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)     

Age-related changes in the circadian and homeostatic regulation of human sleep

The reduction of electroencephalographic (EEG) slow-wave activity (SWA) (EEG power density between 0.75-4.5 Hz) and spindle frequency activity, together with an increase in involuntary awakenings during sleep, represent the hallmarks of human sleep alterations with age. It has been assumed that this decrease in non-rapid eye movement (NREM) sleep consolidation reflects an age-related attenuation of the sleep homeostatic drive. To test this hypothesis, we measured sleep EEG characteristics (i.e., SWA, sleep spindles) in healthy older volunteers in response to high (sleep deprivation protocol) and low sleep pressure (nap protocol) conditions. Despite the fact that the older volunteers had impaired sleep consolidation and reduced SWA levels, their relative SWA response to both high and low sleep pressure conditions was similar to that of younger persons. Only in frontal brain regions did we find an age-related diminished SWA response to high sleep pressure. On the other hand, we have clear evidence that the circadian regulation of sleep during the 40 h nap protocol was changed such that the circadian arousal signal in the evening was weaker in the older study participants. More sleep occurred during the wake maintenance zone, and subjective sleepiness ratings in the late afternoon and evening were higher than in younger participants. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep and spindle frequency-the latter was phase-advanced relative to the circadian melatonin profile. Therefore, we favor the hypothesis that age-related changes in sleep are due to weaker circadian regulation of sleep and wakefulness. Our data suggest that manipulations of the circadian timing system, rather than the sleep homeostat, may offer a potential strategy to alleviate age-related decrements in sleep and daytime alertness levels.     

Are age differences in sleep due to phase differences in the output of the circadian timing system?

Our aim was to evaluate whether age-related changes in the phase of the output of the circadian timing system (CTS) can explain age differences in habitual bedtime/wake time and in sleep consolidation parameters. Analyses focused on a group of healthy elderly people (older than 70 years) with no sleep problems and with similar subjective sleep quality as a young control group. The 2-week sleep diary data and 24h laboratory temperature recordings were examined for 70 subjects (22 young men [YM], 19 old men [OM], 29 old women [OW]). Polysomnographic (PSG) sleep data recorded during temperature data acquisition were also available for 62 subjects. These analyses made use of our recently developed technique to demask temperature rhythm data. As expected, compared to the young subjects, older subjects showed earlier habitual bedtime and wake time, more disturbed sleep, and a tendency for an earlier minimum of the circadian temperature rhythm. Despite sleep consolidation differences, the groups showed very similar habitual phase-angle differences (interval between the time occurrence of the fitted temperature minimum and habitual wake time). Both elderly and young subjects woke up on average 3h after the temperature minimum. After controlling for the effects of age group, habitual bedtime and wake time were related to clock time phase of the circadian temperature rhythm, with an earlier phase associated with earlier habitual bedtime and wake time. None of the sleep consolidation parameters were linked to the temperature phase angle. In conclusion, sleep consolidation changes associated with healthy aging do not appear to be related to changes in the phase-angle difference between the output signal from the CTS and sleep.     

Age‐related Changes in the Circadian and Homeostatic Regulation of Human Sleep

The reduction of electroencephalographic (EEG) slow‐wave activity (SWA) (EEG power density between 0.75–4.5 Hz) and spindle frequency activity, together with an increase in involuntary awakenings during sleep, represent the hallmarks of human sleep alterations with age. It has been assumed that this decrease in non‐rapid eye movement (NREM) sleep consolidation reflects an age‐related attenuation of the sleep homeostatic drive. To test this hypothesis, we measured sleep EEG characteristics (i.e., SWA, sleep spindles) in healthy older volunteers in response to high (sleep deprivation protocol) and low sleep pressure (nap protocol) conditions. Despite the fact that the older volunteers had impaired sleep consolidation and reduced SWA levels, their relative SWA response to both high and low sleep pressure conditions was similar to that of younger persons. Only in frontal brain regions did we find an age‐related diminished SWA response to high sleep pressure. On the other hand, we have clear evidence that the circadian regulation of sleep during the 40 h nap protocol was changed such that the circadian arousal signal in the evening was weaker in the older study participants. More sleep occurred during the wake maintenance zone, and subjective sleepiness ratings in the late afternoon and evening were higher than in younger participants. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep and spindle frequency—the latter was phase‐advanced relative to the circadian melatonin profile. Therefore, we favor the hypothesis that age‐related changes in sleep are due to weaker circadian regulation of sleep and wakefulness. Our data suggest that manipulations of the circadian timing system, rather than the sleep homeostat, may offer a potential strategy to alleviate age‐related decrements in sleep and daytime alertness levels.     

