocytes, and a total of 13 differentially methylated CpG sites were common between these two cohorts.Conclusions: The DNA methylation changes in SCZ are largely tissue specific. A few CpG loci overlapping between brain and blood may perhaps be useful as biomarkers.Keywords: schizophrenia, DNA methylation, brain, blood, arraySupported By: a Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology(24791216)

753. Sexually Dimorphic DNA Methylation Sites are Conserved Across Human Brain and BloodChunyu Liu

University of Illinois at Chicago, Chicago, IL

Background: Discovery of molecular biomarkers for sex will be critical for our understanding of diseases with sexually different prevalences. A few studies have reported sexually dimorphic gene expression or DNA methylation, but the knowledge is still limited.Methods: We collected genome-wide DNA methylation data on 153 postmortem cerebellum brain samples from SMRI, 108 prefrontal cortex samples from Brain Cloud, 150 individuals with four different brain regions from NIA, 96 adult blood samples from B-SNIP, 305 cord blood samples from the Boston Birth Cohort, and 77 HapMap LCLs. All data used Infinium HumanMethylation27 BeadChip. After strict quality control and data filtering, we used T-tests to identify sexually dimorphic methylation (SDM).Results: Using FDR q ≤ 0.05 and female-male methylation level difference ≥ 5% as criteria, we identified 616 to 723 SDMs. Most SDMs were located on sex chromosomes (>83%). Over 70% of sex chromosomal CpG sites were SDMs. Females had higher methylation than males for some loci, but lower for others. 467 SDMs were shared across all tissues studied, and 659 SDMs were shared by different brain regions. Two loci showed significant interaction (FDR q ≤ 0.05) between sex and age in the Brain Cloud data.Conclusions: Many CpG sites are differentially methylated by sex. Most of the

sex-associated CpG sites are conserved across blood and brain. Some SDMs are on autosomes, but most are on sex chromosomes. Interaction between sex and age can affect DNA methylation level. SDMs may be associated with disease-candidate genes, including autism candidate genes.Keywords: DNA methylation, sex, brain, blood, age

754. Measuring Cell-Specific Epigenomes Using Human Brain TissueCarolina Montano

Johns Hopkins University School of Medicine, Baltimore, MD

Background: Epigenetic mechanisms in the human brain have been postulated for the coordination of developmental plasticity during neurogenesis, fate specification, and synaptic connectivity in mature neurons. Studying these mechanisms and their role in disease has been difficult due to the cellular heterogeneity of the human brain. DNA methylation is a stable epigenetic mark that can be used to assess the distribution of cells in whole tissue.Methods: To test the hypothesis that DNA methylation profile of human neurons differs from that of glia, and that these profiles could be used to measure relative cell-type frequencies in samples from whole brain, we isolated and sorted post-mortem human brain nuclei using NeuN antibody. The neuronal and glial fractions from prefrontal cortex (n=4), hippocampus (n=4), and temporal cortex (n=3) underwent genome-wide methylation measurements using CHARM. The neuronal and glial methylation signals were used to build a statistical model to estimate cell fractions in whole tissue. This model was validated using an independent calibration data set with known mixtures and applied to heterogeneous samples.Results: We found that neurons and glia have distinct methylation profiles and that the proportion of neurons in a brain region influences the identification of differentially methylated regions in the brain.Conclusions: Therefore, it is crucial to adjust for neuronal cell proportions when comparing the methylome of different brain regions or between individuals. We show that statistical modeling of neuronal and non-neuronal methylation data can aid in deconvolving tissue heterogeneity in the human brain and become a necessary tool for studies using post-mortem brains.Keywords: methylation, cell heterogeneitySupported By: P50HG003233

SymPoSiumThe Promise of Machine Learning Approaches:

Can we Really Translate Neuroimaging Findings into Patient Benefit?

Saturday, May 18, 2013, 3:00 PM - 5:00 PMYosemite B - Ballroom Level

Chair: Paola DazzanCo-Chair: Mary Louise Phillips*

*Supported By: R01 MH076971, U01 MH092221, R01 MH073953, R01 MH060952

755. Are Support Vector Machine Analyses Able to Discriminate Truth from Lie Brain Function in Sneaky Humans?Michael C. Stevens

Olin Neuropsychiary Research Center, Yale University School of Medicine, CT

Background: It recently has been shown that classification approaches based upon machine learning can successfully discriminate truthful from false



statements using fMRI-measured anterior cingulate and insular cortex activity information. The current study asked a) can one “fool” a support vector machine (SVM) into incorrectly classifying a deliberate falsehood as truth through straightforward experimental manipulation, and b) whether the addition of regional activation information outside cingulate and insular cortex targets could improve classification inaccuracy.Methods: Fifteen adults performed an event-related fMRI lie detection task where trials to respond True/False to autobiographical or general factual statements were covertly cued for truth versus lying, and self-inflicted mild-to-moderate pain during responses designed to increase cingulate-insular activation levels (i.e., 2 x 2 TRUTH versus PAIN design). Rather than simply disrupt classification accuracy, the experimental intent was to purposefully create an inaccurately inflated baseline for lie-related brain function so that all further responses were categorized as truthful statements.Results: SPM8-estimated activation in anterior cingulate and insular cortex differed between conditions in hypothesized ways (pain elicited greater activation than lying), and SVM classification accuracy was dramatically altered by the experimental manipulation.Conclusions: In addition to reasonably well-known caveats and guidelines about the relative performance of various machine learning algorithms, the current project illustrates the crucial point that application of such approaches to clinical problems remains subject to gross bias in terms of what data is used to determine classification rules. The study findings also weaken arguments for the legal admissability of “fMRI lie detection” into legal/forensic settings.Keywords: machine learning, lie detection, fMRI, classification

756. Pattern Recognition and Clinical Neuroimaging: Potential and CaveatsJanaina Mourao-Miranda

University College London, London, United Kingdom

Background: Pattern recognition approaches have been successfully used to classify groups of individuals (e.g. healthy subjects and patients) based on their patterns of brain activity or structure. In these applications brain scans are treated as spatial patterns and statistical learning models are used to identify statistical properties of the data that can be used to discriminate between groups of subjects (classification models), predict a continuous measure (regression models) or detect outliers with respect to a normative basis. These approaches represent an important paradigm shift in neuroimaging data analysis, moving towards a more direct application of neuroimaging into clinical practice as they enable predictions at individual level.Methods: We have applied a general analysis framework in pattern recognition analysis of multiple neuroimaging datasets, acquired in different modalities, in patients with psychiatric disorders (schizophrenia, affective psychoses, depression). We have applied the basic principles of commonly used pattern recognition models, and evaluated advantages and limitations of variations in these approaches.Results: 3 series of applications of pattern recognition approaches to neuroimaging-based diagnosis of psychiatry disorders were successfully completed including: (1) Diagnosis and prognosis as a standard two class problem based on patterns of brain activation for a specific stimuli; (2) Group discrimination based on the within-group predictive probability for different stimulus; (3) Application of the one-class SVM to treat patient classification as an outlier detection problem.Conclusions: Pattern recognition approaches combined with neuroimaging techniques have promising clinical utility in the evaluation of diagnosis and prognosis of psychiatric illnesses.Keywords: Pattern Recognition, MRI, Psychosis, DepressionSupported By: Wellcome Trust

757. Classification of Schizophrenia Patients and Healthy Controls from Structural MRI Scans in Two Large Independent SamplesHugo Schnack1, Mireille Nieuwenhuis2, Neeltje van Haren2, Wiepke Cahn2, Hilleke Hulshoff Pol2, Rene Kahn2

1University Medical Center Utrecht, Utrecht, Netherlands, 2Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands

Background: Machine learning techniques have been shown to separate schizophrenia patients from healthy subjects based on their structural MRI scans with accuracies ranging from 70-90%. The generalizability of these classification models was not tested, due to the relatively small sample sizes. To confirm the predictive capacity of a classification model it is necessary to build and test it on two, independent, large data sets.Methods: Structural magnetic resonance brain images of 283 schizophrenia patients and 233 healthy controls were taken from two independent data sets. A support vector machine (SVM) was trained on the first set to separate patients from controls based on gray matter densities (VBM). The generalizability of the model was tested by applying it to the second set (and leave-one-out (LOO) cross-validation on the training set).Results: The discriminative patterns of the model included decreases in frontal and superior temporal gray matter densities. The model’s LOO-accuracy was 71.4%; application to the replication set yielded 70.4% accuracy.

Conclusions: We confirmed the feasibility to use structural MRI for individualised prediction whether a subject is a schizophrenia patient or a healthy subject, with an accuracy of 70.4%. The good results on the test set indicate that we can detect patterns of brain abnormalities in schizophrenia patients that are not unique to the training set, but are also able to classify “new” individuals almost equally well.Keywords: machine learning, schizophrenia, MRI, classification

758. Using Support Vector Machine Approaches to Identify the Neuroanatomical Predictors of Short and Long-Term Outcome in First Episode PsychosisPaola Dazzan

Institute of Psychiatry, King’s College London, London, United Kingdom

Background: Response to treatment and long-term outcome following the first-episode of psychosis are very heterogeneous, with only about 50% of patients responding to antipsychotics within 3-months, and approximately 30% developing an incapacitating illness course. The early identification of individuals destined to have a worse illness course is therefore crucial.Methods: Magnetic Resonance Imaging was used in multiple International datasets of patients at their first psychotic episode (n=260), followed them up clinically for 5-6 years. We used Support Vector Machine (SVM) approaches in



both single and combined datasets of grey matter maps obtained with SPM8.Results: The occurrence of subsequent illness episodes was predicted with significant accuracy in individual datasets (70% correctly classified; p=0.005). Furthermore, it was possible to combine datasets acquired with different protocols and in different scanners to accurately predict illness course (68% correctly classified), and higher accuracy was achieved when the datasets are combined in the training phase.Conclusions: Distributed brain alterations are present already at illness onset and may be used to identify those individuals destined to a poorer outcome. Evidence will be discussed in the context of data from a new, independent, dataset of first episode psychosis patients. In these, we have shown that worse widespread white matter integrity and reduction in gyrification (hypogyria) across multiple brain regions characterize individuals who will not respond to even short-term (12-week) treatment. Neuroanatomical data can therefore considerably help patient stratification in psychiatry, ultimately allowing individualised patient management from the time of the first presentation to services.Keywords: MRI, Outcome, Psychosis, Pattern Recognition, Neuroanatomy

SymPoSiumRole of HPA Axis Genes in Risk for and Biology of

Depression and AnxietySaturday, May 18, 2013, 3:00 PM - 5:00 PM

Continental 6 - Ballroom LevelChair: Alan F. Schatzberg*Co-Chair: Ned H. Kalin**

*Supported By: NIH and Pritzker**Supported By: R01 MH046729, R21 MH09258, R01 MH081884, P50 MH84051, R21 MH091550

759. CRH-R1 and CRH-R2 Genetic Variation in Anxious Young Rhesus MonkeysNed Kalin

University of Wisconsin, Madison, WI

Background: The CRH system mediates the stress response and has been implicated in anxiety and depressive disorders. Using a large mulitgenerational pedigree of rhesus monkeys, we examined whether variation in genes encoding for CRH R1 and CRH R2 accounts for the early life risk to develop anxiety and depressive disorders.Methods: Exons for both genes were sequenced for over 200 animals to identify SNPs. Putatively functional SNPs were further examined in relation to their ability to predict anxious temperament (AT), cortisol, and regional brain metabolic activity assessed with FDG-PETResults: Findings demonstrated that variation in both genes was relevant to understanding AT. Of particular interest was variation in exon 6 of the CRH R1 gene that predicted both AT and metabolic activity in the anterior hippocampus and dorsal amygdala. Exon 6 encodes for the beta isoform of CRH R1 and is unique to primates.Conclusions: Taken together, these results suggest that variation in the genes encoding for the CRH receptors may provide the early life substrate for AT which could interact with trauma to result in severe psychopathology later in life.Keywords: CRH, anxiety, depression, primateSupported By: R01 MH046729, R21 MH09258, R01 MH081884, P50 MH84051, R21 MH091550

760. Region-Specific Alterations in the Corticotropin Releasing Factor (CRF) and Glucocorticoid Receptors (GR) in the Postmortem Brain of Suicide VictimsGhanshyam N. Pandey

University of Illinois at chicago, Chicago, IL

Background: Abnormalities of hypothalamic-pituitary-adrenal (HPA) axis in depression and suicide are among the most consistent findings in biological psychiatry. However, the specific molecular mechanism associated with HPA axis abnormality in the brain of depressed or suicidal subjects is not clear. To study the role of HPA axis in teenage suicide we determined the protein and gene expression of CRF, CRF receptors, and GR in the prefrontal cortex (PFC), hippocampus and amygdala of teenage suicide victims and teenage normal control subjects.Methods: The postmortem brain samples were obtained from 24 teenage suicide victims and 24 normal teenage control subjects were obtained from the Maryland Brain Collection at the Maryland Psychiatric Research Center. Protein expression was determined using Western blot and gene expression (mRNA) was determined using real-time RT-polymerase chain reaction (qPCR) technique. The data were analyzed using Pearson Product-Moment correlation, t-test and mixed-effect model.Results: We observed that the protein and gene expression of the CRF was significantly increased in the PFC (Brodmann area 9) and in amygdala, but not in the hippocampus, of teenage suicide victims compared with normal control subjects. We also observed a significant decrease in the protein and mRNA expression of GR, but not MR, in the PFC and amygdala.Conclusions: These results thus indicate that suicidal behavior is associated with increased CRF and decreased GR in certain specific areas of the brain of suicide victims compared with controls.Keywords: glucocorticoid receptors, corticotropin releasing factor, hypothalamic-pituitary-adrenal axis, postmortem brain, suicideSupported By: ROIMH048153

761. Genetic Variation and HPA Axis Activity: Implications for Risk for Depression and PsychosisAlan F. Schatzberg

Stanford University School of Medicine, Stanford, CA

Background: We explored HPA Axis genetic contribution to cortisol overactivity and psychosis in endogenous major depression.Methods: 122 study participants-43 PMD’s, 35 with nonpsychotic depression (NPMD) and 44 healthy controls.On the Stanford GCRC, an i.v. line was inserted at 4pm and blood collected hourly from 6pm-9am the next day. Mean cortisol levels for each subject for 6 pm-1 am and 1 am-9 am were used in analyses. 70 SNP’s for HPA axis genes for CRH(6), CRHR1(21), CRHR2(18), NR3C1 (glucocorticoid receptor, GR-10), NR3C2(15), and FKBP5(2) were selected using a previously described protocol. A genecentric logistic regression strategy was used with all SNPs for a specific gene entered as independent predictors and a gene-wide test performed based on the significance of the entire model. Individual SNP contributions were assessed based on the same model, with the effect of each SNP adjusted for all others.Results: Only one of the 6 genes-NR3C1 significantly predicted cortisol from 6pm-1am accounting for 20.1% of the variance (F(9,84)=2.56, p=.012), above the 6.5% accounted by age (total % variance=26.6). Four SNPs attained significance. Only the NR3C1 gene significantly predicted 1am-9am cortisol, accounting for 18.2% of the variance (F(9,84)=2.50, p=.014), above 14.0% explained by age. Four attained significance.CRHR1 predicted depression, Χ2 (20) = 33.91, p=.027 and both NR3C1 and CRHR1 significantly predicted psychosis: NR3C1, X2(9)=21.02, p=.013, CRHR1, X2(20)=36.02, p=.015.



Conclusions: NCR-1 alleles account for a significant proportion of cortisol activity as well as risk for psychosis. CRH R-1 alleles were associated with risk for depression and psychosis.Keywords: Cortisol, Major Depression, PsychosisSupported By: NIMH

762. Molecular Mechanisms for Gene X Environment Interaction in Depression and Anxiety: Focus on FKBP5Elisabeth B. Binder

Psychiatry and Behavioral Sciences, Max-Planck Institute of Psychiatry, Munich, Germany

Background: Polymorphisms in the glucocorticoid receptor(GR)-regulating co-chaperone FKBP5 have been shown to interact with early trauma to predict depression and anxiety. Here, we illustrate potential molecular mechanisms of how environment and genetic variation in FKBP5 interact to moderate the risk for these disorders.Methods: Using reporter gene assays, chromatin-conformation-capture experiments and mRNA and protein expression measures in peripheral blood cells as well as lymphoblastoid cell lines and a hippocampal progenitor cell line, we characterize how functional polymorphisms in FKBP5 moderate GR-induced FKBP5 gene expression and by this stress hormone system regulation. These data are complemented by next generation sequencing of the FKBP5 locus as well as locus-specific and genome-wide DNA methylation measures.Results: We can show that genetic variants (specifically rs1360780) in FKBP5 alter chromatin conformation and transcriptional activation. In combination with exposure to early trauma this leads to de-methylation in GR-response elements and further de-repression of FKBP5. The changes in human blood cells are paralleled by GR agonist-induced epigenetic changes in hippocampal progenitor cells. Interestingly, genome-wide child abuse-related DNA methylation changes in peripheral blood in risk allele carriers overlap to a significant degree with changes following GR agonist treatment in the neuronal cells line.Conclusions: Our data suggest that genetic variants that alter the stress-related induction of FKBP5 increase the risk for mood and anxiety disorders by leading to allele-specific epigenetic changes in FKBP5 as well as a number of additional loci on a genome-wide level. Data on functional polymorphisms from the next-generation sequencing experiment will also be presented.Supported By: #281388Gx# Molmech, MH071538, MH58922

SymPoSiumAntidepressant Induced Manic Symptoms in Youth:

Evidence of Neurobiological Predictors and SequelaeSaturday, May 18, 2013, 3:00 PM - 5:00 PM

Imperial A - Ballroom LevelChair: Kiki Chang

Supported By: R01MH066134

763. Antidepressant Induced Mania in Adolescents At-Risk for Bipolar DisorderMelissa DelBello1, Caleb Adler2, Jeffery Strawn1, 2, Stephen Strakowski2

1University of Cincinnati, Cincinnati, OH, 2Psychiatry, University of Cincinnati, Cincinnati, OH

Background: A recent meta-analysis found that youth have a 1 in 15 chance of exhibiting with antidepressant induced mania (AIMS) when exposed to SSRIs and suggested that SSRIs may be particularly problematic in youth with a high risk for bipolar disorder. Therefore, we examined the impact of antidepressant exposure in our cohort of youth at-risk for bipolar disorder and whether amygdala

connectivity prior to antidepressant exposure is associated with risk for AIMS.Methods: Youth without bipolar disorder and at least one parent with bipolar disorder were prospectively assessed for exposure to antidepressants and AIMS. All youth participated in a fMRI scan while performing a continuous performance task with emotional and neutral distractors.Results: Twelve (57%) of 21 youth with antidepressant exposure had AIMS; most commonly increases in irritability (n=7) and aggression (n=5). Logistic regression revealed that for every year decrease in age the risk of an adverse reaction to antidepressats increased by 1.8 times (95% CI= 1.0, 3.4, p=0.05). Right amygdala connectivity was decreased with left insula, left anterior cingulate, and left medial frontal cortex and increased with bilateral parahippocampal gyri and left amygdala connectivity was increased in right parahippocampal gyrus and right putamen and decreased in the left posterior cingulate and left superior frontal gyrus in those with vs. without AIMS.Conclusions: Our findings suggest that a majority of at-risk youth with antidepressant exposure exhibit AIMS. Controlled studies of antidepressants and biological predictors of AIMS in this population are needed.Keywords: antidepressants, bipolar disorder, youthSupported By: P50MH077138

764. Antidepressant Induced Manic Symptoms in Youth: Definitions and Phenomenological and Genetic Risk FactorsKiki Chang

Stanford University, Stanford, CA

Background: Antidepressants (ADs), particularly the serotonin reuptake inhibitors (SSRIs), have been widely used to treat pediatric anxiety disorders and depression. While effective, there are concerns that antidepressants may also precipitate mania in certain children. Placebo-controlled trials of SSRIs in youth have reported fairly low rates of antidepressant induced mania (AIM), averaging 2% (Cheung et al., 2005) for AIM, but 5-20% for manic symptoms (Carlson & Mick, 2003). Reports from other clinical trials and from clinical populations report mania or manic symptoms occurring in 5.4 - 58% of youth treated with antidepressants (Baumer et al., 2006; Faedda et al., 2004; Go et al., 1998; Martin et al., 2004; Wilens et al., 2003). In this talk we will review the incidence and definitions of antidepressant-induced mania (AIM) in youth, and provide retrospective data regarding antidepressant exposure in youth with and at-risk for bipolar disorder (BD).Methods: We obtained medication exposure and age at onset of mania (AAO) histories from 106 youth with a parent with BD (63 with BD, and 43 with subsyndromal BD). 52 of these children were interviewed for past AIM and genotyped for 5-HTLPPR polymorphisms.Results: SSRI exposure did not decrease AAO of mania. AIM occurred in 26 youth (50%). Diagnosis of bipolar I disorder and increased comorbidities were associated with AIM, but 5-HTLPPR status was not.Conclusions: AIM remains a common but understudied occurrence in youth. More rigorous study of risk factors for and management of AIM need to be conducted.Keywords: antidepressants, mania, children, bipolarSupported By: The Prechter Fund, K24MH07761

765. Genetic and Neurobiological Predictors of Aims in Youth at High Risk for Bipolar DisorderMeghan E. Howe

Stanford, Stanford, CA

Background: Antidepressants (AD) are used widely to treat children. However, at least 29 published case reports describe pediatric patients with antidepressant-induced mania (AIM). In 21% of these patients, there was a family history of BD. We sought to determine possible genetic, neurobiologic, and phenomenologic risk factors for AIM in a cohort of children at high-risk for bipolar disorder.Methods: 100 subjects aged 9 - 18 years, with a parent with BD, and either Major Depressive Disorder or ADHD themselves were included. We interviewed



the subject and/or parent for any psychologically adverse reactions that had arisen within three months of starting or increasing the dose of an antidepressant. AIM was defined as a manic episode, but only requiring one day in duration. MRI images were collected on a 3T GE Signa scanner. Amygdalae were traced by blinded raters. DNA was extracted and genotyped for 5-HTTLPR.Results: Twenty-nine of 52 (56%) subjects who had AD exposure had a history of AIM. Presence of the 5-HTTLPR s-allele and a smaller amygdalar volume was significantly associated with AIM (p = 0.002). Subjects with higher mania scores, comorbid anxiety, and ADHD were more likely to be AIM + (p < .01)Conclusions: Youth at high risk for BD may have genetic and neurobiological characteristics that predispose them to AIM. However, amygdalar findings may have been a sequelae of AIM. Prospective studies of high-risk youth treated with SSRIs need to be conducted.Keywords: Antidepressants, Amygdala, Serotonin, Youth, BipolarSupported By: R01MH046640

766. Antidepressants Exposure in Youth at High Risk for Bipolar Disorder: Data from the Bios StudyDavid Axelson

University of Pittsburgh, Pittsburgh, PA

Background: This study evaluated whether the exposure to antidepressant medication is associated to higher risk of future onset of bipolar spectrum disorders (BPSD - BP-I, II or NOS) in the offspring of parents with BP.Methods: 516 children (ages 2-18) of 266 parents with BP-I or BP-II were assessed every two years with KSADS-based instruments (ages 2-17) or the Structured Clinical Interview for DSM-IV (ages 18 and older) by interviewers blind to parental diagnosis. Past and current use of antidepressant medication was obtained at the intake and follow-up assessments.Results: Lifetime exposure to antidepressants occurred in 22.7% of the offspring. Lifetime antidepressant exposure was associated with a diagnosis of BPSD and 50% of BPSD offspring had been exposed to antidepressants. However, only 28% of BPSD subjects were exposed prior to the onset of BPSD, so that prior antidepressant exposure was not associated with onset of BPSD (HR=1.28, 95% CI 0.8-2.05, p=.30). Similar results were obtained when restricting the analyses to offspring with BP-I, while controlling for prior onset of a major depressive episode (HR=1.3, 95% CI 0.4-4.1, p=.71).Conclusions: These findings indicate that in offspring at genetic risk for BP, there is no significant elevation in risk for future onset of BPSD associated with exposure to antidepressants.Keywords: antidepressants, bipolar disorder, high-risk studySupported By: NIMH RO1MH60952

SymPoSiumPlasticity in Schizophrenia:

From Dysfunction to FunctionSaturday, May 18, 2013, 3:00 PM - 5:00 PM

Imperial B - Ballroom LevelChair: Zafiris Jeffrey Daskalakis

Supported By: NIH, CIHR, NARSAD

767. Changes in FMRI Brain Function Associated with Computerized Cognitive Training in Recent Onset SchizophreniaDaniel H. Mathalon

University of California, San Francisco, San Francisco, CA

Background: Computer-based cognitive training (CT) has been shown to ameliorate cognitive deficits in chronic schizophrenia. However, the functional brain changes

induced by CT remain obscure, particularly in recent onset schizophrenia.Methods: Recent-onset schizophrenia patients were randomized to 8 weeks (40 hours) of either computer-based CT of auditory/verbal processing (n=18; Posit Science, Inc.) or computer games (CG; n=20). Cognitive testing (MATRICS) and FMRI were conducted pre- and post- training/games. FMRI was acquired during a visual working memory task involving encoding, maintenance, and recognition memory across 3 loads (2, 5, or 8 letters). Encode and memory Probe FMRI contrasts showing significant (p<.001, uncorrected, voxelwise and/or p<.05, corrected clusterwise) Group (CT vs. CG) x Time (Baseline vs. Post-treatment) interactions were identified.Results: CT did not produce significant improvement in cognitive test performance relative to CG. However, relative to the CG group, the CT group showed significantly greater baseline to post-training activation increases during Encode in inferior frontal gyri (IFG), basal ganglia (BG), temporal pole, cerebellum, superior parietal and supplementary motor areas, and during Probe in hippocampus and cerebellum. Across all patients, Encode-related activation increases in IFG, BG, and cerebellum, and Probe-related activation increases in hippocampus and cerebellum were correlated with improvements in MATRICS working memory performance.Conclusions: While CT did not significantly improve cognitive test performance relative to CG, it resulted in greater recruitment of fronto-parietal, subcortical, cerebellar, and hippocampal regions during working memory task performance, suggesting that FMRI may be more sensitive than neuropsychological assessments to the pro-cognitive neuroplastic effects of CT.Keywords: Cognitive Training, Schizophrenia, Working Memory, Cognitive DeficitsSupported By: Brain and Behavior Research Foundation; Stanley Foundation

768. Magnetoencephalographic (MEG) Studies of Cortical Plasticity Induced by Cognitive Training in SchizophreniaSophia Vinogradov

UCSF/SFVAMC, San Francisco, CA

Background: We have previously reported behavioral outcomes in clinically stable adult outpatients with schizophrenia randomly assigned to participate either in 50 hours of “neuroplasticity-based” computerized cognitive training or 50 hours of a computer games control condition. The computerized training consists of exercises that place implicit, increasing demands on auditory perception and accurate aural speech reception. This psychophysical training is embedded within a suite of increasingly complex auditory and verbal working memory/verbal learning exercises. We find that training results in significant improvement in cognitive outcome measures.Methods: Here, we report longitudinal MEG data obtained from a syllable identification task and an auditory working memory task before and after the intervention.Results: We find the following MEG evidence of cortical plastic changes as a function of training, obtained in the active condition but not the control subjects: 1) Increased M100 response in auditory cortex accompanied by increased early prefrontal gamma band activation during a syllable identification task; 2) Increased gamma-band activation in the speech-encoding network during an auditory working memory task. These increases in neural activation patterns are correlated with behavioral improvements.Conclusions: Taken together, our data indicate that 50 hours of this form of cognitive training drives changes in cortical functioning consistent with “restoration” of key neurocognitive processes.Keywords: schizophrenia, cognition, cortical plasticity, cognitive training, magnetoencephalographySupported By: RO1MH068725



769. Plasticity in the Prefrontal Cortex in Schizophrenia and Healthy SubjectsTarek K. Rajji

Centre for Addiction and Mental Health, Toronto, ON, Canada

Background: Paired associative stimulation (PAS) is a transcranial magnetic stimulation (TMS) protocol that was developed to study plasticity in the human cortex. Here we present pilot data on the use of PAS to demonstrate for the first time plasticity in humans DLPFC and plasticity deficits in schizophrenia.Methods: PAS involves the pairing of peripheral nerve stimulation of the right median nerve with TMS of the contralateral motor cortex (M1. When this pairing is repeated it results in potentiation of the motor evoked potential (MEP) of a hand muscle. Combining TMS with electroencephalography (TMS-EEG) we assessed the effect of PAS on MEP and cortical evoked activity (CEA) in M1. Then, we assessed the effect of PAS when delivered to DLPFC on CEA in DLPFC in healthy participants and in participants with schizophrenia.Results: Among four participants PAS to M1 resulted in potentiation of CEA F(3,6) = 6.92, p < 0.05). MEP and CEA correlated strongly (Pearson’s r = 0.72; p = 0.002). In another sample of seven healthy participants and a sample of five participants with schizophrenia, PAS to DLPFC resulted in a maximal increase in CEA of 156% in healthy participants but only 116% in patients with schizophrenia. The difference in maximal CEA potentiation between healthy participants and patients with schizophrenia is of a large effect size (Cohen’s d = 0.80).Conclusions: PAS is novel brain stimulation that, when combined with TMS-EEG approach, can assess plasticity in DLPFC of patients with schizophrenia.Keywords: Plasticity, Dorsolateral prefrontal cortex, SchizophreniaSupported By: MOP 244041; NARSAD YIA17826; CFI 25861

770. Magnetic Resonance Spectroscopy (MRS) Studies of Glutamate and GABA and Implications for Plasticity in SchizophreniaDost Ongur

McLean Hospital/Harvard Medical School, Belmont, MA

Background: Synaptic plasticity in the central nervous system relies on regulation of glutamatergic and GABAergic neurotransmission. Magnetic resonance spectroscopy (MRS) allows in vivo detection of parenchymal glutamate (Glu), glutamine (Gln), and GABA levels non-invasively in human subjects. Therefore, MRS measures of Glu and GABA provide an opportunity to study abnormalities in plasticity in psychiatric conditions.Methods: In these studies we collect proton MRS data from two voxels in the anterior cingulate cortex and posterior cingulate cortex at 4 Tesla. We utilize J-resolved PRESS for Glu/Gln and MEGAPRESS for GABA quantification. There sequences have been validated in phantom and human test-retest studies. Data are analyzed using LCModel. We recruit patients diagnosed with schizophrenia or schizoaffective disorder in acute exacerbated or stable condition who are taking medication, as well as age- and gender-matched healthy controls with no personal or first degree family history of psychiatric disorder.Results: Chronically ill schizophrenia patients show a normal Gln/Glu ratio but elevated GABA levels. We do not find any relationship between these measures and medication status/dosage. These findings are in contrast to reports from other groups on patients experiencing a first episode of illness where Gln/Glu is elevated and GABA may be reduced.Conclusions: The pattern of Gln/Glu and GABA abnormalities suggest dynamic changes in neurotransmitter regulation during the evolution of illness in schizophrenia. The findings will be discussed in the context of known effects of Glu and GABA neurotransmission on synaptic plasticity and their implications for abnormal plasticity in schizophrenia.Keywords: Glutamate, Gaba, Plasticity, Schizophrenia, PsychosisSupported By: R01 MH094594; R21MH096107

SymPoSiumCircuitry Disturbances in the Prefrontal Cortex and Hippocampus: Common Mechanisms and

Interactions in the Pathophysiology of SchizophreniaSaturday, May 18, 2013, 3:00 PM - 5:00 PM

Yosemite A - Ballroom LevelChair: Vaibhav A. Diwadkar*Co-Chair: Bernat Kocsis**

*Supported By: MH68680**Supported By: MH83199, MH87777

771. Empirical and Computational Study of Cortical Gamma Oscillations in Schizophrenia: Implications for Understanding Pathophysiologic and Therapeutic MechanismsRaymond Y. Cho


Background: Cognitive and sensory impairments in schizophrenia are associated with cortical gamma oscillations disturbances. However, what therapeutic mechanisms might ameliorate gamma disturbances in the illness has been poorly explored. Here, we present integrated empirical and computational findings from investigating dopamine as a neuromodulator of gamma oscillations in schizophrenia and healthy controls.Methods: 12 healthy and 12 schizophrenia subjects participated in a double-blind, cross-over, placebo-controlled study of single-dose amphetamine administration. After administration, subjects performed the EEG auditory steady-state response paradigm. Spectral analyses employed wavelet transformations. Computational simulations used a biophysically realistic network to model dopamine effects through modulation of excitability of fast-spiking interneurons.Results: On placebo, patients showed lower gamma (40 Hz) power compared to controls, replicating previous studies. However, patients showed gamma increases with amphetamine compared to placebo, while controls showed decreased gamma. These findings were specifically significant for 40 Hz driving (and not at 30 or 20 Hz). Computational simulations demonstrated that parametric increases in the excitability of fast-spiking interneurons could give rise to the frequency specific inverted-U pattern that would be consistent with the empirical findings.Conclusions: Our study findings indicate that dopamine increases increase gamma activity in schizophrenia while impairing it in healthy subjects, consistent with an inverted-U relationship between cortical activation and dopamine. Our computational findings offer putative biophysical mechanisms by which dopamine’s effects on interneuron excitability could give rise to such dynamics at the network level. Our findings provide a framework for developing a neuromodulatory approach to ameliorating gamma oscillatory impairments in schizophrenia.Keywords: Schizophrenia, dopamine, oscillations, computational modelingSupported By: K08MH080329; P50MH084053; NARSAD

772. Cortico-Hippocampal Theta Coupling in a Neurodevelopmental Animal Model of SchizophreniaBernat Kocsis

Harvard Medical School, Boston, MA

Background: Although high frequency oscillations (e.g. gamma) have been the main focus of ongoing schizophrenia research, low frequency (e.g. theta) synchronization, critical in providing the primary mechanism coordinating



locally generated gamma oscillations in distant structures, is also impaired by the disorder. Hippocampal theta rhythm co-occurs with enhanced cortical gamma activity and represents a key signal establishing transient hippocampo-cortical coupling through the mechanism of cross-frequency modulation. The aim of this study was to quantify the cortico-hippocampal interactions, including essential directional influences, in a neurodevelopmental rodent model of schizophrenia.Methods: EEG signal over the frontal, parietal, and occipital cortices and in the hippocampus and PFC were recorded in control rats and in rats prenatally (E17) treated with an antimitotic toxin (MAM). Hippocampo-cortical coherence and Granger causality were calculated during specific theta-intensive behaviors, i.e. during REM sleep and exploration of novel environment.Results: During REM sleep there was a dominant theta drive from hippocampus to PFC, whereas Granger causality values were close to equal in either direction during waking exploration. There was a remarkable difference between the peak frequencies pointing in the two directions. In MAM treated rats, PFC-hippocampal coherence and directional influence in the hippocampo-cortical direction was reduced and the difference between the peak frequencies widened.Conclusions: These data indicate that the directional influences synchronizing neuronal activity and gamma oscillations between hippocampus and PFC, impaired in the model of schizophrenia, are active in both directions such that dominant hippocampo-PFC and PFC-hippocampal flows are concentrated at different frequencies within the theta range.Keywords: theta oscillation, prefrontal cortex, hippocampus, MAMSupported By: MH831999, MH87777

773. Frontal-Hippocampal Dysfunction in Schizophrenia: Computational Models of FMRI and Behavior Demonstrate Disordered ConnectivityVaibhav A. Diwadkar

Wayne State University SOM, Detroit, MI

Background: Frontal-hippocampal dysfunction in schizophrenia is associated with both glutamatergic and dopaminergic dysfunction (Castner & Williams, 2007), yet the bases of disordered brain network interactions is relatively unknown. We present integrative studies combining computational modeling of behavioral data, activation metrics of fMRI data, and modeling of dynamic causal interactions between fMRI signals in schizophrenia patients during fronto-hippocampal associative learning.Methods: Behavioral and fMRI data from twenty-four subjects (early course SCZ and controls) were acquired using an object-location learning paradigm (Diwadkar et al., 2008). Behavioral data were compared to performance of a computational model with a neurobiologically plausible architecture (modules representing specialization of the “what”/object and “where”/location pathways; parameters representing synaptic plasticity and hippocampal capacity). fMRI data acquire during learning were analyzed using three classes of models: activation models (activation differences), seed-based models (Friston et al., 1997; differential hippocampal modulation of cortical networks) and dynamic causal models (Stephan et al., 2010; differential neuronal coupling and contextual modulation of neuronal connections).Results: The computational model demonstrated schizophrenia-like learning impairments under conditions of reduced synaptic plasticity. fMRI analyses indicated inefficient hyper-activation across fronto-striatal-hippocampal structures, but reduced hippocampal modulation in SCZ (p<.05, cluster level corrected). Finally DCM results indicated disordered neuronal coupling in a sub-network involving dorsal PFC, the basal ganglia and the hippocampus (p<.05, Bonferroni corrected).Conclusions: This integration extends animal models to the study of in vivo fronto-hippocampal dysfunction in schizophrenia. Frontal-hippocampal dys-connection and synaptic dys-plasticity (Stephan et al., 2007), appear as proximate markers in the pathophysiology of schizophrenia.Keywords: Schizophrenia, fMRI, Hippocampus, Prefrontal Cortex, Computational ModelingSupported By: MH68680

774. Hippocampus Abnormalities in Schizophrenia: Multi-Modal Imaging Applications to Study Neurochemistry and FunctionAdrienne C. Lahti1, Meredith Reid2, Nathan Hutcheson2, Nina Kraguljac2, David White2, Mark Bolding3

1University of Alabama at Birmingham, Birmingham, AL, 2Psychiatry, UAB, Birmingham, AL, 3Vision Sciences, UAB, Birmingham, AL

Background: To clarify the neurobiology of hippocampal abnormalities in schizophrenia, we used multi-modal imaging approaches and studied both medicated (n=28) and unmedicated (n=27) participants with schizophrenia (SZ).Methods: We studied medicated SZ and matched healthy controls (HC) using functional MRI (fMRI) during a memory task and single-voxel proton magnetic resonance spectroscopy (1H-MRS) of the hippocampus. We combined structural MRI and 1H-MRS of the hippocampus to study unmedicated SZ.Results: We found significantly decreased blood oxygen level-dependent (BOLD) signal in inferior frontal gyrus during encoding and in anterior cingulate cortex during retrieval (Hutcheson, et al, 2012). We found no significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate + glutamine (Glx/Cr) levels between the groups, but there was a significant positive correlation between NAA/Cr and Glx/Cr in the HC, but not the SZ group. In a subsequent study (Kraguljac, et al., 2012), we confirmed the decoupling of NAA and Glx in an extended group of 50 medicated SZ. In unmedicated SZ we found a significant hippocampal volumetric deficit, significantly higher Glx/Cr levels and decoupling of NAA/Cr and Glx/Cr. Furthermore, we found significant correlations between hippocampal volume and Glx/Cr in SZ but not HC.Conclusions: Reduced BOLD signal in prefrontal cortex during memory performance in SZ is indicative of fronto-hippocampal dysfunction. The decoupling of NAA and Glx in both medicated and unmedicated SZ might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria. The relationship between elevated Glx and smaller hippocampal volumes may be indicative of excitotoxicity processes.Keywords: schizophrenia, hippocampus, fMRI, MR Spectroscopy, Structural MRISupported By: R01MH081014

SymPoSiumOf Mice and Women: Novel Translational Models

Examining Estrogen Effects on Cognition and Emotion

Saturday, May 18, 2013, 3:00 PM - 5:00 PMContinental 7-9 - Ballroom Level

Chair: Paul A. Newhouse*Co-Chair: Cynthia Neill Epperson**

*Supported By: R01 AG021476**Supported By: K24 DA030301; P50 MH099910 R01 AG030641, Shire Pharmaceuticals, Eli Lilly, Novartis

775. Estrogen, Depression, and Hippocampal PlasticityLori L. McMahon

University of Alabama, Birmingham, Birmingham, AL

Background: Declining ovarian hormones during postpartum or menopause may be linked to increased susceptibility to stress and the development of depression in women, which often is accompanied by hippocampal learning and memory impairment. Stress-induced elevations in glucocorticoids decrease dendritic spine density and LTP at hippocampal synapses, while proestrous



levels of estradiol increase spine density and LTP, likely contributing to enhanced cognitive function.Methods: We tested whether estradiol opposes the detrimental effects stress on hippocampal plasticity and decreases acquisition of helplessness in ovariectomized female rats using the Learned Helplessness preclinical model of depression. Hippocampal slice electrophysiology and Golgi staining was used to investigate whether helplessness is associated with deficits in dendritic spine density and LTP at CA3-CA1 synapses. Significant differences were determined using with an independent, two sample t-test at p≤0.05.Results: 55% of vehicle-treated ovariectomized rats reached criteria for helplessness, while only 22% were helpless when treated with estradiol. Importantly, helplessness was associated with decreased spine density and a deficit in LTP, while spine density and LTP in rats experiencing the same inescapable shock but demonstrate resilience during escape testing are equivalent to non-shocked controls. Moreover, estradiol replacement reversed previously established helpless behavior in 40% of rats tested.Conclusions: Our novel findings show that estradiol replacement can protect against acquisition of helplessness and prevent hippocampal dysfunction associated with depression. These results may be relevant to the potential use of estradiol replacement in some women to enhance resilience to stress and for treating cognitive deficits in depression when estrogen levels decline.Keywords: estradiol, long term plasticity, learned helplessness, LTP, depressionSupported By: NIMH R01 MH082304; NARSAD

776. The Influence of Estrogen on the Neurobiology of Fear Extinction in Women and Female RatsMohammad Milad

Harvard Medical School, Charlestown, MA

Background: The study of the neural correlates of fear extinction has moved forward in the past decade. The plethora of data published in this domain have identified a network of brain regions the function of which appears critical in mediating conditioned fear learning and fear inhibition. These same regions appear to also be dysfunctional in patients with anxiety disorders such as posttraumatic stress disorder. One aspect that lags behind in this field is the understanding of how sex hormones may influence and interact with the function of this network in the context of fear inhibition. This is especially surprising given the substantial difference in prevalence of anxiety disorders between men and womenMethods: We have used a translational approach to investigate the role of sex hormones, estrogen in particular, in fear extinction and how such hormones may modulate the functional reactivity of this network. We have also recently began to examine how hormonal contraceptives may interact with the behavioral expression of conditioned fear extinctionResults: Data will be presented showing that estrogen enhances the functional activation of the ventromedial prefrontal cortex in both female rats and in women. More recent data will also be presented showing that oral contraceptives may impair fear extinction in women. Lastly, recent evidence showing that a single administration of estrogen to women may help facilitate fear extinctionConclusions: These data raise a number of issues that will be discussed regarding the clinical implications to the potential use of estrogen as adjunct to therapy.Keywords: estrogen, fear learning, PTSD, progesteroneSupported By: 1R01MH097880-01

777. Verbal Memory Performance and Brain Activation: Impact of Menopause Stage, Duration of Hypogonadism and Serotonin StatusCynthia Neill Epperson

Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA

Background: Focus and memory complaints are common among peri and postmenopausal women. Whether the menopause transition and its associated decline in estradiol contribute to a worsening in performance on prefrontal cortex (PFC) driven tasks beyond that expected with aging is unclear.Methods: In a 15-year longitudinal study of women undergoing a natural transition to menopause, participants (n=390) were given yearly assessments of verbal memory (immediate and delayed) and processing speed. Relevant demographic, mood, and hormonal measures were included as covariates. A partially overlapping group of 17 women underwent fMRI while completing a working memory task (letter n-Back) under conditions of tryptophan (TD) and sham depletion. With months since final menstrual period (FMP) as a covariate, we conducted a region of interest analysis.Results: Using generalized estimating equations and controlling for age, race, education, BMI, reproductive hormones, perceived stress, depression and anxiety, menopause stage was associated with a decline in both immediate (p<0.01) and delayed (p<0.03) verbal recall, but not processing speed. TD was associated with a reduction in right dorsal lateral PFC, orbital FC, and left posterior cingulate cortex BOLD signal, with the effect becoming more pronounced in the latter two regions with time since FMP.Conclusions: For the first time, we report that the menopause transition exerts an age-independent effect on verbal memory even after controlling for important covariates. Brain imaging data would suggest that integrity of the serotonin system is critical for neural structures involved in working memory and that extended hypogonadism may accentuate this interaction.Keywords: menopause, estrogen, serotonin, prefrontal cortex, verbal memorySupported By: R01 AG030641, P50 MH099910, K24 DA03031

778. Estrogen Modulation of Emotional Processing in Pre- and Postmenopausal WomenJulie A. Dumas

University of Vermont College of Medicine, Burlington, VT

Background: Women are twice as likely as men to suffer from mood disorders and previous studies suggest that hormonal influences on brain physiology may play a significant role. In prior studies estradiol treatment in postmenopausal women produced negative emotional responses after psychosocial stress. However, other studies have shown an enhancement of psychological well-being and a decreased risk of depression after estradiol treatment. Thus far, the effects of both estrogen treatment after menopause and estrogen variation throughout the menstrual cycle on the underlying neural circuitry involved in emotional responding remain to be elucidated.Methods: This talk will present functional task-based and intrinsic connectivity imaging data illustrating how estrogen modulates neural circuitry involved in emotional processing in women. We have examined the effects of postmenopausal estradiol treatment as well as normal estradiol fluctuations during the menstrual cycle on amygdala, subgenual cingulate, and medial prefrontal cortex activation during an emotional stimulation task. We have also examined estradiol effects on intrinsic connectivity in these regions.Results: The task-based data show that increased estradiol levels is associated with increased subgenual cingulate and medial prefrontal activation during emotional evaluation. The connectivity data show that increased estradiol is associated with increased connectivity in emotion-related networks including the medial prefrontal and medial temporal lobes.Conclusions: These data demonstrate how estrogen affects emotional circuitry during the top-down evaluation of emotional information in healthy pre- and



postmenopausal women. The implications for neurobiological the mechanisms associated with gonadal steroids and the relationship to mood disorders in women will be discussed.Keywords: Menopause, Estrogen, Emotion, fMRI, connectivitySupported By: NIA K01 AG030380

SymPoSiumPharmacological Modulation of Anxiety

Circuits: Transient Plasticity Revealed Through Neuroimaging


Chair: Christian GrillonSupported By: MH002798

779. Acute Administration of Pregabalin Attenuates Amygdala and Insula During Emotional Face Processing and Anticipation in Healthy VolunteersMartin P. Paulus

University of California San Diego, La Jolla, CA

Background: Pregabalin (PGB) has shown potential as an anxiolytic for treatment of generalized and social anxiety disorder. PGB binds to voltage-dependent calcium channels, leading to upregulation of GABA inhibitory activity and reduction in the release of various neurotransmitters.Methods: In this double-blind, placebo-controlled, randomized crossover study, 16 healthy controls completed a paradigm involving (a) an emotional face-matching task and (b) anticipation of negative and positive affective images during fMRI approximately one hour after administration of placebo, 50 mg, or 200 mg PGB.Results: During the emotional face processing task, linear mixed model analysis revealed that pregabalin dose-dependently decreased left amygdala activation during fearful face-matching and left anterior insula activation during angry face-matching. The 50 mg dose exhibited more robust effects than the 200 mg dose in the right anterior insula and ventral ACC. During the anticipation task, linear mixed model analysis revealed that PGB was associated with (1) decreases in left amygdala and anterior insula activation and (2) increases in anterior cingulate (ACC) activation, during anticipation of positive and negative stimuli.Conclusions: These results support the notion that pregabalin decreases insula and amygdala responses during emotional face processing, similar to what has been reported previously for benzodiazepines and SSRIs. Moreover, attenuation of amygdala and insula activation during anticipatory or emotional processing may represent a common regional brain mechanism for anxiolytics across drug classes.Keywords: anxiety, fMRI, pharmacology, amygdala, insulaSupported By: MH65413, MH64122 and MH075792

780. Contextual and Pharmacological Modulation of Human Hippocampal Theta OscillationsBrian R. Cornwell1, Cassie Overstreet2, Lynne Lieberman2, Christian Grillon2

1National Institute of Mental Health, Bethesda, MD, 2Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD

Background: Preclinical data have long pointed to central involvement of the hippocampus in anxiety states. Rhythmic population activity between 4-12Hz, called theta activity, is a prominent electrophysiological signature of hippocampal

functioning, which has been shown to be highly sensitive to anxiolytic action. We performed two experiments in humans to link hippocampal theta to anxiety states and characterize the pharmacological effects of a classical anxiolytic (benzodiazepine alprazolam) on these oscillatory phenomena.Methods: Hippocampal theta (2-8Hz) was measured noninvasively with whole-head magnetoencephalography (MEG) while healthy participants navigated a virtual Morris water maze to a hidden escape platform. In Experiment 1, two mazes were navigated, one in which participants (N=25) were at risk of receiving shocks unpredictably to elicit anxiety and one in which they were safe. In Experiment 2, participants (N=12) performed the same virtual navigation task on two separate days, approximately 4h after receiving a single dose of alprazolam (1mg) or placebo (double-blinded, randomized, cross-over design). MEG beamformer source analyses were conducted to estimate theta in the hippocampus.Results: In Experiment 1, anxiety during navigation in the shock context was associated with anterior hippocampal theta activity (t=3.19, p=.005). In Experiment 2, alprazolam produced a shift in navigation-related hippocampal theta toward slower oscillatory activity relative to placebo (t=3.34, p=.007).Conclusions: These findings link anxiety to anterior hippocampal theta and offer a first glimpse into how anxiolytics may alter hippocampal theta dynamics. Importantly, they extend to humans a wealth of data in animals implicating hippocampal theta in the dynamic underpinnings of anxiety states.Keywords: anxiety, hippocampus, theta oscillations, magnetoencephalography, benzodiazepineSupported By: NIMH Intramural Program; NARSAD Young Investigator Award

781. The Role of Serotonin In Inhibition of the Neural Circuitry of AnxietyOliver J. Robinson

National Institute of Mental health, Bethesda, MD

Background: Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for anxiety disorders. Yet they were discovered serendipitously and their mechanism of action is unknown. In two novel studies we used acute tryptophan depletion (ATD) to lower serotonin synthesis in healthy volunteers in an attempt to clarify the role of serotonin in the neural circuitry of anxiety.Methods: We used 1) a translational fear- and anxiety-potentiated startle paradigm to examine the role of serotonin on neural circuitry too small for conventional fMRI resolution (i.e., the bed nucleus of the stria terminalis; BNST), alongside 2) a pharmaco-fMRI paradigm to examine the role of serotonin in a previously delineated dorsal prefrontal-amygdala anxiety circuit.Results: ATD 1) increased anxiety (F(2,38)=4.5,p=0.02) but not fear (F(1,19)=0.09,p=0.76) potentiated startle and 2) increased positive dorsal prefrontal activity (xyz=14,18,26,t=2.6,p(FWE)=0.045) and amygdala coupling (xyz=16,14,26,t=2.69,p(FWE)=0.039) during the processing of aversive (vs.appetitive) stimuli.Conclusions: Study 1 highlights, by translation, the role of serotonin in inhibition of CRH mediated lateral central nucleus of the amygdala-BNST anxiety circuitry, study 2 highlights the role of serotonin in inhibiting a dorsal prefrontal-amygdala ‘aversive amplification’ circuit. Taken together these studies provide candidate anxiety-specific, serotonin-dependent, neural circuitry which may be the target of SSRIs.Keywords: serotonin, anxiety circuitry, bed nucleus of the stria terminalis, dorsal prefrontal, amygdalaSupported By: NIMH Intramural



782. Convergent Effects of Pharmacological and Psychological Treatments on Attentional Bias in AnxietyCatherine Harmer

University of Oxford, Oxford, United Kingdom

Background: Attentional bias towards threat is a key maintaining factor in anxiety. However, there is a time-lag in the effects of conventional pharmacological and psychological treatments for anxiety. We hypothesized that anxiolytic treatments would normalize attentional bias prior to their therapeutic action on symptoms but that these effects would be important in driving later therapeutic change.Methods: The visual probe paradigm was used to provide a behavioral index of attentional bias following different treatment application. In study one, volunteers were randomized in a double-blind design to receive either placebo, the SSRI citalopram and the NRI reboxetine for 7 days. In study two, patients with panic disorder and agoraphobia were randomized to receive a single session cognitive behavioral therapy (CBT) intervention or equivalent experimenter contact. Attentional bias was assessed the day after treatment and related to therapeutic change at 4 weeks.Results: Drug treatments used for anxiety decreased attentional bias towards threat in the absence of change in subjective state. CBT had a similar effect, apparent the first day after a single session treatment and before therapeutic change. The magnitude of this early effect on attentional bias was predictive of improvement in agoraphobia 4 weeks later.Conclusions: Attentional bias is targeted by interventions which are effective in the treatment of anxiety disorders and there is a convergent effect between pharmacological and psychological approaches. Early change in attentional bias is predictive of later changes in anxiety symptoms suggesting that correction of these psychological processes could be a key mechanism of anxiolytic action.Keywords: Anxiety, anxiolytic drugs, attentional bias, biomarkersSupported By: Medical Research Council

SymPoSiumImaging the Effects of Development and Adolescent

Alcohol Exposure in Humans and Animal ModelsSaturday, May 18, 2013, 3:00 PM - 5:00 PM

Yosemite C - Ballroom LevelChair: Cindy L. Ehlers*

Co-Chair: Fulton Crews***Supported By: NIH**Supported By: AA020023; AA020024

783. Imaging Human Brain Development: Impact of AlcoholElizabeth Sowell

University of Southern California, Los Angeles, CA

Background: Human brain structure continues to change through adolescence consistent with developmental changes in brain structure contributing to maturation of brain function.Methods: We used structural magnetic resonance imaging (MRI) to investigate trajectories of brain change in typically developing children and adolescents, and in children and adolescents with heavy prenatal alcohol exposure (PAE). Further, we examined relationships between changes in brain structure over time and measures of cognitive function.Results: Typically developing individuals showed an inverted-U shaped developmental trajectory of cortical development which varied by region.

Generally, the timing of development follows a caudal to rostral pattern where the most superior and anterior portions of the brain show the slowest trajectory. Changes in the brain over time are related to improved performance on cognitive tests. Children with PAE show very different trajectories of brain development where they exhibit the cortical volume decline across the entire age span studied (7 to 18 years), without the increase in the earlier years followed by declines in early adolescence observed in their unexposed peers.Conclusions: Cortical development observed on MRI is thought to reflect fine-tuning of neural systems which prune un-needed inefficient connections, and enhance connections with increased myelination which quickens transduction speed across axonal fibers. These processes are frequently referred to as experience dependent plasticity, which is altered over time in children and adolescents with PAE, long after the prenatal insults to the brain.Keywords: MRI, Adolescence, Alcohol, Fetal alcohol spectrum disorders, developmentSupported By: U01AA01712201; CIFASD

784. Imaging Adolescent/Adult Rodent Brain Development: Impact of Binge DrinkingFulton T. Crews

University of North Carolina, Chapel Hill, NC

Background: Humans and rodents have characteristic adolescent behaviors including risk taking, reward seeking, and high levels of play behavior and social interaction. Developmental changes in brain structure may contribute to maturation of adolescent behaviors.Methods: We investigated rat brain development using structural MRI, gene expression arrays, histochemistry and behavioral assessments as well as the impact of adolescent intermittent ethanol (AIE; 5gm/kg-i.g., 2 days on-2 off) on brain through adolescence, e.g. post-natal day (P) 28 to P42, into young adulthood, P80.Results: Rat brain volume increased 17% between P28-42, e.g. the 14 days of adolescence and another 13% from P42-80, e.g. 38 days of maturation into adulthood. During adolescence cerebellar, thalamic and ventricle volume increased more than other regions, whereas dorsal striatum and white matter showed the largest volume increases during the P42-P80 transition to young adulthood. Histochemical analysis found increased expression of neural nets and extracellular matrix proteins during adolescence that continue into adulthood. In contrast, brain cholinergic, dopaminergic and peptide mRNA levels were found to decrease about 50% between adolescence and adulthood. AIE was found to impact adult brain regional volumes. In addition, AIE reduced neurotransmitter gene expression that decreased further during maturation. In contrast, AIE increased expression of extracellular matrix proteins, cytokines, and other neuroimmune molecules that persisted into adulthood. Reversal learning deficits and brain circuitry assessments suggest that adolescent binge drinking disrupts frontal cortical brain development.Conclusions: These studies indicate adolescent rodent brain continues to grow into young adulthood and is sensitive to ethanol.Keywords: MRI, adolescence, alcohol, development, neuroimmuneSupported By: AA020023; AA020024

785. Effects of Development and Ethnol Exposure Over Adolescence on Brain Synchrony, Behavior, DTI Volumes, Neurogenisis and Choline Acetyl TransfereaceCindy Ehlers

The Scripps Research Institute, La Jolla, CA

Background: Epidemiological data indicate that excessive alcohol consumption is prevalent among adolescents and may have lasting neurobehavioral consequences. Animal models provide the control necessary to investigate the potentially neurotoxic effects of alcohol on adolescent brain development.



Methods: Wistar rats were exposed to ethanol vapor/air control 14 hrs/ day for 35 days from P22-P57 (average BAC 163 mg%). Rats were withdrawn from vapor for 2-8 weeks and assessed for, open field conflict activity, startle response and immobility in the swim test as adults. Rats were sacrificed at either day 72 or day 127 and either perfused for MRI and histochemical analyses (measures of neurogenesis, ChAT).Results: Alcohol exposed rats displayed a significant reduction in the amplitude of their responses to prepulse stimuli during the startle paradigm, reduced energy and phase locking of ERO gamma activity, disinhibition in the open field conflict and decreased latency to immobility in the swim test. Volumetric analyses of MRI data indicated a reduction in the size of the hippocampus and an increase in the size of the ventricles in the ethanol exposed animals. Measures of neurogenesis were reduced in hippocampus and measures of ChAT were reduced in the basal forbrain in the ethanol exposed animals. Behavioral measures were found to correlate with structural brain findings.Conclusions: These studies demonstrate that behavioral measures of arousal, affective state, disinhibitory behavior, brain synchrony, hippocampal volume and histochemical measures of ChAT and neurogenesis are all significantly impacted by periadolescent ethanol exposure and withdrawal in Wistar rats. (supported by AA019969, AA020022).Keywords: Diffusion Tensor Imaging, Alcohol, Adolescence, neurogenesis, Choline Acetyl TransferaseSupported By: NIH

786. Adolescent Heavy Drinking and the Brain: Gender EffectsLindsay M. Squeglia

University of California, San Diego, San Diego, CA

Background: Adolescence is marked by significant increases in alcohol use. This is concerning, as the brain undergoes marked maturation between puberty and adulthood. Previous cross-sectional research has shown differences in neurocongition in adolescents who use alcohol compared to non-drinkers; however, it is unclear if differences predated or were a consequence of heavy substance use.Methods: This talk will present longitudinal neuropsychological and structural and functional imaging data examining neurocognitive vulnerabilities contributing to future heavy substance use, as well as neural consequences following substance use in 256 healthy adolescents recruited from the San Diego area.Results/Conclusions: Differences in brain activation to cognitive challenges in frontal and parietal regions appear to predate heavy use, while worsening attentional and visuospatial functioning and widespread differences in brain activation and structural abnormalities appear to follow the onset of heavy use. Further, males and females mature at different rates, and appear to be affected differently by substance use, with female adolescents showing greater negative consequences than males.Keywords: adolescent, alcohol, imaging, neuropsychological assessment, genderSupported By: R01 AA13419, PI: Tapert and T32 MH018399, PI: Martin Paulus

SymPoSiumEmerging Models of the Neurobiology of Panic

DisorderSaturday, May 18, 2013, 3:00 PM - 5:00 PM

Continental 3 - Ballroom LevelChair: Richard Maddock*Co-Chair: John Wemmie**

*Supported By: NIH-1R21MH076988**Supported By: NIMH 1R01MH085724-01

787. Serotonin Transporter Deficient Rats Exhibit Increased Panic and Amygdala Responses to Panicogenic Hypercapnic Stimuli and Enhanced Acquisition and Disrupted Extinction of Conditioned FearPhilip L. Johnson1, Lauren M. Federici2, Joey Contreras2, Stephanie D. Fitz3, Andrei Molosh3, William Truitt2, Anantha Shekhar3

1University of Indiana School of Medicine, Indianapolis, IN, 2Anatomy & Cell Biology, Indiana University, Indianapolis, IN, 3Psychiatry, Indiana University, Indianapolis, IN

Background: Serotonergic systems modulate behavioral and physiological responses to aversive stress-related stimuli and are a major therapeutic target for treating panic disorder. Recent data shows that human carriers of the short-allele of the serotonin transporter (SERT) gene-linked polymorphic region have reduced SERT expression and increased anxiety-related traits when combined with environmental adversity during development, which suggests this condition may be associated with a higher incidence of panic disorder and phobias.Methods: Since Klein and colleagues determined that mild hypercapnia (suffocation stimuli) triggers panic attacks in panic disorder patients, but not healthy controls, and serotonergic brainstem neurons express CO2/H+ sensors, we hypothesized that rats with homozygous and heterozygous null mutations of SERT gene would display enhanced panic-associated respiratory responses to mild hypercapnia. Furthermore, since lower SERT expression also appears to facilitate amygdala excitation in humans, we also hypothesized that these rats would have enhanced fear conditioning.Results: Compared to wildtype rats, SERT-/-rats displayed increased baseline anxiety behavior; higher respiratory responses to 7.5% hypercapnic, normoxic gas; and increased cellularresponses (measured with c-Fos immunohistochemistry) in amygdala subnuclei. We also determined that both SERT-/- and SERT-/+ rats showed increased expression of conditioned fears compared to wildtype rats.Conclusions: The preclinical data here is consistent with clinical data where genetic variations of the SERT gene is associated with anxiety-associated traits, and increased amygdala reactivity, and suggests that reduced SERT function may be a genetic risk for developing panic disorder and phobias.Keywords: panic, anxiety, serotonin transporter, amygdala, fearSupported By: RO1 MH 065702 and MH 052619 to AS



788. Acid Sensing Ion Channels and pH Sensitivity in the Fear CircuitJohn Wemmie1, Rebecca Taugher2, Collin Kreple3, Yuan Lu4, Brian Dlouhy5, Rong Fan6

1University of Iowa, Iowa City, IA, 2Neuroscience Program, University of Iowa, Iowa City, IA, 3Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, 4Department of Psychiatry, University of Iowa, Iowa City, IA, 5Neurosurgery, University of Iowa, Iowa City, IA, 6Psychiatry, University of Iowa, Iowa City, IA

Background: Carbon dioxide (CO2) inhalation has long been known to trigger anxiety, fear, and panic, especially in patients with panic disorder. Thus, a better understanding of CO2 sensitivity may reveal important insights into the mechanisms underlying panic. When CO2 is inhaled, pH falls throughout the brain including in the amygdala. We recently found that the amygdala detects CO2 and acidosis and generates fear-related behaviors via acid sensing ion channels (ASICs). Because ASICs are expressed in a number of fear circuit structures besides the amygdala, we hypothesized that additional fear-circuit structures contribute to CO2-evoked fear. One structure where ASIC1a is abundant is the bed nucleus of the stria terminalis (BNST).Methods: To test the role of the BNST in CO2-evoked fear, we took several approaches in mouse models including: 1) lesioning the BNST, 2) microinfusing acidic cerebrospinal fluid directly into the BNST, and 3) manipulating ASIC1a expression in the BNST in transgenic mice with adeno-associated virus (AAV) vectors.Results: We found that BNST lesions significantly impaired CO2-evoked fear behaviors. In addition directly acidifying the BNST produced fear-related freezing in an ASIC1a-dependent manner. Finally, knocking out ASIC1a specifically in the BNST reduced CO2-evoked fear behavior, whereas restoring ASIC1a expression to the BNST of ASIC1a-null mice rescued deficits in CO2-evoked fear.Conclusions: Together, these studies suggest that the BNST contributes to CO2-evoked fear by virtue of its abundant ASIC1a expression and that the BNST plays an important pH chemosensory role in behavior and brain function.Keywords: ASIC, Brain pH, fear, panicSupported By: NIMH 1R01MH085724-01

789. Elevated Activity-Dependent Brain Lactate Accumulation in Panic Disorder and its Relationship to Activation in Acid-Sensitive Brain Regions During Fearful Face ProcessingRichard J. Maddock1, Michael H. Buonocore2, Jong H. Yoon3

1University of California, Sacramento, CA, 2Department of Radiology, University of California Davis, Sacramento, CA, 3Department of Psychiatry, University of California Davis, Sacramento, CA

Background: Brain pH disturbances may have a pathogenic role in panic disorder (PD). Brain lactate responses to neural activation are increased in PD. Given the close relationship between lactate and pH in the brain, we examined two questions about the neurobiological significance of increased lactate responses in PD: 1) Do they reflect a general upregulation of local metabolic responses during brain activation? 2) Are they associated with increased fear-related responses in the amygdala or periaqueductal gray (PAG), two acid-sensitive regions in the fear circuit?Methods: 1) Using MRS, visual cortex lactate and glutamate responses to visual stimulation were measured in 20 PD patients and 11 controls. 2) Using MRS and fMRI, lactate responses to visual stimulation were measured along with BOLD responses to fearful faces in a priori amygdala and PAG ROIs in 26 PD patients.Results: During visual stimulation, patients exhibited increased lactate responses (F(1,29)= 11.8, p<..002) but decreased glutamate responses (F(1,29)= 8.7, p<.01) in the visual cortex compared to controls. In PD patients, visual cortex

lactate responses to visual stimulation predicted BOLD responses to fearful versus calm faces in PAG but not amygdala (r =+.57, n=26, p=.002 and r =+.05, n=26, NS, respectively).Conclusions: Increased brain lactate responses do not reflect a general upregulation of metabolic responses to neural activation, and they predict stronger PAG activation by fear-related stimuli. The findings are consistent with a model of a circumscribed, pH-related, brain metabolic abnormality associated with heightened responsivity in a subset of acid-sensitive circuits mediating fear-related processing in PD.Keywords: Panic disorder, lactate, acid, fear, metabolismSupported By: R21MH076988, R21MH69699

790. Dynamic T1rho and Bold Functional Imaging in Panic DisorderVincent A. Magnotta1, Casey J. Johnson2, Robin Follmer3, Simon Roh2, John A. Wemmie3

1University of Iowa, Iowa City, IA, 2Radiology, The University of Iowa, Iowa City, IA, 3Psychiatry, The University of Iowa, Iowa City, IA

