The role of sex and puberty stages in the association between brain functional connectivity and executive functions in children following traumatic brain injury (TBI)

Pediatric traumatic brain injury (pTBI) during childhood and adolescence poses significant risks to the development of executive functions (EF) and to the organization of large-scale brain networks during a critical period of neurodevelopment. However, the extent to which biological sex and puberty stage shape brain–behavior relationships following pTBI remains insufficiently understood. The present study aims to examine how sex and pubertal stage moderate the associations between pediatric TBI, resting-state functional connectivity (FC), and executive functioning. Specifically, this project investigates whether puberty stage shape the relationship between pTBI-related changes in functional brain connectivity and EF performance, and whether these patterns differ between girls and boys. The study includes 124 children and adolescents aged 8–17 years, comprising participants with a history of pTBI and age-matched healthy controls. All participants underwent resting-state functional MRI and structural MRI, alongside a comprehensive cognitive assessment of executive functions, including measures of inhibition, working memory, and cognitive flexibility. Pubertal stage is assessed using the Pubertal Development Scale (PDS). Resting-state functional connectivity is analyzed using the CONN toolbox, with a focus on large-scale brain networks implicated in cognitive control and salience processing, including the salience network, frontoparietal control network, default mode network, and dorsal attention network. The study is guided by a moderated mediation framework in which functional connectivity is conceptualized as a potential neural mechanism linking pTBI to executive functioning, while pubertal stage is examined as a moderator of these associations. Analyses are conducted separately for girls and boys to capture sex-specific neurodevelopmental patterns, with age included as a covariate in all models. The expected contribution of this work is to improve understanding of how pubertal stage and biological sex influence neurocognitive vulnerability following pediatric brain injury. By integrating developmental stage, sex, and functional brain organization, this project seeks to inform future research and support the development of developmentally sensitive and sex-informed approaches to pediatric neurorehabilitation.