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Sleep disruption is a frequent problem of advancing age, often accompanied by low-grade chronic central and peripheral inflammation. We examined whether chronic neuroinflammation in the preoptic and basal forebrain area (POA-BF), a critical sleep-wake regulatory structure, contributes to this disruption. We developed a targeted viral vector designed to overexpress tumor necrosis factor-alpha (TNFα), specifically in astrocytes (AAV5-GFAP-TNFα-mCherry), and injected it into the POA of young mice to induce heightened neuroinflammation within the POA-BF. Compared to the control (treated with AAV5-GFAP-mCherry), mice with astrocytic TNFα overproduction within the POA-BF exhibited signs of increased microglia activation, indicating a heightened local inflammatory milieu. These mice also exhibited aging-like changes in sleep-wake organization and physical performance, including (a) impaired sleep-wake functions characterized by disruptions in sleep and waking during light and dark phases, respectively, and a reduced ability to compensate for sleep loss; (b) dysfunctional VLPO sleep-active neurons, indicated by fewer neurons expressing c-fos after suvorexant-induced sleep; and (c) compromised physical performance as demonstrated by a decline in grip strength. These findings suggest that inflammation-induced dysfunction of sleep- and wake-regulatory mechanisms within the POA-BF may be a critical component of sleep-wake disturbances in aging., Competing Interests: The authors declare no conflicts of interest.

Objective: The glymphatic system is thought to be responsible for waste clearance in the brain. As it is primarily active during sleep, different components of sleep, subjective sleep quality, and sleep patterns may contribute to glymphatic functioning. This systematic review aimed at exploring the effect of sleep components, sleep quality, and sleep patterns on outcomes associated with the glymphatic system in healthy adults., Methods: PubMed®, Scopus, and Web of Science were searched for studies published in English until December 2021. Articles subjectively or objectively investigating sleep components (total sleep time, time in bed, sleep efficiency, sleep onset latency, wake-up after sleep onset, sleep stage, awakenings), sleep quality, or sleep pattern in healthy individuals, on outcomes associated with glymphatic system (levels of amyloid-β, tau, α-synuclein; cerebrospinal fluid, perivascular spaces; apolipoprotein E) were selected., Results: Out of 8359 records screened, 51 studies were included. Overall, contradictory findings were observed according to different sleep assessment method. The most frequently assessed sleep parameters were total sleep time, sleep quality, and sleep efficiency. No association was found between sleep efficiency and amyloid-β, and between slow-wave activity and tau. Most of the studies did not find any correlation between total sleep time and amyloid-β nor tau level. Opposing results correlated sleep quality with amyloid-β and tau., Conclusions: This review highlighted inconsistent results across the studies; as such, the specific association between the glymphatic system and sleep parameters in healthy adults remains poorly understood. Due to the heterogeneity of sleep assessment methods and the self-reported data representing the majority of the observations, future studies with universal study design and sleep methodology in healthy individuals are advocated., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sotos syndrome (SS) is a genetic disorder characterized by accelerated growth in childhood, developmental deficits, and characteristic craniofacial features. While clinicians and parents have reported unusual sleep habits, only one study by Rutter and Cole in 1991 mentioned sleep complaints (Rutter and Cole, Developmental Medicine and Child Neurology, 1991, 33, 898-902). This study aimed to characterize the sleep habits of individuals with SS. We performed a cross-sectional study of individuals with a definite, probable, or possible diagnosis of Sotos syndrome. Participants were asked to complete the Children's Sleep Habits Questionnaire (CHSQ). We compared our data to historical data available from the literature. Subjects with SS showed more sleep disturbance than typically developing individuals (TD), although their sleep onset was less likely to be delayed and their sleep duration was longer. Participants with SS also showed different sleep patterns compared to children with other forms of intellectual and developmental disabilities (IDD). Individuals with SS exhibited early bed and rise times, frequently used transitional objects, displayed repetitive motion at sleep onset, and did not show a decrease in sleep duration with age. The majority of participants fell asleep at the same time each night, in their own bed, and within 20 min, and rarely showed signs of sleepwalking or night terrors. These results improve our understanding of sleep habits of individuals with SS and may be used to guide treatment and provide normalization for children with SS., (© 2021 Wiley Periodicals LLC.)

The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep-phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian-relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2-related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration., (© 2021 Wiley Periodicals LLC.)

