Cortical Morphometry in Autism Spectrum Disorder

Lead Research Organisation: King's College London
Department Name: Unlisted

Abstract

People diagnosed with Autism Spectrum Disorder (ASD) can have lifelong difficulties with language, social interaction and repetitive behaviours. Studies have shown differences in brain anatomy between people with ASD and typically developing people. Improved understanding of how abnormal brain anatomy develops in ASD, and why it differs amongst people with ASD could advance how we diagnose and treat these increasingly recognised conditions.

One of the most important parts of the brain to show differences in ASD is the cerebral cortex, a highly folded structure which covers the brain and processes information during complex human behaviours. However we know very little about cortical anatomy in ASD.

Our preliminary work suggests that the cortex grows differently in ASD and shows most abnormalities in areas important for social behaviour and language. We now want to better understand cortical anatomy in ASD and how it relates to age, symptoms and genetic make-up.

We will applying a set of new techniques for measuring the cortex from brain scans in a large group of 200 men aged between 18 and 55 - half with ASD and half who are developing normally. It is hoped that this would then lead to future studies in children.

Technical Summary

Autism Spectrum Disorder (ASD) is an increasingly recognised lifespan-persistent neurodevelopmental disorder. It is characterised by disturbances of communication, social reciprocity and a range of repetitive behaviours. There is extensive evidence of abnormal brain structure and function in ASD. The cerebral cortex appears to be particularly affected. However, to date the study of cortical anatomy in ASD has largely been limited to the analysis of grey matter volume (GMV) in small and heterogenous samples.
The aim of this study is to better understand the relationship between cortical anatomy and diagnosis, age and clinical profile in ASD. Specific hypotheses to be tested within ASD have been generated in part by my own pilot work and address (i) selectivity of abnormalities in cortical anatomy to regions important in social cognition and executive functioning, (ii) differences in fronto-temporal cortical maturation (iii) variation of cortical anatomy according to symptom severity. I also hope to begin extending my pilot work on gene-brain relationships, and examining connectivity using structural co-variance.
To do this I wish to be trained (in the USA and UK) in the use of novel methods for the analysis of structural magnetic resonance images (sMRI) to measure cortical GMV, thickness (CT), surface area (SA) and gyrification. These techniques will be applied within what would be the largest sample to be so studied to date - a well-characterised group of 100 adult males with ASD and 100 controls aged 18-55 (MRC UK Autism Multicentre Imaging Study). We also hope to extend these techniques to a sample of children with ASD through the National Institute for Health Research.
The results of such work will improve our understanding of which cortical systems show structural abnormalities in ASD and how these develop over time. CT and SA are closely interrelated, but have differing biological determinants. Revealing how these aspects of cortical anatomy interact and relate to abnormalities of GMV in ASD will help to identify underlying neuropathological mechanisms ASD. Such approaches also have translational potential. By starting to inter-relate behaviour, brain anatomy and genotype the heterogeneity of ASD could be parsed and thus improve our understanding of the biological basis of ASD. Finally this project has a capacity building role as it will establish new research methodologies within the UK and build close links with a US centre which has the largest body of developmental sMRI data in the world.

Publications

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Hedrick A (2012) Autism risk gene MET variation and cortical thickness in typically developing children and adolescents. in Autism research : official journal of the International Society for Autism Research

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Raznahan A (2010) Cortical anatomy in autism spectrum disorder: an in vivo MRI study on the effect of age. in Cerebral cortex (New York, N.Y. : 1991)

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Raznahan A (2012) Allelic variation within the putative autism spectrum disorder risk gene homeobox A1 and cerebellar maturation in typically developing children and adolescents. in Autism research : official journal of the International Society for Autism Research

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Raznahan A (2011) How does your cortex grow? in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Raznahan A (2010) Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence. in Proceedings of the National Academy of Sciences of the United States of America

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Raznahan A (2010) Cortical anatomy in human X monosomy. in NeuroImage

 
Description American College of Neuropsychopharmacology Travel Award/ACNP
Amount £1,000 (GBP)
Organisation American College of Neuropsychopharmacology 
Sector Private
Country United States
Start 12/2010 
End 12/2010
 
Description Fellowship Award for Research Excellence
Amount £1,500 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 10/2011 
End 10/2011
 
Description Gaskell Gold Medal
Amount £1,000 (GBP)
Organisation Royal College of Psychiatrists 
Sector Learned Society
Country United Kingdom
Start 07/2008 
End 07/2008
 
Description Human Brain Mapping Travel Award/organization for human brain mapping
Amount £500 (GBP)
Organisation Organization for Human Brain Mapping (OHBM) 
Sector Learned Society
Country Global
Start 05/2010 
End 05/2010
 
Description MRS Young Investigator Research Award
Amount £1,500 (GBP)
Organisation Medical Research Society 
Sector Learned Society
Country United Kingdom
Start 03/2011 
End 03/2011
 
Title Mapping synchronous change within the cortical sheet 
Description Extension of correlational methods to longitudinal anatomical change 
Type Of Material Data analysis technique 
Year Produced 2011 
Provided To Others? Yes  
Impact paper using this method currently in press 
 
