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bioRxiv · 10.64898/2026.07.03.736397

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

Rajagopalan, P.·Kim, G. S.·Overholtzer, L. N.·Gleave, E.·Benavidez, S. M.·Retika, C.·Thompson, P.·Lawrence, K. E.
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Abstract

BackgroundPrevious 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 and may obscure subtle focal differences. Whole brain voxel-based morphometry (VBM) analyses enable greater spatial precision to identify and localize previously undetected neuroanatomical alterations. PurposeTo rigorously identify voxel-wise GM and white matter (WM) volume differences in autism in the largest VBM mega-analysis to date. Materials and MethodsThis retrospective mega-analysis included structural 3D volumetric T1-weighted MRI brain scans from 3,051 participants (15.0 {+/-} 8.2 yrs; 76.8% male; 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 ResultsAutism was associated with widespread lower GM volume involving cortical, subcortical, and cerebellar regions (peak t=7.39, peak {beta}=0.13); such GM differences were most notably detected in the bilateral 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 (peak t=6.74, peak {beta}=0.08), including the corona radiata, internal capsule, corpus callosum, and cerebellar peduncles. These findings remained consistent in sensitivity analyses, including covarying for full-scale IQ and the application of increasingly strict motion exclusion criteria. ConclusionAutism is associated with smaller voxel-wise GM and WM volume involving widespread cortical, subcortical, and cerebellar regions. This high-resolution identification and localization of structural brain differences support the involvement of distributed neural systems in autism that underlie reward processing, sensory integration, and motor functioning in autism. Summary statementIn the largest voxel-based morphometry study of autism to date, widespread smaller gray and white matter volumes were identified across distributed brain regions implicated in reward and sensorimotor function. Key ResultsO_LIOur largest voxel-based morphometry mega-analysis to date in autism (N=3,051), identified widespread gray and white matter alterations (peak t=7.39, peak {beta}=0.13). C_LIO_LIWe reveal novel associations within thalamic mediodorsal nuclei by leveraging finer voxel-wise volumetric analyses. C_LIO_LIAdditional associations in orbitofrontal cortex, amygdala, and cerebellum, along with extensive white matter alterations across projection, commissural, association fibers, reinforce reward-processing, sensory and motor development theories in autism. C_LI

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Rajagopalan, P., Kim, G. S., Overholtzer, L. N., Gleave, E., Benavidez, S. M., Retika, C., Thompson, P., Lawrence, K. E.. 2026-07-04. Structural brain alterations in autism: A large-scale voxel-based morphometry mega-analysis. https://doi.org/10.64898/2026.07.03.736397

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