Economic hardship mediates differences in brain network dynamics associated with family history of substance use disorder in a sex-specific manner

Abstract

Family history of substance use disorder (SUD) is associated with brain differences before substance exposure, but the pathways linking familial risk to brain function may differ by sex. Using baseline data from the Adolescent Brain Cognitive Development (ABCD) Study, we tested whether environmental adversity mediates previously observed sex-specific associations between family history of SUD and transition energy, a network control theory-derived measure of the energetic cost of transitioning between brain activity states. We derived three environmental dimensions - economic hardship, family-school neglect, and parental mental illness - and fit sex-stratified mediation models at global, network, and regional scales. Environmental mediation was significant in females and was driven primarily by economic hardship, which mediated higher transition energy across default mode, visual, ventral attention, and somatomotor networks, with widespread positive regional effects. In males, mediation was weaker and more heterogeneous, with more negative transition-energy patterns that were less explained by the measured environmental pathways. In an exploratory extension, state policy environments associated with smaller FH+ versus FH- economic-hardship gaps were projected to partially attenuate FH-related transition energy gaps, especially in females. These findings suggest that familial SUD risk is embedded in brain dynamics through sex-distinct pathways, with economic hardship representing a potentially modifiable pathway linking familial risk to large-scale brain function in early adolescence.