Jeanne F. Duffy

Exposure to bright light and darkness to treat physiologic maladaptation to night work.

Working at night results in a misalignment between the sleep-wake cycle and the output of the hypothalamic pacemaker that regulates the circadian rhythms of certain physiologic and behavioral variables. We evaluated whether such physiologic maladaptation to nighttime work could be prevented effectively by a treatment regimen of exposure to bright light during the night and darkness during the day. We assessed the functioning of the circadian pacemaker in five control and five treatment studies in order to assess the extent of adaptation in eight normal young men to a week of night work. In the control studies, on the sixth consecutive night of sedentary work in ordinary light (approximately 150 lux), the mean (+/- SEM) nadir of the endogenous temperature cycle continued to occur during the night (at 3:31 +/- 0:56 hours), indicating a lack of circadian adaptation to the nighttime work schedule. In contrast, the subjects in the treatment studies were exposed to bright light (7000 to 12,000 lux) at night and to nearly complete darkness during the day, and the temperature nadir shifted after four days of treatment to a significantly later, midafternoon hour (14:53 +/- 0:32; P less than 0.0001), indicating a successful circadian adaptation to daytime sleep and nighttime work. There were concomitant shifts in the 24-hour patterns of plasma cortisol concentration, urinary excretion rate, subjective assessment of alertness, and cognitive performance in the treatment studies. These shifts resulted in a significant improvement in both alertness and cognitive performance in the treatment group during the night-shift hours. We conclude that maladaptation of the human circadian system to night work, with its associated decline in alertness, performance, and quality of daytime sleep, can be treated effectively with scheduled exposure to bright light at night and darkness during the day.

Association of sleep-wake habits in older people with changes in output of circadian pacemaker

Many elderly people complain of disturbed sleep patterns but there is not evidence that the need to sleep decreases with age; it seems rather that the timing and consolidation of sleep change. We tried to find out whether there is a concurrent change in the output of the circadian pacemaker with age. The phase and amplitude of the pacemakers output were assessed by continuous measurement of the core body temperature during 40 h of sustained wakefulness under constant behavioural and environmental conditions. 27 young men (18-31 years) were compared with 21 older people (65-85 years; 11 men, 10 women); all were healthy and without sleep complaints. The mean amplitude of the endogenous circadian temperature oscillation (ECA) was 40% greater in young men than in the older group. Older men had a lower mean temperature ECA than older women. The minimum of the endogenous phase of the circadian temperature oscillation (ECP) occurred 1 h 52 min earlier in the older than in the young group. Customary bedtimes and waketimes were also earlier in the older group, as was their daily alertness peak. There was a close correlation between habitual waketime and temperature ECP in young men, which may lose precision with age, especially among women. These findings provide evidence for systematic age-related changes in the output of the human circadian pacemaker. We suggest that these changes may underlie the common complaints of sleep disturbance among elderly people. These changes could reflect the observed age-related deterioration of the hypothalamic nuclei that drive mammalian circadian rhythms.

Adverse Metabolic Consequences in Humans of Prolonged Sleep Restriction Combined with Circadian Disruption

