Sex-specific differences in brain activity dynamics of youth with a family history of substance use disorder

An individual’s risk of substance use disorder (SUD) is shaped by potent biosocial factors. Family history is one of the strongest predictors, yet its impact on the brain before substance exposure remains unclear. Here we apply network control theory to estimate transition energies (TEs)—the input required for the brain to shift between activity patterns—in youth from the Adolescent Brain Cognitive Development Study. Family history of SUD was associated with altered TE, expressed as sex-divergent effects across brain scales alongside elevated TE in specific regions in both sexes. Females with a family history showed higher TE in the default mode network, whereas males showed lower TE in dorsal and ventral attention networks. These findings demonstrate sex-specific influences of family history on brain dynamics and underscore the importance of considering sex as a biological variable when studying adolescent neurodevelopment and mechanisms of SUD risk.