Sleep Restriction Masks the Influence of the Circadian Process on Sleep Propensity

Previous forced desynchrony studies have highlighted the close relationship between the circadian rhythms of core body temperature (CBT) and sleep propensity. In particular, these studies have shown that a “forbidden zone” for sleep exists on the rising limb of the CBT rhythm. In these previous studies, the length of the experimental day was either ultrashort (90?min), short (20?h), or long (28?h), and the ratio of sleep to wake was normal (i.e., 1:2). The aim of the current study was to examine the relative effects of the circadian and homeostatic processes on sleep propensity using a 28-h forced desynchrony protocol in which the ratio of sleep to wake was substantially lower than normal (i.e., 1:5). Twenty-seven healthy males lived in a time-isolation sleep laboratory for 11 consecutive days. Participants completed either a control (n?=?13) or sleep restriction (n?=?14) condition. In both conditions, the protocol consisted of 2?×?24-h baseline days followed by 8?×?28-h forced desynchrony days. On forced desynchrony days, the control group had 9.3?h in bed and 18.7?h of wake, and the sleep restriction group had 4.7?h in bed and 23.3?h of wake. For all participants, each 30-s epoch of time in bed was scored as sleep or wake based on standard polysomnography recordings, and was also assigned a circadian phase (360°?=?24?h) based on a cosine equation fitted to continuously recorded CBT data. For each circadian phase (i.e., 72?×?5° bins), sleep propensity was calculated as the percentage of epochs spent in bed scored as sleep. For the control group, there was a clear circadian rhythm in sleep propensity, with a peak of 98.5% at 5° (～05:20?h), a trough of 64.9% at 245° (～21:20?h), and an average of 82.3%. In contrast, sleep propensity for the sleep restriction group was relatively high at all circadian phases, with an average of 96.7%. For this group, the highest sleep propensity (99.0%) occurred at 60° (～09:00?h), and the lowest sleep propensity (91.3%) occurred at 265° (～22:40?h). As has been shown previously, these current data indicate that with a normal sleep-to-wake ratio, the effect of the circadian process on sleep propensity is pronounced, such that a forbidden zone for sleep exists at a phase equivalent to evening time for a normally entrained individual. However, these current data also indicate that when the ratio of sleep to wake is substantially lower than normal, this circadian effect is masked. In particular, sleep propensity is very high at all circadian phases, including those that coincide with the forbidden zone for sleep. This finding suggests that if the homeostatic pressure for sleep is sufficiently high, then the circadian drive for wakefulness can be overridden. In future studies, it will be important to determine whether or not this masking effect occurs with less severe sleep restriction, e.g., with a sleep-to-wake ratio of 1:3. (Author correspondence: charli.sargent@cqu.edu.au)     

Time-of-day mediates the influences of extended wake and sleep restriction on simulated driving

Although a nonlinear time-of-day and prior wake interaction on performance has been well documented, two recent studies have aimed to incorporate the influences of sleep restriction into this paradigm. Through the use of sleep-restricted forced desynchrony protocols, both studies reported a time-of-day × sleep restriction interaction, as well as a time-of-day × prior wake × sleep dose three-way interaction. The current study aimed to investigate these interactions on simulated driving performance, a more complex task with ecological validity for the problem of fatigued driving. The driving performance of 41 male participants (mean?±?SD: 22.8 ±2.2 yrs) was assessed on a 10-min simulated driving task with the standard deviation of lateral position (SDLAT) measured. Using a between-group design, participants were subjected to either a control condition of 9.33 h of sleep/18.66 h of wake, a moderate sleep-restriction (SR) condition of 7 h of sleep/21 h of wake, or a severe SR condition of 4.66 h of sleep/23.33 h of wake. In each condition, participants were tested at 2.5-h intervals after waking across 7 × 28-h d of forced desynchrony. Driving sessions occurred at nine doses of prior wake, within six divisions of the circadian cycle based on core body temperature (CBT). Mixed-models analyses of variance (ANOVAs) revealed significant main effects of time-of-day, prior wake, sleep debt, and sleep dose on SDLAT. Additionally, significant two-way interactions of time-of-day × prior wake and time-of-day × sleep debt, as well as significant three-way interactions of time-of-day × prior wake × sleep debt and time-of-day × sleep debt × sleep dose were observed. Although limitations such as the presence of practice effects and large standard errors are noted, the study concludes with three findings. The main effects demonstrate that extending wake, reducing sleep, and driving at poor times of day all significantly impair driving performance at an individual level. In addition to this, combining either extended wake or a sleep debt with the early morning hours greatly decreases driving performance. Finally, operating under the influence of a reduced sleep dose can greatly decrease performance at all times of the day.     

