Autism spectrum disorder (ASD) exhibits a pronounced male predominance in prevalence and may involve distinct neural characteristics across sexes. While functional connectivity gradients provide a powerful framework for understanding brain hierarchy, the sex-specific gradient alterations in the insula remain poorly understood in ASD. Resting-state functional magnetic resonance imaging data including 808 individuals were analyzed in this study. We mapped the dominant (G1) and secondary (G2) functional connectivity gradients of the insula and investigated diagnosis-by-sex interactions. These gradient alterations were further assessed for associations with clinical symptoms and spatially decoded against transcriptomic and neurotransmitter profiles. Significant diagnosis-by-sex interactions were identified in both the G1 and G2 of the insula. These gradient alterations were associated with clinical symptom profiles in ASD and showed spatial correlations with patterns of gene expression and neurotransmitter distributions. Our findings reveal a sex-specific neurofunctional profile of the insula in ASD across functional and molecular levels, providing novel insights into the potential neurobiological correlates of its sex-specific heterogeneity.
Gao et al. (Fri,) studied this question.