Background: Recent studies suggest the hypothesis that abnormal brain pH dynamics may contribute to panic disorder. To investigate this hypothesis we developed two independent pH-sensitive imaging strategies, T1 relaxation in the rotating frame (T1rho) and 31P spectroscopy. We compare these measures in participants with panic disorder and normal controls at baseline and during visual activation using a flashing checkerboard task. We also explored the relationship of symptoms and functional imaging in the panic subjects using the Beck Anxiety Inventory.Methods: Data was collected from 13 participants with panic disorder and 13 controls. Dynamic T1rho, BOLD, and 31P imaging were performed using a full field-flashing checkerboard. The resulting activation maps were compared between the subjects with panic disorder and controls (p<0.05, corrected for multiple comparisons).Results: The results showed significant increase in T1rho during the visual activation task in the panic subjects as compared to controls in the superior cuneus bilaterally and a significant decrease in the anterior cingulate bilaterally. There was a trend (p<0.06) toward lower pH measured using 31P in panic subjects as compared to controls in the baseline condition. The BOLD data showed a significant reduction in the BOLD response in the right lingual gyrus in panic disorder. Significant relationships between the Beck Anxiety Inventory were found with T1rho and 31P but not BOLD in panic subjects.Conclusions: Dynamic T1rho imaging technique may provide new insights into panic disorder. These results suggest abnormal pH signaling in panic disorder.Keywords: Panic Disorder, Functional Imaging, SpectroscopySupported By: DANA Foundation



oral SeSSionInflammatory, Stress, and Developmental

Approaches to DepressionSaturday, May 18, 2013, 3:00 PM - 5:00 PM

Continental 1 - Ballroom LevelChair: Daniel S. Pine

791. Chronic Lithium Increases Growth Rate and Basal Calcium Expression in Human Olfactory-Derived Neural Precursor CellsMichael Tseng1, 2, Dharshini Ganeshan1, Martha A. Green1, Ian J. Witterick3, Margaret Fahnestock4, Bernadeta Michalski4, Richard D. McCurdy5, Jerry J. Warsh1, 6

1Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, Toronto, ON, Canada, 2Dept. of Psychiatry and Institute of Medical Science, University of Toronto, Toronto, ON, Canada, 3Department of Otolaryngology - Head & Neck Surgery, University of Toronto, Toronto, ON, Canada, 4Department of Psychiatry & Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada, 5Center for Neurobiology - Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 6Depts of Psychiatry, Pharmacology and Toxicology, and Medical Sciences and Program in Neuroscience, University of Toronto, Toronto, ON, Canada

Background: Advances in stem cell technologies have stimulated interest in using patient-derived neural cells for disease modeling and drug development. We report the use of olfactory epithelium-derived neural precursors (ONP) to evaluate BDNF expression and calcium homeostasis abnormalities implicated in bipolar I disorder (BD-I), and the effect of cellular exposure to the mood stabilizer lithium on these putative biomarkers.Methods: ONP cell lines were generated from BD-I patients (N=9) and healthy sex and age matched controls (N=11) providing olfactory epithelial samples via nasal biopsy. After regrowth from frozen stock without differentiation, ONP growth rates, BDNF mRNA (q-PCR) and protein levels (ELISA), and basal intracellular calcium levels ([Ca2+]B, ratiometric fluorometry) were determined at 7-11 passages in culture after acute (24 hr) and chronic (7 days) exposure to 1mM lithium.Results: Nestin, MAP2, β-tubIII, and GFAP immunostaining confirmed neural precursor phenotype. Repeated measures ANOVA revealed higher growth rates (14%, p=0.006) in lithium- vs. vehicle-treated ONP, and lower BDNF expression with time in culture (mRNA, 33%; protein, 39%; p’s<0.05). Two trends were noted; increased growth rate of BD-I vs. control ONPs (35%, F1,4=3.97, p=0.066), and lithium attenuation of the reduction on BDNF mRNA levels (16.5%, F1,15= 2.93, p=0.11). Lithium treatment increased [Ca2+]B (6.8%, F1,12=78.3, p<0.001) across treatment times.Conclusions: These results corroborate lithium-induced stem cell growth and extend this finding to ONP. Lithium’s attenuation of BDNF mRNA reduction suggests mechanisms other than BDNF production may be involved in ONP growth. The lithium-induced increase of [Ca2+]B validates similar effects in B lymphoblast lines.Keywords: Olfactory, Stem Cells, Bipolar Disorder, Calcium, BDNFSupported By: CIHR Fellowship (MT), CIHR Operating grant MOP 93577 (JJW, MT), OMHF Research Training Fellowship (MT)

792. Inflammatory Markers, Distal and Proximal Stress, and Gender Affect Cortico-Limbic Regional Cerebral Blood Flow in AdolescenceAmy E. Ramage1, Consuelo Walss-Bass2, Rene L. Olvera2, Douglas E. Williamson3

1Psychiatry, Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, 2Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 3Psychiatry, Research Imaging Institute, Epidemiology & Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX

Background: Exposure to stress in early life alters brain structure and function with life-long behavioral consequences. Stress is one condition under which cytokines cross the blood-brain barrier, i.e., the immune system affects brain. We explore the interactions of inflammatory markers, measures of distal and proximal stress and regional cerebral blood flow (rCBF) in adolescence to examine the temporal evolution of stress-immune-brain relationships.Methods: 244 adolescents (12-15 years, F:M, 128:116) were enrolled in an ongoing study of interactions between stress, the immune system and brain development. Blood samples, brain imaging, and assessments of distal and proximal stress were obtained. Inflammatory markers were assayed using Millipore’s multiplex HCYTMAG-60K-PX39 Luminex panel. Analysis of the immune system markers with varimax rotation identified unique factors that were entered into multivariate general linear models to examine the relation between gender, stress, and immune system markers on rCBF.Results: Inflammatory markers, distal/proximal stress, and gender interacted to alter rCBF in right-sided anterior insula, frontal, and parahippocampal cortex. Distal stress interacted with inflammatory factors and gender to differentially alter rCBF to the putamen, somatosensory and dorsal anterior cingulate cortex (ACC) whereas proximal stress affected the rostral ACC and midbrain. These findings were most strongly associated with a factor that includes IL-6.Conclusions: Stress results in inflammatory phenotypes that alter rCBF to cortico-limbic brain areas. Distal stress was uniquely associated with altered rCBF to the putamen and dorsal ACC, particularly in females. In contrast, proximal stress was associated with meso-cortical areas associated with emotional and reward processing.Keywords: neuroimaging, development, stress, inflammatory markers, blood flowSupported By: R01AA016274, R01MH087493-01

793. Stress Induced Increases in Inflammation are Associated with White Matter Integrity and Increased Depressive Symptoms in Adolescent MalesDouglas E. Williamson1, Amy E. Ramage2, Milena Girotti3, David A. Morilak3, Rene L. Olvera2, Consuelo Walss-Bass2

1Psychiatry, Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, 2Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 3Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX

Background: In our pre-clinical studies, chronic stress causes depression-like behavior, induces IL-6 expression in the hypothalamus, and reduces expression of mRNA for MOBP in the amygdala. Extending from our pre-clinical studies, we examine the relation between stress, inflammatory markers, and gender as they impact white matter acquisition and their association with depressive symptoms in adolescents.Methods: A sample of 317 adolescents (F:M = 161:156), aged 12-15 years, underwent diffusion tensor imaging (DTI) with white matter integrity indexed by fractional anisotropy (FA). Stress was assessed with the Stressful Life Events



Schedule (SLES). Inflammatory markers were assessed using Millipore’s multiplex HCYTMAG-60K-PX39 Luminex panel. Factor analysis of the inflammatory markers with varimax rotation generated factors used in multivariate general linear models to examine the relation between gender, stress, and inflammatory markers on FA values.Results: There was a gender-stress-inflammatory interaction for several white matter tracts including the cortical spinal tract (F1,303 = 4.32, P ≤ .04), cingulum (F1,303 = 8.67, P ≤ .003), and fornix (F1,303 = 8.67, P ≤ .043) for an immune factor that included IFN-g, MDC, IL-8, MIP-1a, MIP-1b, and TNF-α. Further analyses revealed a significant gender-cingulum interaction for depressive symptoms (F1,268 = 4.23, P ≤ .04) due to higher symptom levels of depression associated with lower cingulum FA in males (t 134 -2.71, P < .008), but not females (t 133=1.08, NS).Conclusions: Stress related inflammation appears to impact white matter during a pivotal developmental period and is associated with an elevated risk for depressive symptoms in males.Keywords: White Matter, Stress, Depression, GenderSupported By: R01AA016274; R01MH087493

794. The Early Care Environment and the Epigenome: Genetic and Environmental Influences on DNA Methylation in ChildhoodKieran J. O’Donnell1, Chen Li2, Tie Yuan Zhang1, Helene Gaudreau1, Alison Fleming3, Leslie Atkinson4, James L. Kennedy5, Michael Kobor6, Joanna D. Holbrook2, Michael J. Meaney1

1Psychiatry, McGill University, Montreal, QC, Canada, 2Clinical Sciences, Singapore Institute for Clinical Sciences, Singapore, Singapore, 3Psychology, University of Toronto, Toronto, ON, Canada, 4Psychiatry, Ryerson University, Toronto, ON, Canada, 5Psychiatry, University of Toronto, Toronto, ON, Canada, 6Centre for molecular medicine, University of British Columbia, Vancouver, BC, Canada

Background: Rodent models highlight the profound effect of postnatal maternal care on offspring neurodevelopment. These effects are mediated in-part by epigenetic modifications, such as DNA methylation, and may be moderated by genetic factors. We sought to determine if the early care environment, indexed by infant attachment style, is associated with DNA methylation profiles in childhood, using a peripheral source of DNA.Methods: Participants were drawn from the Maternal Adversity And Neurodevelopment (MAVAN), prospective longitudinal cohort. Infant attachment style was assessed at 18 months using the Strange Situation. Psychometric assessments, buccal swab collections and genotyping occurred at 8 years of age (n=45). Genome-wide DNA methylation was assessed using the Illumina 450K Infinium BeadChip array.Results: Infant attachment (secure/insecure) was associated with differential methylation of 695 CpG sites from 345 genes (all β ≥ 0.05, p <0.05) with significant enrichment of Rho/Ras GTPase signalling and immune function pathways (p <0.05). The DRD4 locus showed differential methylation at multiple CpGs as a function of attachment security and genotype. Carriers of the 7-repeat allele (exon 3 variable number tandem repeat) showed significantly lower DRD4 locus methylation. No interaction between infant attachment and genotype to predict DRD4 methylation was observed in the current sample.Conclusions: Our findings demonstrate a persisting effect of the early care environment and DRD4 genotype on child DNA methylation profiles, highlighting the utility of peripheral DNA for clinical epigenetic studies. The additional importance of these findings for child emotional/behavioral outcomes will be determined by on-going work in this sample.Keywords: Epigenetics, maternal care, DNA methylation, DRD4, neurodevelopmentSupported By: CIHR and Sackler Program for Epigenetics & Developmental Psychobiology

795. DRD4 7-Repeat Polymorphism, Maternal Depression, and Difficult Infant Temperament: A Moderation HypothesisMaria Muzik, Erika London Bocknek, Alex Busuito, Amanda Broderick, Tony King, Katherine Rosenblum, Israel Liberzon

Psychiatry, University of Michigan, Ann Arbor, MI

Background: Maternal postpartum depression is associated with negative infant outcomes, but research findings are heterogeneous, suggesting potential moderators (Goodman, Rouse, Connell, Broth, Hall & Heyward, 2011; McGrath, Records & Rice, 2008; Tikotzky, Chambers, Gaylor & Manber, 2010). As a possible moderator, we examine a polymorphism in the DRD-4 gene which has been associated with neural networks related to executive functioning and self-regulation in later childhood, behavioral outcomes for which infant negativity is a precursor.Methods: This study (N=76) represents a preliminary analysis of mothers at risk for psychopathology and their infants, selected from a larger longitudinal dataset (N=243) investigating the impact of childhood maltreatment on postpartum wellbeing. Mothers reported on their depression using the PDSS , on their infants’ temperament with the Infant Behavior Questionnaire-Revised (Garstein & Rothbart, 2003) yielding domain scores for Sadness, Fear, and Distress to Limitations, and underwent a laboratory interactive stress paradigm (the Still Face Procedure SFP; T, rated by independent coders on infant distress and negative affect. Maternal-and observer rated temperament scores loaded on one factor, Difficult Infant Temperament ; loadings on this factor range from .59-.76.Results: We found a significant association between maternal depression and correlates of difficult infant temperament (β=.37, p=.04) in the subgroup of infants who are determined to be DRD4 7-allele carriers; this relationship is non-significant for non-carriers (β=.05, p=.76).Conclusions: These findings suggest the DRD-4 7-repeat polymorphism may moderate the association between maternal depression and infant outcomes.Keywords: DRD4, maternal depression, infant outcomesSupported By: K23MH080147

796. Harsh Parenting and Neural Fear Circuitry Function in High and Low Anxious YouthsFrancoise S. Maheu1, Valérie La Buissonnière-Ariza2, Jean R. Séguin1, Michel Boivin3, Daniel S. Pine4, Richard E. Tremblay5

1Psychiatry, University of Montreal, Montreal, QC, Canada, 2Psychology, University of Montreal, Montreal, QC, Canada, 3Psychology, Laval University, Quebec, QC, Canada, 4Emotional Development Branch, NIMH, Bethesda, MD, 5School of Public Health, University College, Dublin, Ireland

Background: Harsh parenting practices may increase risk for anxiety disorders. This could reflect dysfunctions in the neural “fear” circuit (amygdala, hippocampus, prefrontal cortex (PFC)). We aim at understanding the functioning of the fear circuit as it relates to anxiety and harsh parenting in youths.Methods: Adolescents phenotyped since they were 5 months old according to their anxiety level and their mothers’ harsh parenting practices were recruited. Youths are split in 4 groups: (1) high-harsh parenting/high anxiety (n=21); (2) high-harsh parenting/low anxiety (n=24); (3) low-harsh parenting/high anxiety (n=21); (4) low-harsh parenting/high anxiety (n=20). fMRI event-related fear conditioning and extinction tasks were used, data analysis was conducted using SPM8.Results: Greater left amygdala and left anterior hippocampus activation were observed during conditioning in groups 1, 2 and 3 vs. group 4 (Ts > 5.95, ps corr < 0.05). During extinction, groups with high levels of anxiety (grs 1, 3) showed lower right PFC activation (xyz: 14, 50, 22mm; T > 2.7, p uncorr < 0.02) vs. group 4. In contrast, the high-harsh parenting/low anxiety group showed greater left PFC activation (xyz: -4, 14, 30mm; T > 2.0, p uncorr < 0.02) vs. group 4.Conclusions: Lower PFC function is linked to anxiety, while greater PFC function is linked to resilience to anxiety in adults. Our findings suggest these



neural markers may predict vulnerability or resilience to anxiety in youths. This could guide intervention strategies. Performing this work in youths is crucial as it may effectively prevent anxiety from becoming chronic.Keywords: Development, harsh parenting, anxiety, fear circuitry, fMRISupported By: Canadian Institutes of Health Research MOP-97983 to FS Maheu

797. Variation of the Mineralocorticoid Receptor Gene is Associated with Memory Bias in Formerly Depressed Patients Who Experienced Childhood Trauma but not Recent AdversityJanna N. Vrijsen1, Iris van Oostrom1, Guillen Fernandez2, 3, Susanne Vogel2, 3, Alejandro Arias-Vásquez1, 2, 3, 4, Barbara Franke1, 2, 4, Eni S. Becker5, Anne Speckens1

1Psychiatry, Radboud University Medical Centre, Nijmegen, Netherlands, 2Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands, 3Department of Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, Netherlands, 4Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands, 5Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, Netherlands

Background: Biased memory is considered an appropriate intermediate phenotype for depression. A recent study (Vogel et al., submitted) in healthy individuals shows a relation between a functional SNP (rs5534) within the mineralocorticoid receptor (MR; involved in regulation HPA axis) gene and memory bias. This association was confined to individuals with high life adversity. We attempted to extend this finding to formerly depressed patients, who are generally characterized by negative memory bias.Methods: 327 formerly depressed patients (66% female) performed the Incidental Learning and Free Recall task to assess self-referent memory bias for positive over negative verbal stimuli. Childhood trauma was measured with a validated questionnaire. The genotype (minor/risk-allele carriers vs major-allele homozygotes) by childhood trauma (yes, no) interaction on memory bias was analyzed using ANCOVAs with age and gender as covariates.Results: A significant interaction between genotype and childhood trauma was uncovered, p=.005. Risk-allele carriers with traumatic childhood had stronger negative memory bias than major-allele homozygotes with childhood trauma. However, major-allele homozygotes without a traumatic childhood showed stronger negatively biased memory than major-allele homozygotes with childhood trauma or risk-allele carriers without childhood trauma.Conclusions: MR seems mechanistically involved in depression and childhood trauma may moderate its effect on memory bias. Although speculative, the results indicate that formerly depressed patients may learn to overcome the detrimental effects of childhood trauma by retrieving more positive relative to negative information from memory. This effect seems most effective in individuals who are not predisposed for depression on the MR gene.Keywords: depression, genetic risk, memory bias, mineralocorticoid receptor, stressful life events

798. Transient Postnatal Fluoxetine Administration to Mice Decreases Brain Arachidonic Acid Metabolism in Adulthood: Long Term Metabolic Effects of Early SSRIStanley I. Rapoport1, Helene Blanchard1, Yewon Cheon1, Meredith A. Fox2, Mireille Basselin1, Epolia Ramadan1

1Brain Physiology and Metabolism Section, National Institute on Aging, Bethesda, MD, 2Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD

Background: Early exposure to SSRIs can disturb late-life behavior, while early SSRI administration to mice alters behavior, increases brain 5-HT

reuptake transporter (5-HTT) density and decreases 5-HT concentration (Altieri, Neuropsycharm 38, S1, 2012) in adulthood. We tested whether early fluoxetine also would alter brain metabolism of arachidonic acid (AA), a second messenger released during 5-HT2A/2C receptor initiated activation of cytosolic phospholipase A2 (cPLA2). :Methods: Incorporation coefficients k* and rates Jin of unesterified plasma AA into brain were imaged using quantitative autoradiography in unanesthetized adult mice treated postnatally (P4-P21) with fluoxetine (10 mg/kg/day, i.p.) or saline. Brain enzyme and 5-HTT expression, and head-twitches following DOI (5-HT2A/2C agonist), were measured.Results: k* and Jin were decreased significantly in 49 and 81 brain regions, respectively, of 92 measured, in fluoxetine- compared to saline-treated mice. cPLA2 and secretory sPLA2 activities were unchanged, while Ca2+-independent iPLA2 activity was increased. The protein level of cytochrome P450 4A, which converts AA to 20-HETE, was reduced 74%. Head-twitches after DOI were unaltered.Conclusions: Postnatal fluoxetine administration to mice decreases brain AA metabolism on neuroimaging, P450 4A expression and iPLA2 activity at adulthood. These changes may underlie the behavioral disturbances following early life fluoxetine. They may reflect reduced brain 5-HT, since brain AA metabolism is upregulated on neuroimaging when extracellular 5-HT is elevated in rats given fluoxetine during adulthood and 5-HTT knockout mice. Positron emission tomography with [1-11C]AA might be used to test for reduced brain AA incorporation, as a biomarker of early SSRI exposure, in human subjects.Keywords: f luoxetine, arachidonic, neonatal, brain, imagingSupported By: National Institutes on Aging and of Health

oral SeSSionBipolar Disorder Pathophysiology


Chair: Francis J. McMahon

799. Abnormalities in Reward-Related Brain Activity in Subsyndromal Bipolar DisorderRobin Nusslock1, Christina Young2, Narun Pornpattananangkul2, Xiaoqing Hu2, Todd Parrish3, Ellen Reynolds4

1Psychology and Psychiatry, Northwestern University, Evanston, IL, 2Psychology, Northwestern University, Evanston, IL, 3Radiology and Biomedical Engineering, Northwestern University, Chicago, IL, 4Psychology, Columbia University, New York, NY

Background: Research indicates bipolar disorder involves a hypersensitivity to cues of possible reward which can lead to excessive goal-directed motivation. Reward-relevant life events can trigger bipolar episodes and individuals with bipolar disorder display excessive reward-related brain activity during reward-anticipation. It is unclear, however, whether reward hypersensitivity is a preexisting risk factor for bipolar disorder or a consequence of the illness. To address this issue, we conducted two studies, one using fMRI and the other event-related potentials (ERP), to examine the relationship between reward-related brain activity and subsyndromal bipolar symptoms.Methods: In Study 1, forty-six adults with no diagnosable psychiatric history completed either a goal-directed or neutral mood induction. fMRI data were then collected while participants performed a monetary incentive delay task to examine reward-related brain function. In Study 2, twenty-two adults with no diagnosable psychiatric history completed a novel affective-based Go/Nogo paradigm to assess neural processes associated with the inhibition of a pre-potent response to reward-relevant stimuli (happy faces). In both studies, bipolar symptoms were assessed.



Results: In Study 1, elevated bipolar symptoms were associated with elevated reward-related brain function (caudate head; substantia nigra) during reward anticipation following a goal-directed mood induction. In Study 2, elevated bipolar symptoms were associated with reduced neural activity associated with conflict monitoring (N2) when inhibiting behavioral responses to rewarding stimuli.Conclusions: This study provides compelling evidence that abnormalities in reward-processing and reward-related brain activity are observed across the entire bipolar spectrum and that reward-hypersensitivity may reflect a preexisting vulnerability for bipolar spectrum disorders.Keywords: Bipolar Disorder, Reward-Processing, fMRI, ERP, Dimensional psychopathology

800. Functional Imaging of Emotional Memory in Individuals at High Familial Risk of Bipolar Disorder with and without DepressionHeather C. Whalley, Jessika E. Sussmann, Liana Romaniuk, Jeremy Hall, Stephen M. Lawrie, Andrew M. McIntosh

Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom

Background: Abnormalities of mood-related brain circuitry are understood to underlie the core symptoms of Bipolar disorder (BD) and major depressive disorder (MDD). It is however, unclear whether such abnormalities are related to the presence of the disorder, or whether they are present in unaffected relatives, representing trait-related features of illness.Methods: In the current study we examined a group of young individuals at familial risk of mood disorder (n=83), of whom twenty had developed MDD, along with a group of healthy controls (n=52). All participants performed an emotional memory paradigm involving the encoding of positive and neutral stimuli whilst undergoing functional magnetic resonance imaging.Results: All groups demonstrated emotional modulation of memory and demonstrated typical amygdala, hippocampal and cingulate activation for emotional versus neutral stimuli. There were significant group differences in activation across both emotional and non-emotional stimuli versus baseline, with no evidence of a group-by-condition interaction. Those at risk of mood disorder with MDD demonstrated increased activation of the amygdala and hippocampus versus the other groups, and decreased activation of the anterior cingulate. Findings remained significant after removing medicated individuals. Activation in the left hippocampus was significantly associated with the severity of depressive symptoms at the time of the scan.Conclusions: These results demonstrate neuroimaging abnormalities in mood-related brain circuitry in those at familial risk in the early stages of the development of mood disorder that relate to the presence of illness and severity of symptoms.Keywords: mood disorder, depression, familial risk, fMRI, hippocampusSupported By: Royal Society, Wellcome Trust, Healthy Foundation, Brain and Behaviour Research Foundation, Scottish Funding Council

801. Elevated Serum Measures of Lipid Peroxidation and Abnormal Prefrontal White Matter in Euthymic Bipolar Adults: Toward Peripheral Biomarkers of Bipolar DisorderAmelia Versace1, Ana Andreazza2, Trevor L. Young2, Jay Fournier1, Jorge Almeida1, Vishwajit Nimgaonkar1, David Kupfer1, Mary Phillips1

1Psychiatry, WPIC, Pittsburgh, PA, 2Psychiatry, University of Toronto, Toronto, ON, Canada

Background: Diffusion tensor imaging(DTI) studies consistently reported abnormalities in fractional anisotropy(FA) and radial diffusivity(RD), measures of the integrity of white matter (WM), in bipolar disorder (BD), that may

reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily-obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD.Methods: We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA(and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE)and 19 age- and gender- matched healthy adults (CONT).Results: There was a significant effect of group upon FA in these a priori WM tracts (BDE<CONT:F[1,41]=6.8;p=0.013) and RD (BDE>CONT:F[1,41]=10.3;p=0.003), and a significant between-group difference in LPH (BDE>CONT:t[40]=2.4;p=0.022), but not 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59% and 51% of the variance of FA and RD across all study participantsConclusions: This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically-relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.Keywords: global probabilistic tractography, fractional anisotropy, oxidative stress, lipid peroxidation, bipolar disorderSupported By: R01 MH076971-01l NARSAD (A. Versace)

802. Identifying Biomarkers of Risk for Bipolar Disorder and Affective Pathology in Youth Mary Louise Phillips


Background: There are no known biological measures that accurately predict future bipolar disorder(BD)/affective pathology. We adopted two neuroimaging approaches to identify biomarkers denoting risk for these disorders in at-risk youth.Methods: We used: 1. fMRI and a monetary reward paradigm to examine activity in reward neural circuitry in n=85 10-17 year-olds with subthreshold/fully syndromal mania (assessed by Elevated Symptoms of Mania score, ESM), to identify biomarkers of positive mood deregulation in youth; 2. fMRI during face emotion processing and machine learning to individually classify (assign a predictive probability to) n=16 healthy youth genetically at-risk for BD/other mood disorders and n=16 low-risk healthy youth, and identify individual at-risk youth most likely to develop psychiatric disorders.Results: 1. Accounting for potentially confounding clinical and demographic variables, ESM was positively associated with activity to reward in left middle prefrontal cortex, subserving reward-related decision-making, across all n=85 youth (p<0.05, corrected), regardless of diagnosis. 2. Activity, especially in ventromedial prefrontal cortex and superior temporal sulcus, emotion evaluation regions, to neutral faces presented with happy faces significantly differentiated groups:75% accuracy (sensitivity=75%;specificity=75%). Predictive probabilities were significantly higher(p<0.05) for high-risk youth who developed a psychiatric disorder, versus those remaining healthy, up to 4 years’ follow-up.Conclusions: Specific patterns of abnormal activity in neural regions evaluating rewarding or emotional contexts may characterize bipolar disorder/affective pathology in youth, and may act as biomarkers reflecting underlying pathophysiologic processes to help identify, and guide treatment for, youth at future risk of these disorders.Keywords: Bipolar diosrder, Risk, Youth, Neuroimaging, RewardSupported By: R01 MH076971; R01 MH073953; R01 MH060952



803. Brain Transcriptome in Bipolar DisorderNirmala Akula1, Jennifer Barb2, Xueying Jiang1, Jens Wendland1, Kwang Choi3, Shurjo K. Sen4, Liping Hou1, David T. W. Chen1, Gonzalo Laje1, Barbara K. Lipska5, Joel E. Kleinman5, Hector Corrada-Bravo6, Sevilla Detera-Wadleigh1, Peter J. Munson2, Francis J. McMahon1

1Human Genetics Branch, National Institute of Mental Health Intramural Research Program (NIMH-IRP), National Institutes of Health, Bethesda, MD, 2Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD, 3Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, 4Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 5Neuropathology Section, Clinical Brain Disorders Branch, NIMH-IRP, National Institutes of Health, Bethesda, MD, 6Department of Computer Science, University of Maryland, Bethesda, MD

Background: RNA-sequencing (RNA-seq) technology has revolutionized the study of gene expression in health and disease. RNA-seq is a highly sensitive method to detect differences in gene expression and splicing not well represented on microarrays. We used RNA-seq to characterize differential expression of brain transcripts in bipolar disorder (BP).Methods: We performed deep-sequencing of high quality total RNA (RNA-integrity number ≥ 7) extracted from dorsolateral prefrontal cortex from 11 individuals diagnosed with BP and 11 age- and gender-matched controls. Principal Component Analysis was performed with JMP, differential expression was analyzed with DESeq, and gene-set enrichment analysis (GSEA) was performed with DAVID. Enrichment for genome-wide association (GWAS) signals was tested by re-sampling results from a published GWAS in BP.Results: The first 3 principal components explained ~65% of the variance. At a false-discovery rate of <5%, we detected 5 differentially-expressed genes and 809 differentially-expressed exons in 741 genes, most of which have not been previously implicated in BP. Many of the findings were replicated in an independent sample. GSEA analysis implicated enrichment of several Gene Ontology categories particularly, genes in “neuron development” and “ion binding” which also showed significant enrichment of markers with small p-values in GWAS data.Conclusions: RNA-seq identifies several differentially expressed genes and exons in BP which converge on a few common pathways, some of which may contribute to etiology. The identified genes may help define common pathways for inherited and non-inherited influences on disease risk and may thus constitute good targets for novel therapies.Keywords: RNA-sequencing, functional annotation, microarrays, gene ontology, genome-wide association studiesSupported By: NIMH Grant# ZIAMH002810

804. Genetic Risk of Bipolar Disorder: Prediction of Later Depression Using Brain ImagingAndrew McIntosh

University of Edinburgh, Edinburgh, United Kingdom

Background: Bipolar disorder (BD) is a highly heritable condition. First-degree relatives have a more than a ten-fold risk of developing BD, and a three-fold risk of developing major depression (MDD) than the general population. It is unclear whether differences in brain activation reported in BD and MDD are present before the onset of illness and could be used to predict later illness.Methods: We studied 98 unaffected individuals at high risk of BD and 58 healthy controls using functional Magnetic Resonance Imaging (fMRI) scans and a task involving executive and language processing. Twenty of the high-risk subjects developed MDD after the baseline fMRI scan, 2 years later.Results: At baseline the high-risk subjects who later developed MDD

demonstrated relatively increased activation in the insula, compared to controls and high risk subjects who remained well. In the healthy controls and high-risk group who remained well, this region demonstrated reduced engagement with increasing task difficulty. The high risk subjects who subsequently developed MDD did not demonstrate this normal disengagement. Activation in this region correlated positively with measures of cyclothymia and neuroticism at baseline, but not with measures of depression.Conclusions: These results suggest that increased activation of the insula differentiates individuals at high-risk of bipolar disorder who later develop MDD from healthy controls and those at risk who remain well. These findings may provide a means of predicting MDD in unaffected individuals who are at increased risk.Keywords: Bipolar Disorder, Major Depressive Disorder, Predict, high-risk, cohortSupported By: NARSAD; The Health Foundation; Scottish Funding Council

805. Longitudinal and Cross-Sectional Studies of LTP-Like Cortical Plasticity in Subjects with Bipolar Disorder and Healthy ControlsTorbjørn Elvsåshagen1, Erlend Bøen1, Torgeir Moberget2, Nina Harkestad3, Robert Murison3, Birgitte Boye1, Ulrik F. Malt1, Stein Andersson1, 2

1Dept of Neuropsychiatry and Psychosomatic Med, Oslo University Hospital, Oslo, Norway, 2Center for the Study of Human Cognition, University of Oslo, Oslo, Norway, 3Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway

Background: We recently reported evidence for impaired visual evoked potential (VEP)-plasticity - an in vivo correlate of LTP-like cortical plasticity - in bipolar II disorder (BD-II; Elvsåshagen et al. Biol Psychiatry 2012). The aims of the present study were 1) to longitudinally examine VEP-plasticity in healthy controls (HCs) and subjects with BD-II, 2) to examine whether impaired VEP-plasticity in BD-II is a stable trait or mood state-related, and 3) to examine the relationship between VEP-plasticity and cortisol.Methods: 29 HCs and 16 subjects with BD-II underwent examinations of VEP-plasticity as described previously (Elvsåshagen et al. Biol Psychiatry 2012) at time point (T)1 and 2.4 years later at T2. At T2, VEP-plasticity was examined in additionally 13 subjects with BD-II and three samples of saliva were collected (7:30AM, 8:00AM, 12:30PM) for cortisol measurement.Results: VEP-plasticity was significantly reduced in patients (N=16) at T1 (P=0.001) and T2 (P<0.001) relative to HCs. At T2, VEP-plasticity was significantly reduced in the whole patient sample (N=29; P=0.004) and a significant negative correlation was observed between VEP-plasticity and MADRS score (r=-0.40, P=0.03). Euthymic patients (N=21) had significantly impaired plasticity relative to controls (P=0.011). VEP-plasticity was significantly associated with cortisol levels in HCs (r=0.52, P=0.004), but not in patients. VEP-plasticity remained significantly reduced in patients after correcting for cortisol levels (P<0.001).Conclusions: These findings suggest that impaired LTP-like cortical plasticity is a stable trait of BD-II, that the plasticity might further deteriorate during depressive episodes, and that cortisol does not underlie the cortical plasticity impairment.Keywords: Bipolar Disorder, LTP, Cortical Plasticity, Cortisol, Visual Evoked PotentialSupported By: Research Council of Norway and the South-Eastern Norway Regional Health Authority



806. Induced Pluripotent Stem Cell Models of Bipolar DisorderMelvin G. McInnis1, Haiming Chen1, Monica Bame1, Cindy DeLong2, Sue O’Shea2

1Department of Psychiatry, University of Michigan, Ann Arbor, MI, 2Cell and Developmental Biology, University of Michigan, Ann Arbor, MI

Background: The development of cellular models for complex neuropsychiatric disorders such as Bipolar Disorder (BP) offers a valuable approach to the study of disease development and etiology. The goal of this study is to develop and characterize iPSC lines from BP individuals and controls to better understand the cellular basis of BP and suggest novel treatment approaches.Methods: 45 iPSC lines have been developed from 3 BP and 4 control subjects. Neural differentiation was assessed using antibodies to: nestin, Sox3, GFAP, βIII tubulin, MBP, neurotransmitters. Calcium fluorescent imaging was performed at days 28 and 75 of differentiation using Fluo-4 AM to track intracellular calcium on addition of agonists to the cultures. RNAs from undifferentiated control and BP iPSC (n=3 each) were used to probe Affy U133 Plus 2 microarrays. Transcripts with > 2-fold mean differences, p < 0.05 were analyzed in R and David to identify significantly altered signaling pathways and gene expression.Results: Microarray analysis identified changes in genes associated with development, specifically with nervous system development, neuronal migration and transcription factor activity. Several calcium channel genes, and membrane receptors that showed differential expression between BP and normal control subjects. There were 48 down-regulated and 36 up-regulated genes common to iPSC lines and differentiated neuronal cells. No differences identified in current fluorescent imaging.Conclusions: We have identified alterations in membrane receptors between BP and C neurons and changes in genes involved in maturation of the nervous system, and in genes involved in cell-cell interactions and in calcium pathways.Keywords: BIPOLAR DISORDER, IPSC, MODELINGSupported By: Prechter Bipolar Research Fund, Steven Schwartzberg Memorial Fund, Thomas B and Nancy Upjohn Woodworth Professorship in Bipolar Disorder and Depression

PoSter SeSSionPoster Session 3

Saturday, May 18, 2013, 5:00 PM - 6:30 PMGoldengate 1-8 - Lobby Level

807. Oxidative Stress in Early - Adolescent - and not Adult-Life Impairs Parvalbumin Interneurons: Reversal by N-AcetylcysteineKim Q. Do

Department of Psychiatry, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly-Lausanne, Switzerland

Background: A hallmark of the pathophysiology of schizophrenia is the dysfunction of parvalbumin-expressing fast-spiking interneurons, essential for coordinating neuronal synchrony during sensory and cognitive processing. Oxidative stress as observed in schizophrenia affects parvalbumin interneurons. It is however unknown whether the effect of oxidative stress is particularly prevalent during specific brain developmental time windows.Methods: We used mice with impaired synthesis of glutathione (Gclm KO) to investigate the effect of redox dysregulation and additional insults applied at various periods of postnatal development on maturation and long-term integrity of parvalbumin interneurons in the anterior cingulate and somatosensory cortices.

Results: A redox dysregulation, as in Gclm KO mice, renders parvalbumin interneurons, but not calbindin or calretinin interneurons, highly vulnerable and prone to exhibit oxidative stress. A glutathione deficit delays maturation of parvalbumin interneurons including their perineuronal net. Moreover, an additional oxidative challenge in preweaning or pubertal, but not in adult Gclm KO mice, reduces the number of parvalbumin-immunoreactive interneurons. This effect is long lasting and can be prevented with the anti-oxidant N-acetylcysteine.Conclusions: In Gclm KO, the early- and adolescent-life (but not adult-life) insults inducing oxidative stress are detrimental to parvalbumin interneurons. In analogy, individuals carrying genetic risks to redox dysregulation would be potentially vulnerable to early-life environmental insults, during the maturation of parvalbumin interneurons. Our data support the notion of a vulnerability period of parvalbumin interneurons to oxidative stress and the need to develop therapeutic approaches based on anti-oxidant and redox regulator compounds, which could be used preventively in young at-risk subjects.Keywords: GABA interneurons, Oxidative Stress, Development, N-acetyl-cysteineSupported By: Swiss National Science Foundation, Loterie Romande, Damm-Etienne Foundation, Alamaya Foundation

808. The Electroretinogram as a Biomarker for Psychiatric Disorders: The Possible Implication of GSK3Joelle Lavoie1, 2, Peter S. Klein3, Marc Hébert1, 4, Jean-Martin Beaulieu1, 2

1Centre de recherche, Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada, 2Department of Psychiatry and Neuroscience, Université Laval, Quebec City, QC, Canada, 3School of Medicine, University of Pennsylvania, Philadelphia, PA, 4Department of Ophthalmology and Otorhinolaryngology, Université Laval, Quebec City, QC, Canada

Background: Electroretinogram (ERG) anomalies have been reported in patients with psychiatric disorders. For example, a decrease in cone a-wave amplitude was observed in schizophrenic patients and a decrease in rod b-wave was described in children at high risk (HR) to develop schizophrenia or bipolar disorder. Impaired inhibition of glycogen synthase kinase-3 (GSK3) might be associated with some psychiatric disorders. The goal of this experimentation is to investigate the origin of those ERG anomalies by studying the implication of the two isoforms of GSK3, GSK3α and GSK3β, in the ERG.Methods: Cones and rods ERGs were recorded on knockout mice for GSK3α (GSK3α-KO), GSK3β (GSK3β-KO) and on mice expressing a ~20% increase in GSK3β (prpGSK3β). Luminance-response function protocols were used to analyse the ERG parameters namely the amplitude and implicit time of the a-wave (representing the photoreceptors) and the b-wave (representing the bipolar cells).Results: A decrease in rod b-wave amplitude was observed [F(1,26)=19.327,p<0.001] in prpGSK3β mice, which corroborates the ERG anomalies of the HRs. The GSK3β-KO mice have an increased b-wave amplitude for the rods [F(1,22)=6.868,p=0.016] and the cones [F(1,19)=7.059,p=0.016] systems. GSK3α-KO mice show an increased a-wave [F(2,23)=9.219,p=0.001] and b-wave [F(2,23)=4.923,p=0.017] amplitude for the cones system and an increased b-wave amplitude [F(2,32)=5.849,p=0.007] for the rods system.Conclusions: The expression of GSK3 impacts the b-wave amplitude of the ERG. The a-wave amplitude seems to be increased only in GSK3α-KO mice. These results support that impairments in GSK3 expression could be implicated in the ERG anomalies observed in psychiatric disorders.Keywords: Electroretinogram, Biomarker, GSK3, Schizophrenia, Animal model



809. Prefrontal Cortical-Striatal Hippocampal Dysfunction Measured on the Radial-Arm Maze is Predictive of Cocaine Sensitization in Rats with Neonatal Ventral Hippocampal Lesions Kalyan N. Rao1, Alena Sentir1, Alan Breier2, R. Andrew Chambers1

1Department of Psychiatry, Indiana University School of Medicine, Laboratory for Translational Neuroscience of Dual Diagnosis & Development, Institute of Psychiatric Research, Indianapolis, IN, 2Department of Psychiatry, Indiana University School of Medicine, Indiana University Psychotic Disorders Program, Indianapolis, IN

Background: Substance disorder vulnerability in schizophrenia may reflect dysfunctional prefrontal cortical-striatal hippocampal circuitry. Rats with neonatal ventral hippocampal lesions (NVHL) develop an array of schizophrenia-like symptoms including cognitive deficits and increased addiction vulnerability. This study is aimed to understand the relationship between cognitive dysfunction and psychomotoric vulnerability to cocaine sensitization in the NVHL model, and test whether treatment with N-acetyl cysteine (NAC)--a glutamatergic modulating agent--can alter these dual diagnosis measures.Methods: Adolescent NVHLs vs. SHAM-operated rats (N=80) were randomized to receive NAC vs. saline injections until the start of Radial-arm maze (RAM) testing in early adulthood, when half of all NAC rats reverted back to saline. Subsequently, all groups underwent cocaine sensitization, followed by discontinuation of injections and a cocaine challenge 2 weeks later.Results: NVHL profiles in RAM performance were characterized by overall deficits in learning and working memory and over-consumption of the food reward. NAC treatment had no main effect or interaction with NVHLs on these variables. NVHLs showed enhanced short- and long-term cocaine sensitization. Significant predictive correlations were observed between NVHL-related abnormalities in RAM performance and subsequent patterns of cocaine sensitization.Conclusions: This study identifies NVHL-based cognitive deficits indicative of prefrontal cortical-striatal-hippocampal network disconnection in an animal model of schizophrenia. This endophenotype is not substantially altered by NAC treatment but is predictive of subsequent abnormal increases in cocaine sensitization, affirming the importance of this neural network in the pathogenesis of addiction vulnerability in mental illness and suggestive of clinical performance measures of dual diagnosis vulnerability in humans.Keywords: Schizophrenia, Dual diagnosis, Neunatal ventral hippocampal lesion, Addiction, N-acetylcysteineSupported By: Indiana University School of Medicine Biomedical Research Grant

810. Disturbed Gene Expression and Behavioral Deficits Reminiscent of Schizophrenia in Mice Deficient in Disc-M, A Gene Encoding a Transcriptional RegulatorTetsuo Ohnishi1, Akiko Watanabe1, Kazuyuki Yamada2, Fumiko Arima3, Rumi Kurokawa4, Yoshimi Iwayama1, Makoto Arai5, Hisako Ohba1, Manabu Toyoshima1, Tomoe Ichikawa5, Mitsuhio Miyashita5, Toshiya Manabe3, Toshihiko Hosoya4, Masanari Itokawa5, Takeo Yoshikawa1

1Lab. for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan, 2Animal Section, Bioresources Center, RIKEN Brain Science Institute, Wako, Japan, 3Institute of Medical Science, University of Tokyo, Tokyo, Japan, 4Lab. for Local Neuronal Circuits, RIKEN Brain Science Institute, Wako, Japan, 5Schizophrenia Research Group, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Background: Disturbed gene expression and behavioral deficits reminiscent of schizophrenia in mice deficient in Disc-M, a gene encoding a transcriptional

regulator. We have recently reported a schizophrenic patient with a de novo mutation, a balanced chromosomal translocation [t(4;13)(p16.1;q21.31)]. We attempted to determine the break point within chromosome 4 and found that it located at the upstream region of a gene we named DISC-M (Disrupted_In_Schizophrenia, Matsuzawa). This gene encodes a putative transcriptional regulator. However, it remains unknown whether and how the functional loss of the gene really impacts on the etiology of schizophrenia in the patient.Methods: To approach these problems, we analyzed mice lacking the corresponding gene using multifaceted approaches.Results: The homozygous mice were viable. Behavioral assessments showed that they are hyperactive, and hypersensitive to MK-801, an NMDA antagonist. In addition, the mice have a severe impairment in auditory fear conditioning test, suggesting deficits in learning/memory abilities. Similar to some of other model mice for schizophrenia, Disc-M knockout mice exhibited lowered adult neurogenesis in hippocampal dentate gyrus. As a result of microarray analysis, we found that Disc-M controls the expression of multiple genes, which may be involved in neuronal function or development, in the hippocampus and the cerebral cortex of mice.Conclusions: Disc-M knockout mice showed some of phenotypes reminiscent of schizophrenia, potentially as a result of disturbed gene expression. Since biological function of the gene remains largely unknown, further investigation will be needed.Keywords: schizophrenia, behavior, microarray, MK-801, knockoutSupported By: MEXT of Japan

811. Aberrant “Coupling” of Gene Expression in Medial Prefrontal Cortex (MPFC) and Nucleus Accumbens (NAC) After Neonatal Ventral Hippocampal Lesions (NVHLS)Neal R. Swerdlow1, Gregory A. Light1, 2, Michelle R. Breier1, Samantha R. Hines1, Susan B. Powell1

1Dept. of Psychiatry, University of California San Diego, La Jolla, CA, 28VISN 22, Mental Illness Research, Education & Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA

Background: After NVHLs, adult rats exhibit deficits relevant to schizophrenia, including reduced prepulse inhibition (PPI). The regulation of PPI by the VH is mediated via interactions with the mPFC and NAC. We assessed PPI, and expression of 7 PPI- and schizophrenia-related genes in the mPFC and NAC, in adult rats after sham- or real NVHLs.Methods: Male Buffalo (BUF) pups (d7; n=36) received either vehicle or ibotenic acid infusion into the VH. PPI was measured on d56. After electrophysiological measures (reported separately), brains were processed for RT-PCR (fold-change) measures of mPFC and NAC comt, erbb4, grid2, ncam1, slc1a2, nrg1 and reln. Hippocampal histology was assessed blind to results.Results: NVHL rats exhibited significant PPI deficits (p=0.005), and the degree of PPI deficit was associated with lesion size. Sham vs. NVHL rats did not differ in gene expression levels in mPFC or NAC. As we previously reported, gene expression levels were generally highly correlated within- (mean R’s≈0.5), but not across-brain regions (mean R’s≈0). However, for two genes - comt and slc1a2 - after NVHLs, expression levels became highly correlated, or “coupled,” across the mPFC and NAC, and the degree of “coupling” was associated with VH lesion size (R’s≈0.5-0.67 overall; 0.72-0.73 for largest 50% lesions).Conclusions: After NVHLs that disrupt PPI, expression levels of comt and slc1a2 suggest an abnormal functional “coupling” or “brain lock” of mPFC and NAC. This model of VH-mPFC-NAC network dysfunction after NVHLs has implications for understanding the neural basis for PPI- and related deficits in schizophrenia patients.Keywords: prepulse inhibition, schizophrenia, hippocampus, nucleus accumbens, prefrontal cortexSupported By: MH059803, MH065571, MH042228



812. Non-Competing NMDA Receptor Antagonists Alter EEG and Auditory Event-Related Potentials (ERP) in the RatElyse M. Sullivan1, L. Elliot Hong2, Patricio O’Donnell1

1Anatomy & Neurobiology, University of Maryland, Baltimore, Baltimore, MD, 2Maryland Psychiatric Research Center, University of Maryland, Baltimore, Catonsville, MD

Background: Neurophysiologic endophenotypes such as event-related potentials (ERP) in the electroencephalogram (EEG) are promising candidate biomarkers that can be non-invasively obtained in both humans and rodents and inform about cortical information processing. This work explores whether these EEG measures are altered in rodent models of schizophrenia.Methods: We recorded skull-surface EEG and LFP signals from the auditory cortex in rats during auditory paradigms including auditory steady state responses (ASSR), frequency oddball, and paired-click gating. Animals were recorded at baseline, after acute MK-801 (0.1 mg/kg i.p) injection, and after 21-day chronic MK-801. Neurophysiological signals were analyzed using custom matlab routines.Results: During paired-click sensory gating we found a significant frequency x drug main effect (p=.043) in central EEG channels. Post-hoc tests on each frequency band showed a significant effect of drug at high gamma (>85 Hz) (p=0.015) and gamma (41-85 Hz) (p=0.012), indicating that acute MK-801 increases EEG gamma power. No significant effects of chronic MK-801 administration were found. Additionally, during the 20 and 40 Hz ASSR, acute MK-801 significantly increased auditory cortex intertrial coherence (ITC) at 20 Hz (p=0.012, t(5)=3.85), whereas 21 days of chronic MK-801 did not affect ITC compared to pre-drug baseline. A similar trend was seen with 40 Hz ASSR (p=0.119).Conclusions: Using EEG recording paired with LFP recordings in awake-behaving rats we were able to elicit several auditory evoked potentials commonly examined in human schizophrenia research. We found that acute, but not chronic, MK-801 enhances gamma power and increases ITC during 20 and 40 Hz ASSR.Keywords: EEG, NMDAR, gamma oscillationsSupported By: R01 MH85646

813. Ethanol Intake in Rodent Models of Gastric Bypass Surgery for Weight LossStephen Craig Benoit

University of Cincinnati, Cincinnati, OH

Background: Roux-en-Y gastric bypass (RYGB) surgery is the most effective treatment for obesity and associated complications. Importantly, several recent reports suggest the RYGB procedure ttenuates reward-related consummatory behaviors. The present experiments assessed the hypothesis that RYGB surgery attenuates ethanol intake and reward in the context of frequent ethanol consumption.Methods: Self-report of ethanol intake was examined in human bariatric patients (n = 6165) before and following the RYGB procedure. In addition, we employed a rat model of RYGB and asessed ethanol consumption and reward in male ethanol-preferring (P) rats, which are bred to consume pharmacologic doses of ethanol.Results: First, patients that self-reported frequent consumption of ethanol before RYGB reported decreased consumption following RYGB surgery. Moreover, the RYGB procedure decreased ethanol intake and the reinforcing properties of ethanol in P rats. The effect of RYGB surgery on ethanol consumption was associated with ethanol-induced release of the gut hormone glucagon-like peptide-1 (GLP-1). Finally, pharmacologic administration of GLP-1 agonists attenuated ethanol consumption in sham P rats. Ghrelin, on the other hand, restored ethanol consumption in RYGB rats.Conclusions: Together, these findings suggest a potential of RYGB surgery to

attenuate ethanol consumption in some humans and rats. Our data indicate that this regulation is achieved, in part, through reduction of reward and is modified by the gut hormones GLP-1 and ghrelin.Keywords: RYGB, ethanol, ghrelin, GLP-1Supported By: Ethicon Endo-Surgery

814. Stress and Drug Addiction. “A Focus on Corticotropin-Releasing Factor”Sajoy P. Varghese

Department of Mental Health, Captain James A. Lovell, FHCC, North Chicago, IL

Background: In this study we hypothesized that over expressed Corticotrophin Releasing Factor (CRF) plays an important role in increasing the vulnerability to drug addiction and may predispose one to further drug seeking behavior. We then investigated whether conditionally over expressed CRF in forebrain corticotrophin hormone over-expressed(FbCRHOE) aka CT mice’s forebrain made them vulnerable to drug addiction vs. wild-type (WT)mice with normal expression of CRF.Methods: We have demonstrated that Morphine enhances drug seeking behavior in both WT and CT mice. The Condition place preference (CPP) test is an anxiety-related test useful to determine limbic system damage and is also a used to test the effectiveness of anxiolitic drugs/addictive drugs. We also studied Locomotor Activity based on Morphine Sensitization on CT and WT mice.Results: We found that the WT mice when compared to the CT mice, spent equal or slightly greater time in the light chamber after being injected with morphine. We had expected the mice in general to spend more time in the light chamber after receiving morphine as it is positive reinforcement. Yet we expected the CT mice to spend more time in the light chamber than the WT mice as they are predisposed to drug addiction, P value-Not Significant. We observed that morphine exposed CT mice exhibited more locomotor activities compared to WT p value = 0.001.Conclusions: Our preliminary data showed that post CT mice has an increased tendency for drug seeking behavior compared to WT mice.

Keywords: Addiction, Stress, Opiate Withdrawal, FbCRHOE mice, CRF receptors



815. Brain Ventricular Volume Enlargement Following Intermittent Ethanol-Vapor Intoxication in Mice, A Serial Magnetic Resonance Imaging Study Rajas Kale1, Slobodan Macura1, Kendall Lee2, Mark Frye1, Doo Sup Choi1, Osama A. Abulseoud1

1Psychiatry and Psychology, Mayo Clinic, Rochester, MN, 2Neurosurgery, Mayo Clinic, Rochester, MN

Background: Mice lacking alcohol-sensitive equilibrative nucleotide transporter type-1 (ENT1-/-) drink more ethanol, exhibit diminished aversive effects to ethanol, and show increased resistance to acute ethanol intoxication compared to their wild-type littermates. This study aims to investigate the effect of acute ethanol intoxication on brain ventricular volume (VV) in ENT1 mice as model of alcohol dependence.Methods: The effect of ethanol vapor chamber exposure on the brain VV of 12 adult female mice (6-ENT1-/-, and 6-ENT1+/+) were compared to 12 (6-ENT1-/-, and 6-ENT1+/+) air control littermate mice with structural MRI, conducted immediately following (MRI 1), one-day (MRI 2) , and seven-days after (MRI 3) ethanol vapor chamber exposure (16h/ day X 3 days). Volume measurements were done semi-automatically using Analyze software.Results: No significant differences were observed in total brain volume between groups. However, VV was significantly increased in intoxicated wild-type mice compared to other groups at all three time points.Conclusions: ENT1-/- mice did not show significant change in VV secondary to intoxication. This could be one factor contributing to their high tolerance to alcohol. The observed ventricular dilatation only in intoxicated ENT1+/+ mice following three days of intermittent ethanol vapor chamber remained dilated at one and seven days post intoxication. Longer term follow up studies with histological examination of brain tissue are needed to better understand the neurobiological underpinnings of this finding.

Mean ± SEM VV in different groups

Scan/Group Ethanol ENT1+/+

Ethanol ENT1-/- Air ENT1+/+ Air ENT1-/-

One-way ANOVA (p-value)

Day 0 3765±689.4 2131±255.6 1538±139 1943±88.55 0.0316

Day 1 4500±861.9 2136±172.2 1566±148 1684±149.1 0.0036

Day 7 3890±884.5 2427±292 1545±202.7 1815±204.5 0.0502

Keywords: ethanol-vapor intoxication, Brain ventricular volume, equilibrative nucleotide transporter type 1, magnetic resonance imaging, Alcohol dependenceSupported By: NIH/NCRR CTSA KL2

816. Unique Developmental Properties of NMDA Receptors in Normal Prefrontal Neurons and in Animal Models for SchizophreniaWen-Jun Gao1, Melissa A. Snyder2

1Drexel University College of Medicine, Philadelphia, PA, 2Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA

Background: The NMDAR has long been associated with learning and memory processes as well as diseased states, particularly in schizophrenia. Additionally, schizophrenia is increasingly recognized as a neurodevelopmental disorder with cognitive impairments often preceding the onset of psychosis. However, the cause of these cognitive deficits and what initiates the pathological process is unknown. Growing evidence has implicated the glutamate system and in particular NMDAR dysfunction in the pathophysiology of schizophrenia. Yet, the vast majority of schizophrenia-related research has focused on NMDAR function in adults leaving the role of NMDARs during development uncharacterized.

Methods: We have investigated the developmental changes of NMDARs in the prefrontal neurons.Results: We found that although NMDARs in fast-spiking interneurons exhibited significant switch of NR2B-to-NR2A subunits and dramatic changes in glutamatergic receptors during peri-adolescent period, NMDARs in pyramidal neurons maintain a relatively high level of NR2B subunits without clear subunit switch until adulthood. Furthermore, prenatal methylazoxymethanol (MAM) exposure leads to dramatic NMDAR alterations (e.g., significant reduction of NR2B) during early development and lasting learning and memory deficits whereas postnatal treatment with NMDAR antagonist induced distinct cell-type specific changes of glutamatergic receptors. We expect that risk genes for schizophrenia (e.g., DISC1 gene mutant) will also induce mis-expression and dysfunction of NMDARs during development in the mouse model but the question is when and how.Conclusions: These data indicate that the properties of NMDARs in the prefrontal circuitry are uniquely organized and that the highly dynamic NR2B may make the PFC vulnerable to risk factors leading to schizophrenia.Keywords: NMDA receptors, Schizophrenia, Prefrontal cortex, Development, Animal modelSupported By: Supported by NARSAD young investigator awards (M.A.Snyder and W-J.Gao), and NIH R21 grant MH232307 and NIH R01 grant MH232395 (W-J.Gao).

817. Impact of Serum Levels of BDNF, Oxidative Markers and Chemokines on Cognition in SchizophreniaElson Asevedo1, Ary Gadelha1, Cristiano Noto1, Rodrigo B. Mansur1, André Zugman1, Síntia I. N. Belangero1, Arthur A. Berberian1, Bruno S. Scarpato1, Emilie Leclerc1, Antônio Lúcio Teixeira2, Clarissa S. Gama3, Rodrigo A. Bressan1, Elisa Brietzke1

1Psychiatry, Federal University of São Paulo, São Paulo, Brazil, 2Psychiatry, Federal University of Minas Gerais, São Paulo, Brazil, 3Psychiatry, Federal University of Rio Grande do Sul, São Paulo, Brazil

Background: The underlying neurobiological mechanisms of cognitive deficits in Schizophrenia (SZ) remain largely unknown. Abnormalities in several mediators of neuroplasticity such as brain-derived neurotrophic factor (BDNF), mediators of oxidative stress and chemokines have been found in SZ and have the ability to modulate cognition in both health and neuropsychiatric diseases. In spite that, their role in cognitive impairments in SZ are insufficiently explored. Objective: Compare serum levels of BDNF, oxidative markers and chemokines between patients with SZ and healthy controls and investigated the impact of these biomarkers in cognitive performance.Methods: Thirty individuals with SZ according DSM-IV chronically medicated from the Schizophrenia Program at UNIFESP and 27 healthy controls were included. A blood sample of 5mL was withdrawn from all the subjects, and the following biomarkers’ levels were determined according manufacturers’ instructions: BDNF, TBARS, protein carbonyl content (PCC) and the chemokines IP-10/CXCL-10, IL-8/CXCL-8, CCL-11, CCL-24/Eotaxin-2, CCL-2/MCP-1, MIP-1/CCL-3. The neuropsychological tasks were selected to assess verbal learning (Hopkins Verbal Learning Test (HVLT)), verbal fluency (FAS test), working memory (Visual Working Memory Task (VWM), Keep Track Task, Letter Memory Task), set shifting (Plus-minus task, Number-letter task), inhibition (Computerized Stroop Task, Semantic Generation Task) and complex executive function tasks (Tower of London (ToL), the shortened version of the WCST-64).Results: Compared with the healthy control group, individuals with SZ presented significantly higher levels of BDNF and the chemokine CCL-11 and lower levels of TBARS and the chemokine IP-10/CXCL-10. Compared with healthy controls, individuals with SZ exhibited deficits in verbal learning (Hopkins test). When we examined only the SZ group, BDNF levels were positively correlated with semantic generation tasks (Spearman correlation test; r = 0.38, p = 0.044),



which is a timing measure. Working memory ability, as evaluated by keep track task, was negatively correlated with PCC (Spearman correlation test; r = - 0.45, p = 0.014). Regarding chemokines, CCL-11 was negatively correlated to performance in working memory test (Spearman correlation test; r = - 0.40, p = 0.034), and positively correlated with cognitive flexibility task (r = 0.51, p = 0.007). IL-8/ CXCL-8 was positively correlated with verbal fluency (Spearman correlation test; r = 0.38, p = 0.048). CCL-24/Eotaxin-2 was positively correlated with semantic generation ability (r = 0.42, p = 0.024) and letter memory task (Spearman correlation test; r = 0.38, p = 0.049).Conclusions: Our results indicate that cognitive performance in SZ is associated with mediators of neuroplasticity that can be measured peripherally. In addition, it was the first time that chemokines were associated with these cognitive deficits.Keywords: schizophrenia, cognition, chemokines, BDNF, oxidative stressSupported By: CNPq (Brazil) and FAPESP (Brazil)

818. Mitochondrial DNA Content in Bipolar DisorderRafael T. de Sousa1, Marcus V. Zanetti1, Miyuki Uno2, Wagner F. Gattaz1, Suely K. N. Marie3, Rodrigo Machado-Vieira1

1Department and Institute of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil, 23Departament of Neurology, University of Sao Paulo, Sao Paulo, Brazil, 3Department of Neurology, University of Sao Paulo, Sao Paulo, Brazil

Background: Consistent evidences support the role for mitochondrial dysfunction in Bipolar Disorder (BD) pathophysiology. Also, BD is associated with clinical and neuropsychiatric conditions which show any mitochondrial compromise, such as type 2 diabetes mellitus and Alzheimer’s disease, illnesses that showed altered mitochondrial DNA (mtDNA) content. Mitochondrial DNA (mtDNA) content has been proposed as a biomarker in several clinical conditions. The present study evaluates mtDNA content in patients with bipolar depression, comparing to healthy controls.Methods: BD patients in a depressive episode (n=23) (≥18 in the 21-item Hamilton Depression Scale) and no more than 5 years of mood disorder diagnosis entered the study. Patients were drug free for at least 4 weeks before inclusion. mtDNA copy number in patients was compared with healthy controls (n=24). Correlation between depressive symptoms and mtDNA copy number was calculated. mtDNA copy number (per cell) in leukocytes of patients and controls was determined by real time-PCR .Results: mtDNA copy number showed no significant difference between patients and controls (ANCOVA, F=0.56; df=1, 47; p=0.46). Also, no significant correlation was found between depressive symptoms and mtDNA content (Spearman, r=0.28, p=0.19). Conclusions: To the best of our knowledge, this is the first study evaluating mtDNA content in BD. The results suggest that mtDNA is not altered in depressive episodes of recent-onset BD.Keywords: Bipolar Disorder, Depression, Mitochondria, Mitochondrial DNA, PathophysiologySupported By: FAPESP

819. Genome-Wide Assessment of DNA Methylation in Post-Mortem Human HippocampusW. Brad Ruzicka

Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, MA

Background: Prior studies of schizophrenia (SZ) and bipolar disorder (BD) have demonstrated disease specific defects of the GABAergic system in discrete regions of the human hippocampus. These changes involve aberrant expression of genes within the GAD67 regulatory network, and resultant effects on GABAergic neuronal function. To investigate the hypothesis that DNA methylation plays a prominent role in the dysregulation of this gene network in SZ and BD, we have

developed a methodology to reliably assess DNA methylation within isolated hippocampal subregions dissected from post-mortem human brain.Methods: Using the Illumina HumanMethylation450 Beadarray, methylation levels at >480,000 CpG sites across the genome were measured in DNA extracts from tissue microdissected from stratum oriens (SO) of regions CA3/2 or CA1 of post-mortem human hippocampus. 4 cases (2 SZ and 2 control) were included in this preliminary study.Results: This methodology successfully measured methylation levels at 99.7% of the CpG sites interrogated by the assay. The assay is highly reliable, as technical replicates of control DNA yielded a correlation coefficient of 0.992. This work has produced promising data with >2 fold changes in methylation levels in schizophrenia within a subset of the genes of interest (CCND2, DAXX, GAD1, GRIK2, SMURF1). Consistent with existing gene expression data, greater variability of DNA methylation was observed in SO of CA3/2 as compared to SO of CA1.Conclusions: This work has successfully established a methodology that is currently being applied to a larger cohort for comparison of methylation profiles across diagnostic categories of SZ, BD, and control.Keywords: DNA methylation, hippocampus, post-mortem, epigenetics, microarraySupported By: R01MH77175

820. Association Between Tyrosine and Smoking in Patients with SchizophreniaJyoti Kanwar1, 2, Olaoluwa Okusaga1, 2, 3, Dietmar Fuchs4, Olesja Muravitskaja2, Ayesha Ashraf2, Sarah Hinman2, Ina Giegling5, Annette Hartmann5, Bettina Konte5, Marion Friedl5, Dan Rujescu5, 6, Teodor Postolache7, 8, 9

1Psychiatry, St Elizabeths Hospital, Washington, DC, 2University of Maryland, Mood and Anxiety Program, Baltimore, MD, 3Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, 4Division of Biological Chemistry, Biocenter, Medical University, Innsbruck, Austria, 5Section of Molecular and Clinical Neurobiology, Ludwig Maximilians University, Munich, Germany, 6Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany, 7Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, 8Psychiatry, VA Capitol Health Care Network Mental Illness Research Education and Clinical Center, Baltimore, MD, 9Child and Adolescent Mental Health Innovations Center, University of Maryland, Baltimore, MD

Background: Patients with schizophrenia are known to have higher rates of smoking. Smoking has been implicated in various inflammatory processes. Inflammation decreases tetrahydrobiopterin levels that are in turn essential for functioning of tyrosine hydroxylase enzyme that aids conversion of phenylalanine to the essential amino acid tyrosine, precursor of dopamine. Thus, we tested the hypothesis that patients with schizophrenia who smoke will have decreased tyrosine and elevated phenylalanine levels.Methods: Tyrosine, phenylalanine, tryptophan and kynurenine levels were measured in 950 patients (Male 600, Female 350, Age range 38± 11.6) with diagnosis of schizophrenia confirmed by SCID. Patients were recruited in both inpatient and outpatient setting in Munich, Germany. History of smoking was obtained by detailed clinical interviews and Fagerstrom nicotine dependence test. Data on PANNS scores, BMI and antipsychotic doses (in chlorpromazine equivalents) were also obtained. Statistical methods included paired t test and logistic regression multivariate models with adjustment for demographics and medication use.Results: ‘Smoker’ status was significantly associated with decreased tyrosine levels (p = 0.012. Differences in phenylalanine, phenylalanine/ tyrosine ratio, tryptophan, kynurenine and their ratio were not significant. Tyrosine -smoking association remained significant after multivariate adjustment for demographics, socioeconomic status, PANSS (p =0.048).Conclusions: Our study, limited by its cross-sectional design, suggests that



decreased tyrosine may play a role in mediating or moderating the previously reported association of smoking and schizophrenia, and provides a rationale for further investigation including proof of concept tyrosine supplementation trials in selected subgroups of patients. .Keywords: Tyrosine, Smoking, Schizophrenia, Phenylalanaine, tetrahydrobiopterin

821. Early Induction of Myelin-Oligodendrocyte Basic Protein (MOBP) Gene Expression in Primary Human Neuroglia Exposed to AntipsychoticsGursharan Chana1, Efstratios Skafidas2, Chad A. Bousman1, Christos Pantelis3, Ian P. Everall1

1Melbourne Brain Centre, Department of Psychiatry, The University of Melbourne, Parkville, Australia, 2Centre for Neural Engineering, Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, Australia, 3Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Parkville, Australia

Background: Identifying genes that are induced early by antipsychotic medications may provide a window into their therapeutic mechanism. The aim of this investigation was to assess gene expression changes of previously identified candidate genes for schizophrenia and/or antipsychotics in primary human neuroglia exposed to antipsychotics.Methods: Primary human fetal neuroglia were exposed to Haloperidol [50nM], Clozapine [1.5µM] and Risperidone [50nM] for 24hrs as well as non-exposed controls. RNA was extracted using a Qiagen miRNeasy kit followed by cDNA synthesis using Qiagen Omniscript RT. cDNA was hybridized to a customized SABioscience quantitative real-time PCR array containing validated probes for 90 candidate genes. We utilised 2-ΔΔCt to calculate fold change and a student’s t test to compare differences between medication versus controls at p<0.05.Results: RIN were between 8.9-10.0. A total of 8 genes were significantly differentially regulated by antipsychotics, however, only expression of MOBP was significantly increased by both Clozapine (p= 0.02577, fold change +3.32) and Risperidone (p = 0.026901, fold change +3.22) and while Haloperidol also increased MOBP expression, this failed to reach significance (p = 0.089, +3.45).Conclusions: Evidence for involvement of oligodendroglia and myelin related genes in schizophrenia have come from neuropathological and brain gene expression investigations. Our findings are of interest given that MOBP is the third largest constituent of myelin, and while the function of MOBP is poorly understood it is likely involved in compaction and stabilization of myelin, and therefore point to a potential therapeutic role for antipsychotics in preserving compromised brain circuits in schizophrenia.Keywords: Antipsychotic, Gene Expression, Myelin, Psychosis, SchizophreniaSupported By: Early Career Research Grant from University of Melbourne

822. Microglial Cell Populations in Prefrontal Grey and White Matter in Schizophrenia and Bipolar DisorderClare Beasley, Christa Hercher

Psychiatry, University of British Columbia, Vancouver, BC, Canada

Background: It has been proposed that low-grade inflammation may be present in SCZ and BPD. However, while increased levels of inflammatory markers have been reported in the periphery in SCZ, it is not clear whether inflammation is also present in the brain in either disorder. The major hallmark of chronic brain inflammation is activation of microglial cells. Post-mortem and brain imaging studies are suggestive of an increase in microglia in SCZ, however, immunocytochemical studies are inconsistent and have several limitations. The aim of this study was to quantify the density and distribution of microglial

populations in prefrontal grey matter and superficial white matter in control, SCZ and BPD cases.Methods: Paraffin sections of prefrontal grey and white matter, comprising SCZ (n=20), BPD (n=20) and control (n=20) subjects, were acquired from the Stanley Medical Research Institute. Microglia were identified using immunohistochemisty for IBA-1. Mean density and size of resting and activated microglia and measures of cell clustering were compared between groups by ANOVA.Results: Preliminary analyses revealed a decrease in the density of resting microglia in female bipolar disorder patients in grey matter. We found no change in the density of activated microglia, cell size or cell clustering. In white matter microglial density was unchanged between groups, however, cell clustering was altered in male bipolar disorder patients.Conclusions: Our data suggests that subtle microglial alterations are present in both grey and white matter in BPD patients. We were not able to find evidence of significant microglial activation in SCZ.Keywords: glia, white matter, inflammationSupported By: Canadian Institutes of Health Research, Stanley Medical Research Institute, Michael Smith Foundation for Health Research.

