Volumetric Brain Differences in Adults with Autistic Spectrum Disorder - the Result of Two Distinct Neuropathological Mechanisms?

Background: Previous neuroimaging studies investigating brain anatomy in Autism Spectrum Disorder (ASD) have typically examined volumetric measures in either individual brain regions or in the whole brain (e.g. voxel-based approaches).  However, cortical volume (CV) is the product of cortical thickness (CT) and surface area (SA).  Therefore, it is unknown whether previous reports of differences in CV of individuals with ASD are driven by differences in CT, SA or both.  This is potentially  highly significant as recent evidence suggests that CT and SA may have distinct genetic determinants. CV may therefore represent at least two distinct sources of genetic effects. The region-specific influence of CT and SA on CV has, however, not yet been explored.

Objectives: This first aim of this study was to investigate volumetric brain differences in adults with ASD by exploring CT, SA and CV in isolation.  Secondly, we aimed to examine the relationship between these volumetric measures (i.e. degree of spatial overlap) in order to elucidate their potential multi-factorial aetiology.

Methods: Structural MRI data was collected on 84 well-characterized adult males with ASD (right-handed, mean age = 26 yrs, mean FSIQ = 110), and 84 age/IQ matched healthy right-handed male controls.  Subjects were recruited with the support of the MRC AIMS (Autism Imaging Multi-centre Study) program.  All individuals with ASD were diagnosed using ADI-R, ADOS, and ICD-10 research criteria.  For each participant, a set of three morphological parameters (CV, CT, SA) was obtained at each spatial location on the cortical surface (i.e. vertex) using FreeSurfer software (http://surfer.nmr.mgh.harvard.edu).  Initially, a vertex-based approach employing the general linear model (GLM) was used to examine differences in individual volumetric measures between groups.  Subsequently, we examined the degree of spatial overlap between maps representing significant differences for each morphometric feature.

Results: Overall, individuals with ASD had significantly larger values in all three parameters (CV, CT and SA).  Furthermore, there was little spatial overlap between maps for CT and SA, suggesting an independent and region specific effect of CT and SA, particularly in frontotemporal regions. Overall, the map of CV was a linear combination between CT and SA, with region-specific parameter weights.

Conclusions: The data suggests that volumetric brain differences in adults with ASD are the result of region-dependent variations in two distinct volumetric measures, CT and SA.  These two morphological parameters most likely have distinct genetic and neuropathological mechanisms and should therefore be explored independently.  We suggest that the spatial pattern presented here may reflect the multifactorial aetiology of ASD, and that future research should include examination of both CT and SA to  explore the specific genetic and neuropathological  underpinnings of ASD.