Derk-Jan Dijk

Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression

1 Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non‐linear relationship to illuminance. The dose‐response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. 2 Twenty‐three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. 3 We demonstrate that humans are highly responsive to the phase‐delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose‐response curve, as do many circadian responses to light in mammals. 4 Contrary to expectations, we found that half of the maximal phase‐delaying response achieved in response to a single episode of evening bright light (≈9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of ≈100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.

Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans

The contribution of the circadian pacemaker and the sleep homeostat to sleep tendency and consolidation was quantified by forced desynchrony of the sleep-wake cycle from the circadian pacemaker in eight men who lived in time-isolation for 33-36 days. Analysis of 175 polygraphically recorded sleep episodes revealed that the circadian pacemaker and the sleep homeostat contribute about equally to sleep consolidation, and that the phase relationship between these oscillatory processes during entrainment to the 24-h day is uniquely timed to facilitate the ability to maintain a consolidated bout of sleep at night and a consolidated bout of wakefulness throughout the day.

PER3 Polymorphism Predicts Sleep Structure and Waking Performance

Circadian rhythmicity and sleep homeostasis interact to regulate sleep-wake cycles [1-4], but the genetic basis of individual differences in sleep-wake regulation remains largely unknown [5]. PERIOD genes are thought to contribute to individual differences in sleep timing by affecting circadian rhythmicity [6], but not sleep homeostasis [7, 8]. We quantified the contribution of a variable-number tandem-repeat polymorphism in the coding region of the circadian clock gene PERIOD3 (PER3) [9, 10] to sleep-wake regulation in a prospective study, in which 24 healthy participants were selected only on the basis of their PER3 genotype. Homozygosity for the longer allele (PER3(5/5)) had a considerable effect on sleep structure, including several markers of sleep homeostasis: slow-wave sleep (SWS) and electroencephalogram (EEG) slow-wave activity in non-rapid eye movement (non-REM) sleep and theta and alpha activity during wakefulness and REM sleep were all increased in PER3(5/5) compared to PER3(4/4) individuals. In addition, the decrement of cognitive performance in response to sleep loss was significantly greater in the PER3(5/5) individuals. By contrast, the circadian rhythms of melatonin, cortisol, and peripheral PER3 mRNA expression were not affected. The data show that this polymorphism in PER3 predicts individual differences in the sleep-loss-induced decrement in performance and that this differential susceptibility may be mediated by its effects on sleep homeostasis.

Dose-response relationship for light intensity and ocular and electroencephalographic correlates of human alertness

Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to <3 lux for several hours. Light exerted an acute alerting response as assessed by a reduction in the incidence of slow-eye movements, a reduction of EEG activity in the theta-alpha frequencies (power density in the 5-9 Hz range) as well as a reduction in self-reported sleepiness. This alerting response was positively correlated with the degree of melatonin suppression by light. In accordance with the dose response function for circadian resetting and melatonin suppression, the responses of all three indices of alertness to variations in illuminance were consistent with a logistic dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.

Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms.

1 The circadian timing system has been implicated in age‐related changes in sleep structure, timing and consolidation in humans. 2 We investigated the circadian regulation of sleep in 13 older men and women and 11 young men by forced desynchrony of polysomnographically recorded sleep episodes (total, 482; 9 h 20 min each) and the circadian rhythms of plasma melatonin and core body temperature. 3 Stage 4 sleep was reduced in older people. Overall levels of rapid eye movement (REM) sleep were not significantly affected by age. The latencies to REM sleep were shorter in older people when sleep coincided with the melatonin rhythm. REM sleep was increased in the first quarter of the sleep episode and the increase of REM sleep in the course of sleep was diminished in older people. 4 Sleep propensity co‐varied with the circadian rhythms of body temperature and plasma melatonin in both age groups. Sleep latencies were longest just before the onset of melatonin secretion and short sleep latencies were observed close to the temperature nadir. In older people sleep latencies were longer close to the crest of the melatonin rhythm. 5 In older people sleep duration was reduced at all circadian phases and sleep consolidation deteriorated more rapidly during the course of sleep, especially when the second half of the sleep episode occurred after the crest of the melatonin rhythm. 6 The data demonstrate age‐related decrements in sleep consolidation and increased susceptibility to circadian phase misalignment in older people. These changes, and the associated internal phase advance of the propensity to awaken from sleep, appear to be related to the interaction between a reduction in the homeostatic drive for sleep and a reduced strength of the circadian signal promoting sleep in the early morning.

