Aristotle Voineskos MD, PhD, FRCP(C)

Head, Kimel Family Translational Imaging-Genetics Research Lab

Staff Psychiatrist, Geriatric and Schizophrenia Programs, CAMH

Assistant Professor, Department of Psychiatry, University of Toronto

Translational Imaging-Genetics: Making a Clinical Impact

Language Deficits

Autism Schizophrenia Bipolar I Disorder

Psychosis (Delusions/Hallucinations)

Socio-emotional Deficits

Stereotyped Behaviours

Mood Instability/Impulsivity

Cognitive Deficits/Burden

Severe Moderate Mild

Shared Genetic Susceptibility for SCZ and BD: The ZNF804A Gene

1. Evidence from Whole Genome Association Studies:O’Donovan et al Nat Gen, 2008; ISC, Nat, 2009, Steinberg Mol Psych, 2010, Riley Mol Psych, 2010

2. Bioinformatic Analysis: Risk SNP likely lies in a myelin/ oligodendrocyte transcription factor binding site Riley, 2010

3. Neurocognitive Phenotypes: Attention, Working Memory, Episodic Memory Balog GBB 2010, Walters JT Arch Gen Psych, 2010

3. Imaging Phenotypes: Altered connectivity (Esslinger, Science 2009); Altered white and gray matter volumes (Lencz, NPP, 2010)

Fronto-temporal disconnectivityPrefrontal interhemispheric disconnectivity

ZNF804A: Influencing Connectivity Phenotypes Relevant to the Major Psychoses

Esslinger et al, Science, 2009

ZNF804A variation and DLPFC/hippocampal functional coupling

Rasetti R, Arch Gen Psych, 2011

ZNF804A’s effects on cortical thickness occurred at cortical regions with shared neural vulnerability for SCZ and BD

Voineskos, Lerch et al, Neuropsychopharmacology, 2011

Working Memory Deficits in Schizophrenia

Working Memory Performance Deficits Across the Adult Lifespan in Schizophrenia

235 Schiz,333 Healthy controls

Rajji, Voineskos et al, AJGP, in press

γ Oscillations and DLPFC Function• Gamma (30-50Hz) Oscillations (γ) in DLPFC

• Represent important electrophysiological measures which are generated through the execution of higher order cognitive tasks (e.g., working memory) in the DLPFC(Tallon-Baudry, 1999; Lewis, 2005).

Cho et al, PNAS, 2006

Glutamate decarboxylase 1 (GAD1) gene

• Encode the GAD67 protein responsible for catalyzing L-glutamic acid to GABA

• 2q31; 46 kb; 17 exons• GAD1 is key to the

development of inhibitory interneurons

Lewis DA, Nat Med, 2006

GAD1, Brain Structure, Function and Cognition

Rs7557793 and BOLD fMRI during NBACK WM Task Marenco et al, NPP, 2011

Straub et al, Mol Psych, 2007

GAD1, Hippocampal Volume, and Fronto-Limbic Circuitry

• rs1978340: F1,65=7.658, p=0.007

• rs3749034: F1,65=5.513, p=0.022

Lett et al

Repetitive Transcranial Magnetic Stimulation (rTMS): A Therapeutic Tool for Working Memory Deficits

• rTMS involves stimulation of the cortex by train of magnetic pulses at frequencies between 0.5 to 50 Hz.

• rTMS increases : • (1) GABA mediated cortical

inhibition • (2) oscillatory activity

during the n-back memory task.

Sham ActiveC

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Mea

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Sum

of γ

Pow

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A)

B)

FrontalPosterior

Brain Region

-0.5

0.5

1.5

2.5

3.5

Sham Active

p < 0.001

Barr et al. Neuropsychopharmacology 2009

A pilot rTMS treatment trial for working memory deficits in schizophrenia

Assessed for Eligibility(n=42)

Randomized(n=33)

Excluded (n=9)Did not meet inclusion

criteria (n=2)Declined participation (n=7)

rTMS (n=16)

Received at least one treatment session

Sham Control(n=17)

Received at least one treatment session

Enr

olm

ent

Allo

catio

nFo

llow

-up

Discontinued Prior to Week 1 Completion of Treatment

(n=1)Discontinued Prior to Week 2

Completion of Treatment (n=1)

Discontinued Prior to Week 3 Completion of Treatment

(n=1)Discontinued Prior to Week 4

Completion of Treatment (n=0)

Discontinued Prior to Week 1 Completion of Treatment

(n=1)Discontinued Prior to Week 2

Completion of Treatment (n=2)

Discontinued Prior to Week 3 Completion of Treatment

(n=0)Discontinued Prior to Week 4

Completion of Treatment (n=0)

Analyzed(n=13)

Analyzed(n=14)

Barr et al, under review

-8

-4

0

4

8

12

16

N-Back Condition

Active

Sham

1-Back 3-Back

Percent change correct response to

target

rTMS improves WM performance

Barr et al, under review

White Matter Tract Structure Modulates Cortical Function

Voineskos, Farzan et al, Biological Psychiatry, 2010

Imaging-Genetics Relevant to AD

Filipinni, N, PNAS, 2009

ApoE4 allele modulates brain function decades before any evident clinical process

BDNF – Key in Disease and Therapeutics

1. Long-term potentiation and plasticity –learning and memory

2. BDNF highly expressed in entorhinal cortex and hippocampus

3. BDNF mediates myelination; provides trophic support for oligodendrocytes

4. A Novel Therapeutic Agent (Blurton-Jones, 2009, PNAS) (Nagahara, AH Nat Med, 2009)

Voineskos, Lerch, et al, Arch Gen Psych, 2011

Voineskos, Lerch, et al, Arch Gen Psych, 2011

BDNF: Treatment Implications

Nagahara et al, Nat Med, 2009

BDNF treatment reduces Abeta production in primary neurons

BDNF treatment reduces Abeta levels in wild type but not SORL1 deficient mice

J Neurosci, 2009

Rogaeva et al, Nat Gen, 2007

The Sortilin Related Receptor SORL1 and Genetic Risk for Late-Onset Alzheimer Disease

Rogaeva et al, Nat Gen, 2007

Arch Neurol, 2008

SORL1 risk variants, and integrity of WM tracts susceptible in early AD

Felsky et al

Kimel Family Translational Imaging-Genetics Research LaboratoryMallar Chakravarty Tris LettDan FelskyArash NazeriScott McCainWilliam RazmyAysah Amath

Geriatric Mental Health ProgramBenoit MulsantBruce PollockTarek RajjiDielle Miranda

Schizophrenia ProgramJeff DaskalakisGeorge FoussiasGary Remington

Neuroscience/NeurogeneticsJim KennedyFang LiuArun TiwariNatalie FreemanClement Zai

Kimel Family, Michael and Sonja Koerner, and Paul Garfinkel New Investigator Award

Acknowledgements/Support

HSC – Jason Lerch, Stephanie Ameis

APA/APIRE

CAMH R.I.C. – Nancy Lobaugh