Enhancing Precision Sleep Medicine in Traumatic Brain Injury: Examining the Feasibility of Home-Based Measurement of Circadian Timing
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 31
- 试验地点
- 1
- 主要终点
- Feasibility of Home Dim Light Melatonin Onset (Self-Collected Saliva)
研究概览
简要总结
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 after-effects such as depression, chronic pain, and fatigue. Current research suggests that TBI can impact numerous systems involved in sleep, suggesting that insomnia can have various causes and that a "one-size-fits-all" approach to treatment is likely inadequate. As such, it is necessary to determine which Veterans may benefit from standard evidence-based treatments, such as Cognitive Behavior Therapy for Insomnia, and which 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 disruptions of key circadian rhythms involved in sleep regulation (e.g., melatonin production), as well as the onset 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.
详细描述
Background and Significance:
Insomnia is a pervasive problem among Veterans with traumatic brain injury (TBI). Veterans with TBI frequently experience sleep disturbances following their injury. Insomnia, an impairing disorder characterized by difficulty initiating or maintaining sleep, is the most common sleep disturbance reported following TBI. Indeed, Veterans with TBI are 50% more likely to develop future insomnia compared to their non-injured peers.
The development of insomnia following TBI can delay recovery and contribute to functional impairments. Compared to TBI patients with normal sleep, those with insomnia have up to eightfold greater odds of functional impairment in the six months after injury. Post-TBI, United States (U.S.) Veterans who had poor sleep were more likely to report pain was interfering with their lives, have diminished health-related quality of life, and perform worse on neurobehavioral measures. A large-sample study found that insomnia was associated with decreased life satisfaction both immediately following TBI and one-year post-injury. Furthermore, insomnia is strongly associated with, and can exacerbate, other TBI sequelae such as depression, chronic pain, and fatigue, which can further delay rehabilitation and recovery from TBI.
Mechanisms underlying insomnia in TBI are heterogeneous, indicating that a "one-size-fits-all" approach to treatment is likely inadequate. While the precise mechanisms that underlie insomnia after TBI remain unknown, the extant research suggests that TBI can impact numerous systems that regulate sleep and wake states. Insomnia can result from damage to specific brain regions involved in sleep initiation (e.g., basal forebrain). Widespread brain damage, such as diffuse axonal injury, can disturb sleep through disruption of neuronal signaling, buildup of cellular waste byproducts, and toxic metabolic cascades. Perturbation of hormonal systems are also associated with insomnia following brain injury. Moreover, physical and psychological sequelae of TBI, such as pain, depression, or posttraumatic stress disorder (PTSD), can contribute to insomnia. Therefore, it is necessary to differentiate Veterans who may benefit from standard evidence-based treatments, such as Cognitive Behavioral Therapy for Insomnia (CBTI), and those who may require enhanced treatments targeting specific underlying mechanisms.
One distinct, but understudied, causal mechanism implicated in post-TBI insomnia is disruption to the circadian system. Circadian rhythms are changes in biochemical, physiological, or behavioral processes that repeat over the course of approximately 24 hours and are responsive to external cues such as light exposure. A mismatch between circadian and desired sleep timing (i.e., "circadian misalignment") can disturb sleep, manifesting as insomnia or circadian rhythm sleep-wake disorders (CRSDs) like delayed or advanced sleep phase disorders. Following TBI, circadian misalignment is common, as seen in perturbations of key circadian rhythms involved in sleep regulation (e.g., melatonin production), as well as the manifestation of CSRDs. This may be because TBI dysregulates the expression of circadian clock genes, which in turn is correlated with disruption of day/night activity rhythms. Another potential pathway linking TBI to circadian misalignment is the immune system, which communicates bidirectionally with the circadian system and is activated following TBI. Post-TBI inflammation may induce circadian desynchrony-a lack of temporal coordination across tissues, organs, and molecular processes-thus impairing homeostatic control and driving a pathological feedback loop of further inflammation, circadian misalignment, and resulting sequelae. Indeed, many impairments that arise from TBI, including sleep-wake disturbances, are also observed in cases of circadian desynchronization, further implicating circadian misalignment in TBI symptomatology.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 64 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •History of traumatic brain injury
- •Current insomnia
排除标准
- •Alcohol or substance abuse in the past 12 months
- •History of psychotic or bipolar disorders
- •Currently using of beta-blockers or melatonin-related substances (including over-the-counter or herbal products)
- •Currently participating in a sleep-targeted psychotherapy
- •Transmeridian travel (i.e., change in at least 2 time zones) in the past month
- •Shift work (i.e., at least 6 hours between 10 pm and 8 am) in the past 6 months
- •Currently pregnant or lactating
- •Current untreated sleep apnea
- •Lack of access to a home freezer
- •Blindness
- •Inability to independently provide informed consent
研究组 & 干预措施
Veterans
Veterans will be the primary cohort for this study. Veterans who will be enrolled with have current insomnia and a history of traumatic brain injury.
