Cortical surface area lateralisation as a neural substrate for sex-differential social behaviours in autism

Abstract

Abstract Background Sex-specific phenotype heterogeneity, e.g. social behaviour differences have been commonly observed in autism spectrum disorder (ASD) and pose substantial challenges for accurate diagnosis. The neural and biological basis of these differences remains unclear. Given the sex-differential brain lateralisations, we aim to examine the roles of cortical morphologic lateralization in sex-related social behaviour differences and explore the possible biolgical mechanisms. Methods Structural magnetic resonance imaging data from 942 right-handed individuals with ASD and 1,079 typically controls were obtained from the ABIDE I and II datasets. Cortical surface area was extracted from 68 Desikan–Killiany atlas regions, and asymmetry indices were calculated as (L − R)/(L + R) . Linear mixed-effects models assessed the sex effects on regional asymmetry, adjusting for age and sites. Generalised linear models were used to test associations between significant asymmetry measures and Social Responsiveness Scale (SRS) scores. Imaging-transcriptomic analyses based on the Allen Human Brain Atlas were followed by pathway and cell-type enrichment analyses. Neurotransmitter–neuroimaging associations were assessed by spatially correlating sex-effect maps with cortical neurotransmitter distributions. Results Cortical surface area asymmetry measures in four regions, i.e. superior frontal, caudal middle frontal, superior temporal, and banks of the superior temporal sulcus regions showed significant sex effects ( PFDR P β = -0.11~-0.12, P β = -0.178, P = 0.037). Transcriptomic analyses further showed gene enrichment in neural development, synaptic function and mitochondrial function, and cell-type enrichment in astrocytes. Sex-specific cortical area asymmetry alterations showed negatively correlations with spatial density of mGluR5, NMDA, FAAH, and VAChT ( R = -0.27~-0.43, all P