823. Increased GAD MRNA in Orbital Prefrontal Cortex in AlcoholicsMark D. Underwood, Tea Tsaava, Mihran J. Bakalian, Andrew J. Dwork, J. John Mann, Victoria Arango

Psychiatry - M.I.N.D., Columbia University - NYSPI, New York, NY

Background: Alcohol increases inhibitory neurotransmission, an effect mediated through actions on GABA receptors. With chronic alcohol exposure, there is neuronal adaptation and the inhibitory effects are reduced. Glutamic acid decarboxylase (GAD) catalyzes glutamate to bring about the synthesis of GABA. We sought to determine the amount of GAD in the prefrontal cortex of alcoholics postmortem.Methods: Frozen blocks of prefrontal cortex containing either anterior cingulate cortex (BA24) or orbital prefrontal cortex (BA45) were sectioned (10 µm) for in situ hybridization of 35S-labelled riboprobe for GAD65/67 mRNA. Studies were performed in 16 pairs of normal control or alcoholics matched for age and sex; DSM-IV diagnosis of alcohol dependence or abuse was made through psychological autopsy. Cases with positive neuropathology or toxicology for psychoactive substances other than alcohol were excluded. Gray matter and white matter in BA24 and BA45 were analyzed for labeled mRNA and area by quantitative densitometry.Results: Alcoholics had more GAD mRNA than controls in the gray matter of BA45 (p=.03), but not in BA24 (p=.37). GAD mRNA in white matter from either region was not different between controls and alcoholics (p>0.05). GAD mRNA levels did not change with age in either BA24 or BA45, but GAD mRNA did increase with duration of alcoholism in alcoholics in BA45 (r=.864, p=.006). Greater GAD mRNA in alcoholics was not due to differences in age or sex.Conclusions: The increase in GAD mRNA in alcoholics suggests chronic alcohol exposure adaptation includes greater expression of GAD mRNA in the orbital prefrontal cortex.Keywords: human, postmortem, in situ hybridization, GABA, prefrontal cortexSupported By: AA11293; MH62185; MH064168

824. Bidirectional Modification of Response-Outcome Decision-Making Strategies by Cocaine and Rho-KinaseAndrew M. Swanson, Shannon L. Gourley

Graduate Program in Neuroscience, Department of Pediatrics, Yerkes National Primate Research Center, Emory University, Atlanta, GA

Background: Goal-directed decision-making is based on the association between an action and a desired outcome. With repeated performance, behaviors that



are initially goal-directed can assume stimulus-elicited, or ‘habitual,’ qualities. A range of insults, including drug exposure, can predispose both humans and animals to the formation of premature habits that occur at the expense of engagement in goal-directed action-outcome response strategies. A growing literature has identified mechanisms by which decision-making shifts from response-outcome-based to stimulus-response-based habit systems, but reversing habits has proven difficult.Methods: The prelimbic prefrontal cortex is necessary for goal-directed decision-making. Here, we isolate the role of Rho-kinase, a key regulator of the actin cytoskeleton, within the prelimbic cortex, with the hypothesis that cytoskeletal plasticity is a fundamental determinant of decision-making strategies. Mice were instrumentally trained, followed by response-outcome contingency degradation and outcome devaluation. The effects of the Rho-kinase inhibitor HA-1077 on decision-making strategies were contrasted against those of cocaine. Effects on prelimbic cortical dendritic spines were quantified.Results: HA-1077 restores goal-directed decision-making in mice that otherwise developed stimulus-response habits, while cocaine induces habitual responding; our findings suggest that both compounds act on consolidation processes. Moreover, deep-layer prelimbic dendritic spine density predicts decision-making strategies, such that higher densities are associated with stimulus-response habits, while lower densities are associated with engagement in goal-directed response strategies.Conclusions: These findings support the perspective that Rho-kinase inhibition promotes goal-directed decision-making by enhancing the plasticity of deep-layer medial prefrontal cortical dendritic spines, and that it has therapeutic potential in the context of cocaine dependence.Keywords: decision-making, habits, cocaine, addiction, dendritic spinesSupported By: CHOA; NCRR P51RR165; ORIP/OD P51 OD11132; NIDA T32 DA015040; NINDS P30NS055077

825. High Serum Glutamate Level is Associated with Positive Response to Acamprosate TreatmentHyung Wook Nam1, Victor M. Karpyak2, Xiaofan Li2, Denise L. Walker2, David J. Hinton1, Hoil Choi1, Osama A. Abulseoud2, Mark A. Frye2, David A. Mrazek2, Doo-Sup Choi1

1Molecular Pharmacology, Mayo Clinic College of Medicine, Rochester, MN, 2Psychiatry, Mayo Clinic College of Medicine, Rochester, MN

Background: Acamprosate, a homo-taurine analogue, is approved for treatment of alcohol dependence. Meta-analyses favor acamprosate for its ability to support abstinence, which is the most stable type of remission in alcoholics. Yet, only a limited number of treatment-seeking alcoholics use acamprosate, most likely because of individual differences in response and the lack of response predictors.Methods: We used a pharmacometabolomics approach to investigate metabolic response in serum amino acid metabolites (including acamprosate) between responders and non-responders to acamprosate treatment. Serum samples were collected before and after 3 months of acamprosate treatment. Efficacy was defined by self-reported abstinence during acamprosate treatment and average gamma-glutamyl transferase (GGT) levels at baseline and 3-month follow up were used to confirm abstinence. Of those, 14 responders and 18 non-responders comprised an investigation cohort and an additional 30 responders and 28 non-responders comprised a replication sample.Results: Initial metabolite screening was conducted using 32 alcohol dependent subjects. Glutamate levels were significantly higher at baseline in the 14 responders compared to the 18 non-responders [t(30)=2.7, p < 0.05]. Following acamprosate treatment serum glutamate levels in the responder group significantly decreased compared to baseline [t(26)=3.3, p < 0.05]. Similarly, in a replication sample of 58 additional alcohol-dependent subjects, responders had significantly higher glutamate levels at baseline compared to the non-responder group [t(88)=2.8, p < 0.05], which decreased significantly after acamprosate treatment [t(86)=3.6, p < 0.05].Conclusions: Our findings suggest that high glutamate levels may be a biomarker to predict the efficacy of acamprosate treatment in alcohol-dependent subjects.Keywords: acamprosate, glutamate, metabolomics, personalized treatment, alcoholism

Supported By: P20AA017830

826. Chronic, but Not Acute, Methamphetamine Exposure Decreases the Expression of Glutamate AMPA Receptors by Causing Hypoacetylation of Histone H4 in the Dorsal StriatumJean Lud Cadet, Subramaniam Jayanthi

Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD

Background: Psychostimulant addiction is associated with neuroadaptations at glutamatergic synapses. These adaptations are accompanied by prolonged changes in gene and protein expression in the rat striatum. However, the epigenetic bases for these changes is not understood.Methods: Male Sprague-Dawley rats were used in the experiments. Animals were housed in a humidity and temperature-controlled room with free access to food and water. Rats were assigned to two groups (8 rats each) and were injected daily for 2 weeks with either saline or METH. Sixteen hours after the last saline or METH injection, the animals were euthanized. In another set of experiments, rats were also treated with the HDAC inhibitor, valproic acid (300 mg/kg) given twice a day 30 min prior to either saline or METH injections.Results: Repeated injections of increasing METH doses caused significant decreases in mRNA and protein levels of AMPA receptor (AMPAR) subtypes, GluA1 and GluA2, in the striatum. Chromatin immunoprecipitation assays revealed that METH caused significant decreases in the enrichment of acetylated histone H4 on the gene promoters. METH also increased the protein expression of histone deacetylases (HDAC2 and SIRT2), REST, and CoREST. CoREST, but not REST, showed increased enrichment on GluA1 and GluA2 gene sequences. METH also induced interactions of CoREST with HDAC2 and SIRT2. Finally, the effects of METH on AMPAR expression were prevented by valproic acid.Conclusions: Our results indicate that chronic administration of METH is associated with alterations in histone acetylation that might be responsible for decreased expression of AMPA receptors. Keywords: Epigenetics, Methamphetamine, dorsal striatum, glutamate receptors, Valproic acidSupported By: NIH/NIDA IRP

827. Chronic Hypoactivity of Raphe Serotonergic Neurons Inhibits Cocaine Sensitization; A Study Using Designer Receptors Exclusively Activated Designer DrugsHidehiro Oshibuchi1, Daniel Urband2, Ethelyn Layco1, Michael Donovan1, Bryan Roth2, Laurence H. Tecott1

1Psychiatry, UCSF, San Francisco, CA, 2Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC

Background: Although raphe serotonergic projections to dopaminergic pathways implicated in psychostimulant responses are believed to generally suppress their activity, studies examining serotonergic pharmacological manipulations on pyschostimulant actions have produced inconsistent results. In this study, we examined the net effect of raphe serotonergic neurons on cocaine responses using mice expressing “designer receptors exclusively activated by designer drugs (DREADD)”.Methods: G protein coupled receptors signaling pathways Gq (hM3Dq) or Gi (hM4Di) and green fluorescent gene (GFP) were transferred by bilateral raphe nucleus injections of Cre dependent adeno-associated virus into mice expressing Cre recombinase in serotonergic neurons. Three experimental groups (hM3Dq+GFP, hM4Di+GFP or GFP, n = 10 each) were respectively activated, silenced or unaffected by Clozapine-N-oxide in drinking water. Locomotor activity (LA) was measured by photobeam breaks under three conditions: novel environment, single dose of cocaine, and re-challenge of cocaine after cocaine-sensitization.Results: Novel environment did not elicit differences in exploratory behavior



among the three groups. Single dose of cocaine 15 mg/kg stimulated LA in all animals (p = 0.001, One factorial ANOVA), without differences among groups. Upon cocaine re-challenge, hM3Dq and GFP groups showed significantly higher LA compared to that seen following a single dose (p = 0.017, 0.014 each, two-factorial ANOVA and Bonferroni’s post hoc study). In contrast, cocaine sensitization was suppressed in the hM4Di group (p = 0.281).Conclusions: Chronic hypoactivity of raphe serotonin neurons inhibited cocaine sensitization, but not acute responses to cocaine or to a novel environment. Potential mechanisms through which this may occur will be discussed.Keywords: serotonin-dopamine interaction, DREADD, cocaine sensitization, dopamine related behavior, locomotor activity

828. Fibroblast Growth Factor 2 Expression in Selectively Bred High-Responder and Low-Responder Rats is Differentially Impacted by the Interaction Between Cocaine and the EnvironmentMaria Waselus1, Shelly B. Flagel1, 2, 3, Cortney A. Turner1, Terry E. Robinson2, Huda Akil1, 3, Stanley J. Watson1, 3

1Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, 2Psychology, University of Michigan, Ann Arbor, MI, 3Psychiatry, University of Michigan, Ann Arbor, MI

Background: The selectively bred lines of high-responder (bHR) and low-responder (bLR) rats differ in behaviors related to addiction. Genes sensitive to cocaine treatment and environmental manipulation, such as fibroblast growth factor 2 (FGF2), are differentially expressed in bHR and bLR rats. This study took advantage of the unique differences in addiction liability between the selectively bred lines to examine how repeated cocaine administration and/or living in an enriched environment impact FGF2 mRNA expression.Methods: 68 adult male bHR and bLR rats received saline (1mg/kg) or cocaine (7.5, 15, or 30mg/kg D1 and D14; 15mg/kg D2-13) injections for 14-days. Effects of phenotype (bHR, bLR), treatment (saline, cocaine) and “group” (24-hour or 60-day abstinence +/- enrichment) on FGF2 mRNA expression were evaluated in the hippocampal dentate gyrus (DG) and nucleus accumbens core (AcbC) using in situ hybridization.Results: FGF2 expression was impacted by a phenotype-treatment-group interaction in both the DG (F(2,30)=4.16,p=0.02) and AcbC (F(2,32)=4.23,p=0.02). The differential effects of cocaine and/or enrichment onFGF2 expression in bHR and bLR rats were brain-region specific. For example, 60d of cocaine abstinence decreased FGF2 expression in the DG of bLRs, and enrichment exacerbated this decrease. In contrast, enrichment “rescued” FGF2 expression in the AcbC of cocaine-treated bHRs, but not bLRs.Conclusions: FGF2 expression is differentially impacted in bHR and bLR rats by interactions between past cocaine exposure and environmental conditions during prolonged cocaine abstinence. These findings support an interaction between genes and the environment in determining the long-term consequences of cocaine.Keywords: hippocampus, nucleus accumbens, addiction, individual differencesSupported By: NIDA 5P01DA021633,ONR N00014-09-1-0598, ONR N00014-12-1-0366, T32 DA007267

829. Repetitive Transcranial Magnetic Stimulation for Bipolar DepressionGuohua Xia

Department of Psychiatry and Behavioral Sciences UCDavis Med Ctr, Davis, CA

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) has approved efficacy in treating major depressive disorder. However, few studies have been focusing on rTMS treatment of bipolar depression (BD). This presentation will review the published studies and report the results of an unpublished study

on use of conventional figure-8 coil and a study using novel H1-coil that can stimulate deeper and wider range of brain structure.Methods: Study A is an open labeled study (N=15) on treatment resistant BD (DSM-IV standard) with the mood-stabilizing medication on and antidepressant discontinued. In this study, 20Hz, 100%MT rTMS with 3sec-on, 27sec-off, total 2400 stimuli are applied at left dorsal lateral prefrontal cortex (LDLPFC) for 15 sessions in 3weeks. Study B is a pilot study (N=19) using H1-coil and similar protocol (20 Hz, 2s on, 20s off, totaling 1680 stimuli at LDLPFC, 20-sessions/4-week). Both studies use Hamilton Depression Scale (HDRS) for outcome measures.Results: Both study A and B found significant post-rTMS decreases of mean HDRS scores (P<0.001 two-tail T-test). Response rates were 60% and 63.2%, Remission rates 47% and 52.6% correspondently. Treatment was well tolerated in terms of headache and overall discomfort. There were no significant change in cognitive functioning and no treatment emerged mania. One case of none-complicated seizure occurred in Study B.Conclusions: 20Hz rTMS via both conventional figure-8 coil and H-coil significantly improves bipolar depression in acute treatment. Both treatment protocols yield benign safety profile in acute treatment phase. Further studies via randomized controlled trials are warranted to confirm the efficacies.Keywords: Repetitive Transcranial Magnetic Stimulation, bipolar depression, none-pharmacological treatment, deep rTMS, interventional psychiatrySupported By: NARSAD and Brainsway

830. Cannabinoid Modulation of Acute PainRichard A. Sewell

Psychiatry, VACHS/Yale University School of Medicine, West Haven, CT

Background: Preclinical and clinical studies indicate potent antinociceptive effects of cannabinoids. There are six different types of acute pain, each modulated by different neurotransmitters and nerve pathways: chemical pain, mechanical pain, thermal pain (hot and cold), electrical pain, and visceral pain. One objective way of measuring pain is by using the pepper-family derivative capsaicin, subcutaneous injection of which elicits glutamate release at dorsal horn neurons, increasing their sensitivity and resulting in allodynia and hyperalgesia in the injection site area. This pilot study systematically tested the effect of Δ9-THC (tetrahydrocannabinol) using two doses and several human experimental pain models. Our hypotheses were that THC has antinociceptive effects that occur at a sub-psychoctive dose.Methods: A randomized double-blind prospective pilot study in which six cannabis-abstinent subjects were administered low-or high-dose intravenous THC or placebo on three separate days, then pain threshold and tolerance tested. Pain was experimentally induced in four ways: chemical pain through capsaicin injection, thermal pain (hot and cold) with a thermode, and electrical pain through transcutaneous electrical stimulation. Outcome measures were the size of hyperalgesic patch induced by capsaicin and pain threshold and tolerance to electrical and thermal pain.Results: THC had no significant effect on capsaicin-induced allodynia, or pain threshold or tolerance to heat, cold, or electrical pain.Conclusions: THC has no antinociceptive effects in a variety of acute pain models in healthy volunteers. Given recent interest in medical marijuana, and legislated indications for pain control, further study in chronic pain patients (who show pain sensitization) is warranted.Keywords: cannabinoids, acute pain, capsaicin, THC, nociceptionSupported By: Department funds



831. Emphasis on Neurobiology Predicts Successful Family Psychoeducation for Borderline Personality DisorderOlivia Mandelbaum1, Valerie Porr2

1Clinical Psychology, Long Island University, Brooklyn, NY, 2Family PsychoEd, TARA National Association for Personality Disorder, New York, NY

Background: Current research demonstrates the importance of family psychoeducation as a supplement to treatment for Borderline Personality Disorder. In other words, research shows that when someone has BPD, the family can make a difference by acting as a therapeutic ally (Hoffman & Fruzzetti, 2007; Hoffman, Fruzzetti, & Buteau, 2007; Hooley, 2004). Still, the degree and quality of change within the family environment depends upon the type of psychoeducation, and especially relates to the kind of information received by families (Hoffman, Buteau, Hooley, Fruzzetti,& Bruce, 2003). This study examined outcome data from a program for BPD family members that emphasized teaching of underlying neurobiology.Methods: We used a retrospective self-report design to survey 74 family members who had previously participated in a class for BPD family members through the Treatment and Research Advancement Association for Personality Disorder (TARA-APD). The TARA class primarily focused on teaching family members BPD neurobiology. We assessed the extent to which family members were able to function as effective therapeutic allies who could help decrease the frequency and intensity of incidents involving BPD dysregulation.Results: We found significant decreases on many outcome measures assessing for intensity and frequency of incidents, including violent arguments, financial bailouts, police calls, suicide threats, avoidant behavior, and hospitalizations.Conclusions: These findings should be taken in support of the inclusion of neurobiology in psychoeducation training for BPD family members. It should also be considered further evidence for BPD family psychoeducation as an adjunct to treatment.Keywords: BPD, Neurobiology, Psychoeducation, Family, Personality

832. Asenapine Once Daily Dosing is Associated with Improved Effectiveness and Patient Acceptance as Compared to Twice Daily DosingXiaowei Sun, Joseph McEvoy

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC

Background: Asenapine is an oral second-generation antipsychotic that is administered sublingually. It has been released with FDA labeling for twice daily dosing of 5 to 10 mg bid. However, the terminal half-life of Asenapine is 24 hours and once daily dosing is likely to be effective in reducing psychopathology. In addition, once daily dosing is likely associated with improved patient acceptance relative to twice daily dosing.Methods: In order to investigate whether once daily dosing will alter Asenapine effectiveness as well as patient acceptance, we randomly assigned 17 patients, who had a psychotic exacerbation of schizophrenia or schizoaffective disorder, to up to 14 days of treatment with either Asenapine 5 mg BID or Asenapine 10 mg QHS. Brief Psychiatric Rating Scale (BPRS) were measured at baseline, day 3, day 7 and day 14 after receiving treatment to evaluate psychopathology of patients. Patient acceptance of the medication is rated as a scale of 1-7 with 1 as very acceptable and 7 as completely unacceptable.Results: 9 patients were randomly assigned to once daily dosing and 8 were assigned to twice daily dosing. In once daily group, 2 patients discontinued treatment before 14 days due to inadequate effect; whereas in twice daily group, 2 patients discontinued treatment due to inadequate effect and 3 patients discontinued treatment due to intolerable side effect such as daytime drowsiness. Patient acceptance scale is 2.0±0.73 (Mean±SE) in once daily group and 4.0±0.8

in twice daily group. BPRS in once daily group was reduced from 39.75±2.73 to 25.0±2.58 after Asenapine treatment. In twice daily group, BPRS was 37.5±1.7 at baseline and 32.8±3.5 after treatment.Conclusions: Our results indicate that Asenapine once daily dosing is associated with improved effectiveness, patient acceptance as compared to twice daily dosing. Further study is under investigation to determine whether this result could be applied to a larger patient population.Keywords: Asenapine, Dosing, Patient Acceptance, EffectivenessSupported By: Merck

833. A Placebo-Controlled, Single-Blind, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Drug Interaction Of GSK1034702 (M1 Receptor Agonist) After Repeat Doses in Healthy Subjects for Up to 28 DaysJesper Lund1, Gordon Dear2, Martin T. Lowy3, James Graham3

1Research & Development, Leo Pharma, Ballerup, Denmark, 2Platform Technology & Science, GlaxoSmithKline, Ware, United Kingdom, 3Neurosciences Therapy Area, GlaxoSmithKline, Durham, NC

Background: GSK1034702 is a potent allosteric agonist at cholinergic M1 receptors investigated for schizophrenia or cognitive impairment. The objective was to investigate safety, tolerability, and pharmacokinetics of GSK1034702; effect on CYP2D6 activity; effects on cognition; and effects on salivary secretion.Methods: GSK study MAA110792 was a single-blind, randomized, placebo-controlled, parallel group study. The study included 3 sequential cohorts (2 mg tablets, a 5 mg liquid and 5 mg tablets). Interaction with dextromethorphan (2D6 substrate) was investigated in the third cohort.Results: 42 subjects received GSK1034702 for up to 28 days. No deaths or serious adverse events occurred. Repeat doses up to 5 mg were well tolerated. Salivary hypersecretion increased with increased doses. Body temperature was increased on both 5 mg regimes with no correlation with symptoms of feeling hot. Increases of mean systolic and diastolic BP were observed on all doses of GSK1034702; however, no individual subject’s BP met criteria for clinical concern. All GSK1034702 dosages demonstrated a slight mean increase from baseline in QTcF, however the increase was not dose related. There was a slight increase in ALT and AST with repeat doses of 5 mg. Plasma accumulation of GSK1034702 was observed on all dosages. Single and repeat doses of GSK1034702 5 mg markedly increased exposure to dextromethorphan, suggesting that GSK1034702 is an inhibitor of CYP2D6. Both 5 mg regimes showed a decline in performance on CogState cognition tests although results were not consistent.Conclusions: Repeat doses of GSK1034702 were reasonably well tolerated. Frequencies of adverse events were higher with 5 mg.Keywords: cognition, schizophreniaSupported By: GlaxoSmithKlline

834. The Relationship of Social Cognition, to Neurocognition, Negative Symptoms and Social Functioning in Patients with SchizophreniaAnzalee Khan1, Mark Opler2, Jean-Pierre Lindenmayer1, Brian Rothman2, Luka Lucic2

1Psychopharmacology Research Program, Manhattan Psychiatric Center, Wards Island, NY, 2Research and Training Development, ProPhase LLC, New York, NY

Background: How does social cognition relate to neurocognition, negative symptoms and social functioning? The three areas of social cognition in schizophrenia include impairments in: affect perception; social perception; attributional style; and theory of mind (ToM). Social cognition encompasses



the interface of emotional and cognitive processing, while neurocognition is somewhat affect-neutral. However, negative symptoms could be a result of a similar affective processing deficit as social cognitive impairments. For example, anhedonia may contribute to subtypes of social cognitive deficits. Otherwise, lack of empathy may lie beneath deficits in ToM and also leading to negative symptoms. Little is known about whether social cognition, negative symptoms and neurocognition are independent dimensions of illness and if so, whether patients with schizophrenia can be categorized based on these dimensions (PANSS domain, MCCB-MATRICS).Methods: The current study used structural equation modeling: Are social cognition (measured by a dynamic social cognition scale) and neurocognition (measured by DSCB) displayed as separate constructs? Are social cognition and negative symptoms displayed as separate constructs? Is social cognition related to neurocognition or to negative symptoms?Results: Negative symptoms were associated with difficulties in ToM, non-verbal emotion perception and internal bias. Social cognition and neurocognition are distinct, however linked, concepts. Structural Equation showed a higher correlation between all domains of social cognition and negative symptoms as measured by the PANSS Negative domain. Analysis of social cognition and social functioning (PSP) are underway.Conclusions: Aims for future research should be the association of these deficits to certain clinical symptoms, and the relationship to clinical outcomes. Imaging studies may provide evidence of the connection or disconnection in the neural correlates between neurocognitive, negative symptoms and social cognition.Keywords: Negative Symptoms, Social Cognition, Schizophrenia, Neurocognition, Social Functioning

835. Clinical Characteristics in People with Schizophrenia Enrolling in a Clinical Trial with or without Lifetime Alcohol and Cannabis UseMaju Mathew Koola1, Robert P. McMahon1, Fang Liu1, David A. Gorelick2, Robert W. Buchanan1, Marilyn A. Huestis2, Jared Linthicum1, Stephanie Feldman1, Deanna L. Kelly1

1Psychiatry, Maryland Psychiatric Research Center, Baltimore, MD, 2Chemistry and Drug Metabolism, National Institute on Drug Abuse, Baltimore, MD

Background: Patients with a history of substance may have lingering effects of past use. The objective of this study was to compare baseline symptoms in people with schizophrenia with or without significant lifetime substance use during enrollment in a clinical study.Methods: Fifteen patients with schizophrenia were enrolled in a clinical trial who had stable symptoms, no current DSM-IV-TR substance dependence within the last six months and substance abuse within the last one month. Lifetime substance use history was collected with a modified Addiction Severity Index interview. Lifetime use was defined as ≥5 years of substance use. No/minimal use was defined as <5 years of lifetime substance use.Results: Ten of fifteen (67%) people enrolled were lifetime substance users. Positive symptoms were higher in those with lifetime substance use than in those without (9.6 ± 2.5 versus 5.7 ± 2.4, respectively; p=0.02). Brief Psychiatric Rating Scale negative symptoms were significantly lower in those with lifetime substance use than without lifetime substance (4.7 ± 1.3 versus 8.1 ± 2.3, respectively; p=0.01).Conclusions: Patients with schizophrenia and lifetime substance use had significantly more positive symptoms and fewer negative symptoms than patients without lifetime substance use. These findings suggest that more attention should be paid to past history of substance use in patients who do not have substance use disorder, a group that is typically eligible to enroll in clinical trials. In this study we show that the symptom profiles of these two groups may differ, resulting in different responses to treatment.Keywords: Schizophrenia, Substance use, Clinical symptomsSupported By: Supported by National Institutes of Mental Health (NIMH) grants R34 MH 077839 (PI Buchanan) and P30 068580 (PI Buchanan), the

Intramural Research Program, National Institute on Drug Abuse (NIDA), and NIDA Residential Research Support Services Contrac

836. A Positive Take on Schizophrenia Negative Symptoms Scales: Correlations and Formulas for Converting NSA, SDA and SANS ScoresAdrian Preda1, Theo G. M. van Erp1, Dana D. Nguyen1, Juan R. Bustillo2, Aysenil Belger3, Daniel O’Leary4, Sarah McEwen5, Daniel H. Mathalon6, Judith Ford6, Steven G. Potkin1, FBIRN1Psychiatry and Human Behavior, University of California Irvine, Orange, CA, 2Psychiatry, University of New Mexico, Albuquerque, NM, 3Psychiatry and Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 4Psychiatry, University of Iowa, Iowa City, IA, 5Psychology, University of California Los Angeles, Los Angeles, CA, 6Psychiatry, University of California San Francisco, San Francisco, CA

Background: Negative symptom severity in schizophrenia have been commonly measured with the Scales for the Assessment of Negative Symptoms (SANS), the Schedule for the Deficit Syndrome (SDS), the Negative Symptoms Assessment (NSA), and Negative Symptom Scale of the Positive And Negative Syndrome Scale (PANSS). However, despite the common use of these scales there is no direct conversion of scores that would allow the comparison of treatment effects, conducting meta-analyses or pooling of data across multiple data sets that use different negative symptom ratings measurements.Methods: 209 schizophrenia patients participating a multicenter brain imaging study (FBIRN) were assessed with the SANS, SDS and NSA. Group training sessions with experienced raters and videotape ratings were performed for comparisons with expert assessments to standardize ratings across sites. Mean scores and standard deviations were computed. Conversion formulas were derived based on linear regression analysis of these scores.Results: SDS_GLOBAL_SEVERITY (mean±SD=2.08±1.49), SANS (mean±SD=22.97±14.53) and NSA (mean±SD=2.95±1.49) were highly and significantly correlated (r=0.61 and 0.78, p<0.0001, respectively). Linear regression derived equations allowed for reliable score conversions. conversionsConclusions: Our results suggests these commonly used negative symptoms scales measure a similar construct, thus validating the concept of a separate negative symptoms core in schizophrenia. A negative symptoms conversion algorithm is essential in fostering meta-analysis studies that plan to examine negative symptoms as moderator variables, as well as for data pooling in multicenter studies using different negative symptom data from different rating scales.Keywords: schizophrenia, negative symptoms, NSA, SDS, SANSSupported By: Function Biomedical Informatics Research Network (NIH 1 U24 U24 RR021992) and the BIRN Coordinating Center (http://www.birncommunity.org; NIH 1 U24 RR025736-01).

837. Restoration of Omega-3 Status Among Aggressive Alcoholics: Effects on Neurotransmitter Metabolites, Affective Symptoms and Drinking BehaviorsJoseph R. Hibbeln1, John C. Umhau2, Sharon Majchrzak-Hong1, Norman Salem1

1Section on Nuritional Neurosciences, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, 2Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD

Background: Chronic alcohol dependence depletes omega-3 highly unsaturated fatty acids (n-3 HUFAs) including docosahexaenoic acids (DHA). Proposed mechanisms underlying efficacy for n-3 HUFAs in reducing aggressive and depressive symptoms include restoration of serotonergic and dopaminergic function.



Methods: After 3 weeks of inpatient treatment, n=99 alcohol dependent subjects with elevated Brown-Goodwin Lifetime aggressions scores were enrolled. After baseline tests, subjects were randomized to either 2 gm/dof n-3 HUFAs (n=48) or corn/soy oil placebo (n=48) for 16 weeks of supervised outpatient therapy and quantification of daily alcohol and drug use. After grouping by a priori compliance criteria, subjects either elevated (n=28 active+n=1 placebo, mean change), and or did not elevate (n=38 placebo+n=8 active ) n-3 HUFAs in cerebrospinal fluid (CSF) and blood.Results: Comparing groups in baseline and final assessments , there were no differences in CSF 5-hydroxyindolacetic acid or homovanillic acid concentrations, Hamilton depression, Speilberger State Trait Anger, Buss -Perry Aggression, Barrets Impulsivity, Perceived Stress Scores or NEO personality measures. Larger ventricle size (% total intracranial vol.) was correlated with lower plasma DHA concentrations (r=-0.42, p<0.0002) at baseline, but did not differ by treatment. A serendipitous finding was fewer drinking days among elevated n-3 HUFA subjects (3.2 d, 95%CI 2.5-4.9) compared to subjects (n=46) with unchanged n-3 HUFA’s (17.4 d/90, 95%CI 12.6-19.8) with an effect size of 0.84 (Hedges g), p<0.005.Conclusions: Sobriety had a large effect in reducing anger, impulsivity, stress and depression scores. Specific assessment of elevating n-3 HUFA compositions on reduction of alcohol relapse is warranted.Keywords: Omega-3, Alcohol, Aggression, Serotonin, Relapse

838. Attention and Positive Affect in Bipolar Disorder: An FMRI StudyThilo Deckersbach1, Andrew K. Corse1, Tina Chou1, 2, Amanda Arulpragasam1, Navneet Kaur1, Scott L. Rauch1, 3, Andrew A. Nierenberg1, Darin D. Dougherty1

1Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, 2Psychology, Harvard University, Cambridge, MA, 3Psychiatry, McLean Hospital, Belmont, MA

Background: Bipolar disorder is characterized by recurrent depressive and/or manic mood episodes that interfere with psychosocial functioning. A prominent feature of bipolar disorder is cognitive impairment, which contributes to impairments in psychosocial functioning. This study examined the impact of positive affect on neural networks involved in attention in patients with bipolar disorder with depressive symptoms.Methods: 40 individuals with DSM-IV bipolar-I disorder (23 females, HAMD: M=12.2, SD=6.6; YMRS: M=4.8, SD=5.1) and 34 healthy controls (15 females; HAMD: M=1.0; SD=1.4; YMRS: M=0.4; SD=0.9) matched for age and education (all right-handed) completed an affective attention task while undergoing fMRI. In the paradigm, subjects were shown three-digit numbers (100, 020 or 003). The task was to decide which number was different (e.g. 1 0 0 - correct answer = 1). The numbers were superimposed on affectively valenced pictures from the International Affective Picture System (IAPS; Lang, Bradley, & Cuthbert, 2005). Regions of activations with p<.001 are reported. Results: For the contrast positive-neutral, controls had higher activations in the striatum and the insula. Compared to controls, patients had higher activations in the prefrontal cortex (Brodmann Area [BA 47]), the inferior frontal gyrus (BA 45), and the parahippocampal gyrus.Conclusions: To our knowledge this is the first study that investigates the functional neuroanatomy of task irrelevant positive affect during concurrent completion of a cognitive task. There was increased activation for patients with bipolar disorder in frontal and temporal areas that may reflect emotional regulation processes during completion of the cognitive component of the attention task.Keywords: attention, positive affect, cognition, bipolar disorder, emotion regulationSupported By: K23 MH074895

839. BDNF Plasma Levels of Schizophrenic Patients Classified According to Their Cognitive Function in Comparison to Healthy SubjectsRodrigo Nieto1, Hernan Silva1, Manuel Kukuljan2, Cecilia Rojas3, Alejandra Armijo4, Ruben Nachar5, Alfonso Gonzalez5, Carmen Paz Castaneda5, Cristian Montes1, Cristian Aguirre1, Daniel Castillo4, Andrea Silva1

1Clinica Psiquiatrica Universitaria, Biomedical Neurosciences Institute (BNI), Universidad de Chile, Santiago, Chile, 2Laboratorio de Neurobiologia Celular y Molecular, Biomedical Neurosciences Institute (BNI), Universidad de Chile, Santiago, Chile, 3Facultad de Medicina, Universidad de Chile, Santiago, Chile, 4Programa de Antipsicoticos Atipicos, Instituto Psiquiatrico Dr. Jose Horwitz Barak, Santiago, Chile, 5Sector 1, Instituto Psiquiatrico Dr. Jose Horwitz Barak, Santiago, Chile

Background: Schizophrenia is characterized by positive, negative, cognitive and affective symptoms. Cognitive symptoms are important because they are significantly related to quality of life. Despite the relevance of cognitive symptoms, the study of the biological basis of this deficit is still insufficient. Several studies have linked BDNF not only to the pathogenesis of schizophrenia, but also to neuronal plasticity, learning, and memory.Methods: We measured BDNF plasma levels with ELISA in 20 subjects, 14 schizophrenia patients and 6 control group subjects, and we evaluated cognitive functioning with the Montreal Cognitive Assessment (MOCA).Results: We found significantly lower BDNF plasma levels in schizophrenia patients (2.1 ng/ml) in comparison to control subjects (3.2 ng/ml) (p = 0.03). We classified schizophrenia patients into two subgroups according to their performance in MOCA, and found that patients with a normal cognitive evaluation had significantly lower BDNF plasma levels (1.6 ng/ml) than control subjects (p = 0.02), but patients with cognitive deficit had no significant differences in BDNF levels (2.6 ng/ml) in comparison to controls (p = 0.27).Conclusions: Consistent with prior reports, BDNF plasma levels were lower in schizophrenic patients than in healthy subjects. However, the finding of lower BDNF levels in the subgroup of patients with a normal cognitive evaluation, instead of as expect in the subgroup with cognitive deficit, has not been previously reported and may add new information on the role of BDNF in schizophrenia.Keywords: BDNF, Schizophrenia, Cognition, Plasma, LevelsSupported By: Biomedical Neuroscience Institute (BNI)

840. Lack of Insight in Late-Life Schizophrenia: A Function of Illness Severity and Premorbid Intellectual FunctioningPhilip Gerretsen, Benoit H. Mulsant, Angela Y. Yiu, Eric Granholm, Mahesh Menon, Bruce G. Pollock, David C. Mamo, Tarek K. Rajji

Geriatric Mental Health Program, Centre for Addiction and Mental Health, Toronto, ON, Canada

Background: Impaired insight in schizophrenia is associated with executive dysfunction, IQ, and to a lesser degree attention. Aging may contribute to a decline in these cognitive functions. Thus, the relationship between cognition and insight in late-life schizophrenia may differ from that observed in younger adults.Methods: This study analyzed data collected from baseline assessments of individuals with schizophrenia, age ≥60 years, who particpated in a CBSST trial for older persons with schizophrenia. Insight was assessed using PANSS Insight and Judgment item (PG12) and the Birchwood Insight Scale (BIS). Pearson correlations were used to evaluate the bivariate associations between insight, cognition and cognitive insight (BCIS). A hierarchal regression analyis was performed to assess the degree to which tests of cognition explained impaired insight.



Results: Data from 59 participants were analyzed. PG12 item scores correlated with premorbid IQ (r=-0.554, p<0.001), TMT-B time (r=0.451, p=0.001), LNS raw score (r=-0.408, p=0.003), BACS raw score (r=-0.421, p=0.003), and CPT (r=-0.456, p=0.003). BIS did not correlate significantly with PG12 or measures of cognition. No significant relationship was found between insight and BCIS. Illness severity explained 20.1% (p=0.003) and premorbid IQ explained 23.4% (p<0.001) of the variance of PG12.Conclusions: Impaired insight in late-late schizophrenia appears to be, in part, a function of illness severity and premorbid IQ; and unexplained by conventional measures of cognition and cognitive insight. These findings suggest impaired insight is, in large part, independent of other cognitive measures in late-life schizophrenia and that any relationship that exists is accounted for by premorbid intelligence.Keywords: Insight, Schizophrenia, Geriatric, Elderly, PsychosisSupported By: AFP Innovation Fund

841. Maturation and Chronicity Impact on Brain Correlates Underlying Executive Function in Schizophrenia: An FMRI Exploratory StudyLaure Jaugey1, Sébastien Urben1, Pascal Vianin2, Pierre Marquet3, Eleonora Fornari4, Olivier Halfon1, Pierre Bovet2, Pierre Magistretti3, Laurent Holzer1

1Service Universitaire de Psychiatrie de l’Enfant et de l Adolescent, University of Lausanne, CHUV, Lausanne, Switzerland, 2Service de Psychiatrie Générale, University of Lausanne, CHUV, Lausanne, Switzerland, 3Centre de Neurosciences Psychiatriques, University of Lausanne, CHUV, Lausanne, Switzerland, 4Service de Radiologie, Centre Hospitalier Universitaire Vaudois, CHUV, Lausanne, Switzerland

Background: Prefrontal anomalies represent a core feature of Schizophrenia. The duration of illness (DOI) is mainly related to a reduction of prefrontal areas’ volume in adult patients. Furthermore, the prefrontal cortex matures until early adulthood. However, less is known about prefrontal metabolism of patients who develop schizophrenia during adolescence as well as DOI impact on prefrontal activity in adult with schizophrenia.Methods: Three patients groups were assessed with a verbal fluency task within an fMRI block design: 6 adolescents (mean age (mA)=16.5yrs±.05) with a schizophrenia spectrum disease (SCZ-ado group), 6 young adults patients (mA=21.5yrs) with a schizophrenia spectrum disease (SCZ-adu group); 6 adult patients (mA=38.3yrs) with a chronic schizophrenia spectrum disease (CH-SCZ group, DOI: 72-210mths).Results: The SCZ-adu when contrasted to the CH-SCZ demonstrated a greater recruitment of the inferior frontal gyrus (p. triangularis) and the superior medial gyrus while the CH-SCZ group revealed activations in a wide pattern of more posterior areas. The SCZ-adu when contrasted to SCZ-ado recruited more intensively the precentral gyrus and the temporal pole to resolve the fluency task. In contrast, the SCZ-ado showed greater activation of the insula, the thalamus and the hIP1.Conclusions: The comparison between the two adult groups shows a deleterious impact of chronic schizophrenia on frontal lobe activity. On the other hand, adolescents with schizophrenia adopt less frontal mediated strategic processes to resolve the fluency task and seem to privilege strategies mediated by semantic and language processes, perhaps due to the late maturation of the frontal lobe.Keywords: Schizophrenia, Chronicity, executive function, adolescence

842. DISC1 Gene Locus Disruption Impairs Corticostriatal Circuit FunctionSunil Kumar1, Dalton Hughes2, Brittany M. Katz1, Kinsley E. Johnson1, Lizhen Li3, Hanna Jaaro-Peled4, William C. Wetsel1, 5, 6, David Dunson7, Akira Sawa4, Kafui Dzirasa1, 5, 8, 9, 10

1Dept. of Psychiatry and Behavioral Sciences, Duke University, Duke University Medical Center, Durham, NC, 2Meyerhoff Scholarship Program, University of Maryland Baltimore, Baltimore, MD, 3Duke Institutes for Brain Sciences, Duke University, Durham, NC, 4Dept of Psychiatry and Behavioral Sciences, Johns Hopkins University, School of Medicine, Baltimore, MD, 5Duke Institutes for Brain Sciences, Duke University, Duke University Medical Center, Durham, NC, 6Dept. of Cell Biology, Duke University, Duke University Medical Center, Durham, NC, 7Dept of Statistical Sciences, Duke University, Durham, NC, 8Dept. of Bioengineering, Duke University, Duke University Medical Center, Durham, NC, 9Dept. of Neurobiology, Duke University, Duke University Medical Center, Durham, NC, 10Center for Neuroengineering, Duke University, Duke University Medical Center, Durham, NC

Background: Genetic variations in DISC1 (in particular, chromosomal translocation at [(1: 11)(q42.1;q14.3)] directly co-segregate with affective disorders including schizophrenia, bipolar disorder, and major depressive disorder. Cortico-striatal circuit dysfunction has been implicated in mediating symptoms across these illnesses; nevertheless, the role of the DISC1 gene locus plays in regulating these circuits remain to be clarified. In our current study, we investigate the effect of a DISC1 gene locus disruption on cortico-striatal circuit function using and auditory evoked potential (AEP) gating task.Methods: DISC1 locus disruption mutant (DISC1-MU) mice and their WT littermates (n=8-11 for each group) were chronically implanted with recording electrodes and in-vivo neurophysiological brain activity (LFP and unit activity) was recorded from prelimbic cortex (PrL) and dorsal medium striatum (DMS) while mice were subjected to a classic AEP gating test. Startle responses were also recorded in real-time and stored along with our neurophysiological data. Data was analyzed using customized matlab scripts.Results: The prepulse stimulus significantly reduced the induction of PrL beta (15-30Hz) oscillations by the startle stimulus in WT mice. Also low gamma (30-55Hz) PrL gating responses were significantly correlated with the behavioral gating response across WT mice (R = 0.74, P = 0.009 using linear regression). Finally, we found that PrL and DMS unit responses encoded sensorigating signals in the WT mice. These neurophysiological responses were altered in the DISC1-MU mice.Conclusions: Our results showed that disruption of the DISC1 locus is sufficient to disrupt normal physiological processing across cortical striatal circuits.Keywords: Disc1, Affect, PPI, Sensorimotor gating, CorticostriatalSupported By: Duke Institute of Brain Sciences

843. Spatiotemporal Imaging of Language Reveals Dissociations Between Prediction Generation and Belief Updating in SchizophreniaEllen Lau1, 2, 3, Kirsten Weber1, 2, Nate Delaney-Busch1, 2, Candida Ustine1,

2, Kristina Fanucci1, 2, Matti Hamalainen2, Gina R. Kuperberg1, 2, 3

1Department of Psychology, Tufts University, Boston, MA, 2Department of Psychiatry and Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, 3Department of Linguistics, University of Maryland, College Park, MD

Background: To make sense of the world, we continually generate predictions, updating our beliefs if these predictions are disconfirmed. A breakdown of this prediction-updating cycle may characterize schizophrenia. But where exactly does the breakdown occur? Can patients mobilize stored knowledge to generate new predictions? Or is main problem in integrating new information and using



it to update stored knowledge? Dissociating activity across these two phases is challenging because they cycle continuously and are inherently dependent on one another.Methods: We used ERP, fMRI and MEG to determine whether schizophrenia patients are able to use top-down strategies to generate semantic predictions. Using a semantic priming paradigm, we examined semantic facilitation under conditions of high versus low predictive validity, established by manipulating the proportion of semantically associated items across blocks.Results: Like controls, patients showed clear modulation of activity within the anterior temporal cortex between 300-500ms following the onset of associated words under conditions of high versus low predictive validity.Conclusions: Patients have the capacity to generate semantic predictions and use these predictions to facilitate semantic processing of upcoming words. We suggest that language processing abnormalities in schizophrenia arise primarily from a failure to recruit frontal and parietal cortices in response to words that disconfirm predictions in higher-order contexts (e.g. Kuperberg et al., 2008). Within the language system, an autonomous generation of memory-based predictions, with increased and prolonged activity within temporal cortices, may intrude upon production (positive thought disorder) and perception (auditory verbal hallucinations).Keywords: schizophrenia, language, prediction error, fMRI, MEG/ERPSupported By: R01 MH071635

844. Comparing Auditory Event Related Potential Deficits in Schizophrenia and Bipolar DisorderMei-Hua Hall1, Deborah L. Levy2, Dean F. Salisbury3, Bruce M. Cohen4, Mary Lohan1, Dost Öngür1, Jordan W. Smoller5

1Psychotic Disorders Division, McLean Hospital, Harvard Medical School, Belmont, MA, 2Psychology Research Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA, 3Clinical Neurophysiology Research Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, PA, 4Shervert Frazier Research Institute, McLean Hospital, Harvard Medical School, Belmont, MA, 5Psychiatric Genetics Program in Mood and Anxiety Disorders, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Background: Historically, bipolar disorder [BPD] and schizophrenia [SZ] have been considered distinct disorders with largely different etiologies. Growing evidence suggests that there are some overlapping genetic and environmental influences that contribute to risk for both of these disorders. Patients with SZ have shown robust deficits in measures of the auditory P300, N100, P200, and sensory gating event related potentials [ERP]. Less is known as to whether these ERP deficits are also present in patients with BPD. To address this issue, this study examined whether patients with BPD showed auditory deficits similar to those observed in SZ patients in a large cohort sample.Methods: One hundred fifty four patients with BPD (n=114) or schizoaffective bipolar (n=40) disorder, 76 patients with schizophrenia (n=50) or schizoaffective depressed type (n=26), and 117 control subjects were evaluated. P300, N100, P200 ERPs were elicited during an auditory discrimination task (20% 1000 Hz target tone, 80% 1500 Hz standard tone). Sensory gating was measured using a dual-click paradigm. Age, sex, and EEG equipment were included as covariates.Results: In all auditory measures, patients with BPD and SCZ showed similar deficits compared to healthy control subjects. No significant differences were found between the two patient groups.Conclusions: The results of this study provide supporting evidence of shared neurophysiological deficits in SZ and BPD. These dysfunction are relevant to early sensory processing, attention, working memory, information processing speed, and inhibitory mechanisms of the brain. The relationship of these shared deficits to shared genetic and environmental factors merits study.Keywords: schizophrenia, bipolar disorder, event related potentials, cognitive dysfunctionSupported By: 5K01MH086714

845. The Influence of Prefrontal and Striatal Dopaminergic Genes on Cognitive Control in High and Low SchizotypyCaroline Gurvich1, Stephanie Louise1, Tamsyn Van Rheenen2, Erica Neill1, Susan Rossell1, 2

1Monash Alfred Psychiatry research centre, Monash University, Melbourne, Australia, 2Brain and Psychological Sciences Research Centre, Swinburne University, Melbourne, Australia

Background: Healthy individuals with schizotypal features exhibit subtle cognitive deficits that are similar, although less severe, to the cognitive deficits observed in schizophrenia. Converging evidence from pharmacological investigations, genetic studies and schizophrenia research indicates an important influence of prefrontal and striatal dopaminergic systems in areas of cognitive control. The association between schizotypy and cognitive performance was explored in a sample of healthy adults in relation to polymorphisms in the COMT gene (rs4680) and the dopamine D2 receptor (DRD2) gene (rs6277) that are associated with prefrontal and striatal dopaminergic functioning, respectively.Methods: 91 healthy volunteers were assessed for schizotypy using the Oxford-Liverpool Inventory of Feelings and a median split on the Unusual Experience scale created high and low schizotypy groups. Cognitive performance was assessed across working memory (letter-number-span) and inhibition (STROOP). Genotyping of the val(158)met polymorphism of the COMT gene (met/met, met/val, val/val) and the C957T polymorphism of the DRD2 gene (TT, C/T, CC) was performed.Results: ANOVAs revealed a significant interaction between DRD2 C957T variants and high/low schizotypy on working memory (p=.008), with the poorest performance observed in the high schizotypy / TT group. There were no interactions observed between COMT variants and schizotypy on cognition.Conclusions: This research has shown that the functional polymorphism C957T (rs6277) on the DRD2 gene, that has been found to predict striatal DRD2 binding potential, interacts with schizotypy and influences working memory. This finding extends previous research that has independently linked striatal dopamine availability to schizophrenia, schizotypal features in healthy volunteers, and cognitive control.Keywords: Dopaminergic genes, cognition, schizotpy, COMT, DRD2Supported By: NHMRC

846. Transcranial Direct Current Stimulation and Sensory-motor Dysfunction in SchizophreniaPejman Sehatpour1, 2, Aleksandra Kaszowska1, Stephanie Rohrig1, Devin Adair1, Jamie Sanchez1, Michael Epstein1, Emily Parker1, Daniel C. Javitt1, 2

1Program in Schizophreniaand Cognitive Neuroscience, Nathan Kline Institute, Orangeburg, NY, 2Psychiatry, Columbia University, New York, NY

Background: Transcranial direct current stimulation (tDCS) is a technique for modulating local brain function by applying constant low (<2 mA) direct currents to corresponding regions of the scalp. It is noninvasive and can be repeated over time within the same subject, therefore representing a practical new treatment modality for schizophrenia and other neurocognitive disorders. We observed the effects of tDCS on modulating the activity in a critical cortical network engaged during a motor sequence task (MST) through an innovative combination of tDCS, behavioral measures and EEG data.Methods: 10 patients and 18 matched controls performed the MST (pressing four color-coded keys according to a prompted sequence) under three tDCS conditions: anodal, cathodal and sham. Simultaneous EEG recordings were acquired over all three sessions administered on different days. Multivariate analyses of variance (MANOVA) were performed to assess the modulations in task-relevant EEG changes (ERP) and reaction time (RT) behavior.Results: MANOVA revealed significant main effects of condition (F2,25 = 6.4,



p = 0.006) on ERP recorded over the motor scalp area as well as RT measures (F2,25 = 3.2, p = 0.05) across the groups.Conclusions: Characterization of the neurophysiologic changes brought about by tDCS greatly contributes to our understanding of mechanisms of neurocognitive deficits as well as this method of intervention. The present results indicate that tDCS brings about statistically significant modulations of task relevant behavior and electrophysiology in patients and controls and that the sensory-motor deficits observed in schizophrenia would be amenable to tDCS intervention.Keywords: Schizophrenia, tDCS, EEG, motor, sensorySupported By: P50 MH086385

847. SCN2A (RS10174400) Differentially Modulates Prefrontal Efficiency in N-Back Task in Healthy Adults and Schizophrenia PatientsGraham L. Baum1, Joseph H. Callicott1, Dwight Dickinson1, Daniel R. Weinberger2, 3

1Clinical Brain Disorders Branch, DIRP, National Institute of Mental Health, Bethesda, MD, 2Johns Hopkins Medical Campus, Lieber Institute for Brain Development, Baltimore, MD, 3Depts. of Psychiatry, Neurology, Neuroscience, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Medical Campus, Baltimore, MD

Background: SCN2A is a brain-specific gene that encodes the α2 subunit of neuronal sodium channels. Sodium channels play a pivotal role in facilitating the initiation and propagation of action potentials. This gene has previously been associated with a spectrum of epilepsies (Shi et al, 2012), while emergent findings suggest that minor allele homozygotes at SNP rs10174400 show significant increases in general cognitive ability (g) in healthy adults, but decreases in patients with schizophrenia (Dickinson et al., in process). We hypothesized that SCN2A would modulate prefrontal efficiency during the N-back working memory task in healthy adults and schizophrenia patients in this disease-specific manner.Methods: 401 healthy volunteers and 87 schizophrenia patients completed an N-back working memory task during a 3-Tesla MRI session. To assess the effect of SCN2A genotype (rs10174400) on prefrontal efficiency we performed two ANCOVAs using SPM5, one for each diagnosis group. Age, sex, and 2-back performance were included as nuisance covariates.Results: We found a main effect for SCN2A genotype on prefrontal cortex (PFC) efficiency in both groups. As with g, the minor allele conferred significant PFC efficiency for healthy subjects. In contrast, minor allele homozygotes with schizophrenia showed the opposite relationship - with maximum inefficiency.Conclusions: These findings suggest a differential effect of SCN2A on prefrontal efficiency and working memory between healthy adults and schizophrenia patients that mirrors effects seen for g. These data suggest that the relationship between PFC efficiency and g as modulated by SCN2A, as well as between SCN2A and schizophrenia, warrant further exploration.Keywords: Schizophrenia, fMRI, Working memory, Genetics, SCN2A

848. Clinical and Genetic Predictors of Response to Cognitive Remediation in SchizophreniaJean-Pierre Lindenmayer1, Anzalee Khan2, Lisa Hoffman2, Saurabh Kaushik2, Deborah Wance2, Zarif Taufiq2, Amod Thanju2, Susan McGurk3

1Psychiatry, New York University, Wards Island, NY, 2Psychiatry, Manhattan Psychiatric Center, Wards Island, NY, 3Psychiatry, Boston University, Boston, MA

Background: Factors predicting response to computerized cognitive remediation intervention are not well understood.Objectives: Neurocognitive, demographic, psychopathology variables, and Val108/28Met polymorphisms were investigated to predict response to a 12 week cognitive remediation intervention.

Methods: 125 patients with schizophrenia or schizoaffective disorder were genotyped. Clinical and neurocognitive variables were assessed at baseline and at endpoint. A binary logistic regression model for potential predictive variables was performed. The Reliable Change Index (RCI) was used to measure of improvement at the individual level in the context of observed changes over time. Patients were classified into improvers and non-improvers.Results: No significant demographic, neuropsychological or functional differences were seen between the 2 groups at baseline. Reliable improvement was predicted by age (p = .007), level of education (p = .020), scores on the Personal and Social Performance Scale (PSP; p = .034), attention/vigilance (p = 0.038), PANSS Negative Factor (p = 0.041), and COMT genotype.Conclusions: Younger age, higher education, lower baseline scores on the PSP, lower scores on attention/vigilance at baseline, lower scores on the Negative Symptom domain and the presence of the Met allele (p = .010) predicted better performance.Keywords: Cognitive Remediation, Predictors, Genetic predictors, Clinical predictors, SchizophreniaSupported By: NIMH

849. The Dynamic Social Cognition Scale (DSCB): A Novel Scale for Assessing Domains of Social Cognition in Patients with SchizophreniaMArk Opler1, Anzalee Khan1, Brian Rothman1, Luka Lucic2, Christian Yavorsky3, Jacob White4

1Psychopharmacology Research Program, Manhattan Psychiatric Center, Wards Island, NY, 2Research and Training Development, ProPhase, New York, NY, 3Clinical Director, CroNOS CCS, Hamilton, NJ, 4Media Department, ProPhase, New York, NY

Background: Social cognition has been broadly studied in autism spectrum disorders, and includes impairments in: affect perception; social perception; attributional style; and theory of mind (ToM). Abnormalities in emotion processing are linked to cognitive deficiencies of schizophrenia. Dynamic facial stimuli, as opposed to static images, may be more precise measures of performance because they are more near to what is observed in everyday life. Ecological validity of such stimuli is debatable. There is growing evidence of specialized brain systems that are preferentially activated by “biological motion” stimuli (including moving faces) giving further support to the need for dynamic stimuli. Objectives: (1) To describe a toolkit to assess social cognition utilizing dynamic images for: Emotion Perception, ToM: Dynamic Image Theory of Mind Scale, Test of Attributional Styles. (2) To assess the intraclass correlation, concurrent validity, internal consistency and sensitivity to change of the DSCB.Methods: All participants completed both dynamic and static social cognitive tests. ANOVAs and t-tests were performed for comparison of static (FEDT, FEIT, ER-40) and dynamic faces (DSCB) and a two-way ANOVA (emotion state x display type) varied across emotion states for accuracy rates.Results: Preliminary analysis was performed on 20 patients with schizophrenia. The dynamic images were ≥ 80% accurate for correct emotion. Schizophrenics were more successful in recognizing emotional states presented in dynamic images than static images. The intraclass correlation, concurrent validity and internal consistency of the scales was high (≥ 0.85). High correlations were observed between the change in DSCB domains and change in social functioning as assessed by the DSCB.Conclusions: Because looking at static faces only occurs when looking at photographs, an emotion perception task using dynamic images is more generalizable to everyday functioning, and may be more linked to the performance on work and social activities in schizophrenia.Keywords: Social Cognition, Dynamic emotion processing, schizophrenia, theory of mind, emotion statesSupported By: ProPhase LLC



850. Mismatch Negativity Abnormalities Are Associated with Poorer Functioning in Youth at Clinical High Risk for Psychosis: Evidence from the NAPLS StudyRachel A. Hay1, 2, Brian J. Roach1, 2, Suneth S. Attygalle1, 2, Kristin Cadenhead3, Ricardo Carrion4, Peter Bachman5, Jason Johannesen6, Erica Duncan7, Aysenil Belger8, Margaret Niznikiewicz9, Robert W. McCarley9, Gregory Light3, Neelan Pillay10, Jean Addington11, Tyrone Cannon12, Barbara Cornblatt4, Thomas McGlashan6, Diana Perkins8, Larry Seidman9, Ming Tsuang3, Elaine Walker13, Scott Woods6, Franc Donkers8, NAPLS Consortium, Daniel H. Mathalon1, 2

1Psychiatry, San Francisco VA Medical Center, San Francisco, CA, 2Psychiatry, University of California, San Francisco, San Francisco, CA, 3Psychiatry, University of California, San Diego, San Diego, CA, 4Psychiatry, Zucker Hillside Hospital, New York, NY, 5Psychiatry, University of California, Los Angeles, Los Angeles, CA, 6Psychiatry, Yale University, New Haven, CT, 7Psychiatry, Emory University and Atlanta VAMC, Atlanta, GA, 8Psychiatry, University of North Carolina, Chapel Hill, NC, 9Psychiatry, Harvard University, Boston, MA, 10Clinical Neurosciences, University of Calgary, Calgary, AB, Canada, 11Psychiatry, University of Calgary, Calgary, AB, Canada, 12Psychology, Yale University, New Haven, CT, 13Psychology, Emory University, Atlanta, GA

Background: Neurophysiological abnormalities in auditory deviance processing, as reflected by the mismatch negativity (MMN) ERP component, have been observed both in schizophrenia and in individuals at clinical high risk (CHR) for psychosis. In schizophrenia, MMN deficits have been further associated with poor functioning, as measured by the Global Assessment of Functioning (GAF) scale. We asked whether MMN deficits are also associated with poor social and role functioning in CHR youth.Methods: MMNs were derived from electroencephalographic recordings in response to 3 types of auditory deviants (pitch, duration, and dual pitch+duration) in 281 CHR patients and 156 healthy controls (HC) as part of the multi-site NAPLS study. Global, social, and role functioning were assessed using GAF, GAF-Social, and GAF-Role scales, respectively.Results: In CHR patients, poor role functioning was associated with reduced MMN amplitudes for all deviant types, and poor social functioning was associated with reduced duration MMN (p<0.05). While no relationship was seen between current GAF and MMN, highest GAF in the past year was associated with reduced duration and dual deviant MMN (p<0.05). When CHR social and role functioning scores were split based on the median, MMN did not differentiate high functioning CHR patients from HC, but both groups differed significantly (p<0.05) from low functioning CHR patients.Conclusions: MMN deficits are associated with poorer social/role functioning in CHR patients prior to psychosis onset and are not evident in high functioning CHR patients. MMN is sensitive to functional impairment across the clinical course of schizophrenia, from CHR to chronic states.Keywords: Mismatch negativity, Schizophrenia, Social Function, Prodrome, High RiskSupported By: NIMH U01-MH082022

851. Does Targeted Social Cognitive Training Enhance Cortical and Subcortical Activation in Schizophrenia During Reward ProcessingKaruna Subramaniam1, Srikantan Nagarajan2, Christine Hooker3, Sophia Vinogradov1

1Department of Psychiatry, UCSF, San Francisco, CA, 2Department of Radiology and Biomedical Imaging, UCSF, San Francisco, CA, 3Department of Psychology, Harvard, Cambridge, MA

Background: Schizophrenia patients (SZ) suffer from deficits across a range of cognitive, social and affective processes, including impairments in reward processing and motivated behavior. In the present study, we examined whether targeted training of social cognitive processes would enhance behavioral performance and brain activation patterns during reward processing on a monetary incentive delay (MID) task.Methods: SZ and healthy comparison subjects (HC) performed a MID task during fMRI scanning at baseline. Patients then received approximately 80 hours of computerized social cognitive training over 16 weeks. Subjects underwent a second fMRI session after training was completed.Results: At baseline, during monetary reward incentive trials versus non-incentive trials, HC subjects showed increased activation in the right middle frontal gyrus and the insula/putamen during the cue phase, signaling anticipation of reward. During the feedback phase, signaling reward outcome, HC subjects revealed activation in the insula/putamen and caudate. By contrast, SZ patients showed impaired performance compared to HC subjects, and blunted activation in insula/putamen during both the reward incentive cue and feedback phases. Preliminary data indicate that after 16 weeks of social cognitive training, SZ subjects show increased activation in insula/putamen during both the reward incentive cue and outcome phases, similar to what is seen in HC subjects.Conclusions: The present findings suggest that computerized social cognitive training may “normalize” some of the disrupted patterns of neural activity in schizophrenia subjects, with these subjects showing increased activation in the appropriate neural networks during both anticipation of reward and during reward outcome after the intervention.Keywords: fMRI, schizophrenia, monetary incentive delay task, reward processing, cognitive trainingSupported By: R01MH082818

852. Between Site Reliability of Startle Prepulse Inhibition Across Two Early Psychosis ConsortiaKristin Cadenhead1, Jean Addington2, Tyrone Cannon3, Barbara Cornblatt4, Camilo de la Fuente5, Daniel Mathalon6, Thomas McGlashan7, Diana Perkins8, Larry Seidman9, Ming Tsuang1, Elaine Walker10, Scott Woods7, North American Prodromal Longitudinal Studies Consortium, University of California Institute for Mexico andthe United States1Psychiatry, University of California San Diego, La Jolla, CA, 2Psychiatry, University of Calgary, Calgary, AB, Canada, 3Psychology, Yale University, New Haven, CT, 4Psychiatry, Zucker Hillside, Long Island, NY, 5Psychiatry, Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico, 6Psychiatry, University of California San Francisco, San Francisco, CA, 7Psychiatry, Yale University, New Haven, CT, 8Psychiatry, University of North Carolina, Chapel Hill, NC, 9Psychiatry, Harvard University, Cambridge, MA, 10Psychology, Emory Universtiy, Atlanta, GA

Background: Startle prepulse inhibition (PPI) and reactivity are important biobehavioral markers in psychopathology research. Previous studies have shown that PPI and startle reactivity are stable over repeated within site assessment but between site reliability of startle measures has not been established. In two separate consortia investigating early psychosis, traveling subjects studies were



performed as part of quality assurance procedures and to establish fidelity of data across sites.Methods: In the North American Prodromal Longitudinal Studies (NAPLS) Consortium, 8 normal subjects traveled to each of the 8 NAPLS sites and were tested twice at each site on the startle PPI paradigm. In preparation for a binational study that included the startle paradigm, 9 healthy subjects were assessed twice in both San Diego and Mexico City.Results: Intraclass correlations between and within sites were significant for PPI and startle response magnitude (0.34-0.98, p’s<0.05), confirming the reliability of startle measures across sites in both consortia. There were between site differences in startle magnitude in the NAPLS study that did not appear to be related to methods or equipment.Conclusions: In planning multi-site studies, it is essential to institute quality assurance procedures early and establish between site reliability to assure comparable data across sites.Keywords: startle, prepulse, magnitude, reliabilitySupported By: U01 MH081944, R01 MH60720 and K24 MH76191; UCMEXUS

853. Stable Cognitive Control Deficits in First Episode Schizophrenia: A One-Year Longitudinal FMRI StudyTyler A. Lesh1, Tara A. Niendam1, Jong H. Yoon1, Michael J. Minzenberg1, J. Daniel Ragland1, Marjorie Solomon2, Cameron S. Carter1

1Psychiatry, University of California, Davis, Sacramento, CA, 2MIND Institute, University of California, Davis, Sacramento, CA

Background: While cognitive control deficits are consistently observed in patients with schizophrenia (SZ), few studies have examined the course of cognitive control performance and associated fronto-parietal activity longitudinally in first episode samples. Such longitudinal studies are critical for understanding the early course of illness progression and differentiating between models of proximal or progressive neuropathology. Using the AX-CPT, we anticipated that SZ patients would show performance deficits and reduced dorsolateral prefrontal cortex (DLPFC) activation compared to healthy controls (HC) at intake as well as stably persisting deficits at follow-up.Methods: SZ (n=29) and HC (n=43) were identified from referrals to the UC Davis EDAPT clinic and completed the AX-CPT at intake and one year follow-up. Functional magnetic resonance imaging (fMRI) data were obtained on a 1.5T GE scanner, and analyses were conducted (SPM8) for the whole brain and regions of interest (i.e., DLPFC).Results: SZ participants showed a stable pattern of poor cognitive control performance (higher BX errors and lower d’-context scores) as well as reduced activation in DLPFC under conditions of high cognitive control compared to HC across both time points.Conclusions: SZ participants showed a stable pattern of cognitive control impairment and reduced prefrontal cortex recruitment at baseline and one year later. These data suggest that prefrontally-based cognitive deficits are present very early on in the disorder and remain stable over time. These data are in contrast to alternative views that propose a course of progressive neurodegeneration in patients with schizophrenia. Relationships with clinical symptomatology will also be explored.Keywords: AX-CPT, longitudinal, fmri, schizophrenia, dlpfcSupported By: 5R01MH059883

854. Multi-Site Investigation of Impaired Prefrontal Functioning as a Potential Marker of Long-Term Outcome in Psychosis Risk StateTara A. Niendam1, J. Daniel Ragland1, Erin Floyd1, Andrea Auther2, Barbara Cornblatt2, Steven Adelsheim3, Rod Calkins4, Ryan Melton4, Tamara Sale4, Elizabeth Spring-Nichols5, Stephen Taylor6, William Cook7, William McFarlane7, Cameron S. Carter1