Caregivers
Caregivers of enrolled veterans will be an optional cohort for this study. If applicable and willing to participate, caregivers of enrolled Veterans will be asked to provide collateral information regarding the Veteran's experience with the study.
结局指标
主要结局
Feasibility of Home Dim Light Melatonin Onset (Self-Collected Saliva)
时间窗: One week
This outcome will be considered feasible if 70% participants provide adequate data for measurement of dim light melatonin onset (DLMO). For the self-collected salivary DLMO method, adequate data will entail: 1) collection and return of at least 5 saliva samples; 2) \<5 minutes discrepancy between the reported and pre-specified collection times for the two saliva samples ultimately used to establish DLMO; and 3) 50 lux of light exposure within 30 minutes of the two saliva samples ultimately used to establish DLMO.
Feasibility of Home Dim Light Melatonin Onset (Actigraphy)
时间窗: One week
This outcome will be considered feasible if 70% participants provide adequate data for measurement of dim light melatonin onset (DLMO). For the actigraphy DLMO method, adequate data will entail wearing the actigraphy device for at least 2 continuous days, with no interval of missing data (e.g., from covering the light sensor) during that time greater than 2 consecutive hours.
Number of Participants With Adequate Data for Estimation of Dim Light Melatonin Onset (Self-Collected Saliva)
时间窗: One week
This outcome will be considered feasible if 70% participants provide adequate data for measurement of dim light melatonin onset (DLMO). DLMO will be estimated via the observed salivary melatonin levels using a variable threshold method, defined as the time of day when melatonin rises above the mean of the individual's first three saliva samples plus two standard deviations of those first three samples. Additionally, adequate data will entail: 1) collection and return of at least 5 saliva samples; 2) \<5 minutes discrepancy between the reported and pre-specified collection times for the two saliva samples ultimately used to estimate DLMO; and 3) 50 lux of light exposure within 30 minutes of the two saliva samples ultimately used to establish DLMO. Each individual who meets these criteria will be considered a successful estimation of salivary-based DLMO.
Number of Participants With Adequate Data for Estimation of Dim Light Melatonin Onset (Actigraphy)
时间窗: One week
Dim light melatonin onset (DLMO) will be estimated using observed light exposure and sleep data via the extended Kronauer limit-cycle model of the human circadian pacemaker. This outcome will be considered feasible if 70% participants provide adequate actigraphy data. Adequate data will entail wearing the actigraphy device for at least 2 continuous days, with no interval of missing data (e.g., from covering the light sensor) during that time greater than 2 consecutive hours. Each Veteran who meets these criteria will be considered a successful estimation of actigraphy-based DLMO.
次要结局
- Functional Impairment (WHODAS 2.0 Summary Score)(Baseline)
- Sleep Disturbance (PROMIS Sleep Disturbance Total Score)(Baseline)
- Functional Impairment (WHODAS 2.0 Summary Score)(From baseline up to 1 week)
- Sleep Disturbance (PROMIS Sleep Disturbance Total Score)(From baseline up to 1 week)