520-d Isolation and confinement simulating a flight to Mars reveals heightened immune responses and alterations of leukocyte phenotype.

During interplanetary exploration, chronic stress caused by long term isolation and confinement in the spacecraft is one of the major concerns of physical and psychological health of space travelers. And for human on Earth, more and more people live in an isolated condition, which has become a common social problem in modern western society. Collective evidences have indicated prolonged chronic stress could bring big influence to human immune function, which may lead to a variety of health problems. However, to what extent long-term isolation can affect the immune system still remains largely unknow. A simulated 520-d Mars mission provided an extraordinary chance to study the effect of prolonged isolation. Six healthy males participated in this mission and their active neuroendocrine and immune conditions were studied with saliva and blood samples from all participants on chosen time points during the isolation period. As a typical neuroendocrine parameter, stress hormone cortisol was measured in the morning saliva samples. Immune phenotype changes were monitored through peripheral leukocyte phenotype analysis. Using an ex vivo viral infection simulation assay we assessed the immune response changes characterized by the ability to produce representative endogenous pro-inflammatory cytokines. The results of this study revealed elevated cortisol levels, increased lymphocyte amount and heightened immune responses, suggesting that prolonged isolation acting as chronic stressors are able to trigger leukocyte phenotype changes and poorly controlled immune responses.

Fetal exposure to narcotics: neonatal sleep as a measure of nervous system disturbance.

Newborn infants, chronically exposed in utero to low doses of methadone with or without concomitant heroin, display more rapid eye movement sleep and less quiet sleep than control infants, while babies fetally exposed to both opiates and nonopiates have less organization of sleep states. Other perinatal factors, such as birth weight and gestational age, are related more to the amount of fetal drug exposure than to the type.

Leukocytosis and natural killer cell function parallel neurobehavioral fatigue induced by 64 hours of sleep deprivation.

The hypothesis that sleep deprivation depresses immune function was tested in 20 adults, selected on the basis of their normal blood chemistry, monitored in a laboratory for 7 d, and kept awake for 64 h. At 2200 h each day measurements were taken of total leukocytes (WBC), monocytes, granulocytes, lymphocytes, eosinophils, erythrocytes (RBC), B and T lymphocyte subsets, activated T cells, and natural killer (NK) subpopulations (CD56/CD8 dual-positive cells, CD16-positive cells, CD57-positive cells). Functional tests included NK cytotoxicity, lymphocyte stimulation with mitogens, and DNA analysis of cell cycle. Sleep loss was associated with leukocytosis and increased NK cell activity. At the maximum sleep deprivation, increases were observed in counts of WBC, granulocytes, monocytes, NK activity, and the proportion of lymphocytes in the S phase of the cell cycle. Changes in monocyte counts correlated with changes in other immune parameters. Counts of CD4, CD16, CD56, and CD57 lymphocytes declined after one night without sleep, whereas CD56 and CD57 counts increased after two nights. No changes were observed in other lymphocyte counts, in proliferative responses to mitogens, or in plasma levels of cortisol or adrenocorticotropin hormone. The physiologic leukocytosis and NK activity increases during deprivation were eliminated by recovery sleep in a manner parallel to neurobehavioral function, suggesting that the immune alterations may be associated with biological pressure for sleep.

Commentary: future considerations for models of human neurobehavioral function.