The intertwining between epilepsy, sleep disorders and beta amyloid pathology has been progressively highlighted, as early identification and stratification of patients at high risk of cognitive decline is the need of the hour. Modification of the sleep-wake activity, such as sleep impairment or excessive daytime sleepiness, can critically affect cerebral beta amyloid levels. Both mice models and human studies have demonstrated a substantial increase in the burden of beta amyloid pathology after sleep-deprivation, with potential negative effects partially restored by sleep recovery. The accumulation of beta amyloid has been shown to be an early event in the course of Alzheimer's disease dementia. Beta amyloid accumulation has been linked to epileptic seizures epileptic seizures, with beta amyloid being itself pro-epileptogenic in mice models already at oligomeric stage, well before plaque deposition. Further supporting a potential relationship between beta amyloid and epilepsy: i) seizures happen in 1 out of oofut 10 patients with Alzheimer's disease in the prodromal stage, ii) epileptic activity accelerates cognitive decline in Alzheimer's disease, iii) people with late-onset epilepsy present a critically high risk of developing dementia. In this Review we highlight the role of beta amyloid as a potential shared mechanisms between sleep disorders, late-onset epilepsy, and cognitive decline., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Despite a growing body of evidence suggesting that short sleep duration may be linked to adverse metabolic outcomes, how these associations differ between age groups remains unclear. We use eight years of data from the UK National Diet and Nutritional Survey (NDNS) (2008-2016) to analyse cross-sectional relationships between sleep duration and metabolic risk in participants aged 11-70 years., Methods: Participants (n = 2008) who provided both metabolic risk and sleep duration data were included. Self-reported sleep duration was standardised by age, to account for differences in age-related sleep requirements. A standardised metabolic risk score was constructed, comprising: waist circumference, blood pressure, serum triglycerides, serum high-density lipoprotein cholesterol, and fasting plasma glucose. Regression models were constructed across four age groups from adolescents to older adults., Results: Overall, decreased sleep duration (hrs) was associated with an increased metabolic risk (standard deviations) with significant quadratic (B:0.028 [95%CI: 0.007, 0.050]) and linear (B:-0.061 [95%CI: -0.111, -0.011]) sleep duration coefficients. When separated by age group, stronger associations were seen among mid-aged adults (36-50y) (quadratic coefficient: 0.038 [95%CI: 0.002, 0.074]) compared to other age groups (e.g. adolescents (11-18y), quadratic coefficient: -0.009 [95%CI: -0.042, 0.025]). An increased difference between weekend and weekday sleep was only associated with increased metabolic risk in adults aged 51-70 years (B:0.18 [95%CI: 0.005, 0.348])., Conclusions: Our results indicate that sleep duration is linked to adverse metabolic risk and suggest heterogeneity between age groups. Longitudinal studies with larger sample sizes are required to explore long-term effects of abnormal sleep and potential remedial benefits., Competing Interests: The authors have declared that no competing interests exist.

Wearable devices have been increasingly used in research to provide continuous physical activity monitoring, but how to effectively extract features remains challenging for researchers. To analyze the generated actigraphy data in large-scale population studies, we developed computationally efficient methods to derive sleep and activity features through a Hidden Markov Model-based sleep/wake identification algorithm, and circadian rhythm features through a Penalized Multi-band Learning approach adapted from machine learning. Unsupervised feature extraction is useful when labeled data are unavailable, especially in large-scale population studies. We applied these two methods to the UK Biobank wearable device data and used the derived sleep and circadian features as phenotypes in genome-wide association studies. We identified 53 genetic loci with p<5×10-8 including genes known to be associated with sleep disorders and circadian rhythms as well as novel loci associated with Body Mass Index, mental diseases and neurological disorders, which suggest shared genetic factors of sleep and circadian rhythms with physical and mental health. Further cross-tissue enrichment analysis highlights the important role of the central nervous system and the shared genetic architecture with metabolism-related traits and the metabolic system. Our study demonstrates the effectiveness of our unsupervised methods for wearable device data when additional training data cannot be easily acquired, and our study further expands the application of wearable devices in population studies and genetic studies to provide novel biological insights., Competing Interests: The authors have declared that no competing interests exist.

The objectives of this study were to characterize the sleep habits of 50 clinically referred individuals with Angelman syndrome (AS) and to retrospectively compare the effectiveness/tolerability of the three most commonly prescribed sleep medications in the sample. An experienced physician assigned a Clinical Global Impressions-Severity scale (CGI-S) score for each subject's AS-specific symptoms. Caregivers completed the Child Sleep Habits Questionnaire (CSHQ; screen for sleep problems in school-aged [4-10 years] children), a screening assessment for sleep problems. Caregivers provided information about medication trials targeting disturbed sleep, with the physician assigning a CGI-Improvement scale (CGI-I) score for each trial. Linear regression showed significant negative association between age and CSHQ score. In their lifetime, 72% of participants had taken a medication for sleep, most commonly melatonin, clonidine and trazodone. The majority continued these for 6 months or longer. With these medications, many demonstrated significant improvement in sleep disturbances, with no difference in odds of improvement between medications. Disturbed sleep was common in this cohort and significantly worse in younger-aged participants. The majority received at least one medication trial for disturbed sleep and each of the most commonly prescribed medication was effective for a substantial percentage of participants. Most participants remained on medication for at least 6 months, suggesting favorable tolerability., (© 2020 Wiley Periodicals, Inc.)

