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

摘要。双相谱系障碍（BPSD）影响高达4.5%的美国人，是第四大原因， 在世界范围内，残疾的发病高峰在成年早期。然而，要识别有风险的青少年是非常困难的 对于BPSD，因为没有BPSD风险的客观生物标志物。可以通过以下方式促进识别这些生物标志物： 阐明易导致BPSD关键症状的行为的神经生物标志物：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，并易患焦虑， 抑郁、焦虑、情感和人格障碍。冲动性感觉寻求（Impulsive Sensation Seeking，ISS） 冲动性和寻求感觉的成分特征。高特质ISS表征BPSD，并倾向于 年轻人的轻躁狂和躁狂。因此，高特质ISS倾向于低/躁狂，情绪化 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，检查精神病理学维度的神经生物标志物， 在跨诊断招募的年轻人中，我们显示（n=100）阳性神经预测因子 特质ISS与奖励回路活动之间的关联：左腹外侧前额叶皮层（vlPFC）和 腹侧纹状体（VS）在不确定的奖励预期（RE）。左侧vlPFC和VS活动增加至不确定 RE也通过BPSD与健康成人显示。在MH 100041中，左侧大vlPFC-顶叶皮质功能 与不确定RE的连接性（FC）与扫描后6个月的躁狂严重程度相关; 左侧VS-左侧vlPFC静息状态FC，具有较高的特质ISS。相比之下，杏仁核活动越大， 杏仁核-背侧/头侧前扣带皮层（dACC/rACC）FC，在情绪加工和调节中的作用 与更大的情绪失调、焦虑和抑郁有关， 人格障碍因此，升高的奖励回路活动和FC到不确定的RE和休息是有希望的 神经生物标志物的低/躁狂风险，并与上述杏仁核-ACC异常，可能倾向于 BPSD。我们建议将MH 100041更新为：1.在一个新的研究中复制和扩展我们的神经生物标志物发现， 180名年轻成年人的队列（18-30岁;跨诊断招募;无BPSD）; 2.确定这些神经 一组新的60名年龄和性别比例匹配的BPSD成人（30名双相情感障碍患者）中存在生物标志物， I型障碍，30例双相情感障碍II型，BPSD的典型类型;缓解以避免高度严重的混淆 症状;未用药/特定药物）; 3.在原始和新的非BPSD队列中识别神经 特质ISS和情绪失调的生物标志物，可预测低/躁狂恶化与焦虑恶化 和抑郁症超过延长（2年）随访，并探讨哪些神经生物标志物易患BPSD vs.其他疾病。确定BPSD风险的神经生物标志物将有助于更好地识别BPSD风险的年轻人 成年人，并提供新的神经靶点（例如，神经调节）干预以延迟或预防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.