Locomotor Activation and Mania Spectrum Risk: Circadian and Reward Mechanisms

摘要 双相谱系障碍[BSD]是损害和昂贵的精神疾病，通常出现在晚期 青春期和成年早期。阈下躁狂症症状，在持续时间内严重程度增加， 几个月到几年，仍然是未来BSD发作的最重要的症状前兆。然而，只有一个子集 有阈下躁狂症状的年轻人转变为BSD，无论后来的临床诊断如何， 这些症状严重影响了现实世界的功能和临床结果。虽然早期治疗 阈下躁狂症状对于良好的预后似乎越来越重要，这些症状是 很难与其他精神疾病区分开来。太多时候，延迟的症状识别导致 有害的治疗和不良的预后。即使躁狂症的症状被正确识别， 个别人士会发展至更严重的病程，因此需要更密集的早期治疗。因此，在本发明中， 临床上仍然迫切需要确定客观的生物行为风险标志物，以改善预防 以及对所有躁狂症的干预精神活动-增加活动或能量-是一个基本的 躁狂症谱的特征，可以通过运动活动的客观测量来量化。中 综合实验室评估和自然主义的后续研究，我们建议揭示生物行为 （昼夜节律，奖励）机制驱动运动激活和躁狂谱风险。我们将招募N=170 年龄在16至24岁的青少年和年轻人在一系列终身阈下躁狂症状 但之前没有使用过BSD参与者将完成为期2周的实地运动活动监测 腕关节活动记录仪，然后对探索性运动行为进行全面的实验室评估， 昼夜节律功能和奖赏敏感性。在随访期间，将记录活动记录自发活动和临床状态。 每6个月进行一次前瞻性索引，持续3年。我们的主要目标是检验 运动激活是躁狂症状严重程度和进展的行为标志[目的1]， 昼夜节律和奖励系统的神经生物学失调驱动运动激活[目的2]和躁狂 症状随时间的进展[目标3]。我们将使用高维建模方法来识别 多变量运动、昼夜节律、奖励特征预测躁狂症状及其随时间的进展， 这将为躁狂症谱提供更全面的生物行为预测模型。探索性 分析将1）从一个新的反向翻译开放领域的任务， 和2）检查我们的模型对躁狂症与其他临床结果的特异性。我们的研究结果有可能 1）通过实时、客观的运动活动监测改善躁狂症状的早期检测， 2)提供躁狂相关的昼夜节律和奖励目标的行为，时间，或神经调节 比当前最佳实践方法更有效地缓解或预防躁狂症状的干预措施。

ABSTRACT Bipolar spectrum disorders [BSD] are impairing and costly psychiatric conditions that typically emerge in late adolescence and early adulthood. Subthreshold mania symptoms, increasing in severity over the span of months-to-years, remain the most important symptomatic precursor of future BSD onset. However, only a subset of young people with subthreshold mania symptoms transition to a BSD and, regardless of later clinical diagnosis, these symptoms severely impact real-world functioning and clinical outcome. While early treatment of subthreshold mania symptoms appears increasingly imperative for a favorable prognosis, these symptoms are difficult to distinguish from other psychiatric conditions. Too often, delayed symptom recognition results in detrimental treatments and poor prognosis. Even if mania symptoms are correctly identified, it is unclear which individuals will progress to a more severe course and thus require more intensive early treatment. As a result, there remains a pressing clinical need to identify objective biobehavioral risk markers that will improve prevention and intervention for the full mania spectrum. Psychomotor activation - increased activity or energy - is a cardinal feature of the mania spectrum that can be quantified through objective measurement of locomotor activity. In a comprehensive laboratory assessment and naturalistic follow-up study, we propose to uncover the biobehavioral (circadian, reward) mechanisms driving locomotor activation and mania spectrum risk. We will recruit N=170 adolescents and young adults aged 16 to 24 years-old across a range of lifetime subthreshold mania symptoms but with no prior history of a BSD. Participants will complete 2 weeks of field-based locomotor activity monitoring with wrist actigraphy, followed by a comprehensive lab-based assessment of exploratory locomotor behavior, circadian function, and reward sensitivity. Over follow-up, actigraphic locomotor activity and clinical status will be indexed prospectively every 6-months for up to 3-years. Our primary aims will test the overarching hypothesis that locomotor activation is a behavioral marker of mania symptom severity and progression [Aim 1], and that neurobiological dysregulation of the circadian and reward systems drive locomotor activation [Aim 2] and mania symptom progression over time [Aim 3]. We will use high-dimensional modeling approaches to identify multivariate locomotor, circadian, reward profiles predictive of mania symptoms and their progression over time, which will inform more comprehensive biobehavioral predictive models for the mania spectrum. Exploratory analyses will 1) incorporate more nuanced locomotor metrics from a novel reverse-translational open field task and 2) examine the specificity of our model to mania vs other clinical outcomes. Our results have the potential to 1) improve early detection of mania symptoms through real-time, objective locomotor activity monitoring and 2) provide mania-relevant circadian and reward targets for behavioral, chronotherapeutic, or neuromodulatory interventions that alleviate or prevent mania symptoms more effectively than current best-practice approaches.