1Psychiatry & Behavioral Sciences, University of California, Davis, Sacramento, CA, 2Feinstein Institute for Medical Research, Zucker Hillside Hospital, Long Island, NY, 3Psychiatry, University of New Mexico, Albuquerque, NM, 4EAST Program, Mid-Valley Behavioral Healthcare Network, Salem, OR, 5Youth Services, Washtenaw Community Health Organization, Ypsilanti, MI, 6Psychiatry, University of Michigan, Ann Arbor, Ann Arbor, MI, 7PIER Program, Maine Medical Center, Portland, ME

Background: It is unclear how changes in prefrontal lobe structure and functioning manifest and effect functioning prior to psychosis onset. A multi-site study used a computerized cognitive control measure (AXCPT) to examine prefrontal function in individuals selected to be on a continuum of psychosis risk, including clinical high risk for psychosis (CHR), early psychosis (EP), and help-seeking/no syndrome controls (HS/NS). We hypothesized CHR and EP individuals would show more severe deficits on the AXCPT relative to HS/NS, and such impairments would be associated with poorer CHR outcome.Methods: CHR (n=143), EP (n=13), and HS/NS (n=61) participants from six Early Detection Intervention for the Prevention of Psychosis Program (EDIPPP) sites completed the AXCPT during baseline behavioral testing and clinical follow up after 24 months. Fifty-two percent (n=112) of participants also completed the AXCPT at 24-month follow up.Results: All participants demonstrated impaired cognitive control performance on the AXCPT at ascertainment. Poorer cognitive control at baseline was associated with future conversion to psychosis (n=7). Further, poor outcome - including conversion to psychosis or persistent attenuated symptoms - was associated with stable impairment in cognitive control over follow up. Improvement in cognitive control was associated with better clinical and functional outcome across all groups.Conclusions: Poor cognitive control may represent a stable warning indicator for those at highest risk for future psychotic illness. However, a subset of individuals show improvement in cognition associated with dynamic changes in clinical/psychosocial functioning. Findings support early intervention strategies targeting cognition across the psychosis continuum.Keywords: Prodrome, Schizophrenia, High risk, Outcome, cognitive controlSupported By: Robert Wood Johnson Foundation, NIMH 1K23MH087708-01A1 to TAN, NIMH 5R01MH059883 to CSC

855. Memantine Effects on Matrics Consensus Cognitive Battery Performance in Healthy Adults and Schizophrenia PatientsHsun-Hua Chou1, Savita G. Bhakta1, 2, Jo A. Talledo1, Sarah N. Lamb1, Bryan Balvaneda1, Gregory A. Light1, Elizabeth W. Twamley1, Neal R. Swerdlow1

1Dept of Psychiatry, University of California, San Diego, La Jolla, CA, 2Psychiatry, VISN-22 MIRECC, VAHCS, San DIego, La Jolla, CA

Background: Cognitive deficits contribute to functional disability in schizophrenia. Memantine is a partial NMDA antagonist and pro-cognitive agent; reports differ in its effects on schizophrenia symptoms. We tested the effects of memantine on MATRICS Consensus Cognitive Battery (MCCB) performance in healthy individuals (NCS) and schizophrenia patients.Methods: The effects of 10 mg memantine on MCCB performance (T-scores for composite (Comp) and 7 domains: speed of processing (SP), attention/vigilance (A/V), working memory (WM), verbal learning (VerL), visual learning (VisL),



reasoning/problem solving (R/PS), and social cognition (SC)) were evaluated in 15 NCS and 20 schizophrenia patients in an ongoing, double-blind, placebo-controlled crossover design.Results: At baseline, significant performance deficits were detected in patients in the MCCB Comp score (p<0.0015), and in domains of SP, A/V, WM, VisL and VerL (p’s < 0.05-0.0005). In patients, Comp scores correlated significantly with GAF (Global Assessment of Function) scores (p<0.02), as did scores for VerL (p<0.02) and SC (p<0.05). ANOVA of MCCB revealed significant effects of diagnosis (p<0.002) and domain (p<0.0001), and a significant interaction of dose x domain (p<0.045), reflecting small effect size increases (VerL (d=0.28)) and decreases (VisL (d=0.22)) across domains in both NCS and patients.Conclusions: A single, acute dose of memantine did not significantly alter composite MCCB scores, but tended to elevate domain scores (VerL) most associated with global function in patients. We are presently studying effects of higher memantine doses on MCCB performance in patients, and will assess the ability of memantine to augment the therapeutic impact of cognitive interventions.Keywords: memantine, neurocognition, schizophrenia, MATRICS, PACTSupported By: R34MH093453; R01MH094320; R01MH059803; T32MH018399; APF/Merck Award

856. Reduced Amplitude of Low Frequency Bold Fluctuations in Resting State FMRI is AssociatedwWith Attention Deficits in Schizophrenia: Evidence from the FBIRN StudyMichael Brandel1, 2, Judith M. Ford1, 2, Jessica A. Turner3, Theodorus G. Van Erp4, James Voyvodic5, Adrian Preda4, Aysenil Belger6, Juan Bustillo7, Daniel O’Leary8, Bryon Mueller9, Kelvin O. Lim9, Sarah C. McEwen10, Vince D. Calhoun3, 11, Michelle Diaz5, Gary Glover12, Douglas Greve13, Cindy Wible14, Jatin Vaidya8, Steven G. Potkin4, FBIRN, Daniel H. Mathalon1, 2

1Psychiatry, University of California, San Francisco, San Francisco, CA, 2Mental Health, San Francisco VA Medical Center, San Francisco, CA, 3Psychiatry, Mind Research Network, Albuquerque, NM, 4Psychiatry, University of California, Irvine, Irvine, CA, 5Psychiatry, Duke University, Raleigh-Durham, NC, 6Psychiatry, University of North Carolina, Chapel Hill, NC, 7Psychiatry, University of New Mexico, Albuquerque, NM, 8Psychiatry, University of Iowa, Iowa City, IA, 9Psychiatry, University of Minnesota, Minneapolis, MN, 10Psychiatry, University of California, Los Angeles, Los Angeles, CA, 11Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM, 12Radiology, Stanford University, Stanford, CA, 13Radiology, Massachusetts General Hospital, Boston, MA, 14Psychiatry, Harvard University, Boston, MI

Background: Correlations of low frequency BOLD signal fluctuations between brain regions in resting state FMRI (rsFMRI) have defined multiple intrinsic connectivity networks (ICNs). However, while the amplitude of these low frequency fluctuations (ALFF) is thought to reflect variation in spontaneous neural activity, its functional significance remains unclear. ALFF reductions have been observed in unmedicated schizophrenia patients and shown to increase with clinical improvements following antipsychotic treatment. However, the neurocognitive implications of reduced ALFF in schizophrenia are unknown. Accordingly, we examined ALFF in 3 ICNs known to interact in the service of higher order cognition: Central Executive Network (CEN), Ventral Default Mode Network (VDMN), and Anterior Salience Network (ASN). We asked whether ALFF within these ICNs was associated with attentional impairments in schizophrenia.Methods: Schizophrenia patients (SZ; n=92) and healthy controls (HC; n=80) underwent rsFMRI as part of the multi-site FBIRN study. Fractional ALFF (fALFF; amplitude of low frequencies relative to all frequencies) was calculated for a priori CEN, VDMN, and ASN networks and correlated with accuracy scores (d-prime) from the Continuous Performance Test-Identical Pairs Version (CPT-IP).Results: Relative to HC, SZ showed reduced fALFF across all 3 ICNs and impaired CPT-IP performance (p<.001). Reduced fALFF was significantly

associated with reduced CPT-IP scores in SZ but not HC for all 3 ICNs (all slope differences p<.05).Conclusions: Reduced fALFF was evident in SZ patients in 3 key neurocognitive ICNs, the CEN, the VDMN, and the ASN. These fALFF reductions were associated with poorer sustained attention in SZ but not in HC.Keywords: Resting State fMRI, Schizophrenia, Attention, Amplitude of Low Frequency Fluctuations, Default ModeSupported By: NIH U24 RR021992

857. Heterogeneity in Cognitive Improvement After Intensive Cognitive Training in SchizophreniaSophia Vinogradov

University of California, San Francisco VA Medical Center, San Francisco, CA

Background: Schizophrenia is characterized by dysfunction in the distributed neural systems that subserve verbal memory. We have found that 40-50 hours of “neuroplasticity-based” cognitive training of auditory and verbal learning processes can drive significant improvement in verbal memory and global cognition in patients. A range of responses is observed, with approximately 65% of patients showing an improvement > 0.2 SD on a Global Cognition summary score.Methods: We report here on genetic, behavioral, and neuroimaging findings that are associated with a positive cognitive response to this form of cognitive training.Results: Individuals with the A/A genotype of the COMT variant rs165599 show statistically significant greater improvement in cognition after training than those with the G/G or A/G genotype. Baseline factors such as age, IQ, symptom severity, gender, and cognition do not show an association with treatment outcome. However, self-ratings on the Behavioral Activation Scale do show a positive association with cognitive improvement, even after controlling for hours of training. Gains in auditory processing speed in the first 20 hours of training predict increases in Global Cognition after the intervention. Finally, reduced resting state functional connectivity in the alpha band in prefrontal and parietal regions (measured via magnetoencephalography) shows a significant correlation with improvement in cognition.Conclusions: Taken together, these data indicate that it should be possible to identify specific genetic, behavioral, and neural system bio-signatures that predict an individual’s “plasticity capacity” in terms of response to this form of cognitive training and in so doing, provide a window into the underlying heterogeneity of schizophrenia.Keywords: schizophrenia, cognition, cortical plasticity, cognitive trainingSupported By: RO1MH068725

858. Self-Reflection in Adolescents with Transient Psychotic Symptoms; An FMRI StudyMartin Debbané1, Marine Lazouret1, Pascal Vrticka1, Deborah Badoud1, David Sander1, Stephan Eliez2

1Psychology, University of Geneva, Geneva, Switzerland, 2Psychiatry, University of Geneva, Geneva, Switzerland

Background: Clinical and phenomenological accounts of schizophrenia suggest that impairments in self-reflective processes significantly contribute to pathological expression. Recent imaging studies observe atypical cerebral activation patterns during self-reflection, both in psychosis-prone adults and individuals with schizophrenia. Given that self-reflection processes consolidate during adolescence, and that early transient expression of psychosis (schizotypy) also arises during this period, the present study sought to examine whether atypical cerebral activation during self-reflection task could be associated with early schizotypic expression during adolescence.Methods: Forty-two neurotypical adolescent participants (19 females) aged from 12 to 19 (19.92±1.9) underwent a self-reflection task using functional neuroimaging (fMRI), where they had to evaluate trait adjectives (1 to 4 ratings) about themselves or their same sex best friend. The Schizotypal



Personality Questionnaire (SPQ) and Cardiff Anomalous Perceptions Scale (CAPS) were employed to assess schizotypic expression.Results: Results showed that schizotypic dimensions significantly correlated withcerebral activation patterns comparable to those observed in psychosis-prone adults. Importantly however, gender appeared to moderate these associations. In female adolescents, positive schizotypy was associated with activation in the left superior frontal gyrus (SFG) and right lateral prefrontal cortex (PFC). In male adolescents, ventromedial PFC, insula and SFG activations were associated with positive schizotypy.Conclusions: The results are consistent with previous imaging literature on self-reflection and schizophrenia. They further highlight that the relationship between self-reflection processes and schizotypic expression can observed as early as adolescence. Important gender differences may inform early prevention strategies targeting self-reflection processes.Keywords: Positive symptoms, cerebral connectivity, gender, prefrontal cortex, selfSupported By: Swiss National Fund for Research (100014- 135311/1)

859. Efficiency Measures in Schizophrenia Suggest Differential Speed-Accuracy Trade-Off During Saccade PerformanceLingxi Chi1, Benjamin Austin2, Cynthia Krafft1, Qingyang Li3, Amanda Rodrigue1, Kara Dyckman1, Jennifer E. McDowell1

1Department of Psychology, University of Georgia, Athens, GA, 2Wisconsin ADRC Imaging Group, University of Wisconsin, Madison, WI, 3Child Mind Institute, Child Mind Institute, New York City, NY

Background: Cognitive control is critical for successful execution of goal-oriented behaviors and can be assessed using various types of saccade measures, including complex antisaccades, as compared with basic prosaccades. People with schizophrenia are similar to healthy subjects on prosaccade task performance but differ on antisaccade task by error rate and reaction times. Within-group data, however, suggest that fewer errors often cluster with slower reaction times. In this study, the speed-accuracy trade-off is quantified as “task efficiency” (Oosterlann et al., 1998). These analyses were conducted to evaluate saccadic task efficiency changes with task practice in normal and schizophrenia participants.Methods: Participants diagnosed with schizophrenia (sz; n=20) and healthy participants (hp; n=24) were tested at pre- and post-test using the same pro- and anti-saccade paradigms. Inbetween they practiced one assigned task daily - either prosaccades (sz=9, hp=12) or antisaccades (sz=11, hp=12). Task efficiency was calculated as the ratio of percent correct over correct reaction time. Group by time two-way ANOVAs with a repeated measure factor were conducted.Results: In the antisaccade condition, efficiency increased in both groups, although it was greater in the healthy group. In the prosaccade practice condition, efficiency increased to a greater extent in the healthy group than in the schizophrenia group.Conclusions: These preliminary results suggest that saccadic efficiency improves as a result of task practice, with the healthy group more than the schizophrenia group. Efficiency may be a particularly useful variable for evaluating whether people with schizophrenia show a similar speed-accuracy trade-off as healthy people.Keywords: schizophrenia, Saccade Efficiency, Speed-accuracy trade-off, PracticeSupported By: MH076998 MH001852

860. Clozapine Tolerance is Mediated by 5-HT2A/2C Receptors in the Medial Prefrontal CortexJun Gao

Psychology Department, University of Nebraska-Lincoln, LINCOLN, NE

Background: Repeated clozapine treatment is known to cause a tolerance effect in various animal behavioral tests, including the conditioned avoidance response model (CAR). Our previous systemic pharmacological study suggests that

this long-term effect of clozapine is likely mediated by 5-HT2A/2c and D2/3 receptors. The present study investigated the central receptor mechanisms of clozapine tolerance, focusing on the medial prefrontal cortex (mPFC).Methods: Forty-eight well-trained rats were systemically administered clozapine (10.0 mg/kg, s.c.) following by central injections of saline, or 5-HT2A/2C agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI, 5.0, and 25.0 µg/side) into the mPFC. Their conditioned avoidance responses were tested daily for 5 consecutive days. After 2 days of drug-free retraining, the clozapine tolerance effect was assessed in a challenge test in which all rats were injected with clozapine (10.0 mg/kg).Results: Results show that DOI (5.0 or 25.0 µg/side) in mPFC did not reverse the acute clozapine induced disruption of avoidance through the 5 drug-testing days (all p>0.05). In the challenge day, repeated DOI dose-dependently attenuated the tolerance-like effect of clozapine (5.0 µg/side, p=1.000; 25.0 µg/side, p=0.007).Conclusions: These findings suggest that the chronic (not acute) effects of clozapine are mediated by 5-HT2A/2C agonism initiated neural processes in the mPFC. The clozapine-induced tolerance effect in the CAR may have implications for its unique clinical effects in the treatment of schizophrenia.Keywords: 5-HT2A/2C receptor, medial prefrontal cortex, clozapine, conditioned avoidance response, toleranceSupported By: R01MH085635

861. Attentional Modulation of Sensory Signals in First Hospitalized PsychosisDean F. Salisbury

Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA

Background: The N1/P2 (vertex) evoked potentials are reduced at first hospitalization for schizophrenia. Augmentation of the N1 response by attention has been shown to be abnormal in chronic schizophrenia (and chronic bipolar disorder). Here we examined the effects of attention on N1 and P2 in first hospitalized psychosis.Methods: 340 standard 1000 Hz tone pips (50 ms, 5 ms rise/fall, 73 dB) and 60 target 1200 Hz pips were presented with a 1 sec ISI (± 200 msec balanced jitter). Subjects attended (counting the targets) or ignored the stimuli (watching a silent video). Fifteen controls, 11 first hospitalized schizophrenia subjects, and 9 first hospitalized manic psychosis subjects, matched for age, participated.Results: Both first hospitalized psychotic patient groups showed significantly reduced N1/P2 responses compared to controls with and without attention. Control participants and first hospitalized bipolar participants modulated their N1 and P2b with attention, with larger amplitudes when tones were attended. First hospitalized schizophrenia subjects showed no modulation of their vertex potentials by attention.Conclusions: These results replicate reductions of N1 and P2 to standard tones on an auditory oddball task in first hospitalized schizophrenia, and show that the reductions are also present in first hospitalized manic psychosis. However, first episode schizophrenia and mania differed in the ability to modulate the N1 and P2 with top-down attention. It is possible that disease trajectories for attentional modulation of sensory gain or inhibitory weight may differ early in the disease course.Keywords: first episode psychosis, sensory ERPs, attention, schizophrenia, bipolar disorderSupported By: NIH R01MH58704



862. Epistasis Between COMT Val(158)Met and DRD3 SER(9)Gly Polymorphisms on Cognitive Function of Individuals with SchizophreniaAlexandre A. Loch, Martinus T. van de Bilt, Danielle S. Bio, Carolina M. do Prado, Rafael T. de Sousa, Leandro L. Valiengo, Ricardo A. Moreno, Marcus V. Zanetti, Wagner F. Gattaz

Institute of Psychiatry, University of Sao Paulo, São Paulo, Brazil

Background: The present study aimed to determine the influence of cathecol-O-methyl-transferase(COMT) Val158Met and dopamine receptor D3 (DRD3) Ser9Gly polymorphisms on cognitive functioning of individuals with schizophrenia and controls.Methods: Fifty-eight outpatients with schizophrenia from the Institute of Psychiatry, Sao Paulo, and 89 controls from the same geographical area with no psychiatric or neurological disorders were recruited. Neurocognitive battery assessed: attention, verbal memory, visual memory, visuospatial function, language, psychomotor speed, executive function, intelligence. DNA was extracted from peripheral blood and genotyped for COMT Val158Met and DRD3 Ser9Gly; real-time PCR allelic discrimination with TaqMan®SNP Genotyping Assays was used. Analyses of variance (ANOVAs) controlling for sex, age and years of education were used to compare neuropsychological performance between both genotypes in controls and in patients.Results: Worst executive function was observed for DRD3 Ser/Gly carriers in controls (r=0.07,p=0.04); no DRD3 genotype effect was seen in patients. Regarding COMT, Val/Val patients had significantly worse attention (r=0.12,p=0.02); for Met/Met both patients (r=0.15,p=0.02) and controls (r=0.10,p=0.01) showed worse executive functioning. For the interaction of COMT and DRD3 polymorphisms, genotypes had significant effect among executive function in controls and patients (ES=0.137,p=0.006); all controls had similar scores. COMT Val/Val patients also performed equally to controls. As COMT Met allele frequency increased, cognitive functioning worsened in patients; this effect was maximum when combined with DRD3 Ser/Ser.Conclusions: Results support the influence of combined genetic polymorphisms related to dopamine in cognitive functioning in schizophrenia. More studies considering epistatic effects of multiple polymorphisms should be conducted to assess candidate endophenotypes.Keywords: endophenotype, dopamine, cognition, geneticSupported By: FAPESP 2009/17960-1

863. Behavioural Assessment of Incentive Motivation Deficits in SchizophreniaGagan Fervaha1, 2, Ariel Graff-Guerrero1, 2, 3, Konstantine K. Zakzanis4, George Foussias1, 2, 3, Ofer Agid2, 3, Gary Remington1, 2, 3

1Institute of Medical Science, University of Toronto, Toronto, ON, Canada, 2Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, ON, Canada, 3Psychiatry, University of Toronto, Toronto, ON, Canada, 4Psychology, University of Toronto, Scarborough, ON, Canada

Background: Motivational impairments are a core feature of schizophrenia and although there are numerous reports studying this feature using clinical rating scales, objective behavioural assessments are lacking. Here, we use a translational paradigm to measure incentive motivation in individuals with schizophrenia.Methods: Outpatients with schizophrenia receiving a stable regimen of antipsychotic medication (n=16; mean age ± S.D.=28.0±4.6 years) and matched healthy controls (n=16; mean age ± S.D.=27.5±4.5 years) completed a modified version of the Effort Expenditure for Rewards Task that accounts for differences in motoric ability. Briefly, subjects were presented a series of trials where they may choose to expend a greater amount of effort for a larger monetary reward versus less effort for a smaller reward. Additionally, the probability of receiving money for a given trial was varied at 12%, 50% and 88%.Results: Patients and controls did not differ in their trial choices for the 12%

and 88% trials (Cohen’s d<0.7; p>0.05). For 50% trials, however, patients opted to expend greater effort significantly less than controls (d=1.1; p<0.01). Patients and controls did not differ in their valuation for the monetary reward (d=0.03; p>0.05). Although patients had slower responses overall (p<0.01), their maximum button pressing rate did not correlate with their decisions (p>0.05).Conclusions: Our findings offer novel support for incentive motivation deficits in schizophrenia. Patients selectively exhibited a reduced willingness to work for rewards whilst valuing the reward to a similar degree. This objective translational paradigm may guide future investigations of the neural circuitry underlying these motivational impairments.Keywords: Schizophrenia, Incentive motivation, Apathy, Effort, Decision-making

864. Habituation of Novelty and Target Stimulus-Evoked ERPS in First Episode SchizophreniaElisabetta C. del Re1, 2, Margaret Niznikiewicz2, 3, Taiga Hosokawa2, 3, Robert W. McCarley2, 3, Kevin M. Spencer2, 3

1Psychiatry, VA Boston Healthcare System, Brookline, MA, 2Psychiatry, Harvard University, Boston, MA, 3Psychiatry, VA Boston Healthcare System, Brockton, MA

Background: The P3a event-related brain potential (ERP) is elicited by highly salient, “novel” rare stimuli in the oddball paradigm and is characterized by habituation, where its amplitude decreases after repeated exposure to the stimuli. There is also evidence that the amplitude of the P3b evoked by rare target stimuli habituates. Here we examined habituation effects on ERPs in auditory “classic” and “novelty” oddball tasks in first episode schizophrenia patients (FE) and healthy control subjects (HC).Methods: Subjects were 21 HC and 16 FE matched on age, gender, and parental socio-economic status. The electroencephalogram was recorded at 71 scalp sites and re-referenced to averaged mastoids. In the classic oddball task, subjects counted rare target tones (36) interspersed among standard tones (144). In the novelty oddball task, rare novel sounds (36) were also presented. Habituation was evaluated by averaging EEG segments to the first 1/3 (A1), the second 1/3 (A2), and the last 1/3 (A3) of the target (P3b), novel (P3a), and standard (N100) stimuli.Results: The amplitude of the P3a in the novelty oddball task (p < 0.05) and the target-evoked P3b in the classic oddball task was reduced (p < 0.001) in FE compared to HC. P3a and P3b amplitude habituated in HC (p’s < 0.01) but not FE (p’s > 0.8).Conclusions: This study confirms habituation of P3a and P3b in healthy individuals. These habituation patterns are absent in first episode schizophrenia, suggesting deficits in processes related to attentional orienting and contextual representation updating.Supported By: NIH

865. Towards a Mechanistic Understanding of Cognitive Disturbances in SchizophreniaAlan Anticevic1, John D. Murray2, Xiao-Jing Wang3, Philip R. Corlett4, John H. Krystal4

1Yale University, New Haven, CT, 2Physics, Yale University, New Haven, CT, 3Neurobiology, Yale University, New Haven, CT, 4Psychiatry, Yale University, New Haven, CT

Background: Mechanistically understanding cognitive disturbances such as working memory (WM) in schizophrenia remains a challenge for developing targeted treatments. We discuss findings across three approaches that help inform mechanisms of cognitive deficits: i) clinical findings, grounding our basic understanding of WM disruptions in schizophrenia. ii) we compare clinical findings with pharmacological neuroimaging where we manipulated NMDAR function using ketamine. iii) we juxtapose clinical and pharmacological results with a biophysically-realistic computational model of WM.



Methods: 28 patients and 24 controls underwent fMRI while performing a delayed-response WM task faced with distraction, which we compare to experimental findings while 19 volunteers performed a delayed spatial WM task under ketamine. We compare results with computational models of spatial WM, implemented with spiking neurons and realistic synaptic conductances in which we incorporate a leading hypothesis of schizophrenia neuropathology, cortical disinhibition, and examine model performance under distraction.Results: Patients failed to deploy dorsolateral prefrontal cortex activity, irrespective of distracter type, pointing to a general filtering deficit and the key role of this region in resisting interference. Ketamine disrupted task-dependent activation and connectivity as observed in patients and in line with computational modeling simulations.Conclusions: We link clinical observations with glutamate’s role in the functioning of neural systems and cognitive disturbances in schizophrenia. Via biophysically-realistic computational modeling we detail the importance of excitation/inhibition balance for cortical microcircuit function and cognition. We discuss aligning computational models, grounded in animal physiology, with cognitive probes, conferring the possibility for understanding of cognitive function from cells, to circuits, to behavior.Keywords: schizophrenia, working memory, NMDA receptor, ketamine, computational modelingSupported By: 2P50AA012870-11; AstraZeneca Pharmaceuticals

866. Linking Sleep Trouble to Neuroticism, Emotional Control, and ImpulsivenessLily A. Preer, Olga Tkachenko, Hannah Gogel, Zachary J. Schwab, Maia Kipman, Sophie DelDonno, Mareen Weber, Christian A. Webb, Scott L. Rauch, William D. S. Killgore

Center for Depression, Anxiety, and Stress Research, McLean Hospital, Belmont, MA

Background: Sleep disturbance is often linked to negative affect and plays a role in psychopathology. In addition, impulsiveness and maladaptive thought control strategies have both been associated with insomnia and lack of sleep. It was hypothesized that trouble falling asleep would be related to a high degree of neuroticism, emotional control, and impulsiveness.Methods: Sixty-one healthy adults (31 men) aged 18 to 45 completed a questionnaire about typical sleep habits, indicating whether they had trouble falling asleep and how many minutes they took to fall asleep, the Revised NEO Personality Inventory (NEO-PI-R), the Courtauld Emotional Control Scale (CECS), and the Barratt Impulsiveness Scale (BIS). A multivariate analysis of variance (MANOVA) was used to compare groups in terms of neuroticism, emotional control, and impulsiveness, and followed up with correlational analyses between these variables.Results: The MANOVA was significant (p=.015), and showed that trouble sleeping was associated with greater neuroticism (p=.013), emotional control (p=.042) and impulsiveness (p=.008). Minutes to fall asleep on weekdays was significantly positively associated with neuroticism (r=.475, p<.001) and impulsiveness (r=.394, p=.002), but not emotional control (p=.196).Conclusions: Neuroticism, emotional control, and impulsiveness were higher in people with trouble falling asleep than normal sleepers. Likewise, minutes to fall asleep was associated with neuroticism and impulsiveness. These findings indicate that trouble falling asleep is related to degree of characteristic negative affect, the extent to which individuals are unable to cope with their negative emotions, and impulsiveness. Findings may have implications for treatment of sleep trouble, mood disturbance, and impulsive behavior.Keywords: Sleep, Neuroticism, Impulsiveness, EmotionSupported By: W81XWH-09-1-0730

867. Individual Differences in Alexithymia and Dissociation in PTSDHannah Gogel1, David J. Crowley2, Scott L. Rauch1, Isabelle M. Rosso1, Olga Tkachenko1

1Center for Depression, Anxiety, and Stress Research, McLean Hospital, Belmont, MA, 2Neuroimaging Center, McLean Hospital, Belmont, MA

Background: Alexithymia is a personality trait characterized by a deficiency in the ability to feel, identify, or describe one’s emotional state. It has been suggested that alexithymia may predispose to maladaptive responses to both intense emotions and traumatic experiences, including an increased risk of dissociative reactions. However, the literature germane to a possible relationship of alexithymia to emotional dysregulation and dissociation is sparse, particularly in the context of PTSD. This study examined the relationship of alexithymia and dissociation in healthy adults and PTSD patients.Methods: Thirty-three participants (15 males, 18 females; 16 PTSD, 17 healthy controls) were administered the Toronto Alexithymia Scale (TAS-20) and the Dissociative Experiences Scale II (DES II). Scores were compared between groups and correlations were calculated to investigate the relationships between alexithymia and dissociative symptoms.Results: Participants with PTSD scored significantly higher on the DES II and the TAS. TAS scores were positively correlated with the DES II (r = .618, p < .001). The relationship was significant for participants with PTSD (r = .680, p < .01) but not for healthy controls (r = .357, ns.). Analyses are in preparation to examine whether history of trauma moderates the association of TAS and DES II scores.Conclusions: These results corroborate burgeoning evidence of a relationship between individual differences in alexithymia and dissociative reactions, and suggest that this relationship may be especially strong in PTSD. This suggests that intervention for alexithymic symptoms in PTSD patients may assist in reducing dissociative symptoms, perhaps complementing traditional trauma-focused exposure therapies.Keywords: Alexithymia, PTSD, DissociationSupported By: Dana Foundation

868. Effects of Reward and Punishment on Brain Activations Associated with Inhibitory Control in Cigarette SmokersMaartje Luijten1, David A. O’Connor2, Sarah Rossiter2, Ingmar H. A. Franken1, Robert Hester2

1Institute of Psychology, Erasmus University Rotterdam, Rotterdam, Netherlands, 2Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia

Background: Difficulties inhibiting substance related behaviors may be the result of the preference for an immediate small reward relative to a larger delayed reward or may be the result of insensitivity to punishment. The current fMRI study examined the neural basis of inhibiting an immediately rewarding stimulus in order to obtain a larger delayed reward in smokers. We also investigated whether punishment insensitivity contributed to deficient inhibitory control.Methods: The Monetary-Incentive Go/NoGo task consists of different reward outcomes contingent on inhibitory control performance over rewarding stimuli: inhibition failure was either followed by no monetary reward (Neutral), a small monetary reward with immediate feedback (Reward) or immediate monetary punishment (Punishment). In the Reward and Punishment conditions, successful inhibitory control resulted in larger delayed rewards. Nineteen smokers (cigarettes per day M=18.95, SD=4.40; range 15-30, Age=26.89, SD=8.11, 6 male) were compared with seventeen matched non-smokers (Age=27.47, SD=7.79, 7 male).Results: Smokers showed hyperactivation in the pre-SMA, r-anterior insula, r-IFG/MFG and r-DLPFC (ROI-analyes, p<0.01) both during the Neutral and Reward condition. Group differences in brain activity were not significant in



the Punishment condition, most likely as a result of increased activation in non-smoking controls.Conclusions: The current results suggest that smokers need additional neural resources to inhibit rewarding stimuli and provide tentative evidence that smokers are less sensitive to punishment as a strategy to guide control over rewarding stimuli.Supported By: This research was supported by the Australian Research Council Grant (DP1092852) and National Health and Medical Research Council Fellowship (519730) for R.H.

869. Impulsivity and Response Inhibition in Methamphetamine Users with Methamphetamine-Induced ParanoiaRasmon Kalayasiri1, Robert T. Malison2, Chiang-Shan R. Li2

1Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 2Psychiatry, Yale School of Medicine, New Haven, CT

Background: Methamphetamine (MA) can induce paranoia, the most common psychotic symptom occurs in MA-psychosis. Previous studies reported different cognitive functions between MA users and non-users and between individuals with and without primary psychotic disorder. To our knowledge, no study ever investigates cognitive functions of MA users with MA-induced paranoia (MIP).Methods: In this study, reaction time (RT) and stop signal reaction time (SSRT) from the stop-signal task (SST), a task widely used to investigate impulsivity and response inhibition, were compared among MA users with and without MIP (n=24 and 49, respectively) and non-users (n=74) by using unpaired t-test.Results: Mean RT of MA-users with MIP was significantly “shorter” than non-users (493 ± 121 vs 582 ± 153 seconds, t96 = -2, p = 0.01) but did not differ from those without MIP (p > 0.5). However, mean SSRT of MA-users with MIP had a tendency to be “longer” than those without (194 ± 37 vs 174 ±47, t71 = 1.8, p = 0.08).Conclusions: MA users with MIP may have better response inhibition than those without. The fact that individuals with MIP had higher impulsivity than those in healthy controls may not be due to paranoia as MA users also had higher impulsivity in comparison to control group (p < 0.05).Keywords: Impulsivity, Response inhibition, Methamphetamine, Paranoia, Stop-signal taskSupported By: Ratchadapiseksompoj grant, Chulalongkorn University and the Thailand Research Fund

870. Decision Making, Affective Temperament and Cognition in Individuals Detoxificated from AlcoholAgnieszka Kalwa

Addiction Prevention and Treatment Unit, Institute of Psychiatry and Neurology, Warsaw, Poland

Background: The aim of work was to find the relationship between decision making, affective temperament and cognitive function in patients detoxificated from alcohol. Decision-making disorders are present in early stages of drinking, persist in alcohol addiction and are associated with impulsivity that in these patients can be understood not only in terms of temperamental traits, but also as behavioral disturbances related to cognitive function disorders.Methods: 62 individuals (53 males, 9 females) in final stages of detoxification from alcohol, that in Poland, lasts up to 10 days; were investigated.Assessment: 1. Evaluation of decision-making processes: Iowa Gambling Task computer version by Bechara. 2. Evaluation of affective temperament : TEMPS-A questionnaire by Akiskal. 3. Cognitive function evaluation:Wisconsin Card Sorting Test by Heaton, computer version. Stroop TestTrail Making Test (TMT) by ReitanAdditionally, all investigated patients were evaluated with:HDRS only patients scored below 12 points were included to the studySDS (Severity of Dependence Scale)Results: 1.No R-Spearman correlations were found between decision-making, affective temperament and results of neuropsychological tests.2.Worse results of neuropsychological tests were correlated with lower number of years of education, greater severity of alcohol addiction and higher number of years of addiction.Conclusions: Although number of years of alcohol addiction and it’s severity was related to worse cognitive functioning of investigated alcohol-addicted individuals during detoxification treatment; there was no straightforward relation between decision-making, affective temperament and cognition in these patients.Keywords: Alcohol, Detoxification, Decision Making, Affective Temperament, Cognitive Function

871. Response Inhibition in Alcohol Dependent Patients: An FMRI Comparison with Depressed/Anxious Patients and Healthy ControlsZsuzsika Sjoerds1, 2, Wim van den Brink3, Aartjan T. F. Beekman1, Brenda W. J. H. Penninx1, 4, 5, Dick J. Veltman1

1Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands, 2Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, 3Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, 4Department fo Psychiatry, Leiden University Medical Center, Leiden, Netherlands, 5Department of Psychiatry, University Medical Center of Groningen, Groningen, Netherlands

Background: Impulsivity is a key feature of most substance-use disorders, but findings in alcohol dependence (AD) are inconsistent, possibly due to frequent comorbidity with depression/anxiety. AD patients with comorbid depression/anxiety may resemble patients with depression/anxiety only and show low impulsivity. In this study, we aimed to distinguish response inhibition impairments in AD patients from those associated with depression/anxiety.Methods: 31 AD patients with comorbid depression/anxiety, 18 patients with depression/anxiety only (D/A) and 16 healthy controls (HC) performed a Stop-Signal Task. BOLD-fMRI data for successful stop-trials versus go-trials was analyzed using ANOVA and correlation analyses between activated brain areas, behavioral data, and addiction and depression/anxiety characteristics. Results



were corrected for multiple comparisons.Results: Groups performed equally, but AD severity was associated with impulsivity (r(29)=.400;P=.026), while depression/anxiety severity was not. AD showed hyperactivity in putamen (Z=3.57) and thalamus (Z=3.58) compared with D/A and HCs. Thalamus activation was negatively correlated with AD duration (r(29)=-.477;P=.007). AD and D/A showed hypoactivity in the supplementary motor area (SMA) (Z=3.48) compared with HCs, but this effect was only significant between AD and HC. In HCs, SMA activity was negatively correlated with depressive symptom severity (r(14)=-.515;P=.041).Conclusions: AD patients were not more impulsive than D/A patients or HCs, but revealed inhibition impairments with increasing AD severity. A shift from cortical to subcortical engagement in AD patients during response inhibition may represent an alternative strategy, decreasing with longer drinking history, suggesting the presence of an AD-specific endophenotype which is subject to alcohol use characteristics like severity and disease duration.Table 1. Sample characteristics

Alcohol dependent patients (N=31)

Depression/anxiety patients (N=18)

Healthy controls (N=16)

Mean (SD) Mean (SD) Mean (SD) p-value

Demographic data

Age 46.5 (8.5) 46.7 (10.2) 47.1 (8.5) .971Gender (female), N (%) 14.0 (45.2) 10.0 (55.6) 6.0 (37.5) .567Years of education 13.3 (3.7) 13.2 (3.6) 13.1 (3.6) .993Handedness (Right), N (%) 27.0 (87.1) 17.0 (94.4) 13.0 (81.2) .500Clinical data

Alcohol use (AUDIT score) 18.4 (7.9) 1.7 (1.5) 4.6 (2.9) .000**Smokers, N (%) 19.0 (61.3) 4.0 (22.2) 0.0 (0.0) .000**

Amount of cigarettes (within smoking groups) 21.3 (11.2) 7.5 (5.0) n.a. .035*

Fagerstrom score (within smoking groups) 5.8 (2.4) 3.3 (1.7) n.a. .057

Depression severity (IDS score) 22.2 (11.5) 16.8 (9.6) 3.6 (4.2) .000**

Anxiety severity (BAI score) 12.3 (10.1) 10.2 (7.6) 1.8 (3.0) .000**

Keywords: Alcohol dependence, Response inhibition, fMRI, Cognitive Control, Mood DisordersSupported By: ZonMW31160004

872. Attenuated Activation in Striatum During Reward Processing Predicts Relapse in Methamphetamine Dependent IndividualsJoshua L. Gowin1, Martin P. Paulus1, 2

1Psychiatry, University of California San Diego, La Jolla, CA, 2Psychiatry Service, VA San Diego Healthcare System, La Jolla, CA

Background: Previous neuroimaging results suggest that neural activation during decision-making may be able to predict future abstinence in methamphetamine-dependent individuals (MDI). However, the processes that contribute to relapse-likelihood are still poorly understood. This investigation hypothesized that inadequate brain responses to rewards during risk-taking contribute to the likelihood of relapse.Methods: MDI (N=63) were recruited from a treatment program and had been abstinent a mean of 28 days prior to participating. MDI performed the risky gains task (RGT) during event-related functional magnetic resonance imaging. During the RGT, individuals could select a “safe” response with a small reward or a “risky” response that could result in either a larger reward or a loss. One year after participation, follow-up calls determined if MDI had relapsed (N=18) or were in full remission (N=45). Neuroimaging analysis compared group differences associated with receiving the small reward relative to the large reward.Results: Behaviorally, both in-remission and relapse groups selected similar numbers of safe and risky responses. However, the neural activation during the receipt of a reward differentiated relapsers from non-relapsers. Specifically, relapsers failed to show enhanced activation in the dorsal striatum when receiving a large versus a small reward.Conclusions: These results show that brain activation, but not behavior, on a risk-taking task may help to predict who will relapse and will not. More specifically, inadequate brain response to reward may represent a failure to process rewards appropriately, which may put individuals at risk for seeking means to enhance reward-related processing using dopaminergic agonists, i.e. methamphetamine.Keywords: Risk-taking, Neuroimaging, Caudate, PutamenSupported By: National Institute of Drug Abuse

873. Neurocorrelates of Marijuana Use in Adolescents with and without ADHDMarie R. Ehrler, Melissa Lopez-Larson, Allison E. Locatelli, Erin C. McGlade, Jennifer M. DiMuzio, Deborah Yurgelun-Todd

Cognitive Neuroimaging Lab, University of Utah Brain Institute, Salt Lake City, UT

Background: Research suggests adolescents are more vulnerable than adults to neurocognitive abnormalities associated with marijuana (MJ) use; however, the impact of preexisting risk factors, such as ADHD, is unclear. This study examines differences in self-reported impulsivity in the dorsolateral prefrontal cortex (DLPFC) among MJ-using adolescents with and without comorbid ADHD.Methods: Forty-five adolescents with chronic MJ use (MJ aged 17.9 ± 1.2) and 12 adolescents with MJ use and ADHD (MJ+ADHD aged 17.3 ± 1.6) had a 3T MRI. Subjects completed a diagnostic interview and Barratt Impulsivity Scale. Morphometric analyses were performed in Freesurfer and DLPFC volumes were extracted and corrected for total brain volume. Group differences in DLPFC were examined via Univariate analyses, and correlations with BIS scores and MJ use indices were performed.Results: MJ+ADHD reported higher total impulsivity (p=.003) and higher impulsivity on subscales of non-planning (p=.01) and attention (p=.05). MJ+ADHD trended toward being younger at age of first use compared to MJ only (p=0.07). There were no significant differences in DLPFC volumes between groups; however MJ+ADHD demonstrated a positive correlation between right DLPFC and age at first use (r=.579, p=.048) and left hemisphere DLPFC and age at regular use (r=.646, p=.023), while MJ only users did not.Conclusions: Adolescents with MJ+ADHD had increased levels of impulsivity compared to MJ users. Although MJ users with and without ADHD did not differ



in volumes or MJ use variables, MJ+ADHD and MJ users evidenced differential associations between DLPFC and age of onset of initial and regular use.Keywords: Adolescents, Marijuana, Neuroimaging, Neuropsychology, CognitionSupported By: R01DA020269

874. Childhood Trauma Predicts Decreased Gray Matter Volume in Limbic Regions, Independent of Substance Dependence and Lifetime Psychiatric HistoryNicholas T. Van Dam1, Kenneth Rando1, Marc N. Potenza1, Keri Tuit1, Joseph Guarnaccia2, Rajita Sinha1

1Psychiatry, Yale University School of Medicine, New Haven, CT, 2Neurology, Yale University School of Medicine, New Haven, CT

Background: Childhood trauma is associated with risk of major psychiatric and physical illnesses. While preclinical studies clearly show its detrimental effects on limbic regions such as the hippocampus, human studies assessing these effects independent of psychiatric disorders are rare. Thus, here we examined the effects of childhood trauma on whole brain gray matter volume (GMV) in a large sample of healthy community adults and abstinent, recovering substance dependent individuals.Methods: 148 community participants with no current psychiatric disorders and 80 early recovering substance dependent adults (total N-228 adults, 63.2% male), completed the Childhood Trauma Questionnaire (CTQ), and other psychiatric and health assessments along with a structural magnetic resonance imaging (MRI) protocol. Whole-brain voxel-based-morphometry (VBM) analysis was performed adjusting for age, gender, minority status, and total intracranial volume.Results: Childhood trauma was associated with lower GMV in the hippocampus, amygdala and parahippocampus, bilaterally (Family-wise-error-corrected p < .05). Region of interest analysis for these medial temporal volume clusters predicted lifetime history of psychiatric disorders. However, anatomically defined volumes of the hippocampus and parahippocampus were only significantly predicted by childhood trauma (p’s < .01), not substance dependence or lifetime psychiatric history.Conclusions: These findings indicate that increasing levels of childhood trauma is associated with lower brain volume in critical stress, emotional, and memory regions of the hippocampus and parahippocampus in adulthood, independent of psychiatric illnesses. Lower volume in these critical limbic regions may mediate risk of psychiatric and chronic physical illnesses in adulthood.Keywords: Trauma, Limbic Neuroanatomy, Substance Dependence, Affective Disorders, HippocampusSupported By: UL1-DE19586, PL1-DA24859; R01-AA013892, RL1-AA17539

875. Persistent Viral Pathogens and Cognitive Impairment Across the LifecourseKara Tarter, Amanda M. Simanek, Allison E. Aiello

Epidemiology, University of Michigan, Ann Arbor, MI

Background: Herpesviruses have been associated with cognitive impairment in older populations and those with co-morbid mental illness. We examined whether herpes simplex virus-1 (HSV-1) and/or cytomegalovirus (CMV) seropositivity are associated with cognitive impairment across the lifecourse in the general U.S. population.Methods: Data were from 4565 children aged 6-16 assessed with the Wechsler Intelligence Scale for Children-Revised/Wide Range Achievement Test-Revised (WISC-R/WRAT-R), 5398 adults aged 20-59 assessed for Central Nervous System function, and 5301 adults aged 60+ assessed with the Mini-Mental State Examination (MMSE) and tested for CMV and/or HSV-1 seropositivity in the

National Health and Nutrition Examination Survey III. Multiple linear and logistic regressions were used to assess associations between seropositivity and cognitive impairment.Results: HSV-1 seropositive children scored lower on the WISC-R/WRAT-R math (p=0.0170), reading (p=0.0004) and block design tests (p<0.0001), compared to those seronegative. HSV-1 and CMV seropositivity were associated with greater odds of longer test time for the Symbol-Digit Substitution Test among adults aged 20-59 (odds ratio (OR) 2.24 (95% CI: 1.75, 2.86) and 1.71 (95% CI: 1.16, 2.51, respectively). HSV-1 seropositive adults aged 60+ had 3.26 (95% CI 1.66, 6.37) times greater odds of immediate memory impairment compared to those seronegative. Models were adjusted for age, gender, race/ethnicity, and poverty or education level.Conclusions: HSV-1 seropositivity was associated with cognitive impairment across the lifespan and CMV seropositivity was associated with cognitive impairment in middle-aged adults. Further examination of biological pathways by which CMV and HSV-1 seropositivity may influence cognitive functioning across the lifecourse is therefore warranted.Keywords: Cognitive Impairment, Viral infections, Herpesvirus, Lifecourse, Memory Impairment

876. Association Between Toxoplasma Gondii Infection and TCI Personality TraitsSana A. Kamal1, 2, Aamar Sleemi1, 2, Ayesha Ashraf2, Sara J. Hinman2, Ina Giegling3, Annette M. Hartmann3, Bettina Konte3, Marion Friedl3, Dan Rujescu3, Teodor T. Postolache1, 2

1Department of Mental Health, Saint Elizabeths Hospital, Washington, D.C., DC, 2Mood and Anxiety Program (MAP), University of Maryland School of Medicine, Baltimore, MD, 3Section of Molecular and clinical Neurology, Ludwig Maximillans University, Munich, Germany

Background: One third of the population worldwide is infected with the protozoan parasite Toxoplasma gondii. (T.gondii). Chronic T.gondii infection is minimally symptomatic. Nevertheless, certain neurological and psychiatric conditions, such as seizures, schizophrenia, bipolar disorder, and personality disorders have been associated with chronic toxoplasmosis. Several studies have reported gender-dependant personality traits associated with T. gondii. As psychopathology was not adequately ruled out in those studies, it may have led to identifying spurious parasite-personality associations.Methods: The Temperament and Character Inventory (TCI) was administered to 1000 participants (490 males, 510 females, mean age of 53.5) recruited from the Munich metropolitan area. Blood T. gondii IgG antibodies were measured with ELISA. Psychopathology was ruled out with SCID I and II. TCI temperament (novelty-seeking, harm-avoidance, reward-dependence, and persistence) and character (self-directedness, cooperativeness and self-transcendence) scores were related to T. gondii seropositivity and serointensity. Statistical analyses included T. tests, ANCOVAs and linear regression, with age adjustment.Results:T. gondii positive participants had higher self-transcendence scores (p=0.018). The association was significant only in males (p=0.012). Seropositive males also reported high harm- avoidance (p=0.044). No significant TCI associations were found with serointensity.Conclusions: This is the first study on TCI-T. gondii associations in individuals confirmed to be psychiatrically healthy by structured interviews. Chronic toxoplasmosis may be associated with increased self transcendence through microorganism’s enzymatic capacity to synthesize dopamine, or alternatively, through immune mediation. This report, limited by its cross-sectional design, adds to the growing literature on microorganism-host behavioral interactions.Keywords: Toxoplasma Godii, Temperament, Character, Cloninger’s TCISupported By: AFSP, PI Postolache



877. Schizophrenia Subtypes Going Going Gone Since 2001David L. Braff1, James Ryan1, William T. Carpenter2

1Dept. of Psychiatry, UCSD, La Jolla, CA, 2Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD

Background: Bleuler recognized that there is a “group of schizophrenias”. DSM subtypes have been used for years. But are they being utilized in 21st Century (starting in 2001) clinical and translational research? The answer is no. It makes sense to exclude them for DSM-V. Subtypes have been challenged because traditional subtypes of schizophrenia:• are not strong heuristically• are not stable over time• are not supported genomically• are unclear and have other weaknessesMethods: From 2010, subtypes were used in less than 10% of journal articles. How long has this been going on? The articles on schizophrenia in 5 high citation index ranked Journals were examined from a one year epoch from 2001.Results:Journal Articles SubtypesMolecular Psychiatry 33 3Am Journal of Psychiatry 41 4Archives of General Psychiatry 23 2Schizophrenia Bulletin 56 5Biological Psychiatry 34 9

Less than 15% of studies utilized DSM-IV (TR) schizophrenia subtypes as far back as 2001.Conclusions: • Use of traditional schizophrenia subtypes has been uncommon since 2001.• With DSM V and ICD-1 approaching their “due dates” in 2013, now is a reasonable time to drop the use of subtypes in schizophrenia nosology.• Subtypes do not clarify the trenchant heterogeneity and polygenicity of schizophreniaKeywords: Schizophrenia, Nosology, DSM-V, SubtypesSupported By: MH065571; MH042228; MH085265; MH084071; MH093533

878. Novel Replacement Strategy for the Molecular Dissection of NMDA Receptor Trafficking and RegulationJohn A. Gray, Roger A. Nicoll

Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, CA

Background: NMDA-type glutamate receptors (NMDARs) play crucial roles in synaptic plasticity and neuronal development and disturbances in NMDAR function have been implicated in a broad range of neuropsychiatric disorders. The functional and regulatory properties of NMDARs are largely determined by their GluN2 subunit composition, which is tightly regulated at synapses. However, the mechanisms involved in modulating NMDAR subunit composition are poorly understood.Methods: We have developed a novel molecular replacement strategy in hippocampal cultures from mice with conditional knock-out alleles for both GluN2A and GluN2B. Slices are transfected with Cre recombinase and simultaneous whole-cell recordings are obtained from transfected and neighboring control cells. After measuring synaptic NMDAR currents, local application of NMDA to the cell pair assesses the whole-cell complement of NMDARs, allowing for a rigorous analysis of both synaptic and extrasynaptic NMDARs.Results: Cre expression in the conditional KO mice eliminates NMDAR responses and co-expression with wild-type GluN2 subunits precisely and

reproducibly recovers both synaptic and whole cell responses, suggesting tight cellular regulation of NMDAR subunit expression. Additional preliminary findings include a role for a known GluN2B phosphorylation site in regulating post-endocytic sorting, and a novel non-PDZ domain involved in the synaptic targeting of GluN2A subunits.Conclusions: Synaptic and extrasynaptic NMDAR pools are independently and tightly regulated, allowing for hypothesis-driven dissection of the mechanisms involved in NMDAR targeting and trafficking. This approach will facilitate the identification of novel trafficking proteins and cellular mechanisms for NMDAR regulation and may yield insights into the pathophysiology of schizophrenia and other neuropsychiatric disorders.Keywords: NMDA, NR2B, Synapses, Electrophysiology, GlutamateSupported By: 5R01MH080379

879. Poverty of Thought at Onset Predicts Prognosis in PsychosisJames Wilcox1, Ming T. Tsuang2, Syed Quadri3, David Briones4

1Psychiatry - VAMC, University of Arizona, Tucson, AZ, 2Psychiatry, University of California, San Diego, CA, 3Psychiatry, University of Arizona, Tucson, AZ, 4Psychiatry, Texas Tech University, El Paso, TX

Background: Previous authors have linked formal thought disorder to possible conversion to psychosis. This study examines the specific types of thought disorder in relationship to conversion within a three year time frame.Methods: Subjects with new onset psychosis were examined using the Brief Psychiatric Rating Scale (BPRS), the Structured Clinical Interview for DSM (SCID) and the Scale for Assessment of Thought, Language and Communication (TLC). They were also asked demographic data about age, gender, education, family history and substance abuse. The SCID was given again at one year, two years and three years after initial exam to look at conversion status to full diagnosis. Data was studied using multiple regression analysis to examine predictive value of variables on conversion to a major psychiatric disorder at these intervals.Results: The initial TLC scores were correlated to initial BPRS scores, ( r = .78, p<.01 ). The initial TLC scores as a whole were not predicitve of conversion to psychosis, however, the subscores on poverty of speech and poverty of content were highly predicitve of conversion to psychosis within a one year time frame, (F = 4.64, p<.01 and F = 5.43, p<.01), respectively.Conclusions: The negative symptoms of the TLC were strongly predicitve of diagnosis over a three year time frame. We found that patients with poverty of content and poverty of speech were very likely to convert to a psychotic condition as diagnosed by the SCID within one year of evaluation.Keywords: thought disorder, prognosis, psychosis, schizophrenia, predictiveSupported By: NIMH MH60485



880. Increased Kynurenine Levels in Schizophrenia Patients with High Anti-Gliadin Immunoglobulin G Antibodies Olaoluwa O. Okusaga1, 2, Dietmar Fuchs3, Ina Giegling4, Annette M. Hartmann4, Bettina Konte4, Marion Friedl4, Dan Rujescu4, 5, Teodor T. Postolache1, 6

1Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, 2Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, , Houston, TX, 3Division of Biological Chemistry, Biocenter- Innsbruck Medical University, Innsbruck, Austria, 4Section of Molecular and Clinical Neurobiology, Ludwig Maximilians University, Munich, Germany, 5Department of Psychiatry, University of Halle-Wittenberg, Halle-Wittenberg, Germany, 6Child and Adolescent Mental Health Innovations Center, University of Maryland, Baltimore, MD

Background: Gliadine sensitivity in schizophrenia has been reported in several studies but its connection to psychotic symptoms is poorly understood. As immune mechanisms have been implicated in the pathophysiology of schizophrenia, and as certain immune mediators increase kynurenine and reduce tryptophan levels, we now compared plasma levels of these molecules in patients with, versus those without, elevated anti-gliadin IgG.Methods: We measured anti-gliadin IgG, kynurenine and tryptophan in 950 patients with schizophrenia [age: 38.0±11.6, 600 (63%) males] and 1000 healthy controls [age: 53.5 ± 15.8, 490 (49%) males]. Patients with antibody level at the 90th percentile or higher of control participants were classified as having elevated anti-gliadin IgG. T-test and ANCOVAs were used to compare tryptophan, kynurenine and kynurenine-tryptophan ratio between patients with, and those without elevated anti-gliadin IgG. The correlation between anti-gliadin IgG and tryptophan, kynurenine and the ratio was also evaluated in schizophrenia patients.Results: Kynurenine and kynurenine-tryptophan ratio were elevated in patients with elevated anti-gliadin IgG (3.13 ± 1.49 vs. 2.58 ± 1.83, p<0.0001 and 0.053 ± 0.034 vs. 0.045 ± .0301, p=0.002 respectively), findings robust to adjustment for potential confounders (age, gender, level of education, BMI and illness severity). Anti-gliadin IgG correlated with kynurenine and kynurenine-tryptophan ratio in unadjusted (p <0.0001) and adjusted analysis (p = 0.002). Tryptophan levels did not differ between the 2 patient groups and did not correlate with anti-gliadin IgG.Conclusions: Elevated kynurenine in schizophrenia provides additional insights connecting gliadine sensitivity with psychotic illness and hints towards potential individualized treatment targetsKeywords: Anti-gliadin IgG, Knurenine, Tryptophan, Inflammation, Gliadin sensitivitySupported By: Supported by a grant from the American Foundation for Suicide Prevention (PI Postolache, co PI Rujescu).

881. Association Between Schizophrenia and Autoimmune Diseases in the National Hospital Discharge Survey (NHDS) Natalya S. Weber1, Rakel A. Larsen1, Jared A. Fisher1, David N. Cowan1, Marlene E. Gubata1, David W. Niebuhr2

1Preventive Medicine, Walter Reed Army Institute of Research, Silver Spring, MD, 2Preventive Medicine and Biometrics, Uniformed Services University of Health Sciences, Bethesda, MD

Background: Prior studies showed that autoimmune processes may precede schizophrenia onset. Evaluating schizophrenia comorbidity with a range of autoimmune diseases in a large US nationally representative set of hospital discharges may help to clarify these associations. NHDS data provide insight into comorbidities of relatively uncommon diseases not available elsewhere.Methods: We used the National Hospital Discharge Survey (NHDS) data collected and maintained by the United States National Center for Health

Statistics. The data were compiled using a stratified multi-stage probability design and contain over six million hospital discharge records from 1979 to 2006. Based on ICD-9 codes, 70,063 records with schizophrenia and 169,217 records with almost 30 autoimmune diseases were identified in the data set. The likelihood (odds ratio) of comorbidity between schizophrenia and autoimmune diseases was calculated in a subset of hospitalizations with non-psychiatric primary diagnoses.Results: The overall odds ratio between schizophrenia and any autoimmune disease was 1.3 (95% CI: 1.2-1.4). Significant (p<0.05) associations were detected with psoriasis (2.2), diabetes type I (1.5), thyrotoxicosis (1.4), Crohn’s Disease (0.7), and rheumatoid arthritis (0.4).Conclusions: Several autoimmune diseases were comorbid with schizophrenia, providing support to the hypothesis that they may share common etiologic and/or pathogenic pathways. These findings are mostly consistent with the existing literature and indicate a need for further exploration of possibly shared pathways between psychotic and autoimmune disorders.Disclaimer: The views expressed are those of the authors and should not be construed to represent the positions of the Department of the Army or Department of Defense.Keywords: schizophrenia, autoimmune, comorbidity, psoriasis, diabetesSupported By: Stanley Medical Research Institute, Department of the Army

882. Obesity, Bariatric Surgery and Alcohol Dependence, is There an Association? A Retrospective StudyAlfredo B. Cuellar

1. Universidad Autonoma de Nuevo Leon, 2. Mayo Clinic, 1. Monterrey, 2. Rochester, Mexico

Background: The aim of this study was to determine the alcohol use disorder (AUD) diagnosis and alcohol consumption patterns before and after bariatric surgery (BS), and in alcohol dependent obese controls.Methods: A retrospective review of AUD treatment-unit evaluations, during the interval between 2007 and 2012 (n=824) was performed; among those 44 (5.3%) patients had a history of BS. An age-matched obese control group (n=122) in the same treatment setting was selected.Results: 95% of BS patients had Roux-en-Y gastric bypass, 70% were females, mean age of 46 ±8.7 years and, mean BMI of 30.4 ±4.9. Only 10 patients met DSM-IV criteria for alcohol dependence preoperatively versus 43 after surgery. BS patients reported worsening of alcohol consumption 2.5 ± 1.7 years following surgery and sought treatment after 5.4 ± 2.8 years. The number of drinks per drinking day and number of drinking days per week significantly increased postoperatively (2.5 ± 2.7 vs.7.8 ± 8, p<0.0001; 2.1 ± 2.2 vs. 4.5 ± 2.1, p<0.0001); the same consumption patterns were significantly higher in controls compared to BS patients (9.3 ± 5.3 vs.7.8 ± 8, p=0.005; 5.5 ± 1.9 vs. 4.5 ± 2.1, p=0.001). There was no difference in maximum drinks number/day lifetime between groups (BS 13 ± 8.8 vs. obese controls 14.7 ± 7.6, p= 0.1).Conclusions: Alcohol dependence diagnosis and consumption in BS patients significantly increased postoperatively; consumption patterns in BS patients remained below obese controls.Keywords: bariatric surgery alcohol, alcohol dependence, obesity, weight loss surgery



883. The Phenomenology of High Dose Social DrinkingAlastair J. S. McKean1, Osama A. Abulseoud1, John D. Port2, Victor M. Karpyak1, Doo-Sup Choi3, David J. Hinton1, Lee J. Gunderson1, Mark A. Frye1

1Psychiatry and Psychology, Mayo Clinic, Rochester, MN, 2Radiology, Mayo Clinic, Rochester, MN, 3Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN

Background: DSM5 will recognize cravings, a strong desire or compulsion to use a substance, as diagnostic criteria for alcohol use disorders. The phenomenology of social drinkers, those who do not meet criteria for alcohol dependence but regularly drink alcohol, is poorly understood. Whether social drinkers experience cravings or whether this is a marker of disease is not known. We wanted to explore the social drinker phenotype as an intermediary to alcohol use disorders.Methods: 10 high dose social drinkers (mean age = 33.8±9.1) defined by >14 drinks/week for men and >7 drinks/week for women were recruited into this study. 10 normal controls (mean age = 27.9±7.1) and 31 alcohol dependent individuals (mean age=43.71±13.47) were used as comparison groups to evaluate alcohol consumption, quantified using time line follow back (TFLB7/30) and alcohol cravings as measured by the Penn Alcohol Craving Scale (PACS) and Alcohol Urge Questionnaire (AUQ).Results: Social drinkers drank more per day (3.95±3.05 drinks/day) than normal controls (0.45±0.76 drinks/day) but less than alcohol dependent individuals (7.70±6.56 drinks/day). Social drinkers experienced higher cravings (PACS: 5.5±4.45; AUQ: 13.6±7.37) than normal controls (PACS: 1.4±2.07; AUQ: 9.9±3.14) and less than those with alcohol dependence (PACS: 16.06±7.98; AUQ: 20.5±9.43).Conclusions: Social drinkers do experience cravings; however, they are less severe than those with alcohol dependence. Based on consumption and phenomenology, social drinkers appear to be an intermediary between infrequent drinkers and alcohol dependence. Further elucidating the biology of social drinkers may enhance the understanding of alcohol use disorders.Keywords: Cravings, Alcohol Dependence, Social Drinking, Phenomenology

884. Adolescent Binge Drinking and Low Level of Response to Alcohol in American Indian and Mexican American Young AdultsDavid A. Gilder, Cindy L. Ehlers

Molecular and Cellular Neurosciences Department, The Scripps Research Institute, La Jolla, CA

Background: Binge drinking is a common behavior during adolescence. A low level of response (LR) to alcohol is a genetically mediated response associated with increased alcohol use and use disorders, yet the relationship between LR and adolescent binge drinking is not known.Methods: Alcohol use history, and DSM-III-R diagnoses were obtained from 447 reservation swelling American Indians and 454 Mexican American young adults (age 18-30 yrs). LR was assessed using the expectancy version of the subjective high assessment scale (SHAS-E). Multiple regression was used to assess the association of frequent binge drinking (≥5/≥4 (Male/Female) at ≥ once per month at maximum drinking frequency) prior to age 18 years with three separate outcomes: SHAS-E total, terrible, and great in the presence of gender, age at interview, antisocial personality disorder, ethnicity, major depression, panic, agoraphobia, social phobia, and obsessive-compulsive disorder.Results: Frequent binge drinking in adolescence was associated (B, p-value) with significantly lower SHAS total (-29.013, <0.001) and SHAS terrible (-3.108, <0.001), but not SHAS great (0.097, 0.902), scores. American Indian ethnicity was associated with significantly lower SHAS total (-33.632, <0.01) and SHAS great (-2.140, 0.008), but not SHAS terrible (-.400, 0.620), scores. Frequent binge drinking was also associated with significantly lower SHAS total when both samples were assessed independently.

Conclusions: A novel unpublished finding of this study is that frequent binge drinking in adolescence is associated with low LR, especially for feeling “terrible” in young adulthood, even in the presence of several potentially confounding covariates.Keywords: American Indian, Mexican American, adolescent, binge drinking, alcohol use disordersSupported By: R37AA010201; R01AA006420; AA016479; DA030976

885. Modeling Copy Number Variants in Human Psychiatric DiseaseNicholas Katsanis

Duke University, Durham, NC

Background: A pervasive challenge in the interpretation of CNV discovery is the transition from the detection of a genomic lesion to causality at specific transcript(s).Methods: We have taken an orthogonal approach to the problem, grounded on two key observations: a) that some CNVs associated with neurodevelopmental traits also exhibit quantitative anatomical phenotypic surrogates; and b) that some CNVs exhibit mirror phenotypes. Based on these observations, we have designed in vivo assays to systematically assay dosage sensitivity of all genes within CNVs and to identify transcripts that contribute to neuroanatomical defects seen in patients.Results and Conclusions: We will discuss how these approaches, when combined with human genetics, accelerate the identification of genes that contribute to the pathomechanism of the CNVs and offer new biological insights.Keywords: Copy number variants, zebrafishSupported By: Simons Foundation, MINH P50 MH094268

886. The Phosphodiesterase 4B Mutant: Cognitive Enhancement and a Novel Therapeutic Approach to PTSDAlexander McGirr1, Tatiana Lipina2, Ho-Suk Mun3, John Georgiou2, Dongxu Zhai4, Fang Liu4, Steven Clapcote5, John Roder6

1Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada, 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada, 3Samuel Lunenfeld Research Institute, University of Toronto, Toronto, ON, Canada, 4CAMH Research, Centre for Addiction and Mental Health, Toronto, ON, Canada, 5Institute of Membrane and Systems Biology, University of Leeds, Leeds, United Kingdom, 6Department of Medical Genetics, University of Toronto, Toronto, ON, Canada

Background: Phosphodiesterases are the only known regulators of cAMP. PDE4B is an important candidate gene in neuropsychiatric disorders and a binding partner of major susceptibility gene DISC1. We investigated allelic variation in neuropsychiatric phenotypes.Methods: Using ENU mutagenesis, we generated a PDE4B missense mutant and conducted extensive behavioural, biochemical, neuroanatomical, and neurophysiological characterization.Results: The missense mutation produces impaired binding with neuropsychiatric susceptibility gene DISC1, impaired cAMP hydrolysis, and consequently baseline increased phosphorylated CREB. Mutant mice demonstrate cognitive enhancement on working, short-and long-term spatial memory tasks and an anxiolytic phenotype and the absence of fear-induced memory impairments. Though mutant mice acquire and consolidate memory during fear conditioning, they display exposure-independent decreases in fear memory (reconsolidation) in the week following training, an effect replicated in control mice by pharmacological PDE4 inhibition. We demonstrate biochemical, neuroanatomical, and electrophysiological mechanisms underlying PDE4B mutant mice’s resistance to aversive memory despite facilitation for spatial and social memory.



