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

患有创伤性脑损伤的退伍军人经常失眠，这与迟发性脑损伤有关 康复，更严重的功能障碍，以及抑郁等致残脑损伤后遗症的加重， 慢性疼痛和疲劳。目前的研究表明，脑外伤可以影响许多涉及睡眠的系统 监管，表明失眠可能是由各种原因引起的，而且“一刀切”。 治疗方法可能不够充分。因此，有必要区分可能受益的退伍军人 来自标准的循证治疗，如失眠的认知行为疗法，来自那些 可能需要针对特定潜在机制的强化治疗。 一项新的证据表明，昼夜节律紊乱与脑外伤后的脑损伤之间存在联系。 失眠。昼夜节律与所需睡眠时序之间的不匹配(即“昼夜节律错位”)是常见的 在TBI之后，如涉及睡眠调节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针对昼夜节律的专门治疗(即， “计时疗法”)，如定时睡眠窗或加强光照，作为标准疗法 方法可能无法解决甚至加剧潜在的昼夜节律失调。因此， 昼夜节律失调代表了一种新的和可修改的治疗靶点，并有可能 改善患有脑外伤和失眠的退伍军人的功能结果。 昼夜节律失调的检测和时间疗法的最佳使用需要测量的能力 昼夜节律阶段(即，中央昼夜节律时钟的时序)。然而，目前在TBI中的睡眠药物是 由于缺乏衡量昼夜节律的实用选择，这一点受到阻碍。这是因为实验室昏暗 光褪黑素发作(DLMO)是衡量昼夜节律的黄金标准，时间和成本都令人望而却步， 需要专门的样本(如唾液)收集设施，并给患者带来沉重的负担。 最近，已经开发了新的DLMO测量方法，这些方法可以提高DLMO的可及性和 昼夜节律评估的实用性，尽管，到目前为止，它们还没有被用于退伍军人合并脑外伤。 拟议的单臂纵向研究旨在评估两种方法的可行性。 颅脑损伤伴失眠退伍军人家庭环境DLMO测定：1)直接测量 自身收集的唾液褪黑素；以及2)使用活动和光间接估计DLMO- 通过动作记录法收集的暴露数据。此外，这项研究还试图探索这些关系 脑外伤退伍军人的昼夜节律失调、睡眠障碍和功能障碍之间的关系。 本研究的具体目的是：1)评价两种家庭DLMO方法的可行性 对患有脑外伤和失眠的退伍军人进行测量(即自我收集的唾液褪黑素和活动描记数据)； 和目的2)检查昼夜节律错位之间的关联(即 DLMO和试图入睡)、睡眠障碍和功能障碍。患有脑损伤的退伍军人和 失眠症患者将被要求佩戴基于手腕的活动记录设备一周，该设备将收集光线数据 暴露和睡眠唤醒状态。然后，他们将被要求在昏暗的情况下每小时自我采集七个唾液样本 在他们自己家里的照明条件下，并使用提供的预付费运输标签将它们邮寄到测试机构。 唾液样本将用于直接测量DLMO，活动数据将用于间接估计 DLMO使用已建立的人体昼夜节律起搏器的数学模型。评估可行性 家庭DLMO测量是提高退伍军人精准睡眠医学的关键第一步 有脑外伤和失眠。研究结果将为量身定制的睡眠干预措施的开发和测试提供信息 供这些患者使用。

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.