Yoder, KarmenMurray, Olivia KayHulvershorn, LeslieConroy, SusanDzemidzic, MarioTruitt, William2025-05-292025-05-292025-05https://hdl.handle.net/1805/48466IUIBackground: Risky decision-making deficits are associated with substance use risk. However, sex differences in risky decision-making neural processing among adolescents with externalizing disorders (EXT), like ADHD and conduct disorder, have been understudied though EXT youth are at high risk for developing substance use disorders (SUDs), partially due to impaired decision-making. While males with EXT tend to engage in more risky behavior, the neural mechanisms underlying these patterns may differ for EXT females. This dissertation presents two studies exploring 1) sex differences in brain activation during risky decision-making, and 2) how these differences relate to problematic substance use in EXT youth. Method: The first study included 168 adolescents (81 EXT males, 39 EXT females, 33 control males, 15 control females), who completed the Balloon Analogue Risk Task (BART) during a magnetic resonance imaging (MRI) session. The second study utilized 115 drug-naive EXT adolescents (78 males, 37 females) who also completed the BART during an MRI session and were assessed for problematic substance use during longitudinal follow-up. Statistical analyses compared sex and EXT differences in brain activation during risky decision-making and the associated risk of substance use using Cox proportional hazards models, respectively. Results: EXT males showed greater activation in the cingulo-opercular network during risky versus safe choice as that choice became riskier (modulated) compared to EXT females and controls. Greater modulated activation in the right nucleus accumbens (NAc) during risky versus safe choice was associated with less problematic substance use in EXT females, but not in EXT males. Greater unmodulated choice phase activation in the NAc in males and in the subgenual anterior cingulate cortex in females were associated with less problematic substance use. Conclusions: This dissertation highlights significant sex differences in both the neural processing of risky decision-making and its connection to substance use in EXT youth. These findings suggest that proper risk processing in the cingulo-opercular and reward networks may protect against substance use, with distinct patterns in males and females. These results underscore the importance of sex-specific approaches for prevention and intervention in youth at risk for substance misuse.en-USadolescent substance use riskBalloon Analogue Risk Taskexternalizing psychopathologyfunctional neuroimagingrisky decision-makingsex differencesThesis