Sleep-Wake Disturbances After Traumatic Brain Injury: Synthesis of Human and Animal Studies.
Sleep
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.
10.1093/sleep/zsx044
The sleep-wake cycle and Alzheimer's disease: what do we know?
Lim Miranda M,Gerstner Jason R,Holtzman David M
Neurodegenerative disease management
Sleep-wake disturbances are a highly prevalent and often disabling feature of Alzheimer's disease (AD). A cardinal feature of AD includes the formation of amyloid plaques, associated with the extracellular accumulation of the amyloid-β (Aβ) peptide. Evidence from animal and human studies suggests that Aβ pathology may disrupt the sleep-wake cycle, in that as Aβ accumulates, more sleep-wake fragmentation develops. Furthermore, recent research in animal and human studies suggests that the sleep-wake cycle itself may influence Alzheimer's disease onset and progression. Chronic sleep deprivation increases amyloid plaque deposition, and sleep extension results in fewer plaques in experimental models. In this review geared towards the practicing clinician, we discuss possible mechanisms underlying the reciprocal relationship between the sleep-wake cycle and AD pathology and behavior, and present current approaches to therapy for sleep disorders in AD.
10.2217/nmt.14.33
Animal models of human insomnia.
Journal of sleep research
Insomnia disorder (chronic sleep continuity disturbance) is a debilitating condition affecting 5%-10% of the adult population worldwide. To date, researchers have attempted to model insomnia in animals through breeding strategies that create pathologically short-sleeping individuals or with drugs and environmental contexts that directly impose sleeplessness. While these approaches have been invaluable for identifying insomnia susceptibility genes and mapping the neural networks that underpin sleep-wake regulation, they fail to capture concurrently several of the core clinical diagnostic features of insomnia disorder in humans, where sleep continuity disturbance is self-perpetuating, occurs despite adequate sleep opportunity, and is often not accompanied by significant changes in sleep duration or architecture. In the present review, we discuss these issues and then outline ways animal models can be used to develop approaches that are more ecologically valid in their recapitulation of chronic insomnia's natural aetiology and pathophysiology. Conditioning of self-generated sleep loss with these methods promises to create a better understanding of the neuroadaptations that maintain insomnia, including potentially within the infralimbic cortex, a substrate at the crossroads of threat habituation and sleep.
10.1111/jsr.13845
Alzheimer's disease: Neurotransmitters of the sleep-wake cycle.
Van Erum Jan,Van Dam Debby,De Deyn Peter Paul
Neuroscience and biobehavioral reviews
With aging, our sleeping pattern alters. Elderly often wake unrested because their sleep time and sleep efficacy is reduced. In Alzheimer's disease (AD) patients, these alterations are even more pronounced and may further aggravate cognitive decline. Therefore, sleep disturbances greatly impact self-care ability, caregiver exhaustion and institutionalization rate. Reestablishing an effective sleep-wake cycle in these patients still remains an unresolved challenge, partly because sleep physiology is quite complex and multiple neurotransmitter systems contribute to a single process. Gaining a better understanding of sleep physiology will be crucial for further research. Conjointly, animal models, along with a multidisciplinary approach, will be of great value to establish a common ground between AD and sleep disturbances and work towards a potential therapeutic application.
10.1016/j.neubiorev.2019.07.019
Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models.
Vanderheyden William M,Lim Miranda M,Musiek Erik S,Gerstner Jason R
The Journal of neuroscience : the official journal of the Society for Neuroscience
Sleep-wake abnormalities are common in patients with Alzheimer's disease, and can be a major reason for institutionalization. However, an emerging concept is that these sleep-wake disturbances are part of the causal pathway accelerating the neurodegenerative process. Recently, new findings have provided intriguing evidence for a positive feedback loop between sleep-wake dysfunction and β-amyloid (Aβ) aggregation. Studies in both humans and animal models have shown that extended periods of wakefulness increase Aβ levels and aggregation, and accumulation of Aβ causes fragmentation of sleep. This perspective is aimed at presenting evidence supporting causal links between sleep-wake dysfunction and aggregation of Aβ peptide in Alzheimer's disease, and explores the role of astrocytes, a specialized type of glial cell, in this context underlying Alzheimer's disease pathology. The utility of current animal models and the unexplored potential of alternative animal models for testing mechanisms involved in the reciprocal relationship between sleep disruption and Aβ are also discussed..
10.1523/JNEUROSCI.1135-17.2017