Social behavior in ASD males: The interplay between cognitive flexibility, working memory, and functional connectivity deviations.

Autism spectrum disorder (ASD) is highly heterogeneous in presentation. While abnormalities in brain functional connectivity are consistently observed in autistic males, the neurobiological basis underlying the different domains of autism symptoms is unclear. In this study, we evaluated whether individual variations in functional connectivity deviations map to social behavior in ASD males. Using neuroimaging data from the Autism Brain Imaging Data Exchange (ABIDE), we modeled normative trajectories of between-network resting-state functional connectivity (rsFC) in non-ASD males across childhood (n = 321). These normative charts were then applied to ASD males (n = 418) to calculate individual deviation scores (z-scores) that reflect the degree of rsFC atypicality. Deviations in rsFC patterns among the default mode network (DMN), ventral attention network (VAN), frontoparietal network (FPN), and somatomotor network (SMN) were associated with distinct dimensions of social behavior. Cognitive flexibility and working memory mediated the association between VANxDMN z-scores and social behavioral problems. Our findings underscore the potential of normative models to identify atypical brain connectivity at an individual level, revealing the neurobiological patterns associated with social behavioral problems in ASD that are critical for precision diagnosis and intervention. Social outcomes in ASD males may be improved by targeting cognitive flexibility and working memory.