Time-of-Day Mediates the Influences of Extended Wake and Sleep Restriction on Simulated Driving

Although a nonlinear time-of-day and prior wake interaction on performance has been well documented, two recent studies have aimed to incorporate the influences of sleep restriction into this paradigm. Through the use of sleep-restricted forced desynchrony protocols, both studies reported a time-of-day?×?sleep restriction interaction, as well as a time-of-day?×?prior wake?×?sleep dose three-way interaction. The current study aimed to investigate these interactions on simulated driving performance, a more complex task with ecological validity for the problem of fatigued driving. The driving performance of 41 male participants (mean?±?SD: 22.8 ±2.2 yrs) was assessed on a 10-min simulated driving task with the standard deviation of lateral position (SDLAT) measured. Using a between-group design, participants were subjected to either a control condition of 9.33?h of sleep/18.66?h of wake, a moderate sleep-restriction (SR) condition of 7?h of sleep/21?h of wake, or a severe SR condition of 4.66?h of sleep/23.33?h of wake. In each condition, participants were tested at 2.5-h intervals after waking across 7?×?28-h d of forced desynchrony. Driving sessions occurred at nine doses of prior wake, within six divisions of the circadian cycle based on core body temperature (CBT). Mixed-models analyses of variance (ANOVAs) revealed significant main effects of time-of-day, prior wake, sleep debt, and sleep dose on SDLAT. Additionally, significant two-way interactions of time-of-day?×?prior wake and time-of-day?×?sleep debt, as well as significant three-way interactions of time-of-day?×?prior wake?×?sleep debt and time-of-day?×?sleep debt?×?sleep dose were observed. Although limitations such as the presence of practice effects and large standard errors are noted, the study concludes with three findings. The main effects demonstrate that extending wake, reducing sleep, and driving at poor times of day all significantly impair driving performance at an individual level. In addition to this, combining either extended wake or a sleep debt with the early morning hours greatly decreases driving performance. Finally, operating under the influence of a reduced sleep dose can greatly decrease performance at all times of the day. (Author correspondence: raymond.matthews@unisa.edu.au)     

Circadian regulation gene polymorphisms are associated with sleep disruption and duration,and circadian phase and rhythm in adults with HIV

Genes involved in circadian regulation, such as circadian locomotor output cycles kaput [CLOCK], cryptochrome [CRY1] and period [PER], have been associated with sleep outcomes in prior animal and human research. However, it is unclear whether polymorphisms in these genes are associated with the sleep disturbances commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Thus, the purpose of this study was to describe polymorphisms in selected circadian genes that are associated with sleep duration or disruption as well as the sleep–wake rhythm strength and phase timing among adults living with HIV/AIDS. A convenience sample of 289 adults with HIV/AIDS was recruited from HIV clinics and community sites in the San Francisco Bay Area. A wrist actigraph was worn for 72?h on weekdays to estimate sleep duration or total sleep time (TST), sleep disruption or percentage of wake after sleep onset (WASO) and several circadian rhythm parameters: mesor, amplitude, the ratio of mesor to amplitude (circadian quotient), and 24-h autocorrelation. Circadian phase measures included clock time for peak activity (acrophase) from actigraphy movement data, and bed time and final wake time from actigraphy and self-report. Genotyping was conducted for polymorphisms in five candidate genes involved in circadian regulation: CLOCK, CRY1, PER1, PER2 and PER3. Demographic and clinical variables were evaluated as potential covariates. Interactions between genotype and HIV variables (i.e. viral load, years since HIV diagnosis) were also evaluated. Controlling for potentially confounding variables (e.g. race, gender, CD4+ T-cell count, waist circumference, medication use, smoking and depressive symptoms), CLOCK was associated with WASO, 24-h autocorrelation and objectively-measured bed time; CRY1 was associated with circadian quotient; PER1 was associated with mesor and self-reported habitual wake time; PER2 was associated with TST, mesor, circadian quotient, 24-h autocorrelation and bed and wake times; PER3 was associated with amplitude, 24-h autocorrelation, acrophase and bed and wake times. Most of the observed associations involved a significant interaction between genotype and HIV. In this chronic illness population, polymorphisms in several circadian genes were associated with measures of sleep disruption and timing. These findings extend the evidence for an association between genetic variability in circadian regulation and sleep outcomes to include the sleep–wake patterns experienced by adults living with HIV/AIDS. These results provide direction for future intervention research related to circadian sleep–wake behavior patterns.     