A model of human sleep homeostasis based on EEG slow-wave activity: Quantitative comparison of data and simulations

EEG slow-wave activity (SWA; spectral power in the 0.75-4.5 Hz band) is a function of the duration of prior waking and, thereby, an indicator of sleep homeostasis. We present a model that accounts for both the declining trend of SWA during sleep and for its variation within the successive nonrapid eye movement (non-REM) sleep episodes. The values of the model parameters were estimated by an optimization procedure in which empirical SWA of baseline nights (16 subjects, 26 nights) served as a reference. A sensitivity analysis revealed the model to be quite robust to small changes (+/- 5%) of the parameter values. The estimated parameter values were used to simulate data sets from three different experimental protocols (sleep in the evening or sleep in the morning after prolonged waking, or extended sleep initiated at the habitual bedtime; n = 8 or 9). The timing of the REM trigger parameter was derived from the empirical data. A close fit was obtained between the simulated and empirical SWA data, and even the occasional late SWA peaks during extended sleep could be reproduced. Minor discrepancies suggest indirect or direct circadian influences on SWA. The simulations demonstrate that the concept of sleep homeostasis as proposed in the two-process model of sleep regulation can be refined to account in quantitative terms for empirical data and to predict the changes induced by the prolongation of waking or sleep.

Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day

The interaction of homeostatic and circadian processes in the regulation of waking neurobehavioral functions and sleep was studied in six healthy young subjects. Subjects were scheduled to 15-24 repetitions of a 20-h rest/activity cycle, resulting in desynchrony between the sleep-wake cycle and the circadian rhythms of body temperature and melatonin. The circadian components of cognitive throughput, short-term memory, alertness, psychomotor vigilance, and sleep disruption were at peak levels near the temperature maximum, shortly before melatonin secretion onset. These measures exhibited their circadian nadir at or shortly after the temperature minimum, which in turn was shortly after the melatonin maximum. Neurobehavioral measures showed impairment toward the end of the 13-h 20-min scheduled wake episodes. This wake-dependent deterioration of neurobehavioral functions can be offset by the circadian drive for wakefulness, which peaks in the latter half of the habitual waking day during entrainment. The data demonstrate the exquisite sensitivity of many neurobehavioral functions to circadian phase and the accumulation of homeostatic drive for sleep.

Effect of unilateral somatosensory stimulation prior to sleep on the sleep EEG in humans

SUMMARY  The hypothesis that local activation of brain regions during wakefulness affects the EEG recorded from these regions during sleep was tested by applying vibratory stimuli to one hand prior to sleep. Eight subjects slept in the laboratory for five consecutive nights. During a 6‐h period prior to night 3, either the left or the right hand was vibrated intermittently (20 min on‐8 min off), while prior to night 5 the same treatment was applied to the contralateral hand. The sleep EEG was recorded from frontal, central, parietal and occipital derivations and subjected to spectral analysis. The interhemispheric asymmetry index (IAI) was calculated for spectral power in nonREM sleep in the frequency range 0.25‐25.0 Hz for 0.5‐Hz or 1‐Hz bins. In the first hour of sleep following right‐hand stimulation, the IAI of the central derivation was increased relative to baseline, which corresponds to a shift of power towards the left hemisphere. This effect was most prominent in the delta range, was limited to the first hour of sleep and was restricted to the central derivation situated over the somatosensory cortex. No significant changes were observed following left‐hand stimulation. Although the effect was small, it is consistent with the hypothesis that the activation of specific neuronal populations during wakefulness may have repercussions on their electrical activity pattern during subsequent sleep.

EEG Power Density during Nap Sleep : Reflection of an Hourglass Measuring the Duration of Prior Wakefulness

The relation between the duration of prior wakefulness and EEG power density during sleep in humans was assessed by means of a study of naps. The duration of prior wakefulness was varied from 2 to 20 hr by scheduling naps at 1000 hr, 1200 hr, 1400 hr, 1600 hr, 1800 hr, 2000 hr, and 0400 hr. In contrast to sleep latencies, which exhibited a minimum in the afternoon, EEG power densities in the delta and theta frequencies were a monotonic function of the duration of prior wakefulness. The data support the hypothesis that EEG power density during non-rapid eye movement sleep is only determined by the prior history of sleep and wakefulness and is not determined by clock-like mechanisms.

Light Treatment for Sleep Disorders: Consensus Report VI. Shift Work

The unhealthy symptoms and many deleterious consequences of shift work can be explained by a mismatch between the work-sleep schedule and the internal circadian rhythms. This mismatch occurs because the 24-h zeitgebers, such as the natural light-dark cycle, keep the circadian rhythms from phase shifting to align with the night-work, day-sleep schedule. This is a review of studies in which the sleep schedule is shifted several hours, as in shift work, and bright light is used to try to phase shift circadian rhythms. Phase shifts can be produced in laboratory studies, when subjects are kept indoors, and faster phase shifting occurs with appropriately timed bright light than with ordinary indoor (dim) light. Bright light field studies, in which subjects live at home, show that the use of artificial nocturnal bright light combined with enforced daytime dark (sleep) periods can phase shift circadian rhythms despite exposure to the conflicting 24-h zeitgebers. So far, the only studies on the use of bright light for real shift workers have been conducted at National Aeronautics and Space Administration (NASA). In general, the bright light studies support the idea that the control of light and dark can be used to overcome many of the problems of shift work. However, despite ongoing practical applications (such as at NASA), much basic research is still needed.