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The impact of sleep disorders on active duty Soldiers' medical readiness is clinically significant. Sleep disorders often present high comorbidity with disease states impacting readiness ranging from obesity and drug dependence. Patient data generated from military health databases can be accessed to examine such relationships. The current study performed a risk assessment of sleep disorders, obesity, tobacco use, and substance abuse based on geographical distribution of active duty Army installations through a comprehensive analysis of the Office of the Army Surgeon General Health of the Force report, specifically for Fiscal Year 2017, which summarizes data collected during 2016.Health incidences (percent active duty per installation) were queried from the Health of the Force Fiscal Year 2017 (n = 471,000; 85.5% male,70% between 18 and 34). Nonparametric ranked tests identified active duty Army installations at low risk (green;25% percentile relative to mean rank), moderate risk (amber; 25%-50% percentile relative to mean rank), and high risk (red;75% percentile relative to mean rank). Pearson's correlations determined extent of generalized comorbidity of sleep disorders with obesity, tobacco use, and substance abuse across all installations.Large combat arms and training installations of the Southern U.S. were at highest risk for sleep disorder. Mean rank comparisons for sleep disorders versus obesity (P = .306), tobacco use (P = .378), and substance abuse (P = .591) did not differ for each installation. There was a high degree of generalized comorbidity of diagnosed sleep disorder with obesity (P.001; rThese risk assessments mirror geographical risk data from civilian populations which is surprising because there is a large degree of inter-individual variability in geographical origin, race/ethnicity, and socioeconomic statuses within a single Army installation. Nevertheless, these data demonstrate strong geographical influences on medical readiness in active duty Soldiers comparable to civilian sectors.

The TNFα G308A gene polymorphism has been reported to influence performance impairment during total sleep deprivation (TSD). We investigated this effect in a randomized, double-blind, crossover lab...

Fil: Folgueira, Agustín. Hospital Militar Central. Departamento de Neurología; Argentina Fil: Folgueira, Agustín. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Cronofisiología; Argentina Fil: Folgueira, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Simonelli, Guido. Walter Reed Army Institute of Research. Behavioral Biology Branch; Estados Unidos Fil: Plano, Santiago Andrés. Universidad Nacional de Quilmes. Laboratorio de Cronobiología; Argentina Fil: Plano, Santiago Andrés. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Cronofisiología; Argentina Fil: Plano, Santiago Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Tortello, Camila. Universidad Nacional de Quilmes. Laboratorio de Cronobiología; Argentina Fil: Tortello, Camila. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Cronofisiología; Argentina Fil: Tortello, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cuiuli, Juan Manuel. Comando Conjunto Antártico; Argentina Fil: Blanchard, Abel. Comando Conjunto Antártico; Argentina Fil: Patagua, Alejandro. Comando Conjunto Antártico; Argentina Fil: Brager, Allison J. Walter Reed Army Institute of Research. Behavioral Biology Branch; Estados Unidos Fil: Capaldi, Vicente F. Walter Reed Army Institute of Research. Behavioral Biology Branch; Estados Unidos Fil: Aubert, André E. Katholieke Universiteit Leuven. Faculty of Psychology and Educational Sciences; Bélgica Fil: Barbarito, Marta. Instituto Antártico Argentino; Argentina Fil: Golombek, Diego A. Universidad Nacional de Quilmes. Laboratorio de Cronobiología; Argentina Fil: Golombek, Diego A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Vigo, Daniel Eduardo. Katholieke Universiteit Leuven. Faculty of Psychology and Educational Sciences; Bélgica Fil: Vigo, Daniel Eduardo. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Cronofisiología; Argentina Fil: Vigo, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Abstract: During Antarctic isolation personnel are exposed to extreme photoperiods. A frequent observation is a sleep onset phase delay during winter. It is not known if, as a result, daytime sleeping in the form of naps increases. We sought to assess sleep patterns - with focus on daytime sleeping - and alertness in a Latin American crew overwintering in Argentine Antarctic station Belgrano II. Measurements were collected in 13 males during March, May, July, September and November, and included actigraphy and psychomotor vigilance tasks. Sleep duration significantly decreased during winter. A total of eight participants took at least one weekly nap across all measurement points. During winter, the nap onset was delayed, its duration increased and its efficiency improved. We observed a significant effect of seasonality in the association of evening alertness with sleep onset. Our results replicate previous findings regarding sleep during overwintering in Antarctica, adding the description of the role of napping and the report of a possible modulatory effect of seasonality in the relation between sleep and alertness. Napping should be considered as an important factor in the scheduling of activities of multicultural crews that participate in Antarctica.

The military lifestyle often includes continuous operations whether in training or deployed environments. These stressful environments present unique challenges for service members attempting to achieve consolidated, restorative sleep. The significant mental and physical derangements caused by degraded metabolic, cardiovascular, skeletomuscular, and cognitive health often result from insufficient sleep and/or circadian misalignment. Insufficient sleep and resulting fatigue compromises personal safety, mission success, and even national security. In the long-term, chronic insufficient sleep and circadian rhythm disorders have been associated with other sleep disorders (e.g., insomnia, obstructive sleep apnea, and parasomnias). Other physiologic and psychologic diagnoses such as post-traumatic stress disorder, cardiovascular disease, and dementia have also been associated with chronic, insufficient sleep. Increased co-morbidity and mortality are compounded by traumatic brain injury resulting from blunt trauma, blast exposure, and highly physically demanding tasks under load. We present the current state of science in human and animal models specific to service members during- and post-military career. We focus on mission requirements of night shift work, sustained operations, and rapid re-entrainment to time zones. We then propose targeted pharmacological and non-pharmacological countermeasures to optimize performance that are mission- and symptom-specific. We recognize a critical gap in research involving service members, but provide tailored interventions for military health care providers based on the large body of research in health care and public service workers.