Conclusions: PDE4B is a putative target for disorders of fear and fear memory.Keywords: PDE4B, PTSD, Cognitive enhancement

887. Regulation of Neuron Development in the Cortex and Basal Ganglia by CoupTF2Jia Sheng Hu, John L. Rubenstein

Psychiatry, University of California, San Francisco, San Francisco, CA

Background: Neural circuits are composed of projection neurons and interneurons. Defects in either neurons can result in excitation-inhibition imbalance and cognitive dysfunction that may underlie many psychiatric disorders, including Autism and Schizophrenia. To understand the etiologies of these diseases, it is important to elucidate genetic mechanisms that control the development of these neurons. Many telencephalic interneurons are derived from the medial ganglionic eminences (MGE), which give rise to several interneuron subtypes that differentially modulate neuronal activity. Some transcription factors have been identified that have broad functions in interneuron development (i.e. Ascl1, and Dlx1&2). However, little is known about the transcription factors that regulate particular MGE interneuron subtypes. This is in part due to little knowledge about the functions of other transcription factors that are expressed there. Coup-TF2 is an example.Methods: To uncover Coup-TF2’s role in interneuron development, we employed the Cre-lox mouse system to remove Coup-TF2 in the MGE by using the Nkx2.1-Cre allele. Conditional mutants were analyzed by in situ hybridization with probes detecting markers of MGE interneuron development at embryonic ages.Results: We found that expression of MGE interneuron differentiation markers, such as Somatostatin and Lhx6, were decreased in multiple MGE derivatives, including the neocortex, striatum, and globus pallidus. Associated with this change was an increased expression of a MGE progenitor marker, Nkx2.1, in the MGE subventricular zone.Conclusions: Our data shows that Coup-TF2 is a regulator of MGE interneuron development. Coup-TF2 may regulate its development by promoting its differentiation while suppressing its progenitor state.Keywords: NR2F2, interneuron, GABA, basal ganglia, medial ganglionic eminenceSupported By: NIH T32 Neuroscience and Schizophrenia Postdoctoral Fellowship

888. Neurodevelopmental Alcohol Exposure Elicits Long-Term Changes to Gene Expression That Alter Molecular Pathways Dependent on Timing of ExposureMorgan L. Kleiber, Katarzyna Mantha, Randa L. Stringer, Shiva M. Singh

Biology, University of Western Ontario, London, ON, Canada

Background: Maternal alcohol consumption during pregnancy is known to adversely affect fetal neurodevelopment. While it is known that alcohol dose and timing play a role in the cognitive and behavioural changes associated with prenatal alcohol exposure, it is unclear what molecular neurodevelopmental processes are disrupted that may lead to these phenotypes.Methods: Mice (n=6 per treatment per developmental time) were exposed to an acute dose of alcohol (5 g/kg) at a neurodevelopmental time representing the human first, second, or third trimester equivalent. Mice were reared to adulthood and changes to their adult brain transcriptome were assessed using expression arrays. These were then categorized based on Gene Ontology annotations, canonical pathway associations, and relationships to interacting molecules.Results: The results suggest that ethanol disrupts biological processes that are actively occurring at the time of exposure. These include cell proliferation during trimester one, cell migration and differentiation during trimester two, and cellular

communication and neurotransmission during trimester three. Further, although ethanol altered a distinct set of genes depending on developmental timing, many of these show interrelatedness and can be associated with one another via “hub” molecules and pathways such as those related to Huntingtin and Brain-derived neurotrophic factor.Conclusions: These changes to brain gene expression represent a “molecular footprint” of neurodevelopmental alcohol exposure that is long-lasting and correlates with active processes disrupted at the time of exposure. This study provides further support that there is no neurodevelopmental time when alcohol cannot adversely affect the developing brain.Keywords: fetal alcohol spectrum disorders, development, brain, mouse, gene expressionSupported By: Natural Sciences and Engineering Research Council of Canada, Ontario Mental Health Foundation, Canadian Institutes of Health Research

889. Downregulation of ZNF804A in an Activity-Dependent Manner in the Dentate Gyrus Region of the Hippocampus and in Response to NMDA-Receptor Mediated Activity in Primary Neuronal Cells Anne Kirtley1, 2, Valerie Vingtdeux-Didier3, Toni-Shay Chandon1, 2, Phil Borger2, Anil Malhotra1

1The Center for Psychiatric Neuroscience, The Zucker Hillside Hospital, Glen Oaks, NY, 2The Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, 3Litwin-Zucker Center for Research in Alzheimer’s Disease and Memory Disorders, The Feinstein Institute for Medical Research, Manhasset, NY

Background: Variation in Znf804a rs1344706 SNP is strongly associated with schizophrenia. The risk allele is associated with disturbed functional connectivity between DLPFC, hippocampus and amygdala. Risk allele carriers with schizophrenia perform better on episodic memory tasks. We hypothesized that Znf804a is regulated in hippocampal-dependent associative long-term memory (episodic-like memory) and by NMDA-receptor mediated activity.Methods: Znf804a mRNA expression was assayed in adult rat brain hippocampal sections using radioactive in situ hybridization. Znf804a mRNA levels were determined, by image densitometry, in rats 30 min following contextual-fear conditioning and novel context, footshock and naïve control rats. ZNF804A protein expression was assayed in primary neurons by Western blot following glutamate exposure.Results: Znf804a mRNA expression was downregulated, by 27%, in dentate gyrus (DG) after associative learning relative to baseline and novel context controls. Znf804a mRNA expression in footshock control rats was also downregulated, by 24%, in DG relative to baseline. No Znf804a regulation was present in CA1, CA2 or CA3. ZNF804A protein was downregulated by 80% in primary neurons when exposed to glutamate. This downregulation was reversed in the presence of NMDA-receptor antagonist MK-801.Conclusions: Znf804a is regulated in an activity-dependent manner specifically in DG. These findings do not dissociate whether this regulation is associated with stress component of the memory, generalized stress and/or footshock related pain. Of note DG receives stress related inputs that promote robust emotional memory formation. Additionally ZNF804A protein was downregulated in response to NMDA-receptor activity. We hypothesize that downregulation of Znf804a in DG is mediated through NMDA-receptor activity.Keywords: Znf804a, Memory, Dentate gyrus, mRNA expression, NMDA-receptorSupported By: NIMH Grant: 5P50MH080173



890. Phosphorylation of MeCP2 in Reward-Related Circuits is Required for Amphetamine-Induced Conditioned Place Preference in MiceAnthony S. Zannas1, Jay V. Deng2, Ashley N. Hutchinson2, William C. Wetsel1, Anne E. West2

1Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, 2Neurobiology, Duke University Medical Center, Durham, NC

Background: Amphetamine has been shown to produce conditioned place preference (CPP) in rodents and to induce phosphorylation at Ser421 of methyl CpG-binding protein-2 (MeCP2). Here we examine whether phosphorylation of MeCP2 (pMeCP2) in reward-related circuits is required for amphetamine-induced CPP in mice.Methods: Adult male (8-12 week old) C57BL6/J mice or wildtype (WT) and Mecp2 Ser421Ala knock-in (KI) littermates were subjected to CPP. Each side of a three-chambered apparatus was alternately paired three times with either vehicle or 2, 3 or 4 mg/kg amphetamine daily over six days. A control group of mice received only vehicle. After a one-day break from pairing, the time spent in each chamber was assessed. Two hours later the mice were sacrificed and coronal brain sections through the nucleus accumbens (NAc) and prelimbic cortex (PLC) were quantitatively immunostained for pMeCP2 and Fos.Results: In both C57BL6/J mice and the MeCP2 WT littermates, CPP was induced by amphetamine. Although pMeCP2 was not detected in the NAc at the time of preference testing, pMeCP2 immunofluorescence was found in the PLC. CPP resulted in significantly increased Fos immunofluorescence in both NAc and PLC. However in the KI mice, amphetamine did not induce CPP and Fos was reduced in both brain regions.Conclusions: These data suggest that phosphorylation of MeCP2 in reward-related brain regions is required for either the development or the expression of amphetamine-induced place preference. This effect may be mediated by induction of immediate early genes in these brain regions.Keywords: Amphetamine, Conditioned place preference, Immediate early genes, Nucleus accumbens, RewardSupported By: NIH DA022202; NIH DA033815

891. Oxytocin Gene Variants Modulate Core Dimensions of Borderline Personality DisorderM. Mercedes Perez-Rodriguez1, Pei-Hong Shen2, Laura Bevilacqua2, Qiaoping Yuang2, Zhifeng Zhou2, Colin Hodgkinson2, Luis Ripoll1, Marianne Goodman1, Harold Koenigsberg1, DAVID GOLDMAN2, Larry J. Siever1, Antonia S. New1

1Psychiatry, Mount Sinai School of Medicine and MIRECC at James J Peters VAMC, New York, NY, 2Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD

Background: Deficits in the attachment/affiliative system, modulated by the neuropeptide oxytocin, may underlie the impulsive aggressive reactions to perceived rejection found in Borderline Personality Disorder (BPD). We examined associations between single nucleotide polymorphisms (SNPs) and haplotypes of the OXT gene and empathy, attachment style, and BPD dimensions of impulsivity, aggression and affective lability.Methods: Subjects:156 healthy controls (HCs), 181 patients with BPD, and 196 subjects with other personality disorders. Four tag SNPs (rs4813625, rs877172, rs2740210, and rs3761248) of the oxytocin gene (OXT) were genotyped. Haplotypes were derived for a haplotype block including two SNPs (rs877172, rs3761248). We tested for an association between the SNPs/haplotypes and empathy (Interpersonal Reactivity Index (IRI)), attachment style (Experiences in close relationships inventory (ECRI)), impulsivity (Barratt impulsivity scales-11 (BIS)), aggression (Buss-Perry Aggression Questionnaire (BPAQ)) and affective lability (Affect Lability Scale (ALS)) using ANOVA.Results: SNP analyses: We found an association between BIS scores and SNP

rs3761248 (F=3.2;DF=2;p=0.042); between the IRI Personal Distress (PD) scores and SNP rs4813625 (F=5,144;DF=2;p=0.012); between SNP rs877172 and IRI PD scores (F=7.10,df=2,p=0.004). We did not find any association between BPAQ, ALS or ECRI scores and any SNPs. Haplotype analyses: Haplotype rs877172 C, rs3761248 T was significantly associated with BPAQ scores (F=4,023,df=2,p=0.019). Haplotype rs877172 C, rs3761248 C was significantly associated with BPAQ scores (F=4,982,df=2,p=0.008). Haplotype rs877172 C, rs3761248 C was associated with BIS scores (F=4.11,df=2,p=0.018). No haplotypes were significantly associated with IRI, ALS or ECRI.Conclusions: We found an association between OXT SNPs/haplotypes and impulsivity, aggression and empathy.Thus, oxytocin genes may modulate impulsivity, aggression and empathy.Keywords: Oxytocin, Single Nucleotide Polymorphism, Empathy, Impulsivity, AggressionSupported By: MIRECC; MH56140; MH63875; VA Merit Review Grant (7609-028); MO1-RR-00071; VA Merit award (9001-03-0051

892. Congenital Heart Disease In 22Q11.2 Deletion Syndrome in School Age Children is Not Associated with Increased Psychopathology or Neurocognitive ImpairmentJames J. Yi1, Sunny X. Tang2, Daneen A. Whinna2, Donna M. McDonald-McGinn3, Alice Bailey3, Margaret C. Souders3, Nathaniel Meyers3, Nancy Burnham4, James W. Gaynor4, Elizabeth Goldmuntz5, Elaine H. Zackai3, Beverly S. Emanuel3, Ruben C. Gur2, Raquel E. Gur2

1Child and Adolescent Psychiatry, Children’s Hospital of Philadelphia, Philadelphia, PA, 2Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 3Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, 4Cardiothoracic Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA, 5Cardiology, Children’s Hospital of Philadelphia, Philadelphia, PA

Background: 22q11.2 deletion syndrome (22q11DS) presents with variable conditions including psychiatric, neurocognitive, and congenital cardiac disease (CHD). CHD has been implicated in neuropsychiatric outcomes, but its role in 22q11DS is poorly understood. In this study we explore the contribution of CHD in 22q11DS in psychiatric and neurocognitive outcomes.Methods: 15 school-age children with 22q11DS with CHD (22q11DS+CHD) were assessed using semi-structured interviews, self-report questionnaires and collateral information. The assessment provides psychiatric diagnosis and risk status for psychosis. The participants also performed the Penn Computerized Neurocognitive Battery assessing multiple domains for accuracy and speed. Symptoms, including anxiety, ADHD, obsessive-compulsive and psychosis were compared to 22q11DS without CHD and non-deleted CHD (ND-CHD) controls (matched for age, gender, and heart disease). Neurocognitive domains were analyzed using linear regression between 22q11DS and control groups.Results: There was a significant increase in psychiatric disorders in 22q11DS+CHD than in ND-CHD. The prevalence of psychopathology in ND-CHD group was 20% anxiety disorder, 13% ADHD, and 13% at-risk for psychosis. In comparison the 22q11DS+CHD group had 33% anxiety disorders, 60% ADHD and 73% at-risk for psychosis. The prevalence of co-morbid psychiatric disorders was significantly higher in 22q11DS+CHD than in ND-CHD. There was no significant difference in the prevalence of psychiatric symptoms in the 22q11DS+CHD versus 22q11DS without CHD. While 22q11DS was significantly associated with neurocognitive deficits, presence of CHD did not influence neurocognitive outcomes.Conclusions: CHD in children with 22q11DS does not influence the prevalence of psychiatric symptoms nor does it correlate with neurocognitive deficits observed in 22q11DS.Keywords: 22q11.2 Deletion Syndrome, Congenital Heart Disease, Psychopathology, Neurocognition, PsychosisSupported By: RO1MH087626; RO1MH087636



893. Clock Gene Polymorphism and Metabolic Syndrome in Patients with SchizophreniaIN-WON CHUNG1, 2, Nam-Young Lee1, Tak Youn1, Se-Hyun Kim3, Yong-Min Ahn4, Yong-Sik Kim1

1Neuropsychiatry, Dongguk University International Hospital, Goyang-Si, Korea, Republic of, 2Pharmacogenetics, Institute of Clinical Psychopharmacology, Goyang-Si, Korea, Republic of, 3Human Behavioral Medicine, Seoul National University Medical Research Center, Seoul, Korea, Republic of, 4Psychiatry and Behavioral Science, Seoul National University College of Medicine, Seoul, Korea, Republic of

Background: It is well known that the rates of metabolic syndrome (MetS) in patients with schizophrenia and bipolar disorder are much higher than that of general populations. The genetic susceptibility of MetS in these populations is postulated. So the association between genetic polymorphisms and metabolic parameters in patients with schizophrenia and bipolar disorder was studied with CLOCK genes which have been reported the association with metabolic disturbance.Methods: Genotyping of CLOCK 3111T/C (rs1801260) was conducted in 121 patients with schizophrenia and 110 patients with bipolar disorder. Continuous metabolic syndrome risk score (cMetS) and rate of metabolic syndrome was calculated and their association with polymorphisms was analyzed.Results: Mean values of cMetS and BMI were significantly higher in C allele carriers of CLOCK 311T/C than T allele carriers in patients with schizophrenia (p=0.007 and p=0.026 respectively)., but not in patients with bipolar disorder. However, rate of MetS and mean values of all subcomponents of MetS were not statistically different between patients with C allele and T allele both in patients with schizophrenia and bipolar disorder. Mean values of cMetS and BMI were significantly higher in C carriers of CLOCK 311T/C than TT carriers in patients with schizophrenia (p=0.005 and p=0.030 respectively). Results of analysis according to genotype (C carriers vs. TT carriers) were similar with analysis with allele in both diagnostic groups.Conclusions: The association between polymorphism of CLOCK gene and cMetS and obesity in patients with schizophrenia was demonstrated in this study.Keywords: CLOCK gene, polymorphism, schizophrenia, metabolic syndrome

894. WITHDRAWN

895. CNVS in CHRFAM7A and Their Associations with Expression of CHRNA7 and CHRFAM7AWhitney C. McFadden1, Ye Tianzhang2, Daniel Weinberger2, Joel Kleinman1, Barbara Lipska1

1National Institute of Mental Health, National Institute of Health, Bethesda, MD, 2Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD

Background: CHRNA7 (chr 15q13.3) codes for the α-7 nicotinic acetylcholine receptor thought to have a functional role in cognition via interneuron modulation of dopamine and glutamate signaling. CHRNA7 and its partially duplicated chimeric gene CHRFAM7A have been implicated in schizophrenia through linkage and association studies. We investigated whether a previously reported CNV (a deletion of CHRFAM7A) is enriched in patients with mental illness, and whether it is associated with expression of CHRNA7 and CHRFAM7A mRNA in post-mortem brain.Methods: We performed a high density SNP analysis (Illumina 1M Duo BeadArrays) of CNVs using PennCNV2010 and QuantiSNP, in brain DNA in a large sample of controls and patients with psychiatric disorders (n=600), and examined the effects of deletion of CHRNA7A on gene expression in the dorsolateral prefrontal cortex by Human HT-12_V3 Illumina BeadArrays and quantitative PCR.

Results: We identified four subjects with a hemi-deletion of CHRFAM7A: 2 patients with schizophrenia (out of 195), 1 control subject (out of 161), and 1 subject with major depressive disorder (out of 156). In these subjects, expression of CHRNA7 and CHRFAM7A was not significantly different from all other subjects (p>0.3). There were no cases with the homozygous deletions of CHRFAM7A.Conclusions: We found four subjects with the hemi-deletion of CHRNA7A. There was no relationship between this CNV and expression of CHRNA7 and CHRNA7A. Given the rarity of this CNV and the lack of an associated molecular phenotype, it is unlikely that this hemi-deletion contributes to mental illness.Supported By: NIHMRSP

896. WITHDRAWN

897. Differential Expression of MicroRNAs in Cerebrospinal Fluid in Patients with SchizophreniaJuan A. Gallego1, 2, Todd Lencz1, 2, 3, Marc L. Gordon1, 2, 3, Jason Gentile1, Anil K. Malhotra1, 2, 3

1Psychiatry research, The Zucker Hillside Hospital, Glen Oaks, NY, 2Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, 3Department of Psychiatry, Hofstra North Shore LIJ Health System, Hempstead, NY

Background: Recent studies have linked alterations in miRNA expression to schizophrenia and other psychiatric disorders. However, most of these studies have used post-mortem brain tissue or whole blood as the source of transcript. By contrast, examination of microRNAs in cerebrospinal fluid (CSF) might provide an in vivo biomarker more directly reflecting functional changes in the brain.Methods: Four patients with schizophrenia-spectrum disorders and four healthy volunteers underwent lumbar puncture. Expression of 381 validated microRNAs was assessed from CSF for each of the subjects with the Taqman MicroRNA array (Applied Biosystems), Of those 381 miRNAs examined using microarray analysis, 10 miRNAs (mir-9, mir-34a, mir-125a, mir-132, mir-137, mir-174, mir-195, mir-212, mir-328 and mir-346) were selected for differential expression analysis using t-test.Results: A mean of 180.5 (SD=11.2) miRNAs were obtained in schizophrenia patients and a mean of 136.5 (SD=11) miRNAs were obtained from CSF in healthy volunteers. Approximately one-third of all expressed microRNAs demonstrated robust levels of expression (Ct<30). 58 (23.4%) of the miRNAs were expressed in one or more CSF samples of schizophrenia patients but not in CSF samples from healthy controls. Out of the 10 miRNAs selected for this analysis, four miRNAs were significantly upregulated in schizophrenia patients compared to healthy controls: mir-9 (p=0.005), mir-125b (p=0.01), mir-328 (p=0.001) and mir-346 (p=0.003).Conclusions: Some miRNAs are differentially expressed in CSF in schizophrenia patients compared to healthy controls. Therefore, the investigation of these miRNAs may help establish an illness-specific miRNA signature that could help with a better classification and understanding of schizophrenia.Keywords: MicroRNA, cerebrospinal f luid, schizophrenia, biomarker, gene expressionSupported By: R01MH079800; P50 MH080173-04; M01RR018535

898. Pleiotropy and Power: Methods for Improving Gene Discovery in Psychiatric GWASWesley K. Thompson1, Ole Andreassen2

1Psychiatry, University of California, San Diego, La Jolla, CA, 2Psychiatry, Oslo University, Oslo, Norway

Background: Schizophrenia (SCZ) and bipolar disorder (BD) share several clinical characteristics, including impairment of cognitive functions. Both disorders also have a high heritability, estimated to 0.7-0.8, but are regarded as



complex disorders with a polygenic architecture. However, in published GWAS few SNPs have been discovered in either SCZ or BD that meet GWAS signficance.Methods: We propose a new methodology based on local false discovery rate (locfdr). The locfdr for a given SNP is its posterior probability of null status conditional on its effect size. Our extension of this methodology, termed “covariate modulated local false discovery rate” (cmlocfdr), incorporates pleiotropic relationships of one phenotype with another, potentially leveraging information from multiple GWAS.Results: We found a high level of enrichment of SNP effects for BD when taking into consideration pleiotropy of effects with SCZ. Q-Q plots of effects (Fig. 1) showing the potiential for enormous increases in power to detect true effects below the tradtional GWAS threshold using the cmlocfdr methodology we have developed. This resulted in an almost 50-fold increase in BD SNPs surpassing an fdr cut-off of .05.Conclusions: Our results demonstrate the potentially sizeable gains in power for gene discovery available from incorporating pleiotropic relationships into hypothesis testing. Crucially, this enables us to borrow power from large GWAS for detection and replication of SNPs in smaller GWAS.

Keywords: Schizophrenia, Bipolar Disorder, GWAS, Pleiotropy, Statistical MethodsSupported By: R01AG031224-05

899. Is Met Variant of the BDNF VAL66MET - Combined with Childhood Trauma - A Risk Factor of Brain Abnormalities in Psychoses?Monica Aas1, 2, Unn K Haukvik1, 3, Srdjan Djurovic1, 4, Ørjan Bergmann1, Steinar Lorentzen1, 2, Ole A Andreassen1, 2, Ingrid Agartz1, 3, Ingrid Melle1, 2

1Institute of Clinical Medicine, University of Oslo, Oslo, Norway, 2Psychosis Research Unit, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway, 3Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway, 4Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

Background: Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF Val66Met polymorphism interacts with childhood trauma associated with brain abnormalities in patients with psychoses.Methods: 106 Caucasians with broad DSM-IV schizophrenia spectrum or bipolar disorder (mean±age: 32.67±10.85; gender: 48.6% males) were consecutively recruited to the Thematically Organized Psychosis Study. History of childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ). BDNF Val66Met was genotyped using the Affymetrix Human SNP Array 6.0. Regression analyses were conducted investigating BDNF Val66Met, childhood trauma, and sMRI measures (hippocampus, and lateral ventricles). 1.5 T T1-weighted MRI scans were acquired, and the FreeSurfer software (v 4.5.0) was used to automatically obtain measures of interest. All analyses presented were corrected for age, gender, diagnosis, and intracranial volume. Results were

corrected for multiple comparisons.Results: Met carriers exposed to high levels of childhood sexual abuse present smaller right hippocampal volume (r2 =0.43; p=0.008), and larger right and left lateral ventricles (r2 =0.37; p=0.002, and r2 =0.27; p=0.009, respectively). Met carriers exposed to high levels of physical neglect present larger right and left lateral ventricles (r2 =0.24; p=0.003, and r2 =0.26; p=0.043, respectively), compared to all other groups.Conclusions: Met carriers of the BDNF Val66Met with high levels of childhood trauma demonstrate smaller hippocampal volume, and larger lateral ventricles, compared to all other groups. Our data indicates the importance to take into account both genetic, as well as environmental factors, when targeting brain abnormalities in psychoses.Supported By: This study was funded by the Eastern Norway Health Authority (#2004123, #2006258) and the Research Council of Norway (#190311/V50, #167153/V50).

900. Psychopathology from Childhood to Adulthood in Individuals with Chromosome 22Q11.2 Deletion SyndromeSunny X. Tang1, James J. Yi2, Daneen A. Whinna1, Donna M. McDonald-McGinn3, Margaret C. Souders3, Elaine H. Zackai3, 4, Beverly S. Emanuel3, 4, Ruben C. Gur1, Raquel E. Gur1

1Psychiatry, University of Pennsylvania, Philadelphia, PA, 2Child and Adolescent Psychiatry, Children’s Hospital of Philadelphia, Philadelphia, PA, 3Human Genetics, University of Pennsylvania and Children’s Hospital of Philadelphia, Philadelphia, PA, 4Pediatrics, University of Pennsylvania, Philadelphia, PA

Background: Chromosome 22q11.2 deletion syndrome (DS) is associated with increased risk for a wide range of psychopathology. Our purpose is to characterize the trajectory of multiple psychopathologies in this vulnerable population, with the eventual goal of identifying the key genetic factors that contribute to elevated risk.Methods: This is a cross-sectional study of 117 subjects with confirmed 22q11.2DS. Each was administered a semi-structured assessment including the Structured Interview for Prodromal Symptoms (SIPS) and modified Schedule for Affective Disorders and Schizophrenia for School-age Children (K-SADS). Phenotypes assessed were threshold and subthreshold psychosis, depression, mania, generalized and separation anxiety, obsessions/compulsions, inattention/hyperactivity, and substance use. To compare psychopathology across developmental stages, participants were separated into 4 groups: children (8≤x<12yrs), adolescents (12≤x<18yrs), young adults (18≤x<24yrs), and adults (x≥24yrs). Statistical analyses were done using STATA v12.1.Results: Of 117 participants, 50% are female and 91% are Caucasian. Mean age is 18yrs (range 8-47yrs), with 27% children, 34% adolescents, 18% young adults, and 21% adults. Overall, 13% are psychotic with an additional 42% prodromal/at-risk, 21% are diagnosed with a depressive disorder, 20% with ADHD, and 19% with an anxiety disorder. While anxiety disorders are similarly prevalent across all ages, subthreshold psychosis peaks in adolescents (62%, p=0.001) and depressive disorders in young adults (48%, p<0.001), with a non-significant trend toward increased ADHD in children (32%, p=0.23).Conclusions: The burden of psychiatric diseases changes across development in individuals with 22q11.2DS; children are affected disproportionately by inattention and hyperactivity, adolescents by subthreshold psychosis, and young adults by depressive disorders.Keywords: 22q11.2, psychosis, schizophrenia, genetics, prodromalSupported By: RO1MH087626; RO1MH087636



901. GWAS Analysis and Effect of Migration on Suicide Attempt in Schizophrenia Vincenzo Deluca, Ali Bani Fatemi, Aaron Howe, Roy Kahmi, Nuwan Hettige

Psychiatry, University of Toronto, Toronto, ON, Canada

Background: Schizophrenia, a common psychiatric disorder, increases the risk for suicide. Suicide is a complex behaviour in which genetic factors might play a role in modulating the risk. Here, we conduct a genome-wide association study (GWAS) to search for genetic loci associated with suicide attempt in schizophrenia.Methods: We collected a well characterized sample of 172 patients with schizophrenia recruited from CAMH and genotyped for 2.5 millions single nucleotide polymorphisms (SNP) using the Illumina 2.5 chip.Schizophrenia diagnosis was ascertained by the mean of the structured interview for DSM-IV and the place of birth and lifetime migration was recorded at the time of the interview. The presence of one suicide attempt lifetime was assessed by the means of the Columbia Suicide Severity Rating Scale (C-SSRS). The main outcome considered in this study is the presence of suicide attempt lifetime and the main interacting factor was the presence of migration.Results: We did not find any significant association at genome-wide level and migration did not interact with any SNP in conferring risk for suicide attempt.Conclusions: In summary, this proposal explored a specific hypothesis that migration and genetic factors interact in conferring risk for suicide attempt. We did not find any significant association after multiple test correction, however the same analysis should be performed in larger samples to rule out the effect of genes and migration on suicide attempt in schizophrenia.Keywords: suicide, schizophrenia, genetics, migration, gwasSupported By: CIHR

902. Genomic Survey of Prepulse Inhibition (PPI) and its Sensitivity to Amphetamine (AMPH) in Healthy AdultsSavita G. Bhakta1, Jo Talledo2, Sarah N. Lamb2, Justin Kei2, Brinda K. Rana3, Hsun-Hua Chou2, Neal R. Swerdlow2

1Psychiatry, VISN-22 MIRECC VA San Diego HealthCare System; University of California, San Diego, La Jolla, CA, 2Psychiatry, University of California, San Diego, La Jolla, CA, 3Genetics, University of California, San Diego, La Jolla, CA

Background: Convergent findings suggest that specific genes regulate PPI in humans or animal models; here, we surveyed these gene effects on PPI in healthy adults, and examined their moderating effects on PPI sensitivity to the dopamine (DA) releaser, AMPH.Methods: 60 healthy adults were screened for baseline PPI; the effects of AMPH (placebo vs. 20 mg po) on PPI were then tested in a double-blind, crossover design. Subjects were genotyped by RT-PCR for 13 single nucleotide polymorphisms (SNPs) in 7 genes: COMT, NRG1, CHRNA7, SLC6A3, CSNK1E, GRID2 and GRIK3. Gene effects on baseline PPI and PPI AMPH sensitivity were assessed by ANOVAs, with sex and genotype as between- and AMPH dose and prepulse interval as within-subject factors. Where minor allele frequencies did not permit robust statistical contrasts, genotypes were combined for exploratory analyses.Results: 6 startle “non-responders” were excluded from analyses. Of the 7 genes surveyed in the remaining 54 subjects, ANOVAs suggested significant gene effects on baseline PPI and/or PPI AMPH sensitivity for COMT (rs4680, rs174696 and rs174697) and GRID2 (rs2870699 and rs1583337); both genes also showed evidence for sex-specific effects on PPI or its AMPH sensitivity.Conclusions: These findings support the association of COMT and GRID2 gene expression with differences in PPI and/or PPI AMPH sensitivity and suggest that some of these effects may be mediated via regulation of DAergic substrates, and may be sexually dimorphic. These findings are being extended in a replicate sample to permit a complete assessment of genes with limited frequencies.

Keywords: genotype, prepulse inhibition, Catechol-O-methyl transferase, amphetamine, healthy subjectsSupported By: R01MH065571; R01MH059803; MIRECC

903. Genome-Wide Significant Localization for Working and Spatial Memory: Insights for the Genetics of IntelligenceEmma Knowles1, Melanie A. Carless2, Marcio A. A. De Almeida3, Joanne E. Curran4, David Reese McKay1, Emma Sprooten1, Thomas D. Dyer3, Harald H. Goring3, Rene Olvera5, Peter Fox6, Laura Amasy7, Ravi Duggirala3, Jack Kent3, John Blangero3, David C. Glahn1

1Department of Psychiatry, Yale University, New Haven, CT, 2Texas Biomedical Research Institute, Department of Genetics, San Antonio, TX, 3Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, 4Department of Genetics, Texas Biomedical Research Institute, New Haven, TX, 5Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, 6Imaging, Research Imaging Institute, San Antonio, TX, 7Department of Psychiatry, Texas Biomedical Research Institute, San Antonio, TX

Background: While the genetic influence on intelligence is well established, attempts to isolate genetic loci or specific genes have been met with difficulty; this lack of progress is a reflection, in part, of the phenotypic complexity intelligence. The aim of this study was to characterise the genetic architecture of cognition using phenotypically detailed models rather than relying on general IQ or individual neuropsychological measures.Methods: The sample comprised 1,269 Mexican American individuals from extended pedigrees for whom comprehensive neuropsychological and genetic data were available. Participants were genotyped for 1M SNPs on Illumina microarrays. Three-tier hierarhical models of genetically clustered cognitive traits were subjected to linkage and gene identification analyses.Results: Two significant QTLs were identified for working memory on chromosome 8 (8q24.22 LOD = 4.13 and 8q21.11 LOD = 4.03) and for spatial memory on chromosome 17 (17q23.2 LOD = 3.96 and 17q25.1 LOD = 3.50). No significant association was found for general cognitive ability. Post-hoc analyses revealed genetic variants that contribute to memory ability.Conclusions: Using a new phenotypic approach we identified a number of QTLs for working and spatial memory performance. The creation of detailed and realistic phenotypic models seemingly enhanced the power to detect genetic effects. Spatial and working memory are well-established endophenotypes for psychosis - identifying the genes that influence these phenotypes will provide empirically nominated candidate genes for psychosis.Keywords: Psychosis, Cognition, Linkage, GWAS, IntelligenceSupported By: Financial support for this study was provided by the National Institute of Mental Health grants MH078143 (PI: DC Glahn), MH078111 (PI: J Blangero), and MH083824 (PI: DC Glahn). SOLAR is supported by NIMH grant MH059490 (J Blangero).

904. ABCD-1 Genotype Affects Spontaneous Sleep, but Not Sleep Changes After an AntidepressantAxel Steiger1, Michael Kluge1, 2, Bastian Wollweber1, Martin Dresler1, Alexander Yassouridis1, Manfred Uhr1

1Dept. Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany, 2Department of Psychiatry, University of Leipzig, ;Leipzig, Germany

Background: The ABCB (MDR)1-gene product P-glycoprotein is an integral membrane protein that actively translocates substrates out of the intracellular compartment. One of the major sites of its action is the blood-brain-barrier. It is highly expressed in brain capillary endothelial cells and involved in limiting the access of substrate drugs to the CNS. A SNP of the ABCB1-gene was identified



by Uhr et al and showed a different treatment response to antidepressants depending on the genotype. We tested the hypothesis that healthy subjects with different genotypes of that SNP will have different brain levels of sleep regulating endogenous substances at baseline and of an antidepressant after intake resulting in differences of sleep EEG.Methods: 40 young healthy subjects (20 males, 20 females) participated in the study and were selected for their ABCB1-genotype. Sleep EEG was recorded at baseline and after 6 days of treatment with the 5HT reuptake inhibitor escitalopram.Results: At baseline in male subjects the time spent in rapid eye movement (REM) sleep (TT mean +/- SEM 52.2 +/- 6.5 min vs CT 44.6 +/- 7.1 min) and wakefulness (TT 60.4 +/- 9.9 min vs CT 84.6 +/- 24.6 min) differed between genotypes. As expected sleep EEG was changed after escitalopram, particularly REM sleep was suppressed. However, there was no influence of the genotype on these changes.Conclusions: Our findings suggest an influence of the ABCB-1 genotype on spontaneous sleep regulation in male subjects. In contrast sleep-EEG changes after escitalopram do not appear to be influenced by the genotype.Keywords: ABCB-1-Genotype, Sleep EEG, Biomarker, Escitalopram, Sleep regulation

905. Genetic Determinants Vary Across Early Cigarette Smoking and Nicotine Dependence Phenotypes In AdolescentsNancy C. Low1, Jennifer O’Loughlin2, Aurelie Labbe3, Marie-Helene Roy-Gagnon4, Erika Dugas5, Jamie C. Engert6

1Psychiatry, McGill University, Montreal, QC, Canada, 2Social and Preventative Medicine, University of Montreal, Montreal, QC, Canada, 3Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada, 4Epidemiology, CHU Sainte Justine Research Center, Montreal, QC, Canada, 5Social and Preventative Medicine, University of Montreal Hospital Research Centre, Montreal, QC, Canada, 6Medicine and Human Genetics, McGill University, Montreal, QC, Canada

Background: Most genetic studies on smoking are conducted in adults. While several studies have been undertaken in youth, none investigate more than five genes, and few examine multiple phenotypes concurrently. The objectives of this study were to identify genetic determinants of early smoking and nicotine dependence (ND); to assess if genetic determinants differ across phenotypes; and to examine if the determinants differ according to whether or not the phenotype indicator is uni- or multidimensional.Methods: 371 adolescents participating in a prospective cohort study who reported smoking in at least three of 21 cycles over 7-8 years were identified. 325 single-nucleotide polymorphisms (SNPs) in 23 candidate genes were tested for association with six smoking and ND phenotypes using multiple linear mixed models.Results: 12 SNPs in six genes (ANKK1, DRD2, COMT, DBH, EGLN2, OPRM1) were significantly associated with at least one phenotype. The pattern of association between specific SNPs and ND phenotypes was similar for ICD-10, ND/cravings, self-medication, and to a lesser extent, the mFTQ. Number of cigarettes smoked and withdrawal each had unique patterns of association with the genes investigated.Conclusions: Five of the six genes (11 of the 12 SNPs) identified in this study are involved in the dopamine reward pathway, suggesting that the rewarding psychoactive effects of nicotine may be particularly salient during early smoking. In addition, identified genetic determinants vary across different ND dimensions. Finally, number of cigarettes should not be viewed as a proxy for ND in genetic studies.Keywords: smoking, genetic, nicotine, adolescentsSupported By: Canadian Cancer Society

906. Network Analysis of the Whole Saliva Transcriptome, Psychosocial Stressor Exposure and Tobacco UseAaron Wacholder1, Denise Nishita1, Jessica Bowers2, Judy Andrews3, Andrew W. Bergen1

1Center for Health Sciences, SRI International, Menlo Park, CA, 2Research and Development, Genisphere LLC, Hatfield, PA, 3Oregen Research Institute, Oregon Research Institute, Eugene, OR

Background: We characterized the whole saliva transcriptome in young adults stratified by psychosocial stressor exposure from a population-based longitudinal cohort, the Oregon Youth Substance Use Project.Methods: We conducted genome-wide gene expression analysis on whole saliva RNA using the Affymetrix Gene ST 1.0 array, and we applied Weighted Gene Co-expression Network Analysis (WCGNA) to identify and to relate clusters of correlated genes among 47 samples to clinical, histological, or intracellular organization and functional characteristics.Results: Using WCGNA, we constructed a gene expression network from saliva genome-wide gene expression data, which we found to be similar to a network we constructed from publicly available cell-free saliva genome-wide gene expression data. Functional characterization of the WGCNA modules suggested that most modules shared an expression profile similar to circulating antigen presenting cell types. We identified a significant relation between one module of whole saliva genome-wide gene expression and smoking behavior (p=0.002, multivariate model), and one with psychosocial stressor exposure (p=0.004, multivariate model). The smoking-related module was significantly related to mitochondrial gene expression (p=0.013), and ever-smokers were found to have reduced overall mitochondrial gene expression (0.63 fold). To determine whether reduced expression could be explained by reduction in mitochondrial DNA, we measured mtDNA copy number variation within genomic DNA from 400 OYSUP participants. We found that daily smoking is associated with increased mtDNA copy number (p=0.009).Conclusions: The network structure of whole saliva gene expression reveals likely tissue sources, and significant associations with gender, psychosocial stressors, substance use behavior, and mtDNA copy number.Keywords: salivary transcriptome, weighted coexpression gene network analysis, young adults, psychosocial stressors, ever-smokingSupported By: RC2DA028793

907. DRD2 Variation Predicts Resilience to Substance Use Disorders in High Risk Offspring from Multiplex Alcohol Dependence FamiliesSarah D. Lichenstein1, 2, Jessica W. O’Brien1, 2, Shirley Y. Hill1, 2

1Department of Psychology, University of Pittsburgh, Pittsburgh, PA, 2Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA

Background: Offspring from families with a high density of alcohol dependence are at increased risk for both alcohol and drug use disorders, yet the precise mechanisms by which risk is conferred remains poorly understood. The identification of predictors of resilience to any substance use disorder (SUD) would be of great clinical relevance.Methods: Structural neuroimaging was used to examine orbitofrontal cortex (OFC) volume along with DRD2 variation (SNPrs2677) as predictors of resilience to SUD in a sample of high-risk (HR) offspring from multiplex alcohol dependence families and low-risk (LR) control families. The Multidimensional Personality Questionnaire Control subscale and the Novelty Seeking subscale of the Tridimensional Personality Questionnaire were obtained as measures of impulsivity. Resilience was defined by the absence of any SUD diagnosis by age 20, based on annual clinical assessments.Results: Main effects on SUD outcome were observed for familial risk status



(p=.022) and DRD2 genotype (p=.020), such that LR status and the presence of the c-allele independently predicted resilience in young adulthood. HR offspring also exhibited reduced ratio of right/left OFC volume compared to offspring from control families (p=.008), which was associated with lesser inhibitory control (p=.026) and greater novelty seeking (p=.036).Conclusions: Familial risk is associated with greater likelihood of SUD, reduced volume of the OFC in the right hemisphere, and increased impulsivity. Importantly, familial risk and DRD2 variation predict resilience at age 20.Keywords: Substance Use Disorder, Dopamine D2 Gene, Orbitofrontal Cortex, Impulsivity, High-riskSupported By: NIAAA AA018289; NIAAA AA05909; NIAAA AA015168

908. The Role of FAAHC385A in Human Threat AnticipationFrancisco J. Amador1, Carmen L. Cadilla1, Andrew Holmes2, Gregory J. Quirk1, Karen G. Martinez1

1Psychiatry, UPR School of Medicine, San Juan, PR, 2Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD

Background: FAAH (fatty acid amide hydroxylase) breaks down the endogenous endocannabinoid anandamide. A common genetic variation (FAAHC385A, A-allele) results in 50% less enzyme activity and therefore increased endocannabinoid levels. In humans, the A-allele is associated with increased substance abuse and obesity. A recent publication reports that healthy Caucasian A-allele carriers showed faster habituation during threat (Gunduz-Cinar et al., 2012). Our aim was to investigate fear conditioning, together with neuroticism and threat processingMethods: Forty-eight consenting healthy adults (31 female, mean age 32) were screened with the Structural Clinical Interview, matched by demographics, and grouped as A-allele carriers & C-allele non-carriers from saliva samples. Subjects completed the NEO personality inventory & STAI questionnaires, performed the Emotional Stroop Test (EST), and were trained in fear conditioning and extinction.Results: Our Hispanic population showed a high A-allele frequency (A=0.40, C=0.60, HWE x2=1.2, p=0.297). Both A-allele carriers & non-carriers expressed similar levels of conditioned fear (skin conductance response) during conditioning & recall of extinction phases. However, A- allele carriers showed higher levels of neuroticism (52 vs. 43; p=0.005), and delayed disengagement to threat words in the EST (-4ms vs. -26ms; p=0.024). They also chose lower shock levels (1.9mA vs. 2.7mA; p=0.014). There was no difference in STAI levels.Conclusions: Early findings from EST, neuroticism, and shock level suggest that A-allele carriers have increased anticipation to threat, however, there were no differences in physiological fear responses. The higher frequency of the A-allele within the Hispanic population suggests an increased risk for reward-related pathologies.Keywords: FAAHC385A, endocannabinoids, threat, neuroticism, Emotional Stroop Task

909. GABA B Deficits and Depression Severity in Children and AdolescentsPaul E. Croarkin1, Paul Nakonezny2, Tabatha Melton3, Charles P. Lewis1, Graham Emslie4, F. A. Kozel5, Zafiris J. Daskalakis6

1Psychiatry and Psychology, Mayo Clinic, Rochester, MN, 2Psychiatry and Clinical Sciences, UT Southwestern, Dallas, TX, 3Psychiatry and Psychology, UT Southwestern, Dallas, TX, 4Psychiatry, UT Southwestern, Dallas, TX, 5Psychiatry and Neuroscience, USF, Tampa, FL, 6Psychiatry, Centre for Addictions and Mental Health, Toronoto, ON, Canada

Background: Recent evidence demonstrates that deficits in gamma-aminobutyric acid (GABA) neurotransmission play an integral role in the

pathophysiology of depression but there is a dearth of information with regard to children and adolescents. In the present study we examined the relationship between depression severity and GABA B functioning by measuring the cortical silent period (CSP) in a sample of depressed youth.Methods: The CSP was measured in 24 depressed, child and adolescent subjects with single pulse transcranial magnetic stimulation and electromyography. Subjects maintained tonically active abductor pollicis brevis contraction (20% maximum contraction), with simultaneous stimulation at 140% of resting motor threshold delivered to the contralateral motor cortex. Ten trials were performed bilaterally and the CSP was averaged. Depression severity was assessed with the Quick Inventory of Depressive Symptomatology (QIDS-A17-SR) and the Children’s Depression Rating Scale Revised (CDRS-R). A simple correlation analysis (Spearman’s r) was used to assess the relationship between CSP and two respective depression measures.Results: The mean (SD) CDRS-R of the sample was 59.0(8.6) and the mean (SD) QIDS-A17-SR was 12.5(5.6). Note the length of the CSP corresponds with GABA B neurotransmission. There was an inverse relationship between CSP and both depression measures. This did not reach statistical significance with the CDRS-R (Left hemisphere: r=-0.17, p=0.440; Right hemisphere: r=-0.25, p=0.267) but was statistically significant with the QIDS-A17-SR (Left hemisphere: r=-0.43, p=0.047; Right hemisphere: r=-0.56, p=0.009).Conclusions: This suggests that degree of impairment in GABA B mediated neurotransmission may correlate with depression severity in children and adolescents.Keywords: GABA B, Cortical Silent Period, Children and Adolescents, Depression, Transcranial Magentic StimulationSupported By: NARSAD Young Investigator Award

910. Alterations of Endogenous Cannabinoids in Complex PTSD and Borderline Personality DisorderF. Markus Leweke1, Carola Schaefer1, Juliane K. Mueller1, J. Malte Bumb1, Joachim Klosterkötter2, Martin Hellmich3, Dagmar Koethe4, Christian Schmahl5, Martin Bohus5, Frank Enning1

1Dept. of Psychiatry and Psychotherapy, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany, 2Dept. of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany, 3Institute for Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany, 4Dept. of General Psychiatry, Heidelberg University, Heidelberg, Germany, 5Dept. of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany

Background: The endocannabinoid system plays an important role in the pathophysiology of psychiatric disorders like schizophrenia. Due to its neuromodulatory potential, its role in emotion regulation and in extinction of aversive memory, the endocannabinoid system might be another potential candidate system, affecting a broad range of psychopathology in both, posttraumatic stress disorder (PTSD) and/or borderline personality disorder (BPD).Methods: We addressed the question by analyzing serum levels of the endogenous cannabinoids anandamide and 2 arachidonoyl-sn-glycerol (2-AG) and the structurally related endogenous lipids oleoylethanolamide and palmitoyletnanolamide. Based on our previous approach we developed and validated a specific and sensitive method using high performance liquid chromatography coupled with tandem mass spectroscopy (HPLC-MS/MS). We analyzed human serum samples from patients suffering from BPD (n = 23) or PTSD (n = 21) as well as from matched healthy controls (n=34).Results: Levels of anandamide were significantly elevated in both PTSD and BPD patients (Figure 1A), while palmitoylethanolamide was significantly elevated in BPD with a trend in PTSD and oleoylethanolamide was significantly elevated in PTSD with a trend in BPD when compared to controls. In contrast, 2-AG was significantly elevated in BPD when compared to both, controls and PTSD, where no alteration in 2-AG was found. An independent analysis within



BPD revealed no difference between those patients suffering PTSD in parallel and those who did not.Conclusions: Our data raise evidence that the endocannabinoid system may play a functional role in the pathophysiology of both PTSD and BPD and warrant further investigation of this contribution.Keywords: Endocannabinoid, Borderline Personality Disorder, PTSD, Childhood trauma, Emotion regulationSupported By: Koeln Fortune Program

911. Increased Protein Oxidative Stress in Siblings of Patients with SchizophreniaRaffael Massuda, Joana Bücker, Mariana Pedrini, Bruna S. Panizzutti, Carolina M. Gubert, Pamela Ferrari, Gabriela D. Colpo, Monise Costanzi, Ramiro F. X. Reckziegel, Tiago Aguiar, Flavio Kapczinski, Clarissa S. Gama

INCT Translational Medicine - Molecular Psychiatry Laboratory., Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

Background: There is strong evidence that oxygen free radicals may play an important role in the pathophysiology of schizophrenia (SZ). Increased protein and lipid preoxidation and impaired antioxidant defense have been previously reported in first episodes, early and late stages of SZ. Thiobarbituric acid-reactive substances (TBARS) and Protein Carbonyl Content (PCC) are respectively serum markers of lipid and protein peroxidation. Glutatione Peroxidase (GPx) is an enzyme that works against oxidative damage. The aim of this study was to compare serum TBARS, PCC and GPx in healthy siblings of SZ with controls to determine if oxidative stress (OS) could be considered an endophenotype of SZ.Methods: Thirty-seven healthy siblings of SZ (Sb) (20 females, age mean 37.4 ± 11.4) were compared with thirty-seven healthy controls matched by age (19 females, age mean 37.6 ± 12.2). Diagnoses and screenings were carried out using the SCID.Results: Siblings of schizophrenia showed significant higher PCC than controls (p=0.02), however there were no differences in TBARS (p=0.72) and GPx (p=0.53) measurements.Conclusions: On our concern, this is the first study to access PCC in Sb. It is reasonable to argue that the higher concentration of PCC in Sb could be considered an endophenotype of SZ. We haven’t found differences in lipid OS or altered defenses mechanisms against OS in Sb. Our findings support the hypothesis of a state dependent process of OS in SZ, and support the notion that interventions at the level of OS may be of potential value to treatment.Keywords: Oxidative Stress, TBARS, Carbonyl, GlutationeSupported By: FAPERGS; CNPQ

912. Mapping Psychotic Symptoms on Brain Systems to Disentangle Heterogeneity: The Language, Limbic and Motor System in SchizophreniaWerner Strik

University Hospital of Psychiatry, Bern, Switzerland

Background: Dissociation of thinking, feeling and acting was Bleuler’s rationale to create the term schizophrenia. However, schizophrenic subgroups were never consistently defined according to this conception. Instead, the positive-negative dichotomy and neuropsychological deficits have been used to stratify patient groups for research.Methods: To link characteristic psychotic symptoms to possible dysfunctions of brain systems, we defined auditory hallucinations, thought and motor disorders as quanitative and qualitative deviations from normal functions of the language, the limbic and the motor system. To allow an operational assessment, we developed and validated a clinical rating scale (Bern Psychopathology Scale for Psychoses, BPS; Strik et al, 2010). The scale was applied to stratify patients for functional

and structural brain imaging studies.Results: The symptom distribution in a group of 160 psychotic patients supported three symptom dimensions corresponding to the candidate brain systems, and regional, systems-specific brain abnormalities were linked to the respective symptom domains. In particular, hyperperfusion and reduced grey matter in Wernicke’s area were linked to formal thought disorders, structural abnormalities in the ventral striatum were found in patients with emotional dysregulation, and correlations were found between volume and fractional anisotropy of the right SMA with motor retardation.Conclusions: The results of our clinical and imaging studies support the presence of clusters of psychotic symptoms which are related to structural and metabolic abnormalities of specific brain systems, relevant for human behavior and communication. Providing a new, systematic perspective on Bleuler’s dissociation, these symptom dimensions are unequally affected in different patients, but not mutually exclusive.Keywords: Schizophrenia, Dimension, Brain imaging, Brain systems, PsychopathologySupported By: Swiss National Fund

913. Interactions between Purine Metabolites and Monoamine Neurotransmitters in First-Episode PsychosisJeffrey K. Yao1, 2, 3, George G. Dougherty1, 2, Ravinder D. Reddy2, Debra M. Montrose2, Wayne R. Matson4, Rima Kaddurah-Daouk5, Matcheri Keshavan2, 6

1Medical Research Service, VA Pittsburgh Healthcare System, Pittsburgh, PA, 2Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 3Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, 4Medical Research Service, Bedford VA Medical Center, Bedford, MA, 5Department of Psychiatry, Duke University Medical Center, Durham, NC, 6Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard University, Boston, MA

Background: Schizophrenia is a biochemically complex disorder characterized by widespread abnormalities in multiple pathways whose dynamic interactions, until recently, have been difficult to examine. A metabolomic approach has the potential to yield valuable insights into the likely complex pathophysiological mechanisms, and thereby offer multiple windows of therapeutic opportunities.Methods: Using high-pressure liquid chromatography with a coulometric multi-electrode array system, we are able to simultaneously evaluate multiple metabolites in a network of interacting biochemical pathways between healthy controls (HC) and first-episode neuroleptic-naïve schizophrenia patients (FENNS).Results: There are tightly correlated precursor and product relationships within purine pathways. Although some of these correlations persist across disease or medication status, others appear to be lost among FENNS. As for within-pathway correlations, there are extensive cross-pathway correlations between respective purine and tryptophan pathway metabolites. By contrast, purine metabolites show significant cross-pathway correlation only with tyrosine, not with its metabolites. Furthermore, several purine metabolites (uric acid, guanosine, or xanthine) are each significantly correlated with 5-hydroxyindoleacetic acid (5-HIAA) in HC, but not in FENNS at baseline or 4-week after neuroleptic treatment.Conclusions: Taken together, purine catabolism strongly interacts with the tryptophan pathways leading to serotonin and kynurenine metabolites; this possibly results from general dietary or other common influences upon purines and tryptophan metabolism. The Lack of significant correlations between purine metabolites and 5-HIAA, suggests alterations in key serotonin pathways that may both be modified by and contribute to oxidative stress via purine catabolism in FENNS.Keywords: Schizophrenia, First-episode psychosis, Purine catabolism, Monoamine neurotransmittersSupported By: Supported in part by the VA Merit Review, MH58141, MH45156, and MH84941 grants



914. Heritability of Brain Volume, Cortical Thickness and Surface Area in Psychotic DisordersPranav Nanda1, Christoforos I. Giakoumatos1, Neeraj Tandon1, Ian Mathew1, Elizabeth R. Howard1, Alan N. Francis1, Nicolas R. Bolo1, Brett A. Clementz2, Godfrey D. Pearlson3, John A. Sweeney4, Gunvant Thaker5, Carol A. Tamminga4, Matcheri S. Keshavan1, 6

1Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, 2Psychology and Neuroscience, Bio-Imaging Research Center, University of Georgia, Athens, GA, 3Olin Neuropsychiatry Research Center, Hartford Hospital/Institute of Living, Hartford, CT, 4Psychiatry, University of Texas Southwestern Medical School, Dallas, TX, 5Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 6Psychiatry, Harvard Medical School, Boston, MA

Background: Heritability - the proportion of trait variability due to genetic differences - is one of the requirements a trait has to meet to be an endophenotype. Endophenotypes describe genetically determined phenotypes that may be part of complex illnesses. This study investigated heritability of brain volume, cortical thickness and surface area in patients with psychotic disorders to evaluate these traits as endophenotypes.Methods: Subjects included 222 individuals with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder I, and 290 of their relatives, enrolled in the Bipolar Schizophrenia Network on Intermediate Phenotypes study. Volumes, cortical thickness and surface area were obtained from 3T structural MRI using FreeSurfer software. Heritability was determined by polygenic trait analysis using Sequential Oligogenic Linkage Analysis Routine (SOLAR) covarying for age, sex and intracranial volume.Results: Results showed heritable volumes, cortical thickness and surface area in all lobes, bilaterally (p<0.0001, SE=0.08-0.11). Specifically, heritability values ranged from 0.44 (right limbic) to 0.85 (left temporal) for volume, and from 0.45 (right limbic) to 0.81 (left temporal) for surface area.Conclusions: We found brain structural measures to be heritable, suggesting that they could be viable endophenotypes for psychotic disorders. As endophenotypes these traits would help identify genetic risk factors that often interact with non-genetic factors to produce psychotic syndromes. Future work will involve testing whether these heritable measures meet the other criteria of endophenotypes set by Gottesman and Gould (2003).Keywords: Heritability, Structural MRI, PsychosisSupported By: MH077945; MH077862; MH077851; MH078113; MH085485

915. Obstetric and Perinatal Complications Are Associated with Cortical Folding Abnormalities in Young Relatives at Risk for SchizophreniaJai L. Shah1, 2, 3, 4, Neeraj Tandon1, C. Iraklis Giakoumatos1, Adam Joseph1, Ian Mathew1, Debra M. Montrose5, Diana Mermon5, Jean M. Miewald5, Matcheri S. Keshavan1, 4, 5

1Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, 2Department of Psychiatry, Yale School of Medicine, New Haven, CT, 3Department of Psychiatry, Connecticut Mental Health Center, New Haven, CT, 4Department of Psychiatry, Harvard Medical School, Boston, MA, 5Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA

Background: Individuals with schizophrenia are more likely to have a history of obstetric and perinatal complications (OPCs) than the general population. However, the specific effects of OPCs on brain development remain unclear. One potential manifestation of altered neurodevelopment may be cortical folding (‘gyrification’), a process beginning in the second trimester of gestation and continuing into early life. We explored whether OPCs are associated with gyrification abnormalities in young relatives at risk for schizophrenia.Methods: OPCs for 30 healthy controls and 40 high-risk offspring of individuals

with schizophrenia or schizoaffective disorder were recorded based on maternal recall using a modified version of the Pregnancy History Instrument (PHI). The same adolescent subjects underwent 1.5T structural MRI scanning in Pittsburgh, PA, with automated calculation of a three-dimensional local gyrification index (LGI). ANCOVAs were used to examine differences between high-risk and control groups in PHI scores, regional LGI, and PHI-LGI interaction, covarying for age and gender.Results: Controls and offspring differed in the Toxic subscale of the PHI instrument (p < 0.0001), but not in overall PHI or additional subscales. Group differences in LGI emerged in multiple regions in both hemispheres (p < 0.002-0.05). We found significant region-specific group-by-OPC interactions for LGI using the Toxic, Hypoxic and Other PHI subscales (p < 0.0003-0.05).Conclusions: OPCs are associated with abnormal cortical folding in high-risk offspring. Acquired risk factors such as OPCs may interact with genetic factors to alter neurodevelopmental trajectories, contributing to psychopathology and psychosis. This has important implications for early intervention strategies.Keywords: Gyrification, Cortical folding, Obstetric complications, Perinatal complications, SchizophreniaSupported By: Dupont-Warren Research Fellowship, Harvard Medical School (JS); NIH MH01180, MH64023, MH78113 (MSK); NARSAD Independent Investigator Award (MSK)

916. Increased Visual Gamma Power in Schizo-Affective DisorderJennifer Brealy, Suresh Muthukumaraswamy, John Evans, Krishna Singh, Paul A. Keedwell

Institute of Neuroscience and Mental Health, Cardiff University, Cardiff, United Kingdom

Background: Genetic, preclinical and post-mortem investigations implicate glutamate dysfunction in mood disorder and psychosis. MRS estimates of glutamate/glutamine (GLX) in psychosis and mood disorder are inconsistent and may not relate to functioning at the synaptic level. MEG provides a direct measure of neuronal function. Fast (gamma) oscillations may index AMPA glutamate receptor function: AMPA antagonists and ketamine reduce and increase induced gamma power IGP, respectively, in rodents. The aim of this study was to investigate the relationship between GLX and IGP in schizoaffective disorder SAD and healthy controls.Methods: Sustained IGP responses to a simple visual grating stimuli were recorded in 10 remitted SAD and 17 age/sex matched controls using a 275 channel MEG. Power-frequency plots were derived using beamformer analysis. SABP patients were taking a variety of psychotropic medications.Results: There was a trend toward a positive correlation between GLX and IGP in healthy volunteers (p=0.1) but not SAD. SAD had significantly higher sustained IGP compared with controls (p=0.002). There were no group differences in GLX (p=0.986).Conclusions: Remitted SAD individuals have increased IGP, suggestive of greater cortical excitability/coherence. This could relate to increased glutamate activity: increases in somato-sensory peak gamma power were observed in depressed individuals in response to ketamine in a recent study. Further research is required to separate effects of illness and medication on IGP and GLX in psychosis and mood disorder.



Keywords: Gamma, Schizoaffective disorder, MEG, Mood disorder, PsychosisSupported By: Academy of Medical Science

917. Improvement in Attention After Antipsychotic Dose Reducton in Late-Life Schizophrenia: A Pilot Pet-Cognition StudyShinichiro Nakajima1, 2, 3, Tarek Rajji1, 3, Hiroyuki Uchida1, 2, Takefumi Suzuki2, Fernando Caravaggio1, Philip Gerretsen1, 3, Benoit Mulsant1,3, Bruce Pollock1, 3, David Mamo1, 3, 4, Ariel Graff-Guerrero1, 3

1Geriatric Mental Health Program, Centre for Addiction and Mental Health, Toronto, ON, Canada, 2Department of Neuropsychiatry, Keio University, School of Medicine, Tokyo, Japan, 3Department of Psychiatry, University of Toronto, Toronto, ON, Canada, 4Department of Psychiatry, University of Malta, Malta

Background: Dopamine receptor blockade by antipsychotics may be a contributing factor to cognitive impairment in schizophrenia. Our previous studies using population pharmacokinetics or positron emission tomography (PET), suggested that individuals with schizophrenia with an estimated dopamine D2/3 receptor (D2/3R) occupancy level of ≥ 75% were more cognitively impaired, in particular, in attention. However, causal attribution could not be made because of their cross-sectional design.Methods: In an open-label prospective PET study, participants ≥50 years with schizophrenia clinically stable for 6 months underwent a gradual 40% antipsychotic dose reduction. Clinical and cognitive assessments were performed before and after the dose reduction. The D2/3R occupancy in the putamen was assessed using [11C]-raclopride PET scans, before and after the dose reduction.Results: Eight participants were included in this analysis. During the dose reduction, the D2/3R occupancy in the putamen decreased from 73±8% to 62±11% (the median = 9%). Cognitively, the large change group (19.2 + 6.9%) experienced a significant larger improvement in attention than the small change group (2.6 + 1.8%) (p = 0.042). No difference was observed in any other cognitive measures. The changes in attention and D2/3R occupancy were linearly correlated.Conclusions: This preliminary result extends the current literature on the relationship between D2/3R blockade and deficits in attention in schizophrenia. This also suggests that these deficits are potentially reversible with appropriate dosing. In the absence of a clinically effective cognitive treatment, antipsychotic dose reduction may be an option to minimize the cognitive impairment in this population.Keywords: antipsychotics, schizophrenia, cognition, dosing, geriatricsSupported By: Canadian Institutes of Health Research (MOP-97946); National Institutes of Health (RO1MH084886).

918. Reinforcement Learning and Working Memory Deficits in Schizophrenia PatientsFlorian Schlagenhauf1, 2

1Dep. of Psychiatry, Charite Universitätsmedizin Berlin, Berlin, Germany, 2Max Planck Fellow Group “Cognitive and affective control of behavioural adaptation”, Max Planck Institute for Human and Cognitive Brain Sciences, Leipzig, Germany

Background: Abnormalities in reinforcement learning and working memory are a key finding in schizophrenia patients potentially related to dysfunctional dopaminergic neurotransmission. The ability to form predictions about future outcomes is fundamental for environmental interactions and depends on neuronal teaching signals, like reward prediction errors (PE). Dysfunctional PE signaling was conceptualized to contribute to aberrant salience and positive symptoms.Methods: Schizophrenia patients and healthy controls underwent functional MRI during a WM task and a reversal learning task. Dynamical causal modeling was used to assess effective connectivity during WM task. Detailed computational modeling was applied to analyze reversal learning performance and was utilized for model-based fMRI.Results: Prefrontal activation differences during WM between patients and controls were mediated by task performance while WM-dependent effective connectivity from prefrontal to parietal cortex was reduced in schizophrenia patients independent of performance and current psychopathology. During reversal learning, we found that unmedicated schizophrenia patients display reduced PE activation in the ventral striatum (VS). However, modeling task strategies revealed that a substantial number of psychotic patients did not adjust their behavior according to PEs and therefore this finding may be confounded by different task-solving strategies between patients and controls.Conclusions: Taken together these results show the contribution of fronto-parietal dysconnectivity to WM deficits and the role of the VS in reinforcement learning in schizophrenia patients. Reduced effective WM-dependent connectivity may prove a potential diagnostic marker.Keywords: schizophrenia, reinforcement learning, functional imaging, effective connectivitySupported By: German Research Foundation

919. Duration of Untreated Psychosis and Brain Activation During Letter Fluency Task in Schizophrenia: A Multi-Channel Near-Infrared Spectroscopy StudyPo-Han Chou1, 2, Shinsuke Koike1, Ryu Takizawa1, Yukika Nishimura1, Yoshihiro Satomura1, Shingo Kawasaki3, Kiyoto Kasai1

1Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2Department of Psychiatry, Taichung Veterans General Hospital, Taichung City, Taiwan, 3Optical Topography Group, Application Development Office, Hitachi Medical Corporation, Tokyo, Japan

Background: Duration of untreated psychosis (DUP) is associated with poor clinical outcomes in patients with schizophrenia. However, little is known between DUP and brain function. In this study, we investigated the influences of DUP on brain functions in schizophrenia using near-infrared spectroscopy (NIRS).Methods: A total of 44 patients, including 19 with first episode psychosis (FEP) and 25 with chronic schizophrenia (CSZ) matched for IQ and gender were recruited. Mean oxygenated hemoglobin ([oxy-Hb]) changes in 52 channels during the letter fluency task were measured as an index of brain activation by using multi-channel NIRS and DUP data were logarithmically transformed for the skewed distribution. We then analyzed the correlation between DUP and [oxy-Hb] changes in each group adopting the false discovery rate (FDR) method.