Sleep is a naturally occurring physiological state that is required to sustain physical and mental health. Traditionally viewed as strictly regulated by top-down control mechanisms, sleep is now known to also originate locally. Glial cells are emerging as important contributors to the regulation of sleep-wake cycles, locally and among dedicated neural circuits. A few pioneering studies revealed that astrocytes and microglia may influence sleep pressure, duration as well as intensity, but the precise involvement of these two glial cells in the regulation of sleep remains to be fully addressed, across contexts of health and disease. In this overview article, we will first summarize the literature pertaining to the role of astrocytes and microglia in the regulation of sleep under normal physiological conditions. Afterward, we will discuss the beneficial and deleterious consequences of glia-mediated neuroinflammation, whether it is acute, or chronic and associated with brain diseases, on the regulation of sleep. Sleep disturbances are a main comorbidity in neurodegenerative diseases, and in several brain diseases that include pain, epilepsy, and cancer. Identifying the relationships between glia-mediated neuroinflammation, sleep-wake rhythm disruption and brain diseases may have important implications for the treatment of several disorders. © 2020 American Physiological Society. Compr Physiol 10:687-712, 2020., (Copyright © 2020 American Physiological Society. All rights reserved.)

As we age, we experience changes in our nighttime sleep and daytime wakefulness. Individuals afflicted with Alzheimer's disease (AD) can develop sleep problems even before memory and other cognitive deficits are reported. As the disease progresses and cognitive changes ensue, sleep disturbances become even more debilitating. Thus, it is imperative to gain a better understanding of the relationship between sleep and AD pathogenesis. We postulate a bidirectional relationship between sleep and the neuropathological hallmarks of AD; in particular, the accumulation of amyloid-β (Aβ) and tau. Our research group has shown that extracellular levels of both Aβ and tau fluctuate during the normal sleep-wake cycle. Disturbed sleep and increased wakefulness acutely lead to increased Aβ production and decreased Aβ clearance, whereas Aβ aggregation and deposition is enhanced by chronic increased wakefulness in animal models. Once Aβ accumulates, there is evidence in both mice and humans that this results in disturbed sleep. New findings from our group reveal that acute sleep deprivation increases levels of tau in mouse brain interstitial fluid (ISF) and human cerebrospinal fluid (CSF) and chronic sleep deprivation accelerates the spread of tau protein aggregates in neural networks. Finally, recent evidence also suggests that accumulation of tau aggregates in the brain correlates with decreased nonrapid eye movement (NREM) sleep slow wave activity. In this review, we first provide a brief overview of the AD and sleep literature and then highlight recent advances in the understanding of the relationship between sleep and AD pathogenesis. Importantly, the effects of the bidirectional relationship between the sleep-wake cycle and tau have not been previously discussed in other reviews on this topic. Lastly, we provide possible directions for future studies on the role of sleep in AD.

Alzheimer's disease (AD), which accounts for most of the dementia cases, is, aside from cognitive deterioration, often characterized by the presence of non-cognitive symptoms such as activity and sleep disturbances. AD patients typically experience increased sleep fragmentation, excessive daytime sleepiness and night-time insomnia. Here, we sought to investigate the link between sleep architecture, cognition and amyloid pathology in the APP23 amyloidosis mouse model for AD. By means of polysomnographic recordings the sleep-wake cycle of freely-moving APP23 and wild-type (WT) littermates of 3, 6 and 12 months of age was examined. In addition, ambulatory cage activity was assessed by interruption of infrared beams surrounding the home cage. To assess visuo-spatial learning and memory a hidden-platform Morris-type Water Maze (MWM) experiment was performed. We found that sleep architecture is only slightly altered at early stages of pathology, but significantly deteriorates from 12 months of age, when amyloid plaques become diffusely present. APP23 mice of 12 months old had quantitative reductions of NREM and REM sleep and were more awake during the dark phase compared to WT littermates. These findings were confirmed by increased ambulatory cage activity during that phase of the light-dark cycle. No quantitative differences in sleep parameters were observed during the light phase. However, during this light phase, the sleep pattern of APP23 mice was more fragmented from 6 months of age, the point at which also cognitive abilities started to be affected in the MWM. Sleep time also positively correlated with MWM performance. We also found that spectral components in the EEG started to alter at the age of 6 months. To conclude, our results indicate that sleep architectural changes arise around the time the first amyloid plaques start to form and cognitive deterioration becomes apparent. These changes start subtle, but gradually worsen with age, adequately mimicking the clinical condition., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Sleep disturbance is a common complaint in cancer patients. However, less is known about the parameters of sleep in patients with nasopharyngeal cancer (NPC) and their family caregivers (FCs) when they are about to begin treatment. We investigated the sleep quality in patients with NPC and their FCs before treatment and determined the related factors that predict sleep disturbance in these patients before therapy. A total of 101 patient-FC dyads were recruited. They completed the Pittsburgh Sleep Quality Index (PSQI) prior to treatment. No differences were found in sleep disturbance between patients (38.6%) and their FCs (31.7%). Patients reported significantly higher rates of short sleep duration than their FCs (P = 0.011). Logistic regression analyses showed that older patients were more prone to suffer from poor sleep quality before treatment (OR = 1.06, 95% CI = 1.01-1.10, P = 0.008), while patients with a higher BMI were less likely to experience sleep disturbance (OR = 0.83, 95% CI = 0.71-0.96, P = 0.012). Sleep disturbance is a significant problem in patients with NPC and their FCs before therapy. Older patients and those with a lower BMI appear to be more inclined to suffer from poor sleep before treatment.