Introduction Insufficient sleep increases pain sensitivity in healthy individuals. Additionally, extending sleep (eg, increasing nocturnal sleep time or adding a mid-day nap) has been shown to restore pain sensitivity to baseline levels in sleep deprived/restricted individuals. Whether sleep extension can reduce pain sensitivity beyond baseline levels in non-sleep restricted/deprived individuals remains unknown. Methods In a sample of 27 healthy, pain-free, normally-sleeping individuals (17 males, mean age ∼24 yrs), we examined the impact of five nights of sleep extension on pain sensitivity. Pain threshold (elapsed time until the participant reported pain) and pain tolerance (total time the participant kept the hand submerged in the cold water) were measured using the Cold Pressor Task. Furthermore, we assessed the extent to which self-reported sleep amount in relation to the minimal subjective sleep requirement for adequate performance (sleep credit) was associated with pain sensitivity changes. Results On average individuals slept almost 2 extra hours per night. Our results indicate that sleep extension increases pain tolerance beyond baseline levels. However, sleep extension did not impact pain threshold. We also found that individuals with a smaller sleep credit (ie, those who habitually obtain less sleep than they feel they need) experienced greater increases in pain tolerance after extending sleep. Conclusions The present findings suggest that sleep extension may increase pain tolerance but not pain threshold in healthy individuals who normally sleep the recommended amount. Our findings also support the idea that sleep credit may be a strong indicator of sleep debt in the context of pain sensitivity.

Introduction The impact of sleep disorders on active duty Soldiers’ medical readiness is clinically significant. Sleep disorders present high comorbidity with disease states directly impacting medical readiness, ranging from musculoskeletal injury (MSK-I), obesity, and drug dependence. The current study performed a risk assessment of sleep disorder comorbidity with MSK-I, obesity, and drug dependence across active duty United States Army installations. Methods Health incidences (percent active duty per installation) were queried from the Office of the Surgeon General Health of the Force (HoF) report, specifically for Fiscal Year (FY) 2017 (n = 471,000; 85.5% male, > 70% between 18 -34). Nonparametric ranked tests identified active duty Army installations at low risk (green; < 25% percentile relative to mean rank), moderate risk (amber; 25% - 50%), and high risk (red; > 75% percentile). Linear regressions determined extent of comorbidity of sleep disorders with MSK-I, obesity, and drug dependence (tobacco use and substance abuse). Results Mean rank comparisons for sleep disorders vs. injury index (p=0.499), obesity (p=0.306), tobacco use (p=0.378), and substance abuse (p=0.591) did not differ for each installation. Further, there was a high degree of co-morbidity for mean percentage of diagnosed sleep disorder with injury index (p Conclusion In general, large infantry and artillery training units located in the Southeastern United States were “in the red” for not meeting medical readiness standards. A few exceptions include Virginia-Maryland triangle, a heavily populated area. These data demonstrate strong geographical influences on health risk comorbidity in active duty Soldiers comparable to civilian sectors. Support Military Operational Medicine Research Program

Poor sleep is a hazard of daily life that oftentimes cannot be avoided. Gender differences in daily sleep and wake patterns are widely reported; however, it remains unclear how biological sex, which is comprised of genetic and endocrine components, directly influences sleep regulatory processes. In the majority of model systems studied thus far, sex differences in daily sleep amount are predominant during the active (wake) phase of the sleep-wake cycle. The pervasiveness of sex differences in sleep amount throughout phylogeny suggests a strong underlying genetic component. The goal of the current study is to determine if sex differences in active-phase sleep amount are dependent on sex chromosomes in mice.Sleep was examined in the four-core genotype (FCG) mouse model, whose sex chromosome complement (XY, XX) is independent of sex phenotype (male or female). In this line, sex phenotype is determined by the presence or absence of the Sry gene, which is dissociated from the Y chromosome. Polysomnographic sleep recordings were obtained from gonadectomized (GDX) FCG mice to examine spontaneous sleep states and the ability to recover from sleep loss. We report that during the active-phase, the presence of the Sry gene accounts for most sex differences during spontaneous sleep; however, during recovery from sleep loss, sex differences in sleep amount are partially driven by sex chromosome complement. These results suggest that genetic factors on the sex chromosomes encode the homeostatic response to sleep loss.

Sleep disturbances, posttraumatic stress disorder, and traumatic brain injury are highly prevalent in military personnel and veterans. These disorders can negatively impact military performance. Although literature evaluating how posttraumatic stress disorder and traumatic brain injury directly impact military performance is limited, there is evidence supporting that these disorders negatively impact cognitive and social functioning. What is not clear is if impaired performance results from these entities individually, or a combination of each. Further research using standardized evaluations for the clinical disorders and metrics of military performance is required to assess the overall performance decrements related to these disorders.

Objective Individuals vary in response to sleep loss: some individuals are “vulnerable” and demonstrate cognitive decrements following insufficient sleep, while others are “resistant” and maintain baseline cognitive capability. Physiological markers (e.g., genetic polymorphisms) have been identified that can predict relative vulnerability. However, a quick, cost-effective, and feasible subjective predictor tool has not been developed. The objective of the present study was to determine whether two factors—“subjective sleep need” and “subjective resilience”—predict cognitive performance following sleep deprivation. Methods Twenty-seven healthy, sleep-satiated young adults participated. These individuals were screened for sleep disorders, comorbidities, and erratic sleep schedules. Prior to 40 hours of in-laboratory total sleep deprivation, participants were questioned on their subjective sleep need and completed a validated resilience scale. During and after sleep deprivation, participants completed a 5-minute psychomotor vigilance test every 2 hours. Results Both subjective resilience and subjective sleep need individually failed to predict performance during sleep loss. However, these two measures interacted to predict performance. Individuals with low resilience and low sleep need had poorer cognitive performance during sleep loss. However, in individuals with medium or high resilience, psychomotor vigilance test performance was not predicted by subjective sleep need. Higher resilience may be protective against sleep loss-related neurobehavioral impairments in the context of subjective sleep need. Conclusions Following sleep loss (and recovery sleep), trait resilient individuals may outperform those with lower resiliency on real-world tasks that require continuous attention. Future studies should determine whether the present findings generalize to other, operationally relevant tasks and additional cognitive domains.