Results: In patients with CSZ, there is significant negative correlation between DUP and brain activation in channels approximately in left superior and middle temporal gyrus, right dorsolateral prefrontal cortex, right inferior frontal gyrus, and right frontopolar area (FDR-corrected p=0.0003 to 0.0087, r=-0.709 to -0.533). However, in FEP patients, there is no correlation between DUP and brain activation in all 52 channels.Conclusions: DUP is negatively correlated with brain activation in CSZ patients, and this correlation is not observed in FEP patients. Previous study revealed that, for FEP patients, the influence of DUP on clinical outcomes is not obvious at first presentations, which is consistent with our results. However, larger studies are warranted to validate our findings.Keywords: DUP, duration of untreated psychosis, schizophrenia, first episode psychosis, NIRSSupported By: Hitachi Medical Corporation

920. Progressive Gray Matter Volume Reduction in Parietal Lobe in First-Episode SchizophreniaTaiga Hosokawa1, Martha E. Shenton1, Margaret Niznikiewicz1, Dean F. Salisbury2, Elisabetta del Re1, Robert W. McCarley3

1Psychiatry, Harvard Medical School, Boston, MA, 2Cognitive Neuroscience Laboratory, McLean Hospital, Belmont, MA, 3Psychiatry, Boston Veterans Affairs Healthcare System, Brockton, MA

Background: Schizophrenia studies suggest progressive gray matter (GM) volume reduction in frontal and temporal lobe. However, few studies have evaluated parietal lobe despite its important roles in attention, memory and thought abnormal in schizophrenia.Methods: We performed longitudinal studies in first-episode schizophrenia (FESZ) and first-episode affective psychosis (FEAFF) patients. 1.5-Tesla MRI scans were obtained from 21 FESZ and 24 FEAFF at first hospitalization for psychosis and 23 matched healthy control (HC). They underwent follow-up scans 1.5 years later. We segmented parietal lobe into angular gyrus (AG), supramarginal gyrus (SMG), postcentral gyrus (PCG), superior parietal gyrus (SPG) and precuneus, and performed gyri-based manual drawing to measure GM volumes. We examined the volume changes and analyzed correlations with clinical symptom measures such as BPRS and PANSS.Results: Group comparisons by ANOVA revealed bilateral AG, PCG and precuneus GM volumes in FESZ were significantly smaller than those of HC and FEAFF at initial scans as well as follow-up. Longitudinally, the decrease in bilateral AG was significantly larger than other subregions. Some changes of clinical scores including thought disturbance correlated with the volume changes.Conclusions: FESZ showed smaller bilateral AG, PCG and precuneus GM volumes even at early stage of illness, and progressive reduction in inferior parietal lobe, particularly AG. Inferior parietal lobe is brain region plays critical role as biological substrate of thought. Inferior parietal lobe and precuneus belong to default mode network corresponds to self-referential thought. This finding contributes to comprehensive understanding of neural substrates of thought disorder in schizophrenia.Keywords: First-episode Schizophrenia, First-episode Affective Disorder, Neuroimaging, Longitudinal Study, Parietal LobeSupported By: R01MH40799; R01MH052807; R01MH50747; K02MH01110

921. Shifted Neuronal Balance During Stimulus-Response Integration in Schizophrenia - An FMRI StudyEdna C. Cieslik1, Veronika Müller1, Tanja Kellermann2, Christian Grefkes3, Sarah Halfter2, Simon B. Eickhoff1

1Institute for Clinical Neuroscience and Medical Psychology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany, 2Dept. of Psychiatry, University Hospital Aachen, Aachen, Germany, 3Dept. of Neurology, University of Cologne, Cologne, Germany

Background: Schizophrenia is characterized by deficits in psychomotor and executive functions, with consistent dysfunctional control of goal-directed actions in anti-saccade tasks. Recent studies, however, suggest that the anti-saccade represent only one manifestation of more general deficits of stimulus-response (SR) integration.Methods: Neuronal correlates of SR integration were investigated using a manual SR compatibility task in eighteen schizophrenic patients and eighteen matched controls. Gradient EPI volumes were acquired on a 3T scanner and analyzed using SPM8. All reported results were significant at p<0.05 (cluster level FDR-corrected).Results: Incongruent vs. congruent responses revealed common activation across groups in a parietal-premotor-prefrontal circuitry. When testing for the main-effect across all conditions, patients showed significantly lower activation of the right DLPFC and, in turn, increased activation in a left hemispheric network including parietal and premotor areas and the supplementary motor area. When testing for condition specific group differences, during incongruent responding patients showed increased activation in the same left hemispheric network. However, these activations were even more pronounced than those found for the main effect across conditions and accompanied by additional activation in parietal and premotor regions in the right hemisphere.Conclusions: The present study shows that hypoactivity in the right DLPFC in schizophrenia is accompanied by hyperactivity in several fronto-parietal regions associated with task execution. This hyperactivity is present during general task performance but is even more pronounced during incongruent responding. Impaired top-down control due to a dysfunctional DLPFC might thus be partly compensated by an up-regulation of task-relevant regions in schizophrenia.Keywords: Executive control, Schizophrenia, Prefrontal, Parietal, SpatialSupported By: R01-MH074457-01A1

922. Negative Schizotypy and Positive Schizotypy Show Different Abnormalities in Brain Structure and Resting-State Spontaneous ActivitiesYi Wang1, Chao Yan1, Ming-xia Fan2, Da-zhi Yin2, Ci-ping Deng3, Raymond CK Chan1

1Neropsychology and Applied Cognitive Neuroscience Lab, Key Lab of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China, 2Shanghai Key Laboratory of MRI, East China Normal University, Shanghai, China, 3Department of Psychology, East China Normal University, Shanghai, China

Background: Individuals with schizotypy are characterized by a set of behavioural and personality features similarity but in a milder manifestation to those of clinical symptoms demonstrated in patients with schizophrenia. It has been suggested that schizotypy can be decomposed into some dissociable subtypes similar to the subtypes of schizophrenia-like symptoms. However, very little is known about the differential impairment of brain structures and spontaneous brain activity in schizotypy subtypes.Methods: Based on the Chapman Psychosis Proneness Scales, sixty-four participants (11 negative schizotypy, 16 positive schizotypy, 16 mixed schizotypy, and 21 healthy controls) were identified and invited to participate the subsequent brain scans. 3T whole brain T1-weighted images and resting state images were



acquired. Segmentations of grey and white matter were conducted using VBM DARTEL. Amplitudes of low-frequency fluctuation (ALFF) and fractional ALFF were generated using REST. Structural and resting state images comparisons were analyzed among subgroups using SPM8.Results: Positive schizotypy showed grey matter reduction anda lower ALFF and fALFF value in superior temporal gyrus. For negative schizotypy, however, significant differences were demonstrated in the grey matter reduction in superior/inferior frontal gyrus, and a higher ALFF value in frontal lobe. Higher white matter density was found in both negative and positive schizotypy in superior longitudinal fasciculus (SLF).Conclusions: The preliminary findings suggested that schizotypy, particularly the negative schizotypy, demonstrated structural abnormalities in frontal lobe, and spontaneous activity changes on temporal lobe.Keywords: schizotypy, VBM, resting-stateSupported By: XDB02030200; 81088001; 91132701; KSCX2-EW-J-8;2012BAI36B01

923. CYP3A43 Genetic Variants Affect Brain FunctionJeran Trangle, Kristin Bigos, Daniel Weinberger

Pharmacogenetics, Lieber Institute for Brain Development, Baltimore, MD

Background: Cytochrome P450 genes are known for their role in xenobiotic metabolism. The CYP3A43 isoform is highly expressed in human brain and therefore may impact brain function. We previously identified CYP3A43 SNPs that are associated with antipsychotic drug metabolism. In this study, we aimed to test whether these CYP3A43 SNPs, which presumably alter enzyme function, also impact brain activity.Methods: Healthy subjects completed 3 functional MRI tasks, targeting brain regions implicated in psychiatric illness: the N-Back working memory task (n=505), an emotional memory task (n=277), and an emotional face matching task (n=339). Subjects were grouped by genotype and matched for age, sex, IQ, years of education, and task performance. BOLD fMRI data was analyzed using SPM5, with a threshold of Puncorrected<0.001 for whole brain analyses and PFDRcorrected<0.05 for all ROIs. A linear regression was used to test the relationship between CYP3A43 genotypes and temperament measures using the NEO.Results: CYP3A43 SNPs (rs680055, rs472660, rs61469810) significantly predict neural activity. Healthy subjects carrying a frame shift mutation (hemideletion of A allele; rs61469810) have increased left medial frontal cortical activity during the encoding of aversive scenes (Punc.<0.001, PFDR=0.061, T=4.15). Healthy subjects carrying an A allele of the intronic SNP rs472660 and the missense mutation CC genotype (rs680055) each separately predict decreased amygdala activity during the matching of emotional faces (Punc.<0.001, PFDR<0.010, T>3.43).Conclusions: This study shows that genetic variation in CYP3A43 significantly predicts brain activity in the amygdala, middle frontal gyrus, hippocampus and parahippocampus; all regions implicated in psychiatric illness.Keywords: CYP450, fMRI, Brain, Humans, Genetics

924. Neural Correlates of Reward Processing in Adults with 22Q11DsLiesbet Goossens1, Koen Schruers1, Fabiana da Silva Alves2, Nicole Schmitz2, Johan van der Meer3, Thérèse van Amelsvoort1

1Psychiatry & Psychology, Maastricht University, Maastricht, Netherlands, 2Dept. of Psychiatry, Academic Medical Centre Amsterdam, Amsterdam, Netherlands, 3Dept. of Clinical Neurophysiology, Academic Medical Centre Amsterdam, Amsterdam, Netherlands

Background: 22q11 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22. The gene coding for catechol-O-methyl-transferase (COMT) is located at the deleted region, resulting in COMT haplo-insufficiency and disrupted dopaminergic neurotransmission in 22q1DS which is thought to contribute to their increased risk to develop psychosis. Reward processing deficits are present in psychosis and have been associated with dopaminergic abnormalities. Reward processing has not yet been investigated in 22q11DS.Methods: This study aims to investigate neural activity during anticipation of monetary reward and loss in adult patients with 22q11DS. We measured blood-oxygen-level dependent activity in 16 patients with 22q11 DS and 12 healthy controls during a monetary incentive delay task using a 3T Philips Intera MRI system. Data were analyzed using SPM8.Results: During anticipation of reward the 22q11DS group alone displayed significant (p<0.05 corrected) activation in left parietal brain regions. Compared to healthy controls, the 22q11DS group had significantly less activation in left cingulate regions during anticipation of reward. ROI analysis of striatum revealed significant activation in controls but not in the 22q11DS group. During anticipation of loss, both groups activated frontal brain regions. Between group comparisons revealed no significant differences in activation during anticipation of loss.Conclusions: This is the first study to investigate reward processing in 22q11DS. Our preliminary results suggest that people with 22q11DS fail to activate brain regions that are normally implicated in reward processing. Abnormalities in the reward circuitry in 22q11DS could explain vulnerability for psychosis in these patients.Keywords: Reward, 22Q11DS, fMRI, psychosis, MIDSupported By: NARSAD

925. Striatal Dopamine Receptor Binding in People at Clinical and Genetic High Risk for PsychosisTherese van Amelsvoort1, Erik Boot2, Oswald Bloemen2, Mariken de Koning2, Jan Booij3

1Department of Psychiatry and Psychology, Maastricht University, Maastricht, Netherlands, 2Department of Psychiatry, Academic Medical Centre, Amsterdam, Netherlands, 3Department of Nuclear Medicine, Academic Medical Centre, Amsterdam, Netherlands

Background: Psychosis is accompanied by increased mesolimbic dopaminergic neurotransmission. Moreover, dopaminergic abnormalities have been observed in people at clinical high risk prior to emergence of clinical psychosis. People with 22q11 deletion syndrome (22q11DS) are at genetic high risk (30%) of developing psychosis, probably partially because of catechol-O-methyltransferase (COMT) haplo-insufficiency. 20-30% of people at clinical high risk for psychosis according to standard ultra-high risk criteria (UHR) will make a transition to psychosis within 2-3 years. We wished to study whether there are any differences in dopamine receptor binding between genetic and clinical high risk populations.Methods: We included 15 adults with 22q11DS without previous psychiatric history and 16 adults fulfilling standard criteria of UHR by means of CAARMS assessments. All participants were antipsychotic- and psychostimulant naive. Striatal dopamine receptor binding was determined using 123I-IBZM SPECT. Data were analysed using SPSS version 20. Dopamine receptor binding was correlated to PANSS scores.



Results: Dopamine receptor binding was significantly higher in the 22q11DS (1.18 ± 0.18) group compared to the UHR group (0.84 ± 0.15; p< 0.000). This remained significant after correction for age. PANSS total and positive symptom scores were significant higher in the UHR group compared to the 22q11DS group (p < 0.000 and p < 0.03 respectively). There was a negative correlation between positive symptoms and dopamine receptor binding in the UHR group, but not in the 22q11DS group.Conclusions: Dopamine receptor binding and its relation with positive symptoms is different in genetic versus clinical high risk populations.Keywords: DOPAMINE, PSYCHOSIS, 22Q11DS, UHR, SPECTSupported By: NARSAD, ZonMW

926. Structural Abnormalities of the Fusiform Gyrus in Patients with Childhood-Onset Schizophrenia, Their Nonpsychotic Siblings, and Healthy VolunteersHarrison McAdams, Marcel E. Moran, Sarah Johnson, Brian Weisinger, Reva Stidd, Deanna Greenstein, Rachel Miller, Liv Clasen, Andy Mattai, Judith L. Rapoport, Nitin Gogtay

Childhood Psychiatry Branch, National Institute of Mental Health, Bethesda, MD

Background: The fusiform gyrus has been indicated in the regulation of facial perception, an essential aspect of human communication. Abnormalities in the activity of the fusiform gyrus have been reported in patients with both autism spectrum disorders (ASD) as well as schizophrenia, both mental disorders characterized in part by the inability to form normal social relationships. Of great importance in psychiatric research is determining the physical basis of these deficits, and discerning their trait marker or state marker nature.Methods: Patients with Childhood-Onset Schizophrenia (COS) (n = 101, 264 scans), a rare, severe, and continuous form of schizophrenia, their full nonpsychotic siblings (n = 79, 176 scans), and unrelated healthy volunteers (n = 101, 258 scans) were followed longitudinally with structural magnetic resonance imaging scans at two-year intervals. Automated brain imaging software segmented the fusiform gyrus of each individual with resultant volume measurements.Results: Patients with COS had significantly reduced left, right, and total fusiform gyrus volume (p > 0.01), after adjusting for multiple comparisons. Healthy siblings of patients with COS did not differ from controls significantly in total fusiform volume, suggesting that this deficit is a marker of the disease state. A high proportion (30-50%) of patients with COS are comorbid for ASD, and when the COS patients were classified by ASD diagnosis; those with a positive diagnosis had significantly increased fusiform gyrus volume.Conclusions: This evidence fits strongly with other evidence linking ASD patients with oversized brain regions, and emphasizes the specific time course of both disorders.Keywords: fusiform, schizophrenia, childhood, mri, structuralSupported By: NIH Intramural Research Program

927. At the Boundary of the Self: Abnormalitites in the Insular Cortex in Patients with Childhood-Onset Schizophrenia, their Healthy Sibling and Normal VolunteersMarcel E. Moran, Brian Weisinger, Deanna Greenstein, Pete Gochman, Rachel Miller, Judith Rapoport, Nitin Gogtay

Child Psychiatry, National Institute of Mental Health, Bethesda, MD

Backgrounds: The insular cortex (insula), whose normal function involves delineating the boundary between self and non-self stimuli, has been implicated in the pathophysiology of the positive symptoms of schizophrenia, including hallucinations and delusions. Childhood-Onset Schizophrenia (COS) with the onset of psychosis before age 13, is a severe and continuous form of the illness

which shows profound and global progressive cortical brain abnormalities during adolescence which merge in the adult pattern with age.Methods: Using prospectively acquired anatomic brain magnetic resonance imaging (MRI) scans, a matched sample of COS patients (n = 98; 234 scans), their non psychotic full siblings (n = 71; 153 scans) and healthy volunteers (n = 100; 248 scans), we measured insular volume using the FreeSurfer automated software.Results: COS patients had significantly lower right (p = 0.003), left (p < 0.001), and total (p < 0.001) insular volumes than healthy volunteers. Right insular volume negatively correlated with positive symptoms as measured by SAPS (p = 0.02), while both left and right insula volumes were positively correlated with overall functioning, as measured by the Children’s Global Assessment Scale (CGAS) scores (p = 0.006). COS siblings, on the other hand, did not differ significantly from normal volunteers suggesting that the insular deficits are more related to the illness state than a familial endophenotype.Conclusions: These results highlight the salience of the insula in positive symptoms of schizophrenia perhaps resulting from the inability to discriminate between self from the non-self in COS. Further work to connect insular deficits to other neurocircuitries is warranted.Keywords: Schizophrenia, Imaging, MRI, Endophenotype, PsychosisSupported By: NIH Intramural Research Program

928. Resting State Oscillatory Brain Dynamics During Adolescence in Childhood-Onset SchizophreniaNora S. Vyas1, Daniel Y. Rubinstein2, Gang Chen3, Frederick W. Carver2, Deanne Greenstein1, Tom Holroyd2, Brian Weisinger1, Christopher N. David1, Cheryl Turner1, Liv Clasen1, Rachel Miller1, Richard Coppola2, Judith L. Rapoport1, Nitin Gogtay1

1Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 2MEG Core Facility, National Institutes of Health, Bethesda, MD, 3Scientific and Statistical Computing Core, National Institutes of Health, Bethesda, MD

Background: The “resting-state” network of brain function is reported to be differentially affected in schizophrenia. We examined resting-state networks using magnetoencephalography (MEG) in childhood-onset schizophrenia (COS) patients, compared to healthy controls. We hypothesized a lack of theta and gamma brain oscillatory activity in COS patients compared to healthy controls.Methods: 36 COS probands (17.56±3.97), and 36 normal volunteers (17.74±5.19) received a 4-minute eyes-closed resting-state MEG. 3-D brain activity was determined using synthetic aperture magnetometry across all major frequency bands. The power in each brain voxel was calculated across 220secs of the 4-minute resting-state sequence.Talairach-aligned volumes were computed to produce two 3D-mean maps of brain activity, and compared using linear mixed-effects modelling, followed by false discovery rate (FDR) correction.Results: COS showed reduced activity in the alpha bandwidth in the insula, but increased activity in the precuneus, compared to healthy controls (P=.01,q=.05), and reduced activity in the theta band in the insula (P=.008,q=.05). COS also showed reduced activity in the gammabandwidth in the occipital regions, including the cuneus, precuneus and lingual gyrus (P<0.001,uncorrected) in comparison to healthy controls.Conclusions: COS showed reduced activity for the alpha band in the insula, a region sustained by isolated thalamic networks, and increased activity in alpha in the precuneus, a key node in the resting-state network, that also shows abnormal activity in adult onset schizophrenia. Reduced ability to differentiate external versus internal stimuli in schizophrenia may be relevant to our findings of reduced activity in gamma bandwidth in the precuneus region during resting-state.Keywords: schizophrenia, adolescence, resting state, default-mode network, MEGSupported By: NIH Intramural Research Program. NSV is supported by the Fulbright Distinguished Scholar Award by the US-UK Fulbright Commission.



929. Auditory Abnormalities in Schizophrenia: A Study of Magnetoencephalography (MEG), Cortical Thickness and Diffusion Tensor Imaging (DTI)Jose M. Canive

Psychiatry and Neurosicences, New Mexico VA Health Care System and University of New Mexico, Albuquerque, NM

Background: Both electrophysiological and fMRI studies have shown superior gemporal gyrus (STG) and frontal abnormalities in schizophrenia (SZ) when processing auditory information. The goals of this study were to examine association between functional (STG and prefrontal cortex (PFC) auditory responses) and structural measures (STG and PFC cortical thickness and STG-PFC white matter tracts).Methods: The paired-click task was administered to 19 SZ (14 males) and 21 HC (15 males) subjects while 306-channel MEG was collected. T1-weighted structural MRI was obtained for magnetic source analysis and cortical thickness. VESTAL (Huang et al., 2006) source analysis examined 50ms and 100ms first-click activity. DTI was used to map white matter tracts connecting STG and PFC regions identified in MEG group maps.Results: Decreased left STG and abnormal PFC M50 and M100 activity (decreased right inferior frontal and increased superior frontal activity) was observed in SZ than HC. SZ had less STG and PFC cortical thickness than HC bilaterally. Groups did not differ on STG-PFC white matter integrity. In HC only, left gray and white matter predicted 44% and 60% of left STG M50 and M100 source strength, respectively.Conclusions: Findings of decreased left 50 and 100 ms STG activity and abnormal frontal activity in SZ indicate that SZ engage different STG-PFC pathways than HC when encoding auditory information. Left STG cortical thickness as well as left STG-PFC white matter integrity predicted left STG M50/M100 source strength in HC but not SZ, supporting the hypothesis of fronto-temporal dysconnectivity in SZ.Keywords: Auditory processing abnormalities, Schizophrenia, MEG, DTI, ConnectivitySupported By: VA Merit CSR&D: IIR-04-212-3; 2R01 MH065304

930. Psychosis as a Dimensional Construct: Cortical Development in Schizophrenia Spectrum Diagnosed Siblings of Patients with Childhood-Onset SchizophreniaKatharine Ludovici, Brian Weisinger, Deanna Greenstein, Liv Clasen, Francois Lalonde, Rachel Miller, Peter Gochman, Judith Rapoport, Nitin Gogtay

Child Psychiatry, NIMH, Bethesda, MD

Background: Cerebral gray matter (GM) deficits in childhood-onset schizophrenia (COS) are progressive during adolescence, beginning in the parietal lobe and spreading to the temporal lobe and the prefrontal cortex. Recent evidence shows that healthy, nonpsychotic siblings of COS siblings share some of these GM abnormalities, providing support for the familial/genetic-loading model of COS, which however normalize in siblings by age 17. We investigated this framework further by examining cerebral GM in schizophrenia spectrum diagnosed siblings of patients with COS, who may be viewed as phenotypic intermediates between COS patients and their healthy siblings.Methods: Eleven schizophrenia spectrum diagnosed siblings of COS patients (aged 11 through 28), 22 unrelated healthy siblings, and 28 controls matched for age and gender were scanned every two years and MRI data measuring cortical GM was collected. Type I error was controlled for per hemisphere using the false-discovery rate (FDR) procedure.Results: Significant GM deficits in both the prefrontal and temporal regions remained through age 20 in schizophrenia spectrum siblings (t statistic > 2, corrected), while healthy siblings showed early deficits in the same regions that

normalized by about age 17. In spectrum siblings, symptom severity positively correlated with GM loss. There were no trajectory differences between the three subject groups.Conclusions: Schizophrenia spectrum siblings show an intermediate degree of GM loss compared to COS patients and non-psychotic siblings. Such results add support to the familial/genetic model of COS and promote the idea of psychosis as a dimensional construct.Keywords: schizophrenia, psychiatry, imaging, childhood, psychosisSupported By: NIH Intramural Research Program

931. Predictions Break Down Between Motor Plans and Their Consequences in SchizophrneiaVanessa Palzes

Psychiatry, San Francisco VA Medical Center, University of California, San Francisco, California, USA, San Francisco, CA

Background: Motor actions are preceded by an efference copy of the motor command, resulting in a corollary discharge of the expected sensation in sensory cortex. These mechanisms allow animals to predict sensations, suppress responses to self-generated sensations, and thereby process sensations efficiently and economically. During talking, patients with schizophrenia show less evidence of pre-talking activity and less suppression of the speech sound, consistent with dysfunction of efference copy and corollary discharge, respectively. We asked if patterns seen in talking would generalize to pressing a button to hear a tone, a paradigm translatable to less vocal animals.Methods: In 28 patients (26 schizophrenia, 2 schizoaffective) and 23 healthy controls, suppression of the N1 component of the auditory event-related potential was calculated by subtracting N1 to a playback of tones from N1 to tones delivered by a button press. The lateralized readiness potential (LRP) associated with the motor plan preceding the press was calculated by subtracting left from right hemisphere neural activity. The relationship between N1 suppression and LRP amplitude was assessed.Results: Patients had less N1 suppression to the tones resulting from the button press. LRP amplitude and N1 suppression were correlated in controls but not in patients.Conclusions: These results suggest better motor planners (with larger LRPs) are better at suppressing the sensory consequences of their actions. Effects seen during vocalization extend to other motor acts. Together they suggest a break down in predictions resulting from self-generated actions in psychosis.Keywords: Schizophrenia, ERP, Corollary discharge, Prediction errorSupported By: NIMH, San Francisco VA Medical Center

932. Resting State FMRI in Schizophrenia and Bipolar DisorderMiklos Argyelan1, Toshikazu Ikuta1, Pamela DeRosse1, Raphael J. Braga1, Katherine E. Burdick2, Majnu John1, Peter B. Kingsley3, Anil K. Malhotra1, Philip R. Szeszko1

1Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, 2Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, 3Department of Radiology, North Shore University Hospital, Manhasset, NY

Background: Both schizophrenia and bipolar disorder overlap in their clinical manifestation, which has been supported by recent genetic findings. Neuroimaging, in particular resting state fMRI (rsfMRI), offers a performance neutral approach for investigating potential biomarkers for these disorders. The present study used rsfMRI to evaluate differences in the functional architecture between these two disorders.Methods: We collected rsfMRI data in 19 patients with bipolar disorder, 18 patients with schizophrenia and 32 healthy volunteers. We used the FSL/AFNI based functional connectomes script library to preprocess our images, which were collected on a 3T system. We then computed the correlations among 266



predefined regions and computed connectivity strength, which was the average correlation of a particular region.Results: We were able to replicate the findings of Lynall et al. (2010) findings in schizophrenia. In addition, we demonstrate that patients with bipolar disorder have similar disconnectivity in several regions (Figure 1). The degree of disconnectivity in bipolar disorder was intermediate to that of patients with schizophrenia and healthy volunteers. Disconnectivity in both groups of patients negatively correlated with cognitive performance in several domains (p<0.05), as well as with clinical symptoms (p=0.04).Conclusions: Our results further support the disconnectivity hypothesis in schizophrenia, and indicate a similar neurobiological signature in bipolar disorder. Correlations with this finding and clinical and cognitive measures support their use as potential biomarkers in neuroimaging studies.

Keywords: schizophrenia, bipolar disorder, connectivity, resting state fMRI

933. Antipsychotic Treatment Effects on the Functional Connectome in First-Episode PsychosisDeepak Sarpal1, Miklos Argyelan1, Toshikazu Ikuta1, 2, Delbert Robinson1, 2, 3, Anil K. Malhotra1, 2, 3, Philip R. Szeszko1, 2, 3

1Department of Psychiatry, The Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, 2Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, 3Department of Psychiatry, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY

Background: The effects of antipsychotic medications on the functional architecture of the brain remain largely unknown. First episode patients with psychosis are a unique population with minimal prior exposure to antipsychotic medications, which may confound the interpretation of brain imaging studies. The present study examined the effect of treatment with second generation antipsychotics on functional connectivity measures during the resting state in patients experiencing a first-episode of psychosis.Methods: Twenty-five patients experiencing their first-episode of psychosis, and twenty-five healthy controls, matched for age, sex, and handedness participated in the study. Patients were scanned during the resting state and evaluated with the Brief Psychiatric Rating Scale (BPRS) at baseline and following twelve weeks of treatment with either risperidone or aripiprazole. Healthy volunteers were scanned during rest at baseline and 12 weeks later, but were not treated. BOLD fMRI was collected and a global functional connectivity (GFC) measure was computed among 266 predetermined nodes.Results: Following 12 weeks of antipsychotic treatment, patients showed an overall trend (p = .06) for a reduction in GFC compared to their baseline scan. Changes in BPRS scores did not correlate significantly with changes in GFC in patients. Also, BPRS score did not correlate significantly with GFC either at baseline or at 12 weeks. No significant difference between time points was evident for GFC among healthy volunteers.Conclusions: Consistent with previous findings, treatment with second generation antipsychotics was associated with a reduction in GFC. This reduction was not correlated with changes in symptom severity.Keywords: Schizophrenia, First episode, resting state, functional connectivity, antipsychotic

Supported By: ROIMH

934. Left Temporal Lobe Failure in Schizophrenic Patients : Datas from an Meg StudyFREDERIC HAESEBAERT1, Francoise Lecaignard2, Marie-Françoise Suaud-Chagny1, Thierry d’Amato1, Mohamed Saoud1, Olivier Bertrand3, Jerome Brunelin1

1EA 4615 – SIPAD - Unité de Recherche UCB Lyon 1/CH Le Vinatier, Université de lyon, BRON CEDEX, France, 2CERMEP – Imagerie du vivant, CERMEP – Imagerie du vivant, LYON, France, 3Centre des Neurosciences de Lyon, Universite de Lyon, BRON, France

Background: Neuroimaging studies have consistently linked auditory hallucinations (AH) in schizophrenia to abnormalities in regions of the left hemisphere involved in speech generation and perception. On the other hand, thanks to results obtained with EEG, it has been proposed the absence of modulation of the N1 component evoked by a syllabic stimulus during speech production (inner and overt) as a marker of AH. Here, we aimed to determine that AH are specifically associated with an impaired treatment of speaking stimulus by auditory cortex, which could be more prominent in the left hemisphere.Methods: Six patients with schizophrenia suffering from chronic hallucinations and 12 healthy volunteers were enrolled in a magnetoencephalography study. The auditory M100 evoked by a syllabic or a control white noise stimulus was measured during four cognitive conditions (listening, inner speech, overt speech, resting).Results: While M100 amplitudes evoked by white noise did not differ between groups, we found a significant hemisphere x condition x group interaction for the syllabic stimulus (df=3; F=4.7043; p=0.0031). In the right hemisphere, M100 modulations were comparable between patients and controls. In the left hemisphere, in contrast to controls, we found an absence of M100 modulation in patients whatever the cognitive condition.Conclusions: Our results outline a disruption of auditory processing in the left hemisphere of hallucinating patients.We suggest that AH could permanently modulate the activity of the left auditory cortex preventing any further modulation by external stimuli and impacting thus the cognitivemechanisms involving this area.Keywords: schizophrenia, magnetoencephalography, auditory hallucinations, temporal lobe, pathophysiologySupported By: CSR

935. The Multimodal Connectivity of the Hippocampal Complex in Auditory and Visual HallucinationsAli Amad1, Arnaud Cachia2, Pierre Thomas1, Renaud Jardri1

1Psychiatry, University Medical Center, Lille, France, 2Psychiatry and neurosciences, INSERM U-894, Centre de Psychiatrie & Neurosciences, Paris, France

Background: Hallucinations constitute one of the most representative and disabling symptoms of schizophrenia. Several MRI findings support the hypothesis that distinct patterns of connectivity, particularly within networks involving the hippocampal complex (HC), could be associated with different hallucinatory modalities. The aim of this study was to investigate HC connectivity as a function of the hallucinatory modality, i.e., auditory or visual.Methods: Two carefully selected subgroups of schizophrenia patients with only auditory hallucinations (AH) or with audio-visual hallucinations (A+VH) were compared using three complementary multimodal MRI Methods resting state functional MRI, diffusion MRI and structural MRI were used to analyze seed-based Functional Connectivity (sb-FC), Tract-Based Spatial Statistics (TBSS) and shape analysis, respectively.Results: Sb-FC was significantly higher between the HC, the medial prefrontal



cortex and the caudate nuclei in A+VH patients compared with the AH group. Conversely, AH patients exhibited a higher sb-FC between the HC and the thalamus in comparison with the A+VH group. In the A+VH group, TBSS showed specific higher white matter connectivity in the pathways connecting the HC with visual areas, such as the forceps major and the inferior-fronto-occipital fasciculus than in the AH group. Finally, shape analysis showed localized hippocampal hypertrophy in the A+VH group.Conclusions :Functional results support the fronto-limbic dysconnectivity hypothesis of schizophrenia, while specific structural findings indicate that plastic changes are associated with hallucinations. Together, these results suggest that there are distinct connectivity patterns in patients with schizophrenia that depend on the sensory-modality, with specific involvement of the HC in visual hallucinations.Keywords: schizophrenia, hippocampus, neuroplasticity, hallucinations, visualSupported By: Pierre Houriez foundation (hosted by the Fondation de France)

936. Disrupted Hippocampal Resting State Functional Connectivity and Glutamate in Unmedicated Patients with SchizophreniaNina V. Kraguljac1, David M. White1, Jennifer A. Hadley1, Meredith A. Reid2, Adrienne C. Lahti1

1Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 2Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL

Background: Using the blood oxygen-level dependent (BOLD) signal during functional MRI (fMRI), functional connectivity investigates the synchrony of spontaneous neural activity between brain regions. Given the known association between BOLD signal and glutamate, we tested the hypothesis that alterations in hippocampal resting state functional connectivity (rsFC) in schizophrenia were related to hippocampal glutamate levels, as measured using magnetic resonance spectroscopy (MRS).Methods: We conducted an fMRI and MRS study in 19 unmedicated patients with schizophrenia (SZ) and 19 matched healthy controls (HC). All imaging was performed on a 3T scanner. The rs scan was acquired during a five-minute gradient recalled EPI sequence. Preprocessing included slice time correction and realignment, normalization to MNI space, smoothing using DARTEL. Nuisance regressors included the six motion parameters, and components of white matter and CSF explaining 90% of signal variance identified using a principal component analysis. Connectivity statistical parametric maps of the hippocampus were calculated for each participant by extracting the first principle component of the time series from a structurally defined mask of the left hippocampus (AAL atlas). The resulting volume of interest was regressed on whole brain BOLD signal to produce a connectivity map of the left hippocampus with every other voxel in the brain. To assess connectivity strength, eigenvariates were extracted from the hippocampus and precuneus, correlated and then z-transformed. MRS data were collected from a voxel in the hippocampus using the point resolved spectroscopy sequence (PRESS; TR/TE=2000/80 ms) and analyzed in jMRUI. Spectra were quantified in the time domain using the AMARES algorithm. Glutamate+glutamine (Glx) were quantified with respect to creatine (Cr).Results: We found hippocampal rsFC to the precuneus to be significantly decreased in SZ compared to HC [t(4.76), kE= 726, pFDRcorr= .001, MNI coordinates: x= -2, y= -56, z= -46]. Glx/Cr did not differ between groups. Connectivity strength between hippocampus and precuneus were correlated to Glx/Cr in HC (r= 0.44; p= .04) but not SZ (r= -0.18; p= .25); a difference that was statistically significant (z= -1.84; p= .03).Conclusions: Our results indicate that deficits in hippocampal rsFC may be related to a disruption in glutamate signaling in patients with schizophrenia. Further studies will need to be conducted to replicate and further explore these findings.

Keywords: glutamate, resting state, functional connectivity, magnetic resonance spectroscopy, hippocampusSupported By: RO1 MH081014

937. A Large-Scale Meta-Analysis of Subcortical Brain Volume Abnormalities in Schizophrenia via the Enigma ConsortiumTheo G. M. van Erp1, Derrek P. Hibar2, Jerod Rasmussen1, Ole A. Andreassen3, Unn K. Haukvik3, 4, Ingrid Agartz3, 4, Steven G. Potkin1, Hilleke Hulshoff-Pol5, Roel Ophoff6, Neeltje E. M. van Haren5, Oliver Gruber7, Bernd Krämer7, Stefan Erlich8, Johanna Hass8, Lei Wang9, Kathryn Alpert9, Paul M. Thompson2, Jessica A. Turner10, 11, the ENIGMA-Schizophrenia Working Group1Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, 2Imaging Genetics Center, Lab of Neuro Imaging, University of California Los Angeles, Los Angeles, CA, 3K.G. Jebsen Centre for Psychosis Research, University of Oslo, Institute of Clinical Medicine, Oslo, Norway, 4Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway, 5Neuroimaging Research Group, University Medical Center Utrecht, Utrecht, Netherlands, 6Departments of Psychiatry and Human Genetics, University of California Los Angeles, Los Angeles, CA, 7Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry, Georg August University, Goettingen, Germany, 8Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany, 9Departments of Psychiatry and Behavioral Sciences and Radiology, Northwestern University, Chicago, IL, 10Albuquerque, Mind Research Network, Irvine, NM, 11Departments of Psychiatry and Psychology, University of New Mexico, Albuquerque, NM

Background: Schizophrenia patients show significant subcortical brain abnormalities but considerable heterogeneity exists across studies. This large-scale meta-analysis provides effect sizes for subcortical volume differences between schizophrenia patients and healthy controls based on standardized automated image analysis and quality assurance procedures performed by multiple schizophrenia studies participating in the Enhancing Neuro Imaging Genetics



Through Meta-Analysis (ENIGMA) Consortium.Methods: The ENIGMA schizophrenia study consortium currently comprises the TOP, FBIRN, UMCU, NU, HMS, CliNG, and MCIC (840 patients and 887 controls, age range=17-65) and encourages other sites to join ongoing collaborative analysis efforts. At each site, total intracranial and subcortical volumes (for pallidum, hippocampus, putamen, lateral ventricle, amygdala, caudate, thalamus, nucleus accumbens) were extracted using FreeSurfer from high-resolution structural MRI scans of schizophrenia patients and healthy volunteers of similar mean age and sex distribution. For each subcortical region, we computed Cohen’s d effect sizes within each study and weighted mean effect sizes for group differences across all studies.Results: Effect sizes for group differences varied for subcortical and intracranial volumes. Largest effect sizes in terms of deficit and excess volume in schizophrenia patients compared to healthy volunteers were obtained for the hippocampus and pallidum, respectively.Conclusions: Combining data from many large cohorts through consortia such as ENIGMA, using harmonized methods, can provide robust effect size estimations. Such analyses may be particularly useful in research areas where study samples are traditionally small (e.g., high-risk, first-episode and medication studies in schizophrenia). Future work will explore factors that consistently influence disease effects within the consortium infrastructure.Keywords: meta-analysis, subcortical, MRI, imaging, schizophreniaSupported By: Norwegian Research Council (grant numbers 160181/V50, 190311) and South-Eastern Norway Regional Health Authority; U24 RR021992; U24 RR025736; 1R01 MH084803, P50 MH071616, R01 MH056584; 1R01 MH094524-01A1;NARSAD YIA to SE

938. Abnormalities of Neural Activation During Working Memory Predict Conversion to Psychosis in Clinical High-Risk Youth: A Preliminary Analysis from the North American Prodrome Longitudinal StudyJennifer K. Forsyth1, Sarah McEwen1, Dylan G. Gee1, Jean Addington2, Carrie E. Bearden3, Kristin S. Cadenhead4, Barbara A. Cornblatt5, Daniel H. Mathalon6, Thomas H. McGlashan7, Diana O. Perkins8, Larry J. Seidman9, Ming T. Tsuang4, Elaine F. Walker10, Scott W. Woods7, Tyrone D. Cannon11

1Psychology, University of California, Los Angeles, Los Angeles, CA, 2Psychiatry, University of Calgary, Calgary, AB, Canada, 3Psychiatry, University of California, Los Angeles, Los Angeles, CA, 4Psychiatry, University of California, San Diego, San Diego, CA, 5Psychiatry, Zucker Hillside Hospital, Long Island, NY, 6Psychiatry, University of California, San Francisco, San Francisco, CA, 7Psychiatry, Yale University, New Haven, CT, 8Psychiatry, University of North Carolina, Chapel Hill, Chapel Hill, NC, 9Psychiatry, Massachusetts General Hospital, Boston, MA, 10Psychology, Emory University, Atlanta, GA, 11Psychology, Yale University, New Haven, CT

Background: Individuals with prodromal symptoms are at very high risk for developing psychosis. Studying these individuals prospectively offers a powerful tool to identify differences in neural functioning that are predictive of later conversion to full psychosis.Methods: As part of the North American Prodrome Longitudinal Study, 154 healthy comparison subjects, 217 clinical-high risk subjects who had not converted to schizophrenia by time of data analysis (CHR-NC), and 15 clinical-high risk subjects who converted to psychosis by time of data analysis (CHR-C) underwent functional magnetic resonance imaging while performing a modified verbal Sternberg Item Recognition Paradigm with four working memory loads. Subjects were followed clinically for about 1 year, on average.Results: Averaged across working memory loads, control and CHR-NC subjects showed similar neural activation on trials for which they gave correct responses compared with rest. Conversely, compared with both control and CHR-NC subjects, CHR-C subjects showed hypoactivation across several

structures, including cerebellum, thalamus, putamen, lateral occipital cortex, anterior cingulate cortex, and dorsolateral prefrontal cortex. Additionally, group comparisons of neural activation varied by memory load such that control, CHR-NC and CHR-C groups showed more similar activation at the lowest load; however, at the highest memory load, both CHR-NC and CHR-C subjects showed bilateral hypoactivation across many of these subcortical and cortical regions compared with control subjects, with CHR-C subjects showing more extreme deviations than CHR-NC subjects.Conclusions: Abnormalities in neural activation patterns during verbal working memory processing precede and predict the onset of fully psychotic symptoms among clinical high-risk individuals.Keywords: schizophrenia, fMRI, prodromal, working memory, clinical high-riskSupported By: National Institute of Mental Health collaborative U01 award: MH081902 to TDC, MH081988 to EW, U01 MH081928 to LJS, MH081984 to JA, U01MH066160 to SWW, and NSF Graduate Research Fellowship to JKF

939. Behavioral and Neuroanatomic Alterations Implicating Dopaminergic Dysregulation in Patients with 22Q11.2 Deletion SyndromeRachel K. Jonas1, Maria Jalbrzikowski2, Arati Patel1, Carolyn Chow1, Caroline A. Montojo1, 2, Carrie E. Bearden1, 2

1Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, 2Department of Psychology, University of California, Los Angeles, Los Angeles, CA

Background: 22q11.2 Deletion Syndrome (22qDS) is a neurogenetic disorder that results from a 1.5-3.0 megabase deletion and encompasses at least 30 genes. 22qDS patients exhibit elevated rates of psychiatric disorders associated with dopaminergic dysfunction, particularly schizophrenia and ADHD. Due to their clinical profile and the known functions of genes in the deletion region, we hypothesized that 22qDS patients would show abnormalities in behavioral and anatomical measures known to rely on prefrontal cortical dopaminergic function.Methods: 27 patients with 22qDS (mean age 14.18+/-5.68) and 20 healthy controls (mean age 15.65+/-3.70) were administered the Balloon Analog Risk Task (BART), a measure of decision-making and risk-taking. Our primary outcome measure was the number of adjusted pumps (i.e., pumps resulting in successful trials). Participants also underwent a structural MRI scan. Due it its role in decision-making and reward processing, we examined cortical thickness in the orbitofrontal cortex (OFC).Results: On the BART task, 22qDS patients made significantly fewer adjusted pumps than healthy controls (p=0.025). 22qDS patients also had thicker bilateral lateral and medial OFC than healthy controls (all p<.01), and OFC thickness correlated negatively with BART performance (left: lateral p=0.001, medial p=0.009; right: lateral p=0.015, medial p=0.059).Conclusions: Patients with 22qDS had less optimal performance on the BART task than controls, which was associated with cortical thickness in brain regions relevant to reward processing. Alterations in dopamine-mediated behavior and brain structure may be due to hemizygosity of dopamine-mediating genes such as catechol-o-methyltransferase (COMT) within the 22q11.2 locus.Keywords: 22q, dopamine, structural MRI, orbitofrontal, BARTSupported By: NIMH R01MH085953



940. Differential Neural Activation in 22Q11.2 Deletion Syndrome Patients and Healthy Adults During Performance on a Working Memory Capacity TaskCaroline A. Montojo1, 2, Katherine H. Karlsgodt3, Carolyn C. Chow1, Casey Dawson1, 4, Amira Ibrahim1, Rachel K. Jonas1, Carrie E. Bearden1, 2, 5

1Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, 2Department of Psychology, University of California, Los Angeles, Los Angeles, CA, 3Feinstein Institute for Medical Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, 4School of Psychology, Fielding Graduate University, Santa Barbara, CA, 5Brain Research Institute, University of California, Los Angeles, Los Angeles, CA

Background: 22q11.2 Deletion Syndrome (22qDS) is a recurrent genetic mutation that is highly penetrant for psychosis. Behavioral research in 22qDS suggests that patients exhibit a characteristic neurocognitive phenotype involving deficits in spatial working memory (WM). Notably, spatial WM has also been proposed as an endophenotype for idiopathic psychotic disorder (Glahn 2000). Here we investigated underlying neural activity in 22qDS patients compared to controls during performance of a spatial WM task.Methods: Fifteen 22qDS patients (mean age 24 years; 9 female) and 8 healthy adults (matched for age and gender) performed a functional MRI (fMRI) spatial capacity WM task, which included a parametric manipulation of load and variable delay lengths. BOLD fMRI data were analyzed using a voxel-wise GLM run in FSL, and results were corrected for multiple comparisons.Results: Healthy adults showed neural activity consistent with previous WM capacity literature (e.g, Jha et al., 2000), with increased activity in intraparietal sulcus and superior parietal lobule for high loads relative to baseline. Patients with 22qDS showed similar activity in parietal regions, but with more diffuse activation that extended into anterior cingulate cortex, bilateral inferior, middle, and superior frontal gyri, bilateral temporal gyrus, and occipital cortex.Conclusions: Patients with 22qDS exhibit a more diffuse extent of activation compared to healthy controls during spatial WM performance. These results offer complementary neural evidence to previous behavioral findings indicating spatial WM deficits in 22qDS. Further, this pattern of neural activity is comparable to that of patients with idiopathic schizophrenia, suggesting similar neural endophenotypes characterize 22qDS.Keywords: 22q11.2 Deletion Syndrome, fMRI, working memory, endophenotype, psychosisSupported By: NIMH R01MH085953, 5 T32 MH082719-04

941. Youth at Clinical High-Risk for Psychosis Fail to Suppress Default Mode Regions During Task PerformanceSusanna L. Fryer1, 2, Scott W. Woods3, Kent A. Kiehl4, 5, Vince D. Calhoun3, 5, 6, Godfrey D. Pearlson3, 7, 8, Brian J. Roach2, Judith M. Ford1, 2, 3, Thomas H. McGlashan3, Daniel H. Mathalon1, 2, 3

1Psychiatry, University of California, San Francisco, San Francisco, CA, 2Mental Health Service, San Francisco VA Medical Center, San Francisco, CA, 3Psychiatry, Yale University, New Haven, CT, 4Psychology, University of New Mexico, Albuquerque, NM, 5Translational Neuroscience, The Mind Research Network, Albuquerque, NM, 6Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM, 7Olin Neuropsychiatry Research Center, Institute of Living, New Haven, CT, 8Neurobiology, Yale University, New Haven, CT

Background: The default mode network (DMN) is a set of brain regions typically activated at rest and suppressed during cognitive task performance. Schizophrenia is associated with a failure of normative DMN activity suppression, though the

extent to which DMN alterations predate psychosis onset is unclear. This study examined task-related DMN suppression in youth at clinical high-risk (CHR) for psychosis, relative to healthy controls (HC) and early schizophrenia patients (ESZ).Methods: During performance of a multi-load Sternberg working memory task, fMRI data were collected from CHR (n=32), ESZ (n=24), and HC (n=54) youth, ages 12-30. Group-x-Load interactions during working memory probes were identified within DMN regions-of-interest, to evaluate the hypothesis that ESZ would fail to suppress DMN activation at higher working memory loads relative to HC, and that CHR would show an intermediate pattern of DMN suppression.Results: Significant working memory retrieval Group-x-Load interactions were observed within medial prefrontal, posterior cingulate, and right lateral parietal cortices. Follow-up testing, corrected for multiple comparisons (p<.05), indicated that within posterior cingulate and right lateral parietal DMN network nodes, Group-x-Load effects resulted from less suppression of higher-load DMN activity in ESZ than HC, with CHR differing from neither group. In medial prefrontal cortex, both CHR and ESZ groups showed less higher-load DMN suppression, relative to HC.Conclusions: While HC modulated DMN suppression by cognitive load, CHR individuals showed a reduction in higher-load DMN suppression that was similar, but less pronounced, than ESZ patients. These data suggest that DMN dysfunction in schizophrenia predates psychosis onset.Keywords: psychosis prodrome, ultra high-risk, schizophrenia, default mode network, working memorySupported By: RO1MH076989

942. Muscarinic M1 Receptor Sequence, Cognition and Grey Matter Volume in Schizophrenia and Healthy ControlsVanessa L. Cropley1, Alex Fornito1, Chad Bousman2, Christos Pantelis1, Elizabeth Scarr3, Brian Dean3

1Melbourne Neuropsychiatry Centre, University of Melbourne, Carlton South, Australia, 2Department of Psychiatry, University of Melbourne, Carlton South, Australia, 3Rebecca Cooper Laboratory, Mental Health Research Institute, Parkville, Australia

Background: We have previously demonstrated that schizophrenia patients who are homozygous at the c.267C>A single nucleotide polymorphism of the muscarinic M1 receptor (CHRM1) show increased perseveration on the Wisconsin Card Sorting Test than those who are heterozygous. However, the effect of CHRM1 sequence on brain volume has not been investigated. The present study investigated the effect of CHRM1 sequence on cognition, symptoms and brain volume in schizophrenia patients and healthy controls (HC).Methods: Cognitive, imaging and CHRM1 sequence data were obtained from 227 schizophrenia patients and 122 HC from the Australian Schizophrenia Research Bank. Regional brain volume was analysed with voxel-based morphometry (VBM) using Statistical Parametric Mapping. Genotype comparisons on brain volume were performed controlling for age, ICV, site and gender.Results: A genotype-diagnosis interaction was found on verbal fluency, with post-hoc analyses showing impaired performance in the C/C compared to the C/A group in the HC only. There was no effect of genotype on other tasks or symptoms. VBM showed significant genotype effects on brain volume. In HC, C/C genotype was associated with decreased volume in the right medial and lateral parietal regions but increased volume in left PFC compared to the C/A group. In schizophrenia, C/C individuals showed decreased volume in right PFC.Conclusions: Taken together with previous studies, our results suggest that CHRM1 sequence affects different executive processes and brain regions in HC and schizophrenia. Homozygosity at the CHRM1 SNP is associated with reduced brain volume in parietal regions in HC, but in frontal regions in schizophrenia.Keywords: schizophrenia, genetics, imaging, muscarinic, cognition



943. Schizophrenia is Associated with Decreased White Matter Volumes in Superior Frontal, Superior Parietal and Inferior Temporal RegionsStéphane Potvin1, Adham Mancini-Marie1, Cherine Fahim2, Emmanuel Stip1

1Psychiatry, University of Montreal, Montreal, QC, Canada, 2Psychology, University of Lausanne, Lausanne, Switzerland

Background: Voxel-based morphometry has been regularly used to examine structural magnetic resonance images in schizophrenia. Thus far, the VBM literature has focused mostly on grey matter alterations, and has shown that schizophrenia is associated with reduced grey matter densities in frontal, cingulated, temporal and limbic regions. Unfortunately, much less attention has been paid to attention to white matter abnormalities. The objective of the current study was to examine white matter volumes (WMV) in schizophrenia, using the improved DARTEL tools of SPM8.Methods: An optimized modulated VBM study involving 23 medicated schizophrenia patients and 23 healthy volunteers was undertaken. Exploratory analyses were performed for WMV, using a smoothing of 12mm and a level of significance of p<0.05 (corrected for FamilyWise Error).Results: We found reduced WMV in schizophrenia patients, relative to controls, mostly in superior frontal, superior parietal and inferior temporal regions. No increases in WMV were observed in schizophrenia. White matter changes did not correlate with positive, negative and depressive symptoms.Conclusions: These results of this current cross-sectional study are generally consistent with results acquired with previous versions of VBM (SPM2 & SPM5). These results are consistent with fronto-temporal models of schizophrenia. Less expectedly, our results also suggest that fronto-parietal alterations may be play a key role in the pathology of schizophrenia. These results may have implications for future studies analyzing altered connectivity in schizophrenia, using functional magnetic resonance imaging and/or diffusion tensor imaging. The clinical correlates of our results will need to be determined.Keywords: Schizophrenia, White matter, Voxel-based morphometry, Frontal lobeSupported By: AstraZeneca

944. Brain Structure and Cognitive Development in Young Children at High Genetic Risk for Schizophrenia Shaili C. Jha1, Sarah J. Short2, Barbara D. Goldman3, J. Steven Reznick3, 4, Sandra Woolson5, Martin Styner2, 6, John H. Gilmore1, 2

1Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC, 2Department of Psychiatry, University of North Carolina, Chapel Hill, NC, 3FPG Child Development Institute, University of North Carolina, Chapel Hill, NC, 4Department of Psychology, University of North Carolina, Chapel Hill, NC, 5Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 6Department of Computer Science, University of North Carolina, Chapel Hill, NC

Background: Schizophrenia is a neurodevelopmental disorder of early developmental origin, affecting brain structure and function. Research examining children at genetic high-risk for schizophrenia has mainly focused on prodromal periods. Although little is known about the earliest stages of development in high-risk populations, our previous research has shown that high-risk males have enlarged gray matter (GM) and intracranial volumes (ICV) at birth. The current study is a follow-up of this cohort at ages 1 and 2.Methods: Structural magnetic resonance imaging scans were acquired from infants at a genetic high-risk for schizophrenia (N=25 at age 1; N=20 at age 2) and from matched control infants (N=52 at age 1; N=40 at age 2). Cognitive function was evaluated using the Mullen Scales of Early Learning. Brain structure was compared using ICV, total GM, white matter (WM), cerebral spinal fluid (CSF), and lateral ventricle volumes.

Results: Mullen composite scores were significantly reduced in the high-risk group at ages 1 and 2, with greater reduction at age 2 (p <0.01). At age 1, no significant structural differences were observed (p> 0.05). At age 2, significant group differences in total WM (p<0.05) and marginally significant differences in ICV and total GM volumes were observed.Conclusions: High-risk children seem to display aberrant cognitive function as early as age 1 while structural differences in brain development are present at age 2. Results suggest that abnormalities in early cognitive function are detectable in children at genetic high-risk for schizophrenia and may serve as precursors to altered brain development.Keywords: Shizophrenia, Neurodevelopment, High-Risk, Cognitive developmentSupported By: NIMH P50 MH064065

945. Grey Matter Volume Differentiates Psychosis Patients According to Cognitive AbilityAlana M. Shepherd1, 2, Yann Quidé1, 2, Richard W. Morris3, Nicholas C. Vella1, Jesseca E. Rowland1, Meelah K. Hamilton1, Philip Mitchell1,

4, 5, Melissa J. Green1, 2

1School of Psychiatry, University of NSW, Sydney, Australia, 2-, Schizophrenia Research Institute, Sydney, Australia, 3Brain and Mind Research Institute, University of Sydney, Sydney, Australia, 4-, Black Dog Institute, Sydney, Australia, 5-, Prince of Wales Hospital, Randwick, Sydney, Australia

Background: Brain-based intermediate phenotypes may be common to schizophrenia (SZ) and bipolar I disorder (BD-I) in association with shared genetic vulnerability. We used voxel-based morphometry (VBM) to identify grey matter volume (GMV) related to working memory performance regardless of diagnosis.Methods: Using VBM8 toolbox, GMV in SZ (n = 37) and BD-I (n = 21) were assessed relative to healthy controls (HC; n = 39) and each other. Focal analyses were conducted for groups defined by performance on a working memory task: patients achieving less than 50% accuracy were treated as ‘poor performers’ (PP, n = 26); those above 50% were grouped as ‘good performers’ (GP, n = 31). 31 HCs performed above 50%.Results: After controlling for age, sex, years of education and medication dosage, analyses of cases by performance revealed that, relative to HC, PP patients showed GMV reductions in medial frontal cortex, and the GP patients showed reductions in precuneus; additionally, reduced inferior frontal gyrus differentiated PP from GP. Traditional group analyses demonstrated GMV reductions in anterior cingulate cortex for Sz relative to HC (p < 0.0001 uncorr), and in precentral gyrus and precuneus (p < 0.05 FWE) for BD-I relative to HC and SZ.Conclusions: In the context of discrete grey matter reductions in SZ and BD-I, GMV successfully differentiated patients with poor working memory (regardless of diagnosis) in regions relevant for successful task performance. These findings point toward the existence of shared brain-based intermediate phenotypes among SZ and BD-I cases with more severe cognitive deficits.Keywords: schizophrenia, bipolar disorder, structure, imaging, working memorySupported By: NHMRC Project Grant 630471 (MG); NHMRC Scholarship 1039941 (AS)

946. Functional Dysconnectivity in Schizophrenia Transcends Cognitive StateHaleh Karbasforoushan1, Brittney Duffy-Alberto1, Baxter P. Rogers2, Neil D. Woodward1

1Psychiatric Neuroimaging Program, Vanderbilt University Medical Center, Nashville, TN, 2Institute of Imaging Science, Vanderbilt University, Nashville, TN

Background: Resting-state fMRI has provided ample support for dysconnectivity models of schizophrenia. However, it is not clear if abnormal functional



connectivity observed at rest is idiosyncratic to resting state or persists during cognition. To address this limitation, we examined functional connectivity during resting-state and performance of a cognitive task.Methods: 26 Patients with schizophrenia and 21 healthy subjects underwent fMRI scanning during resting-state, and while performing a 2 and 4 choice reaction time (CRT) block design task. Functional connectivity within the low frequency (0.01-0.1 Hz) range of the BOLD signal was calculated for a-priori defined networks, the default mode (DMN), executive control (ECN), and dorsal attention networks (DAN), and on a voxel-wise basis for the key nodes associated with these networks, the posterior cingulate cortex (PCC), dorsolateral prefrontal cortex (dlPFC), and superior parietal lobule (SPL). The data were analyzed using a 2-way ANOVA to determine the effects of task condition (resting-state, 2-CRT, 4-CRT), group, and the task condition by group interaction.Results: Functional connectivity of the DMN and DAN decreased slightly during task conditions compared to resting-state; however, the connectivity profiles of the PCC, dlPFC, and SPL were remarkably similar across conditions. Functional connectivity between the dlPFC and anterior ventrolateral PFC was decreased in schizophrenia during resting-state and task performance. No group by condition interactions were observed.Conclusions: Functional connectivity networks observed at rest remain remarkably coherent during cognitive task performance. Functional dysconnectivity of the dlPFC observed at rest in schizophrenia persists during cognition.Keywords: Resting-state, fMRI, Schizophrenia, Cognition, Prefrontal CortexSupported By: Brain and Behavior Research Foundation

947. Increased Dorsal Anterior Cingulate Modulation of Frontal-Parietal Cortices During Conflict in Schizophrenia Patients: FMRI Evidence of Inefficient Inter-Cortical InteractionsNino M. Papale1, Richard White1, Chris Walker2, Vaibhav A. Diwadkar1, Raymond Cho2

1Dept of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, 2Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA

Background: A major research focus in schizophrenia has been on deficits in cognitive control during tasks eliciting processing conflict. However, the bases of these deficits in terms of brain network interactions are unknown. We applied network analyses (e.g., Bakshi et al., 2011) to investigate differences in dorsal anterior cingulate cortex (dACC) modulation of cortical regions during conflict.Methods: fMRI (3T) was collected during a validated cognitive control paradigm in 24 First Episode Schizophrenia (SCZ), and 14 healthy control (HC) subjects. During the task a cue signaled the response direction to a subsequently presented probe (arrow pointing left or right). During conflict conditions, subjects were required to respond in the direction opposite to that indicated by the probe, inducing conflict and recruiting the cognitive control network. Data were analyzed in SPM8, using standard methods. PPI analysis (Friston et al., 1997) was used to examine dACC modulation of cognitive function (Conflict > Non-Conflict Trials). Analyses were restricted to correct trials to ensure compatibility in fMRI analyses across groups (Carter et al., 2008).Results: Both groups activated the dACC, frontal and parietal cortex. 2nd level random effects analyses of the PPI revealed significantly increased dACC modulation of frontal-parietal regions in SCZ patients compared to controls (p<.05, cluster level).Conclusions: Increased signaling from the dACC may reflect inefficiencies in the cognitive control network and/or compensation for disturbances in conflict signaling in schizophrenia. These results constitute a novel network-based extension of cortical inefficiencies that have been previously associated with schizophrenia (e.g., Callicott et al., 2001).Keywords: dACC, Schizophrenia, PPI, Cognitive Control, modulationSupported By: MH080329

948. Learning Proficiency and Brain Structure: Systematic Brain-Behavior Relationships in Controls but not in Patients with Schizophrenia or Bipolar DisorderVaibhav A. Diwadkar1, Marcella Bellani2, Brooklyn Yanos1, Gianluca Rambaldelli2, Cincia Perlini2, Richard White1, Michele Tansella2, Paolo Brambilla3

1Psychiatry & Behavioral Neuroscience, Wayne State University SOM, Detroit, MI, 2Psychiatry, University of Verona, Verona, Italy, 3Psychiatry, University of Udine, Udine, Italy

Background: The hippocampus is central in memory formation and also related to the pathophysiology of both schizophrenia (SCZ; Diwadkar et al., 2008) and bipolar disorder (BP; Brambilla et al., 2011). Hippocampal volume is generally associated with episodic memory integrity (Rodrigue & Raz, 2004), and the relationship between behaviorally measured memory integrity and volume may distinguish patients from healthy controls. We investigated behavior-brain relationships in SCZ and BP using an associative learning paradigm and Voxel Based Morphometry (VBM).Methods: A hippocampal-based paired associative learning task (Diwadkar et al., 2008) was administered the same day that structural MRI data were collected. Learning rates from the task were derived based on fitting negatively accelerated learning curves (performance=1-e-rate*time) to individual subject data. Data were obtained from 17 SCZ (7 F, mean age:36 yrs., mean learning rate=0.17, sd=.1), 12 BP (8 F, mean age:41 yrs., mean learning rate= 0.34, sd=.4) and 21 HC (8 F, mean age:33 yrs.; mean learning rate=1.24, sd=.4). MRI were analyzed using DARTEL (SPM8; Ashburner, 2007), and regressions with learning rate were investigated in 2nd level analyses (p< .05).Results: Figure 1.Conclusions: HC were characterized by systematic positive relationships between hippocampal structure and learning related function; these correlations were absent in patient groups. These negative results imply that SCZ and BP (relative to HC) may be characterized by dysfunctional hippocampal structure-function relationships.



