Neural Markers of Reward Valuation and Impulsive Decision-Making in Mania Risk.

Importance: Mania or hypomania, the pathognomonic feature of bipolar disorder (BD), is associated with reward hypersensitivity and impulsive decision-making, but the neural mechanisms underlying these distinct behavioral facets remain unclear. Reward expectancy (RE)-associated activation in the left ventrolateral prefrontal cortex (L-vlPFC) and pre-supplementary motor area (pre-SMA) is elevated in individuals at risk of mania or hypomania, but it is unknown whether elevated activation in these regions and associations with risk-related behavioral facets reflect convergent or dissociable pathways to mania or hypomania risk or whether depression severity impacts these associations. Objective: To test whether RE-associated L-vlPFC and pre-SMA activation exhibit distinct associations with delay discounting behavior-indexing reward valuation (lower discounting) vs impulsive decision-making (higher discounting)-and whether these associations are moderated by depression severity. Design, Setting, and Participants: In this cross-sectional study, 2 independent samples of adults aged approximately 18 to 30 years at varying risk of mania or hypomania (142 in the discovery set and 86 in the replication set) completed a functional magnetic resonance imaging reward task and a delay discounting assessment. Major exclusion criteria included current or lifetime BD, primary psychotic disorders, neurological disorders, recent substance use disorders, systemic medical illnesses, and magnetic resonance imaging contraindications. The study took place from 2019 to 2026 at the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania. Exposure: RE-associated L-vlPFC and pre-SMA activation. Main Outcomes and Measures: Main outcomes were mania or hypomania risk per Mood Spectrum Self-Report-Lifetime mania score and delay discounting behavior per 27-Item Monetary Choice Questionnaire rate. Associations were tested using regression models, including moderation by depression severity. Results: Across 228 individuals (discovery: mean [SD] age, 23.79 [3.32] years; 96 [67.6%] female; replication: mean [SD] age, 26.09 [3.15] years; 64 [74.4%] female), L-vlPFC and pre-SMA activation were both positively associated with mania or hypomania risk in the discovery sample (l-vlPFC: β, 0.544; 95% CI, 0.440 to 0.649; z, 10.24; P < .001 and pre-SMA: β, 0.496; 95% CI, 0.341 to 0.650; z, 6.30; P < .001) and replication sample (l-vlPFC: β, 0.503; 95% CI, 0.241 to 0.765; z, 3.77; P < .001 and pre-SMA: β, 0.684; 95% CI, 0.410 to 0.957; z, 4.90; P < .001). In the discovery sample, these regions showed dissociable delay discounting associations: greater L-vlPFC activation was associated with lower discounting (β, -0.305; 95% CI, -0.561 to -0.050; P = .02), whereas greater pre-SMA activation was associated with higher discounting (β, 0.521; 95% CI, 0.146 to 0.895; P = .007). The L-vlPFC-lower discounting association replicated (β, -0.704; 95% CI, -1.400 to -0.008; P = .048). A pre-SMA activation × depression severity interaction was observed in the replication sample (β, -0.427; 95% CI, -0.792 to -0.063; P = .02), such that higher depression severity attenuated the association between elevated pre-SMA activation and higher discounting. This interaction was detectable in the discovery sample in individuals with elevated pre-SMA activation (β, -0.285; 95% CI, -0.565 to -0.005; t63 = -2.03; P = .046). Conclusions and Relevance: The findings in this cross-sectional study suggest that RE-associated L-vlPFC and pre-SMA activation may represent dissociable neural pathways to mania or hypomania risk. Elevated L-vlPFC activation was associated with sensitivity to reward value, whereas elevated pre-SMA activation was associated with impulsive decision-making, and this latter association was moderated by depression severity.