Burke, TM, Lisman, PJ, Maguire, K, Skeiky, L, Choynowski, JJ, CapaldiII, VF, Wilder, JN, Brager, AJ, and Dobrosielski, DA. Examination of sleep and injury among college football athletes. J Strength Cond Res 34(3): 609-616, 2020-The purpose of this study was to characterize subjective sleep metrics in collegiate football players at the start of the season, determine the relationship between preseason subjective sleep measures and in-season objective sleep characteristics, and examine the association between subjective and objective sleep metrics and incidence of time-loss injury during the competitive season. Ninety-four Division I football players completed 5 validated sleep-related questionnaires to assess sleep quality, insomnia severity, daytime sleepiness, sleep apnea risk, and circadian preference before the start of the season. Clinical thresholds for sleep questionnaires were used to determine risk of sleep disorders. Continuous wrist actigraphy was collected throughout the season to generalize sleep behaviors. Time-loss injury incidence data were recorded and used for analysis. Results indicated that 67.4% (60 of 89) of athletes scored above clinical threshold in at least 1 questionnaire to indicate sleep disorder risk. At the start of the season, players subjectively reported an average sleep duration of 7:16 ± 1:18 hours:minutes, which was in contrast to the 6:04 ± 0:41 hours:minutes measured through actigraphy during the season. Logistic regression models adjusted for age and body mass index revealed no significant associations between injury and subjective (odds ratio [OR] = 1.00; 95% confidence interval [CI] = 0.99-1.01) and objective (OR = 1.01; 95% CI = 0.99-1.02) sleep duration or measures attained from sleep questionnaires (ORs ranged from 1.01 to 2.87). Sleep metrics (quantity and quality) were not associated with increased risk of injury in this cohort of collegiate football players.

Study Objectives The purpose of the present study was to assess the extent to which sleep extension followed by sleep deprivation impacts performance on an attentional task with varying cognitive and attentional demands that influence decisions. Methods Task performance was assessed at baseline, after 1 week of sleep extension, and after 40 h of total sleep deprivation. Results One week of sleep extension resulted in improved performance, particularly for high cognitive load decisions regardless of the emotional salience of attentional distractors. Those who extended sleep the most relative to their habitual sleep duration showed the greatest improvement in general performance during sleep extension. However, a higher percentage of time spent in slow-wave sleep (SWS) on the last night of the sleep extension phase was negatively correlated with performance on more difficult high cognitive load items, possibly reflecting a relatively higher level of residual sleep need. Sleep deprivation generally resulted in impaired performance, with a nonsignificant trend toward greater performance decrements in the presence of emotionally salient distractors. Performance overall, but specifically for high cognitive load decisions, during total sleep deprivation was negatively correlated with longer sleep and higher SWS percentage during subsequent recovery sleep. Conclusions The present findings suggest two possibilities: those who performed relatively poorly during sleep deprivation were more vulnerable because (1) they utilized mental resources (i.e. accrued sleep debt) at a relatively faster rate during wakefulness, and/or (2) they failed to “pay down” pre-study sleep debt to the same extent as better-performing participants during the preceding sleep extension phase.

Brager, AJ and Mistovich, RJ. Game times and higher winning percentages of west coast teams of the National Football League correspond with reduced prevalence of regular season injury. J Strength Cond Res 31(2): 462-467, 2017-West coast teams of the National Football League are more statistically likely to win home night games against east coast opponents. The alignment of game times with daily rhythms of alertness is thought to contribute to this advantage. This study aims to determine whether rates of turnovers and injuries during the regular season, putative measures of mental and physical fatigue, impact winning percentages. Regular season schedules and rates of turnovers for each of the 32 teams were obtained from Pro-Football-Reference. We developed our own metric of injury risk for each position obtained from depth charts and regular season schedules. This metric compared cumulative weeks on injury reserve with cumulative time zone travel. West coast teams traveled 4 times as often as east coast teams. However, teams traveling eastward won twice as many games. There was no relationship between the extent and direction of travel and number of turnovers. Losing teams had more turnovers. The offensive and defensive lines in Central Time (CT) were placed on injury reserve 4 times as often as offensive and defensive lines in Pacific Time (PT). Injury prevalence in CT vs. PT was most prominent midseason. Plotting midseason game time relative to biological time revealed that PT teams play games closer to endogenous peaks in alertness, whereas CT teams play games closer to endogenous troughs in alertness. Overall, closer alignment of game time with the endogenous "alerting" signal may protect west coast teams from fatigue-related injuries and suggests for modified strength and conditioning programs.