Keywords: Learning, Brain Structure, Structure Function Relationships, Schizophrenia, Bipolar DisorderSupported By: Cooperint Program, Visiting Professorship

949. Differential Susceptibility of White Matter Tracts for Immune Mediators in Schizophrenia: An Integrated DTI Study Konasale M. Prasad1, Catherine Upton1, Vishwajit Nimgaonkar1, Matcheri Keshavan2

1Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, PA, 2Psychiatry, Harvard Medical School, Boston, MA

Background: Schizophrenia is proposed as a neuronal disconnection syndrome that is supported by impaired anatomical and functional connectivity. Besides genetic factors, immune mediators, e.g. interleukin-6 (IL-6) and C-Reactive Protein (CRP) may affect connectivity. We examined anatomical connectivity using diffusion tensor imaging (DTI) hypothesizing that the fronto-parietal, fronto-temporal and fronto-thalamic connectivity would be impaired in early-course medicated clinically stable schizophrenia (mean illness duration=5 years; n=39) compared to healthy controls (HC=29), and IL-6 and CRP levels would be correlated with connectivity.Methods: DTI was acquired in 30 directions with 2 averages. Fractional anisotropy (FA) maps were processed using FSL4.1.9 and Tract-Based Spatial Statistics (TBSS). Threshold free clusters (TFCE) were examined employing family-wise error (FWE) corrections for multiple testing. IL-6 and CRP were assayed using sandwich immunoassay.Results: Mean age of schizophrenia (25.04±8.09 years) and HC (25.93±5.78 years; p=0.68) and sex (SZ M/F 13/9; HC M/F 6/13; p=0.08) did not differ. FA was reduced in the left parietal bundle of the superior longitudinal fasciculus (p=0.001), forceps minor that connects bilateral PFCs (p=0.032), and right uncinate fasciculus (p=0.04) among schizophrenia subjects compared to HC. IL-6 and CRP levels did not differ between schizophrenia and HC (p=0.38). IL-6 but not CRP levels positively correlated with right forceps minor FA (r=0.49, p=0.02) with a trend for negative correlation with the right uncinate fasciculus FA (r=−0.37, p=0.08) among schizophrenia but not HC.Conclusions: Our results suggest interhemispheric hypoconnectivity between the PFCs, and fronto-limbic and fronto-parietal translobar hypoconnectivity with differential susceptibility to immune mediators.Keywords: Anatomical connectivity, White matter, Schizophrenia, Immune mediators, Psychotic disorderSupported By: MH072995, MH093540

950. Thalamo-Cortical Connectivity Disturbances in Schizophrenia and Bipolar Illness: Evidence for Functionally Related Sensory and Prefrontal DisturbancesAlan Anticevic1, Cole W. Cole2, Grega Repovs3, John D. Murray4, Margaret S. Brumbaugh1, Anderson M. Winkler5, Aleksandar Savic1, John H. Krystal1, Godfrey D. Pearlson1, David C. Glahn1

1Psychiatry, Yale University, New Haven, CT, 2Psychology, Washington University, St. Louis, MO, 3Psychology, University of Ljubljana, Ljubljana, Slovenia, 4Neurobiology, Yale University, New Haven, CT, 5Centre for Functional MRI of the Brain, Oxford University, Headington, United Kingdom

Background: A fundamental aspect of large-scale brain organization across mammalian species are recurrent thalamo-cortical circuits. Its complex multi-nuclear structure enables the thalamus to serve as a nexus for parallel information routes through which cortical and subcortical functions are integrated, which may be profoundly impaired in neuropsychiatric disease. Indeed, schizophrenia affects large-scale neural connectivity and growing evidence postulates significant

thalamo-cortical communication disturbances. Incomplete characterization of large-scale thalamic networks in such complex neuropsychiatric illness limits our understanding of its relationship to symptoms and to diagnoses with shared clinical presentation, such as bipolar illness.Methods: Using resting-state fMRI, we characterized thalamic connectivity in 90 schizophrenia patients versus 90 matched controls via: i) subject-specific anatomically-defined thalamic nuclei; ii) anatomical and data-driven clustering to assay within-thalamus dysconnectivity; iii) machine learning to classify diagnostic membership via thalamic connectivity for schizophrenia and for 47 bipolar patients and 47 matched controls.Results: Schizophrenia analyses revealed functionally related disturbances: over-connectivity with all sensory cortices, which predicted symptoms, but thalamic under-connectivity with prefrontal-cerebellar regions relative to controls, possibly reflective of both sensory gating and top-down control disturbances. Clustering revealed this dysconnectivity was most prominent for thalamic nuclei densely connected with prefrontal cortex. Classification and cross-diagnostic results suggest thalamic dysconnectivity may be a marker for neural disturbances across schizophrenia and bipolar illness.Conclusions: Collectively, these findings, using the largest schizophrenia and bipolar neuroimaging samples to date, inform basic understanding of large-scale thalamo-cortical systems and provide vital clues about the complex nature of its disturbances in severe mental illness.Keywords: schizophrenia, bipolar, thalamus, connectivity, resting-stateSupported By: DP5OD012109-01;2P50AA012870-11;MH096801;MH43775;MH077945;MH074797

951. Dopamine Dysfunction and Impaired Learning From Reward and Punishment in Schizophrenia and Affective DisordersAndreas Heinz

Department of Psychiatry and Psychotherapy Campus Mitte, Berlin, Germany

Background: A dimensional approach tries to map mental disorders including schizophrenia along basic behavioral and neurobiological dimensions of positive affect or learning from reward and punishment and their respective alterations. Here we compare neuronal activation elicited by reward prediction as well as affectively negative stimuli in 30 healthy controls and 150 unmedicated patients suffering from schizophrenia, major depression, mania, alcohol dependence and ADHD.Methods: All subjects were unmedicated. Aversive and neutral pictures from the International Affective Picture System were presented to elicit limbic brain activation. Reward-predicting and neutral cues were presented within a Monetary Incentive Delay (MID) task. Age and gender were used as co-variates.Results: Reward-predicting stimuli elicited ventral striatal activation in all subjects, with patients suffering from schizophrenia and alcohol-dependence dispalying a significantly blunted functional response. Impaired reward anticipation correlated with severity of depression across all subjects. Aversive versus neutral pictures activated the amygdala in all subjects, however, no significant group difference was found when adequately controlling for covariates and multiple testing.Conclusions: A neurobiological correlate of reward anticipation, ventral striatal activation,was impaired in unmedicated schizophrenia patients and contributed to negative mood across disease entities. Amygdala activation, on the contrary, elicited by aversive cues did not differ significantly between patient groups and we observed no psychopathological correlate of the functional response across disease entities. Our findings support the hypothesis that reward anticipation constitutes a basic dimension of mental health relevant for the patients’ mood states.Keywords: learning, Schizophrenia, fMRI, negative moodSupported By: DFG FOR 1617



952. The Impact of Schizophrenia Susceptibility Gene Variants on Anatomic Connectivity: A Potential Correlate of Impaired NeuroplasticityThomas Nickl-Jockschat1, 2, Tony Stoecker2, 3, Axel Krug4, Valentin Markov1, Ruiwang Huang3, Frank Schneider1, 2, Ute Habel1, 2, Klaus Zerres5, Markus M. Nöthen6, Jens Treutlein7, Marcella Rietschel7, N. Jon Shah2, 3, 8, Tilo Kircher9

1Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany, 2Translational Brain Medicine, Juelich Aachen Research Alliance, Juelich - Aachen, Germany, 3Institute of Neurosciences and Medicine-4, Juelich Research Center, Juelich, Germany, 4Department of Psychiatry and Psychotherapy., University of Marburg, Marburg, Germany, 5Institute of Human Genetics, RWTH Aachen University, Aachen, Germany, 6Department of Genomics, , Life & Brain Center, University of Bonn, Aachen, Germany, 7Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany, 8Department of Neurology, RWTH Aachen University, Aachen, Germany, 9Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany

Background: Brain structure anomalies have been consistently described in schizophrenia patients. While a comparatively large number of studies exist on grey matter abnormalities, changes in fiber tract architecture have increasingly gained attention as a potentially important part of schizophrenia pathophysiology. Convergent evidence indicates reduced fiber tract integrity in the left frontal and temporal lobes of schizophrenia patients, but current literature mirrors a considerable heterogeneity. Although the exact pathogenesis of these fiber tract anomalies yet remains to be clarified, a genetic component is highly likely. A variety of schizophrenia susceptibility genes have been shown to be involved in processes of neuroplasticity such as axon guidance, neurite outgrowth and morphology. Studies examining associations between schizophrenia susceptibility gene variants and fiber tract anomalies could provide pivotal clues about a genetic influence on white matter integrity and thereby on neuroplasticity.Methods: We here aim to give an overview over the current literature on schizophrenia risk gene variants and fiber tract anomalies as detected by diffusion tensor imaging (DTI). Moreover, we present data from a sample of healthy young subjects that underwent DT imaging after genotyping for several schizophrenia risk gene variants, such as Dysbindin, Neuregulin-1, G72 and ZNF804a.Results: Results suggests an influence of gene variants on fiber tract architecture as a potential correlate of neuroplasticity also in healthy subjects.Conclusions: A better characterization of the impact of schizophrenia risk variants on white matter changes might be a promising approach for a more comprehensive understanding of the aetiopathogenesis of schizophrenia.Keywords: imaging genetics, diffusion tensor imaging, schizophrenia, bipolar disorder, tbssSupported By: DFG

953. A Couple of Hours Can Make A Difference: Self-Reported Sleep Correlates with Prefrontal-Amygdala Connectivity and Emotional FunctioningWilliam D. S. Killgore, Zachary J. Schwab, Maia Kipman, Sophie DelDonno, Scott L. Rauch, Mareen Weber


Background: Prior research suggests that sleep deprivation is associated with declines in some aspects of emotional intelligence and increased severity on indices of psychological disturbance. Sleep deprivation is also associated with reduced prefrontal-amygdala functional connectivity, potentially reflecting impaired top-down modulation of emotion. It remains unknown whether this

“functional disconnect” may be observed in relation to more typical levels of sleep curtailment. We examined whether self-reported sleep duration the night before the assessment would be associated with these effects.Methods: Sixty-five healthy adults (33 men, 32 women), ranging in age from 18-45 years documented their hours of sleep from the previous night, completed the Bar-On Emotional Quotient Inventory (EQ-i), Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT), Personality Assessment Inventory (PAI), and underwent resting-state functional magnetic resonance imaging (fMRI). Connectivity data were analyzed using the Functional Connectivity Toolbox for SPM8.Results: Greater self-reported sleep the preceding night was associated with higher scores on all scales of the EQ-i but not the MSCEIT, and with lower symptom severity scores on half of the psychopathology scales of the PAI. Longer sleep was also associated with stronger inverse functional connectivity between the right ventromedial prefrontal cortex and right amygdala. Moreover, greater inverse connectivity between these regions was associated with higher EQ-i and lower symptom severity on the PAI.Conclusions: Self-reported sleep duration from the preceding night is significantly correlated with inverse prefrontal-amygdala connectivity, perceived emotional intelligence, and the severity of subjective psychological distress. More sleep was associated with higher emotional and psychological strength.Keywords: Sleep, Emotional intelligence, Personality, Amygdala, Prefrontal cortexSupported By: W81XWH-09-1-0730

954. Problems with Sleep Initiation and Sleep Maintenance Correlate with Functional Connectivity Among Primary Sensory CorticesWilliam D. S. Killgore, Zachary J. Schwab, Maia Kipman, Sophie DelDonno, Scott L. Rauch, Mareen Weber


Background: According to the hyperarousal theory of insomnia, difficulty initiating or maintaining sleep occurs as a result of increased cognitive and physiological arousal brought on by acute stressors and associated cognitive rumination, placing the individual in a perpetual cycle of hyperarousal and increased sensitivity to sensory stimulation. We tested the hypothesis that difficulty initiating or maintaining sleep would be associated with increased functional connectivity among primary sensory processing and motor planning regions.Methods: Fifty-eight healthy adults (29 men, 29 women), between 18-45 years completed a self-report inventory about sleep onset and maintenance problems and underwent a 6-minute resting state functional MRI scan at 3T. Bilateral regions of interest (ROIs) were placed in primary visual cortex, auditory cortex, olfactory cortex, and the supplementary motor cortex and the mean processed signal timecourse was extracted and correlated with the other ROIs.Results: Difficulty falling asleep was associated with increased functional connectivity between the primary visual cortex and other sensory regions such as the primary auditory cortex, olfactory cortex, and the supplementary motor cortex. Primary auditory cortex also showed greater connectivity with supplementary motor cortex for those with sleep initiation problems. Problems with sleep maintenance were associated with greater connectivity between the primary visual cortex and olfactory cortex.Conclusions: Consistent with the predictions of the hyperarousal model, difficulty falling asleep was associated with greater functional connectivity among primary sensory and supplementary motor cortices. Such augmented functional connectivity may contribute to sustained sensory processing of environmental stimuli, potentially prolonging the latency to sleep.Keywords: Sleep initiation, Sleep maintenance, fMRI, Connectivity, Sensory regionsSupported By: W81XWH-09-1-0730



955. Brain Connectivity in Body Dysmorphic Disorder Compared with Controls: A Diffusion Tensor Imaging StudyBen Buchanan1, Susan Rossell2, Jerome J. Maller3

1School of Psychology and Psychiatry, Monash University, Melbourne, Australia, 2Brain and Psychological Sciences Research Centre (BPsyC), Swinburne University of Technology, Melbourne, Australia, 3Monash Alfred Psychiatry Research Centre, Monash University, Melbourne, Australia

Background: Several neuroimaging studies have investigated brain gray matter in people with body dysmorphic disorder (BDD), showing possible abnormalities in the limbic system, orbitofrontal cortex, caudate nuclei and temporal lobes. This study takes these findings forward by investigating white matter properties in BDD compared to controls using diffusion tensor imaging. It was hypothesised that the BDD sample would have widespread significantly reduced white matter connectivity as characterized by fractional anisotropy.Methods: Twenty participants with BDD and 20 healthy controls matched on age, sex and handedness underwent diffusion tensor imaging. Fractional anisotropy (FA), a measure of water-diffusion within a voxel, was compared between groups on a voxel-by-voxel basis across the brain using Tract Based Spatial Statistics within FSL.Results: Results showed that, compared with healthy controls, BDD patients demonstrated significantly lower (p <.05) FA in most major white matter tracts throughout the brain, including in the superior longitudinal fasciculus, inferior fronto-occipital fasciculus and corpus callosum. Lower FA levels could be accounted for by increased radial diffusivity as characterised by eigenvalue 2 and 3. No area of higher FA was found in BDD.Conclusions: This study provided the first evidence of compromised white matter integrity within BDD patients. This suggests that there are inefficient connections between different brain areas, which may explain cognitive deficits within BDD patients, and may underpin the problems they manifest with executive regulation of emotional distress.Supported By: Monash Strategic Grant

956. Alcohol Dependent Stimulant Abusers Differ from Alcohol Dependents: Neurobiology and Self-RegulationDieter J. Meyerhoff

UC San Francisco/VA Medical Center, San Francisco, CA

Background: The brain reward/executive oversight system (BREOS) is implicated in the development / maintenance of addictive disorders. Our recent magnetic resonance studies have focused on BREOS biological integrity and the neurocognitive functions it subserves. Here, we compare one-month-abstinent alcohol-dependent individuals (ALC) to ALC with comorbid stimulant dependence [i.e., polysubstance users (PSU)]. This data will help us better understand the neurobiological factors associated with cognitive dysfunction and relapse in ALC and PSU.Methods: PSU differed from ALC on numerous BREOS MR-based and cognitive measures. Specifically, PSU had morphometric abnormalities in the BREOS, primarily DLPFC and OFC, which were not found in ALC. PSU had larger lobar white matter volumes than ALC and controls (CON). PSU performed worse than ALC and CON in various cognitive domains and showed greater impulsivity than ALC. Greater cognitive and impulse control deficiencies in PSU correlated with smaller total BREOS volume and thinner cortex (primarily DLPFC, OFC). Spectroscopy indicated neuronal injury/glial changes primarily in the DLPFC of only PSU; greater metabolic abnormalities were associated with higher cocaine (not alcohol) use and poorer visuospatial learning and memory.Results: Results suggest that substance use sequelae, injury mechanisms, and/or predisposition differ between one-month-abstinent PSU and ALC. PSU

appear to exhibit greater abnormalities in markers of neuronal and glial function, perhaps related to increased oxidative stress.Conclusions: Future studies need to consider duration of abstinence, drug interactions and/or cumulative drug abuse effects on neurobiological outcomes. As the neurobiological and cognitive phenotypes differ between PSU and ALC, they may require unique pharmacological and behavioral treatment interventions.Keywords: addiction, neuroimaging, cognition, polysubstance abuse, alcoholSupported By: AA10788, DA025202

957. A Neural Signature of Decisions to Smoke MarijuanaGillinder Bedi1, 2, Martin A. Lindquist3, Margaret Haney1, 2

1Psychiatry, Columbia University, New York, NY, 2Division on Substance Abuse, New York State Psychiatric Institute, New York, NY, 3Biostatistics, Johns Hopkins University, New York, NY

Background: Despite evidence of altered decision-making in addiction, little is known about the neurobehavioral processes underlying the most clinically-relevant decisions drug users make: decisions to buy and use drugs. We employed an fMRI neuroeconomics task combined with laboratory drug self-administration to investigate neural substrates underlying decisions to smoke marijuana (MJ).Methods: 21 non-treatment-seeking MJ smokers (16 M; 5 F), smoking 6.9 (± 0.3) days/week, underwent a 10-hour outpatient session. During the session, they completed an fMRI neuroeconomics task, making repeated decisions about whether to purchase 1 - 12 standardized MJ (0.0, 5.6%THC) ‘puffs’ for varying costs ($0.25 - $5/puff). Following scanning, one randomly-selected choice was implemented. If the selected choice had been bought, the cost was taken from study earnings and the participant smoked the purchased MJ in the laboratory; otherwise they remained in the laboratory without MJ. BOLD fMRI data were analyzed using whole-brain machine learning analyses with leave-one-out cross-validation to classify brain activation during choices to buy versus to decline MJ.Results: 17 participants purchased sufficient offers for inclusion. The classifier discriminated with 100% accuracy in a forced-choice discrimination between BOLD activation patterns for purchased versus refused MJ. Dorsal and ventral striatal regions, insula, and anterior and posterior cingulate cortex contributed significantly to the classification.Conclusions: Distributed neural activation patterns identified with fMRI can predict choice to use MJ with a high degree of accuracy. These findings provide the basis for a brain-based characterization of drug-related decision-making, including the impact of psychological and pharmacological interventions on these processes.Keywords: marijuana, fMRI, neuroeconomics, drug self-administration, decision-makingSupported By: NIDA DA009236, DA031005

958. Neural Circuits for Threat and Reward Interact to Predict Problem DrinkingYuliya Nikolova, Ahmad Hariri

Psychology & Neuroscience, Duke University, Durham, NC

Background: Using data from the first 200 participants in the ongoing Duke Neurogenetics Study (DNS), we recently showed that stress-related problem drinking is particularly pronounced in individuals with relatively high reward-related ventral striatum (VS) reactivity and relatively low threat-related amygdala reactivity. This pattern may reflect an increased drive to pursue rewards coupled with a reduced ability to detect the potentially harmful consequences of drinking. In the current study, we extend these earlier findings by exploring a second putative profile of neural circuit function associated with stress-related problem drinking in a larger sample of DNS participants.Methods: Amygdala and VS reactivity were measured using well-characterized face-matching and number-guessing BOLD fMRI paradigms, respectively, in an expanded sample of 375 DNS participants (214 women, mean age 19.73±1.28).



Recent stress and problem drinking were assessed via self-report.Results: We extend prior findings by demonstrating that stress is associated with problem drinking not only in individuals with high VS and low amygdala reactivity, but also in those with low VS and high amygdala reactivity (p’s<0.02). Stress does not, however, correlate with problem drinking in individuals whose VS and amygdala reactivity are either both high or both low (p’s>0.10).Conclusions: Our findings support the existence of two distinct neural profiles associated with stress-related problem drinking: one associated with an increased drive to pursue rewards and reduced threat sensitivity, possibly reflecting drinking for stimulation and positive emotion enhancement; and one associated with decreased reward drive and increased sensitivity to threat, possibly reflecting drinking to reduce negative emotion.Keywords: threat, reward, stress, alcohol, fMRISupported By: Yuliya Nikolova is an HHMI International Student Research Fellow. The Duke Neurogenetics Study is funded by Duke Univeristy

959. Impulsivity as a Trait Risk Factor of Addiction - Impact on Model-Free and Model-Based Control of Decision MakingLorenz Deserno1, 2, Quentin Huys3, 4, 5, Tilmann Wilbertz1, Anette Horstmann6, Jane Neumann6, Andreas Heinz2, Hans-Jochen Heinze7, Schlagenhauf Florian1, 2

1Cognitive and affective control of behavioral adaption, Max-Planck-Insitute of Cognitive and Brain Sciences, Leipzig, Germany, 2Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin, Berlin, Germany, 3Translational Neuroimaging Unit, ETH Zurich, Zurich, Switzerland, 4Psychiatric University Hospital, University Zurich, Zurich, Switzerland, 5Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom, 6Department of Neurology, Max-Planck-Insitute of Cognitive and Brain Sciences, Leipzig, Germany, 7Klinik für Neurologie, Universitätsklinik Magdeburg, Magdeburg, Germany

Background: Model-free andmode-based control are two important features of decision making. It was proposed that a shift towards model-free control crucially contributes to the development and maintenance of addiction disorders. Impulsivity is known as a trait risk factor for addiction andmay therefore be related to such alterations in reward processing and decision making.Methods: To test this assuption formally, we used a two-step Markov decision task during fMRI in a sample of 23 high-impulsive and 22 low-impulsive, clinically health participants. High- and low-impulsive participants were recruited using the Barrat Impulsiveness Scale.Results: Both groups did not differ in their utilization of model-free and model-based aspects of the decision process. On the neuronal level, both groups differ in terms of the relation of a striatal error signal to individual weights of model-free and model-based behavior.Conclusions: This study demonstrates differences in the neural signatures of learning related error signals in the striatum in high- and low-impulsive, healthy participants. Although both groups did not differ regarding their insight to the task structure, these neural differences may constitute a potential vulnerability factor for addiction disorders. On the other hand, this study shows that impulsivity alone does not result in model-free behavior.Keywords: Addiction, Impulsivity, Dopamine, Reinforcement Learning, FMRISupported By: DFG SCHL1969/2-1; SCHL1969/1-1

960. Inverse Correlation Between Glutamate and Craving for AlcoholMark A. Frye1, David J. Hinton1, 2, Victor M. Karpyak1, Osama A. Abulseoud1, Lee J. Gunderson1, Scott E. Feeder1, David A. Mrazek1, Doo-Sup Choi1, 2

1Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, 2Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN

Background: Non-invasive diagnosis methodology using proton magnetic resonance spectroscopy (1H-MRS) in human brain to identify brain metabolites as biomarkers for pathophysiology of neurological and psychiatric disorders is essential. Especially, the identification of brain biomarkers for both depression and alcohol craving would be useful to assess the severity alcohol relapse.Methods: 1H-MRS was used to assess metabolite levels of the midline anterior cingulate cortex (MACC) of 18 individuals diagnosed with alcohol dependence. The Pennsylvania Alcohol Craving Scale (PACS) was used to assess craving and the two-item patient health questionnaire (PHQ-2) was used to quantify symptoms of depression.Results: We found a significant inverse correlation between Glx levels and craving intensity for alcohol measured by PACS in alcohol dependent patients [Spearman r = -0.46, P = 0.05]. When PACS scores were dichotomized into a group with low (< median = 20) and high (≥ median = 20) PACS scores, Glx levels were significantly lower in patients with high PACS scores [t(16) = 2.2, P = 0.04]. A significant inverse correlation was also found between Glx levels and PHQ-2 scores in alcohol dependent patients [Spearman r = -0.50, P = 0.04]. Furthermore, when patients were grouped based on low (< 3) or high (≥ 3) PHQ-2 scores, patients with a high PHQ-2 score had significantly lower Glx levels [t(15) = 2.2, P = 0.04].Conclusions: Our findings suggest that low levels of glutamate are correlated with increased craving and depression symptom severity.Keywords: Glutamate, Alcohol Dependence, Depression, MRS, Anterior CingulateSupported By: S. C. Johnson Family Foundation

961. MGLUR5 Imaging in Cocaine Addiction Using Pet Radioligand [11C]ABP688Michele S. Milella1, Laura Marengo1, Aryan Fotros1, Alain Dagher2, Pedro Rosa-Neto3, Chawki Benkelfat1, Marco Leyton1

1Psychiatry, McGill, Montreal, QC, Canada, 2Montreal Neurological Institute, McGill, Montreal, QC, Canada, 3Center for Studies in Aging, McGill, Montreal, QC, Canada

Background: Animal studies suggest that metabotropic glutamate receptor 5 (mGluR5) could play an important role in cocaine addiction on both the reinforcing effect of the drug and the ability of drug-related cues to induce relapse. Moreover, downregulation of mGluR5 was shown in rat Nucleus Accumbens following cocaine self-administration. Our goal was to investigate mGluR5 availability in striatal and cortical regions of cocaine dependent individuals.Methods: 8 cocaine users meeting DSM-IV diagnostic criteria for current cocaine dependence (CD) and 9 healthy controls (age and sex matched) were recruited from the general population. Availability of mGluR5 (binding potential, BPND) was measured by positron emission tomography (PET HRRT) following the i.v. administration of radioligand [11C]ABP688 that binds with high affinity to the receptor. On a separate day, each subject underwent an anatomical MRI for co-registration purposes.Results: Compared to controls, CD subjects showed significantly reduced (∼30%) BPND values in both left and right Ventral Striatum (Limbic) (repeated measures ANOVA: group and group × region interaction, p = 0.03).Conclusions: Our PET data confirm preclinical evidence of mGluR5 alterations in striatal regions considered crucial in reward-related behavior. Since recent evidence suggests that cocaine-induced mGluR5 alterations can be



pharmacologically reversed, this study could have exciting implications for novel treatments directly targeting this system.Keywords: mGluR5, positron emission tomography, cocaine, addiction, glutamateSupported By: CIHR

962. Brain Morphology in Cannabis Users: Region-Dependent Reductions and Role of Use PatternsValentina Lorenzetti1, Nadia Solowij2, Alex Fornito1, Dan I. Lubman3, Michael J. Takagi1, Ian H. Harding1, Christos Pantelis1, Marc L. Seal4, Murat Yucel1

1Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne, Melbourne, Australia, 2Psychology, School of Psychology, University of Wollongong, Wollongong, Australia, Wollongong, Australia, 3Psychiatry, Turning Point Alcohol and Drug Centre, Eastern Health and Monash University, Melbourne, Australia, Melbourne, Australia, 4Murdoch Childrens Research Institute, Royal Children’s Hospital Melbourne, Melbourne, Australia

Background: While animal studies show that regular cannabis exposure has neurotoxic effects on brain structure, the evidence in human cannabis users remains inconclusive. We aimed to elucidate whether regular cannabis use is associated with alterations in human brain morphology.Methods: A sample of 46 adult cannabis users and 37 age- and gender-matched controls underwent structural MRI. Brain regions with a high concentration of cannabinoid receptors and linked to behaviors altered in cannabis users were selected for analysis, including: the hippocampus (learning and memory), amygdala and pituitary gland, (emotion and stress regulation), nucleus accumbens (reward sensitivity), and caudate nucleus (repetitive behaviors). A series of ANCOVAs and regression analyses were conducted to investigate the impact of group membership (i.e., cannabis versus non-cannabis users) and of cannabis use patterns (e.g., frequency, duration, dosage, age of onset) independent of confounding ‘clinical’ variables’ (i.e., anxiety, depressive, positive and negative psychotic symptoms, intelligence quotient and general functioning) on the investigated regions.Results: Cannabis users showed reduced hippocampal and amygdala volumes, but no difference in other regions, compared to controls. Later age of initiation of cannabis use predicted reduced hippocampal volumes, while higher cannabis dosage predicted smaller amygdala but larger nucleus accumbens and caudate nucleus volumes.Conclusions: Cannabis use was associated with neuroanatomical alterations in medial temporal regions, while specific cannabis use patterns exerted regionally dependent effects. These data suggest that there are complex associations between cannabis use and brain morphological alterations, which may be mediated by the biochemical and functional specificity of the examined brain region.Keywords: cannabis, structural MRI, brain, hippocampus, amygdalaSupported By: National Heath and Medical Research Council ID459111, Melbourne International Research Scholarship, International Postgraduate Research Scholarship

963. Frontal Lobe Structure-Function Alterations in Adolescents Prenatally Exposed to Drugs of AbuseBetty Jo Salmeron

Neuroimaging Research Branch, NIDA, Baltimore, MD

Background: Prenatal drug exposure (PDE) to substances of abuse has subtle effects on behavior and cognitive functioning. We investigated whether brain-behavior relations are altered in a sample of adolescents with PDE (primarily cocaine) and matched community comparison (CC) adolescents .Methods: Freesurfer-generated frontal volumes of 28 PDE (14 M, 14.65 +/- 1.12 y.o.) and 24 CC (9 M, 14.15 +/- 1.26 y.o.) were compared using GLM with exposure status, gender, age, total cortical gray matter volume, and alcohol

and tobacco exposure as independent variables. Interactions between gender and exposures (drugs, alcohol and tobacco) were also included. Regional volumes showing effects of PDE were subsequently correlated with behavioral and cognitive measures (e.g. BASC, BRIEF, CPT, CVLT).Results: In the PDE group, right orbitalis and rACC were larger. Conduct and externalizing problems correlated with right rostral ACC volume. The CC group had larger left lateral orbitofrontal cortex, bilateral rostral middle frontal cortices, and right BA 45. Various behavioral control measures correlated with left lateral OFC and bilateral rostral middle frontal volumes, and cognitive measures (e.g., inhibitory control) correlated with right BA45 and right orbitalis volumes. Interactions with gender for drug and tobacco effects on frontal volumes were driven by males in right orbitalis and rACC. Right caudal middle frontal and BA 45 alcohol effects were driven by females.Conclusions: PDE may alter brain organization, with PDE showing unique relationships of behavior to salience network (rACC) and CC showing unique relationships of behavior to executive control network (bilateral rostral middle frontal cortices).Keywords: Prenatal drug exposure, adolescents, brain structure, frontal lobe, structure function relationshipSupported By: NIDA Intramural Research Program; RO1 DA 021059

964. Relationship Between Harm Avoidance and Nicotinic Acetylcholine Receptor DensitySteven Storage1, Mark Mandelkern2, Jonathan Phuong3, Maggie Kozman3, Arthur Brody4

1School of Medicine, UCLA, Los Angeles, CA, 2Nuclear Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 3Research, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 4Psychiatry, UCLA, Los Angeles, CA

Background: Prior research indicates that disturbance of cholinergic neurotransmission reduces anxiety, leading to the hypothesis that people with heightened cholinergic function have a greater tendency toward anxiety-like and/or harm avoidant behavior. We sought to determine if people with elevated levels of harm avoidance (HA), a dimension of temperament from the Temperament and Character Inventory (TCI), have high α4β2* nicotinic acetylcholine receptor (nAChR) densities.Methods: Healthy adults (n = 105) underwent bolus-plus-continuous infusion positron emission tomography (PET) scanning using the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA). During the uptake period of 2-FA, participants completed the TCI.Results: The central study analysis revealed a significant association between total HA and mean nAChR density, which was based on higher total HA scores being linked with greater nAChR density across brain regions. In examining HA subscales, both ‘Fear of Uncertainty’ and ‘Fatigability’ were significant, based on higher levels of these characteristics being associated with greater nAChR densities.Conclusions: This study adds to a growing body of knowledge concerning the biological basis of personality and may prove useful in understanding the pathophysiology of psychiatric disorders (such as anxiety disorders) that have similar characteristics as HA. Study findings indicate that heightened cholinergic neurotransmission is associated with increased anxiety-like traits.Keywords: Tobacco Dependence, Harm Avoidance, Positron Emission Tomography, Nicotinic Acetylcholine Receptor, Temperament and Character InventorySupported By: R01 DA 20852



965. Frontocingulate Dysfunction During Aversive Interoceptive Processing is Linked to Escalation of Problematic Stimulant UseJennifer L. Stewart1, Jason Parnass1, April C. May1, Martin P. Paulus1, 2

1Psychiatry, UCSD, La Jolla, CA, 2Veterans Administration Healthcare System, Psychiatry Service, La Jolla, CA

Background: Stimulant dependence has been linked to fronto-cingulate dysfunction during decision making as well as alterations in interoceptive processing. However, less is known about the transition from recreational use to stimulant dependence. The present study investigated error processing during an aversive interoceptive challenge in current and former stimulant (cocaine and amphetamine) users using functional magnetic resonance imaging (fMRI).Methods: Young adults who were previously identified as recreational users were followed up three years later. Of these, 18 individuals progressed to problem stimulant use (PSU), whereas 15 desisted stimulant use (DSU). PSU, DSU, and 14 healthy comparison subjects (CTL) performed a two-choice prediction task at three fixed error rates (20, 50, and 80%) during which they anticipated and experienced episodes of inspiratory breathing load.Results: Across subjects, insula activation was greater during breathing load than anticipation and baseline and uncertainty (50% error rate) was associated with greater inferior frontal gyrus (IFG), dorsal anterior cingulate (ACC), and insula activation than 20% and 80% error rates. During breathing load: (1) PSU and DSU exhibited lower thalamus and subgenual ACC than CTL despite no group differences in subjective valence/arousal ratings of the breathing load itself; and (2) PSU demonstrated lower subgenual ACC, IFG, and middle frontal gyrus activation than DSU and CTL. Lastly, in response to failure (80% error rate), PSU showed greater IFG activation than DSU and CTL.Conclusions: Heightened inhibitory processing within the context of failure and attenuated interoceptive responses to aversive stimuli may be markers of the transition to stimulant dependence.Keywords: fMRI, Addiction, Stimulants, Interoception, Error ProcessingSupported By: R01 DA016663-01

966. The Dopamine Transporter in Chronicle Crack Cocaine Users: An in vivo Study with SPECT and TRODAT-1-99MTCIlza R. Batista1, 2, Andrea P. Jackowski1, Marilia Alves dos Reis1, 2, Wagner Ribeiro1, Mario Luiz Castiglioni3, Ronaldo Laranjeira1, Acioly L. T. de Lacerda1, Rodrigo A. Bressan1, 2

1Psychyiatry, UNIFESP, São Paulo, Brazil, 2InCE, Instituto Israelita de Ensino e Pesquisa, São Paulo, Brazil, 3DDI, UNIFESP, São Paulo, Brazil

Background: Crack cocaine is a powerfully addictive substance and can be smoked in “pipes”. Crack cocaine blocks the dopamine transporter (DAT) increasing their extracellular concentrations. This study evaluated the density of striatal DAT in 25 chronic users of crack-cocaine in abstinence and 16 healthy volunteers matched for age and education.Methods: DAT levels measured by TRODAT-1-99mTc SPECT (single photon emission computed tomography) - Hwakeye (GE, U.S.A) with fan beam collimators, have been used to assess the binding potential of the dopamine transporter into the striatum, caudate and putamen right and left.Results: TRODAT-1-99mTc uptake in crack cocaine dependents subjects was higher than healthy controls in all regions investigated: right striatum (1.45 ± 0.28 vs 1.24 ± 0.19, p = 0.01; t = 2.61), left striatum (1.41 ± 0.28 vs 1.22 ± 0.21, p = 0.02, t = 2.29), right caudate (1.83 ± 0.42 vs 1.54 ± 0.32, p = 0.02, t = 2.37), left caudate (1.87 ± 0.44 vs 1.54 ± 0.28, p = 0.01, t = 2, 66), right putamen (1.47 ± 0.34 vs 1.22 ± 0.18, p = 0.01, t = 2.67) and left putamen (1.50 ± 0.45 vs 1.26 ± 0.30, p = 0.03, t = 1.88).Conclusions: Chronic use of crack increases the number of dopamine transporter

in the striatum regions. These results corroborate the findings of other authors. The decrease in the availability of dopamine could explain the intense need and desire for the seeking crack during abstinence.Keywords: crack cocaine, Dopamine transporter, SPECT, TRODAT-1Supported By: FAPESP; IIEPAE

967. Nicotine but not Cocaine Use is Associated with Decreased Metabotropic Glutamate Receptor 5 Density in HumansBoris B. Quednow1, Valerie Treyer2, Anass Johayem3, Katrin H. Preller1, Matthias Vonmoos1, Simon M. Ametamey3, Alfred Buck2, Erich Seifritz4, Lea M. Hulka1

1Experimental and Clinical Pharmacopsycology, University Hospital of Psychiatry, Zurich, Switzerland, 2Division of Nuclear Medicine, University Hospital, Zurich, Switzerland, 3Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland, 4Clinic for Affective and General Psychiatry, University Hospital of Psychiatry, Zurich, Switzerland

Background: Long-lasting neuroadaptations in the glutamatergic cortico-striatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we aimed to investigate if human cocaine users exhibit altered mGluR5 availability compared to drug-naïve control subjects.Methods: Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with [11C]ABP688 to quantify mGluR5 availability in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. Cocaine craving was measured with the brief Cocaine Craving Questionnaire.Results: Cocaine users and controls did not significantly differ in mGluR5 availability. In contrast, smokers (n=24) showed a significant reduction in mGluR5 density throughout the brain (mean 20%) compared to non-smokers (n=11). Reduction of mGluR5 availability were most pronounced in the caudate nucleus (d=1.50), insula (d=1.47), and putamen (d=1.46). Duration of nicotine abstinence was positively related to mGluR5 density in all pre-defined brain regions-of-interest, indicating that mGluR5 expression was particularly decreased in individuals who had smoked very recently.Conclusions: Nicotine use significantly decreased mGluR5 availability in both cocaine users and controls, while cocaine use per se was not associated with alterations in mGluR5 density. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation.Keywords: Cocaine, Nicotine, Glutamate, PET, AddictionSupported By: SNSF PP00P1_123516

968. Decreased Serotonin Release Capacity and Altered 5-Ht2A Receptor Density in MDMA UsersBoris B. Quednow1, Felix Hasler2, Valerie Treyer3, Matthias T. Wyss3, Simon M. Ametamey4, Alfred Buck3, Franz X. Vollenweider2

1Experimental and Clinical Pharmacopsycology, University Hospital of Psychiatry, Zurich, Switzerland, 2Neuropsychopharmacology and Brain Imaging, University Hospital of Psychiatry, Zurich, Switzerland, 3Division of Nuclear Medicine, University Hospital, Zurich, Switzerland, 4Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland

Background: In rodents and non-human primates, repeated MDMA (“Ecstasy”) administration causes sustained depletion of brain serotonin and loss of serotonergic axon terminals. Moreover, MDMA users consistently exhibit dose-



related memory deficits and decreased serotonin transporter densities suggesting that MDMA might also affect the human serotonin system. However, whether chronic MDMA exposure produces a long-lasting and functional serotonin deficiency in humans is unclear so far. Therefore, we developed a novel method to assess serotonin release capacity in the human brain employing [18F]altanserin positron emission tomography (PET) after challenge with the potent serotonin releaser d-fenfluramine.Methods: Fifteen current and 12 former male MDMA users, as well as 15 matched male drug-naïve controls received placebo or 60 mg d-fenfluramine on two days separated by an interval of 14 days. Two hours after drug intake, a 250 MBq bolus of the selective serotonin-2A receptor antagonist [18F]altanserin was administered and dynamic PET data were acquired over 90 min. Moreover, arterial blood samples were drawn for measurement of total activity, d-fenfluramine, and prolactin plasma concentrations.Results: Current MDMA users showed a blunted prolactin response together with decreased serotonin-2A receptor densities and reduced serotonin release capacity in all investigated brain regions when compared to drug-naïve controls. Former MDMA users still showed an attenuated prolactin response and lower serotonin-2A receptor densities, whereas their serotonin release capacity was not significantly different from controls.Conclusions: These first functional data suggest that MDMA use is associated with sustained changes of the serotonin system that might be only in part reversible.Keywords: MDMA, PET, serotonin, memory, neurotoxicologySupported By: SNSF 32003B-116654, SNSF PP00P1_123516

969. Working-Memory Network Function in Heavy Cannabis Users Predicts Changes in Cannabis Use: A Prospective FMRI StudyJanna Cousijn1, 2, Reinout W. Wiers1, K Richard Ridderinkhof1, Wim van den Brink2, Dick J. Veltman2, 3, Anna E. Goudriaan2

1Psychology, University of Amsterdam, Amsterdam, Netherlands, 2Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, 3Psychiatry, VU University Medical Center, Amsterdam, Netherlands

Background: Theoretical models of addiction suggest that a substance use disorder represents an imbalance between hypersensitive motivational processes and deficient regulatory executive functions. Working-memory (a central executive function) may be a powerful predictor of the course of drug use and drug-related problems. Goal of the current functional magnetic resonance imaging (fMRI) study was to assess the predictive power of working-memory network function for future cannabis use and cannabis-related problem severity in heavy cannabis users.Methods: Tensor Independent Component Analysis (Tensor-ICA)was used to investigate differences in working-memory network function between 32 heavy cannabis users and 41 non-using controls during an N-back working-memory task. In addition, associations were examined between working-memory network function and cannabis use and problem severity at baseline and at six-month follow-up.Results: Behavioral performance and working-memory network function did not significantly differ between heavy cannabis users and controls. However, among heavy cannabis users, individual differences in working-memory network response predicted change in cannabis use six months later, over and beyond behavioral predictors of cannabis use (R2 change = .11, F change1,25 = 9.20, p = .006): a stronger network response during the N-back task was related to an increase in weekly cannabis use.Conclusions: These findings imply that heavy cannabis users requiring greater effort to accurately complete an N-back working-memory task have a higher probability of escalating cannabis use. Working-memory network function may be a biomarker for the prediction of course and treatment outcome in cannabis users.

Keywords: Cannabis, Working-memory, fMRI, tensor-ICA, Cannabis use disorderSupported By: ZON-Mw grant #31180002

970. Interoceptive Processing During Inspiratory Breathing Load in Adolescents with Substance Use DisordersLotte Berk1, April C. May1, Jennifer L. Stewart1, Martin P. Paulus1, 2, Susan F. Tapert1, 2

1Psychiatry, University of California, San Diego, La Jolla, CA, 2Psychiatry Service, VA San Diego Healthcare System, La Jolla, CA

Background: Interoception, i.e. processing of stimuli from inside the body, has been considered an important component of drug-taking behavior. Previous results from our group have shown that adolescent substance use disorder individuals (SUD) exhibit interoceptive hyposensitivity to pleasant stimuli but reward-related hypersensitivity. However, it is unclear whether similar patterns exist for aversive interoceptive stimuli. This study examined the involvement of the insula and other brain regions during the anticipation and experience of aversive stimuli.Methods: SUD (n=13) and healthy comparison subjects (CTL; n=16) performed a continuous performance task with intermittent inspiratory breathing load while undergoing functional magnetic resonance imaging (fMRI). During this task, the background color indicated a 1 in 4 chance of experiencing the breathing load.Results: Across subjects, experience of breathing load was associated with greater bilateral inferior frontal gyrus and anterior/posterior insula activation than anticipation of breathing load, highlighting involvement of heightened inhibitory control and interoceptive processing during decision making within the context of aversive bodily states. Furthermore, during breathing load, SUD exhibited increased dorsal ACC activation than CTL. Although groups did not differ in subjective ratings of breathing load intensity, within SUD increased dorsal ACC during breathing load was linked to higher intensity ratings of the aversive stimulus.Conclusions: Substance dependent adolescents show increased activation in dorsal ACC during aversive interoceptive stimulation, which is associated with higher intensity ratings. This combination points toward greater disruption of ongoing activities by aversive stimuli, which may lead to an unstable interoceptive state and an increase propensity to use drugs.Keywords: adolescents, fMRI, interoception, addictionSupported By: P20 DA027834-02

971. Striatal and Insular Hyperactivation During Pleasant Interoceptive Stimuli Characterizes the Transition to Problematic Stimulant Use in Young AdultsApril C. May1, Jennifer L. Stewart1, Jason M. Parnass1, Susan F. Tapert1, 2, Martin P. Paulus1, 2

1Psychiatry, University of California, San Diego, La Jolla, CA, 2Psychiatry Service, Veterans Administration Healthcare System, La Jolla, CA

Background: Mechano-receptive C-fiber (MR-CF) stimulation via soft touch can be employed to investigate interoceptive sensitivity to positively valenced stimuli and determine its relevance for addiction. Although chronic stimulant abusers exhibit reduced insula and striatum activation in response to pleasant interoceptive stimuli, less is known about the transition from recreational use to dependence. This study examined whether occasional stimulant users who transitioned to problem use show similar brain responses to MR-CF stimulation.Methods: Young adults (ages 18-24) previously identified as recreational users were followed up 3 years later. Eighteen had progressed to problem stimulant use (PSU), whereas 15 desisted stimulant use (DSU). PSU, DSU, and 15



healthy comparison subjects (CTL) completed a continuous performance task during functional magnetic resonance imaging while receiving a pleasant interoceptive stimulus. During anticipatory trials, a colored background signaled an impending slow brush stroke administered to the palm or forearm during upcoming interoceptive trials. Visual analog scales (VAS) indexed interoceptive experience (e.g., pleasantness).Results: Across trials, PSU exhibited greater anterior insula activation than DSU and CTL. Moreover, during the experience of soft touch, PSU demonstrated greater ventral striatum and posterior insula activation than DSU and CTL. Although groups did not differ in VAS responses, within CTL greater anterior insula and ventral striatum activations were linked to higher pleasantness ratings, a pattern not evident in PSU or DSU.Conclusions: The transition to stimulant dependence is associated with exaggerated reward responsivity that may contribute to the propensity to try drugs at a young age and increase use into adulthood.Keywords: fMRI, stimulants, reward, interoceptionSupported By: R01 DA016663-01A1

972. Reduced Concentration of N-Acetyl-Aspartate Associated with Volume Reduction of the Hippocampus in Heavy Cannabis UsersMurat Yucel1, Valentina Lorenzetti1, Michael Takagi1, Ian H. Harding1, Christos Pantelis1, Alex Fornito1, Marc Seal2, Dan I. Lubman3, Nadia Solowij4

1Psychiatry, University of Melbourne, Melbourne, Australia, 2Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne, Australia, 3Turning Point Alcohol and Drug Centre, Eastern Health and Monash University, Melbourne, Australia, 4Psychology, University of Wollongong, Sydney, Australia

Background: Converging neuropsychological and neuroimaging evidence indicates that the hippocampus is dysfunctional in heavy cannabis users but very few studies have examined the biochemical basis of such dysfunction.Methods: A 3T Siemens Trio (TR=2000; TE=30; NEX=160) was used to acquire proton magnetic resonance spectroscopy (1H-MRS) data and probe hippocampal biochemistry (see Figure). A total of 46 cannabis users (54% male; 32.5 years of age) and 26 healthy controls (54% male; 30.1 years of age) were recruited from the general community. In all analyses, we statistically controlled for individual differences in age, intelligence, general functioning, as well as depressive and anxiety symptoms.Results: There was a significant reduction in the concentration of hippocampal N-acetyl-aspartate in the cannabis group (p=0.006; 12% reduction relative to controls). Cannabis use indices such as dose, duration, frequency and age of onset were not correlated with concentrations of N-acetyl-aspartate. However, there was a significant association between N-acetyl-aspartate concentration and the degree of hippocampal volume reduction in the cannabis group (r=0.31; p=0.04).Conclusions: These findings indicate that the hippocampus is biochemically abnormal in long-term cannabis using individuals. Reduced N-acetyl-aspartate likely reflects neuronal loss or damage, mitochondrial anomalies or reduced synaptic connections that underpin the more gross structural abnormalities observed in heavy cannabis users. The findings suggest that heavy cannabis use across protracted periods exerts adverse biochemical and anatomical effects on brain tissue.

Keywords: cannabis, marijuana, spectroscopy, neuroimaging, hippocampusSupported By: NHMRC project #459111; NHMRC SRF #1021973

973. Alcohol Use Blunts Nucleus Accumbens Activation to Monetary Reward Anticipation: A Longitudinal FMRI StudyMary Heitzeg, Jillian Hardee, Mary Soules, Davia Steinberg, Robert Zucker, Jon-Kar Zubieta

Psychiatry, University of Michigan, Ann Arbor, MI

Background: Individual differences in reactivity of the reward system have been proposed to underlie vulnerability to problem alcohol use; however, there are competing theories about whether a hypo- or hyper-reactive system confers risk. One reason for this may be a failure to adequately account for effects of alcohol use itself on the reward system. The present longitudinal study was designed to disentangle pre-existing risk factors from effects of alcohol on nucleus accumbens (NAC) response to monetary reward.Methods: Thirty-four participants completed a monetary incentive delay task during functional MRI at baseline (ages 20-23) and follow-up (ages 24-27). Multiple regression was used to determine: 1) whether baseline NAC activation predicted amount of drinking from baseline to follow-up; and 2) whether amount of alcohol consumed from baseline to follow-up predicted change in NAC activation during that time period. Gender, age, family history, diagnosis and baseline lifetime drinking volume were included in each model.Results: NAC activation to reward accounted for a significant amount of variance in later drinking above and beyond other indicators, with greater activation at baseline predicting increased drinking. Furthermore, greater drinking from baseline to follow-up was related to a blunting of NAC activation over that interval.Conclusions: These findings suggest that greater reactivity of NAC to incentives may be a risk factor for problem alcohol use during emerging adulthood. Alcohol use was related to a blunting of NAC activation to monetary incentives, supporting the theory that drugs of abuse may bias the reward system away from natural rewards.Keywords: reward, nucleus accumbens, alcohol, vulnerability, fMRISupported By: K01 DA020088, R01 DA027261, R01 AA12217, R37 AA07065

974. OXT Genotype Predicts Anticipatory Responses to RewardTiffany Love1, Mary-Anne Enoch2, David Goldman2, Colin Hodgkinson2, Jon-Kar Zubieta1

1Psychiatry, University of Michigan, Ann Arbor, MI, 2National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD

Background: Oxytocin is involved in the expression of a variety of reproductive and affiliative behaviors and is hypothesized to affect these behaviors through its influence on motivational networks. Oxytocin and its receptors are observed in primary reward regions including the nucleus accumbens (NAc). As genetic variation at the oxytocin gene may explain differential responses to reward, we examined this possibility using fMRI.Methods: Blood was taken and DNA extracted for forty-five healthy subjects. Four haplotype tagging single nucleotide polymorphisms (SNPs) located in noncoding regions just upstream/downstream of the oxytocin gene (OXT) were identified and were genotyped using the Illumina GoldenGate platform. Subjects were scanned using fMRI while they performed the monetary incentive delay task which robustly activates reward networks.Results: Whole brain group level analyses indicated significant activation within the NAc, bilaterally, in response to anticipated gains relative to neutral trials. Functional data from the left and right NAc were extracted using Marsbar



and used for genetic analyses. Using ANCOVA, we tested for genetic effects for each SNP controlling for sex (minor allele homozygotes were merged with heterozygotes due to low minor allele frequencies). Analyses revealed significant gene effects in the left NAc for 3 of the SNPs tested, which are in strong linkage disequilibrium (rs4813625, p=0.035; rs3761248, p=0.004 rs877172, p=0.074; rs2740210, p=0.498). Similar effects were seen in the right NAc for rs3761248 (p=0.038) but not for rs4813625 (p=0.079), rs877172 (p=0.282) or rs2740210 (p=0.455).Conclusions: These data indicate OXT genotype is associated with neural responses to the anticipation of reward.Keywords: Oxytocin, Genetics, fMRI, Reward, Nucleus AccumbensSupported By: RO1DA022520; R01DA016423

975. The Critical Role of the Cingulate Gyrus in Cigarette Desire: An Fmri StudyStéphane Potvin1, Josiane Bourque1, Adrianna Mendrek2

1Psychiatry, University of Montreal, Montreal, QC, Canada, 2Psychology, Bishop’s University, Lennoxville, QC, Canada

Background: Cigarette smoking is the leading preventable cause of death. Unfortunately, quitting rates remain rather low in smokers. Triggered by cues or by stress, cigarette cravings are among the best predictor of smoking relapse, but their neural correlates are yet to be fully understood. Here, we sought to examine the neural correlates of cue-elicited craving in active smokers, using functional imaging.Methods: Sixteen active smokers (>15 cigarettes per day) were asked to passively view cigarette and neutral pictures while being scanned using functional magnetic resonance imaging (fMRI). Immediately after the scan, smokers were asked to rate each image on a scale from 0 (no cravings) to 10 (worst imaginable craving). fMRI data was analyzed with SPM-5, using a block design.Results: A one-sample t-test revealed that the passive viewing of tobacco images elicited significant activations of the dorso-medial frontal gyrus, the anterior, middle and posterior cingulate gyrus, and the thalamus.Conclusions: Our results are consistent with previous functional imaging studies which showed that cigarette cravings elicit activations in the medial frontal and anterior cingulate cortex. Our results also highlight the potentially under-estimated importance of the posterior cingulate cortex in generating cue-elicited cigarette cravings. Interestingly, the posterior cingulate gyrus has been recently shown to play a critical role in autobiographical memory, which suggests that the passive viewing of cigarettes cues may trigger cravings by activating tobacco-related memories. Future studies will need to examine the potential role of autobiographic memory in cue-elicited cigarettes cravings, using functional imaging.Keywords: Tobacco, Cue-elicited cravings, Functional magnetic resonance imaging, Cingulate gyrusSupported By: Canadian Institutes of Health Research

976. Adolescent Marijuana Users with and without Comorbid Psychiatric Disorders: Clinical and Neurobiological CorrelatesErin McGlade1, 2, Allison Locatelli2, Jace King2, Laura Weis2, Melissa Lopez-Larson1, 2, Deborah Yurgelun-Todd1, 2

1Department of Psychiatry, University of Utah, Salt Lake City, UT, 2Brain Institute, University of Utah, Salt Lake City, UT

Background: Marijuana (MJ) is the most common illicit substance used by adolescents in the US. Although MJ use has been related to clinical and biological factors, there has been limited examination of differences between MJ users with and without comorbid psychiatric disorders. In the current study we hypothesized the relationship between depressive symptoms and hippocampal volume would be different for MJ users with and without comorbid psychiatric diagnoses.

Methods: Sixty-two adolescents (mean age=17.89) with MJ use more than 100 times the prior year participated in this study, including 37 with MJ misuse only and 25 with MJ misuse and one or more additional Axis I disorder(s). Participants had a 3T MRI and completed a diagnostic interview and Hamilton Rating Scale for Depression. Morphometric analysis was run with Freesurfer. Analyses were performed to evaluate group differences in hippocampal (HIP) volumes (corrected for total brain volumes) and for correlations of these structures with depressive symptoms.Results: MJ+Psych participants evidenced significantly more depressive symptoms than MJ only individuals (MJ+Psych=4.71, MJ=1.17, p<0.001). No between-group differences were seen for HIP; however, MJ+Psych participants showed a significant association between left HIP and depressive symptoms (r=-0.56, p=0.02) whereas MJ participants evidenced a significant association between right HIP and depressive symptoms (r=-0.38, p=0.03).Conclusions: Results indicate differential associations between depressive symptoms and hippocampal volumes in MJ users with and without comorbid psychiatric diagnoses. These findings are consistent with previous reports that depression is associated with hippocampal volume and suggest differential lateralization of mood in the MJ only group.Keywords: Adolescents, Marijuana, Imaging, Comorbid psychiatric disorders, Limbic systemSupported By: R01DA020269

977. Modafinil Modulates Resting State Functional Connectivity and Cognitive Control in Alcohol Dependent PatientsLianne Schmaal1, 2, Anna Goudriaan2, Leen Joos3, Anne Maren Kruse2, Geert Dom3, Wim van den Brink2, Dick Veltman1

1Department of Psychiatry, VU University Medical Center, Amsterdam, Netherlands, 2Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, 3Department of Psychiatry, Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp, Antwerp, Belgium

Background: Alcohol dependence (AD) is associated with deficits in cognitive control. Cognitive control is likely to be mediated through the interaction between intrinsic large-scale brain networks involved in externally-oriented executive functioning and internally focused thought processing. Improving the interaction between these functional networks could be an important target for treatment. Therefore, the current study aimed to investigate the effects of the cognitive enhancer modafinil on within- and between-network resting state functional connectivity and cognitive control functions in AD patients.Methods: In a double-blind placebo-controlled cross-over design, resting-state fMRI and a Stroop task were employed in AD patients (N=15) and healthy controls (N=16). Within- and between-network functional connectivity was calculated using a combination of independent component analysis and functional network connectivity (FNC) analysis. Repeated measures ANCOVA’s were conducted on connectivity strength with treatment modeled as a within-subject factor and group as a between-subjects factor. Pearson correlations were calculated between modafinil-induced changes in Stroop task performance and connectivity changes.Results: Modafinil significantly increased the negative coupling between the default mode network (DMN) and salience network (SN) (F(1,13)=6.54,p=0.02), and the DMN and left (F(1,13)=11.23,p<0.01) and right (F(1,13)=5.67,p=0.03) central executive networks (CEN) only in AD. The anti-correlation between the DMN and SN was associated with modafinil-induced improvement in cognitive control (r=-0.67,p<0.01).Conclusions: These findings demonstrate that modafinil at least partly exerts its effects by targeting intrinsic functional relationships between large-scale brain systems underlying cognitive control. The current study therefore provides a neurobiological rationale for implementing modafinil as an adjunct in the treatment of AD.



Keywords: alcohol dependence, modafinil, resting state fMRI, cognitive control, functional network connectivitySupported By: ZonMW grant 31160003

978. Treatment-Related Changes in Brain Activations Underlying Cognitive Control and Reward Processing in Cocaine DependenceMarc N. Potenza1, Elise E. DeVito1, Iris M. Balodis1, Hedy Kober1, Patrick D. Worhunsky2, Guangheng Dong3, Michael C. Stevens1, Godfrey D. Pearlson1, Kathleen M. Carroll1

1Psychiatry, Yale University School of Medicine, New Haven, CT, 2Psychology, Oxford University, Oxford, United Kingdom, 3Psychiatry, Zhejiang Normal University, Jinhua, China

Background: Although behavioral therapies are empirically validated and widely used in treating cocaine dependence (CD), the neural correlates underlying effective therapies are poorly understood. Cognitive behavioral therapy (CBT) involves helping patients identify patterns of behaviors and cognitions that maintain addictive processes and learning and implementing strategies to change. These changes include exerting greater self-control in the setting of immediately rewarding opportunities (e.g., those involving drug use).Methods: FMRI measures of cognitive control and reward processing (using the Stroop and Monetary Incentive Delay (MID) Tasks, respectively) were collected in 34 CD patients before and after CBT. Whole-brain analyses were performed using family-wise-error corrections thresholded at p<0.05.Results: As compared with pre-treatment, post-treatment Stroop fMRI of CD patients revealed relatively diminished activation in inferior frontal gyrus (IFG), anterior cingulate, ventral and dorsal striatum and dorsomedial and dorsolateral prefrontal cortex (PFC)), with changes in IFG and dorsolateral PFC activation associating inversely with measures of long-term abstinence and CBT completion. As compared with pre-treatment, post-treatment MID reward anticipation revealed relatively increased activation in amygdala, hippocampus, insula, and IFG, with changes in activation associating positively with abstinence measures. relatively Post- versus pre-treatment activation in ventral striatum was greater in CBT-homework completers (versus non-completers).Conclusions: These novel, unpublished data suggest that treatment-related changes in cognitive control and anticipatory reward processing show different patterns of changes during CBT treatment in CD, with changes relating both to drug abstinence and CBT completion. These findings suggest CBT may operate mechanistically through changing activity within corticolimbic-striatal circuitry.Keywords: cocaine, fMRI, cognitive control, reward processing, behavioral therapySupported By: NIDA R01 DA020908, P50 DA09241

979. Lower GABA Levels in the Dorsal Anterior Cingulate Cortex Impair Ability to Ignore Smoking-Related Cues in Tobacco-Dependent VolunteersAmy C. Janes, J. Eric Jensen, Stacey L. Farmer, Blaise Frederick, Diego A. Pizzagalli, Scott E. Lukas

Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA

Background: Substance abusers have difficulty ignoring drug-related cues, which contribute to relapse vulnerability. This “attentional bias” towards drug cues translates into an inability to ignore drug-related stimuli that may reflect deficits in brain regions such as the dorsal anterior cingulate cortex (dACC)_a key region in cognitive control and decision-making. Therapies targeted at ameliorating dACC dysfunction may reduce attentional bias, resulting in enhanced smoking cessation. However, neurochemical disruptions within the dACC have yet to be associated with attentional bias for smoking cues.Methods: In 15 nicotine-dependent smokers we assessed smoking cue attentional

bias using the smoking Stroop task and dACC GABA levels using magnetic resonance spectroscopy (MRS). We also measured changes in affect state over the course of the experiment using the Positive and Negative Affect Schedule.Results: We found a negative correlation between attentional bias and dACC GABA levels (r = -0.63, p = 0.01). Smokers with the greatest attentional bias also experienced more negative affect during early nicotine withdrawal (r = 0.77, p < 0.001).Conclusions: Our findings document a relationship between heightened reactivity to drug stimuli and both early withdrawal symptoms and reduced dACC GABA. Because reduced GABA function in frontal brain regions is thought to disrupt cognition, our findings suggest that smokers with diminished dACC GABA may lack the cognitive resources to successfully ignore salient distractors such as smoking stimuli and therefore are more prone to relapse. This relationship between reduced dACC GABA and attentional bias suggests a neurochemical target for future smoking cessation treatment strategies.Keywords: GABA, Anterior Cingulate Cortex, attentional bias, nicotine dependence, smoking cues

980. Heightened Systemic Inflammation: A State or a Trait Marker for Major Depression During Late Pregnancy? William Simpson1, Benicio N. Frey2, Meir Steiner2

1MiNDS Neuroscience, McMaster University, Hamilton, ON, Canada, 2Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada

Background: Numerous studies have reported heightened concentrations of pro-inflammatory cytokines in patients with major depression (MDD). Significant hormonal fluctuations and alternations in circadian rhythms may render pregnant women more susceptible to systemic inflammation. To date, little is known about the relationship between cytokines, circadian rhythms and symptoms of depression in late pregnancy.Methods: Thirty-two pregnant, medication-free women were investigated (mean age= 29.3, mean gestational age= 33.5 weeks). Cytokine concentrations were quantified using Multiplex immunoassays. Lifetime history of depression was assessed using the MINI. Current depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Sleep, circadian rhythms and stress were assessed using the Pittsburgh Sleep Quality Index (PSQI), Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN) and Perceived Stress Scale (PSS).Results: Subjects screening positive for depression (EPDS≥12, n=6) had significantly higher BRIAN, PSQI and PSS scores (all p≤0.003) compared to those who screened negative (n=26); however no significant differences in cytokine concentrations were observed. Subjects with lifetime history of MDD (n=22) had a significantly higher TNF-a/IL-10 ratio (F=4.37, p=0.045) compared to subjects without lifetime MDD (n=10). No significant correlations were observed between cytokine levels and EPDS, PSQI, BRIAN or PSS (all p>0.05).Conclusions: Depressive symptoms in late pregnancy are associated with increased stress, poorer sleep quality and altered circadian rhythms. However, none of these symptoms were correlated with cytokine levels. The positive association between pro/anti-inflammatory ratio and lifetime history of depression suggests that systemic inflammation may be a trait rather than a state marker of depressive illness.Keywords: pregnancy, depression, cytokines, circadian rhythms



981. Lack of Effects of Testosterone Augmentation of Combined Estradiol and Progesterone Replacement on Mood in Women with Primary Ovarian InsufficiencyGioia M. Guerrieri1, Pedro E. Martinez1, Summer P. Klug1, Nazli A. Haq1, Vien Vanderhoof2, Deloris E. Koziol3, Vaishali Popat2, David R. Rubinow4, Peter J. Schmidt1, Lawrence M. Nelson2

1Behavioral Endocrinology Branch, NIMH, Bethesda, MD, 2Integrative Reproductive Medicine Unit, NICHHD, Bethesda, MD, 3Biostatistics and Clinical Epidemiology, NIH, Bethesda, MD, 4Department of Psychiatry, University of North Carolina, Chapel Hill, NC

Background: Women with POI have both low circulating testosterone (T) levels and an increased risk of mood disorders. Moreover, studies suggest that T has mood altering effects in women with primary ovarian insufficiency (POI) independent of estrogen/progestin therapy (EPT). We examined the effects of T-augmentation of EPT on depressed mood in women with POI.Methods: 128 women with POI (not specifically selected for complaints of depression) entered a 12-month placebo-controlled trial investigating the efficacy of T-augmentation of EPT on mood. Depressive symptoms/syndromes were evaluated with standardized rating scales at baseline and after 12 months of treatment. Data were analyzed by Wilcoxon rank-sum and Fisher’s exact-tests.Results: No differences were found in any baseline characteristics including serum hormone levels (P> 0.05). Eight women in each group met criteria for MDE. Fifteen women randomized to T and 7 women randomized to placebo scored > 16 on the CES-D. Baseline mean+SD CES-D scores were 10.7+8.6(T) and 9.2+7.8(placebo) (P=0.35). After 12 months of treatment, serum T levels were significantly higher in women on T (P< 0.001), but measures of depression, quality of life, and self-esteem were not different between treatment groups. Baseline T levels were not associated with clinical response.Conclusions: Our data are not consistent with previous reports of the antidepressant effects of T in hypogonadal women. Negative mood symptoms in POI do not appear to reflect an underlying androgen deficiency and the routine use of T augmentation for mood symptoms in women with POI is not indicated.Keywords: Primary Ovarian Insufficiency, Testosterone, Mood, Depression, Hypoandrogenism

982. Adrenocortical Sensitivity to Endogenous ACTH in the CRH TestBernard J. Carroll1, Doh Kwan Kim2, Holly Rogers3, James C. Ritchie4

1Research, Pacific Behavioral Res Fdn, Carmel, CA, 2Psychiatry, Samsung Medical Center, Seoul, Korea, Republic of, 3Psychiatry, Duke University Medical Center, Durham, NC, 4Pathology, Emory University School of Medicine, Atlanta, GA

Background: CRH testing typically focuses on maximal cortisol level (Fmax) as the cortisol response measure. However, Fmax reflects adrenocortical response capacity at 45-60 minutes rather than adrenocortical sensitivity per se. Using high frequency sampling we characterized the ACTH-cortisol interaction in the early response phase of the CRH test.Methods: Six volunteers aged 18-57 received ovine corticotropin releasing hormone (oCRH) 1 ug/kg IV at 1600h. ACTH and cortisol samples were drawn every 3 minutes. Based on intra-assay variances, criteria for reliably detecting hormone increases were established. The reference point was the time of first reliable cortisol response (TF). Adrenocortical sensitivity was estimated by the relationship between the incremental area under the concentration curve for ACTH (AUCACTH) over 9 minutes preceding TF and the AUCcortisol over 9 minutes spanning TF -3 minutes to TF plus 6 minutes. We compared this sensitivity measure [AUCcortisol (pmol-h/L) divided by AUCACTH (fmol-h/L)] with Fmax.

Results: The first reliably detected ACTH response occurred at 3-9 minutes, with cortisol responses seen at 9-15 minutes. The adrenocortical sensitivity measure exhibited a 2.4-fold range from 34 to 81 units (mean 49; median 45; SD 16). Fmax occurred at 60 minutes (5 cases) or 45 minutes (1 case). Fmax exhibited a 1.39-fold range from 567 to 786 nmol/L (mean 715; median 736; SD 78). There was no significant correlation between the adrenocortical sensitivity measure and the maximal cortisol level (Pearson r = 0.00).Conclusions: Fmax in the CRH test is not a measure of adrenocortical sensitivity to endogenous ACTH.Keywords: Adrenal Cortex, Sensitivity, Acth, Crh Test, HumanSupported By: RO1MH39593

983. Mineralocorticoid Receptor Agonist as a Predictor of Treatment Outcome in Depression with and without Early Life StressMario F. Juruena1, Margaret Castro2, Ayrton C. Moreira2, Frederico G. Graeff3

1Neurosciences and Behavior, FMRP, University of Sao Paulo, Ribeirao Preto, Brazil, 2Department of Internal Medicine , FMRP, University of Sao Paulo, Ribeirao Preto, Brazil, 3Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil

Background: This study compares the HPA axis responses to GR and MR agonists in depression and their association with early life stress (ELS) and response to treatment.Methods: HPA axis response to placebo, fludrocortisone (0.5mg), prednisolone (5mg) and dexamethasone (0.5mg) were evaluated by cortisol in patients with depression (n=45) and controls (n=20). We assessed clinical severity of depression and history of Childhood Trauma on admission and after 60 days of treatment. We divided patients with and without ELS and responders and non-responders to treatment.Results: Awakening salivary cortisol (nmol/L) showed differences regarding time, challenge and its interaction (p<0001). On placebo and prednisolone treatments, patients showed lower awakening cortisol than controls (p<0.05); on fludrocortisone treatment, patients showed lower cortisol at 22h; 30 and 60 minutes (p<0.05); There was no difference on dexamethasone treatment. Salivary cortisol AUC (nmol X h/L) was significant lower after prednisolone (p=0.03) in ELS patients (n=31), and after fludrocortisone (p=0.02) in patients without ELS (n=14) than controls; there was no differences on dexamethasone (p=0.2) or placebo (p=0.1). Salivary cortisol AUC in treatment responders (n=24) was lower after fludrocortisone (p=0.004) and after prednisolone (p=0.01) than in controls; without differences on dexamethasone (p=0.3) or placebo (p=0.3).Conclusions: Depressive patients showed impaired HPA feedback response to mixed MR/GR agonists, suggesting a hypoactivity of the HPA axis. Depressive patients without ELS and/or treatment responders suppressed the HPA more effectively with a selective MR agonist. These data suggest MR function in the neurobiology of depression, as a predictor for good prognosis.Keywords: HPA axis, depression, Early Life Stress, Mineralocorticoid Receptor, Glucocorticoid ReceptorSupported By: FAPESP; CNPq, CAPES, FAEPA



984. Trait Anxiety Affects Amygdala Reactivity in the Follicular Phase for Women with Previous Emotional Side Effcts of Oral ContracepticesMalin Gingnell1, Jonas Engman1, Andreas Frick1, Mats Fredrikson1, Inger Sundström-Poromaa2

1Department of Psychology, Uppsala University, Uppsala, Sweden, 2Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden

Background: Mood related side effects are reported by 4-10% of women using combined oral contraceptives (COC). Prior studies indicate that ovarian steroid hormones affect amygdala reactivity, but also that this effect might be influenced by levels of trait anxiety. In general, high levels of anxiety are associated with increased amygdala reactivity. However, among women with premenstrual dysphoric disorder, higher scores on trait anxiety induced less amygdala reactivity than low scores, but only in the follicular phase. In this study we compared amygdala reactivity in women with previous mood related side effects of COC and high v.s. low levels of trait anxiety.Methods: Twenty-four women with previous experience of mood related side effects while on COC underwent fMRI in early follicular phase (cycle day 4 ±3). During scanning, subjects performed a matching task contrasting emotional and simple geometrical shapes. Amygdala reactivity was compared between subjects with high and low scores on Speilberger State and Trait Anxiety Inventory - Trait version (STAI-T) based on a median split.Results: Eleven subjects were classified as low trait anxiety (STAI-T 31.4 ±0.6) and 13 subjects as high trait anxiety (STAI-T 39.0 ±0.7). Subjects with lower scores on STAI-T had higher reactivity in bilateral amygdala than subjects with higher scores on STAI-T [right 24, 1, -19 p<0.002 z=3.15 k=13; left -24, 1, -14 p<0.011 z=2.44 k=27].Conclusions: Our results confirm that low levels of trait anxiety increases amygdala reactivity during the follicular phase of the menstrual cycle in individuals with increased sensitivity to ovarian steroid hormones.Supported By: Swedish research council

985. Obesity and Depression are Associated with Elevated Levels of Leptin and Interleukin-8 in Mexican-American FemalesRene L. Olvera1, Douglas E. Williamson1, Jennifer J. Donegan2, David A. Morilak2, Susan P. Fisher-Hoch3, Joseph B. McCormick3

1Psychiatry, UTHSCSA, San Antonio, TX, 2Pharmacology, UTHSCSA, San Antonio, TX, 3Epidemiology, Human Genetics and Environmental Health, UTHSC-Houston School of Public Health, Brownsville, TX

Background: Obesity and depression are major public health issues that frequently co-occur. In preclinical models, we have shown that dysregulation of Janus Kinase - Signal Transducer and Activator of Transcription (JAK-STAT) signaling in prefrontal cortex, induces depressive-like cognitive deficits. Leptin is known to activate this signaling pathway which may implicate mechanisms linking obesity and depression. Herein we examine theassociation between adipokine/cytokine levels as they relate to depression and obesity in a population-based cohort of Mexican-American females.Methods: Women (n=319) completed the Center for Epidemiological Studies-Depression (CES-D) scale. Body-mass-index (BMI) was calculated based on measured height and weight and adipokines/cytokines measurement was performed using multiplex ELISA.Results: A total of 117 (37%) of the sample had CES-D scores in the clinically significant range for depression ( ≥ 16). A total of 190 (59%) of the sample were obese (BMI ≥ 30) with 47% classified as mildly obese (BMI 30-39), and 12% severely obese (BMI ≥ 40). There was a significant interaction between depression and obesity (p< 0.001) with higher leptin levels observed in the depressed and severely obese women. Interleukin-8 was significantly elevated (p=0.024) in

severely obese subjects with a trend (p =0.07) for elevation in depressed subjects and no interaction effect. Lastly adiponectin was significantly lower in severely obese subjects (p = 0.03) with a trend for lower adiponectin (p =0.07) in depressed subjects.Conclusions: Altered adipocyte hormones and adipocytokines may provide a link to understanding the co-occurrence of depression in obese individuals.Keywords: Leptin, Depression, Inflammation, ObesitySupported By: MD000170 P20

986. Oxytocin Receptor (OXTR) Gene Polymorphisms Influence Dopamine Transporter Availability in Normal Healthy SubjectsWei Hung Chang1, I. Hui Lee2, 3, Kao Chin Chen2, 3, 4, Yen Kuang Yang2, 3, 5, Tzung Lieh Yeh2, 3, Po See Chen2, 3

1Department of Psychiatry, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan, 2Department of Psychiatry, National Cheng Kung University, Tainan, Taiwan, 3Addiction Research Center, National Cheng Kung University, Tainan, Taiwan, 4Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan, 5Institute of Behavioral Medicine, National Cheng Kung University, Tainan, Taiwan

Background: Evidences had showed oxytocinergic and dopaminergic systems interact in the brain to regulate associated behavior. A recent study further demonstrated the existence of dopamine d2-oxytocin receptor (OXTR) heteromers in the striatum. The current study was aimed to investigate whether a common single nucleotide polymorphism (rs53576) in the OXTR might affect the striatal dopamine transporter (DAT) availability and interact with its correlation with oxytocin levels.Methods: The DAT availability in ninety-five healthy subjects was approximated using single photon emission computed tomography with [99mTc] TRODAT-1.The rs53576polymorphism of the OXTR gene was genotyped and oxytocin levels were measured.Results: The striatal DAT availability in the AG+GG group was significant lower than that of the AA group (2.08±0.47 v.s 1.90±0.32, p=0.04). Furthermore, only individuals with one or two copies of the G allele of rs53576 showed negative correlation between DAT availability and oxytocin levels(r=-0.41 p=0.002).Conclusions: These results indicate that genetic variation of the OXTR modulates the interaction between oxytocinergic and dopaminergic systems.Table 1. Demographic data and comparisons between different OXTR genes

Total(n=95)

AA(n=34)

AG+GG(n=61)

Difference betweenAA vs. AG+GG

Mean± SD Mean± SD Mean± SD t pAge 33.45±12.10 32.99±12.27 33.70±12.10 -0.28 0.78Sex (M/F) 40/55 13/21 27/34 0.33 0.59Oxytocin 25.86±5.95 26.11±6.34 25.73±5.76 0.30 0.77DAT 1.97±0.38 2.08±0.47 1.90±0.32 2.04 0.04*DAT: dopamine transporter *: P<0.05Table 2. Pearson’s correlation between oxytocin level, age, DAT, partial correlation after controlling age

Total AA AG+GGr p r p r p

Pearson’’s correlationAge 0.21 0.04* 0.20 0.26 0.22 0.10DAT -0.17 0.12 0.03 0.87 -0.41 0.002*Partial correlationDAT -0.09 0.41 0.13 0.50 -0.36 0.01*

DAT: dopamine transporter * : p<0.05Keywords: oxytocin receptor, single nucleotide polymorphism, dopamine transporter, oxytocin level, TRODAT



987. Pituitary Volume and Clinical Trajectory in Young Relatives at Risk for SchizophreniaElizabeth R. Howard1, Jai L. Shah1, 2, Neeraj Tandon1, Diana Mermon3, Jean M. Miewald3, Debra M. Montrose3, Matcheri S. Keshavan1, 2, 4

1Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, 2Department of Psychiatry, Harvard Medical School, Boston, MA, 3Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, 4Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, MA

Background: Much remains to be understood regarding the role of the hypothalamic-pituitary-adrenal axis (HPAA) in the onset and evolution of brain disorders. Previous work has suggested a fluctuating course of pituitary volume (PV) during the trajectory from clinical high-risk to first episode to chronic psychosis. However, no research has explored PV in unaffected individuals at familial high risk for schizophrenia (FHR). We sought to examine the relationship between early PV with initial or future psychopathology or psychosis in FHR adolescents.Methods: PV tracing was completed for 1.5T MRI scans of 34 offspring (HR; mean age 15.9) of affected patients and 32 healthy controls (HC; mean age 16.1) in Pittsburgh, PA. Subjects were assessed by SCID or K-SADS clinical interviews and Chapman’s schizotypy scales, then followed for at least 1 year to evaluate for development of new or worsening psychopathology, or psychosis itself. Group PVs were compared using ANCOVAs controlling for gender, age, and intracranial volume.Results: No baseline PV differences were found between HR and HC. PV was not associated with either initial or new/worsening psychopathology in HR. Both Chapman’s scores (p<0.001) and PV (p=0.028) were significantly elevated in HR subjects who later developed psychosis.Conclusions: Baseline PV is predictive of emerging psychosis but not initial, new, or worsening general psychopathology in a high-risk sample. This finding complements the existing literature on PV and the trajectory to psychosis. We discuss implications for understanding the relationships between general psychiatric and psychotic symptomatology, stress and HPAA function.Keywords: High-Risk, Hypothalamic-Pituitary-Adrenal Axis, Pituitary, Psychosis, SchizophreniaSupported By: Dupont-Warren Research Fellowship, Harvard Medical School (JS); National Institutes of Health (NIH) MH01180, MH64023, MH78113 to MSK; National Alliance for Research on Schizophrenia and Depression (Independent Investigator Award to MSK)

988. A Multisite, Longitudinal, Naturalistic Observational Study of Transcranial Magnetic Stimulation (TMS) for Major Depression in Clinical PracticeMark Andrew Demitrack1, Philip G. Janicak2, Linda L. Carpenter3, David G. Brock1, Dafna Bonneh-Barkay1, David L. Dunner4

1Medical Operations, Neuronetics, Inc., Malvern, PA, 2Psychiatry, Rush University Medical Center, Chicago, IL, 3Psychiatry, Butler Hospital, Providence, RI, 4Psychiatry, Center for Anxiety and Depression, Mercer Island, WA

Background: This study examined the long-term effectiveness of TMS in naturalistic clinical practice settings over 52 weeks following successful acute treatment.Methods: Three hundred and seven patients diagnosed with unipolar, non-psychotic major depressive disorder, who had failed to receive benefit from prior antidepressant treatment, received TMS treatment in clinical practice (66.8% women, 48.6 ± 14.2 years). Forty three clinical practices participated. TMS was provided as determined by the evaluating physician, consistent with labeled use.

