Locomotor Activation and Mania Spectrum Risk: Circadian and Reward Mechanisms

摘要 双相情感障碍[BSD]是通常在晚期出现的损害和昂贵的精神疾病 青春期和成年期早期。阈值以下躁狂症状，严重程度在以下几年中增加 从月到年，仍然是未来BSD发病的最重要的症状先兆。然而，只有子集 有阈值以下躁狂症状的年轻人过渡到BSD，无论后来的临床诊断如何， 这些症状严重影响现实世界的功能和临床结果。早期治疗的同时 阈值以下躁狂症状似乎越来越需要良好的预后，这些症状是 很难与其他精神疾病区分开来。通常情况下，延迟症状识别会导致 治疗不利，预后差。即使躁狂症状被正确识别，也不清楚是哪种 个人将进展到更严重的病程，因此需要更密集的早期治疗。结果, 临床上仍然迫切需要确定客观的生物行为风险标记物，以改善预防 以及对所有躁狂症的干预。精神运动激活--增加活动或能量--是最重要的 躁狂症谱系的特征，可通过运动活动的客观测量来量化。在一个 综合实验室评估和自然主义后续研究，我们建议揭示生物行为 (昼夜节律，奖励)驱动运动激活和躁狂症谱风险的机制。我们将招募N=170人 16岁至24岁的青少年和年轻人患有一系列终生亚阈值躁狂症状 但之前没有BSD的病史。参与者将完成为期两周的现场运动活动监测 通过手腕动作图，然后是基于实验室的探索性运动行为的全面评估， 昼夜节律功能和奖励敏感度。在后续的随访中，肌动描记运动活动度和临床状态 预期每6个月编制一次索引，最长可达3年。我们的主要目标将检验最重要的假设 运动激活是躁狂症状严重程度和进展的行为标志[目标1]，而且 昼夜节律和奖赏系统的神经生物学失调导致运动激活和躁狂。 症状随时间进展[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、奖励曲线预测躁狂症状及其随时间的进展， 这将为躁狂症频谱提供更全面的生物行为预测模型。探索性的 分析将1)从一个新的反向平移空地任务中纳入更多细微差别的运动指标 2)检验我们的模型对躁狂症和其他临床结果的特异性。我们的结果有可能 1)通过实时、客观的运动活动监测和改善躁狂症状的早期检测 2)为行为、时间治疗或神经调节提供与躁狂相关的昼夜节律和奖励目标 比目前的最佳做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.