Introduction Sleep deprivation degrades the fidelity of human brain information processing, leading to cognitive impairment. Carriers of the A allele of a single nucleotide polymorphism of the TNFα gene (G308A, rs1800629) have been found to be resilient to cognitive impairment due to sleep deprivation as compared to individuals homozygous for the G allele. Caffeine mitigates the cognitive impairment associated with sleep deprivation. We investigated whether the effects of caffeine and TNFα genotype interact. Methods In an 18-day, controlled, in-laboratory study, 12 healthy adults (age 27.4±6.9; 6 females) underwent three sessions of 48-hour total sleep deprivation (TSD), with each TSD session preceded and followed by three nights of baseline and/or recovery sleep (10 hours time in bed). In randomized, counterbalanced, double-blind, placebo-controlled fashion, during each TSD session a specific dose of caffeine (0, 200, or 300 mg) was administered four times at 12-hour intervals. Vigilant attention was measured every 2 hours during each TSD session with a psychomotor vigilance test (PVT), for which the log of the signal-to-noise ratio (LSNR) derived from the RT distribution was determined as a measure of the fidelity of information processing. Each subject’s TNFα genotype was assessed from a blood sample. Results Subjects homozygous for the TNFα G allele showed greater PVT impairment during sleep deprivation in the 0 mg caffeine (i.e., placebo) condition as compared to carriers of the A allele and as compared to the 200 and 300 mg caffeine conditions (mixed-effects ANOVA, genotype by dose interaction: F2,566=5.23, p=0.005). There was no appreciable caffeine-related difference in performance for carriers of the A allele, who were relatively resilient to TSD regardless of caffeine dose. Conclusion These results suggest non-additive, interacting effects of TNFα genotype and caffeine and a potentially shared mechanism of action with regard to the fidelity of information processing during sleep deprivation. Support This research was supported by ONR. AJB, TJB, VFC, RHR were supported by DoD MOMRP-USAMRDC. The views expressed here are those of the authors and do not represent the official policy or position of the DoD.

Objective/Background It is widely established that insufficient sleep can lead to adverse health outcomes. Paradoxically, epidemiologic research suggests that individuals who report habitual nightly sleep greater than 9 h also are at risk for adverse health outcomes. Further, studies have shown that long sleepers have decreased activity levels, which may partially explain the relationship between long sleep duration and mortality. The influence of sleep extension (longer time in bed) on levels of daily activity has not yet been established. The current study examined whether a week of sleep extension altered activity levels within the subsequent daily waking active and sleep period in order to determine whether increased time in bed indeed is related to decreased activity levels. Methods A total of 26 healthy volunteers wore wrist accelerometer devices (Actiwatch 2.0, Philips) in order to objectively measure sleep and activity for six days during their normal schedules and for six days during a sleep extension (10 h time in bed) intervention. Results There were no significant or clinically-relevant differences in 24-h activity or activity during the active or sleep period between baseline and sleep extension conditions. There were no main or interaction effects of day and condition when daily activity counts were compared between baseline and sleep extension conditions for the 24 h period (Day: F(5, 21) = 1.92, p = 0.12; Condition: F(1,25) = 2.93, p = 0.09; Day by Condition: F(5,21) = 0.32, p = 0.83), Active Waking Period (Day: F(5,25) = 1.53, p = 0.18; Condition: F(1,25) = 0.26, p = 0.61; Day by Condition: F(5,21) = 0.55, p = 0.74) or Nightly Sleep (Day: F(5,21) = 0.86, p = 0.51; Condition: F(1,25) = 1.78, p = 0.19; Day by Condition: F(5,21) = 0.79, p = 0.56) periods. In contrast, there was a main effect of condition when examining sleep duration by day between conditions (Day: F(5,21) = 1.60, p = 0.16; Condition: F(1,25) = 167.31, p Discussion Sleep duration increased during six days of a sleep extension protocol but activity levels remained similar to their baseline (normal) sleep schedule. The current findings suggest that extending time in bed alone does not alter waking activity counts in young healthy adults. The link between extended sleep and adverse health outcomes may be attributable to other phenotypic factors, or other biological correlates of extended sleep and poor health.

IntroductionSleep loss is ubiquitous in military settings, and it can be deleterious to cognitive, physiological, and operational functioning. This is especially true in the military operational context (e.g., training, garrison, combat) where continuous operations prevent adequate time for rest and recuperation. Furthermore, even when servicemembers do have opportunities for sleep, environmental disruptors in the military operational context make it difficult to obtain restorative sleep. Such environmental disruptors are potentially preventable or reversible, yet there is little public awareness of how to minimize or eliminate these sleep disruptors. Therefore, the goal of this review was to outline prominent environmental sleep disruptors, describe how they occur in the military operational context, and also discuss feasible strategies to mitigate these disruptors.Materials and MethodsWe discuss four factors – light, noise, temperature, and air pollution – that have previously been identified as prominent sleep disruptors in non-military settings. Additionally, we extracted publicly-available yearly temperature and pollution data, from the National Oceanic and Atmospheric Association and the Environmental Protection Agency, respectively, for major prominent military installations in the continental US in order to identify the sites at which servicemembers are at the greatest risk for environmental sleep disruptions.ResultsBased on previous literature, we concluded light and noise are the most easily mitigatable sleep-disrupting environmental factors. Air pollution and temperature, on the other hand, are more difficult to mitigate. We also propose that harsh/uncomfortable sleeping surface is a fifth critical, previously unexplored sleep disruptor in the military operational context. Furthermore, we identified several problematic military sites for air pollution for temperature. Specifically, each branch has major installations located in regions with extreme heat (especially the Army), and each branch has at least one major installation in a high air pollution region. These findings show that even when in training or garrison in the US, military servicemembers are at risk for having sleep disruption due to environmental factors.ConclusionsEnvironmental disruptors, such as light, noise, temperature, and air pollution, can negatively impact sleep in the military operational context. Simple, feasible steps can be taken to reduce sleep disruptions that are caused by light and noise. Yet there is a need for research and development on tools to mitigate air pollution, extreme temperatures, and inhospitable sleeping surfaces. Leadership at the discussed military bases and training facilities should focus on improving the sleep environment for individuals under their command. Such interventions could ultimately improve warfighter health, wellness, and operational performance, leading to greater warfighter readiness and lethality.