THE INFLUENCE OF CIRCADIAN PHASE AND PRIOR WAKE ON NEUROMUSCULAR FUNCTION

Previous forced desynchrony (FD) studies have shown that neurobehavioral function is affected by circadian phase and duration of prior wakefulness. There is some evidence that neuromuscular function may also be affected by circadian phase and prior wake, but these effects have not been systematically investigated. This study examined the effects of circadian phase and prior wake on two measures of neuromuscular function—postural balance (PB) and maximal grip strength (MGS)—using a 28-h FD protocol. Eleven male participants (mean?±?SD: 22.7?±?2.5 yr) lived in a sound-attenuated, light- and temperature-controlled time-isolation laboratory for 12 days. Following two training days and a baseline day, participants were scheduled to seven 28-h FD days, with the ratio between sleep opportunity and wake spans kept constant (i.e., 9.3?h sleep period and 18.7?h wake period). PB was measured during 1?min of quiet standing on a force platform. MGS of the dominant hand was measured using a dynamometer. These two measures were obtained every 2.5?h during wake. Core body temperature was continuously recorded with rectal thermistors to determine circadian phase. For both measures of neuromuscular function, individual data points were assigned a circadian phase and a level of prior wake. Data were analyzed by repeated-measures analysis of variance (ANOVA) with two within-subjects factors: circadian phase (six phases) and prior wake (seven levels). For MGS, there was a main effect of circadian phase, but no main effect of prior wake. For PB, there were no main effects of circadian phase or prior wake. There were no interactions between circadian phase and prior wake for MGS or PB. The significant effect of circadian phase on muscle strength is in agreement with previous reports in the literature. In terms of prior wake, both MGS and PB remained relatively stable across wake periods, indicating that neuromuscular function may be more robust than neurobehavioral function when the duration of wakefulness is within a normal range (i.e., 18.7?h). (Author correspondence: charli.sargent@unisa.edu.au)     

An endogenous circadian rhythm in sleep inertia results in greatest cognitive impairment upon awakening during the biological night

Sleep inertia is the impaired cognitive performance immediately upon awakening, which decays over tens of minutes. This phenomenon has relevance to people who need to make important decisions soon after awakening, such as on-call emergency workers. Such awakenings can occur at varied times of day or night, so the objective of the study was to determine whether or not the magnitude of sleep inertia varies according to the phase of the endogenous circadian cycle. Twelve adults (mean, 24 years; 7 men) with no medical disorders other than mild asthma were studied. Following 2 baseline days and nights, subjects underwent a forced desynchrony protocol composed of seven 28-h sleep/wake cycles, while maintaining a sleep/wakefulness ratio of 1:2 throughout. Subjects were awakened by a standardized auditory stimulus 3 times each sleep period for sleep inertia assessments. The magnitude of sleep inertia was quantified as the change in cognitive performance (number of correct additions in a 2-min serial addition test) across the first 20 min of wakefulness. Circadian phase was estimated from core body temperature (fitted temperature minimum assigned 0 degrees ). Data were segregated according to: (1) circadian phase (60 degrees bins); (2) sleep stage; and (3) 3rd of the night after which awakenings occurred (i.e., tertiary 1, 2, or 3). To control for any effect of sleep stage, the circadian rhythm of sleep inertia was initially assessed following awakenings from Stage 2 (62% of awakening occurred from this stage; n = 110). This revealed a significant circadian rhythm in the sleep inertia of cognitive performance (p = 0.007), which was 3.6 times larger during the biological night (circadian bin 300 degrees , approximately 2300-0300 h in these subjects) than during the biological day (bin 180 degrees , approximately 1500-1900 h). The circadian rhythm in sleep inertia was still present when awakenings from all sleep stages were included (p = 0.004), and this rhythm could not be explained by changes in underlying sleep drive prior to awakening (changes in sleep efficiency across circadian phase or across the tertiaries), or by the proportion of the varied sleep stages prior to awakenings. This robust endogenous circadian rhythm in sleep inertia may have important implications for people who need to be alert soon after awakening.     

