Structural brain alterations in autism: A large-scale voxel-based morphometry mega-analysis

Background: Previous large-scale structural MRI analyses of the brain in autism have identified gray matter (GM) differences when using region-of-interest analyses based on gross anatomical regions. However, such analyses have limited spatial specificity for localizing neuroanatomical alterations and may obscure subtle, spatially focal differences. Whole brain voxel-based morphometry (VBM) analyses enable greater spatial precision for localizing GM and white matter (WM) alterations in autism. Purpose: To rigorously identify voxel-wise GM and WM volume differences in autism in the largest VBM mega-analysis to date. Materials and Methods: This retrospective mega-analysis included structural 3D volumetric T1-weighted MRI brain scans from 3,051 participants (1,519 autism; 1,532 neurotypicals) collected across 51 sites/scanners. Voxel-wise GM and WM volumes were quantified using the ENIGMA CAT12 VBM pipeline. Linear mixed-effects regression was performed at each voxel to evaluate the association between diagnostic group and voxel-wise volume while adjusting for standard nuisance covariates Results: A total of 3,051 participants (15.0 {+/-} 8.2 yrs; 2,342 male) were included in the study. Autism was associated with widespread lower GM volume involving cortical, subcortical, and cerebellar regions. The most extensive alterations in autism were detected in the orbitofrontal cortex, amygdala, thalamus, and posterior lobes of the cerebellum. WM volume was lower in autism across major projection, commissural, association, and cerebellar/brainstem tracts, including the corona radiata, internal capsule, corpus callosum, and cerebellar peduncles. These findings remained consistent in sensitivity analyses, including the application of increasingly strict motion exclusion criteria. Conclusion: Autism is associated with smaller voxel-wise GM and WM volume involving widespread cortical, subcortical, and cerebellar regions. Our findings remained robust across supplementary analyses and provide high-resolution localization of structural brain differences in autism. These findings support the involvement of distributed neural systems underlying reward processing, sensory integration, and motor functioning in autism.