In vivo marker of brainstem myelin is associated to quantitative sleep parameters in healthy young men.

The regional integrity of brain subcortical structures has been implicated in sleep-wake regulation, however, their associations with sleep parameters remain largely unexplored. Here, we assessed association between quantitative Magnetic Resonance Imaging (qMRI)-derived marker of the myelin content of the brainstem and the variability in the sleep electrophysiology in a large sample of 18-to-31 years healthy young men (N = 321; ~ 22 years). Separate Generalized Additive Model for Location, Scale and Shape (GAMLSS) revealed that sleep onset latency and slow wave energy were significantly associated with MTsat estimates in the brainstem (pcorrected ≤ 0.03), with overall higher MTsat value associated with values reflecting better sleep quality. The association changed with age, however (MTsat-by-age interaction-pcorrected ≤ 0.03), with higher MTsat value linked to better values in the two sleep metrics in the younger individuals of our sample aged ~ 18 to 20 years. Similar associations were detected across different parts of the brainstem (pcorrected ≤ 0.03), suggesting that the overall maturation and integrity of the brainstem was associated with both sleep metrics. Our results suggest that myelination of the brainstem nuclei essential to regulation of sleep is associated with inter-individual differences in sleep characteristics during early adulthood. They may have implications for sleep disorders or neurological diseases related to myelin.

The Usefulness of Electronic Health Records From Preventive Youth Healthcare in the Recognition of Child Mental Health Problems.

Background and Objectives: Early identification of child mental health problems (MHPs) is important to provide adequate, timely treatment. Dutch preventive youth healthcare monitors all aspects of a child's healthy development. We explored the usefulness of their electronic health records (EHRs) in scientific research and aimed to develop prediction models for child MHPs. Methods: Population-based cohort study with anonymously extracted electronic healthcare data from preventive youth healthcare centers in the Leiden area, the Netherlands, from the period 2005-2015. Data was analyzed with respect to its continuity, percentage of cases and completeness. Logistic regression analyses were conducted to develop prediction models for the risk of a first recorded concern for MHPs in the next scheduled visit at age 3/4, 5/6, 10/11, and 13/14 years. Results: We included 26,492 children. The continuity of the data was low and the number of concerns for MHPs varied greatly. A large number of determinants had missing data for over 80% of the children. The discriminatory performance of the prediction models were poor. Conclusions: This is the first study exploring the usefulness of EHRs from Dutch preventive youth healthcare in research, especially in predicting child MHPs. We found the usefulness of the data to be limited and the performance of the developed prediction models was poor. When data quality can be improved, e.g., by facilitating accurate recording, or by data enrichment from other available sources, the analysis of EHRs might be helpful for better identification of child MHPs.

Psychological distress, cardiometabolic diseases and musculoskeletal pain: A cross-sectional, population-based study of syndemic ill health in a Dutch fishing village.

BACKGROUND: Disease clustering is a growing public health concern and is increasingly linked to adverse socioeconomic conditions. Few population-based studies have focussed on interaction between non-communicable diseases. In this cross-sectional study, we examine clustering of, and synergistic interactions between, frequently occurring non-communicable diseases in Katwijk, a former fishing village in the Netherlands. Additionally, our study identifies contextual variables associated with these clusters of non-communicable diseases. METHODS: In a survey among adults (>19 years) living in the former fishing village Katwijk, Netherlands, were asked about non-communicable diseases, psychological distress, self-rated health scores and contextual factors, eg, socio-demographic, psychosocial and health behavior characteristics. Interaction was measured on the additive and the multiplicative scale. We used generalized ordered logistic regression analysis to examine associations with contextual variables. RESULTS: Three disease clusters were found to be most prevalent among the study participants (n = 1408). Each cluster involved a combination of frequently occurring conditions in this population: psychological distress (n = 261, 19%), cardiometabolic diseases (n = 449, 32%) and musculoskeletal pain (n = 462, 33%). These three diseases interact synergistically on the additive scale to increase the odds of reporting a low self-rated health. None of the disease clusters showed a statistically significant positive interaction on a multiplicative scale. Multiple contextual factors were associated with these disease clusters, including gender, loneliness, experiencing financial stress, and a BMI≥30. CONCLUSION: Our findings imply that psychological distress, cardiometabolic diseases and musculoskeletal pain synergistically interact, leading to a much lower self-rated health than expected. Several contextual factors are related to this interaction emphasizing the importance of a multicomponent, ecological approach.

Favourable outcomes of a preventive screening and counselling programme for older people in underprivileged areas in the Netherlands: The PRIMUS project.

