Deep learning models reveal sex differences in human functional brain organization that are replicable, generalizable, and behaviorally relevant

Ryali et al. do a massive analysis that argues strongly against the notion of a continuum in male-female brain organization, and underscore the crucial role of sex as a biological determinant in human brain organization and behavior.  I pass on the significance and abstract statements. Motivated readers can obtain a PDF of the article from me.  

Significance

Sex is an important biological factor that influences human behavior, impacting brain function and the manifestation of psychiatric and neurological disorders. However, previous research on how brain organization differs between males and females has been inconclusive. Leveraging recent advances in artificial intelligence and large multicohort fMRI (functional MRI) datasets, we identify highly replicable, generalizable, and behaviorally relevant sex differences in human functional brain organization localized to the default mode network, striatum, and limbic network. Our findings advance the understanding of sex-related differences in brain function and behavior. More generally, our approach provides AI–based tools for probing robust, generalizable, and interpretable neurobiological measures of sex differences in psychiatric and neurological disorders.

Abstract

Sex plays a crucial role in human brain development, aging, and the manifestation of psychiatric and neurological disorders. However, our understanding of sex differences in human functional brain organization and their behavioral consequences has been hindered by inconsistent findings and a lack of replication. Here, we address these challenges using a spatiotemporal deep neural network (stDNN) model to uncover latent functional brain dynamics that distinguish male and female brains. Our stDNN model accurately differentiated male and female brains, demonstrating consistently high cross-validation accuracy (>90%), replicability, and generalizability across multisession data from the same individuals and three independent cohorts (N ~ 1,500 young adults aged 20 to 35). Explainable AI (XAI) analysis revealed that brain features associated with the default mode network, striatum, and limbic network consistently exhibited significant sex differences (effect sizes > 1.5) across sessions and independent cohorts. Furthermore, XAI-derived brain features accurately predicted sex-specific cognitive profiles, a finding that was also independently replicated. Our results demonstrate that sex differences in functional brain dynamics are not only highly replicable and generalizable but also behaviorally relevant, challenging the notion of a continuum in male-female brain organization. Our findings underscore the crucial role of sex as a biological determinant in human brain organization, have significant implications for developing personalized sex-specific biomarkers in psychiatric and neurological disorders, and provide innovative AI-based computational tools for future research.