Gray matter covariations and core symptoms of autism. The EU-AIMS Longitudinal European Autism Project

Background Voxel-based Morphometry (VBM) studies in Autism Spectrum Disorder (autism) have yielded diverging results. This might partly be attributed to structural alterations being associating with the combined influence of several regions rather than with a single region. Further, these structural covariation differences may relate to continuous measures of autism rather than with categorical case-control contrasts. The current study aimed to identify structural covariation alterations in autism, and assessed canonical correlations between brain covariation patterns and core autism symptoms. Methods We studied 347 individuals with autism and 252 typically developing individuals, aged between 6 and 30 years, who have been deeply phenotyped in the Longitudinal European Autism Project (LEAP). All participants’ VBM maps were decomposed into spatially independent components using Independent Component Analysis. A Generalized Linear Model (GLM) was used to examine case-control differences. Next, Canonical Correlation Analysis (CCA) was performed to separately explore the integrated effects between all the brain sources of gray matter variation and two sets of core autism symptoms. Results GLM analyses showed significant case-control differences for two independent components. The first component was primarily associated with decreased density of bilateral insula, inferior frontal gyrus, orbitofrontal cortex, and increased density of caudate nucleus in the autism group relative to typically developing individuals. The second component was related to decreased densities of the bilateral amygdala, hippocampus, and parahippocampal gyrus in the autism group relative to typically developing individuals. The CCA results showed significant correlations between components that involved variation of thalamus, putamen, precentral gyrus, frontal, parietal, and occipital lobes, and the cerebellum, and repetitive, rigid and stereotyped behaviors and abnormal sensory behaviors in autism individuals. Limitations Only 55.9% of the participants with autism had complete questionnaire data on continuous parent-reported symptom measures. Conclusions Covaried areas associated with autism diagnosis and/or symptoms are scattered across the whole brain and include the limbic system, basal ganglia, thalamus, cerebellum, precentral gyrus, and parts of the frontal, parietal, and occipital lobes. Some of these areas potentially subserve social-communicative behavior whereas others may underpin sensory processing and integration, and motor behavior. ### Competing Interest Statement JKB has been a consultant to, advisory board member of, and a speaker for Janssen Cilag BV, Eli Lilly, Shire, Lundbeck, Roche, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents or royalties. CFB is director and shareholder in SBGNeuro Ltd. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker's fee by Lilly, Medice, and Shire. He received royalities from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press. TC has received consultancy from Roche and received book royalties from Guildford Press and Sage. DGM has been a consultant to, and advisory board member, for Roche and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. The present work is unrelated to the above grants and relationships. The other authors report no biomedical financial interests or potential conflicts of interest. * ADI : Autism Diagnostic Interview-Revised ADOS : Autism Diagnostic Observational Schedule 2 CCA : Canonical Correlation Analysis DSM-IV : Diagnostic and Statistical Manual-IV EU-AIMS : European Autism Interventions—A Multicentre Study for Developing New Medications FDR : false discovery rate FSIQ : full-scale intelligence quotient GLM : Generalized Linear Model GM : gray matter IC : Independent Component ICA : Independent Component Analysis ICD-10 : International Statistical Classification of Diseases and Related Health Problems 10th Revision ID : intellectual disability IFG : inferior frontal gyrus OFC : orbitofrontal cortex MRI : Magnetic resonance imaging PHG : parahippocampal gyrus RBS : Repetitive Behavior Scale-Revised RRB : Restricted and Repetitive Behaviors SA : social affect SD : standard deviation SRS : Social Responsiveness Scale 2nd Edition SSP : Short Sensory Profile TD : typically developing TFCE : Threshold-Free Cluster Enhancement VBM : Voxel-based Morphometry