Sleep-wake disturbances following traumatic brain injury (TBI) are increasingly recognized as a serious consequence following injury and as a barrier to recovery. Injury-induced sleep-wake disturbances can persist for years, often impairing quality of life. Recently, there has been a nearly exponential increase in the number of primary research articles published on the pathophysiology and mechanisms underlying sleep-wake disturbances after TBI, both in animal models and in humans, including in the pediatric population. In this review, we summarize over 200 articles on the topic, most of which were identified objectively using reproducible online search terms in PubMed. Although these studies differ in terms of methodology and detailed outcomes; overall, recent research describes a common phenotype of excessive daytime sleepiness, nighttime sleep fragmentation, insomnia, and electroencephalography spectral changes after TBI. Given the heterogeneity of the human disease phenotype, rigorous translation of animal models to the human condition is critical to our understanding of the mechanisms and of the temporal course of sleep-wake disturbances after injury. Arguably, this is most effectively accomplished when animal and human studies are performed by the same or collaborating research programs. Given the number of symptoms associated with TBI that are intimately related to, or directly stem from sleep dysfunction, sleep-wake disorders represent an important area in which mechanistic-based therapies may substantially impact recovery after TBI.

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Sleep-Wake Disturbances After Traumatic Brain Injury: Synthesis of Human and Animal Studies.

Sleep in the United States Military.

BACKGROUND Concussion is a heterogeneous mild traumatic brain injury (mTBI) characterized by a variety of symptoms, clinical presentations, and recovery trajectories. By thematically classifying the most common concussive clinical presentations into concussion subtypes (cognitive, ocular-motor, headache/migraine, vestibular, and anxiety/mood) and associated conditions (cervical strain and sleep disturbance), we derive useful definitions amenable to future targeted treatments. OBJECTIVE To use evidence-based methodology to characterize the 5 concussion subtypes and 2 associated conditions and report their prevalence in acute concussion patients as compared to baseline or controls within 3 d of injury. METHODS A multidisciplinary expert workgroup was established to define the most common concussion subtypes and their associated conditions and select clinical questions related to prevalence and recovery. A literature search was conducted from January 1, 1990 to November 1, 2017. Two experts abstracted study characteristics and results independently for each article selected for inclusion. A third expert adjudicated disagreements. Separate meta-analyses were conducted to do the following: 1) examine the prevalence of each subtype/associated condition in concussion patients using a proportion, 2) assess subtype/associated conditions in concussion compared to baseline/uninjured controls using a prevalence ratio, and 3) compare the differences in symptom scores between concussion subtypes and uninjured/baseline controls using a standardized mean difference (SMD). RESULTS The most prevalent concussion subtypes for pediatric and adult populations were headache/migraine (0.52; 95% CI = 0.37, 0.67) and cognitive (0.40; 95% CI = 0.25, 0.55), respectively. In pediatric patients, the prevalence of the vestibular subtype was also high (0.50; 95% CI = 0.40, 0.60). Adult patients were 4.4, 2.9, and 1.7 times more likely to demonstrate cognitive, vestibular, and anxiety/mood subtypes, respectively, as compared with their controls (P < .05). Children and adults with concussion showed significantly more cognitive symptoms than their respective controls (SMD = 0.66 and 0.24; P < .001). Furthermore, ocular-motor in adult patients (SMD = 0.72; P < .001) and vestibular symptoms in both pediatric and adult patients (SMD = 0.18 and 0.36; P < .05) were significantly worse in concussion patients than in controls. CONCLUSION Five concussion subtypes with varying prevalence within 3 d following injury are commonly seen clinically and identifiable upon systematic literature review. Sleep disturbance, a concussion-associated condition, is also common. There was insufficient information available for analysis of cervical strain. A comprehensive acute concussion assessment defines and characterizes the injury and, therefore, should incorporate evaluations of all 5 subtypes and associated conditions.

Concussion Guidelines Step 2: Evidence for Subtype Classification.

A rapidly expanding scientific literature supports the frequent co-occurrence of sleep and circadian disturbances following mild traumatic brain injury (mTBI). Although many questions remain unanswered, the preponderance of evidence suggests that sleep and circadian disorders can result from mTBI. Among those with mTBI, sleep disturbances and clinical sleep and circadian disorders contribute to the morbidity and long-term sequelae across domains of functional outcomes and quality of life. Specifically, along with deterioration of neurocognitive performance, insufficient and disturbed sleep can precede, exacerbate, or perpetuate many of the other common sequelae of mTBI, including depression, post-traumatic stress disorder, and chronic pain. Further, sleep and mTBI share neurophysiologic and neuroanatomic mechanisms that likely bear directly on success of rehabilitation following mTBI. For these reasons, focus on disturbed sleep as a modifiable treatment target has high likelihood of improving outcomes in mTBI. Here, we review relevant literature and present a research agenda to 1) advance understanding of the reciprocal relationships between sleep and circadian factors and mTBI sequelae and 2) advance rapidly the development of sleep-related treatments in this population.

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Sleep, Sleep Disorders, and Circadian Health following Mild Traumatic Brain Injury in Adults: Review and Research Agenda

Traumatic brain injury (TBI) is a major public health concern in the USA and worldwide. Sleep disruption and headaches are two of the most common problems reported by patients after TBI. In this manuscript, we review the current knowledge regarding the relation between post-traumatic sleep disruption and headaches. We also describe the role of the glymphatic system as a potential link between TBI, sleep, and headaches. Recent studies show a reciprocal relation between post-traumatic sleep disruption and headaches: patients with sleep disruption after TBI report more headaches, and post-traumatic headaches are a risk factor for developing disrupted sleep. Despite this clinical association, the exact mechanisms linking post-traumatic sleep disruption and headaches are not well understood. The glymphatic pathway, a newly described brain–wide network of perivascular spaces that supports the clearance of interstitial solutes and wastes from the brain, is active primarily during sleep, and becomes dysfunctional after TBI. We propose a model where changes in glymphatic function caused by TBI and post-traumatic sleep disruption may impair the clearance of neuropeptides involved in the pathogenesis of post-traumatic headaches, such as CGRP. The relation between TBI, post-traumatic sleep disruption, and post-traumatic headaches, although well documented in the literature, remains poorly understood. Dysfunction of the glymphatic system caused by TBI offers a novel and exiting explanation to this clinically observed phenomenon. The proposed model, although theoretical, could provide important mechanistic insights to the TBI-sleep-headache association.

Linking Traumatic Brain Injury, Sleep Disruption and Post-Traumatic Headache: a Potential Role for Glymphatic Pathway Dysfunction.

https://link.springer.com/content/pdf/10.1007%2Fs13311-016-0429-3.pdf

Reuven Ferziger

Papers

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group