Neuroimaging and Autism Dr Matt Roser Lecturer, School of Psychology Plymouth University matt.roser@plymouth.ac.uk

What are the techniques? What are the coloured blobs in an fMRI report? How do we conduct research with autistic people? What are the major findings and areas of current research? How can this help?

Historical Images of the Brain and Mind Brain structure Some still in use today Often Interpretive, labour/skill intensive. Brodmann cytoarchitecture mapsChristopher Wren (1664)

Electrophysiological mapping (1957)Phrenology (19thC) Historical Images of the Brain and Mind Brain function

What do those blobs represent?

Magnetic Resonance Imaging (MRI) Physics Uses a magnetic field and radio energy to produce an image A large magnet (50,000 x Earth) aligns nuclei that have a net magnetic moment Nuclei absorb and re-emit radio frequency energy

Functional MRI (fMRI) The Blood Oxygen Level Dependent (BOLD) Response Relative levels of de/oxyhaemoglobin change from regional cortical activity Regional blood oxygenation actually increases following neural activation. Local field strength is affected by relative levels This affects the local signal in the image. Increased signal is obtained from active regions

The fMRI environment

A simple experimental design Task and Rest conditions can be compared The difference in signal between the conditions is tested at each of thousands of voxels The significant statistics are coloured the blobs show areas of significant condition effects Time Task Rest Task + +

Build Model Realignment & motion correction Smoothing Normalisation Image Data Parameter EstimationAnatomical Reference Kernel Data Design Matrix Statistical Parametric Mapping Contrasts fMRI Preprocessing and Analysis - its complicated!!!

Blobs are clusters of significant statistics for either a main effect or a contrast between two sets of regressors at each voxel Shows areas where the signal change was significantly predicted by the model (or where the degree of prediction differed between contrasted conditions) This is the end result after much preprocessing and analysis Change in the signal is due to regional hemodynamics Thus, activations are distantly related to the underlying neurological events

Diffusion Tensor Imaging (DTI) A structural imaging technique probe tissue microstructure using water diffusion Water molecules in the brain are mobile Diffusion in three dimensions can be assessed by applying magnetic gradients This can tell us about brain structural connectivity

Challenges faced when running a brain-imaging study of autism

Major findings: Brain regional volume Brain structural connectivity Brain functional connectivity and functional reorganisation

Gross brain volume Early increase Grey and white matter Particularly frontal regions (DLPFC, MPFC) Longitudinal studies needed Failure of synaptic pruning, or an excess of synaptogenesis? Amaral, Schumann, & Nordahl (2008). Neuroanatomy of autism. Trends in neurosciences, 31(3), 137-145.

Regional brain volume Numerous widespread areas implicated Cerebellum - Mixed evidence for enlargement - Depends on regional definition - Some evidence for enlargement beyond that of cortex A small number of histological studies suggest decreased cell density in autism Cohort differences histology/MRI? Amaral, Schumann, & Nordahl (2008). Neuroanatomy of autism. Trends in neurosciences, 31(3), 137-145.

Regional brain volume Amygdala involved in memory, emotion (fear), learning Early enlargement (8-12), lack of preadolescent increase in volume Many conflicting histological findings Basal ganglia (particularly caudate) Increased size repetitive behaviours Amaral, Schumann, & Nordahl (2008). Neuroanatomy of autism. Trends in neurosciences, 31(3), 137-145.

Brain structural connectivity An example study: Frontal lobe tracts and the corpus callosum show alterations in diffusion or geometric properties (ASD lower fractional anisotropy) Inclusion criteria for the ASD group (N=32, 5-9 yrs): 1) diagnosis of Autistic Disorder, Aspergers Disorder, or Pervasive Developmental Disorder 2) scores above the cutoff on the Social Communication Questionnaire and Autism Quotient (AQ) Review (Travers, 2013) found generally lower tract integrity in ASD throughout corpus callosum, cingulum and left-temporal lobe Kumar, et al. (2010). Alterations in frontal lobe tracts and corpus callosum in young children with autism spectrum disorder. Cerebral cortex, 20(9), 2103-2113.