Sleep deficiency and out-of-synch circadian rhythms impair pancreatic insulin secretion, a possible precursor to metabolic syndrome and diabetes. A Reason to Go to Bed on Time Our own experience tells us that getting too little sleep or traveling across multiple time zones can impair our ability to function. And people who work on the night shift or who habitually sleep too little are more likely to be obese or have diabetes. But what is it about these stresses that translate into faulty physiology? By simulating the life-style of a shift worker or world traveler in controlled laboratory conditions, Buxton et al. now find that prolonged, simultaneous disruption of our normal sleep and circadian rhythms affects the workings of our insulin-secreting pancreatic cells, creating a prediabetic state. And even worse, under these conditions, people show a drop in their resting metabolic rate that could translate into a yearly weight gain of more than 10 pounds. Getting a firm handle on the effects of life-style changes such as sleep, activity schedule, and diet on pancreatic function is much easier in small animals than humans. But Buxton et al. successfully investigated these questions by hosting 21 human participants in a completely controlled environment for almost 6 weeks and simulating disturbances in sleep and circadian rhythms, while keeping diet constant and scheduling all activities. Because sleep and circadian rhythms are intimately related, they designed a special protocol to independently manipulate these variables. After a stabilization segment in which the participants had adequate sleep at the appropriate time within their circadian rhythms, the participants spent 3 weeks in which they got only 5.6 hours of sleep per 24-hour period, while simultaneously experiencing 28-hour circadian days—a state similar to 4 hours of jet lag accumulating each day. During this time, the participants were often trying to sleep at unusual times within their circadian cycle. A segment of 9 recovery days followed. During the 3-week disruption, the participants’ glucose control went haywire, and they were unable to mount a sufficiently high insulin response after a meal, resulting in too much glucose in their blood, in some cases at a level considered prediabetic. This magnitude of disruption, coupled with a lower resting metabolic rate that also emerged during the 3 treatment weeks, could easily set the stage for development of diabetes and obesity, although the exact process by which this happens awaits further study. These results carry a cautionary message for employers to guard against causing adverse metabolic effects in workers by their shift scheduling practices—and a reinforcement of your mother’s message to go to bed on time and get enough sleep. Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour “days”), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants’ resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.

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.

Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness

Significance The use of light-emitting electronic devices for reading, communication, and entertainment has greatly increased recently. We found that the use of these devices before bedtime prolongs the time it takes to fall asleep, delays the circadian clock, suppresses levels of the sleep-promoting hormone melatonin, reduces the amount and delays the timing of REM sleep, and reduces alertness the following morning. Use of light-emitting devices immediately before bedtime also increases alertness at that time, which may lead users to delay bedtime at home. Overall, we found that the use of portable light-emitting devices immediately before bedtime has biological effects that may perpetuate sleep deficiency and disrupt circadian rhythms, both of which can have adverse impacts on performance, health, and safety. In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. This negative impact on sleep may be due to the short-wavelength–enriched light emitted by these electronic devices, given that artificial-light exposure has been shown experimentally to produce alerting effects, suppress melatonin, and phase-shift the biological clock. A few reports have shown that these devices suppress melatonin levels, but little is known about the effects on circadian phase or the following sleep episode, exposing a substantial gap in our knowledge of how this increasingly popular technology affects sleep. Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety.

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)

Entrainment of the Human Circadian System by Light

The periodic light-dark cycle is the dominant environmental synchronizer used by humans to entrain to the geophysical 24-h day. Entrainment is a fundamental property of circadian systems by which the period of the internal clock (τ) is synchronized to the period of the entraining stimuli (T cycle). An important aspect of entrainment in humans is the maintenance of an appropriate phase relationship between the circadian system, the timing of sleep and wakefulness, and environmental time (a.k.a. the phase angle of entrainment) to maintain wakefulness throughout the day and consolidated sleep at night. In this article, we review these concepts and the methods for assessing circadian phase and period in humans, as well as discuss findings on the phase angle of entrainment in healthy adults. We review findings from studies that examine how the phase, intensity, duration, and spectral characteristics of light affect the response of the human biological clock and discuss studies on entrainment in humans, including recent studies of the minimum light intensity required for entrainment. We briefly review conditions and disorders in which failure of entrainment occurs. We provide an integrated perspective on circadian entrainment in humans with respect to recent advances in our knowledge of circadian period and of the effects of light on the biological clock in humans.