The effects of a split sleep–wake schedule on neurobehavioural performance and predictions of performance under conditions of forced desynchrony

Extended wakefulness, sleep loss, and circadian misalignment are factors associated with an increased accident risk in shiftwork. Splitting shifts into multiple shorter periods per day may mitigate these risks by alleviating prior wake. However, the effect of splitting the sleep–wake schedule on the homeostatic and circadian contributions to neurobehavioural performance and subjective assessments of one’s ability to perform are not known. Twenty-nine male participants lived in a time isolation laboratory for 13?d, assigned to one of two 28-h forced desynchrony (FD) schedules. Depending on the assigned schedule, participants were provided the same total time in bed (TIB) each FD cycle, either consolidated into a single period (9.33?h TIB) or split into two equal halves (2?×?4.67?h TIB). Neurobehavioural performance was regularly assessed with a psychomotor vigilance task (PVT) and subjectively-assessed ability was measured with a prediction of performance on a visual analogue scale. Polysomnography was used to assess sleep, and core body temperature was recorded to assess circadian phase. On average, participants obtained the same amount of sleep in both schedules, but those in the split schedule obtained more slow wave sleep (SWS) on FD days. Mixed-effects ANOVAs indicated no overall difference between the standard and split schedules in neurobehavioural performance or predictions of performance. Main effects of circadian phase and prior wake were present for both schedules, such that performance and subjective ratings of ability were best around the circadian acrophase, worst around the nadir, and declined with increasing prior wake. There was a schedule by circadian phase interaction for all neurobehavioural performance metrics such that performance was better in the split schedule than the standard schedule around the nadir. There was no such interaction for predictions of performance. Performance during the standard schedule was significantly better than the split schedule at 2?h of prior wake, but declined at a steeper rate such that the schedules converged by 4.5–7?h of prior wake. Overall, the results indicate that when the total opportunity for sleep per day is satisfactory, a split sleep–wake schedule is not detrimental to sleep or performance. Indeed, though not reflected in subjective assessments of performance capacity, splitting the schedule may be of some benefit, given its reduction of neurobehavioural impairment at night and its association with increased SWS. Therefore, for some industries that require operations to be sustained around the clock, implementing a split work–rest schedule may be of assistance.     

Plasticity of the intrinsic period of the human circadian timing system

Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light ( approximately 450 lux; approximately 1.2 W/m(2)) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.     

Prediction of Vigilant Attention and Cognitive Performance Using Self-Reported Alertness,Circadian Phase,Hours since Awakening,and Accumulated Sleep Loss

Sleep restriction causes impaired cognitive performance that can result in adverse consequences in many occupational settings. Individuals may rely on self-perceived alertness to decide if they are able to adequately perform a task. It is therefore important to determine the relationship between an individual’s self-assessed alertness and their objective performance, and how this relationship depends on circadian phase, hours since awakening, and cumulative lost hours of sleep. Healthy young adults (aged 18–34) completed an inpatient schedule that included forced desynchrony of sleep/wake and circadian rhythms with twelve 42.85-hour “days” and either a 1:2 (n = 8) or 1:3.3 (n = 9) ratio of sleep-opportunity:enforced-wakefulness. We investigated whether subjective alertness (visual analog scale), circadian phase (melatonin), hours since awakening, and cumulative sleep loss could predict objective performance on the Psychomotor Vigilance Task (PVT), an Addition/Calculation Test (ADD) and the Digit Symbol Substitution Test (DSST). Mathematical models that allowed nonlinear interactions between explanatory variables were evaluated using the Akaike Information Criterion (AIC). Subjective alertness was the single best predictor of PVT, ADD, and DSST performance. Subjective alertness alone, however, was not an accurate predictor of PVT performance. The best AIC scores for PVT and DSST were achieved when all explanatory variables were included in the model. The best AIC score for ADD was achieved with circadian phase and subjective alertness variables. We conclude that subjective alertness alone is a weak predictor of objective vigilant or cognitive performance. Predictions can, however, be improved by knowing an individual’s circadian phase, current wake duration, and cumulative sleep loss.     

Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology

Early attempts to characterize free-running human circadian rhythms generated three notable results: 1) observed circadian periods of 25 hours (considerably longer than the now established 24.1- to 24.2-hour average intrinsic circadian period) with sleep delayed to later circadian phases than during entrainment; 2) spontaneous internal desynchrony of circadian rhythms and sleep/wake cycles--the former with an approximately 24.9-hour period, and the latter with a longer (28-68 hour) or shorter (12-20 hour) period; and 3) bicircadian (48-50 hour) sleep/wake cycles. All three results are reproduced by Kronauer et al.'s (1982) coupled oscillator model, but the physiological basis for that phenomenological model is unclear. We use a physiologically based model of hypothalamic and brain stem nuclei to investigate alternative physiological mechanisms that could underlie internal desynchrony. We demonstrate that experimental observations can be reproduced by changes in two pathways: promotion of orexinergic (Orx) wake signals, and attenuation of the circadian signal reaching hypothalamic nuclei. We reason that delayed sleep is indicative of an additional wake-promoting drive, which may be of behavioral origin, associated with removal of daily schedules and instructions given to participants. We model this by increasing Orx tone during wake, which reproduces the observed period lengthening and delayed sleep. Weakening circadian input to the ventrolateral preoptic nucleus (possibly mediated by the dorsomedial hypothalamus) causes desynchrony, with observed sleep/wake cycle period determined by degree of Orx up-regulation. During desynchrony, sleep/wake cycles are driven by sleep homeostasis, yet sleep bout length maintains circadian phase dependence. The model predicts sleep episodes are shortest when started near the temperature minimum, consistent with experimental findings. The model also correctly predicts that it is possible to transition to bicircadian rhythms from either a synchronized or desynchronized state. Our findings suggest that feedback from behavioral choices to physiology could play an important role in spontaneous internal desynchrony.     

Dueling Hypotheses: Circatidal Versus Circalunidian Battle Basics–Second Engagement

The daily rhythm in body temperature is thought to be the result of the direct effects of activity and the effects of an endogenous circadian clock. Forced desynchrony (FD) is a tool used in human circadian rhythm research to disentangle endogenous and activity-related effects on daily rhythms. In the present study, we applied an FD protocol to rats. We subjected 8 rats for 5 days to a 20h forced activity cycle consisting of lOh of forced wakefulness and lOh for rest and sleep. The procedure aimed to introduce a lOh sleep/ lOh wake cycle, which period was different from the endogenous circadian (about 24h) rhythm. Of the variation in the raw body temperature data, 68–77% could be explained by a summation of estimated endogenous circadian cycle and forced activity cycle components of body temperature. Free-running circadian periods of body temperature during FD were similar to free-running periods measured in constant conditions. The applied forced activity cycle reduced clock-related circadian modulation of activity. This reduction of circadian modulation of activity did not affect body temperature. Also, the effects of the forced activity on body temperature were remarkably small.     

Forced Desynchrony of Orcadian Rhythms of Body Temperature and Activity in Rats

The daily rhythm in body temperature is thought to be the result of the direct effects of activity and the effects of an endogenous circadian clock. Forced desynchrony (FD) is a tool used in human circadian rhythm research to disentangle endogenous and activity-related effects on daily rhythms. In the present study, we applied an FD protocol to rats. We subjected 8 rats for 5 days to a 20h forced activity cycle consisting of lOh of forced wakefulness and lOh for rest and sleep. The procedure aimed to introduce a lOh sleep/ lOh wake cycle, which period was different from the endogenous circadian (about 24h) rhythm. Of the variation in the raw body temperature data, 68-77% could be explained by a summation of estimated endogenous circadian cycle and forced activity cycle components of body temperature. Free-running circadian periods of body temperature during FD were similar to free-running periods measured in constant conditions. The applied forced activity cycle reduced clock-related circadian modulation of activity. This reduction of circadian modulation of activity did not affect body temperature. Also, the effects of the forced activity on body temperature were remarkably small.     

CONTRIBUTION OF CORE BODY TEMPERATURE,PRIOR WAKE TIME,AND SLEEP STAGES TO COGNITIVE THROUGHPUT PERFORMANCE DURING FORCED DESYNCHRONY

Shiftworkers are often required to sleep at inappropriate phases of their circadian timekeeping system, with implications for the dynamics of ultradian sleep stages. The independent effects of these changes on cognitive throughput performance are not well understood. This is because the effects of sleep on performance are usually confounded with circadian factors that cannot be controlled under normal day/night conditions. The aim of this study was to assess the contribution of prior wake, core body temperature, and sleep stages to cognitive throughput performance under conditions of forced desynchrony (FD). A total of 11 healthy young adult males resided in a sleep laboratory in which day/night zeitgebers were eliminated and ambient room temperature, lighting levels, and behavior were controlled. The protocol included 2 training days, a baseline day, and 7?×?28-h FD periods. Each FD period consisted of an 18.7-h wake period followed by a 9.3-h rest period. Sleep was assessed using standard polysomnography. Core body temperature and physical activity were assessed continuously in 1-min epochs. Cognitive throughput was measured by a 5-min serial addition and subtraction (SAS) task and a 90-s digit symbol substitution (DSS) task. These were administered in test sessions scheduled every 2.5?h across the wake periods of each FD period. On average, sleep periods had a mean (± standard deviation) duration of 8.5 (±1.2) h in which participants obtained 7.6 (±1.4) h of total sleep time. This included 4.2 (±1.2) h of stage 1 and stage 2 sleep (S1–S2 sleep), 1.6 (±0.6) h of slow-wave sleep (SWS), and 1.8 (±0.6) h of rapid eye movement (REM) sleep. A mixed-model analysis with five covariates indicated significant fixed effects on cognitive throughput for circadian phase, prior wake time, and amount of REM sleep. Significant effects for S1–S2 sleep and SWS were not found. The results demonstrate that variations in core body temperature, time awake, and amount of REM sleep are associated with changes in cognitive throughput performance. The absence of significant effect for SWS may be attributable to the truncated range of sleep period durations sampled in this study. However, because the mean and variance for SWS were similar to REM sleep, these results suggest that cognitive throughput may be more sensitive to variations in REM sleep than SWS. (Author correspondence: david.darwent@unisa.edu.au)     

