Integrated Reward-Circadian Rhythm Model of First Onset of Bipolar Spectrum Disorders in Adolescence

7.项目总结/摘要 青少年是双相谱系障碍（BSD）首次发病的“风险年龄”。尽管 它们的流行率和公共卫生意义，关于这些机制存在着重大的悬而未决的问题， 涉及BSD的脆弱性。BSDs与对奖励的超敏反应和高奖励有关- 相关的脑功能。然而，研究还没有测试长期高回报反应性（RR） 或在青春期RR发展的增加，超过基线RR，预测BSD的首次发作。一 单独的文献记录了BSD中的昼夜节律破坏，而社会节律破坏（SRD）可以 触发BSD事件。然而，研究还没有测试是否基线昼夜节律失调，慢性社会 和昼夜节律紊乱，或在青春期这些节律紊乱的增加预测发病， BSD。此外，生物钟和奖励方法的BSD大多是并行进行的。然而，我们和 其他人则提出了基于两个系统的证据的BSD的综合奖励-昼夜节律模型 相互影响，相互作用，影响情绪功能。当失调时，奖赏和昼夜节律系统 信号传导可以联合收割机形成正反馈回路，从而加剧一个系统中的失调 另一种是失调。这项提议是对一种新颖的、综合的奖赏昼夜节律的第一次系统性测试。 BSD的第一次发作的模型。我们将使用一种创新的生物行为高风险设计来检查双向 经常资源的多个指数和领域（货币、社会）与社会和经济资源的多个指数之间的关系 昼夜节律及其联合预测首次发作的BSD和双相症状的增加。三 120名14-16岁的参与者（Ps）将完成一项为期3年的前瞻性纵向研究。的ps 在自我报告的RR的整个维度上，将不选择先前的BSD，在高尾处进行过采样 为了增加BSD发作的可能性。在时间1-6，每6个月，Ps将 对奖励相关和SRD生活事件的完整评估，以及对以下事件的自我报告和诊断评估 双相症状和发作。每年，在时间1，3和5，Ps还将完成自我报告的措施， 昼夜节律型（早晨-晚上）和社会节律规律性，唾液昏暗光褪黑激素 发病（DLMO）程序，以评估昼夜节律时相，自我报告，行为和神经（fMRI）评估 货币和社会RR，以及7天EMA期。在每个EMA期间，Ps将完成连续的 测量睡眠/觉醒和活动（活动记录）以及3个日内（上午、下午、晚上）测量 生活事件编码的奖励相关性和SRD，货币和社会奖励反应，积极和 负面情绪，以及轻度/躁狂和抑郁症状。fMRI扫描和DLMO程序将在 每个EMA时段开始前一天，不包括周末。该提案是对以下内容的创新整合 研究奖励和昼夜信号在理解青春期首次发作的BSD。它有 促进奖励和社会/昼夜节律干预的潜力，以治疗和理想地预防BSD。

7. Project Summary/Abstract Adolescence is an “age of risk” for the emergence of first onset of bipolar spectrum disorders (BSD). Despite their prevalence and public health significance, major unanswered questions exist regarding the mechanisms involved in vulnerability to BSDs. BSDs are associated with hypersensitivity to reward and elevated reward- related brain function. However, research has not yet tested whether chronically high reward responsivity (RR) or increases in RR development during adolescence, beyond baseline RR, predicts first onset of BSD. A separate literature documents circadian rhythm disruption in BSDs, and social rhythm disruption (SRD) can trigger BSD episodes. Yet, research has not tested whether baseline circadian dysregulation, chronic social and circadian rhythm disruptions, or increases in these rhythm disruptions during adolescence predict onset of BSD. Further, circadian and reward approaches to BSDs mostly have proceeded in parallel. However, we and others have proposed integrated reward-circadian models of BSDs based on evidence the two systems influence each other and interact to affect mood functioning. When dysregulated, reward and circadian system signaling may combine to form a positive feedback loop, whereby dysregulation in one system exacerbates dysregulation in the other. This proposal is the first systematic test of a novel, integrated reward-circadian model for first onset of BSD. We will use an innovative biobehavioral high-risk design to examine bidirectional relationships between multiple indices and domains (monetary, social) of RR and multiple indices of social and circadian rhythms and their joint prediction of first onset of BSD and increases in bipolar symptoms. Three hundred twenty 14-16 year old participants (Ps) will complete a prospective 3-year longitudinal study. Ps with no prior BSD will be selected along the entire dimension of self-reported RR, with oversampling at the high tail of the dimension in order to increase the likelihood of BSD onsets. At Times 1-6, every 6 months, Ps will complete assessments of reward-relevant and SRD life events and self-report and diagnostic assessments of bipolar symptoms and episodes. Yearly, at Times 1, 3, and 5, Ps also will complete self-report measures of circadian chronotype (morningness-eveningness) and social rhythm regularity, a salivary dim light melatonin onset (DLMO) procedure to assess circadian phase, self-report, behavioral, and neural (fMRI) assessments of monetary and social RR, and a 7-day EMA period. During each EMA period, Ps will complete continuous measures of sleep/wake and activity (actigraphy) and 3 within-day (morning, afternoon, evening) measures of life events coded for reward-relevance and SRD, monetary and social reward responsivity, positive and negative affect, and hypo/manic and depressive symptoms. The fMRI scan and DLMO procedure will occur on the day before the start of each EMA period, excluding weekends. This proposal is an innovative integration of research on reward and circadian signaling in understanding first onset of BSD in adolescence. It has the potential to facilitate reward and social/circadian rhythm interventions to treat, and ideally prevent, BSD.