An aging population is associated with an increased prevalence of diabetes, cardiovascular diseases and depression. Important aspects of programmes targeted at older people are: to reach those at risk, effective screening, optimising advice, and referral to local interventions. We examined the effect of a preventive health consultation (PRIMUS), a multi-behavioural screening programme for persons aged 55-74 years in primary care. In a multi-centre randomised controlled trial, the effects of participating in the PRIMUS intervention were compared to a comparison group receiving personalised summaries and advice by postal mail, both preceded by a health risk assessment via a questionnaire. The intervention consisted of a baseline health risk assessment, followed by a preventive health consultation (after 4 weeks), and a follow-up visit (2 weeks later) in the primary care centre. A newly developed web-based computer-tailored programme supported the nurse practitioner during the consultation. Main outcomes measures were awareness of, and compliance with referral advice for changing unhealthy lifestyles. The PRIMUS preventive health consultation was successful in older people at risk for cardio metabolic diseases compared to the comparison group (compliance: RR 1.43; 95% CI 1.12-1.79; p < 0.05). The intervention was less successful in older people at risk for mental health problems. This preventive health consultation for older people resulted in positive changes in unhealthy behaviours by optimising reach, raising awareness, motivating and assisting individuals to change, and referring to local interventions.

Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial.

UNLABELLED: The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration. INTRODUCTION: Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration. METHODS: This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study. RESULTS: Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern. CONCLUSION: Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.

Effect of subcutaneous insulin detemir on glucose flux, lipolysis and electroencephalography in type 1 diabetes.

The aim of the present study was to investigate the effects of subcutaneous detemir on glucose flux, lipid metabolism and brain function. Twelve people with type 1 diabetes received, in random order, 0.5 units/kg body weight detemir or NPH insulin. Glucose concentration was clamped at 5 mmol/l then increased to 10 mmol/l. Glucose production rate (glucose Ra), glucose uptake (glucose Rd) and glycerol production (glycerol Ra) were measured with a constant intravenous infusion of [6,6(2) H(2)]glucose and [(2)H(5)]glycerol. Electroencephalography direct current (DC) and alternating current (AC) potentials were measured. While detemir induced similar effects on glucose Ra, glucose Rd and glycerol Ra during euglycaemia compared with NPH, it triggered a distinct negative shift in DC potentials, with a significant treatment effect in frontal cerebrocortical channels (p < 0.001). AC spectral power showed significant differences in theta and alpha frequencies during euglycaemia (p = 0.03). Subcutaneous detemir exerts different effects on brain function when compared with NPH in people with type 1 diabetes. This may be an important mechanism behind the limitation of weight gain with detemir.

GPs' perspectives on preventive care for older people: a focus group study.

BACKGROUND: Preventive care traditionally aims to prevent diseases or injuries. For older people, different aims of prevention, such as maintenance of independence and wellbeing, are increasingly important. AIM: To explore GPs' perspectives on preventive care for older people. DESIGN AND SETTING: Qualitative study comprising six focus groups with GPs in the Netherlands. METHOD: The focus-group discussions with 37 GPs were analysed using the framework analysis method. RESULTS: Whether or not to implement preventive care for older people depends on the patient's individual level of vitality, as perceived by the GP. For older people with a high level of vitality, GPs confine their role to standardised disease-oriented prevention on a patient's request; when the vitality levels in older people fall, the scope of preventive care shifts from prevention of disease to prevention of functional decline. For older, vulnerable people, GPs expect most benefit from a proactive, individualised approach, enabling them to live as independently as possible. Based on these perspectives, a conceptual model for preventive care was developed, which describes GPs' different perspectives toward older people who are vulnerable and those with high levels of vitality. It focuses on five main dimensions: aim of care (prevention of disease versus prevention of functional decline), concept of care (disease model versus functional model), initiator (older persons themselves versus GP), target groups (people with requests versus specified risk groups), and content of preventive care (mainly cardiovascular risk management versus functional decline). CONCLUSION: GPs' perspectives on preventive care are determined by their perception of the level of vitality of their older patients. Preventive care for older people with high levels of vitality may consist of a standardised disease-oriented approach; those who are vulnerable will need an individualised approach to prevent functional decline.

Enhanced slow wave sleep and improved sleep maintenance after gaboxadol administration during seven nights of exposure to a traffic noise model of transient insomnia.

