Fetal MRI reveals altered prenatal cortical surface area in fetuses later diagnosed with autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is increasingly conceptualized as a condition rooted in altered prenatal neurodevelopment, yet in vivo evidence from fetal brain imaging remains limited. Using retrospective fetal MRI and surface-based morphometry, we investigated cortical development in 15 fetuses later diagnosed with ASD (77%; mean gestational age [GA] = 26.7 weeks) without major structural brain abnormalities and compared them with 60 typically developing controls (57% male; mean GA = 28.4 weeks). Fetuses later diagnosed with ASD showed significantly reduced whole-brain inner cortical plate surface area compared with controls ({beta} = -0.08 {+/-} 0.02 SE, p = 0.002, partial {superscript 2} = 0.13), corresponding to an estimated [~]7.7% reduction (predicted at GA = 28.1 weeks). Lobar mixed-effects analyses demonstrated broadly distributed reductions across all cortical lobes (FDR-corrected p = <0.001-0.024; Cohens d = -0.06 to -0.10), with modest regional heterogeneity indicating relatively greater frontal and insular involvement (groupxlobe: F = 19.31, p = 0.002, {superscript 2} = 0.08). Surface area findings remained directionally stable across sensitivity analyses, including restriction to neurodevelopmentally confirmed controls and models accounting for image quality variability, although effect sizes were attenuated after quality adjustment. Normative modeling further demonstrated subtle negative deviations from typical prenatal cortical surface area trajectories in ASD (mean Z = -0.27, p = 0.018). These findings suggest that aspects of cortical morphogenesis may diverge prenatally in individuals later diagnosed with ASD and suggest the feasibility of fetal MRI-based surface morphometry for studying early neurodevelopmental variation associated with ASD risk.