Individuals with Angelman syndrome (AS) suffer sleep disturbances that severely impair quality of life. Whether these disturbances arise from sleep or circadian clock dysfunction is currently unknown. Here, we explored the mechanistic basis for these sleep disorders in a mouse model of Angelman syndrome (Ube3am−/p+mice). Genetic deletion of the maternalUbe3aallele practically eliminates UBE3A protein from the brain ofUbe3am−/p+mice, because the paternal allele is epigenetically silenced in most neurons. However, we found that UBE3A protein was present in many neurons of the suprachiasmatic nucleus—the site of the mammalian circadian clock—indicating thatUbe3acan be expressed from both parental alleles in this brain region in adult mice. We found that whileUbe3am−/p+mice maintained relatively normal circadian rhythms of behavior and light-resetting, these mice exhibited consolidated locomotor activity and skipped the timed rest period (siesta) present in wild-type (Ube3am+/p+) mice. Electroencephalographic analysis revealed that alterations in sleep regulation were responsible for these overt changes in activity. Specifically,Ube3am−/p+mice have a markedly reduced capacity to accumulate sleep pressure, both during their active period and in response to forced sleep deprivation. Thus, our data indicate that the siesta is governed by sleep pressure, and thatUbe3ais an important regulator of sleep homeostasis. These preclinical findings suggest that therapeutic interventions that target mechanisms of sleep homeostasis may improve sleep quality in individuals with AS.SIGNIFICANCE STATEMENTAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternal copy of theUBE3Agene. Individuals with AS have severe sleep dysfunction that affects their cognition and presents challenges to their caregivers. Unfortunately, current treatment strategies have limited efficacy due to a poor understanding of the mechanisms underlying sleep disruptions in AS. Here we demonstrate that abnormal sleep patterns arise from a deficit in accumulation of sleep drive, uncovering theUbe3agene as a novel genetic regulator of sleep homeostasis. Our findings encourage a re-evaluation of current treatment strategies for sleep dysfunction in AS, and suggest that interventions that promote increased sleep drive may alleviate sleep disturbances in individuals with AS.

Sleep quality appears to be altered by traumatic brain injury (TBI). However, whether persistent post-injury changes in sleep architecture are present is unknown and relatively unexplored. We conducted a systematic review and meta-analysis to assess the extent to which chronic TBI (>6 months since injury) is characterized by changes to sleep architecture. We also explored the relationship between sleep architecture and TBI severity. In the fourteen included studies, sleep was assessed with at least one night of polysomnography in both chronic TBI participants and controls. Statistical analyses, performed using Comprehensive Meta-Analysis software, revealed that chronic TBI is characterized by relatively increased slow wave sleep (SWS). A meta-regression showed moderate-severe TBI is associated with elevated SWS, reduced stage 2, and reduced sleep efficiency. In contrast, mild TBI was not associated with any significant alteration of sleep architecture. The present findings are consistent with the hypothesis that increased SWS after moderate-severe TBI reflects post-injury cortical reorganization and restructuring. Suggestions for future research are discussed, including adoption of common data elements in future studies to facilitate cross-study comparability, reliability, and replicability, thereby increasing the likelihood that meaningful sleep (and other) biomarkers of TBI will be identified.

Cocaine is a potent disruptor of photic and non-photic pathways for circadian entrainment of the master circadian clock of the suprachiasmatic nucleus (SCN). These actions of cocaine likely involve its modulation of molecular (clock gene) components for SCN clock timekeeping. At present, however, the physiological basis of such an interaction is unclear. To address this question, we compared photic and non-photic phase-resetting responses between wild-type (WT) and Per2 mutant mice expressing nonfunctional PER2 protein to systemic and intra-SCN cocaine administrations. In the systemic trials, cocaine was administered i.p. (20 mg/kg) either at midday or prior to a light pulse in the early night to assess its non-photic and photic behavioral phase-resetting actions, respectively. In the intra-SCN trial, cocaine was administered by reverse microdialysis at midday to determine if the SCN is a direct target for its non-photic phase-resetting action. Non-photic phase-advancing responses to i.p. cocaine at midday were significantly (∼3.5-fold) greater in Per2 mutants than WTs. However, the phase-advancing action of intra-SCN cocaine perfusion at midday did not differ between genotypes. In the light pulse trial, Per2 mutants exhibited larger photic phase-delays than did WTs, and the attenuating action of cocaine on this response was proportionately larger than in WTs. These data indicate that the Per2 clock gene is a potent modulator of cocaine's actions in the circadian system. With regard to non-photic phase-resetting, the SCN is confirmed as a direct target of cocaine action; however, Per2 modulation of this effect likely occurs outside of the SCN.

Brain and muscle-ARNT-like factor (Bmal1/BMAL1) is an essential transcriptional/translational factor of circadian clocks. Loss of function of Bmal1/BMAL1 is highly disruptive to physiological and behavioral processes. In light of these previous findings, we examined if transgenic overexpression of Bmal1/BMAL1 in skeletal muscle could alter metabolic processes. First, we characterized invivo and exvivo metabolic phenotypes of muscle overexpressed mice (male and female) compared to wild-type littermates (WT). Second, we examined invivo and exvivo metabolic processes in the presence of positive and negative homeostatic challenges: high-intensity treadmill running (positive) and acute sleep deprivation (negative). Invivo measures of metabolic processes included body composition, respiratory exchange ratio (RER; VCO2/VO2), energy expenditure, total activity counts, and food intake collected from small animal indirect calorimetry. Exvivo measure of insulin sensitivity in skeletal muscle was determined from radioassays. RER was lower for muscle overexpressed females compared to female WTs. There were no genotype-dependent differences in metabolic phenotypes for males. With homeostatic challenges, muscle overexpressed mice had lower energy expenditure after high-intensity treadmill running. Acute sleep deprivation reduced insulin sensitivity in skeletal muscle in overexpressed male mice, but not male WTs. The present study contributes to a body of evidence showing pleiotropic, non-circadian, and homeostatic effects of altered Bmal1/BMAL1 expression on metabolic processes, demonstrating a critical need to further investigate the broad and complex actions of Bmal1/BMAL1 on physiology and behavior.

