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

申请的母公司补助金没有变化 摘要。双相谱系障碍（BPSD）影响高达4.5%的美国人，是全球第四大残疾， 发病高峰在成年早期然而，很难确定有BPSD风险的年轻人，因为 没有BPSD风险的客观生物标志物。这些生物标志物的鉴定可以通过阐明神经系统的 易患BPSD关键症状的行为生物标志物：轻躁狂和躁狂。虽然情绪激动 失调是BPSD的特征，它也是焦虑、抑郁和焦虑的特征，并易患焦虑、抑郁和焦虑， 情感和人格障碍。冲动性感觉寻求（ISS）包括冲动性成分特征 和寻求刺激高特质ISS是BPSD的特征，在年轻人中易患轻躁狂和躁狂 成年人了因此，高特质ISS容易导致低/躁狂，情绪失调，焦虑和抑郁。 两者的结合可能最终导致BPSD的风险。在R 01 MH 100041的前4年， 精神病理学维度的神经生物标志物和1年预后神经预测因子 在跨诊断招募的年轻成年人中，我们显示（n=100）特质ISS与 奖励回路的活动：左腹外侧前额叶皮层（vlPFC）和腹侧纹状体（VS）在不确定的 奖励期望（RE）。与健康人相比，BPSD也显示了不确定RE的左侧vlPFC和VS活动更大 成年人了在MH 100041中，左vlPFC-顶叶皮质功能连接（FC）与不确定RE之间的联系更大， 与扫描后6个月更严重的躁狂症相关;以及更大的左VS-左vlPFC静息状态FC， 更高的特质ISS相比之下，杏仁核活动更大，杏仁核背侧/喙侧前扣带回活动更低， 皮层（dACC/rACC）FC，在情绪处理和调节过程中与更大的情绪相关 失调、焦虑和抑郁，以及焦虑、情感和人格障碍的风险。高奖励 因此，回路活动和FC到不确定的RE和休息是有希望的低躁狂/躁狂风险的神经生物标志物，并且， 杏仁核-前扣带回异常者易患BPSD。我们建议对MH 100041进行更新，以： 1.在一个新的180名年轻人（18-30岁; 转诊断招募;无BPSD）; 2.确定这些神经生物标志物是否存在于一组新的神经细胞中。 60例年龄和性别比例匹配的BPSD成人（30例双相情感障碍I型，30例双相情感障碍II型，典型 BPSD类型;缓解以避免高严重性症状的混淆;未用药/特定药物）; 3. 在原始和新的非BPSD队列中识别特质ISS和情绪失调的神经生物标志物 预测长期（2年）随访期间低/躁狂恶化与焦虑和抑郁恶化，以及 探索哪些神经生物标志物与其他疾病相比易患BPSD。识别BPSD的神经生物标志物 风险将有助于更好地识别处于风险中的BPSD年轻人，并为新的（例如， 神经调节）干预以延迟或预防BPSD。

No changes from the parent grant requested ABSTRACT. Bipolar Spectrum Disorders (BPSD) affect up to 4.5% of Americans, are the 4th 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.