Modeling human neurobehavioral functions has the goal of identifying work-rest schedules that are safer and more productive. The models of Folkard et al. and of Jewett and Kronauer illustrate excellent progress toward this goal. Examination of these models reveals four additional areas that need to be addressed to facilitate continued development of accurate models of neurobehavioral functions. (1) The choice of neurobehavioral metrics may have a significant influence on model development. The lack of correlation among different neurobehavioral measures may make comparisons of models difficult. Many neurobehavioral measures are confounded by secondary and random error variance that can lead to model distortion. Although different models may ultimately be required for different neurobehavioral functions, measures that have been extensively validated to be sensitive to circadian variation and sleep loss should take priority in model development. (2) Because error variance in neurobehavioral outcomes can be substantial in uncontrolled environments, model validation should proceed from controlled laboratory protocols to real-world scenarios. Once validated, the ability of a model to predict field data can be tested. (3) While neurobehavioral models have been developed to predict behavior over time (i.e., within-subjects), to be useful in the real world, models will also ultimately have to provide estimates of between-subject variation in vulnerability to neurobehavioral dysfunction during night work or sleep loss (e.g., younger versus older workers). (4) Finally, to be theoretically accurate and practically useful, models of human neurobehavioral functions should be able to predict both cumulative effects (i.e., across days or weeks) and the influence of countermeasures (e.g., light, naps, caffeine).

Rapid eye movement sleep disturbance in posttraumatic stress disorder.

The subjective sleep disturbance in posttraumatic stress disorder (PTSD), including the repetitive, stereotypical anxiety dream, suggests dysfunctional rapid eye movement (REM) sleep mechanisms. The polysomnograms of a group of physically healthy combat veterans with current PTSD were compared with those of an age-appropriate normal control group. Tonic and phasic REM sleep measures in the PTSD subjects were elevated on the second night of recorded sleep. Increased phasic REM sleep activity persisted in the PTSD group on the subsequent night. During the study, an anxiety dream occurred in a PTSD subject in REM sleep. The results are consistent with the view that a dysregulation of the REM sleep control system, particularly phasic event generation, may be involved in the pathogenesis of PTSD. The finding of a specific disturbance of sleep unique to PTSD may have significant implications for the design of effective treatments for PTSD.

Rapid eye movement sleep changes during the adaptation night in combat veterans with posttraumatic stress disorder.

BACKGROUND: Hyperarousal in posttraumatic stress disorder (PTSD) is manifested during sleep as well as waking. Elevated rapid eye movement sleep (REMS) phasic activity, likely signifying central nervous system alerting, has been identified in PTSD. The authors reasoned that PTSD compared to control subjects would show particularly increased REMS phasic activity on the first night of polysomnography, with adaptation to a novel environment. METHODS: First-night polysomnograms of 17 veterans with PTSD were compared with those of 11 control subjects. Sleep was also studied in subsets of both groups over two nights. RESULTS: On the first night, the PTSD subjects had a higher density of rapid eye movements in the first REMS period. This measure was increased on the first compared to the second night, but there was no interaction effect between night and group. CONCLUSIONS: REMS changes are again demonstrated in veterans with PTSD. Introduction to a novel environment activated a REMS phasic process, but not differentially in PTSD compared to control subjects.

Neurobehavioral consequences of arousals.

The neurobehavioral deficits of obstructive sleep apnea syndrome (OSAS) are often attributed to the rate of respiratory disturbance or rate of arousals during sleep. However, sleep disordered breathing is also associated with other changes in sleep infrastructure that may account for cumulative waking deficits. This was illustrated in polysomnographic data from 1,521 patients with OSAS where increasing arousal indices were associated with increased duration of stage 1 sleep and concomitant reduction in total sleep time. Similar results have been found in paradigms in which sleep was experimentally fragmented in healthy individuals. It appears that chronic fragmentation of sleep, whether by apneas or acoustic stimuli, leads to cumulative homeostatic pressure for sleep, which may explain a number of phenomenon characteristic of both untreated OSAS patients and experimentally fragmented sleepers: (1) increased arousal threshold, (2) rapid return to sleep after arousal, (3) fewer awakenings over time, (4) increased sleep inertia on awakenings, (5) increased amnesia for arousals, and (6) daytime sleepiness. Elevated homeostatic drive for sleep appears to be a function of both the frequency of arousals within a night and the chronicity of sleep fragmentation across nights, neither of which have been adequately modeled in experimental studies of healthy subjects.

Review of regulations and guidelines for commercial and noncommercial drivers with sleep apnea and narcolepsy.