Study Objectives: Lyme disease (LD) is the most common vector-borne disease in the United States. Approximately 5-15 per cent of patients develop postantibiotic treatment symptoms termed post-treatment Lyme disease syndrome (PTLDS). The primary objective of this study is to examine and quantify sleep quality among patients with early LD during the acute and convalescent periods, including among the subset who met criteria for PTLDS., Methods: This paper draws from a clinical cohort study of participants with early LD (n = 122) and a subcohort of individuals who later met criteria for PTLDS (n = 6). Participants were followed for 1 year after antibiotic treatment. The Pittsburgh Sleep Quality Index and standardized measures of pain, fatigue, depressive symptoms, and functional impact were administered at all visits for participants and controls (n = 26). Participants meeting criteria for PTLDS at 1 year post-treatment were compared with a subset of PSQI-defined poor sleeping controls (n = 10)., Results: At the pretreatment visit, participants with early LD reported poorer sleep than controls. By 6 months post-treatment, participant sleep scores as a group returned to control levels. Participants with PTLDS reported significantly worse global sleep and sleep disturbance scores and worse fatigue, functional impact, and more cognitive-affective depressive symptoms compared with poor sleeping controls., Conclusions: Participants with early LD experienced poor sleep quality, which is associated with typical LD symptoms of pain and fatigue. In the subset of patients who developed PTLDS, sleep quality remains affected for up to 1 year post-treatment and is commonly associated with pain. Sleep quality should be considered in the clinical picture for LD and PTLDS.

Dentatorubropallidoluysian atrophy (DRPLA) is a neurodegenerative disease caused by an expansion of a cytosine-adenine-guanine (CAG) repeat encoding a polyglutamine tract in the atrophin-1 protein. Unlike other CAG repeat diseases, sleep related problems have not been reported in patients with DRPLA. There was a 65-year-old man and his family with DRPLA. They suffered from seizure, gait disturbance, and cognitive decline. The patients commonly showed dream enacting sleep disorder, insomnia. The results from overnight polysomnography showed rapid eye movement (REM) without atonia in patients with DRPLA. The man died 2 years after diagnosis and was subjected for brain autopsy. We report REM sleep behavior disorders in patients with DRPLA confirmed with polysomnography with pathological description of the patient., Competing Interests: Disclosure: The authors have no potential conflicts of interest to disclose.

Both sleep disturbances and decline in white matter microstructure are commonly observed in ageing populations, as well as in age-related psychiatric and neurological illnesses. A relationship between sleep and white matter microstructure may underlie such relationships, but few imaging studies have directly examined this hypothesis. In a study of 448 community-dwelling members of the Whitehall II Imaging Sub-Study aged between 60 and 82 years (90 female, mean age 69.2 ± 5.1 years), we used the magnetic resonance imaging technique diffusion tensor imaging to examine the relationship between self-reported sleep quality and white matter microstructure. Poor sleep quality at the time of the diffusion tensor imaging scan was associated with reduced global fractional anisotropy and increased global axial diffusivity and radial diffusivity values, with small effect sizes. Voxel-wise analysis showed that widespread frontal-subcortical tracts, encompassing regions previously reported as altered in insomnia, were affected. Radial diffusivity findings remained significant after additional correction for demographics, general cognition, health, and lifestyle measures. No significant differences in general cognitive function, executive function, memory, or processing speed were detected between good and poor sleep quality groups. The number of times participants reported poor sleep quality over five time-points spanning a 16-year period was not associated with white matter measures. In conclusion, these data demonstrate that current sleep quality is linked to white matter microstructure. Small effect sizes may limit the extent to which poor sleep is a promising modifiable factor that may maintain, or even improve, white matter microstructure in ageing. Hum Brain Mapp 38:5465-5473, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

