Enhancing Precision Sleep Medicine in traumatic Brain Injury: Examining the feasibility of Home-Based Measurement of Circadian Timing

患有创伤性脑损伤（TBI）的退伍军人经常失眠，这与延迟TBI有关 恢复、更严重的功能障碍和致残性TBI后遗症（如抑郁症）的加重， 慢性疼痛和疲劳目前的研究表明，创伤性脑损伤可以影响许多涉及睡眠的系统 调节，这表明失眠可能表现为各种病因，并认为“一刀切” 治疗方法可能不够。因此，有必要区分可能受益的退伍军人 从标准的循证治疗，如认知行为疗法，从那些谁 可能需要针对特定潜在机制的增强治疗。 一个新兴的证据已经建立了昼夜节律破坏和创伤后脑损伤之间的联系 失眠昼夜节律和期望的睡眠定时之间的不匹配（即，“昼夜节律失调”）是常见的 在TBI之后，如睡眠调节中涉及的关键昼夜节律的扰动所证明的（例如， 褪黑激素的产生），以及昼夜节律睡眠-觉醒障碍的表现。重要的是， 昼夜节律驱动的睡眠障碍需要以昼夜节律为目标的专门治疗（即， “时间疗法”），如定时睡眠窗口或增强光照，作为标准治疗 这些方法可能无法解决或甚至加剧潜在的昼夜节律失调。因此，在本发明中， 昼夜节律失调代表了一种新的和可修改的治疗目标， 改善TBI和失眠退伍军人的功能结果。 昼夜节律失调的检测和最佳使用时间疗法需要能够测量 昼夜节律相位（即，中央生物钟（Central Circadian Clock）然而，目前TBI的睡眠药物是 由于缺乏测量昼夜节律相位的实用选择而受到阻碍。这是因为实验室昏暗 光褪黑激素起效（DLMO），昼夜节律相位的金标准测量，是时间和成本过高的， 需要专门的样品（例如，唾液）收集设施，并给患者带来相当大的负担。 最近，已经开发了DLMO测量的新方法，其可以增强DLMO测量的可访问性和可扩展性。 昼夜节律相位评估的实用性，尽管到目前为止，它们还没有用于TBI退伍军人。 拟议的单臂纵向研究旨在评估两种方法的可行性， 在患有TBI和失眠症的退伍军人的家庭环境中测量DLMO：1）直接测量 和2）使用活动和光间接估计DLMO。 通过活动记录仪收集的暴露数据。此外，本研究旨在探讨 昼夜节律失调、睡眠障碍和功能障碍之间的关系。 本研究的具体目的是：目的1）评估两种家庭DLMO方法的可行性 测量（即，自我收集的唾液褪黑激素和活动记录数据）; 和目标2）检查昼夜节律失调（即，时间上的差异 DLMO和尝试睡眠发作）、睡眠障碍和功能障碍。退伍军人与TBI和 失眠症患者将被要求佩戴一个基于腕部的活动记录仪一周，该设备将收集光的数据 暴露和睡眠-觉醒状态。然后，他们将被要求在昏暗的环境中每小时采集7次唾液样本。 光条件下在自己的家里，并邮寄到测试设施使用提供的预付费运输标签。 唾液样本将用于直接测量DLMO，体动记录数据将用于间接估计 DLMO使用已建立的人类昼夜节律起搏器的数学模型。评估可行性 家庭DLMO测量是增强退伍军人精确睡眠医学的关键第一步 创伤性脑损伤和失眠研究结果将为定制睡眠干预的开发和测试提供信息 用于该患者人群。

Veterans with traumatic brain injury (TBI) frequently experience insomnia, which is linked with delayed TBI recovery, more severe functional impairment, and exacerbation of disabling TBI sequelae such as depression, chronic pain, and fatigue. Current research suggests that TBI can impact numerous systems involved in sleep regulation, suggesting that insomnia may manifest from various etiologies and that a “one-size-fits-all” approach to treatment is likely inadequate. As such, it is necessary to differentiate Veterans who may benefit from standard evidence-based treatments, such as Cognitive Behavior Therapy for Insomnia, from those who may require enhanced treatments targeting specific underlying mechanisms. An emerging body of evidence has established a link between circadian rhythm disruption and post-TBI insomnia. A mismatch between circadian and desired sleep timing (i.e., “circadian misalignment”) is common following TBI, as evidenced by perturbations of key circadian rhythms involved in sleep regulation (e.g., melatonin production), as well as the manifestation of circadian rhythm sleep-wake disorders. Importantly, circadian-driven sleep disturbances require specialized treatments that target circadian rhythms (i.e., “chronotherapies”), such as timed sleep windows or enhanced light exposure, as standard treatment approaches can fail to address or even exacerbate the underlying circadian misalignment. Thus, circadian misalignment represents a novel and modifiable treatment target and has the potential to improve functional outcomes in Veterans with TBI and insomnia. Detection of circadian misalignment and optimal use of chronotherapies require the ability to measure circadian phase (i.e., timing of the central circadian clock). However, current sleep medicine in TBI is hampered by a lack of pragmatic options for measuring circadian phase. This is because laboratory dim light melatonin onset (DLMO), the gold standard measure of circadian phase, is time and cost prohibitive, requiring specialized sample (e.g., saliva) collection facilities and placing substantial burden on the patient. Recently, novel methods of DLMO measurement have been developed that may enhance the accessibility and practicality of circadian phase assessment, although, as of yet, they have not been used in Veterans with TBI. The proposed single-arm, longitudinal study seeks to evaluate the feasibility of two methods of measuring DLMO in the home environment of Veterans with TBI and insomnia: 1) direct measurement of self-collected salivary melatonin; and 2) indirect estimation of DLMO using activity and light- exposure data collected through actigraphy. Additionally, this study seeks to explore the relationships between circadian misalignment, sleep disturbance, and functional impairment in Veterans with TBI. The specific aims of this study are to: Aim 1) evaluate the feasibility of two methods of home DLMO measurement (i.e., self-collected salivary melatonin and actigraphy data) in Veterans with TBI and insomnia; and Aim 2) examine associations between circadian misalignment (i.e., the difference in timing between DLMO and attempted sleep onset), sleep disturbance, and functional impairment. Veterans with TBI and insomnia will be asked to wear a wrist-based actigraphy device for one week, which will collect data on light exposure and sleep-wake states. They will then be asked to self-collect seven hourly saliva samples under dim light conditions in their own home and mail them to a testing facility using a provided pre-paid shipping label. Saliva samples will be used to directly measure DLMO and actigraphy data will be used to indirectly estimate DLMO using established mathematical models of the human circadian pacemaker. Evaluating the feasibility of home DLMO measurement is a crucial first step for enhancing precision sleep medicine for Veterans with TBI and insomnia. Findings will inform the development and testing of tailored sleep interventions for use with this patient population.