Investigating Circadian Rhythms in Youth with Persistent Tic Disorders

摘要 持续性抽动障碍(PTD)，包括抽动障碍(TD)，是一种神经精神疾病，其特点是 动作和/或发声持续时间超过一年，并与音质受损有关 生活的一部分。许多人并没有从现有的行为和药物治疗中显著受益。 加强对PTDS所涉及的病理生理机制的了解可能有助于识别新的 治疗发展的目标。昼夜节律紊乱经常出现在精神病患者和 神经功能障碍，并可能牵涉到PTDS。案例研究表明，早晨暴露在光线疗法中， 已知的提前昼夜节律阶段与适度到大量的抽动减少有关，这表明存在 部分PTDS患者的昼夜节律异常(即相位延迟)可能导致抽动症状 发病、病程和治疗反应，并与潜在的PTD病理生理学有关。昼夜节律是 通常通过昏暗的光线评估褪黑素的发病情况，因为它是最可靠的标志物。最强的相 移位剂是光疗法，它与昼夜节律睡眠的昼夜相移有关。 精神障碍、情绪障碍以及其他精神和神经障碍。此外，光疗法是 与核心精神和神经症状的改善有关。从历史上看，光疗法 包括通过灯箱对明亮的白色光线进行管理。然而，依从性可能会因不利因素而减少 强光带来的副作用，以及由于行动有限和时间限制造成的负担。一个可行的选择是 可穿戴式短波长蓝光疗法--显示出在相移昼夜节律方面更有效 与白光相比，强度更低，持续时间更短。因此，本项目利用一种 翻译方法，以确定和测试在PTDS中目标参与的新机制。这项研究将 评估35名13至17岁青年的昼夜节律和表型，与35名性别和青春期 匹配健康对照受试者，并评估可穿戴式短波长光疗法的程度 针对这一假定的昼夜节律机制，并与抽搐症状的改善有关。在上面绘制 项目共同导师的专业知识：Christopher Colwell博士和John Piacentini博士；以及顾问： Meredith Coles博士、Dana McMakin博士、Helen Burgess博士和Catherine Sugar博士 拟议的项目将提供有关昼夜节律生理学、昼夜节律测量和 治疗；实验性治疗框架，因为它们与儿童精神病理学有关，包括抽动 疾病和睡眠；以及生物统计学。这些发现将加强我们对昼夜节律的作用的理解 在持续性抽动障碍中，并可能为未来的治疗开发提供新的靶点。

Abstract Persistent Tic Disorders (PTD), including Tourette’s Disorder (TD) are neuropsychiatric conditions marked by movements and/or vocalizations present for longer than one year, and associated with impairments in quality of life. Many individuals do not significantly benefit from existing behavioral and pharmacological treatments. Enhanced knowledge of the pathophysiological mechanisms implicated in PTDs may aid identification of new targets for treatment development. Circadian rhythm disruption frequently presents in psychiatric and neurological disorders and may be implicated in PTDs. Case studies show morning exposure to light therapy, known to advance circadian phase is associated with modest to large tic reductions suggesting the presence of circadian abnormalities (i.e., phase delay) in select individuals with PTDs, which may contribute to tic symptom onset, course, and treatment response, and be linked to underlying PTD pathophysiology. Circadian phase is commonly assessed through dim light melatonin onset, as it is the most reliable marker. The strongest phase shifting agent is light therapy, which is associated with circadian phase shifts in circadian rhythm sleep disorders, mood disorders, and other psychiatric and neurological disorders. Moreover, light therapy is associated with improvements in the core psychiatric and neurological symptoms. Light therapy historically has involved administration of bright white light via a light box. However, adherence may be reduced by adverse side effects from bright light, and burden due to limited mobility and time constraints. A viable alternative is wearable short wavelength blue light therapy – shown to be more effective at phase shifting circadian rhythms at lower intensities and shorter durations relative to white light. Therefore, the present project utilizes a translational approach to identify and test a new mechanism for target engagement in PTDs. This study will assess circadian phase and phenotype in 35 youth ages 13 to 17 relative to 35 sex- and pubertal stage- matched healthy control subjects, and assess the degree to which wearable short wavelength light therapy targets this putative circadian mechanism, and is associated with improvements in tic symptoms. Drawing on the expertise of project co-mentors: Christopher Colwell, Ph.D. and John Piacentini, Ph.D.; and consultants: Meredith Coles, Ph.D., Dana McMakin, Ph.D., Helen Burgess, Ph.D., and Catherine Sugar, Ph.D. the proposed project will provide comprehensive training in circadian physiology; circadian measurement and treatment; experimental therapeutic frameworks as they pertain to pediatric psychopathology, including tic disorders and sleep; and biostatistics. Findings will enhance our understanding of the role of circadian rhythms in Persistent Tic Disorders and may provide new targets for future treatment development.