Brain-Based Predictions of Psychiatric Illness–Linked Behaviors Across the Sexes

Individual differences in functional brain connectivity can be used to predict both the presence of psychiatric illness and variability in associated behaviors. However, despite evidence for sex differences in functional network connectivity and in the prevalence, presentation, and trajectory of psychiatric illnesses, the extent to which disorder-relevant aspects of network connectivity are shared or unique across the sexes remains to be determined. In this work, we used predictive modeling approaches to evaluate whether shared or unique functional connectivity correlates underlie the expression of psychiatric illness–linked behaviors in males and females in data from the Adolescent Brain Cognitive Development Study (N = 5260; 2571 females). We demonstrate that functional connectivity profiles predict individual differences in externalizing behaviors in males and females but predict internalizing behaviors only in females. Furthermore, models trained to predict externalizing behaviors in males generalize to predict internalizing behaviors in females, and models trained to predict internalizing behaviors in females generalize to predict externalizing behaviors in males. Finally, the neurobiological correlates of many behaviors are largely shared within and across sexes: functional connections within and between heteromodal association networks, including default, limbic, control, and dorsal attention networks, are associated with internalizing and externalizing behaviors. Taken together, these findings suggest that shared neurobiological patterns may manifest as distinct behaviors across the sexes. Based on these results, we recommend that both clinicians and researchers carefully consider how sex may influence the presentation of psychiatric illnesses, especially those along the internalizing-externalizing spectrum.