Alcohol dependence in aging populations is seen as a public health concern, most recently because of the significant proportion of heavy drinking among "Baby Boomers." Basic animal research on the effects of aging on physiological and behavioral regulation of ethanol (EtOH) intake is sparse, since most of this research is limited to younger models of alcoholism. Here, EtOH drinking and preference were measured in groups of aged Syrian hamsters. Further, because voluntary exercise (wheel-running) is a rewarding substitute for EtOH in young adult hamsters, the potential for such reward substitution was also assessed.Aged (24 month-old) male hamsters were subjected to a three-stage regimen of free-choice EtOH (20% v/v) or water and unlocked or locked running wheels to investigate the modulatory effects of voluntary wheel running on EtOH intake and preference. Levels of fluid intake and activity were recorded daily across 60 days of experimentation.Prior to wheel running, levels of EtOH intake were significantly less than levels of water intake, resulting in a low preference for EtOH (30%). Hamsters with access to an unlocked running wheel had decreased EtOH intake and preference compared with hamsters with access to a locked running wheel. These group differences in EtOH intake and preference were sustained for up to 10 days after running wheels were re-locked.These results extend upon those of our previous work in young adult hamsters, indicating that aging dampens EtOH intake and preference. Voluntary wheel running further limited EtOH intake, suggesting that exercise could offer a practical approach for managing late-life alcoholism.

Cocaine abuse is highly disruptive to circadian physiological and behavioral rhythms. The present study was undertaken to determine whether such effects are manifest through actions on critical photic and nonphotic regulatory pathways in the master circadian clock of the mouse suprachiasmatic nucleus (SCN). Impairment of SCN photic signaling by systemic (intraperitoneal) cocaine injection was evidenced by strong (60%) attenuation of light-induced phase-delay shifts of circadian locomotor activity during the early night. A nonphotic action of cocaine was apparent from its induction of 1-h circadian phase-advance shifts at midday. The serotonin receptor antagonist, metergoline, blocked shifting by 80%, implicating a serotonergic mechanism. Reverse microdialysis perfusion of the SCN with cocaine at midday induced 3.7 h phase-advance shifts. Control perfusions with lidocaine and artificial cerebrospinal fluid had little shifting effect. In complementary in vitro experiments, photic-like phase-delay shifts of the SCN circadian neuronal activity rhythm induced by glutamate application to the SCN were completely blocked by cocaine. Cocaine treatment of SCN slices alone at subjective midday, but not the subjective night, induced 3-h phase-advance shifts. Lidocaine had no shifting effect. Cocaine-induced phase shifts were completely blocked by metergoline, but not by the dopamine receptor antagonist, fluphenazine. Finally, pretreatment of SCN slices for 2 h with a low concentration of serotonin agonist (to block subsequent serotonergic phase resetting) abolished cocaine-induced phase shifts at subjective midday. These results reveal multiple effects of cocaine on adult circadian clock regulation that are registered within the SCN and involve enhanced serotonergic transmission.

The PER2 clock gene modulates ethanol consumption, such that mutant mice not expressing functional mPer2 have altered circadian behavior that promotes higher ethanol intake and preference. Experiments were undertaken to characterize circadian-related behavioral effects of mPer2 deletion on ethanol intake and to explore how acamprosate (used to reduce alcohol dependence) alters diurnal patterns of ethanol intake. Male mPer2 mutant and WT (wild-type) mice were entrained to a 12:12 h light-dark (12L:12D) photocycle, and their locomotor and drinking activities were recorded. Circadian locomotor measurements confirmed that mPer2 mutants had an advanced onset of nocturnal activity of about 2 h relative to WTs, and an increased duration of nocturnal activity (p < .01). Also, mPer2 mutants preferred and consumed more ethanol and had more daily ethanol drinking episodes vs. WTs. Measurements of systemic ethanol using subcutaneous microdialysis confirmed the advanced rise in ethanol intake in the mPer2 mutants, with 24-h averages being ∼60 vs. ∼25 mM for WTs (p < .01). A 6-day regimen of single intraperitoneal (i.p.) acamprosate injections (300 mg/kg) at zeitgeber time (ZT) 10 did not alter the earlier onset of nocturnal ethanol drinking in the mPer2 mutants, but reduced the overall amplitude of drinking and preference (both p < .01). Acamprosate also reduced these parameters in WTs. These results suggest that elevated ethanol intake in mPer2 mutants may be a partial consequence of an earlier nighttime activity onset and increase in nocturnal drinking activity. The suppressive action of acamprosate on ethanol intake is not due to an altered diurnal pattern of drinking, but rather a decrease in the number of daily drinking bouts and amount of drinking per bout.

Background: Alcohol abuse leads to marked disruptions of circadian rhythms, and these disturbances in themselves can increase the drive to drink. Circadian clock timing is regulated by light, as well as by nonphotic influences such as food, social interactions, and wheel running. We previously reported that alcohol markedly disrupts photic and nonphotic modes of circadian rhythm regulation in Syrian hamsters. As an extension of this work, we characterize the hedonic interrelationship between wheel running and ethanol (EtOH) intake and the effects of environmental circadian disruption (long-term exposure to constant light [LL]) on the drive to drink. Methods: First, we tested the effect of wheel running on chronic free-choice consumption of a 20% (v/v) EtOH solution and water. Second, the effect of this alcohol drinking on wheel running in alcohol-naive animals was investigated. Third, we assessed the influence of LL, known to suppress locomotor activity and cause circadian rhythm disruption, on EtOH consumption and wheel-running behavior. Results: Inhibitory effects of wheel running on EtOH intake and vice versa were observed. Exposure to LL, while not affecting EtOH intake, induced rhythm splitting in 75% of the animals. Notably, the splitting phenotype was associated with lower levels of EtOH consumption and preference prior to, and throughout, the period of LL exposure. Conclusions: These results are evidence that exercise may offer an efficacious clinical approach to reducing EtOH intake. Also, predisposition for light-induced (or other) forms of circadian disruption may modulate the drive to drink.