Loss of circadian organization of sleep and wakefulness during hibernation

We investigated circadian and homeostatic regulation of nonrapid eye movement (NREM) sleep in golden-mantled ground squirrels during euthermic intervals between torpor bouts. Slow-wave activity (SWA; 1-4 Hz) and sigma activity (10-15 Hz) represent the two dominant electroencephalographic (EEG) frequency components of NREM sleep. EEG sigma activity has a strong circadian component in addition to a sleep homeostatic component, whereas SWA mainly reflects sleep homeostasis [Dijk DJ and Czeisler CA. J Neurosci 15: 3526-3538, 1995; Dijk DJ, Shanahan TL, Duffy JF, Ronda JM, and Czeisler CA. J Physiol (Lond) 505: 851-858, 1997]. Animals maintained under constant conditions continued to display circadian rhythms in both sigma activity and brain temperature throughout euthermic intervals, whereas sleep and wakefulness showed no circadian organization. Instead, sleep and wakefulness were distributed according to a 6-h ultradian rhythm. SWA, NREM sleep bout length, and sigma activity responded homeostatically to the ultradian sleep-wake pattern. We suggest that the loss of sleep-wake consolidation in ground squirrels during the hibernation season may be related to the greatly decreased locomotor activity during the hibernation season and may be necessary for maintenance of multiday torpor bouts characteristic of hibernating species.     

Melatonin rhythms in delayed sleep phase syndrome

The aim of this study was to compare circadian and sleep characteristics between patients with delayed sleep phase syndrome (DSPS) and healthy controls. The authors studied 8 DSPS patients and 15 normal controls. Serum melatonin concentration was assessed every hour for 24 h under dim light conditions. The sleep phase and the melatonin rhythm in DSPS patients were significantly delayed compared to those in normal controls. Sleep length was significantly greater in DSPS patients compared to that in controls, but the duration of melatonin secretion did not differ between the two groups. The final awakening, relative to melatonin onset, melatonin midpoint, and melatonin offset, was significantly longer in DSPS patients than in controls. By contrast, the timing of sleep onset relative to melatonin rhythm did not differ between the two groups. The authors found a significant positive correlation between sleep phase markers and melatonin phase markers in DSPS. They postulate that a delayed circadian pacemaker may be responsible for delayed sleep phase syndrome. The alteration of phase angle between melatonin rhythm and sleep phase suggested that not only the delay of the circadian clock but also a functional disturbance of the sleep-wake mechanism underlies DSPS.     

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.     

Expression of clock genes in human peripheral blood mononuclear cells throughout the sleep/wake and circadian cycles

The rhythmic expression of circadian clock genes in the neurons of the suprachiasmatic nucleus (SCN) underlies the manifestation of endogenous circadian rhythmicity in behavior and physiology. Recent evidence demonstrating rhythmic clock gene expression in non-SCN tissues suggests that functional clocks exist outside the central circadian pacemaker of the brain. In this investigation, the nature of an oscillator in peripheral blood mononuclear cells (PBMCs) is evaluated by assessing clock gene expression throughout both a typical sleep/wake cycle (LD) and during a constant routine (CR). Six healthy men and women aged (mean±SEM) 23.7±1.6 yrs participated in this five-day investigation in temporal isolation. Core body temperature and plasma melatonin concentration were measured as markers of the central circadian pacemaker. The expression of HPER1, HPER2, and HBMAL1 was quantified in PBMCs sampled throughout an uninterrupted 72 h period. The core body temperature minimum and the midpoint of melatonin concentration measured during the CR occurred 2:17±0:20 and 3:24 ±0:09 h before habitual awakening, respectively, and were well aligned to the sleep/wake cycle. HPER1 and HPER2 expression in PBMCs demonstrated significant circadian rhythmicity that peaked early after wake-time and was comparable under LD and CR conditions. HBMAL1 expression was more variable, and peaked in the middle of the wake period under LD conditions and during the habitual sleep period under CR conditions. For the first time, bi-hourly sampling over three consecutive days is used to compare clock gene expression in a human peripheral oscillator under different sleep/wake conditions.     