Slow wave sleep (SWS) has been reported to correlate with sleep maintenance, but whether pharmacological enhancement of SWS also leads to improved sleep maintenance is not known. Here we evaluate the time-course of the effects of gaboxadol, an extra-synaptic gamma-aminobutyric acid (GABA) agonist, on SWS, sleep maintenance, and other sleep measures in a traffic noise model of transient insomnia. After a placebo run-in, 101 healthy subjects (20-78 y) were randomized to gaboxadol (n = 50; 15 mg in subjects <65 y and 10 mg in subjects ≥65 y) or placebo (n = 51) for 7 nights (N1-N7). The model caused some disruption of sleep initiation and maintenance, with greatest effects on N1. Compared with placebo, gaboxadol increased SWS and slow wave activity throughout N1 to N7 (p < 0.05). Gaboxadol reduced latency to persistent sleep overall (N1-N7) by 4.5 min and on N1 by 11 min (both p < 0.05). Gaboxadol increased total sleep time (TST) overall by 16 min (p < 0.001) and on N1 by 38 min (p < 0.0001). Under gaboxadol, wakefulness after sleep onset was reduced by 11 min overall (p < 0.01) and by 29 min on N1 (p < 0.0001), and poly-somnographic awakenings were reduced on N1 (p < 0.05). Gaboxadol reduced self-reported sleep onset latency overall and on N1 (both p < 0.05) and increased self-reported TST overall (p < 0.05) and on N1 (p < 0.01). Subjective sleep quality improved overall (p < 0.01) and on N1 (p < 0.0001). Increases in SWS correlated with objective and subjective measures of sleep maintenance and subjective sleep quality under placebo and gaboxadol (p < 0.05). Gaboxadol enhanced SWS and reduced the disruptive effects of noise on sleep initiation and maintenance.

Spectral quality of light modulates emotional brain responses in humans.

Light therapy can be an effective treatment for mood disorders, suggesting that light is able to affect mood state in the long term. As a first step to understand this effect, we hypothesized that light might also acutely influence emotion and tested whether short exposures to light modulate emotional brain responses. During functional magnetic resonance imaging, 17 healthy volunteers listened to emotional and neutral vocal stimuli while being exposed to alternating 40-s periods of blue or green ambient light. Blue (relative to green) light increased responses to emotional stimuli in the voice area of the temporal cortex and in the hippocampus. During emotional processing, the functional connectivity between the voice area, the amygdala, and the hypothalamus was selectively enhanced in the context of blue illumination, which shows that responses to emotional stimulation in the hypothalamus and amygdala are influenced by both the decoding of vocal information in the voice area and the spectral quality of ambient light. These results demonstrate the acute influence of light and its spectral quality on emotional brain processing and identify a unique network merging affective and ambient light information.

Acute alertness-promoting effects of a novel histamine subtype-3 receptor inverse agonist in healthy sleep-deprived male volunteers.

The alertness-promoting effect of MK-0249 (10 or 50 mg), a histamine subtype-3 receptor (HRH3) inverse agonist (IA), was evaluated in the stimulant reference sleep deprivation model (SRSDM) using a double-blind, double-dummy, placebo- and modafinil- (200 mg) controlled, four-period crossover design in 24 healthy young men. The two primary hypotheses were related to sleep latency (first appearance of one epoch of stage 2, 3, or 4 or REM sleep, as detected using polysomnography (PSG)) at 8:00 AM on day 2. Statistically significant increases in sleep latency were observed in association with the use of modafinil 200 mg (9.07 min; P < 0.0001), MK-0249 50 mg (5.17 min; P = 0.008), and MK-0249 10 mg (5.45 min; P = 0.005) at the maintenance of wakefulness test (MWT) at 8:00 AM. Sleep latency was higher when averaged over all MWT time points (P < 0.0001 for modafinil and for both doses of MK-0249). The alertness-promoting effect with the use of MK-0249 in the SRSDM suggests that HRH3 IAs may be effective in disorders involving excessive somnolence.

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

Sex differences and the effect of gaboxadol and zolpidem on EEG power spectra in NREM and REM sleep.

Hypnotics that interact with the GABA(A) receptor have marked effects on the electroencephalogram (EEG) during sleep. It is not known whether the effects of hypnotics on EEG power spectra differ between the sexes. The effects of 5, 10 and 15 mg of gaboxadol (GBX) and 10 mg of zolpidem (ZOL) on EEG power spectra were assessed in a randomized, double-blind, placebo-controlled, 5-way cross-over design study using a phase-advance model of transient insomnia. Sleep stage specific EEG power spectra were computed in 36 men and 45 women. GBX enhanced power density in delta and theta activity in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, and suppressed sleep spindle activity in NREM sleep. The increase of delta and theta activity in NREM and REM sleep was significantly larger for women than for men but the suppression of spindle activity did not differ between the sexes. After ZOL administration, no sex differences were observed in the reduction of delta and theta activity in NREM sleep, but the increase in sleep spindle activity in NREM sleep was greater in women than in men. These sex dependent and differential effects of GBX and ZOL may be related to their differential affinity for GABA(A) receptor subtypes and their modulation by neurosteroids.

