Sex moderates family history of alcohol use disorder and childhood maltreatment effects on an fMRI stop‐signal task

Childhood maltreatment (CM) and a family history (FH) of alcohol use disorder (AUD) are each associated with increased impulsivity. However, their unique or shared brain targets remain unknown. Furthermore, both CM and FH demonstrate sex‐dependent effects on brain and behavior. We hypothesized that CM and FH interact in brain regions involved in impulsivity with sex‐dependent effects. 144 first‐year college students (18–19 years old) with varying experiences of CM and/or FH but without current AUD performed an fMRI stop‐signal task. We tested interactions between FH, CM, and sex on task performance and blood oxygen level‐dependent (BOLD) signal during successful inhibitions. We examined correlations between BOLD response and psychiatric symptoms. Significant three‐way interactions of FH, CM, and sex were detected for brain and behavioral data, largely driven by male subjects. In males, CM was associated with poorer response inhibition but only for those with less FH; males with higher levels of both CM and FH demonstrated better response inhibition. Three‐way interaction effects on voxel‐wise BOLD response during response inhibition were found in bilateral middle frontal gyrus, left inferior frontal gyrus, dorsomedial prefrontal cortex, and posterior cingulate cortex. Network‐level analyses implicated the left frontoparietal network, executive control network, and default‐mode network. Greater BOLD response in these networks correlated with lower depressive, impulsive, and attentional symptoms, reduced alcohol misuse, greater resilience scores, and heightened trait anxiety. The results highlight sex‐divergent effects of heritable and environmental risk factors that may account for sex‐dependent expression of psychopathology in response to risk factors. Significant three‐way interactions of family history of alcohol use disorder, childhood maltreatment, and sex were detected for brain and behavioral measures of response inhibition, largely driven by male subjects. Males with the greatest exposure to risk factors exhibited preserved response inhibition and enhanced frontoparietal BOLD responses. Greater BOLD response in these regions was associated with reduced psychopathology and greater self‐reported resilience.