Brain functional reorganisation Many task-specific examples of anomalies, such as reduced amygdala activation during a mentalising task (Reading the Mind in the Eyes) (Baron-Cohen etal., 1999) add to this - language comprehension, working memory, face recognition, and eye movements Trawling through a great number of studies, with different tasks and participants is bewildering Control, Autistic, Both Autistic less activation of left-temporal regions

Brain functional reorganisation Meta-analyses can bring sense to the data General pattern: More diffuse network of regions in ASD Diminished activity in task-related regions and increased activity in task-unrelated regions Philip, R., Dauvermann, M. R., Whalley, H. C., Baynham, K., Lawrie, S. M., & Stanfield, A. C. (2012). A systematic review and meta-analysis of the fMRI investigation of autism spectrum disorders. Neuroscience & Biobehavioral Reviews, 36(2), 901-942. Social tasks reduced fusiform activation in face perception and interpretation of expressions Increased activity in temporal lobe Executive tasks Reduced activation in dorsolateral prefrontal cortex, inferior parietal lobe, insula, and posterior cingulate gyrus, areas associated with inhibitory control and attentional orienting Increased activity in posterior visual areas (visual imagery strategy?)

Brain functional connectivity Brain function comprises networks of active regions (such as Brocas and Wernickes language areas) Activity in these dispersed regions correlates functional connectivity Underconnectivity theory of autism postulates that individuals with autism have a reduced communication bandwidth between frontal and posterior cortical areas Here the ASD group (17 adults) showed more activation than the control group in Wernickes area and less activation than controls in Brocas area Functional connectivity was reduced in ASD Just, M. A., Cherkassky, V. L., Keller, T. A., & Minshew, N. J. (2004). Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity. Brain, 127(8), 1811-1821.

Electroencephalography (EEG) and event-related potentials (ERPs) Relatively non-invasive More clinically available Passive recordings of brain electrical activity Can measure global/regional brain state or processing of specific stimuli Excellent temporal resolution relatively poor spatial resolution

Electroencephalography (EEG) and event-related potentials (ERPs) Oscillatory activity in different bandwidths can be used to index functional connectivity General pattern - abnormal functional connectivity between frontal and posterior regions and enhanced power in the left hemisphere in ASD Local overconnectivity, global underconnectivity

Electroencephalography (EEG) and event-related potentials (ERPs) An ERP example: (Frey et al., 2013) Anomalies in fixation. Manifest in brain sensory electrical response? Peripheral visual stimuli. Sensory ERPs compared (Group N = 22 ASD; 7-17 yrs) Processing of lateralized visual stimuli is different in children and adolescents with ASD compared with age-matched controls. Reflects altered cortical representations of visual space in ASD? Consequence of the more variable fixation behaviour?

How can these techniques help? Brain anatomy as a biomarker for autism (Murphy, et al., 2011) - Identify ASD sample with 85% accuracy using automated analysis of brain anatomy Aiding dignosis? - Targeting support? Good or bad?

How can these techniques help? Measure the effects of interventions - 100 hours of remedial reading training eliminated regional white- matter integrity differences between poor-good readers - Changes suggest myelination Keller TA, Just MA. Altering cortical connectivity: remediation-induced changes in the white matter of poor readers . Neuron. 2009, 10;64(5):624-31.

Future directions Integration of technologies Models of functional connectivity informed by brain structure Temporal and spatial aspects united Larger studies (N = hundreds, not tens) Longitudinal, rather than cross-sectional, designs to address complex developmental trajectories Distinct phenotype subject groups Extension of studies into the adult brain Majority of those with the disorder Freedom from developmental confound may yield novel insights

Finding out more Google Scholar

Finding out more Free access to peer-reviewed science http://explore.tandfonline.com/page/beh/world-autism-day-2014/

Finding out more open-access journals

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HEIGHT COLOUR WIDTH Our fMRI experiment on Relational Integration Participants Aspergers Controls N 13 (2 Female) 13 (3 Female) Age (x, sd) 37 (11) 35 (9) IQ (x, sd) 112 (17) 135 (34)

Our fMRI experiment on Relational Integration Asperger > Control Task v Baseline Middle occipital gyrus, precuneus (BA19) Visuospatial tasks; Empathy; Perspective taking; Motor planning

Diffusion-Tensor Image data Group differences in FA Aspergers > Control Control > Aspergers Our fMRI experiment on Relational Integration