Comparisons of the variability of three markers of the human circadian pacemaker

A circadian pacemaker within the central nervous system regulates the approximately 24-h physiologic rhythms in sleep cycles, hormone secretion, and other physiologic functions. Because the pacemaker cannot be examined directly in humans, markers of pacemaker function must be used to study the pacemaker and its response to environmental stimuli. Core body temperature (CBT), plasma cortisol, and plasma melatonin are three marker variables frequently used to estimate the phase of the human pacemaker. Measurements of circadian phase using markers can contain variability due to the circadian pacemaker itself, the intrinsic variability of the marker relative to the pacemaker, the method of analysis of the marker, and the marker assay. For this report, we compared the mathematical variability of a number of methods of identifying circadian phase from CBT, plasma cortisol, and plasma melatonin data collected in a protocol in which pacemaker variability was minimized using low light levels and regular timing of both the light pattern and the rest/activity schedule. We hoped to assess the relative variabilities of the different physiological markers and the analysis methods. Methods were based on the crossing of an absolute threshold, on the crossing of a relative threshold, or on fitting a curve to all data points. All methods of calculating circadian phase from plasma melatonin data were less variable than those calculated using CBT or cortisol data. The standard deviation for the phase estimates using CBT data was 0.78 h, using cortisol data was 0.65 h, and for the eight analysis methods using melatonin data was 0.23 to 0.35 h. While the variability for these markers might be different for other subject populations and/or less stringent study conditions, assessment of the intrinsic variability of the different calculations of circadian phase can be applied to allow inference of the statistical significance of phase and phase shift calculations, as well as estimation of sample size or statistical power for the number of subjects within an experimental protocol.

Do plasma melatonin concentrations decline with age

PURPOSE Numerous reports that secretion of the putative sleep-promoting hormone melatonin declines with age have led to suggestions that melatonin replacement therapy be used to treat sleep problems in older patients. We sought to reassess whether the endogenous circadian rhythm of plasma melatonin concentration changes with age in healthy drug-free adults. METHODS We analyzed the amplitude of plasma melatonin profiles during a constant routine in 34 healthy drug-free older subjects (20 women and 14 men, aged 65 to 81 years) and compared them with 98 healthy drug-free young men (aged 18 to 30 years). RESULTS We could detect no significant difference between a healthy and drug-free group of older men and women as compared to one of young men in the endogenous circadian amplitude of the plasma melatonin rhythm, as described by mean 24-hour average melatonin concentration (70 pmol/liter vs 73 pmol/liter, P = 0.97), or the duration (9.3 hours vs 9.1 hours, P = 0.43), mean (162 pmol/liter vs 161 pmol/liter, P = 0.63), or integrated area (85,800 pmol x min/liter vs 86,700 pmol x min/liter, P = 0.66) of the nocturnal peak of plasma melatonin. CONCLUSION These results do not support the hypothesis that reduction of plasma melatonin concentration is a general characteristic of healthy aging. Should melatonin replacement therapy or melatonin supplementation prove to be clinically useful, we recommend that an assessment of endogenous melatonin be carried out before such treatment is used in older patients.

Sex difference in the near-24-hour intrinsic period of the human circadian timing system

The circadian rhythms of melatonin and body temperature are set to an earlier hour in women than in men, even when the women and men maintain nearly identical and consistent bedtimes and wake times. Moreover, women tend to wake up earlier than men and exhibit a greater preference for morning activities than men. Although the neurobiological mechanism underlying this sex difference in circadian alignment is unknown, multiple studies in nonhuman animals have demonstrated a sex difference in circadian period that could account for such a difference in circadian alignment between women and men. Whether a sex difference in intrinsic circadian period in humans underlies the difference in circadian alignment between men and women is unknown. We analyzed precise estimates of intrinsic circadian period collected from 157 individuals (52 women, 105 men; aged 18–74 y) studied in a month-long inpatient protocol designed to minimize confounding influences on circadian period estimation. Overall, the average intrinsic period of the melatonin and temperature rhythms in this population was very close to 24 h [24.15 ± 0.2 h (24 h 9 min ± 12 min)]. We further found that the intrinsic circadian period was significantly shorter in women [24.09 ± 0.2 h (24 h 5 min ± 12 min)] than in men [24.19 ± 0.2 h (24 h 11 min ± 12 min); P < 0.01] and that a significantly greater proportion of women have intrinsic circadian periods shorter than 24.0 h (35% vs. 14%; P < 0.01). The shorter average intrinsic circadian period observed in women may have implications for understanding sex differences in habitual sleep duration and insomnia prevalence.