Title Sex Chromosome Aneuploidy Gene Expression 
Description Beadarray data on people with Sex Chromosome Aneuploidies (10 each of XO, XXX, XXY, XYY, XXYY), and controls (10 XX, 10 XY) 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact Analysis underway 
 
Description Developmental Imaging Genetics 
Organisation National Institutes of Health (NIH)
Department National Institute of Mental Health (NIMH)
Country United States 
Sector Public 
PI Contribution Analytic concepts and execution
Collaborator Contribution Statistical, genetics and neuroimaging advice
Impact Publications (all with Giedd as co-author)
Start Year 2008
 
Description Gene expression in lymphoblastoid cell-lines from groups with varying sex chromosome aneuploidies 
Organisation National Cancer Institute (NCI)
Country United States 
Sector Public 
PI Contribution Study design, co-ordination of collaborations, preparation of materials for transcriptomics, data analysis
Collaborator Contribution FISH confirmation of SCA stability through LCL derivationCell lines from XO children
Impact Stability of SCA through LCLC derivation established. Genome wide beadarray-based gene expression measured gathered on all 80 participants Preliminary results from comparative gene expression analysis secured. Detailed analysis currently underway.
Start Year 2010
 
Description Gene expression in lymphoblastoid cell-lines from groups with varying sex chromosome aneuploidies 
Organisation Thomas Jefferson University
Department Department of Pediatrics
Country United States 
Sector Academic/University 
PI Contribution Study design, co-ordination of collaborations, preparation of materials for transcriptomics, data analysis
Collaborator Contribution FISH confirmation of SCA stability through LCL derivationCell lines from XO children
Impact Stability of SCA through LCLC derivation established. Genome wide beadarray-based gene expression measured gathered on all 80 participants Preliminary results from comparative gene expression analysis secured. Detailed analysis currently underway.
Start Year 2010
 
Description Neuroimaging Study of Childhood Turner Syndrome 
Organisation Thomas Jefferson University
Department Department of Pediatrics
Country United States 
Sector Academic/University 
PI Contribution Application of Surface Based Morphometric methods for cortical analysis
Collaborator Contribution Provision of scans which would otherwise not be available
Impact Work still underway
Start Year 2009
 
Description Neuroimaging Study of Velocardiofacial Syndrome 
Organisation Hunter Medical Research Institute
Country Australia 
Sector Academic/University 
PI Contribution Methods for surface-based morphometry of the cortical sheet
Impact Work still underway
Start Year 2009
 
Description Neuroimaging and Histological Study of Mouse Models for Sexually Dimorphic Genetic and Hormonal Determinants of Brain Development 
Organisation Hospital for Sick Children, Toronto
Department Toronto Center for Phenogenomics (TCP)
Country Canada 
Sector Academic/University 
PI Contribution Analysis of parallel models in humans Identifying providers of different mouse models
Collaborator Contribution Expertise in mouse imagingProvision of Mice
Impact Study of XO mice underway (involving further collaboration with Montreal Neuroimaging Institute (histology), Canada and Baylor College of Medicine, Texas, USA (Mouse breeding). Study of mouse model for varying androgen receptor function underway (involving further collaboration with Ann Arbour (provision of mice) Study of XXY mouse model underway
Start Year 2009
 
Description Neuroimaging and Histological Study of Mouse Models for Sexually Dimorphic Genetic and Hormonal Determinants of Brain Development 
Organisation University of California, Los Angeles (UCLA)
Department School of Medicine UCLA
Country United States 
Sector Academic/University 
PI Contribution Analysis of parallel models in humans Identifying providers of different mouse models
Collaborator Contribution Expertise in mouse imagingProvision of Mice
Impact Study of XO mice underway (involving further collaboration with Montreal Neuroimaging Institute (histology), Canada and Baylor College of Medicine, Texas, USA (Mouse breeding). Study of mouse model for varying androgen receptor function underway (involving further collaboration with Ann Arbour (provision of mice) Study of XXY mouse model underway
Start Year 2009
 
Description Neuroimaging of Adolescents with Primary Ovarian Insufficiency 
Organisation National Institutes of Health (NIH)
Department National Institute of Child Health (NICH)
Country United States 
Sector Hospitals 
PI Contribution Neuroimaging expertise
Collaborator Contribution Access to rare population
Impact Protocol passed through IRB and now in final stages of approval
Start Year 2011
 
Description Shape analysis of sub-cortical structured from MRI 
Organisation Hospital for Sick Children, Toronto
Department MICe Toronto
Country Canada 
Sector Hospitals 
PI Contribution provision of imaging data, execution of analysis, writing up of results
Collaborator Contribution provision of methods for data analysis
Impact First methods paper under review Analysis for first developmental paper about to begin
Start Year 2011
 
Description Structural Neuroimaging Study of Young Children with Autism 
Organisation National Institutes of Health (NIH)
Department National Institute of Mental Health (NIMH)
Country United States 
Sector Public 
PI Contribution analysis of data, interpretation of findings, writing-up
Collaborator Contribution Intellectual, provision of data
Impact paper under review, analysis underway for subsequent papers
Start Year 2010
 
Description Article in Wall Street Journal 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Article published about our work in the WSJ. We worked closely with the journalist.

Debate around relevance of our findings for policy in Single Sex Education featured in the journal Science
Year(s) Of Engagement Activity 2011