Objectives: To examine age-related differences in self-reported sleep quality and their associations with health outcomes across four domains: physical health, cognitive health, mental health and neural health., Setting: Cambridge Centre for Ageing and Neuroscience (Cam-CAN) is a cohort study in East Anglia/England, which collected self-reported health and lifestyle questions as well as a range of objective measures from healthy adults., Participants: 2406 healthy adults (age 18-98) answered questions about their sleep quality (Pittsburgh Sleep Quality Index (PSQI)) and measures of physical, cognitive, mental and neural health. A subset of 641 individuals provided measures of brain structure., Main Outcome Measures: PSQI scores of sleep and scores across tests within the four domains of health. Latent class analysis (LCA) is used to identify sleep types across the lifespan. Bayesian regressions quantify the presence, and absence, of relationships between sleep quality and health measures., Results: Better self-reported sleep is generally associated with better health outcomes, strongly so for mental health, moderately for cognitive and physical health, but not for sleep quality and neural health. LCA identified four sleep types: 'good sleepers' (68.1%, most frequent in middle age), 'inefficient sleepers' (14.01%, most frequent in old age), 'delayed sleepers' (9.28%, most frequent in young adults) and 'poor sleepers' (8.5%, most frequent in old age). There is little evidence for interactions between sleep quality and age on health outcomes. Finally, we observe U-shaped associations between sleep duration and mental health (depression and anxiety) as well as self-reported general health, such that both short and long sleep were associated with poorer outcomes., Conclusions: Lifespan changes in sleep quality are multifaceted and not captured well by summary measures, but instead should be viewed as as partially independent symptoms that vary in prevalence across the lifespan. Better self-reported sleep is associated with better health outcomes, and the strength of these associations differs across health domains. Notably, we do not observe associations between self-reported sleep quality and white matter., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Sleep disorders in humans are increasingly appreciated to be not only widespread but also detrimental to multiple facets of physical and mental health. Recent work has begun to shed light on the mechanistic basis of sleep disorders like insomnia, restless legs syndrome, narcolepsy, and a host of others, but a more detailed genetic and molecular understanding of how sleep goes awry is lacking. Over the past 15 years, studies in Drosophila have yielded new insights into basic questions regarding sleep function and regulation. More recently, powerful genetic approaches in the fly have been applied toward studying primary human sleep disorders and other disease states associated with dysregulated sleep. In this review, we discuss the contribution of Drosophila to the landscape of sleep biology, examining not only fundamental advances in sleep neurobiology but also how flies have begun to inform pathological sleep states in humans., (© 2017 Elsevier Inc. All rights reserved.)

Recent studies in mouse models of Alzheimer's disease (AD) and in humans suggest that sleep disruption and amyloid-beta (Aβ) accumulation are interrelated, and may, thus, exacerbate each other. We investigated the association between self-reported sleep variables and neuroimaging data in 51 healthy older adults. Participants completed a questionnaire assessing sleep quality and quantity and underwent positron emission tomography scans using [18F]florbetapir and [18F]fluorodeoxyglucose and an magnetic resonance imaging scan to measure Aβ burden, hypometabolism, and atrophy, respectively. Longer sleep latency was associated with greater Aβ burden in prefrontal areas. Moreover, the number of nocturnal awakenings was negatively correlated with gray matter volume in the insular region. In asymptomatic middle-aged and older adults, lower self-reported sleep quality was associated with greater Aβ burden and lower volume in brain areas relevant in aging and AD, but not with glucose metabolism. These results highlight the potential relevance of preserving sleep quality in older adults and suggest that sleep may be a factor to screen for in individuals at risk for AD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sleep is profoundly altered during the course of infectious diseases. The typical response to infection includes an initial increase in nonrapid eye movement sleep (NREMS) followed by an inhibition in NREMS. REMS is inhibited during infections. Bacterial cell wall components, such as peptidoglycan and lipopolysaccharide, macrophage digests of these components, such as muramyl peptides, and viral products, such as viral double-stranded RNA, trigger sleep responses. They do so via pathogen-associated molecular pattern recognition receptors that, in turn, enhance cytokine production. Altered sleep and associated sleep-facilitated fever responses are likely adaptive responses to infection. Normal sleep in physiological conditions may also be influenced by gut microbes because the microbiota is affected by circadian rhythms, stressors, diet, and exercise. Furthermore, sleep loss enhances translocation of viable bacteria from the intestine, which provides another means by which sleep-microbe interactions impact neurobiology., (© 2016 Elsevier Inc. All rights reserved.)

Despite the known importance of sleep for brain development, and the sharp increase in poor sleep during adolescence, we know relatively little about how sleep impacts the developing brain. We present the first longitudinal study to examine how sleep during adolescence is associated with white matter integrity. We find that greater variability in sleep duration one year prior to a DTI scan is associated with lower white matter integrity above and beyond the effects of sleep duration, and variability in bedtime, whereas sleep variability a few months prior to the scan is not associated with white matter integrity. Thus, variability in sleep duration during adolescence may have long-term impairments on the developing brain. White matter integrity should be increasing during adolescence, and so sleep variability is directly at odds with normative developmental trends., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In addition to cognitive decline, individuals affected by Alzheimer's disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.

Background: Numerous studies have reported the relationship between sleep duration and obesity in elderly adults; however, little is known about the relationship of sleep duration and sarcopenia., Objective: We examined the relationship of sleep duration with obesity and sarcopenia in community-dwelling older adults., Methods: A total of 488 community-dwelling adults (224 men and 264 women) aged ≥65 years were included in the analysis. Self-reported sleep duration and anthropometric data were collected. Skeletal muscle mass was estimated using the predicted equation from a bioelectrical impedance analysis measurement. Obesity and sarcopenia were defined according to the body mass index and the skeletal muscle mass index, respectively., Results: The association between sleep duration and sarcopenia exhibited a U shape in older adults. Compared to adults with 6-8 h of sleep, adults with <6 h of sleep had a nearly 3-fold increased likelihood of sarcopenia (odds ratio, OR: 2.76, 95% confidence interval, CI: 1.28-5.96), while adults with ≥8 h of sleep had a nearly 2-fold increased risk of sarcopenia (OR: 1.89, 95% CI: 1.01-3.54). Older adults with a sleep duration <6 h were more prone to obesity (OR: 2.15, 95% CI: 1.08-4.30). After gender stratification, the association between obesity and short sleep duration was more robust in women., Conclusion: There were significant associations of sleep duration with either obesity or sarcopenia in community-dwelling older adults. Gender differences in these associations were also observed.