The use of melatonin for the treatment of insomnia

The pineal product melatonin is involved in the regulation of the sleep/wake cycle in humans. In blind individuals and in people travelling through time zones, melatonin rhythms are sometimes unsynchronized with the diel cycle, and nocturnal sleep may be disturbed. Low or distorted melatonin rhythms have repeatedly been reported in middle aged and elderly insomniacs. Melatonin administration effectively synchronized the sleep wake cycle in blind individuals and in subjects suffering from jet lag and advanced sleep onset in subjects suffering from delayed sleep phase syndrome. In elderly insomniacs, melatonin replacement therapy significantly decreased sleep latency, and/or increased sleep efficiency and decreased wake time after sleep onset. In addition, melatonin substitution facilitated benzodiazepine discontinuation in chronic users. These data show an association between melatonin rhythm disturbances and difficulties to promote or maintain sleep at night. Specific melatonin formulations may be useful to treat circadian-rhythm-related sleep disorders and age-related insomnia.     

Amplitude reduction and phase shifts of melatonin, cortisol and other circadian rhythms after a gradual advance of sleep and light exposure in humans

Background

The phase and amplitude of rhythms in physiology and behavior are generated by circadian oscillators and entrained to the 24-h day by exposure to the light-dark cycle and feedback from the sleep-wake cycle. The extent to which the phase and amplitude of multiple rhythms are similarly affected during altered timing of light exposure and the sleep-wake cycle has not been fully characterized.

Methodology/Principal Findings

We assessed the phase and amplitude of the rhythms of melatonin, core body temperature, cortisol, alertness, performance and sleep after a perturbation of entrainment by a gradual advance of the sleep-wake schedule (10 h in 5 days) and associated light-dark cycle in 14 healthy men. The light-dark cycle consisted either of moderate intensity ‘room’ light (∼90–150 lux) or moderate light supplemented with bright light (∼10,000 lux) for 5 to 8 hours following sleep. After the advance of the sleep-wake schedule in moderate light, no significant advance of the melatonin rhythm was observed whereas, after bright light supplementation the phase advance was 8.1 h (SEM 0.7 h). Individual differences in phase shifts correlated across variables. The amplitude of the melatonin rhythm assessed under constant conditions was reduced after moderate light by 54% (17–94%) and after bright light by 52% (range 12–84%), as compared to the amplitude at baseline in the presence of a sleep-wake cycle. Individual differences in amplitude reduction of the melatonin rhythm correlated with the amplitude of body temperature, cortisol and alertness.

Conclusions/Significance

Alterations in the timing of the sleep-wake cycle and associated bright or moderate light exposure can lead to changes in phase and reduction of circadian amplitude which are consistent across multiple variables but differ between individuals. These data have implications for our understanding of circadian organization and the negative health outcomes associated with shift-work, jet-lag and exposure to artificial light.     

Effects of obstructive sleep apnea on endogenous circadian rhythms assessed during relaxed wakefulness; an exploratory analysis

