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

未请求对父拨款进行更改 抽象的。双相情感障碍(BPSD)影响着高达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，很难确定年轻人有患bpd的风险，因为在那里 并不是BPSD风险的客观生物标志物。鉴定这些生物标志物可以通过阐明神经细胞 易患BPSD关键症状的行为的生物标记物：轻躁狂和躁狂。虽然情绪化 调节失调是BPSD的特征，它也是焦虑、抑郁和焦虑的特征和易感性， 情感障碍和人格障碍。冲动性感觉寻求(ISS)由冲动性构成 和寻求感官刺激。高特质ISS是BPSD的特征，在年轻人中易患轻躁狂症和躁狂症 成年人。因此，高特质容易患低迷/躁狂、情绪失调、焦虑和抑郁。 两者的结合最终可能会给BPSD带来风险。在R01MH100041的前4年，审查 精神病理学维度的神经生物标志物和1年后的神经预测因素 经诊断招募的年轻人，我们显示(n=100)特质ISS和 奖赏回路活动：不确定时左前额叶腹外侧皮质(VLPFC)和腹侧纹状体(VS) 奖励期望(RE)。BPSD与健康人相比，对于不确定的RE，左VLPFC和VS活动也更大 成年人。在MH100041中，更大的左侧VLPFC-顶叶皮质功能连接(FC)到不确定的RE IS 与扫描后6个月更严重的躁狂相关；以及更大的左侧VLPFC与左侧VLPFC静息状态FC， 更高的性状。相比之下，杏仁核活动较大，杏仁核-背侧/嘴前扣带核较低 情绪处理和调节过程中的大脑皮层(dACC/rACC)Fc与更大的情绪相关 调节失调、焦虑和抑郁，以及焦虑、情感和人格障碍的风险。高额奖励 因此，回路活动和Fc对不确定的RE和REST是有希望的低/躁狂风险的神经生物标志物，并且， 伴有上述杏仁核-ACC异常，可能易患BPSD。我们建议将MH100041续订为： 1.在新的180名年轻人(18-30岁； 跨诊断招募；没有BPSD)；2.确定这些神经生物标记物是否存在于一组新的 60例年龄和性别比例匹配的成人BPSD(30例双相障碍I，30例双相情感障碍II，典型病例 BPSD的类型；缓解以避免高度严重症状的混淆；未用药/特定药物)； 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记物 预测在延长(2年)的随访中，低迷/躁狂与恶化的焦虑和抑郁的恶化，以及 探索哪些神经生物标记物与其他疾病相比易患BPSD。BPSD神经生物标志物的鉴定 风险将有助于更好地识别BPSD高危年轻人，并为新奇(例如， 神经调节)干预以延缓或预防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.