Sex heterogeneity of inter-individual functional hierarchical organization similarity in autism spectrum disorder based on the joint embedding analysis

Autism spectrum disorder (ASD) has been reported to exhibit altered functional connectivity in the brain. While extant research has predominantly examined male samples, sex differences of functional organization in ASD remains poorly characterized. This study aimed to explore the sex heterogeneity of the inter-individual functional hierarchical organization similarity in ASD. Resting-state functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange database, including 284 males/65 females with ASD and 340 male/119 female neurotypical controls (NCs) were used in this study. A joint embedding method was used to embed the functional connectomes of individuals into a common connectivity space and the inter-individual functional hierarchical organization similarity was further calculated within each group. Two-way analysis of variance (ANOVA) was used to explore sex heterogeneity in the functional hierarchical organization similarity in ASD. Significant diagnosis-by-sex interaction effects on the functional hierarchical organization similarity were observed in the default mode network, frontal-parietal network, subcortical network, dorsal attention network, and undefined network. The predictive analysis of symptom severity showed that the functional hierarchical organization similarity of brain regions with significant diagnosis-by-sex interaction effects can predict the social interaction impairments in males with ASD, whereas this relationship was not detected in females with ASD. These findings emphasize the sex heterogeneity of functional hierarchical organization in ASD and underscore the necessity of considering sex differences in future studies of ASD.