Chronobiological characterization of women with primary vasospastic syndrome: body heat loss capacity in relation to sleep initiation and phase of entrainment

Women with primary vasospastic syndrome (VS), but otherwise healthy, exhibit a functional disorder of vascular regulation (main symptom: cold extremities) and often suffer from difficulties initiating sleep (DIS). Diverse studies have shown a close association between distal vasodilatation before lights off and a rapid onset of sleep. Therefore, we hypothesized that DIS in women with VS could be due to a reduced heat loss capacity in the evening, i.e., subjects are physiologically not ready for sleep. The aim of the study was to elucidate whether women having both VS and DIS (WVD) or not (controls) show different circadian characteristics (e.g., phase delay of the circadian thermoregulatory system with respect to the sleep-wake cycle). Healthy young women (n = 9 WVD and n = 9 control) completed a 40-h constant routine protocol (adjusted to habitual bedtime) before and after an 8-h sleep episode. Skin temperatures [off-line calculated as distal-proximal skin temperature gradient (DPG)] and core body temperature (CBT; rectal) were continuously recorded. Half-hourly saliva samples were collected for melatonin assay and subjective sleepiness was assessed on the Karolinska Sleepiness Scale (KSS). Compared with control, WVD showed no differences in habitual bed times, but a 1-h circadian phase delay of dim light-melatonin onset (hours after lights on: WVD 14.6 +/- 0.3 h; control 13.5 +/- 0.2 h; P = 0.01). Similar phase shifts were observed in CBT, DPG, and KSS ratings. In conclusion, WVD exhibit a phase delay of the endogenous circadian system with respect to their habitual sleep-wake cycle, which could be a cause of DIS.     

Predominance of distal skin temperature changes at sleep onset across menstrual and circadian phases

Menstrual cycle-associated changes in reproductive hormones affect body temperature in women. We aimed to characterize the interaction between the menstrual, circadian, and scheduled sleep-wake cycles on body temperature regulation. Eight females entered the laboratory during the midfollicular (MF) and midluteal (ML) phases of their menstrual cycle for an ultradian sleep-wake cycle procedure, consisting of 36 cycles of 60-minute wake episodes alternating with 60-minute nap opportunities, in constant bed-rest conditions. Core body temperature (CBT) and distal skin temperature (DT) were recorded and used to calculate a distal-core gradient (DCG). Melatonin, sleep, and subjective sleepiness were also recorded. The circadian variation of DT and DCG was not affected by menstrual phase. DT and DCG showed rapid, large nap episode-dependent increases, whereas CBT showed slower, smaller nap episode-dependent decreases. DCG values were significantly reduced for most of the wake episode in an overall 60-minute wake/60-minute nap cycle during ML compared to MF, but these differences were eliminated at the wake-to-nap lights-out transition. Nap episode-dependent decreases in CBT were further modulated as a function of both circadian and menstrual factors, with nap episode-dependent deceases occurring more prominently during the late afternoon/evening in ML, whereas nap episode-dependent DT and DCG increases were not significantly affected by menstrual phase but only circadian phase. Circadian rhythms of melatonin secretion, DT, and DCG were significantly phase-advanced relative to CBT and sleep propensity rhythms. This study explored how the thermoregulatory system is influenced by an interaction between circadian phase and vigilance state and how this is further modulated by the menstrual cycle. Current results agree with the thermophysiological cascade model of sleep and indicate that despite increased CBT during ML, heat loss mechanisms are maintained at a similar level during nap episodes, which may allow for comparable circadian sleep propensity rhythms between menstrual phases.     

