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Mania/hypomania is characterized by elevated reward sensitivity and goal overvaluation, impulsivity, and sensation seeking, and is the defining symptom of bipolar disorder. However, in individuals without a clear history of mania/hypomania, bipolar disorder is often misdiagnosed as major depressive disorder. Replicable neural markers of mania/hypomania risk are needed for earlier bipolar diagnosis, as well as for development of pathophysiological treatment that yields fewer adverse effects than current treatments do.

Many features of mania/hypomania can be triggered in reward expectancy contexts. The prefrontal cortical–ventral striatal neural reward network guides reward evaluation, decision-making, and reward-guided learning. Investigators led by Mary Phillips, MD, MD (Cantab) (Distinguished Professor of Psychiatry, Clinical and Translational Science, and Bioengineering, Pittsburgh Foundation-Emmerling Endowed Chair in Psychotic Disorders, and Director of the Center for Neural Circuitry-based Technology Interventions in Psychiatry), previously demonstrated a positive association between left ventrolateral prefrontal cortex activity during reward expectancy and mania/hypomania risk. 

To replicate these findings, to explore the effect of major depressive disorder history on this association, and to compare reward expectancy-related left ventrolateral prefrontal cortex activity in individuals with and at risk of bipolar disorder, investigators including Manan Arora, MBBS (postdoctoral scholar); Henry Chase, PhD (Research Assistant Professor of Psychiatry); Michele Bertocci, PhD (Assistant Professor of Psychiatry); Kristen Eckstrand, MD, PhD (Assistant Professor of Psychiatry); and Dr. Phillips studied three independent cohorts: an initial sample (n=113), and two test samples (n=52 and n=65) of individuals (aged 18-35) who had not yet developed bipolar disorder, but who had a range of affective and anxiety psychopathologies, over nine years. In addition, they examined a group of 37 individuals with bipolar disorder. Study participants underwent functional magnetic resonance imaging during a reward expectancy task. 

“In this study we used the MOODS-SR-L manic domain score as a robust measure of mania/hypomania risk, capturing both threshold and subthreshold symptoms. We had neuroimaging and clinical data of three samples of at-risk individuals and were able to replicate our findings across three independent samples, addressing the replication crisis in functional neuroimaging studies,” said Dr. Arora, first and corresponding author of the study, which was published in JAMA Psychiatry. 

The investigators replicated their previous finding of a positive association between reward expectancy-related left ventrolateral prefrontal cortex activity and mania/hypomania risk in participants  who had not yet been diagnosed with bipolar disorder. The association was evident across both test samples, especially after excluding individuals with a major depressive disorder history and was specific to mania/hypomania risk. They additionally found that individuals with bipolar disorder had significantly lower magnitude of reward expectancy-related left ventrolateral prefrontal cortex activity than those at high risk of bipolar disorder, but did not differ significantly from those at medium and low risk of bipolar disorder, which may have been the result of antipsychotic medication.

“We and others have previously shown that the left ventrolateral prefrontal cortex encodes potential reward outcome value. Like other reward circuitry regions, this region receives dopaminergic input from the midbrain. Our findings therefore suggest that greater reward expectancy-related left ventrolateral prefrontal cortical activity, likely reflecting elevated dopamine transmission during reward expectancy, underlies the elevated reward sensitivity that is associated with Bipolar Disorder, and is a promising and well-replicated neural marker of future mania/hypomania risk,”  said Dr. Phillips, the study’s senior author.

Left Ventrolateral Prefrontal Cortical Activity During Reward Expectancy and Mania Risk
Arora M, Chase H, Bertocci MA, Skeba AS, Eckstrand K, Bebko G, Aslam HA, Raeder R, Graur S, Benjamin O, Wang Y, Stiffler RS, Phillips ML.
JAMA Psychiatry. Published online January 2, 2025. doi:10.1001/jamapsychiatry.2024.4216