Study objectives Episodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia. Methods EEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities (Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings. Results Two days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia. Conclusions These results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome.

STUDY OBJECTIVES Electroencephalographic slow wave activity (SWA) during non-rapid eye movement (NREM) sleep results from the synchronous oscillation of cortical neurons and is the standard measurement of sleep homeostasis. SWA is not a direct measure of sleep pressure accumulation, but rather a measure of the NREM-sleep response to accumulated sleep pressure. Currently, no practical standard for the direct measurement of sleep pressure accumulation exists. Recently, it was demonstrated that rat cortical neurons undergo oscillations during wake that are similar to the cortical oscillations responsible for SWA. Furthermore, these oscillations increase in number as time awake increases. Here we hypothesize that period-amplitude analysis of the electroencephalogram (EEG), which treats the EEG as a series of discrete waves, can measure these cortical oscillations, and thus, is a measure of sleep-pressure accumulation during extended wake. DESIGN Mice were sleep deprived for 24 h by confinement to a slowly rotating wheel in order to assess wake-dependent changes in EEG wave incidence. MEASUREMENTS AND RESULTS Continuous period-amplitude analysis of the waking EEG across 24 h of sleep deprivation revealed that the incidence of 2 to 6 Hz waves increased exponentially over the deprivation period. This increase in wave incidence appeared to occur in two phases with exponential time constants of approximately 0.12 h and 3 h. Further analysis revealed that the changes in wave incidence were significantly correlated with two established markers of sleep pressure, SWA and NREM sleep latency. CONCLUSIONS The data suggest that wave incidence is an effective method of measuring sleep homeostasis in the waking EEG that provides better temporal resolution than spectral power analysis.

Acamprosate suppresses alcohol intake and craving in recovering alcoholics; however, the central sites of its action are unclear. To approach this question, brain regions responsive to acamprosate were mapped using acamprosate microimplants targeted to brain reward and circadian areas implicated in alcohol dependence. mPer2 mutant mice with nonfunctional mPer2, a circadian clock gene that gates endogenous timekeeping, were included, owing to their high levels of ethanol intake and preference. Male wild-type (WT) and mPer2 mutant mice received free-choice (15%) ethanol/water for 3 wk. The ethanol was withdrawn for 3 wk and then reintroduced to facilitate relapse. Four days before ethanol reintroduction, mice received bilateral blank or acamprosate-containing microimplants releasing ∼50 ng/day into reward [ventral tegmental (VTA), peduculopontine tegmentum (PPT), and nucleus accumbens (NA)] and circadian [intergeniculate leaflet (IGL) and suprachiasmatic nucleus (SCN)] areas. The hippocampus was also targeted. Circadian locomotor activity was measured throughout. Ethanol intake and preference were greater in mPer2 mutants than in wild-type (WT) mice (27 g·kg−1·day−1 vs. 13 g·kg−1·day−1 and 70% vs. 50%, respectively; both, P < 0.05). In WTs, acamprosate in all areas, except hippocampus, suppressed ethanol intake and preference (by 40–60%) during ethanol reintroduction. In mPer2 mutants, acamprosate in the VTA, PPT, and SCN suppressed ethanol intake and preference by 20–30%. These data are evidence that acamprosate's suppression of ethanol intake and preference are manifest through actions within major reward and circadian sites.

Alcohol dependence is associated with impaired circadian rhythms and sleep. Ethanol administration disrupts circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol dependence on the circadian timing system. In this study, we extend previous work in C57BL/6J mice to: (i) characterize the suprachiasmatic nucleus (SCN) pharmacokinetics of acute systemic ethanol administration, (ii) explore the effects of acute ethanol on photic and nonphotic phase-resetting, and (iii) determine if the SCN is a direct target for photic effects.First, microdialysis was used to characterize the pharmacokinetics of acute intraperitoneal (i.p.) injections of 3 doses of ethanol (0.5, 1.0, and 2.0 g/kg) in the mouse SCN circadian clock. Second, the effects of acute i.p. ethanol administration on photic phase delays and serotonergic ([+]8-OH-DPAT-induced) phase advances of the circadian activity rhythm were assessed. Third, the effects of reverse-microdialysis ethanol perfusion of the SCN on photic phase-resetting were characterized.Peak ethanol levels from the 3 doses of ethanol in the SCN occurred within 20 to 40 minutes postinjection with half-lives for clearance ranging from 0.6 to 1.8 hours. Systemic ethanol treatment dose-dependently attenuated photic and serotonergic phase-resetting. This treatment also did not affect basal SCN neuronal activity as assessed by Fos expression. Intra-SCN perfusion with ethanol markedly reduced photic phase delays.These results confirm that acute ethanol attenuates photic phase-delay shifts and serotonergic phase-advance shifts in the mouse. This dual effect could disrupt photic and nonphotic entrainment mechanisms governing circadian clock timing. It is also significant that the SCN clock is a direct target for disruptive effects of ethanol on photic shifting. Such actions by ethanol could underlie the disruptive effects of alcohol abuse on behavioral, physiological, and endocrine rhythms associated with alcoholism.