Interactive mathematical models of subjective alertness and cognitive throughput in humans

The authors present here mathematical models in which levels of subjective alertness and cognitive throughput are predicted by three components that interact with one another in a nonlinear manner. These components are (1) a homeostatic component (H) that falls in a sigmoidal manner during wake and rises in a saturating exponential manner at a rate that is determined by circadian phase during sleep; (2) a circadian component (C) that is a function of the output of our mathematical model of the effect of light on the circadian pacemaker, with the amplitude further regulated by the level of H; and (3) a sleep inertia component (W) that rises in a saturating exponential manner after waketime. The authors first construct initial models of subjective alertness and cognitive throughput based on the results of sleep inertia studies, sleep deprivation studies initiated across all circadian phases, 28-h forced desynchrony studies, and alertness and performance dose response curves to sleep. These initial models are then refined using data from nearly one hundred fifty 30- to 50-h sleep deprivation studies in which subjects woke at their habitual times. The interactive three-component models presented here are able to predict even the fine details of neurobehavioral data from sleep deprivation studies and, after further validation, may provide a powerful tool for the design of safe shift work and travel schedules, including those in which people are exposed to unusual patterns of light.     

Nonentrained circadian rhythms of melatonin in submariners scheduled to an 18-hour day.

The human circadian timing system has previously been shown to free run with a period slightly longer than 24 h in subjects living in the laboratory under conditions of forced desynchrony. In forced desynchrony, subjects are shielded from bright light and periodic time cues and are required to live on a day length outside the range of circadian entrainment. The work schedule used for most personnel aboard American submarines is 6 h on duty alternating with 12 h off duty. This imposed 18-h cycle is too short for human circadian synchronization, especially given that there is no bright-light exposure aboard submarines. However, crew members are exposed to 24-h stimuli that could mediate synchronization, such as clocks and social contacts with personnel who are living on a 24-h schedule. The authors investigated circadian rhythms of salivary melatonin in 20 crew members during a prolonged voyage on a Trident nuclear submarine. The authors found that in crew members living on the 18-h duty cycle, the endogenous rhythm of melatonin showed an average period of 24.35 h (n = 12, SD = 0.18 h). These data indicate that social contacts and knowledge of clock time are insufficient for entrainment to a 24-h period in personnel living by an 18-h rest-activity cycle aboard a submarine.     

CONTRIBUTION OF CIRCADIAN PHYSIOLOGY AND SLEEP HOMEOSTASIS TO AGE-RELATED CHANGES IN HUMAN SLEEP

The circadian pacemaker and sleep homeostasis play pivotal roles in vigilance state control. It has been hypothesized that age-related changes in the human circadian pacemaker, as well as sleep homeostatic mechanisms, contribute to the hallmarks of age-related changes in sleep, that is, earlier wake time and reduced sleep consolidation. Assessments of circadian parameters in healthy young (～20–30 years old) and older people (～65–75 years old)—in the absence of the confounding effects of sleep, changes in posture, and light exposure—have demonstrated that an earlier wake time in older people is accompanied by about a 1h advance of the rhythms of core body temperature and melatonin. In addition, older people wake up at an earlier circadian phase of the body temperature and plasma melatonin rhythm. The amplitude of the endogenous circadian component of the core body temperature rhythm assessed during constant routine and forced desynchrony protocols is reduced by 20–30% in older people. Recent assessments of the intrinsic period of the human circadian pacemaker in the absence of the confounding effects of light revealed no age-related reduction of this parameter in both sighted and blind individuals. Wake maintenance and sleep initiation are not markedly affected by age except that sleep latencies are longer in older people when sleep initiation is attempted in the early morning. In contrast, major age-related reductions in the consolidation and duration of sleep occur at all circadian phases. Sleep of older people is particularly disrupted when scheduled on the rising limb of the temperature rhythm, indicating that the sleep of older people is more susceptible to arousal signals genernpated by the circadian pacemaker. Sleep-homeostatic mechanisms, as assayed by the sleep-deprivation–induced increase of EEG slow-wave activity (SWA), are operative in older people, although during both baseline sleep and recovery sleep SWA in older people remains at lower levels. The internal circadian phase advance of awakening, as well as the age-related reduction in sleep consolidation, appears related to an age-related reduction in the promotion of sleep by the circadian pacemaker during the biological night in combination with a reduced homeostatic pressure for sleep. Early morning light exposure associated with this advance of awakening in older people could reinforce the advanced circadian phase. Quantification of the interaction between sleep homeostasis and circadian rhythmicity contributes to understanding age-related changes in sleep timing and quality. (Chronobiology International, 17(3), 285–311, 2000)     