Studies show that persons with sleep disorders, such as sleep apnea and narcolepsy, have an increased incidence of automobile accidents. The goal of this study was to review any regulations or guidelines dealing with fitness to drive of persons with sleep disorders in all the 50 states and countries around the world. Several authorities in the United States and abroad in fact have produced guidelines or regulations stating that certain of these persons are not fit to drive. As of March 1994, only four states in the United States (Maryland, North Carolina, Oregon and Utah) had guidelines for narcolepsy, while two had guidelines for both narcolepsy and sleep apnea (California and Texas). In Maine, guidelines had been proposed for sleep apnea. In contrast, almost all Canadian provinces have guidelines for both sleep apnea and narcolepsy, as does the United Kingdom. There are, however, considerable variations in the nature of the regulations used in different states, Canadian provinces and countries. These variations are not based on scientific data. Currently the impact of these regulations on crash rates or on the practice of sleep medicine has not been assessed.

Time-on-task decrements in "steer clear" performance of patients with sleep apnea and narcolepsy.

Loss of attention with time-on-task reflects the increasing instability of the waking state during performance in experimentally induced sleepiness. To determine whether patients with disorders of excessive sleepiness also displayed time-on-task decrements indicative of wake state instability, visual sustained attention performance on "Steer Clear," a computerized simple RT driving simulation task, was compared among 31 patients with untreated sleep apnea, 16 patients with narcolepsy, and 14 healthy control subjects. Vigilance decrement functions were generated by analyzing the number of collisions in each of six four-minute periods of Steer Clear task performance in a mixed-model analysis of variance and linear regression equations. As expected, patients had more Steer Clear collisions than control subjects (p=0.006). However, the inter-subject variability in errors among the narcoleptic patients was four-fold that of the apnea patients, and 100-fold that of the controls volunteers; the variance in errors among untreated apnea patients was 27-times that of controls. The results of transformed collision data revealed main effects for group (p=0.006), time-on-task (p=0.001), and a significant interaction (p=0.022). Control subjects showed no clear evidence of increasing collision errors with time-on-task (adjusted R2=0.22), while apnea patients showed a trend toward vigilance decrement (adjusted R2=0.42, p=0.097), and narcolepsy patients evidenced a robust linear vigilance decrement (adjusted R2=0.87, p=0.004). The association of disorders of excessive somnolence with escalating time-on-task decrements makes it imperative that when assessment of neurobehavioral performance is conducted in patients, it involves task durations and analyses that will evaluate the underlying vulnerability of potentially sleepy patients to decrements over time in tasks that require sustained attention and timely responses, both of which are key components in safe driving performance.

Dose-response relationship between sleep duration and human psychomotor vigilance and subjective alertness.

Although it has been well documented that sleep is required for human performance and alertness to recover from low levels after prolonged periods of wakefulness, it remains unclear whether they increase in a linear or asymptotic manner during sleep. It has been postulated that there is a relation between the rate of improvement in neurobehavioral functioning and rate of decline of slow-wave sleep and/or slow-wave activity (SWS/SWA) during sleep, but this has not been verified. Thus, a cross-study comparison was conducted in which dose-response curves (DRCs) were constructed for Stanford Sleepiness Scale (SSS) and Psychomotor Vigilance Task (PVT) tests taken at 1000 hours by subjects who had been allowed to sleep 0 hours, 2 hours, 5 hours or 8 hours the previous night. We found that the DRCs to each PVT metric improved in a saturating exponential manner, with recovery rates that were similar [time constant (T) approximately 2.14 hours] for all the metrics. This recovery rate was slightly faster than, though not statistically significantly different from, the reported rate of SWS/SWA decline (T approximately 2.7 hours). The DRC to the SSS improved much more slowly than psychomotor vigilance, so that it could be fit equally well by a linear function (slope = -0.26) or a saturating exponential function (T = 9.09 hours). We conclude that although SWS/SWA, subjective alertness, and a wide variety of psychomotor vigilance metrics may all change asymptotically during sleep, it remains to be determined whether the underlying physiologic processes governing their expression are different.

