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

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ABSTRACT. Bipolar Spectrum Disorders (BPSD) affect up to 4.5% of Americans, are the 4th leading cause of disability worldwide, with onset peaking in early adulthood. Yet, it is very difficult to identify young adults at risk for BPSD, as there are no objective biomarkers of BPSD risk. Identifying these biomarkers can be facilitated by elucidating neural biomarkers of behaviors that predispose to key symptoms of BPSD: hypomania and mania. While emotional dysregulation characterizes BPSD, it also characterizes, and predisposes to, anxiety, depression, and anxiety, affective and personality disorders. Impulsive sensation seeking (ISS) comprises the component traits impulsivity and sensation seeking. High trait ISS characterizes BPSD, and predisposes to hypomania and mania in young adults. Thus, high trait ISS predisposes to hypo/mania, and emotional dysregulation, to anxiety and depression. The combination of both may ultimately confer risk for BPSD. In the first 4 years of R01MH100041, examining neural biomarkers of dimensions of psychopathology and 1-year outcome neural predictors in transdiagnostically-recruited young adults, we show (in n=100) a positive association between trait ISS and activity in reward circuitry: left ventrolateral prefrontal cortex (vlPFC) and ventral striatum (VS) during uncertain reward expectancy (RE). Greater left vlPFC and VS activity to uncertain RE is also shown by BPSD vs healthy adults. In MH100041, greater left vlPFC-parietal cortical functional connectivity (FC) to uncertain RE is associated with greater mania severity 6 months post scan; and greater left VS-left vlPFC resting state FC, with higher trait ISS. By contrast, greater amygdala activity, and lower amygdala-dorsal/rostral anterior cingulate cortical (dACC/rACC) FC, during emotion processing and regulation are associated with greater emotional dysregulation, anxiety and depression, and risk for anxiety, affective and personality disorders. Elevated reward circuitry activity and FC to uncertain RE and rest are thus promising neural biomarkers of hypo/mania risk, and, with the above amygdala-ACC abnormalities, may predispose to BPSD. We propose a renewal of MH100041 to: 1. Replicate and extend our neural biomarker findings in a new cohort of 180 young adults (18-30 years; recruited transdiagnostically; no BPSD); 2. Determine if these neural biomarkers are present in a new group of 60 age- and gender-ratio-matched adults with BPSD (30 bipolar disorder I, 30 bipolar disorder II, prototypical types of BPSD; remitted to avoid confounds of high severity symptoms; unmedicated/ specific medications); 3. Identify across original and new non-BPSD cohorts neural biomarkers of trait ISS and emotional dysregulation that predict worsening hypo/mania vs. worsening anxiety and depression over extended (2 years’) follow up, and explore which neural biomarkers predispose to BPSD vs. other disorders. Identifying neural biomarkers of BPSD risk will help to better identify BPSD at-risk young adults, and provide neural targets for novel (e.g., neuromodulation) interventions to delay, or prevent, BPSD.