Sex-Specific Vulnerability to Externalizing Problems: Sensitivity to Early Stress and Nucleus Accumbens Activation Over Adolescence

Biol Psychiatry. 2024 Jan 24:S0006-3223(24)00038-6. doi: 10.1016/j.biopsych.2024.01.011. Online ahead of print.


Background: Exposure and sensitivity to early-life stress (ELS) are related to increased risk for psychopathology in adolescence. While cross-sectional studies have reported blunted nucleus accumbens (NAcc) activation in the context of these associations, researchers have not yet assessed the effects of ELS on developmental trajectories of activation. We examined whether trajectories are affected by stress and the moderating role of biological sex in predicting vulnerability to symptoms of psychopathology.

Methods: Adolescents (n = 173) completed 3 assessments at 2-year intervals across puberty (ages 9-18 years). At baseline, we assessed objective ELS and stress sensitivity using the Traumatic Events Screening Inventory for Children. At all time points, we assessed NAcc activation using the Monetary Incentive Delay task and externalizing, internalizing, and total problems using the Youth Self-Report. We examined correlations between NAcc trajectories (extracted using linear mixed-effects models) with ELS and stress sensitivity and conducted multivariate regression analysis to examine the interaction of NAcc trajectories and biological sex in predicting symptoms of psychopathology.

Results: Symptoms increased over adolescence. Stress sensitivity, but not objective ELS, was associated with decreasing trajectories of NAcc activation. Biological sex interacted with NAcc trajectories to predict psychopathology; boys, but not girls, with decreasing NAcc activation had more severe externalizing problems in adolescence. These findings were replicated in the putamen and caudate but not in the medial prefrontal cortex or control brain regions.

Conclusions: NAcc activation may be a sex-specific marker of externalizing problems in adolescence. Efforts to reduce stress sensitivity may help to decrease symptoms of psychopathology in adolescent boys.

Keywords: Adolescence; Externalizing problems; Longitudinal neuroimaging; Nucleus accumbens; Sensitivity to early stress; Sex differences.