Temporal placement of a nap for alertness: contributions of circadian phase and prior wakefulness.

Napping can enhance alertness during sustained wakefulness, but the importance of the temporal placement of the nap between days and within the circadian cycle remains controversial. To resolve these issues, a between-groups study was conducted with 41 healthy, young adults permitted a 2-h nap at one of five times during a 56-h period otherwise devoid of sleep. Naps were placed 12 h apart, near the circadian peak (P) or trough (T), and were preceded by 6, 18, 30, 42, or 54 h of wakefulness. Visual reaction time (RT) performance, Stanford Sleepiness Scale (SSS) ratings, and sublingual temperature were assessed every few hours throughout the 56 h, which took place in an environment free of time cues. All groups displayed a circadian-modulated decline in RT measures and increases in SSS functions as sleep loss progressed. A nap placed at any time in the protocol improved RT performance, particularly in the lapse domain, but not SSS ratings. Comparisons within groups of circadian temperature cycles for the first versus second day of the protocol indicated that early naps (P6, T18, P30) tended to prevent the mean drop in temperature across days. The earlier naps (P6, T18) yielded more robust and longer lasting RT performance benefits, which extended beyond 24 h after the naps, despite the fact that they were comprised of lighter sleep than later naps. Circadian placement of naps (P vs. T) did not affect the results on any parameter. In terms of temporal placement, therefore, napping prior to a night of sleep loss is more important for meeting subsequent performance demands than is the circadian placement of the nap. SSS ratings suggest that the napper is not aware of these performance benefits. Because the longest lasting RT gains followed early naps, which were composed of less deep sleep than later naps, napping during prolonged sleep loss may serve to prevent sleepiness more readily than it permits recovery from it.

A survey screen for prediction of apnea.

Questionnaire data from patients presenting at three sleep disorders centers were used to develop and assess a screening tool for sleep apnea based on the reporting of the frequency of various symptoms of sleep apnea and other sleep disorders plus age, body mass index (BMI) and gender. Patients were not specifically referred for suspicion of sleep apnea. Separate factor analyses of survey responses from 658, 193 and 77 respondents from the first, second and third sites, respectively, each yielded four orthogonal factors, one of which accounted for all the questions concerned with the frequency of disordered breathing during sleep. The survey was shown to be reliable in a subset of patients from one of the sites (test-retest correlation = 0.92). Survey data were then compared to a clinical measure of sleep apnea (respiratory disturbance index) obtained from polysomnography. A multivariable apnea risk index including survey responses, age, gender and BMI was estimated using multiple logistic regression in a total sample of 427 respondents from two of the sites. Predictive ability was assessed using receiver operating characteristic (ROC) curves. The area under the ROC curve was 0.79 (p < 0.0001). For BMI alone, it was 0.73, and for an index measuring the self-report of the frequency of apnea symptoms, it was 0.70. The multivariable apnea risk index has potential utility in clinical settings.

Motor dysfunction during sleep in posttraumatic stress disorder.

A subjective disturbance of sleep, including the occurrence of repetitive, stereotypical anxiety dreams, is characteristic of posttraumatic stress disorder (PTSD). The phenomenology of the PTSD anxiety dream has seemed most consistent with an underlying rapid eye movement (REM) sleep dysfunction. However, motor behavior reportedly can accompany PTSD dreams, and normal REM sleep typically involves a nearly total paralysis of the body musculature. As a means of understanding this discrepancy, anterior tibialis muscle activity during sleep was studied in a group of Vietnam combat veterans with current PTSD and in an age-matched normal control group. The PTSD subjects had a higher percentage of REM sleep epochs with at least one prolonged twitch burst; they also were more likely to have periodic limb movements in sleep, during nonrapid eye movement sleep. Both these forms of muscle activation also have been observed in REM behavior disorder (RBD), a parasomnia characterized by the actual enactment of dream sequences during REM sleep. The identification of RBD-like signs in PTSD adds to the evidence for a fundamental disturbance of REM sleep phasic mechanisms in PTSD.

