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

抽象的。双相情感障碍(BPSD)影响4.5%的美国人，是第四大致病原因 世界范围内的残疾，发病高峰在成年早期。然而，很难确定年轻人处于危险之中。 对于BPSD，因为没有BPSD风险的客观生物标志物。识别这些生物标记物可以通过以下方式进行 阐明易患BPSD关键症状的行为的神经生物标记物：轻躁狂和躁狂。 虽然情绪失调是BPSD的特征，但它也是焦虑的特征和倾向， 抑郁，以及焦虑、情感和人格障碍。冲动感觉寻求(ISS)包括 成分特征：冲动和寻求感觉。高特质ISS是BPSD的特征，并容易患上 年轻人的轻躁狂症和躁狂症。因此，高特质的ISS容易患上低/躁狂和情绪化 调节失调，到焦虑和抑郁。两者的结合最终可能会给BPSD带来风险。在 R01MH100041的前4年，检测精神病理学维度的神经生物标记物和1年 在通过诊断招募的年轻人中，我们显示(n=100)结果神经预测因子为阳性 特质ISS与奖赏回路活动的关系：左腹外侧前额叶皮质和 不确定奖赏期望(RE)时的腹侧纹状体(VS)。更大的左VLPFC和VS活动到不确定 BPSD与健康成年人的对比也显示了Re。在MH100041中，左侧大VLPFC-顶叶皮质功能 与不确定RE的连接(FC)与扫描后6个月更严重的躁狂症相关； 左对左VLPFC静息状态FC，ISS较高。相比之下，杏仁核活动更强，而杏仁核更低 杏仁核-背侧/嘴端扣带回前皮质(dACC/rACC)Fc，在情绪处理和调节过程中 与更严重的情绪失调、焦虑和抑郁以及焦虑、情感和精神疾病的风险有关 人格障碍。因此，奖赏回路活动的增加和对不确定的RE和REST的FC是有希望的 神经生物标志物的低/躁狂的风险，并与上述杏仁核-ACC异常，可能倾向于 BPSD。我们建议将MH100041更新为：1.复制和扩展我们的神经生物标记发现在新的 180名年轻人(18-30岁；跨诊断招募；没有BPSD)的队列；2.确定这些神经 生物标志物出现在60名年龄和性别比例匹配的患有BPSD(30名双相情感障碍)的成年人中 障碍I，双相情感障碍II，BPSD的典型类型；缓解以避免高度严重的混乱 症状；非药物/特定药物)；3.跨原始和新的非BPSD队列神经 特质和情绪失调的生物标记物预测恶化的低/躁狂与恶化的焦虑 和抑郁症的长期(2年)随访，并探索哪些神经生物标志物易患BPSD 与其他障碍的对比。识别bpsd风险的神经生物标记物将有助于更好地识别年轻bpsd高危人群。 并为新的干预措施(例如，神经调节)提供神经靶点，以延迟或预防BPSD。

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.