Background: Alcohol dependence is associated with impaired circadian rhythms and sleep. Ethanol administration disrupts circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol dependence on the circadian timing system. In this study, we extend previous work in C57BL/6J mice to: (i) characterize the suprachiasmatic nucleus (SCN) pharmacokinetics of acute systemic ethanol administration, (ii) explore the effects of acute ethanol on photic and nonphotic phase-resetting, and (iii) determine if the SCN is a direct target for photic effects. Methods: First, microdialysis was used to characterize the pharmacokinetics of acute intraperitoneal (i.p.) injections of 3 doses of ethanol (0.5, 1.0, and 2.0 g/kg) in the mouse SCN circadian clock. Second, the effects of acute i.p. ethanol administration on photic phase delays and serotonergic ([+]8-OH-DPAT-induced) phase advances of the circadian activity rhythm were assessed. Third, the effects of reverse-microdialysis ethanol perfusion of the SCN on photic phase-resetting were characterized. Results: Peak ethanol levels from the 3 doses of ethanol in the SCN occurred within 20 to 40 minutes postinjection with half-lives for clearance ranging from 0.6 to 1.8 hours. Systemic ethanol treatment dose-dependently attenuated photic and serotonergic phase-resetting. This treatment also did not affect basal SCN neuronal activity as assessed by Fos expression. Intra-SCN perfusion with ethanol markedly reduced photic phase delays. Conclusions: These results confirm that acute ethanol attenuates photic phase-delay shifts and serotonergic phase-advance shifts in the mouse. This dual effect could disrupt photic and nonphotic entrainment mechanisms governing circadian clock timing. It is also significant that the SCN clock is a direct target for disruptive effects of ethanol on photic shifting. Such actions by ethanol could underlie the disruptive effects of alcohol abuse on behavioral, physiological, and endocrine rhythms associated with alcoholism.

Alcohol abuse leads to marked disruptions of circadian rhythms, and these disturbances in themselves can increase the drive to drink. Circadian clock timing is regulated by light, as well as by nonphotic influences such as food, social interactions, and wheel running. We previously reported that alcohol markedly disrupts photic and nonphotic modes of circadian rhythm regulation in Syrian hamsters. As an extension of this work, we characterize the hedonic interrelationship between wheel running and ethanol (EtOH) intake and the effects of environmental circadian disruption (long-term exposure to constant light [LL]) on the drive to drink.First, we tested the effect of wheel running on chronic free-choice consumption of a 20% (v/v) EtOH solution and water. Second, the effect of this alcohol drinking on wheel running in alcohol-naive animals was investigated. Third, we assessed the influence of LL, known to suppress locomotor activity and cause circadian rhythm disruption, on EtOH consumption and wheel-running behavior.Inhibitory effects of wheel running on EtOH intake and vice versa were observed. Exposure to LL, while not affecting EtOH intake, induced rhythm splitting in 75% of the animals. Notably, the splitting phenotype was associated with lower levels of EtOH consumption and preference prior to, and throughout, the period of LL exposure.These results are evidence that exercise may offer an efficacious clinical approach to reducing EtOH intake. Also, predisposition for light-induced (or other) forms of circadian disruption may modulate the drive to drink.

Chronic ethanol abuse is associated with disrupted circadian rhythms and sleep. Ethanol administration impairs circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol abuse on circadian timing. Here, we extend previous studies to explore the effects of chronic forced ethanol on photic phase-resetting, photic entrainment, and daily locomotor activity patterns in C57BL/6J mice.First, microdialysis was used to characterize the circadian patterns of ethanol uptake in the suprachiasmatic (SCN) circadian clock and correlate this with systemic ethanol levels and episodic drinking of 10 or 15% ethanol. Second, the effects of chronic forced ethanol drinking and withdrawal on photic phase-delays of the circadian activity rhythm were assessed. Third, the effects of chronic ethanol drinking on entrainment to a weak photic zeitgeber (1 minute of 25 lux intensity light per day) were assessed. This method was used to minimize any masking actions of light that could mask ethanol effects on clock entrainment.Peak ethanol levels in the SCN and periphery occurred during the dark phase and coincided with the time when light normally induces phase-delays in mice. These delays were dose-dependently inhibited by chronic ethanol and its withdrawal. Chronic ethanol did not impede re-entrainment to a shifted light cycle but affected entrainment under the weak photic zeitgeber and disrupted the daily pattern of locomotor activity.These results confirm that chronic ethanol consumption and withdrawal markedly impair circadian clock photic phase-resetting. Ethanol also disturbs the temporal structure of nighttime locomotor activity and photic entrainment. Collectively, these results suggest a direct action of ethanol on the SCN clock.

Background: Chronic ethanol abuse is associated with disrupted circadian rhythms and sleep. Ethanol administration impairs circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol abuse on circadian timing. Here, we extend previous studies to explore the effects of chronic forced ethanol on photic phase-resetting, photic entrainment, and daily locomotor activity patterns in C57BL/6J mice. Methods: First, microdialysis was used to characterize the circadian patterns of ethanol uptake in the suprachiasmatic (SCN) circadian clock and correlate this with systemic ethanol levels and episodic drinking of 10 or 15% ethanol. Second, the effects of chronic forced ethanol drinking and withdrawal on photic phase-delays of the circadian activity rhythm were assessed. Third, the effects of chronic ethanol drinking on entrainment to a weak photic zeitgeber (1 minute of 25 lux intensity light per day) were assessed. This method was used to minimize any masking actions of light that could mask ethanol effects on clock entrainment. Results: Peak ethanol levels in the SCN and periphery occurred during the dark phase and coincided with the time when light normally induces phase-delays in mice. These delays were dose-dependently inhibited by chronic ethanol and its withdrawal. Chronic ethanol did not impede re-entrainment to a shifted light cycle but affected entrainment under the weak photic zeitgeber and disrupted the daily pattern of locomotor activity. Conclusions: These results confirm that chronic ethanol consumption and withdrawal markedly impair circadian clock photic phase-resetting. Ethanol also disturbs the temporal structure of nighttime locomotor activity and photic entrainment. Collectively, these results suggest a direct action of ethanol on the SCN clock.