Left Ventrolateral Prefrontal Cortical Activity During Reward Expectancy and Mania Risk
Authors: Manan Arora, Henry Chase, Michele A. Bertocci, Alexander S. Skeba, Kristen Eckstrand, Genna Bebko, Haris A. Aslam, Robert Raeder, Simona Graur, Osasumwen Benjamin, Yiming Wang, Richelle S. Stiffler, Mary L. Phillips
Journal: JAMA Psychiatry (2025)

Importance Mania/hypomania is the pathognomonic feature of bipolar disorder (BD). As BD is often misdiagnosed as major depressive disorder (MDD), replicable neural markers of mania/hypomania risk are needed for earlier BD diagnosis and pathophysiological treatment development. Objective To replicate the previously reported positive association between left ventrolateral prefrontal cortex (vlPFC) activity during reward expectancy (RE) and mania/hypomania risk, to explore the effect of MDD history on this association, and to compare RE-related left vlPFC activity in individuals with and at risk of BD. Design, Setting, and Participants This cross-sectional study was conducted from July 2014 to December 2023 at the University of Pittsburgh, Pittsburgh, Pennsylvania. Three samples were formed comprising young adults (aged 18 to 30 years) without BD and with a range of subsyndromal-syndromal affective and anxiety psychopathologies, including a new sample and 2 test samples from our previous research; a sample of individuals aged 18 to 30 years with euthymic BD was also included. All participants were recruited from the community through advertising. Exposures Functional magnetic resonance imaging during an RE task. Main Outcomes and Measures New sample: whole-brain activity during RE regressed to the Mood Spectrum Self-Report Lifetime Questionnaire (MOODS-SR-L) manic domain score in all participants and in those without history of MDD and RE-related whole-brain activity regressed to the MOODS-SR-L depressive domain score to determine specificity to mania/hypomania risk. Test samples: these associations were examined using parameter estimates of activity extracted from respective masks created from activity in the new sample. A tertile split of MOODS-SR-L manic domain score divided the new sample into 3 mania/hypomania risk groups. Comparison of RE-related activity (extracted parameter estimates) was performed in risk groups and individuals with BD. Results Among the 113 individuals in the new sample, 73 were female, and the mean (SD) age was 23.88 (3.32) years. In each of the test samples, there were 52 individuals (39 female; mean [SD] age, 21.94 [2.12] years) and 65 individuals (47 female; mean [SD] age, 21.39 [2.11] years). The euthymic BD group had 37 individuals (30 female; mean [SD] age, 25.12 [3.81] years). In the new sample, 8 clusters of RE-related activity, including left vlPFC activity, showed a positive association with mania/hypomania risk, which remained after excluding individuals with MDD history and was specific to mania/hypomania risk. In the test samples, this association was shown in test sample 1 only (β, 0.21; 95% CI, 0.08-0.35; P = .002; q (false discovery rate [FDR]), 0.006; R 2 , 0.04). Test sample 2 had a higher proportion with MDD history (49 of 65 [75.3%] compared to 31 of 52 [59.6%] in sample 1). Combining individuals without history of MDD in both test samples replicated the association (β, 0.32; 95% CI, 0.08-0.58; P = .01; q [FDR], 0.023; R 2 , 0.02). RE-related left vlPFC activity was significantly greater in individuals at highest risk vs lowest (Cohen d , 1.01; 95% CI, 0.29-0.79; P &amp;amp;lt; .001) and medium (Cohen d , 0.59; 95% CI, 0.12-0.63; P = .004) risk, as well as the euthymic BD group (Cohen d , 0.54; 95% CI, 0.07-0.58; P = .01), potentially due to medication effects. Conclusion and Relevance Elevated RE-related left vlPFC activity was associated with mania/hypomania risk and attenuated by MDD history. These findings provide a neural target to help develop pathophysiological interventions for individuals with or at risk of mania/hypomania.