The importance of the cerebellum in sleep disorders, and vice versa, is only beginning to be understood. Advanced neuroimaging modalities have revealed cerebellar changes in both common and rare sleep disorders. Sleep disorders in those with genetic cerebellar disease, such as spinocerebellar ataxia, Friedreich ataxia, Joubert syndrome, and ataxia-telangiectasia, include excessive daytime sleepiness, restless legs syndrome, periodic limb movements of sleep, obstructive apnea, central apnea, and rapid eye movement behavior disorder. Sleep medicine is an important and under-recognized part of the neurologic evaluation in those with cerebellar disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Fragmented sleep is a common and troubling symptom in ageing and Alzheimer's disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic ventrolateral preoptic nucleus cause fragmented sleep. We previously proposed that the intermediate nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the ventrolateral preoptic nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate nucleus is important for human sleep, then intermediate nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimer's disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimer's disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimer's disease had fewer galaninergic intermediate nucleus neurons than those without (estimate -2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was <1 year (estimate -0.0013, standard error = 0.0005, P = 0.023). This association did not differ between individuals with and without Alzheimer's disease, and similar associations were not seen for two other cell populations near the intermediate nucleus. These data are consistent with the intermediate nucleus being the human homologue of the ventrolateral preoptic nucleus. Moreover, they demonstrate that a paucity of galanin-immunoreactive intermediate nucleus neurons is accompanied by sleep fragmentation in older adults with and without Alzheimer's disease., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Objectives: To investigate whether subjective sleep quality is associated with brain volume independent of comorbid psychiatric conditions., Design: Cross-sectional., Setting: Department of Veterans Affairs (VA) Medical Center., Participants: One hundred forty-four Gulf War Veterans (mean age 45 years; range: 31-70 years; 14% female)., Interventions: None., Measurements and Results: Total cortical, lobar gray matter, and hippocampal volumes were quantified from 1.5 Tesla magnetic resonance images using Freesurfer version 4.5. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). Multiple linear regressions were used to determine the association of sleep quality with total and regional brain volumes. The global PSQI score was positively correlated with lifetime and current posttraumatic stress disorder (PTSD) and current depressive symptoms (P < 0.001) and was higher in veterans with Gulf War Illness, trauma exposure, and those using psychotropic medication (P ≤ 0.03). After adjusting for these comorbid variables, age, intracranial volume, and multiple comparisons, global PSQI was inversely associated with total cortical and frontal gray matter volume (adjusted P ≤ 0.03). Within the frontal lobe, total PSQI was inversely associated with the superior and middle frontal, orbitofrontal, anterior cingulate, and frontal pole volumes (adjusted P ≤ 0.02). Examination of the 3-factor structure of the PSQI revealed that the associations were driven by perceived sleep quality., Conclusions: Poorer subjective sleep quality was associated with reduced total cortical and regional frontal lobe volumes independent of comorbid psychiatric conditions. Future work will be needed to examine if effective treatment of disturbed sleep leads to improved structural and functional integrity of the frontal lobes.

Sleep spindles are distinctive electroencephalographic (EEG) oscillations emerging during non-rapid-eye-movement sleep (NREMS) that have been implicated in multiple brain functions, including sleep quality, sensory gating, learning, and memory. Despite considerable knowledge about the mechanisms underlying these neuronal rhythms, their function remains poorly understood and current views are largely based on correlational evidence. Here, we review recent studies in humans and rodents that have begun to broaden our understanding of the role of spindles in the normal and disordered brain. We show that newly identified molecular substrates of spindle oscillations, in combination with evolving technological progress, offer novel targets and tools to selectively manipulate spindles and dissect their role in sleep-dependent processes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Goal: The goal of this study was to characterize the sleep problems of children with cancer who were referred for a comprehensive sleep evaluation., Materials and Methods: A retrospective case series review was conducted of all children with cancer referred to the pediatric sleep clinic from 1994 to 2009 for evaluation of a sleep problem. Seventy children were seen and evaluated during this interval; all had a complete sleep history taken, and further objective sleep evaluations were performed as part of their evaluation only when clinically indicated. An overnight polysomnogram was performed in 53 children. In 36 children with a history of excessive daytime sleepiness (EDS), a multiple sleep latency study was performed the following day. Seven children had a 3-4-week actigraphic study., Results: Children with neoplasms of central nervous system (CNS) involving the hypothalamus, thalamus, and brainstem were the most commonly referred children and had the most frequent and severe sleep problems. Excessive daytime sleepiness was the most common sleep problem, seen in 60% of children with cancer and in 80% of children with CNS neoplasms involving the hypothalamus, thalamus, and brainstem. Sleep disordered breathing (SDB) was present in 40% of the entire group of children with cancer and 46% of children with neoplasms involving the hypothalamus, thalamus, and brainstem. Children with CNS neoplasms often had more than one sleep problem, most commonly EDS and SDB. In these children, correction of the SDB often did not eliminate the EDS. In children with leukemia, insomnia was the most common sleep problem identified, present in 39%. The causes of the sleep problems were varied and included neurologic injury caused by the neoplasm and/or the CNS-directed treatments; seizures, adenotonsillar hypertrophy, medication side effects, obesity, pain, anxiety, and drug abuse. Some of the sleep problems were present before the diagnosis of cancer, though most developed after treatment was begun. A wide range of intervention strategies were utilized to address the sleep problems and included sleep hygiene/sleep restriction, behavioral counseling, continuous positive airway pressure, bilevel positive airway pressure, tracheotomy with and without a ventilator, diaphragmatic pacers, sedative hypnotics, stimulants, anticonvulsants, and antidepressants. When the sleep problems and their causes were correctly identified and treatments were directed to the specific cause of the problem, the treatments were generally successful., Conclusions: The sleep problems of children with cancer span the full spectrum of clinical sleep disorders (hypersomnia, sleep disordered breathing, insomnia, parasomnias, and circadian rhythm disorders) and are often present in combinations. Children with neoplasms involving the brainstem, thalamus, and hypothalamus were the most frequently referred for a sleep evaluation, and their sleep problems were most commonly EDS or SDB. Expertise in pediatric sleep disorders can be a valuable resource in the ongoing care of children with cancer.

