Reward, impulsive sensation seeking and emotional dysregulation: neural mechanisms underlying risk for bipolar disorder in young adults

Bipolar Disorder (BD) is often misdiagnosed as Major Depressive Disorder (MDD) and poorly-treated. As risk for mental health problems increases in young adulthood, identifying objective neural marker predictors of future BD vs. MDD in young adults will provide neural markers for early risk identification and neural targets for new interventions to delay or prevent these debilitating disorders. The goal in the initial MERIT Award period was to adopt a transdiagnostic and dimensional approach to identify neural marker correlates and predictors of worsening manic/hypomanic vs. depressive symptoms in young adults, ultimately to distinguish BD from MDD risk. We showed that: elevated reward expectancy-related left ventrolateral prefrontal cortical (vlPFC) and prediction error-related left ventral striatal activity, lower PE-related right amygdala activity, and lower bilateral cingulum bundle fractional anisotropy (FA), a measure of white matter fiber collinearity, predicted current and/or future mania/hypomania; greater largescale (central executive [CEN], salience and default mode) network functional connectivity (FC) and greater CEN dorsolateral prefrontal cortical (dlPFC) activity during emotional regulation predicted current and future depression; while lower right uncinate fasciculus FA and greater left vlPFC and lower left inferior temporal cortical thickness were associated with greater mania/hypomania and depression. In the proposed MERIT extension, to yield robust neural markers of BD vs. MDD risk, we aim to examine: 1. an independent young adult sample (n=150 non mood disordered 18-30 year-olds) to test findings; 2. higher temporal resolution neural, and dopamine transmission, measures using fMRI-based source-localized electroencephalography (EEG) beta power/FC and midbrain neuromelanin contrast to noise ratio; 3. longitudinal neuroimaging to identify neural change predictors of worsening mania/hypomania and depression, and ultimately BD and MDD; 4. relationships among neural measures, response tendencies and symptom trajectories predisposing to BD and MDD, to better understand risk pathways for these disorders; and 5. young adults with 1st and/ or 2nd degree relatives with BD and MDD/ MDD, given their higher BD and MDD risk. RELEVANCE (See instructions): Bipolar Disorder (BD) is often misdiagnosed as Major Depressive Disorder (MDD). The proposed MERIT extension aims to study a new sample of young adults at familial risk of BD and/or MDD using more sensitive measures of brain activity and repeated brain scans, to test present findings, identify robust brain markers of BD vs. MDD risk, improve early BD risk identification, and aid new treatment development.