Regional alignment with sex-typical brain architecture, maternal health and environmental enrichment predict psychiatric symptoms in early life

Robust sex differences in brain morphology and function exist from birth onwards. While traditionally conceptualized as categorical, they were recently shown to be best described along a female-to-male continuum. Here, we probed the under-explored implications of this proposal for understanding early life vulnerability to psychiatric conditions with sex-biased prevalence. We analyzed environmental, clinical and resting state functional neuroimaging data from 411 participants in Developing Human Connectome Project (dHCP) and 214 children from the Oregon ADHD 1000 study. In the dHCP, we identified complementary patterns of neonatal alignment with sex-typical young adult architecture, which overlapped areas rich in nicotinic cholinergic receptors and predicted the same psychiatric symptoms across sexes in toddlerhood. Specifically, for association (compared to sensorimotor) areas, greater alignment with female-typical functional connectivity (FC) patterns foreshadowed higher anxiety, whereas greater alignment with male-typical FC patterns forecasted autism-related problems. The latter effect was weaker among toddlers with an older epigenetic age at birth and exposure to fewer maternal health problems, but greater environmental enrichment. In the independent child sample, patterns of alignment with sex-typical FC, overlapping those observed in neonates, distinguished a history of depression and generalized anxiety (greater alignment with female-typical FC) from a history of separation anxiety, behavioral problems and current ADHD (greater alignment with male-typical FC). Our study speaks to the psychiatric relevance of sex-related functional brain architecture from birth onwards, its value in identifying vulnerable youths and its promise in monitoring the success of environmental interventions.