Background: Anxiety and depression has been found in atrial fibrillation (AF) patients referred to secondary care. Little is known about the level of such distress in AF patients from the general population., Hypothesis: Permanent AF patients from the general population might have more anxiety, depression, and sleep impairment than subjects in sinus rhythm., Methods: Patients with permanent AF and controls in sinus rhythm were recruited from a 75-year-old cohort from 2 Norwegian municipalities. The main outcome variables were anxiety and depression, measured by the Hospital Anxiety and Depression Scale (HADS) and sleep quality measured by Pittsburgh Sleep Quality Index (PSQI) score. Short Form 36 (SF-36) was also completed., Results: Twenty-seven patients with permanent AF and 71 subjects in sinus rhythm participated. No significant score differences were found between AF patients and controls for HADS anxiety (median, inter quartile range, 3 [1, 5] vs 4 [1, 6]; HADS depression, 3 [1,6] vs 2 [1,4]; and PSQI 6 [3, 11] vs 5 [4, 8]). AF patients had significantly poorer scores for SF-36 physical functioning, physical role, general health, vitality, and social functioning compared to subjects in sinus rhythm., Conclusions: Elderly permanent AF patients from the general population had similar levels of anxiety, depression, and sleep quality, despite poorer physical health-related quality of life compared to controls in sinus rhythm. Copyright © 2011 Wiley Periodicals, Inc. This work was supported by unrestricted grants from the governmental Health Region South-East, Norway, and from the Stein Erik Hagen Foundation for Clinical Heart Research, Norway. The authors have no other funding, financial relationships, or conflicts of interest to disclose., (2011 Wiley Periodicals, Inc.)

Background and Objective: In clinical practice, the association between sleep and epilepsy has been increasingly observed in adults and during childhood. The aim of this article is to verify the relationship between sleep and epilepsy in the neonatal period in order to identify evidence and mechanisms to explain how epilepsy or neonatal seizures might disrupt sleep and how sleep might influence seizure occurrence and epilepsy during this age span., Methods: Literature review with search of PubMed database using the key words neonatal seizures and sleep., Results and Conclusion: The complex processes of cortical maturation are closely related to the regulation of sleep-wakefulness cycles. Sleep regulation in the context of neonatal seizures is frequently abnormal, and these alterations may be a result of the maladaptative plasticity of neuronal networks. Furthermore, in this situation altered connectivity might also be associated with other expressions of neurological dysfunction such as cognitive and behavioral problems. EEG background abnormalities and higher frequency of discharges are often associated with disrupted sleep organization. The outcome of newborns with seizures where sleep organization is undifferentiated seems to be more unfavorable., (Copyright 2010 Elsevier B.V. All rights reserved.)

Benign epileptic discharges of childhood (BEDC) are typical age-related EEG patterns associated with idiopathic benign focal epilepsy (BFE). The study of BFE revealed the symptomatic phenocopies in patients with structural brain lesions in infantile cerebral paralysis and malformations. The authors discuss the question of "benignity" of BEDC that may lead to various disturbances of cognitive functions and behavior, i.e. to signs of epileptic encephalopathy. Based on the examination of 1862 children, including 840 patients with epileptic seizures and 1022 neurologic patients, clinical and neurophysiological features of epileptic syndromes associated with prolonged epileptiform EEG activity in children were found. The most rational antiepileptic therapy was determined.

