Sex differences in brain-behavior relationships in the first two years of life

Background Evidence for sex differences in cognition in childhood is established, but less is known about the underlying neural mechanisms for these differences. Recent findings suggest the existence of brain-behavior relationship heterogeneities during infancy; however, it remains unclear whether sex underlies these heterogeneities during this critical period when sex-related behavioral differences arise. Methods A sample of 316 infants was included with resting-state functional magnetic resonance imaging scans at neonate (3 weeks), 1, and 2 years of age. We used multiple linear regression to test interactions between sex and resting-state functional connectivity on behavioral scores of working memory, inhibitory self-control, intelligence, and anxiety collected at 4 years of age. Results We found six age-specific, intra-hemispheric connections showing significant and robust sex differences in functional connectivity-behavior relationships. All connections are either with the prefrontal cortex or the temporal pole, which has direct anatomical pathways to the prefrontal cortex. Sex differences in functional connectivity only emerge when associated with behavior, and not in functional connectivity alone. Furthermore, at neonate and 2 years of age, these age-specific connections displayed greater connectivity in males and lower connectivity in females in association with better behavioral scores. Conclusions Taken together, we critically capture robust and conserved brain mechanisms that are distinct to sex and are defined by their relationship to behavioral outcomes. Our results establish brain-behavior mechanisms as an important feature in the search for sex differences during development. Plain language summary Early childhood differences exist in mental processes and behavior between males and females. The brain-basis for these sex differences may arise in infancy. Indeed, small brain differences in infancy may contribute to major changes in cognitive ability throughout childhood. However, few studies have examined sex differences in brain functionality in infancy and their relationship to future behaviors in early childhood. In this study, we aimed to study this relationship by using sex differences in brain functional measures in neonate, 1, and 2-year-olds and 4-year behavioral outcomes. We identified six functional connections with robust brain-behavior sex differences. These connections were unique to frontal brain regions. Also, these connections were not specific to the brain and were only evident when associated with future behavior. In brief, our analysis shows distinct age-specific brain-behavior relationships in males and females in early childhood. This is helpful for a better understanding of brain-based prediction of behavior and informed intervention of future disorders and disabilities characterized by a sex bias. Highlights ### Competing Interest Statement The authors have declared no competing interest.