Contribution of circadian physiology and sleep homeostasis to age-related changes in human sleep

The circadian pacemaker and sleep homeostasis play pivotal roles in vigilance state control. It has been hypothesized that age-related changes in the human circadian pacemaker, as well as sleep homeostatic mechanisms, contribute to the hallmarks of age-related changes in sleep, that is, earlier wake time and reduced sleep consolidation. Assessments of circadian parameters in healthy young (∼20-30 years old) and older people (∼65-75 years old)—in the absence of the confounding effects of sleep, changes in posture, and light exposure—have demonstrated that an earlier wake time in older people is accompanied by about a 1h advance of the rhythms of core body temperature and melatonin. In addition, older people wake up at an earlier circadian phase of the body temperature and plasma melatonin rhythm. The amplitude of the endogenous circadian component of the core body temperature rhythm assessed during constant routine and forced desynchrony protocols is reduced by 20-30% in older people. Recent assessments of the intrinsic period of the human circadian pacemaker in the absence of the confounding effects of light revealed no age-related reduction of this parameter in both sighted and blind individuals. Wake maintenance and sleep initiation are not markedly affected by age except that sleep latencies are longer in older people when sleep initiation is attempted in the early morning. In contrast, major age-related reductions in the consolidation and duration of sleep occur at all circadian phases. Sleep of older people is particularly disrupted when scheduled on the rising limb of the temperature rhythm, indicating that the sleep of older people is more susceptible to arousal signals genernpated by the circadian pacemaker. Sleep-homeostatic mechanisms, as assayed by the sleep-deprivation-induced increase of EEG slow-wave activity (SWA), are operative in older people, although during both baseline sleep and recovery sleep SWA in older people remains at lower levels. The internal circadian phase advance of awakening, as well as the age-related reduction in sleep consolidation, appears related to an age-related reduction in the promotion of sleep by the circadian pacemaker during the biological night in combination with a reduced homeostatic pressure for sleep. Early morning light exposure associated with this advance of awakening in older people could reinforce the advanced circadian phase. Quantification of the interaction between sleep homeostasis and circadian rhythmicity contributes to understanding age-related changes in sleep timing and quality. (Chronobiology International, 17(3), 285-311, 2000)     

Biological rhythms during residence in polar regions

At Arctic and Antarctic latitudes, personnel are deprived of natural sunlight in winter and have continuous daylight in summer: light of sufficient intensity and suitable spectral composition is the main factor that maintains the 24-h period of human circadian rhythms. Thus, the status of the circadian system is of interest. Moreover, the relatively controlled artificial light conditions in winter are conducive to experimentation with different types of light treatment. The hormone melatonin and/or its metabolite 6-sulfatoxymelatonin (aMT6s) provide probably the best index of circadian (and seasonal) timing. A frequent observation has been a delay of the circadian system in winter. A skeleton photoperiod (2 × 1-h, bright white light, morning and evening) can restore summer timing. A single 1-h pulse of light in the morning may be sufficient. A few people desynchronize from the 24-h day (free-run) and show their intrinsic circadian period, usually >24 h. With regard to general health in polar regions, intermittent reports describe abnormalities in various physiological processes from the point of view of daily and seasonal rhythms, but positive health outcomes are also published. True winter depression (SAD) appears to be rare, although subsyndromal SAD is reported. Probably of most concern are the numerous reports of sleep problems. These have prompted investigations of the underlying mechanisms and treatment interventions. A delay of the circadian system with "normal" working hours implies sleep is attempted at a suboptimal phase. Decrements in sleep efficiency, latency, duration, and quality are also seen in winter. Increasing the intensity of ambient light exposure throughout the day advanced circadian phase and was associated with benefits for sleep: blue-enriched light was slightly more effective than standard white light. Effects on performance remain to be fully investigated. At 75°S, base personnel adapt the circadian system to night work within a week, in contrast to temperate zones where complete adaptation rarely occurs. A similar situation occurs on high-latitude North Sea oil installations, especially when working 18:00-06:00 h. Lack of conflicting light exposure (and "social obligations") is the probable explanation. Many have problems returning to day work, showing circadian desynchrony. Timed light treatment again has helped to restore normal phase/sleep in a small number of people. Postprandial response to meals is compromised during periods of desynchrony with evidence of insulin resistance and elevated triglycerides, risk factors for heart disease. Only small numbers of subjects have been studied intensively in polar regions; however, these observations suggest that suboptimal light conditions are deleterious to health. They apply equally to people living in temperate zones with insufficient light exposure.