Brain functional connectivity, but not neuroanatomy, captures the interrelationship between sex and gender in preadolescents

Understanding sex differences in the adolescent brain is crucial, as these differences are linked to neurological and psychiatric conditions that vary between males and females. Predicting sex from adolescent brain data may offer valuable insights into how these variations shape neurodevelopment. Recently, attention has shifted toward exploring socially-identified gender, distinct from sex assigned at birth, recognizing its additional explanatory power. This study evaluates whether resting-state functional connectivity (rsFC) or cortical thickness more effectively predicts sex and sex/gender alignment (the congruence between sex and gender) and investigates their interrelationship in preadolescents. Using data from the Adolescent Brain Cognitive Development (ABCD) Study, we employed machine learning to predict both sex (assigned at birth) and sex/gender alignment from rsFC and cortical thickness. rsFC predicted sex with significantly higher accuracy (86%) than cortical thickness (75%) and combining both did not improve the rsFC model’s accuracy. Brain regions most effective in predicting sex belonged to association (default mode, dorsal attention, and parietal memory) and visual (visual and medial visual) networks. The rsFC sex classifier trained on sex/gender aligned youth was significantly more effective in classifying unseen youth with sex/gender alignment than in classifying unseen youth with sex/gender unalignment. In females, the degree to which their brains’ rsFC matched a sex profile (female or male), was positively associated with the degree of sex/gender alignment. Lastly, neither rsFC nor cortical thickness predicted sex/gender alignment. These findings highlight rsFC’s predictive power in capturing the relationship between sex and gender and the complexity of the interplay between sex, gender, and the brain’s functional connectivity and neuroanatomy.