Two hundred sixty-four patients consented to long-term follow up over 52 weeks, and were evaluable for statistical analysis. Clinical assessments (CGI-Severity of Illness, PHQ-9 and IDS-SR) were obtained at 3, 6, 9, and 12 months. Two hundred four patients provided data across the entire study period.Results: Compared with baseline, there was a statistically significant reduction in mean [SD] CGI-S, PHQ-9 and IDS-SR total scores at the end of acute treatment (5.1 [0.9] vs 3.2 [1.5], 18.3 [5.2] vs 9.6 [7.0], and 45.7 [11.0] vs 27.4 [15.8], all P<0.0001), which was sustained throughout the 52 week follow-up (3.0 [1.5], 9.4 [7.2], and 27.3 [16.1], all P<0.0001), respectively. Beyond 3 months, 30.2% of patients required subsequent reintroduction of TMS based on symptom worsening. The mean [SD] time to TMS reintroduction was 145 [74] days from entry into long term follow-up.Conclusions: TMS demonstrates a statistically and clinically meaningful durability of acute response over 52 weeks of follow up. Posted on www.clinicaltrials.gov, Listing No. NCT 00104611.Keywords: Longitudinal, Transcranial magnetic stimulation, Major Depression, Clinical trial, AntidepressantSupported By: Neuronetics, Inc.

989. Investigation of the Targeted Effects of Deep Brain Stimulation on Depressive Symptom Profiles: A Pooled AnalysisSakina J. Rizvi1, Sidney H. Kennedy2, Paul E. Holtzheimer3, Peter Giacobbe2, Andres M. Lozano4, Raymond W. Lam5, Theodore T. Kolivakis6, Helen S. Mayberg7

1Psychiatry, Pharmaceutical Sciences and Neuroscience, University Health Network, University of Toronto, Toronto, ON, Canada, 2Psychiatry, University Health Network, University of Toronto, Toronto, ON, Canada, 3Psychiatry, Dartmouth Medical School, Lebanon, NH, 4Division of Neurosurgery, University Health Network, Toronto, ON, Canada, 5Psychiatry, University of British Columbia, Vancouver, BC, Canada, 6Psychiatry, McGill University, Montreal, QC, Canada, 7Psychiatry, Emory University, Atlanta, GA

Background: Deep brain stimulation is a novel therapy for treatment-resistant depression (TRD). Open-label trials of DBS to the subcallosal cingulate gyrus (SCC) have shown a 40-60% response rate with six months of stimulation. It is unclear which symptoms are primarily affected by SCC DBS; identifying treatment-specific symptom profiles that change over time could elucidate the mechanism of action of SCC DBS.Methods: Baseline and 6-month Hamilton Depression Rating Scale (HRSD) scores from three open-label DBS trials for treatment-resistant MDD were pooled (N=56). Individual item change scores were calculated across all participants. Three analyses were conducted to assess overlap and robustness of findings: (1) item-total correlations, (2) stepwise linear regression, (3) parallel factor analysis and principal component factor analysis (PCA).Results: Pooled 6-month response rate from the three studies was 46.4%. The correlation matrix revealed the following items as contributing to HRSD score change (corrected for multiple comparisons, p<.002): mood (r=.71), interest (r=.66), psychic anxiety (r=.54), middle insomnia (r=.51), and suicidality (r=.50). The linear regression revealed a model including mood, interest, psychic anxiety and suicidality, which accounted for 83.6% of total variance (p<.001). The parallel analysis/PCA identified 4 factors associated with response to DBS: mood/sleep, interest/psychomotor retardation, suicidality/appetite, and libido.Conclusions: These findings suggest SCC DBS primarily affects specific depressive symptoms, including mood, interest, psychic anxiety and suicidality. From a neural circuitry perspective, these results suggest DBS may operate by modulating pathways specific to these symptom clusters; based on prior data from neuropharmacology studies, these may including serotonergic and dopaminergic networks.Keywords: Treatment resistant major depression, Deep Brain Stimulation



extremely TRD patients and changes with this novel intervention.Methods: We compared the performance of 17 TRD patients (unipolar and bipolar) with 15 healthy controls on tests of processing speed, memory, and executive function. Change in performance after 6 months of chronic DBS was assessed in the TRD patients.Results: At baseline, TRD patients performed significantly worse than controls on psychomotor and verbal attention tests of processing speed, as measured by response time to emotional words on the Affective Go/No-Go (AGN) task (p<0.001), and the color (p=0.06) and word (p=0.02) conditions on the Stroop task, respectively. After 24 weeks of DBS, TRD patients showed significant improvement on the Stroop color and word conditions (p<0.001), but showed no change in performance on the AGN (p>0.10). No cognitive measures worsened with chronic DBS.Conclusions: Our findings support the neurocognitive safety of SCCwm DBS. Additionally, these data may offer insight into a possible neurocognitive marker of TRD with respect to the differential time course of cognitive changes with DBS. Further research is warranted to confirm these findings in a larger sample with a more comprehensive neurocognitive battery.Keywords: Deep Brain Stimulation, Depression, Neuropsychology, Subcallosal CingulateSupported By: Dana Foundation; Stanley Medical Research Institute; Woodruff Foundation; Emory Healthcare; K23MH077869; Summer Undergraduate Research at Emory (SURE); Scholarly Inquiry and Research at Emory (SIRE)

992. Associations Between Fatigue, Pain, Psychiatric, Medical Factors, and Sleep Disturbance in Young Adults with Crohn’s DiseaseDavid Benhayon1, Kyle P. Duff1, F. Nicole McCarthy1, Melissa Newara1, Margaret A. Kirshner1, Miguel Regueiro2, David G. Binion2, Eva M. Szigethy1

1Psychiatry, University of Pittsburgh, Pittsburgh, PA, 2Gastroenterology, University of Pittsburgh, Pittsburgh, PA

Background: Fatigue, psychopathology, sleep disturbance, and pain are commonly noted in medical illness, but challenging to study. Crohn’s disease (CD) is a chronic gastrointestinal inflammatory illness in which all of these factors are common, making it an ideal model illness in which to study fatigue and its predictors.Methods: 48 young adults (54% female; 94% Caucasian; mean age 23.7) with mild CD activity completed Patient Reported Outcome Measurement Information Systems (PROMIS) measures of depression, pain, sleep disturbance, and fatigue as well as other measures of sleep disturbance (sleepiness and insomnia). Inflammatory markers and CD activity indices were also obtained. Pearson’s correlations and regression analyses were calculated.Results: Correlational analyses are shown (Table 1). Inflammatory markers did not correlate with measures of psychiatric illness in this cohort. Multivariate regression models identified pain and sleep disturbance as the most significant predictors of fatigue (Table 2).Conclusions: Fatigue in this cohort stems primarily from pain and sleep disturbance, rather than inflammatory pathways. Though it might be expected that sleep disturbance would explain a significant amount of fatigue, pain was an even larger contributor to the variance of fatigue, suggesting the importance of potential mechanisms linking pain and fatigue.

990. Double-Blind Optimization of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression: A Pilot StudyRajamannar Ramasubbu1, Susan Anderson2, Angela Haffenden3, Swati Chavda2, Zelma Kiss4

1Psychiatry/ Clinical neurosciences, University of Calgary, Calgary, AB, Canada, 2Clinical neurosciences, University of Calgary, Calgary, AB, Canada, 3Psychology, University of Calgary/Alberta Health Services, Calgary, AB, Canada, 4Clinical neurosciences, University of Calgary/Hotchkiss Brain Institute, Calgary, AB, Canada

Background: Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is a new treatment for treatment-resistant depression (TRD) and early data suggest it is safe and effective. However, the optimal electrical stimulation parameters are not known and generally selected by trial and error. This pilot study investigated the relationship between stimulus parameters and clinical effects in SCC-DBS treatment for TRD.Methods: Four patients with TRD underwent SCC-DBS surgery. In a double-blind stimulus optimization phase, frequency and pulse widths were randomly altered weekly and corresponding changes in mood and depression were evaluated using visual analogue (VAS) and Hamilton Depression Rating Scales (HDRS-17). In the open-label post-optimization phase, depressive symptoms were evaluated bi-weekly for 6 months to determine long-term clinical outcomes.Results: During the stimulus optimization phase, when longer long pulse widths (270,450 µs) were applied, 3 patients showed 50% reduction in HDRS-17 scores and all 4 patients showed maximal happy mood VAS response. Only one patient showed acute clinical or mood effects as a result of changing the stimulation frequency. Two patients responded and one patient partially responded after 6 months of open label therapy. Conclusions: Longer pulse width stimulation may have a role in stimulus optimization for SCC-DBS in TRD. This may relate to the larger apparent current spread with longer pulse durations and suggests that we do not know the actual target or the optimal stimulus parameters. Further investigations using different stimulus parameters are required prior to embarking on large scale randomized controlled trials for this condition.Keywords: Deep Brain Stimulation, Subcallosal Cingulate, Treatment Resistant Depression, Stimulation parameters, PulsewidthSupported By: Hotchkiss Brain Institute/Calgary Health Region

991. Characterizing Neurocognitive Performance in Patients with Treatment Resistant Depression and Changes Following Subcallosal Cingulate White Matter Deep Brain StimulationJared L. Moreines1, Shawn M. McClintock2, Mary E. Kelley3, Paul E. Holtzheimer4, 5, Helen S. Mayberg5, 6

1Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, 2Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, 3Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, GA, 4Departments of Psychiatry and Surgery, Geisel School of Medicine at Dartmouth, Lebanon, NH, 5Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 6Department of Neurology, Emory University School of Medicine, Atlanta, GA

Background: Depression has been clearly associated with cognitive abnormalities that typically improve with successful treatment. Although treatment-resistant depression (TRD) is highly prevalent, little is known about its associated neurocognitive profile and changes with therapy. Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) is a potential therapeutic option for TRD that offers a unique opportunity to study the cognitive status of



994. Voluntary Exercise Restores the Social Recognition Impairment in Dominant Negative DISC1 Mice: Implication for SchizophreniaHadar Segal, Ran Barzilay, Daniel Offen

Human Molecular Genetics & Biochemistry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Petah Tikva, Israel

Background: Current pharmacological treatment options have insufficient effect on negative symptoms of schizophrenia (SCZ), such as social withdrawal, and on the related cognitive deficits. Clinical studies indicate that physical exercise can attenuate negative symptoms and improve cognitive deficits, possibly by enhancing adult neurogenesis. The aim of the present study was to determine whether voluntary wheel running can improve SCZ-associated endophenotypes of dominant-negative DISC1 transgenic mice (DN-DISC1).Methods: DN-DISC1 and wild-type mice were placed for 14 days in a cage with or without free access to a running wheel. Thereafter, mice underwent behavioral tests and brains were processed for tissue analysis.Results: Voluntary exercise markedly reversed the significant deficit in social recognition that was detected in the DN-DISC1 mutant male mice. In addition, female mice which had free access to the running wheel showed a trend toward an improvement in the impairment observed in Y maze spatial memory test. ELISA analysis of female mice showed a two fold increase in BDNF levels in frontal cortex of WT mice after physical exercise. In contrast, in the DN-DISC mice, physical exercise didn’t elevate the BDNF levels.Conclusions: Our results suggest that physical exercise attenuate some of the impaired social and cognitive phenotypes exhibited by the DN-DISC1 mice. Interestingly, we observed no alteration in BDNF levels in the DN-DISC1 mice after physical activity which might be involved in impaired neurogenesis. Our study may serve as a platform to elucidate the mechanisms underlying the positive clinical effect of exercise on SCZ related endophenotypes.Keywords: Voluntary exercise, Transgenic mice, DISC1, Schizophrenia, Social recognition

995. A Pilot Study of Neuroplasticity Based Cognitive Remediation in Adolescents with PsychosisLinmarie Sikich1, Kristine Baluyot1, Lindsey Hazzard1, Cheryl Alderman1, Terrence C. Bethea1, Nancy Noyes2, Mary Verdi3, Rose George4, Mor Nahum5, Jacqueline Johnson1, Ann Maloney6, Stephen Hooper1

1Psychiatry, UNC-Chapel Hill, Chapel Hill, NC, 2Psychiatry, Maine Medical Center, Portland, NC, 3Psychiatry, Maine Medical Center, Portland, ME, 4Psychiatry, University of Utah, Salt Lake City, UT, 5Psychiatry, Brain Plasticity Institute, San Francisco, CA, 6Psychiatry, University of Massachusetts Medical School, Amherst, MA

Background: Neuroplasticity based auditory and visual training programs appear to improve neurocognitive functioning in adults with schizophrenia, but their utility in younger individuals with psychosis has not been determined. We hypothesized that adolescents might play more often and respond better than adults.Methods: Youth 10-19 years with psychosis NOS or a schizophrenia spectrum disorder were provided with a laptop and randomly assigned to play games to enhance basic auditory, visual and social processing and cognition (NPG)or control games with cognitive components such as hangman or sudoku (CG). Neurocognitive function was assessed at baseline, intervention completion and 4 months post treatment.Results: 12 youth (15.5 + 3.2 yrs) were assigned to NPG and 10 (16.2 +2.1 yrs) to CG. More NPG than CG youth completed the prescribed hours of play (92% vs 70% for the 1st 40 hours), though play reduced over time in both groups. Although most neurocognitive functions did not change, the NPG group did

Pearsons Correlation Coefficients Among Measures of Disease

Fatigue Depression Sleep Disturbance Pain CD

Activity ESR CRP

Fatigue -- .455* .663** .770** .495** .110 .077Depression -- .392** .479** .383* .094 .109Sleep Disturbance -- .530** .498** -.201 -.238Pain -- .697** .150 .171CD Activity -- .093 .072ESR -- .731**CRP --*p < .05; **p < .01

Stepwise Multivariate Regressions Predicting FatigueModel B SE B Beta R21 Constant 51.17 2.14 --

CD Activity 0.91 0.36 .39* .15

2 Constant 16.85 7.47 --CD Activity 0.42 0.30 .18Sleep Disturbance 0.69 0.15 .61** .48

3 Constant -2.18 7.08 --CD Activity -0.39 0.29 -.16Sleep Disturbance 0.51 0.12 .45**Pain 0.61 0.13 .63** .69

*p <.05; **p < .01

Keywords: Fatigue, Crohn’s disease, Sleep Disturbance, Pain, DepressionSupported By: American Psychiatric Institute for Research and Education (APIRE)

993. Seizure Duration Decreases over a Course of Bifrontal and not Bitemporal ECTHulegar A. Abhishekh1, Jagadisha Thirthalli2, Hegde Anusha1, Vivek H. Phutane3, Muralidharan Kesavan2, Naveen C. Kumar2, Bangalore N. Gangadhar2

1Medical student, Bangalore Medical College and Research Institute, Bangalore, India, 2Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India, 3Orygen Youth Health, Royal Melbourne Hospital, Melbourne, Australia

Background: Mechanism of action of electroconvulsive therapy (ECT) is unclear. Anticonvulsant action of ECT has also been one among the hypothesized mechanisms. Anticonvulsant effect may manifest during ECT in at least two ways a) increased seizure threshold b) decrease in seizure duration. In depression, increased seizure threshold has been shown to be associated with better antidepressant response. However, relationship between seizure duration and antidepressant activity has been inconsistent. These issues are not investigated in conditions other than depression. We examined this case in schizophrenia patients referred for ECT.Methods: Material for this analysis was obtained from a clinical trial examining the differential efficacy of bifrontal versus bitemporal ECT in schizophrenia patients. As a part of study 122 schizophrenia patients who were prescribed ECT were randomized to receive either bifrontal (BFECT) or bitemporal ECT (BTECT). Final analysis was conducted on the data from 70 patients, as rest of the data either had artifact or there was significant change in medication status. EEG seizure duration was noted in each session for these patients.Results: Seizure duration declined significantly from second ECT to 6th ECT [RMANOVA F=4.255; p=0.006]. When separate analysis was conducted for BTECT and BFECT patients the decline in seizure duration from 2nd to 6th ECT was significant only with BFECT [F=3.94; p=0.014] and not with BTECT [F =0.966; p=0.424].Conclusions: Better anticonvulsant effects with BFECT may explain the better therapeutic observed with BFECT in schizophrenia as well as mania in our earlier studies.



homes, who had Type2 diabetes mellitus, and a psychotic illness. The primary outcome was change in weight from baseline.Results: In initial focus groups, staff expressed skepticism about persuading residents to change their behavior. However, all staff of the homes recruited, agreed to participate. Baseline and endpoint data from 18 subjects, showed weight was lost by all except one subject (mean weight loss 10.06 lb; 95% CI 5.86-14.25lb; P less than 0.0001 [t=5.055; df=17]).Conclusions: Despite initial resistance of the staff, the program was associated with weight loss in almost all of the subjects, the majority of whom lost 5% of their initial body weight. Since the intervention was provided by the existing staff, there was minimal increase of cost to the system. The quasi-experimental design of the study is a limitation, but these encouraging results, should justify a rigorous randomized controlled trial of the intervention in similar settingsKeywords: Diabetes, Psychosis, Schizophrenia, Obesity, Weight-LossSupported By: Public Health Agency of Canada, Canadian Diabetes Strategy

998. Characterization of the Clinical Effect of a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor-2Peter De Boer1, Vikash Sinha2, Eva Hoeben2, Ion-George Anghelescu3, Iva Kezic4, Ella Daly5, Marc Ceusters1, Heidi De Smedt6, Luc Van Nueten1, Justine M. Kent7

1Neuroscience Development, Janssen Research & Development, a division of Janssen Pharmaceutica, Beerse, Belgium, 2Clinical Pharmacology, Janssen Research & Development, a division of Janssen Pharmaceutica, Beerse, Belgium, 3Department of Mental Health, Dr. K. Fontheim’s Hospital for Mental Health, Liebenburg, Germany, 4Biostatistics and Programming, Janssen Research & Development, a division of Janssen Pharmaceutica, Beerse, Belgium, 5Psychiatry, Janssen Research & Development, LLC, Titusville, NJ, 6Biometrics and Reporting, Janssen Research & Development, a division of Janssen Pharmaceutica, Beerse, Belgium, 7Central Nervous System, Janssen Research & Development, LLC, Titusville, NJ

Background: Modulating glutamate may have benefit in treating schizophrenia. Metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) may attenuate excess glutamate release. Prior clinical studies with mGlu2/3 agonists in schizophrenia have shown variable results. The potential spectrum of clinical effects of a novel mGluR2 PAM were therefore further characterized in a ketamine challenge study and in an exploratory treatment study of patients with schizophrenia.Methods: S-ketamine challenge study: In a 2-way crossover design, healthy participants received an intravenous dose of 0.005 mg/kg of S-ketamine over 60 minutes at 3 (N=16), 12 (N=8), and 24 (N=8) hours after administration of a single dose of 500 mg mGluR2 PAM or placebo. Schizophrenia study: 92 patients with stable schizophrenia (with residual positive- or negative symptoms or partially responsive to clozapine) were randomized to placebo (N=19), 50 mg (N=36), and 150 mg (N=37) mGluR2 PAM bid as adjunctive therapy to current antipsychotic medication in a 4-week double-blind treatment phase. Following double-blind treatment, all patients received 150 mg bid mGluR2 PAM open-label for 6-10 weeks.Results: S-ketamine-induced negative symptoms were significantly attenuated by pretreatment with the mGluR2 PAM at 3 hours only. The concentration range at which this effect was observed was similar to the plasma concentrations observed at steady state with an mGluR2 PAM dose of 150 mg bid. In patients with schizophrenia, an efficacy signal was observed in patients with predominant negative symptoms starting mGluR2 PAM at 50 mg bid.Conclusions: Negative symptoms of schizophrenia may benefit from modulating mGluR2 mediated transmission. Keywords: mGluR2 PAM, glutamate modulator, clinical effect, safety, schizophreniaSupported By: Janssen R & D, LLC

show improvement on WRAML Visual learning, WISC Digit Span Forward, Spatial Span Backwards and CPT omission errors. Surprisingly, youth and parent satisfaction was greater in the control games group.Conclusions: There was a signal for improvement in some measures of memory and attention in the NPG. However, youth did not play as frequently or for as long as requested despite providing a laptop for play at home and payment for playing.Keywords: Neuroplasticity, Memory, Attention, Social Cognition, Clinical TrialSupported By: NIMH

996. Proof of Concept of a Patient-Controllable Brain Stimulator (Closed-Loop Limbic Prosthesis) in a Rodent ModelAlik S. Widge1, Chet T. Moritz2

1Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, 2Rehabilitation Medicine & Biophysics, University of Washington, Seattle, WA

Background: Numerous mental disorders, across diagnostic categories, involve a failure of descending prefrontal regulatory control over limbic structures. Existing stimulators, including DBS and rTMS, apply energy at constant parameters and cannot respond to intraday symptom flares. We have proposed a “closed loop” patient-controlled system, where brain stimulation is triggered/shaped as-needed by frontal cortical activity. In addition to matching stimulation to a patient’s needs, this system would help address ethical concerns surrounding psychiatric neuromodulation by placing stimulator control back into the patient’s hands. We present here an initial rodent proof of concept for such a device.Methods: Four adult outbred rats were implanted with prefrontal (PrL/IL) microelectrode arrays, plus stimulating electrodes targeting the medial forebrain bundle (MFB). MFB stimulation produces positive emotional effects and is an investigational DBS target. Prefrontal neural activity was presented to the animal as a feedback cursor, and animals were offered opportunities to guide activity into a target to trigger MFB stimulation. Bootstrap testing was used to estimate chance success rates and determine whether animals were volitionally controlling the stimulator.Results: All animals achieved stimulator control with multiple single neurons, based on (p < 0.05) significance in bootstrap testing. 50% of testing days and 60% of recordable cells were controllable, with the best subject achieving control of 75% of tested cells.Conclusions: Multiple animal subjects can learn to control an implanted stimulator across multiple days and control sources, implying that this paradigm can be a robust platform for development of patient-controllable human neurostimulators.Keywords: Brain stimulation, Neuromodulation, Emotion regulation, Prefrontal cortex, Closed-loop controlSupported By: NSF-funded center seed grant

997. Weight Loss in Individuals with Diabetes and Psychosis: An Intervention for Community Residential SettingsRohan Ganguli, Todd Jenkins, Kinnon McKinnon

Psychiatry, University of Toronto, Toronto, ON, Canada

Background: Diabetes is prevalent at 2-3 times the general population rate in individuals with psychotic illnesses and the rates of diabetic co-morbidities are also higher in this population. The most severely affected often reside in board and care facilities, managed by non-professional staff. We studied the effects of training the staff in behavioral techniques for weight loss, on the weight of diabetic residents.Methods: Staff of 5 board and care homes, serving seriously mentally ill persons, were recruited to participate in a year-long program to improve nutrition and physical activities for residents. The subjects were 23 volunteers living in these



generalized disinhibitory state subjectively experienced as anxiety. A subset of patients comorbid for autism and chronic pain may have vulnerability in GAD65 expression, transport, or regulated functional activity.Keywords: pain, autism, cannabinoid, GABA, anxiety

1001. A Comparative Study of Baclofen vs Lorazepam in the Treatment of Alcohol Withdrawal SyndromeVidyendaran Rudhran, Sydney Moirangthem

Psychiatry, Chettinad Hosptial and Research Institute, Chennai, India

Background: Benzodiazepines are traditionally the drugs of choice in the treatment of alcohol withdrawal syndrome (AWS). Recent data has revealed that baclofen may reduce AWS symptoms. However, studies comparing baclofen with benzodiazepines are scarce. Accordingly, the present study was designed to compare efficacy and tolerability of baclofen versus lorazepam in treatment of uncomplicated AWS.Methods: Forty male patients with AWS were enrolled in the study and randomly divided into 2 groups after informed consent. Baclofen (30 mg/day for 10 consecutive days) was orally administered to 20 patients (median age: 36.4 years). Lorazepam (1mg = 5mg Diazepam) in Diazepam equivalents at a Diazepam dose of (0.5-0.75 mg/kg/day for 6 consecutive days, tapering the dose by 25% daily from day 7 to day 10) was orally administered to 20 patients (median age: 39.5 years). The Clinical Institute Withdrawal Assessment (CIWA-Ar) was used to evaluate physical symptoms of AWS.Results: Both baclofen and lorazepam decreased CIWA-Ar score, without significant differences between the 2 treatments (2-way ANCOVA: F[1,145] = 0.86, P>.05). Both drugs decreased sweating, anxiety and tremor subscale scores, without significant differences between treatments (2-way ANCOVA: F[1, 145] = 1.38, P>.05). Both treatments significantly decreased the agitation score, although baclofen was slightly slower than lorazepam (2-way ANCOVA: F[1, 145] = 3.56, P<.05).Conclusions: The efficacy of baclofen in treatment of uncomplicated AWS is comparable to that of the popularly used lorazepam. These results suggest that baclofen may be a strong contender as an alternative drug for treatment of uncomplicated AWS.Keywords: Baclofen, Lorazepam, Alcohol, Withdrawal

1002. Automated Quantitative Semantic Analysis of Speech Discriminates Acute Effects of ±3,4-Methylenedioxymethamphetamine and MethamphetamineGill Bedi1, 2, Guillermo A. Cecchi3, Diego Fernández Slezak4, Facundo Carrillo4, Harriet de Wit5

1Psychiatry, Columbia University, New York, NY, 2Division on Substance Abuse, New York State Psychiatric Institute, New York, NY, 3Biometaphorical Computing, Computational Biology Center, IBM Research Division, IBM, Yorktown Heights, NY, 4Computer Science Department, University of Buenos Aires, Buenos Aires, Argentina, 5Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL

Background: Abused drugs can produce profound mental state alterations. Measuring these effects by self-report relies on the capacity to accurately report introspective experiences. Analyzing the content of speech during intoxication may present a more direct ‘window’ into these effects. We employed computational analysis of speech semantic structure to study mental state alterations after ±3,4-methylenedioxyethamphetamine (MDMA) and methamphetamine.Methods: In a 4-session, double-blind outpatient study 13 healthy ecstasy users (9 M; 4 F) completed a 10-minute speech after oral MDMA (0.75, 1.5 mg/kg), methamphetamine (20 mg) or placebo. Latent Semantic Analyses identified the

999. The Long-Term Efficacy and Safety of Flexibly-Dosed Adjunctive Intranasal Oxytocin in Patients with Schizophrenia; An Open-Label StudyDavid Feifel, Kai MacDonald, Patrice Cobb, Rebecca McKinney, Allison Hadley

Psychiatry, UCSD Medical Center, San Diego, CA

Background: Recently, several groups including ours have shown the antipsychotic benefit of 20- 48 IU BID intranasal oxytocin (IN OT) in small proof-of-concept, randomized, double blind, placebo-controlled studies (Feifel, et al 2010, Pedersen, et al 2011). Although these findings have significant implications for OT as a novel antipsychotic, more long-term efficacy and safety data is needed, particularly as it relates to different doses. We report here on the first long-term, flexible-dose study of OT in schizophrenia, documenting its efficacy and safety at doses from 24 IU to 168 IU.Methods: In an open-label, 6-month evaluation of IN OT, patients diagnosed with schizophrenia and residual symptoms were administered IN OT (12 IU to 84 IU twice daily) adjunctive to their existing psychotropic medication. Dose was started at 24 IU BID and adjusted according to symptoms and tolerability. We report preliminary data on the first 11 subjects who completed up to 12-weeks of treatment.Results: Average PANSS total and positive symptom subscale scores decreased progressively during the study (P=0.035 and P=0.010, respectively, according to repeated measures ANOVA). Average dose at endpoint was 93 IU. Treatments were well tolerated with no significant study-related adverse effects.Conslusions: To our knowledge, this is the first report of the efficacy and safety of long-term, flexibly dosed IN OT in schizophrenia. Doses were also higher than in previous studies. The reduction in symptoms and tolerability provide further support that OT may be a safe, efficacious, novel treatment for schizophrenia. Future studies confirming these promising findings are warranted.Keywords: Intranasal oxytocin, Schizophrenia, Human, Pharmacology, Dosing

1000. Marijuana Use in Chronic Pain Patients Inversely Correlates with the Density of Comorbid Autistic TraitsJon E. Berner

Woodinville Psychiatric Associates, Woodinville, WA

Background: <BR Recent data from animals with chronic pain suggests that GAD65 expression is down regulated in the brainstem nucleus raphe magnus and this state proximally contributes to hyperalgesia by disinhibiting mu-opioid-receptor expressing cells comprising the descending pain facilitatory system. It is unknown whether this observed defect in GAD65 expression is local to brainstem circuits or representative of a more widespread central nervous system failure of cholecystokinin/parvalbumin-expressing interneurons.Marijuana is commonly used to treat chronic pain with an aggregate number needed to treat of 3.6 in HIV-associated sensory neuropathy. On a cellular level, one of its many effects may be to decrease GABA release from the boutons of cholecystokinin-expressing/GAD65 predominant interneurons via activation of CB1 receptors. This study attempted to identify whether a generalized neuropsychiatric syndrome associated with the efficacy/intolerance of marijuana.Methods: 67 patients with chronic pain in a fee-for service community clinic or local marijuana dispensary completed a survey describing their experience with marijuana. This survey included self-reported estimates of dimensional loading for mitochondrial disorders, schizophrenia, and autism.Results: The frequency of marijuana use uniquely inversely correlated with the core dimensional traits of Aspergers syndrome: aloofness, rigidity, sensitivity to criticism, and anxiety. Agitation and anxiety are the typical side effects limiting the use of marijuana in these patients.Conclusions: Exogenous cannabinoid receptor agonists may produce a



1004. Dissociation of Oxytocin’s Effects in Cocaine Dependence: Enhancement of Small, Short-Term Reward not Social SalienceMary R. Lee1, Matthew Glassman2, Deanne L. Kelly2, Jennifer Schroeder3, Betty Jo Salmeron3

1Laboratory on Clinical and Translational Studies, National Institute On Drug Abuse and Alcoholism, Bethesda, MD, 2University of Maryland School of Medicine, Maryland Psychiatric Research Center, Baltimore, MD, 3Intramural Research Program, Neuroimaging Branch, National Institute on Drug Abuse, Baltimore, MD

Background: Oxytocin(OXT) modulates addiction-related processes such as tolerance, dependence and reinstatement and is a potential therapeutic tool. In contrast to social cognition, there are few studies in humans evaluating the OXT effects on reward processing despite animal literature showing it promotes reward learning. We examined the effect of intranasal OXT in drug dependent patients’ tasks of reward processing (R) and social cognition (SC) as well as desire to use and cue-induced craving.Methods: 23 cocaine dependent inpatients (22males) completed R, SC and drug craving tasks after administering 24 IU intranasal OXT and placebo (PL) on separate days. Paired t-tests and a repeated measures regression were used to test the effects of OXT on these domains.Results: OXT increased desire to use cocaine (p=0.032) with a significant interaction between desire to use and trait anger (p=0.001) (more desire with high trait anger under OXT). Excitement about using also increased under OXT. There was a significant task type x OXT interaction (p=0.021). Interaction contrasts showed a non-significant drug effect for SC tasks (p=0.18), while the drug effect for R tasks showed a trend toward significance (p=0.054).Conclusions:The effect of the peptide in drug dependence is to shift salience to favor small, short term monetary or drug reward rather than to promote social cognition. Further research is needed to understand the mechanisms underlying this shift in OXT response in drug dependence and the results raise caution with respect to the utility of OXT as a therapeutic tool in drug dependence.Keywords: oxytocin, addiction, reward, social cognition, cravingSupported By: NIH/NIDA IRP and NIDA Residential Research Support Services Contract HHSN271200599091CADB

1005. Characterization of Ketamine Use and Associated Psychotic Symptoms in an Inpatient Chinese PopulationKe Xu1, Ni Fan2, Daping Wang2, Xifan Zhang3, Yuping Liu2, Xiaoyin Ke2, Hongbo He2, Chao Zhou2, Yi Ding2, John H Krystal4, Yuping Ning2

1Psychiatry, Yale University, West Hevan, CT, 2Psychiatry, Guangzhou Psychiatric Hospital, Guangzhou, China, 3Psychiatry, Guangzhou Baiyun Mental Health Hospital, Guangzhou, China, 4Psychiatry, Yale University, New Haven, CT

Background: Ketamine has been applied to psychiatric research in schizophrenia and is a potential new treatment for depression. Recently, ketamine abuse has increased worldwide. However, little is known about ketamine abuse. Here, our goal is to characterize clinical features of ketamine use and associated psychotic symptoms.Methods: Patients were recruited from inpatient units of Guangzhou Psychiatric Hospital and Guangzhou Baiyun Mental Health Hospital, China. Self-report ketamine use was collected. Each subject was interviewed by trained psychiatrists using Positive Negative Symptom Scale (PANSS). General liner model (GLM) was used to examine the relationship between ketamine use and PANSS. Exploratory factor analysis was used to characterize PANSS variables.Results: Seventy-three subjects (M/F: 68/5) were interviewed. Average age was 26.35+4.69; onset age was 20.25+4.93; mean years of education was 10.73+2.82. Average daily dose (gram) was 3.79+3.15 and maximal daily dose (gram) was

semantic distance between speech content and concepts relevant to drug effects. Group-level drug effects on semantic distances were assessed. Machine-learning analyses (forced-choice discrimination with leave-one-out cross-validation) assessed individual-level condition prediction using semantic similarity to ‘rapport’, ‘support’ and ‘intimacy’, and verbosity (no. words).Results: Speech on MDMA (1.5 mg/kg) was closer to ‘friend’ than on placebo, MDMA (0.75 mg/kg) and methamphetamine. Speech on MDMA (0.75, 1.5 mg/kg) was closer to ‘rapport’ than on methamphetamine. Speech on MDMA (0.75 mg/kg) was closer to ‘empathy’ than on placebo and MDMA (1.5 mg/kg). Classifiers discriminated between MDMA (1.5 mg/kg) and placebo with 83% accuracy, and MDMA (1.5 mg/kg) and methamphetamine with 95% accuracy. The only conditions not classified above chance were the two MDMA doses.Conclusions: Automated semantic speech analyses capture mental state alterations due to acute drug effects. Moreover, such approaches can identify similarities and differences in drug-induced mental state alterations, discriminating between drug types with a high degree of accuracy.Keywords: MDMA/ecstasy, human behavioral pharmacology, methamphetamine, speechSupported By: NIDA DA02812, DA029679

1003. Ketamine’s Effect on Cravings for Alcohol in a Population of Veterans with Depression and Alcohol DependenceErin Seery, Robert Glenn, Robert Malcolm, Mark Hamner

Psychiatry, Medical University of South Carolina, Charleston, SC

Background: NMDA receptor dysfunction is implicated in the development of alcohol dependence (Petrakis et al., 2004). In detoxified alcoholics, ketamine did not cause an increase in cravings for alcohol despite its similarity to alcohol in discrimination tests (Krystal et al., 1998) There has been limited investigation into Ketamine’s effects on the acutely depressed population with comorbid alcohol dependence.Methods: Treatment seeking male inpatients meeting criteria for alcohol dependence and MDD (n=4). Following baseline assessment, subjects received a one-time infusion of Ketamine 0.5mg/kg IV over 40 minutes. Participants then rated alcohol cravings at 10, 40, 80, 110, and 240 minutes post infusion as well as days 1, 2, 3, and 30.Results: A repeated measures ANOVA was utilized to measure changes in VAS (1-10) for alcohol cravings and for perceived ability to resist alcohol after infusion. There was a significant decrease in craving scores from baseline (p=0.00). At 240 minutes, there was a decrease to 2.5 from 4.5(-1.74, 6.74) and by Day 1 the mean craving score had decreased to 0 (0,0). There was a significant decrease in resisting scores from baseline (p=0.018). At 240 minutes post-infusion, there was a decrease to 3.25 from 5.75 (-.75, 7.25). By Day 1 post-infusion the mean resisting score had decreased to 0 (0,0).Conclusions: Preliminary findings help identify ketamine’s impact on cravings for alcohol use and may have important clinical implications in the treatment of comorbid depression and alcohol dependence. Data collection is ongoing and the full sample will be included in final analyses.Keywords: ketamine, alcohol cravings, veterans, Major Depression, Alcohol DependenceSupported By: R25DA020537



1007. Effect of Chronic Haloperidol on Glutamate Metabolism in Rat CortexGlenn Konopaske, Alo Basu, Joseph Coyle

Psychiatry, Harvard Medical School, Boston, MA

Background: Chronic exposure to oral haloperidol in macaque monkeys reduced astrocyte number in the parietal cortex. Given the central role of astrocytes in glutamate metabolism, this study sought to elucidate the effects of chronic haloperidol on cortical glutamate metabolism.Methods: Adult, male, rats were given daily i.p. injections of haloperidol or saline for 28 days. Twenty-four hours after the last injection, rats were infused intravenously with [1-13C]glucose for 15, 30, 60 or 120 minutes, or[2-13C]acetate for 120 minutes (steady state). Total amino acid levels and 13C enrichments were measured ex vivo in frontoparietal cortex tissue extracts using HPLC and 13C magnetic resonance spectroscopy respectively.Results: Relative to the control rats, haloperidol-administered rats had no changes in total glutamate, glutamine, GABA, alanine, or aspartate levels. 13C enrichment of [2-13C]glutamine (60 min.) and [4-13C]glutamine (120 min.) were increased in the haloperidol group. In contrast, haloperidol administration resulted in decreased 13C enrichment of [3-13C]alanine at all time points. The relative contribution of pyruvate dehydrogenase versuspyruvate carboxylase to glucose metabolism was unchanged. The TCA cycling ratio and 13C enrichment of Acetyl-CoA were increased in haloperidol-administered groups. An assessment of product-precursor relationships revealed an increased synthesis of [2-13C]GABA from [4-13C]glutamate. No changes in amino acid 13C enrichment were observed between groups in [2-13C]acetate-infused rats.Conclusions: Chronic haloperidol administration produced alterations in cerebral metabolic function, along with changes in glutamate and glutamine metabolism. In addition, turnover of GABA might be increased by haloperidol administration.Keywords: 13C magnetic resonance spectroscopy, haloperidol, rat, glutamate, GABASupported By: Brain and Behavior Research Foundation, 1K08MH087640-01A1, 5R01MH51290-08

1008. Repeated Electroconvulsive Seizure Induces HDAC2-Mediated Histone Deacetylation and Down-Regulation of Gene Expression in Rat Frontal CortexSe Hyun Kim1, Hong Geun Park2, Yong Sik Kim3, Yong Min Ahn4

1Institute of Human Behavioral Medicine, Seoul Natioanl University College of Medicine, Seoul, Korea, Republic of, 2Department of Biomedical Sciences, Seoul Natioanl University College of Medicine, Seoul, Korea, Republic of, 3Department of Neuropsychiatry, Dongguk University International Hospital, Dongguk University Medical School, Goyang-si, Gyeonggi-do, Korea, Republic of, 4Department of Psychiatry, Seoul Natioanl University College of Medicine, Seoul, Korea, Republic of

Background: The enzymatic activity of histone deacetylatses (HDACs) leads to a histone deacetylation-mediated condensed chromatic structure resulting in transcriptional repression, which have implicated in the modifications of neural circuits and behaviors. Repeated treatments of electroconvulsive seizure (ECS) induces changes in histone acetylation, various gene expression, intrabrain cellular changes including neurogenesis.Methods: We have examined the effects of repeated ECSs on the expression of class I HADCs and related changes in histone modifications and gene expression in rat frontal cortex.Results: Repeated ECS treatements for 10 days (E10X) up-regulates HDAC2 expression in mRNA and protein level in rat frontal cortex compared to sham-

8.41+4.29. Majority of patients (79%) was frequent users (>3times/week). Age onset was significantly associated with Negative Subscale score of PANSS (t=-2.63, p=0.01). Frequency was associated with General Psychopathology score of PANSS (t=2.62, p=0.01). The distribution of positive and negative subscales showed significant skewness. The range of positive subscale score was 7 to 24, and the range of negative subscale was 7 to 31. Exploratory factor analysis of PANSS indicated 5 factors.Conclusions: Our results suggest that ketamine use is popular among young males with low education. Early age onset in treatment seeking patients contributes to negative symptoms. Future study will focus on better characterizing psychotic symptoms in a larger populationKeywords: Ketamine Abuse, Age onset, Psychotic, PANSSSupported By: National Institute of Drug Abuse, Guangzhou Psychiatric Hospital

1006. Role of MKP-1 (DUSP1) In Clozapine-Induced Effects on the ERK1/2 Signaling Pathway in the Rat Frontal CortexYong Sik Kim1, Se Hyun Kim2, Hyun Sook Yu3, Hong Geun Park3, Yong Min Ahn4

1Department of Neuropsychiatry, Dongguk University International Hospital, Dongguk University Medical Schoo, Goyang-si, Gyeonggi-do, Korea, Republic of, 2Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Korea, Republic of, 3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea, Republic of, 4Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea, Republic of

Background: Clozapine affects the ERK1/2 pathway in the brain, which plays an important role in its antipsychotic action. However, previous findings are inconsistent, and related molecular mechanisms require further clarification.Methods: At 15, 30, 60, and 120 min after intraperitoneal injection of clozapine (5, 10, and 20 mg/kg), changes in ERK1/2, its up-stream canonical kinases (Raf1 and MEK1/2), and its down-stream molecule (p90RSK) were investigated in rat frontal cortex. Based on the immunoblot results, the regulatory effect of MKP-1 on clozapine-induced changes in ERK1/2 pathway was examined.Results: At 15 min, p-Raf1, p-MEK1/2, p-ERK1/2, and p-p90RSK all increased dose-dependently. At 30 min, p-ERK1/2 and p-p90RSK showed no significant changes, while dose-dependent increases in p-Raf1 and p-MEK1/2 were found. At 60 and 120 min, although p-ERK1/2 and p-p90RSK decreased, increases in p-Raf1 and p-MEK1/2 were maintained. A clozapine-induced reduction in ERK1/2 phosphorylation was evident at both tyrosine and threonine residues, suggesting the involvement of DUSPs (MKPs). mRNA expression of seven Dusps that can dephosphorylate ERK1/2 were examined; Mkp-1 (Dusp1) mRNA increased following clozapine treatment. Moreover, MKP-1 protein and phosphatase activity increased, and binding of MKP-1 to ERK1/2 was also upregulated by clozapine administration.Conclusions: In rat frontal cortex, clozapine regulates ERK1/2 phosphorylation via MKP-1 (DUSP1), which induces uncoupling between Raf1-MEK1/2 and ERK1/2-p90RSK activity. These findings suggest an important role of MKP-1 in the mechanism of action of clozapine.Keywords: antipsychotics, mitogen-activated protein kinase, dual specificity phosphataseSupported By: Korea Healthcare Technology R&D Project, Ministry for Health & Welfare (A101507)



1010. Hypocretin/Orexin Deficiency Reduces Alcohol Consumption and Decreases Cocaine Abuse LiabilityBenjamin Boutrel1, Nadia Steiner2, Olivier Halfon3

1Center for Psychiatric Neuroscience/Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland, 2Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland, 3Division of Child and Adolescent Psychiatry/Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland

Background: Compelling evidence indicates that hypocretin/orexin signaling regulates arousal, stress and reward-seeking behaviors. However, most studies on drug reward-related processes have so far described the effects of pharmacological blockers disrupting hypocretin/orexin transmission.Methods: We report here an extensive study on alcohol- and cocaine-related behaviors in hypocretin/orexin-deficient mice (hcrt KO) and their heterozygous (HET) and wildtype (WT) littermates. We evaluated behavioral sensitization following repeated cocaine administrations and preference for an environment repeatedly paired with cocaine injections (15 mg/kg). Mice were also trained to self-administer cocaine (0.5-1.5 mg/kg/infusion) or ethanol (10% w/v), and additionally, we assessed circadian drinking behaviors in socially housed mice with the Intellicage apparatus.Results: Whereas all mice exhibited similar cocaine-related behaviors, we found that loss of hypocretin/orexin transmission attenuated cocaine-seeking behaviors following a period of extinction or abstinence. Further, hcrt deficient mice consumed significantly less alcohol compared to HET and WT littermates, either in the operant conditioning paradigm or during the effortless access condition in the Intellicages.Conclusions: Together, the present findings suggest that hcrt KO mice display a hypoactive phenotype, possibly linked to their reduced alertness concomitant to a decreased exploration of the environment, which significantly impacts their alcohol consumption. We also report that innate disruption of hypocretin/orexin signaling does not alter cocaine reward but significantly reduces vulnerability to relapse after a period of protracted abstinence. Overall, our findings suggest that although hypocretin/orexin deficient mice respond to cocaine rewarding effects, they display signs of resilience to cocaine addiction.Keywords: Hypocretin, Orexin, Cocaine, Alcohol, AddictionSupported By: Swiss National Science Foundation (3100A0-112101 and 31003A-133056)

1011. Novel Therapy for Nicotine Addiction in AlcoholicsMona M. Boules, Bethany Stennett, Zhimin Li, Elliott Richelson

Research, Mayo Clinic, Jacksonville, FL

Background: NT69L, a non-selective neurotensin agonist, provides a potential novel therapy for nicotine addiction in alcoholics by interacting with the common neurotransmitter circuits supporting the rewarding process for both nicotine and alcohol. Considering the behavioral effects of NT69L in attenuating nicotine self-administration in rats and alcohol consumption in mice, we designed a study to assess the effects of NT69L on nicotine self-administration in alcohol dependent rats.Methods: Wistar rats pre-exposed to alcohol vapor or air were allowed to self-infuse nicotine (0.03mg/kg/infusion) or saline. When the rats reached a stable level of responding, the effect of pretreatment with NT69L (1mg/kg i.p.) on the reinforcing effect of nicotine was determined. Additionally, the effect of NT69L on dopamine and glutamate in the nucleus accumbens of rats that were co-injected with nicotine (0.35 mg/kg s.c.) and alcohol (1mg/kg i.p.) was determined with the use of in vivo microdialysis with HPLC and capillary electrophoresis (CE). All animal procedures were approved by the Mayo Clinic Institutional Animal Care and Use CommitteeResults: Animals self-infused nicotine at a significantly (P<0.05) higher rate

treated control group, which was evident in the nucleus of neuronal cells in prefrontal, cingulate, orbital, and insular cortex. Among the known HDAC2 target genes, mRNA expression of NMDA receptor signlaing-related genes, including Egr1, c-Fos, Nr2a, Nr2b, Nrn1, Camk2α, were decreased, and their histone acetylation of H3 and/or H4 protein was also reduced by E10X. ChIP analysis revealed that HDAC2 occupancy in the promoter regions of Egr1, c-Fos, Nr2a, Nr2b, Nrn1, and Camk2α gene was significantly increased. Moreover, the administration of sodium butyrate, a HDAC inhibitor, during the course of E10X ameliorated the ECS-induced down-regulation of genes in the rat frontal cortex.Conclusions: These findings suggest that induction of HDAC2 by repeated ECS treatments could play important roles in the down-regulation of NMDA receptor signaling-related genes through histone modifications in rat frontal cortex.Keywords: ECS, histone acetylation, class I HDACs, Egr1, NMDA receptor signalingSupported By: Korea Healthcare Technology R&D Project, Ministry for Health & Welfare (A101467)

1009. The Effects of Oxytocin on Social Cognition and Olfaction in Adults with Schizophrenia and Healthy SubjectsJosh Woolley, Brandon Chuang, Olivia Lam, Wanda Lai, Daniel H. Mathalon, Kate Rankin, Sophia Vinogradov

Psychiatry, University of California San Francisco, San Francisco, CA

Background: Patients with schizophrenia (SCHZ) have social deficits including difficulty processing paralinguistic cues, and understanding others’ mental states as well as olfactory deficits. Intranasal oxytocin (OT) is a peptide that has potent prosocial effects when administered to humans. OT has been shown to enhance social cognition in SCHZ and as promise in socially relevant olfaction in animals.Methods: We administered OT and placebo intranasally to 30 male adult SCHZ patients and 33 HS of similar age and educational level in a randomized, double-blind, within-subject study, with the two days of testing separated by one week. We measured performance on The Awareness of Social Inference Test (TASIT), which uses video clips of actors to assess subjects’ ability to comprehend counterfactual statements from paralinguistic cues and to make judgments about the actors’ thoughts. A Modified Munich Olfaction Test was used to measure threshold levels of lyral, clove, and anise oils.Results: OT administration to SCHZ patients improved overall performance on TASIT, on White Lie, Sarcasm, Theory of Mind, and Lyral Detection (see table).Conclusions: Our findings indicate that OT significantly improves SCHZ patients’ ability to 1) interpret paralinguistic cues (e.g., white lies and sarcasm), and understand other’s mental states (i.e., theory of mind), and 2) detect lyral at lower concentrations. In sum, our data provide support for using OT to remediate multiple social deficits in SCHZ.

TASIT scores are represented as % correct, lyral detection is % concentration level

Schizophrenia Patients Healthy Controls

Items Oxytocin Placebo Paired t-test (p value) Oxytocin Placebo Paired t-test

(p value)Overall TASIT 72.2 69.3 0.04 84.5 83.8 0.67

Complex Sarcasm 68.2 62.5 0.02 81.1 83.0 0.43

White Lies 77.5 71.7 0.01 84.4 84.1 0.88

Theory of Mind 76.3 68.1 0.01 86.2 86.7 0.73

Lyral Detection 9x10^-5 4x10^-4 0.04 4x10^-4 6x10^-4 0.63

Keywords: Schizophrenia, Oxytocin, Social Cognition, Olfaction, PharmacologySupported By: UCSF Pilot Research Grant



Objectives: To evaluate the association between cytokine profiles and OCD severity before and after intervention, as compared to healthy controls.Methods: Plasma levels of pro-inflammatory (IL-1α, IL-1β IL-2, IL-6, IL-8, TNFα,IFNγ) and anti-inflammatory (IL-10, IL-4, TGFβ) cytokines were evaluated in 70 OCD patients and 101 healthy controls. Clinical and immunological evaluations were performed at baseline and 12 weeks after treatment. The second assessment was performed in 43 OCD patients (59.7%) and 87 healthy controls (86.1%). Cytokine levels were analyzed by glass chip-based-Ab microarrays. Generalized estimating equations were applied to determine associations between cytokines and OCD diagnosis and severity, after controlling for psychotropic medication.Results: Thirty (43%) OCD patients presented with depression (MDD and/or Dysthymia). Cytokine profiles were similar in OCD patients with and without depression and healthy controls, and before and after treatment. There was no significant association between cytokine levels and YBOCS or Beck Depression scores. However, log10 TNFα was associated with reduction in YBOCS scores (0.0104; p=0.047); the presence of IL-1β was associated with 81% reduction of YBOCS scores (-0.201, p=0.046); and the presence of IFNγ (0.2739, p=0.028) was associated with 31% increase of YBOCS scores.Conclusions: OCD patients (with and without depression) did not exhibit different cytokine patterns compared to healthy controls. However, specific cytokines were associated with OCD severity and treatment response.Keywords: obsessive-compulsive disorder, inflammation, immunology, treatmentSupported By: NARSAD, FAPESP

1014. Increased Arterial Stiffness in Subjects with Bipolar DisorderKaren Heisler1, Edwin Meresh1, Aparna Sharma1, Brandon Hage1, Kathryn Morrissey1, James Sinacore2, Angelos Halaris1

1Psychiatry and Behavioral Neurosciences, Loyola University Stritch School of Medicine, Maywood, IL, 2Preventive Medicine and Epidemiology, Loyola University Stritch School of Medicine, Maywood, IL

Background: Augmentation Index (AIx) is a measure of endothelial function that correlates to cardiovascular (CVD) risk. AIx is the percent of central pulse pressure attributable to the reflected pulse wave and is significantly and inversely related to endothelial function. Increased AIx has been reported in depressed patients, suggesting that endothelial dysfunction contributes to cardiovascular morbidity and mortality among depressed patients. However, studies exploring the relationship between bipolar depression (BPD) and AIx have been limited. This ongoing study uses AIx, measured by Applanation Tonometry, to examine endothelial function in BPD subjects. We hypothesize that AIx is higher in BPD subjects after controlling for common CVD risk factors.Methods: To date 10 subjects with BPD and 19 healthy controls (HC) have completed the study. Parameters include CVD risk factors, menopausal status, depression severity, current episode length, and duration of illness. AIx was measured with the Sphygmocor device.Results: Age is correlated with AIx (p=0.032). After controlling for confounding factors, the mean AIx among BPD subjects is 20.12, compared to 13.07 in the HC group. While this did not reach significance, the trend is in the expected direction.Conclusions: These preliminary findings are promising in spite of the limited sample size. The trend when comparing AIx in BPD to HC subjects is in line with the stated hypothesis. With expansion of the sample size weexpect to reach statistical significance and establish the measurement of AIx as a distinctive peripheral biomarker of arterial stiffness and predictor of CVD risk in depression.Keywords: Arterial, Stiffness, Bipolar, Depression, CardiovascularSupported By: Stanley Medical Research Institute

compared to saline in both air- and alcohol vapor- exposed groups. Acute pretreatment with a single injection of NT69L significantly (P<0.05) reduced nicotine self-infusion in both the alcohol vapor- and the air- exposed groups for 5 days post-injection. Additionally, NT69L attenuated the alcohol- and nicotine-induced increase in dopamine and glutamate in the nucleus accumbens.Conclusions: NT agonists may represent a potential novel therapy to treat alcohol and nicotine addiction simultaneously by modulating dopamine and glutamate.Keywords: Neurotensin, nicotine, alcohol, dopamine, glutamateSupported By: Florida Department of Health; Mayo Foundation for Medical Education and Research

1012. Activation of Metabotropic Glutamate Receptor 7 by AMN082 Attenuates the Rewarding Effects of Cocaine and Nicotine in Rats Xia Li1, Astrid Stoker1, Zheng-Xiong Xi2, Eliot Gardner2, Athina Markou1

1Department of Psychiatry, University of California San Diego, La Jolla, CA, 2National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD

Background: The metabotropic glutamate receptor 7 (mGluR7) has received much attention as a potential target for the treatment of depression, anxiety and, most recently, drug dependence. The present study investigated the role of mGluR7 in cocaine and nicotine reward based upon our findings that the selective mGluR7 agonist AMN082 modulated glutamatergic neurotransmission in the nucleus accumbens, a critical reward-related brain region.Methods: The intravenous self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement was used to study the positive reinforcing and motivational effects of cocaine and nicotine.Results: AMN082 (3, 10, 20 mg/kg, intraperitoneal) decreased cocaine and nicotine self-administration under FR and PR schedules of reinforcement. 3 mg/kg AMN082, a dose that did not induce a reduction in cocaine self-administration under an FR2 schedule of reinforcement, significantly inhibited nicotine self-administration under an FR5 schedule. However AMN082 had no effect on sucrose consumption.Conclusions: AMN082 inhibited both the primary reinforcing and incentive motivational effects of cocaine and nicotine but not the rewarding properties of non-drug reinforcers. These findings suggest mGluR7 may be a promising target for treatment of cocaine and nicotine dependence with few undesirable side-effects.Keywords: mGluR7, cocaine, nicotine, rewardSupported By: TRDRP20KT-0046

1013. Does Inflammation Play a Role in Obsessive-Compulsive Disorder?Marni Silverman1, Raony Cassab2, Renan Muniz3, Roseli G. Shavitt3, Maria Cecília Toledo3, Carolina Cappi3, Julian Thayer4, Maria Alice de Mathis3, Juliana B. Diniz3, Marcelo Q. Hoexter3, Carina C. D’Alcante3, Sonia Borcato3, Ana G. Hounie3, Jessie Whitfield5, Elena Belyavskaya1, Esther Sternberg1, Euripedes Miguel3, Andrea H. Marques5

1Neuroendocrine Immunology and Behavior, National Institute of Mental Health, Bethesda, MD, 2Mathematics and Statistics, University of Sao Paulo, Sao Paulo, Brazil, 3Psychiatry, University of Sao Paulo, Sao Paulo, Brazil, 4Psychology, The Ohio State University, Columbus, OH, 5Mallman School of Public Health, Columbia University, New York, NY

Background: Immune dysregulation, such as imbalance between pro and anti-inflammatory cytokines, has been hypothesized to play a role in OCD. Some studies have shown association between specific obsessive compulsive symptoms and certain cytokines.



underlying mechanisms for these associations remain largely unknown. Research consistently links MDD with systemic inflammation yet, to date, studies examining this relationship during pregnancy are equivocal. We sought to examine this relationship in a sample of pregnant, physically healthy women in the third trimester of pregnancy.Methods: Seventy-four pregnant women, free of psychotropic medication, were assessed at 34.5±2.6 weeks of gestation for medical conditions and psychiatric symptoms. Depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS). Serum concentrations of pro- and anti-inflammatory cytokines (IL-1β, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ) were quantified using a Multiplex immunoassay.Results: Subjects screening positive for current depression (EPDS≥12, n=14) had significantly lower IL-10 levels (t=-2.47, df=68, p=0.016) and a significantly higher TNF-α/IL-10 ratio (t= 2.37, df=68, p=0.021) compared to those screening negative for depression (n=56). Regression analyses controlling for age, gestational week, number of previous pregnancies, and time of blood sampling did not alter the results. No associations were observed between depression status and other cytokines.Conclusions: Depressive symptoms in late pregnancy are associated with lower systemic concentrations of IL-10, an anti-inflammatory cytokine, and a higher pro- to anti-inflammatory cytokine ratio. To our knowledge, this is the first study to identify IL-10 as a potential marker for depressive symptoms during late pregnancy.Keywords: depression, pregnancy, inflammation, immunitySupported By: FSORC; OMHF

1017. Ketamine Exposure During Adolescence Causes Delayed Onset Electroencephalographic Deficits in AdultsSteven J. Siegel

University of Pennsylvania, Philadelphia, PA

Background: Schizophrenia is characterized by a prodromal period of subtle changes during adolescence followed by emergence of psychosis in early adulthood. Electroencephalographic studies in humans and preclinical models suggest that deficits in adult patients are linked to alterations in NMDA receptor signaling. Furthermore, emerging evidence suggests that alterations in NMDAR signaling may precede onset of overt psychosis. Therefore, we examined the acute and delayed effects of the NMDAR antagonist ketamine during adolescence and adulthood in mice.Methods: Mice were treated with acute ketamine at 6 or 12 weeks of age. Oscillatory EEG activity was then assessed in each group. We then evaluated the lasting effects of juvenile exposure in a third cohort in which mice were treated between 4 to 6 weeks of age and EEG was assessed at 7 and 12 weeks.Results: Acute ketamine increased baseline gamma power in adult animals, consistent with the pattern of activity in schizophrenia. This change was not present among the juvenile cohort. Similarly, ketamine caused a reduction of evoked gamma power in adults, again consistent with schizophrenia. This effect was also absent among the juvenile group. Data are consistent with the commonly held belief that ketamine has less detrimental effects in juveniles than adults. Juvenile exposure to chronic ketamine blocked the normal developmental increase in baseline gamma activity. Additionally, juvenile exposure to ketamine causes a delayed-onset reduction of evoked gamma activity as an adult, that was not present during the adolescent period.Conclusions: Reduction of NMDAR signaling during adolescence leads to delayed-onset emergence of schizophrenia like changes in gamma oscillations. These data are consistent with the hypothesis that alterations in NMDAR signaling during adolescence may be present prior to the emergence of functional consequences.Keywords: Schizophrenia, Ketamine, NMDAR, gamma, baseline

1015. Depression and Cardiovascular Disease in Women: Does This Comorbidity Have an Immunological Basis? A Theoretical SynthesisLauren Wright1, 2, William Simpson1, 2, Benicio N. Frey1, 2, 3, Meir Steiner1, 2, 3, 4, 5

1MiNDS Neuroscience, McMaster University, Hamilton, ON, Canada, 2Women’s Health Concerns Clinic, St. Joseph’s Healthcare, Hamilton, ON, Canada, 3Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada, 4Institute of Medical Science, University of Toronto, Toronto, ON, Canada, 5Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada

Background: Clinical reports have established an inherent comorbidity between depression and the development of cardiovascular disease (CVD). Furthermore, this comorbidity seems to be more amplified in women than in men.Methods: The Web of Science database was accessed using the keywords: cardiovascular disease, inflammation, depression, and sex differences. The initial search returned 6866 results. This synthesis examines 51 studies (1997 to date). 34 of the studies are based on human populations, and 17 focus on animal models.Results: All 34 of the human studies report chronic elevations of proinflammatory cytokines with this comorbidity. Animal models suggest the mechanisms for this elevation: excess inflammation leads to HPA axis hyperactivity, depletion of 5-HT centrally, and elevation peripherally, and upregulation of angiotensin II, all of which are known factors in the development of depression and CVD. Six studies localize this systemic inflammation to a global deficiency in CD4+CD25+FOXP3 regulatory T cells. Additionally, 7 studies indicate that 17-β estradiol and progesterone modulate cytokine secretion in both humans and animals. This may partially explain the sex differences with this comorbidity.Conclusions: Animal models provide a mechanistic explanation of immune crosstalk between the neuroendocrine and cardiovascular systems. Within human literature, the sex differences of this comorbidity are well established, but the mechanisms remain unclear. Regulatory T cells and hormonal immune modulation need to be examined to fill this gap.

Keywords: cardiovascular disease, inflammation, depression, sex differences

1016. Depressive Symptoms in Late Pregnancy are Associated with a Systemic Pro-Inflammatory Cytokine ProfileMiki Peer1, 2, William Simpson1, 3, Benicio N. Frey1, 3, 4, Claudio N. Soares1, 4, 5, Meir Steiner1, 2, 3, 4, 5

1Women’s Health Concerns Clinic, St. Joseph’s Healthcare, Hamilton, ON, Canada, 2Institute of Medical Science, University of Toronto, Toronto, ON, Canada, 3MiNDS Neuroscience Program, McMaster University, Hamilton, ON, Canada, 4Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada, 5Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada

Background: Major depressive disorder (MDD) is associated with adverse perinatal outcomes and poor infant health and development, however the



1018. Individual Differences in FMRI Cortical Bold Responses to Nicotine Visual Cues in Dependent Cigarette SmokersDavid A. Gorelick1, Henry H. Holcomb2, Douglas L. Boggs2, 3, Jeffrey T. West2, George F. Wittenberg4, Mary R. Lee1, Marilyn A. Huestis1

1Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, 2Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, 3Dept. of Psychiatry, VA CT Healthcare System & Yale University School of Medicine, West Haven, CT, 4Dept. of Neurology, University of Maryland School of Medicine, Baltimore, MD

Background: Drug-dependent individuals show brain activation in response to drug-associated cues; individual differences in such responses are poorly understood.Methods: 47 adult (age 20-56 years, 15 women), right-handed, nicotine-dependent cigarette smokers had fMRI scans during presentation of nicotine-associated, positive non-drug, and neutral visual cues. BrainVoyager® imaging software and Brainsight® neuronavigation system were used to identify the location of maximal blood oxygen level-dependent (BOLD) signal in response to the nicotine-associated cue (subtracting responses to other 2 cue types), constrained to be in frontal lobe within 2 cm of cortical surface (to serve as target for transcranial magnetic stimulation pulses).Results: Subjects had mean (range) 17.7 (6-41) years of smoking, 18.0 (10-40) cigarettes smoked daily, 5.9 (2-9) Fagerstrom score, and 52.6 (0-100) spontaneous craving (100-mm visual-analogue scale) just prior to fMRI. 29 subjects had BOLD response on left side; 18 on right side. Brodmann areas were 6 (n=5), 8 (15), 9 (10), 10 (10), 13 (1), and 46 (6). There was a significant association between BOLD intensity and voxel size (r = 0.58). BOLD response in the dominant (left) hemisphere occurred most often in the dorsolateral prefrontal cortex (71%); response in the non-dominant (right) hemisphere most often in premotor regions (67%). There were no other significant associations between BOLD response and demographic or cigarette smoking characteristics or laterality.Conclusions: There is substantial individual variability in cortical BOLD response to nicotine-associated cues, with some regional differences associated with brain laterality.Keywords: craving, cue-induced, fMRI, nicotine, individual differencesSupported By: NIH/NIDA IRP and NIDA Residential Research Support Services Contract HHSN271200599091CADB

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