Linking mania/hypomania with abnormal reward expectancy- and approach-related neural network activity and dopamine release

ABSTRACT. Mania/hypomania, the defining symptom of Bipolar Disorder (BD), is extremely disabling, leading to significantly impaired health and psychosocial function. Yet, current treatments often have severe side effects; and relapse rates are high. Pathophysiologically-based treatments, guided by an understanding of the neurobiological mechanisms predisposing to mania/hypomania in BD, are urgently needed to treat and reduce recurrence of this defining BD symptom. We seek to elucidate the neurobiological mechanisms underlying two key characteristics that predispose to, and are associated with, mania/hypomania: elevated reward sensitivity/ goal overvaluation and higher than normal levels of often risky, approach-oriented decision-making and behavior, which can be triggered in uncertain reward expectancy (RE) and approach-avoidance decision-making contexts. Based on our prior work, we hypothesize that these characteristics result from: abnormally elevated activity and connectivity in the ventrolateral prefrontal cortex (vlPFC)-reward network (RNet) but abnormally low or no change in activity and connectivity in the central executive network (CEN), and lower CEN-RNet connectivity, especially in the latter decision-making context, for which the etiology is elevated dopamine (DA) release in the RNet. Our goal is to rigorously assess RNet and CEN DA release in 40 unmedicated euthymic BD adults experiencing subsyndromal mania/hypomania, and 40 healthy control adults (HC), using positron emission tomography (PET) during oral amphetamine (AMPH) challenge. By examining relationships among RNet and CEN fMRI activity, functional and effective connectivity (FC, EC), DA release, and subsyndromal mania/hypomania and AMPH- induced increases in mania/hypomania, we will advance understanding of the neurobiological mechanisms underlying mania/hypomania predisposition in BD. We will use [11C]raclopride PET and AMPH challenge to measure striatal DA release; [11C]FLB457 PET and AMPH challenge to measure cortical DA release; and midbrain (substantia nigra pars compacta/ventral tegmental area, SNc/VTA) neuromelanin contrast-to-noise ratio (NM CNR) as a measure of cumulative DA synthesis, to examine relationships between this measure and AMPH-induced DA release. We aim to: 1. Compare groups on: left vlPFC-RNet activity, FC and EC during uncertain RE and approach-avoidance decision-making; right dlPFC-CEN activity, FC and EC, and CEN-RNet FC, EC, during the latter context; and indices of approach-avoidance decision-making; 2. Compare groups on, and examine relationships among: RNet and CEN striatal and prefrontal cortical PET-measured DA release, and SNc/VTA NM CNR; 3. Examine associations among RNet and CEN DA release, network-respective fMRI measures, and indices of approach-avoidance decision-making; 4. Examine relationships among AMPH-induced changes in, and subsyndromal baseline, mania/hypomania and imaging measures; and group differences in AMPH-induced changes in mania/hypomania. Our work will elucidate neural network DA release abnormalities predisposing to mania/hypomania, to help develop targeted therapeutics with fewer side effects.