ABSTRACT

Obstructive sleep apnea (OSA) is associated with hypertension, cardiovascular disease, and a change in the 24 h pattern of adverse cardiovascular events and mortality. Adverse cardiovascular events occur more frequently in the middle of the night in people with OSA, earlier than the morning prevalence of these events in the general population. It is unknown if these changes are associated with a change in the underlying circadian rhythms, independent of behaviors such as sleep, physical activity, and meal intake. In this exploratory analysis, we studied the endogenous circadian rhythms of blood pressure, heart rate, melatonin and cortisol in 11 participants (48 ± 4 years; seven with OSA) throughout a 5 day study that was originally designed to examine circadian characteristics of obstructive apnea events. After a baseline night, participants completed 10 recurring 5 h 20 min behavioral cycles divided evenly into standardized sleep and wake periods. Blood pressure and heart rate were recorded in a relaxed semirecumbent posture 15 minutes after each scheduled wake time. Salivary melatonin and cortisol concentrations were measured at 1–1.5 h intervals during wakefulness. Mixed-model cosinor analyses were performed to determine the rhythmicity of all variables with respect to external time and separately to circadian phases (aligned to the dim light melatonin onset, DLMO). The circadian rhythm of blood pressure peaked much later in OSA compared to control participants (group × circadian phase, p < .05); there was also a trend toward a slightly delayed cortisol rhythm in the OSA group. Rhythms of heart rate and melatonin did not differ between the groups. In this exploratory analysis, OSA appears to be associated with a phase change (relative to DLMO) in the endogenous circadian rhythm of blood pressure during relaxed wakefulness, independent of common daily behaviors.     

Are modifications of melatonin circadian rhythm in the middle years of life related to habitual patterns of light exposure?

The mechanisms underlying age-related changes in the signal from the biological clock have yet to be determined. The authors sought to determine if the phase advance of circadian melatonin rhythm during the middle years of life is related to different patterns of habitual light exposure. Forty-one healthy subjects between the ages of 22 and 58 y were studied. Habitual light exposure was measured by a wrist monitor for 7 days. Participants underwent a 25-h constant routine. They provided saliva samples every 30 min, and melatonin concentration was determined by radioimmunoassay to assess salivary dim light melatonin onset (S-DLMO(1.3)). Aging was associated with earlier S-DLMO(1.3). Increasing age was not related to the time spent at different light intensities. However, it was associated with lower percentage of light exposure during the night (between 0200-0400, 0600-0700, and 2300-2400 h) and with higher percentage of light exposure in the morning (between 0800-1100 h). Earlier S-DLMO(1.3) was associated with lower percentage of light exposure early on in the night (between 2200-0000, 0000-0100, and 0200-0300 h) as well as in the afternoon (between 1500-1600 h) and with higher percentage of light exposure in the morning (between 0800-1100 h). When the effects of age were controlled, there was no significant relationship between S-DLMO(1.3) and percentages of light exposure. Yet increasing age was associated with earlier S-DLMO(1.3) regardless of light exposure patterns. Earlier habitual wake time explained the earlier light exposure patterns of older subjects. Both habitual wake time and age contributed to the prediction of S-DLMO(1.3). The results suggest a phase advance of circadian rhythms in the middle years of life. Whereas a clear change in habitual light exposure patterns was associated with aging and with shifts in S-DLMO(1.3), it did not explain entirely the age-related advance of melatonin circadian phase.     

Commentary: models of sleep regulation: successes and continuing challenges

Quantitative models have been developed to describe salient aspects of human sleep regulation. The two-process model of sleep regulation and the thermoregulatory model of sleep control highlight the interaction between sleep homeostasis and circadian rhythmicity and the association between sleep and temperature regulation, respectively. These models have been successful and inspiring, but continuing progress remains dependent on rigorous testing of some of their basic assumptions. Whereas it has been established that EEG slow-wave activity is a marker of sleep homeostasis, its causal role in regulating the timing of sleep and wakefulness remains to be demonstrated conclusively. Likewise, the causal role of the temperature regulatory system in sleep timing requires further investigation. In both models, many parameters have yet to be associated with specific physiologic processes. This makes it challenging, at least within the framework of these models, to account for interindividual differences or age-related changes in such features as sleep duration and sleep timing, as well as changes in the phase angle between the sleep-wake cycle and accepted markers of the circadian pacemaker, such as the body temperature or melatonin rhythm. Although the models may describe adequately global sleep patterns and their circadian modulation, detailed modeling of the frequent short awakenings from, and the subsequent transitions back to, sleep, as well as the variation of the propensity to awaken across the ultradian non-REM-REM cycle, is not addressed. Incoporation of these aspects of sleep in mathematical models of sleep regulation may further our understanding of a key aspect of sleep regulation, that is, its timing.     