Use of transdermal melatonin delivery to improve sleep maintenance during daytime.

Oral melatonin (MEL) can improve daytime sleep, but the hormone's short elimination half-life limits its use as a hypnotic in shift workers and individuals with jet lag or other sleep problems. Here we show, in healthy subjects, that transdermal delivery of MEL during the daytime can elevate plasma MEL and reduce waking after sleep onset, by promoting sleep in the latter part of an 8-h sleep opportunity. Transdermal MEL may have advantages over fast-release oral MEL in improving sleep maintenance during adverse circadian phases.

Circadian clock genes and sleep homeostasis.

Circadian and sleep-homeostatic processes both contribute to sleep timing and sleep structure. Elimination of circadian rhythms through lesions of the suprachiasmatic nuclei (SCN), the master circadian pacemaker, leads to fragmentation of wakefulness and sleep but does not eliminate the homeostatic response to sleep loss as indexed by the increase in EEG delta power. In humans, EEG delta power declines during sleep episodes nearly independently of circadian phase. Such observations have contributed to the prevailing notion that circadian and homeostatic processes are separate but recent data imply that this segregation may not extend to the molecular level. Here we summarize the criteria and evidence for a role for clock genes in sleep homeostasis. Studies in mice with targeted disruption for core circadian clock genes have revealed alterations in circadian rhythmicity as well as changes in sleep duration, sleep structure and EEG delta power. Clock-gene expression in brain areas outside the SCN, in particular the cerebral cortex, depends to a large extent on prior sleep-wake history. Evidence for effects of clock genes on sleep homeostasis has also been obtained in Drosophila and humans, pointing to a phylogenetically preserved pathway. These findings suggest that, while within the SCN clock genes are utilized to set internal time-of-day, in the forebrain the same feedback circuitry may be utilized to track time spent awake and asleep. The mechanisms by which clock-gene expression is coupled to the sleep-wake distribution could be through cellular energy charge whereby clock genes act as energy sensors. The data underscore the interrelationships between energy metabolism, circadian rhythmicity, and sleep regulation.

Wavelength-dependent modulation of brain responses to a working memory task by daytime light exposure.

In addition to classical visual effects, light elicits nonvisual brain responses, which profoundly influence physiology and behavior. These effects are mediated in part by melanopsin-expressing light-sensitive ganglion cells that, in contrast to the classical photopic system that is maximally sensitive to green light (550 nm), is very sensitive to blue light (470-480 nm). At present, there is no evidence that blue light exposure is effective in modulating nonvisual brain activity related to complex cognitive tasks. Using functional magnetic resonance imaging, we show that, while participants perform an auditory working memory task, a short (18 min) daytime exposure to blue (470 nm) or green (550 nm) monochromatic light (3 x 10(13) photons/cm2/s) differentially modulates regional brain responses. Blue light typically enhanced brain responses or at least prevented the decline otherwise observed following green light exposure in frontal and parietal cortices implicated in working memory, and in the thalamus involved in the modulation of cognition by arousal. Our results imply that monochromatic light can affect cognitive functions almost instantaneously and suggest that these effects are mediated by a melanopsin-based photoreceptor system.

Sleep quantity, sleep difficulties and their perceived consequences in a representative sample of some 2000 British adults.

Sleep problems and sleep restriction are popular topics of discussion, but few representative data are available. We document Britain's sleep based on a nationally representative sample of 1997, 16-93 year olds, who participated in face-to-face interviews. Fifty-eight per cent of respondents reported sleep problems on one or more nights the previous week and 18% reported that the sleep they obtained was insufficient on the majority of nights. Sleep durations were longest in the youngest participants (16-24 years), who slept on average 1 h longer than the 7.04 (SD 1.55) sample average. Sleep duration showed no appreciable change beyond middle age. Men and women reported sleeping similar amounts but women reported more sleep problems. Men reported sleeping less when there were more children in their household. Workers (i.e. employees) reported sleeping less on workdays than on non-workdays, but those based at home and those not employed did not. Inability to switch off from work was related to sleep duration on non-workdays. Across all participants average sleep duration exhibited a non-monotonic association with quality of life (i.e. contribution of sleep to energy, satisfaction and success in work, home and leisure activities). Quality of life was positively associated with sleep duration, for durations up to 9 h, but negatively associated with quality of life beyond this. Comparison of our data with the US national sleep poll revealed that Britain sleeps as little or less, whereas a comparison with data reported 40 years ago revealed no statistically reliable reductions. Although we may not sleep less than four decades ago, when we report sleeping less we also tend to associate that lack of sleep with poor performance and quality of life.