Caffeine eliminates psychomotor vigilance deficits from sleep inertia.

STUDY OBJECTIVES: This study sought to establish the effects of caffeine on sleep inertia, which is the ubiquitous phenomenon of cognitive performance impairment, grogginess and tendency to return to sleep immediately after awakening. DESIGN: 28 normal adult volunteers were administered sustained low-dose caffeine or placebo (randomized double-blind) during the last 66 hours of an 88-hour period of extended wakefulness that included seven 2-hour naps during which polysomnographical recordings were made. Every 2 hours of wakefulness, and immediately after abrupt awakening from the naps, psychomotor vigilance performance was tested. SETTING: N/A. PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: In the placebo condition, sleep inertia was manifested as significantly impaired psychomotor vigilance upon awakening from the naps. This impairment was absent in the caffeine condition. Caffeine had only modest effects on nap sleep. CONCLUSIONS: Caffeine was efficacious in overcoming sleep inertia. This suggests a reason for the popularity of caffeine-containing beverages after awakening. Caffeine's main mechanism of action on the central nervous system is antagonism of adenosine receptors. Thus, increased adenosine in the brain upon awakening may be the cause of sleep inertia.

Cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4-5 hours per night.

To determine whether a cumulative sleep debt (in a range commonly experienced) would result in cumulative changes in measures of waking neurobehavioral alertness, 16 healthy young adults had their sleep restricted 33% below habitual sleep duration, to an average 4.98 hours per night [standard deviation (SD) = 0.57] for seven consecutive nights. Subjects slept in the laboratory, and sleep and waking were monitored by staff and actigraphy. Three times each day (1000, 1600, and 2200 hours) subjects were assessed for subjective sleepiness (SSS) and mood (POMS) and were evaluated on a brief performance battery that included psychomotor vigilance (PVT), probed memory (PRM), and serial-addition testing, Once each day they completed a series of visual analog scales (VAS) and reported sleepiness and somatic and cognitive/emotional problems. Sleep restriction resulted in statistically robust cumulative effects on waking functions. SSS ratings, subscale scores for fatigue, confusion, tension, and total mood disturbance from the POMS and VAS ratings of mental exhaustion and stress were evaluated across days of restricted sleep (p = 0.009 to p = 0.0001). PVT performance parameters, including the frequency and duration of lapses, were also significantly increased by restriction (p = 0.018 to p = 0.0001). Significant time-of-day effects were evident in SSS and PVT data, but time-of-day did not interact with the effects of sleep restriction across days. The temporal profiles of cumulative changes in neurobehavioral measures of alertness as a function of sleep restriction were generally consistent. Subjective changes tended to precede performance changes by 1 day, but overall changes in both classes of measure were greatest during the first 2 days (P1, P2) and last 2 days (P6, P7) of sleep restriction. Data from subsets of subjects also showed: 1) that significant decreases in the MSLT occurred during sleep restriction, 2) that the elevated sleepiness and performance deficits continued beyond day 7 of restriction, and 3) that recovery from these deficits appeared to require two full nights of sleep. The cumulative increase in performance lapses across days of sleep restriction correlated closely with MSLT results (r = -0.95) from an earlier comparable experiment by Carskadon and Dement (1). These findings suggest that cumulative nocturnal sleep debt had a dynamic and escalating analog in cumulative daytime sleepiness and that asymptotic or steady-state sleepiness was not achieved in response to sleep restriction.

An instrument to measure functional status outcomes for disorders of excessive sleepiness.