The benefits of four weeks of melatonin treatment on circadian patterns in resistance-trained athletes

Exercise can induce circadian phase shifts depending on the duration, intensity and frequency. These modifications are of special meaning in athletes during training and competition. Melatonin, which is produced by the pineal gland in a circadian manner, behaves as an endogenous rhythms synchronizer, and it is used as a supplement to promote resynchronization of altered circadian rhythms. In this study, we tested the effect of melatonin administration on the circadian system in athletes. Two groups of athletes were treated with 100?mg?day^?1 of melatonin or placebo 30?min before bed for four weeks. Daily rhythm of salivary melatonin was measured before and after melatonin administration. Moreover, circadian variables, including wrist temperature (WT), motor activity and body position rhythmicity, were recorded during seven days before and seven days after melatonin or placebo treatment with the aid of specific sensors placed in the wrist and arm of each athlete. Before treatment, the athletes showed a phase-shift delay of the melatonin circadian rhythm, with an acrophase at 05:00?h. Exercise induced a phase advance of the melatonin rhythm, restoring its acrophase accordingly to the chronotype of the athletes. Melatonin, but not placebo treatment, changed daily waveforms of WT, activity and position. These changes included a one-hour phase advance in the WT rhythm before bedtime, with a longer nocturnal steady state and a smaller reduction when arising at morning than the placebo group. Melatonin, but not placebo, also reduced the nocturnal activity and the activity and position during lunch/nap time. Together, these data reflect the beneficial effect of melatonin to modulate the circadian components of the sleep–wake cycle, improving sleep efficiency.     

Persistence of sleep-temperature coupling after suprachiasmatic nuclei lesions in rats

The suprachiasmatic nucleus (SCN) regulates the circadian rhythms of body temperature (T(b)) and vigilance states in mammals. We studied rats in which circadian rhythmicity was abolished after SCN lesions (SCNx rats) to investigate the association between the ultradian rhythms of sleep-wake states and brain temperature (T(br)), which are exposed after lesions. Ultradian rhythms of T(br) (mean period: 3.6 h) and sleep were closely associated in SCNx rats. Within each ultradian cycle, nonrapid eye movement (NREM) sleep was initiated 5 +/- 1 min after T(br) peaks, after which temperature continued a slow decline (0.02 +/- 0.006 degrees C/min) until it reached a minimum. Sleep and slow wave activity (SWA), an index of sleep intensity, were associated with declining temperature. Cross-correlation analysis revealed that the rhythm of T(br) preceded that of SWA by 2-10 min. We also investigated the thermoregulatory and sleep-wake responses of SCNx rats and controls to mild ambient cooling (18 degrees C) and warming (30 degrees C) over 24-h periods. SCNx rats and controls responded similarly to changes in ambient temperature. Cooling decreased REM sleep and increased wake. Warming increased T(br), blunted the amplitude of ultradian T(br) rhythms, and increased the number of transitions into NREM sleep. SCNx rats and controls had similar percentages of NREM sleep, REM sleep, and wake, as well as the same average T(b) within each 24-h period. Our results suggest that, in rats, the SCN modulates the timing but not the amount of sleep or the homeostatic control of sleep-wake states or T(b) during deviations in ambient temperature.     

Expression of Clock Genes in Human Peripheral Blood Mononuclear Cells throughout the Sleep/Wake and Circadian Cycles