Sleep disorders in patients with neuromuscular disease are common, but underrecognized by health care providers, and sometimes by patients themselves. Their symptoms may be confused with those of the underlying disease. Their recognition is an important part of the management of patients with neuromuscular disorders, improving quality of life, and sometimes increasing survival. Inadequate ventilation underlies many sleep disorders, and sleep-related disorders may presage daytime ventilatory disorders with disease progression. Involvement of the central or peripheral nervous system, or both, may disrupt sleep, with the relative contribution of each depending on the specific disorder. The pertinent anatomy, physiology, and clinical features of sleep disorders in neuromuscular diseases and a basic approach to their assessment is discussed. Specific neuromuscular disorders in which sleep is commonly affected are reviewed and the principles of management of sleep disorders summarized., (Thieme Medical Publishers.)

There is a strong interaction between sleep and headache. Sleep and headache disorders overlap epidemiologically, and share elements of anatomy and physiology. Perhaps as a result, their treatment is often mutually interdependent. Despite this, headache and sleep disorders tend to be treated separately, by different subspecialties of neurology. The headache disorders and their relationship to sleep, the commonalities of headache and sleep pathophysiology, and headache disorders that are particularly susceptible to sleep modulation (and vice versa) are reviewed. Practical management advice for sleep-modulated headaches is provided., (Thieme Medical Publishers.)

Sleep is a neurochemical process involving sleep promoting and arousal centers in the brain. Sleep performs an essential restorative function and facilitates memory consolidation in humans. The remarkably standardized bouts of consolidated sleep at night and daytime wakefulness reflect an interaction between the homeostatic sleep need that is manifested by increase in sleep propensity after sleep deprivation and decrease during sleep and the circadian pacemaker. Melatonin, the hormone produced nocturnally by the pineal gland, serves as a time cue and sleep-anticipating signal. A close interaction exists between the sleep-wake, melatonin, core temperature, blood pressure, immune and hormonal rhythms leading to optimization of the internal temporal order. With age the robustness of the circadian system decreases and the prevalence of sleep disorders, particularly insomnia, increases. Deviant sleep patterns are associated with increased risks of morbidity, poor quality of life and mortality. Current sleep pharmacotherapies treat insufficient sleep quantity, but fail to improve daytime functioning. New treatment modalities for sleep disorders that will also improve daytime functioning remain a scientific and medical challenge.

Herein are presented the results of research in the area of sleep neuroimaging over the past year. Significant work has been performed to clarify the basic mechanisms of sleep in humans. New studies also extend prior observations regarding altered brain activation in response to sleep deprivation by adding information regarding vulnerability to sleep deprivation and regarding the influence of task difficulty on aberrant responses. Studies in sleep disorder medicine have yielded significant findings in insomnia, depression, and restless legs syndrome. Extensive advances have been made in the area of sleep apnea where physiologic challenges have been used to probe brain activity in the pathophysiology of sleep apnea syndrome.

One of the most popular herbal remedies for the alleviation of sleep problems is valerian. However, research into valerian is sparse, and studies differ greatly with respect to design, measures, and preparations used. This clinical study used standardized sleep EEG and psychometric tests to evaluate the clinical efficacy of a valerian preparation (Li 156). A placebo-controlled three way crossover clinical trial was completed using 16 (5 male and 11 female) sleep-disturbed participants (aged 50 to 64 years, mean age 55.9, SD 4.68). Participants slept overnight in a sleep laboratory, following a 21:00 hours dose of valerian 300 mg, valerian 600 mg, or placebo (double-blind). EEG sleep was recorded for each participant at 23:00 hours until 07:00 hours, when a psychometric evaluation was performed the morning after dose. Test periods were separated by six days washout period. Results showed no significant effect between valerian 300 mg, valerian 600 mg or placebo on any EEG parameter or psychometric measure. This suggests valerian at these doses is ineffective as an acute dose for sleep problems. However, valerian is widely used, and is traditionally sedative. Therefore, more research is required into therapeutic dose, types of valerian preparation, and the optimum period of use for therapeutic effect., (Copyright 2004 John Wiley & Sons, Ltd.)

Sleep complaints and unusual sleep durations have been found to increase the risk for coronary heart disease. One explanation states that insomnia and excess fatigue on final waking are predictive for myocardial infarction because they are part of a state of 'vital exhaustion'. Sleep complaints and sleep durations, however, are usually assessed with retrospective self-report procedures. Such procedures must be interpreted with reserve because in insomniacs, a consistent disparity in the perception of habitual and current sleep has been observed. This caused us to question whether this phenomenon is present in exhausted males also. Two approaches were used. The first one consisted of a retrospective assessment of subjective sleep characteristics, the second one of self-monitoring these sleep characteristics during 21 days. In the second week, subjects slept in a laboratory. No disparity was found in how exhausted males perceive their habitual and current sleep. It appeared that sleep quality is worse and sleep duration is shorter in exhausted males. They also feel more sleepy and take longer naps during the day, indicating that their daytime functioning is impaired. Sleeping in a laboratory reduced time asleep and midsleep wake. Sleep quality, however, was essentially the same as at home. These findings made us conclude that it is not the intrusion of nocturnal wake times per se but more likely the impaired daytime functioning which is the reason for exhausted males to complain about their sleep.