Separation of circadian and wake duration-dependent modulation of EEG activation during wakefulness.

The separate contribution of circadian rhythmicity and elapsed time awake on electroencephalographic (EEG) activity during wakefulness was assessed. Seven men lived in an environmental scheduling facility for 4 weeks and completed fourteen 42.85-h 'days', each consisting of an extended (28.57-h) wake episode and a 14.28-h sleep opportunity. The circadian rhythm of plasma melatonin desynchronized from the 42.85-h day. This allowed quantification of the separate contribution of circadian phase and elapsed time awake to variation in EEG power spectra (1-32 Hz). EEG activity during standardized behavioral conditions was markedly affected by both circadian phase and elapsed time awake in an EEG frequency- and derivation-specific manner. The nadir of the circadian rhythm in alpha (8-12 Hz) activity in both fronto-central and occipito-parietal derivations occurred during the biological night, close to the crest of the melatonin rhythm. The nadir of the circadian rhythm of theta (4.5-8 Hz) and beta (20-32 Hz) activity in the fronto-central derivation was located close to the onset of melatonin secretion, i.e. during the wake maintenance zone. As time awake progressed, delta frequency (1-4.5 Hz) and beta (20-32 Hz) activity rose monotonically in frontal derivations. The interaction between the circadian and wake-dependent increase in frontal delta was such that the intrusion of delta was minimal when sustained wakefulness coincided with the biological day, but pronounced during the biological night. Our data imply that the circadian pacemaker facilitates frontal EEG activation during the wake maintenance zone, by generating an arousal signal that prevents the intrusion of low-frequency EEG components, the propensity for which increases progressively during wakefulness.

Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans.

Endogenous circadian clocks are robust regulators of physiology and behavior. Synchronization or entrainment of biological clocks to environmental time is adaptive and important for physiological homeostasis and for the proper timing of species-specific behaviors. We studied subjects in the laboratory for up to 55 days each to determine the ability to entrain the human clock to a weak circadian synchronizing stimulus [scheduled activity-rest cycle in very dim (approximately 1.5 lux in the angle of gaze) light-dark cycle] at three approximately 24-h periods: 23.5, 24.0, and 24.6 h. These studies allowed us to test two competing hypotheses as to whether the period of the human circadian pacemaker is near to or much longer than 24 h. We report here that imposition of a sleep-wake schedule with exposure to the equivalent of candle light during wakefulness and darkness during sleep is usually sufficient to maintain circadian entrainment to the 24-h day but not to a 23.5- or 24.6-h day. Our results demonstrate functionally that, in normally entrained sighted adults, the average intrinsic circadian period of the human biological clock is very close to 24 h. Either exposure to very dim light and/or the scheduled sleep-wake cycle itself can entrain this near-24-h intrinsic period of the human circadian pacemaker to the 24-h day.

Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights.

Sleep, circadian rhythm, and neurobehavioral performance measures were obtained in five astronauts before, during, and after 16-day or 10-day space missions. In space, scheduled rest-activity cycles were 20-35 min shorter than 24 h. Light-dark cycles were highly variable on the flight deck, and daytime illuminances in other compartments of the spacecraft were very low (5.0-79.4 lx). In space, the amplitude of the body temperature rhythm was reduced and the circadian rhythm of urinary cortisol appeared misaligned relative to the imposed non-24-h sleep-wake schedule. Neurobehavioral performance decrements were observed. Sleep duration, assessed by questionnaires and actigraphy, was only approximately 6.5 h/day. Subjective sleep quality diminished. Polysomnography revealed more wakefulness and less slow-wave sleep during the final third of sleep episodes. Administration of melatonin (0.3 mg) on alternate nights did not improve sleep. After return to earth, rapid eye movement (REM) sleep was markedly increased. Crewmembers on these flights experienced circadian rhythm disturbances, sleep loss, decrements in neurobehavioral performance, and postflight changes in REM sleep.