Sex differences in reward network activation are linked to problematic substance use among high-risk adolescents

Adolescents diagnosed with externalizing disorders—conditions such as attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder that are defined by impulsivity, aggression, and rule-breaking—stand at a markedly elevated risk of developing substance use disorders later in life. A new longitudinal neuroimaging study from Indiana University School of Medicine now reveals that the brain’s reward circuitry signals this risk differently in girls and boys, and that these sex differences could reshape how clinicians identify and protect the most vulnerable adolescents before substance use ever begins.

The research, published in Advances in Drug and Alcohol Research, followed 115 drug-naive adolescents aged 11 to 12 years, all carrying clinician-diagnosed externalizing psychopathology. Seventy-eight participants were male and 37 were female. Because prior longitudinal work on this population has either centered exclusively on male samples or ignored sex altogether, the study addresses a genuine blind spot in addiction science: how the neural machinery of risky decision-making relates to the emergence of problematic substance use differently in females and males with the same diagnoses.

During a magnetic resonance imaging session on a research-dedicated 3.0-Tesla Siemens Prisma scanner, participants performed the Balloon Analogue Risk Task, a well-validated behavioral paradigm that models real-world risk-taking. In the task, adolescents repeatedly chose between inflating a virtual balloon—earning escalating cash rewards but risking an explosion that wipes out the accumulated money—or banking the winnings safely. The probability of explosion rises parametrically with each inflation, from roughly 2 percent at the first pump to nearly 90 percent at the twelfth, allowing researchers to separate brain responses that track escalating risk from those that occur regardless of risk level.

Functional imaging data were preprocessed with distortion correction, motion correction, spatial smoothing, and independent components analysis-based denoising to strip out noise artifacts. The team then isolated two a priori regions of interest: the nucleus accumbens, a core node of reward processing that ascribes emotional and motivational value to choices, and the subgenual anterior cingulate cortex, a region involved in loss avoidance, uncertainty, and the affective evaluation of potential negative outcomes. For each participant, the researchers computed contrasts comparing risky choices against safe ones, both parametrically modulated by explosion probability and unmodulated, and then related standardized activation in these regions to subsequent substance outcomes.

Following the baseline scan, participants and their guardians completed questionnaires every six months for up to 84 months, assessing substance use through a revised Drug Use Screening Inventory covering 25 substance classes. Problematic substance use was operationalized as the endorsement of two or more DSM-5-based consequences for any single substance, reported by either the adolescent or the guardian. Cox proportional hazards models, adjusted for family history of substance use disorder, violence exposure, and parental monitoring, then tested whether brain activation predicted the hazard of reaching that outcome over time.

The central finding concerned the right nucleus accumbens. Higher activation during risky choices as explosion probability increased—the modulated Choose Inflate minus Choose Win contrast—was associated with a lower hazard of problematic substance use across the whole sample, with a hazard ratio of 0.68. Critically, this protective association was significant only in females, who showed a hazard ratio of 0.64, while males showed no significant relationship, and the difference between the sexes’ hazard ratios was itself statistically significant. In other words, girls whose accumbens activation scaled appropriately with rising risk were substantially less likely to develop problematic substance use; boys’ risk-modulated accumbens signaling carried no such protection.

The pattern reversed for unmodulated activation, which ignores the balloon’s risk level. In males, higher overall accumbens activation when choosing to inflate rather than bank was linked to a lower hazard of problematic substance use, with a hazard ratio of 0.60, whereas the same measure was unrelated to outcomes in females. Meanwhile, in the right subgenual anterior cingulate cortex, higher unmodulated activation during risky versus safe choices predicted a lower hazard in females—hazard ratio 0.49—while males trended in the opposite direction, and the sex difference in hazard ratios was significant. Notably, had the researchers analyzed the sample without splitting by sex, the subgenual cingulate finding would have been completely obscured.

The authors interpret these results through the lens of sex-specific adolescent brain maturation. Neuroimaging work has shown that ventral striatal volume rises and then declines in males across adolescence but declines steadily in females, and prior studies have linked larger accumbens volume to sensation seeking and later drinking in alcohol-naive boys but not girls. The new findings suggest that in females with externalizing disorders, appropriately ascribing emotional and motivational valence to choices as risk escalates may constitute a biologically protective system, whereas in males, general engagement of the accumbens during any risky choice—regardless of risk magnitude—appears protective. For the subgenual cingulate, the female-specific result points to intact loss-avoidance signaling during decision-making as a safeguard against later substance problems, a function that may be absent or dysfunctional in boys with the same diagnoses.

Secondary behavioral analyses reinforced the sex divide. Measures of reward sensitivity, derived from the average number of inflations on unexploded balloons, and of reduced loss aversion, derived from continued inflations after explosions, each predicted higher hazard of problematic substance use in the overall sample—but these relationships were driven entirely by males, in whom greater reward sensitivity more than doubled the hazard. The findings align with established evidence that males typically display higher reward sensitivity and lower loss aversion than females, tendencies shaped by a combination of evolutionary pressures and cultural norms around risk.

The study’s implications reach directly into prevention. The authors propose that behavioral interventions targeting decision-making deficits—such as the Impulsive Decision Reduction Training for Youth program developed by their group—could be tailored by sex: for females, therapy might focus on strengthening the assignment of emotional and motivational valence to choices as risk increases, while for males, it might emphasize overall risk calculation and recognition of varying risk signals across different choices. The researchers caution that none of the findings survived correction for multiple comparisons, that the sample contained fewer females than males reflecting the real-world sex distribution of externalizing disorders, and that substance outcomes relied on self- and guardian-report rather than objective toxicology. Even so, the work offers a striking demonstration that the neural signatures of risky decision-making are not one-size-fits-all, and that effective substance use prevention for high-risk adolescents may need to be built differently for girls and boys from the very start.

Subject of Research: Sex differences in reward network activation are linked to problematic substance use among high-risk adolescents

Article Title: Sex differences in reward network activation are linked to problematic substance use among high-risk adolescents

Article References: Murray, O. K., Mattey-Mora, P. P., Aloi, J., Lovins, S., Smoker, M. P., & Hulvershorn, L. A. (2025). Sex differences in reward network activation are linked to problematic substance use among high-risk adolescents. Advances in Drug and Alcohol Research, 5, Article 14591. https://doi.org/10.3389/adar.2025.14591

Image Credits: AI Generated

DOI: 10.3389/adar.2025.14591

Keywords: adolescent substance use, risky decision-making, sex differences, nucleus accumbens, subgenual anterior cingulate cortex, externalizing disorders, fMRI, longitudinal study, differences, reward, network, activation