The rhythmic expression of circadian clock genes in the neurons of the suprachiasmatic nucleus (SCN) underlies the manifestation of endogenous circadian rhythmicity in behavior and physiology. Recent evidence demonstrating rhythmic clock gene expression in non‐SCN tissues suggests that functional clocks exist outside the central circadian pacemaker of the brain. In this investigation, the nature of an oscillator in peripheral blood mononuclear cells (PBMCs) is evaluated by assessing clock gene expression throughout both a typical sleep/wake cycle (LD) and during a constant routine (CR). Six healthy men and women aged (mean±SEM) 23.7±1.6 yrs participated in this five‐day investigation in temporal isolation. Core body temperature and plasma melatonin concentration were measured as markers of the central circadian pacemaker. The expression of HPER1, HPER2, and HBMAL1 was quantified in PBMCs sampled throughout an uninterrupted 72 h period. The core body temperature minimum and the midpoint of melatonin concentration measured during the CR occurred 2:17±0:20 and 3:24 ±0:09 h before habitual awakening, respectively, and were well aligned to the sleep/wake cycle. HPER1 and HPER2 expression in PBMCs demonstrated significant circadian rhythmicity that peaked early after wake‐time and was comparable under LD and CR conditions. HBMAL1 expression was more variable, and peaked in the middle of the wake period under LD conditions and during the habitual sleep period under CR conditions. For the first time, bi‐hourly sampling over three consecutive days is used to compare clock gene expression in a human peripheral oscillator under different sleep/wake conditions.     

Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators

Daily rhythms in sleep and waking performance are generated by the interplay of multiple external and internal oscillators. These include the light-dark and social cycles, a circadian hypothalamic oscillator oscillating virtually independently of behavior, and a homeostatic oscillator driven primarily by sleep-wake behavior. Both internal oscillators contribute to variation in many aspects of sleep and wakefulness (e.g., sleep timing and duration, REM sleep, non-REM sleep, REM density, sleep spindles, slow-wave sleep, electroencephalographic oscillations during wakefulness and sleep, and performance parameters, including attention and memory). The relative contribution of the oscillators varies greatly between these variables. Sleep and performance cannot be predicted by either oscillator independently but critically depend on their phase relationship and amplitude. The homeostatic oscillator feeds back onto the central pacemaker or its outputs. Thus, the amplitude of observed circadian variation in sleep and performance depends on how long we have been asleep or awake. During entrainment to external 24-h cycles, the opposing interplay between circadian and homeostatic changes in sleep propensity consolidates sleep and wakefulness. Some physiological correlates and mediators of both the circadian process (e.g., melatonin and hypocretin rhythms) and the homeostat (e.g., EEG, slow-wave activity, and adenosine release) have been established, offering targets for the development of countermeasures for circadian sleep and performance disorders. Interindividual differences in sleep timing, duration, and morning or evening preference are associated with changes of circadian or sleep homeostatic processes or both. Molecular genetic correlates, including polymorphisms in clock genes, of some of these interindividual differences are emerging.     

Challenging the sleep homeostat does not influence the thermoregulatory system in men: evidence from a nap vs. sleep-deprivation study

The purpose of our study was to understand the relationship between the components of the three-process model of sleepiness regulation (homeostatic, circadian, and sleep inertia) and the thermoregulatory system. This was achieved by comparing the impact of a 40-h sleep deprivation vs. a 40-h multiple nap paradigm (10 cycles with 150/75 min wakefulness/sleep episodes) on distal and proximal skin temperatures, core body temperature (CBT), melatonin secretion, subjective sleepiness, and nocturnal sleep EEG slow-wave activity in eight healthy young men in a "controlled posture" protocol. The main finding of the study was that accumulation of sleep pressure increased subjective sleepiness and slow-wave activity during the succeeding recovery night but did not influence the thermoregulatory system as measured by distal, proximal, and CBT. The circadian rhythm of sleepiness (and proximal temperature) was significantly correlated and phase locked with CBT, whereas distal temperature and melatonin secretion were phase advanced (by 113 +/- 28 and 130 +/- 30 min, respectively; both P < 0.005). This provides evidence for a primary role of distal vasodilatation in the circadian regulation of CBT and its relationship with sleepiness. Specific thermoregulatory changes occur at lights off and on. After lights off, skin temperatures increased and were most pronounced for distal; after lights on, the converse occurred. The decay in distal temperature (vasoconstriction) was significantly correlated with the disappearance of sleep inertia. These effects showed minor and nonsignificant circadian modulation. In summary, the thermoregulatory system seems to be independent of the sleep homeostat, but the circadian modulation of sleepiness and sleep inertia is clearly associated with thermoregulatory changes.