This article reports the development of the functional outcomes of sleep questionnaire (FOSQ). This is the first self-report measure designed to assess the impact of disorders of excessive sleepiness (DOES) on multiple activities of everyday living. Three samples were used in the development and psychometric analyses of the FOSQ: Sample 1 (n = 153) consisted of individuals seeking medical attention for a sleep problem and persons of similar age and gender having no sleep disorder; samples 2 (n = 24) and 3 (n = 51) were composed of patients from two medical centers diagnosed with obstructive sleep apnea (OSA). Factor analysis of the FOSQ yielded five factors: activity level, vigilance, intimacy and sexual relationships, general productivity, and social outcome. Internal reliability was excellent for both the subscales (alpha = 0.86 to alpha = 0.91) and the total scale (alpha = 0.95). Test-retest reliability of the FOSQ yielded coefficients ranging from r = 0.81 to r = 0.90 for the five subscales and r = 0.90 for the total measure. The FOSQ successfully discriminated between normal subjects and those seeking medical attention for a sleep problem (T157 = -5.88, p = 0.0001). This psychometric evaluation of the FOSQ demonstrated parameters acceptable for its application in research and in clinical practice to measure functional status outcomes for persons with DOES. Thus, the FOSQ can be used to determine how disorders of excessive sleepiness affect patients' abilities to conduct normal activities and the extent to which these abilities are improved by effective treatment of DOES.

Night-to-night variability in CPAP use over the first three months of treatment.

The purpose of this study was to examine the relationship between night-to-night variability and nightly duration of continuous positive airway pressure (CPAP) therapy over the first 9 weeks of treatment and to determine when patients begin to establish a nonadherent pattern of use. Data were analyzed from a study of daily CPAP use covertly monitored in 32 diagnosed patients with obstructive sleep apnea (OSA) using a microprocessor monitor encased in a CPAP machine. Patterns of CPAP use were bimodal, based on the frequency of nightly use. Approximately half the subjects were consistent users of CPAP, applying it > 90% of the nights for an average of 6.22 +/- 1.21 hours per night, while the other half comprised intermittent users who had a wide range of daily use averaging 3.45 +/- 1.94 hours per night on the nights CPAP was used. The percent of days skipped was significantly correlated with decreased nightly duration (rho = -0.73, p < 0.0001). Analysis of the night-to-night pattern of use revealed that the two groups differed significantly in the nightly duration of CPAP use by the fourth day of treatment (p = 0.001). Exploration of factors that potentially differentiate the two groups revealed no reliable predictors. However, intermittent users continued to report significantly greater OSA symptoms (snoring, snorting, and apnea) posttreatment, suggesting that they continued to experience sleep disordered breathing.

Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men.

The aim of the current study was to investigate the effects of sleep loss on the diurnal rhythm of circulating leptin levels. An indwelling forearm catheter was used to sample blood at 90-min intervals for a total of 120 h, which included 88 h of sustained sleeplessness, in 10 healthy men. The diurnal amplitude of leptin was reduced during total sleep deprivation and returned toward normal during the period of recovery sleep. This finding provides evidence that sleep influences the nocturnal leptin profile, and may have implications for the understanding of the role of sleep in metabolic regulation and the aetiologies of obesity and the night eating syndrome.

Evaluating hypnotic memory enhancement (hypermnesia and reminiscence) using multitrial forced recall.

Two experiments investigated whether hypnosis enhances memory retrieval per se or merely increases a person's willingness to report recollections. Both experiments assessed immediate and delayed (i.e., 1 week) recall for pictorial stimuli. In Experiment 1, following an initial waking baseline recall, subjects of high or low hypnotic ability completed a series of recall trials conducted either in hypnosis or in the walking condition. The classic hypermnesia effect was obtained, but with no supplemental contribution of hypnosis. In Experiment 2, hypnosis was introduced only after 6 waking-recall trials. Hypnosis again failed to enhance retrieval of new correct items, although it increased the production of new incorrect recall among hypnotizable individuals. The findings provide no evidence for alleged hypermnesic properties of hypnosis.