Effects of melatonin administration on daytime sleep after simulated night shift work.

Disturbed sleep and on-the-job sleepiness are widespread problems among night shift workers. The pineal hormone melatonin may prove to be a useful treatment because it has both sleep-promoting and circadian phase-shifting effects. This study was designed to isolate melatonin's sleep-promoting effects, and to determine whether melatonin could improve daytime sleep and thus improve night time alertness and performance during the night shift. The study utilized a placebo-controlled, double-blind, cross-over design. Subjects (n=21, mean age=27.0 +/- 5.0 years) participated in two 6-day laboratory sessions. Each session included one adaptation night, two baseline nights, two consecutive 8-h night shifts followed by 8-h daytime sleep episodes and one recovery night. Subjects took 1.8 mg sustained-release melatonin 0.5 h before the two daytime sleep episodes during one session, and placebo before the daytime sleep episodes during the other session. Sleep was recorded using polysomnography. Sleepiness, performance, and mood during the night shifts were evaluated using the multiple sleep latency test (MSLT) and a computerized neurobehavioral testing battery. Melatonin prevented the decrease in sleep time during daytime sleep relative to baseline, but only on the first day of melatonin administration. Melatonin increased sleep time more in subjects who demonstrated difficulty in sleeping during the day. Melatonin had no effect on alertness on the MSLT, or performance and mood during the night shift. There were no hangover effects from melatonin administration. These findings suggest that although melatonin can help night workers obtain more sleep during the day, they are still likely to face difficulties working at night because of circadian rhythm misalignment. The possibility of tolerance to the sleep-promoting effects of melatonin across more than 1 day needs further investigation.

Failure of extraocular light to facilitate circadian rhythm reentrainment in humans.

Although extraocular light can entrain the circadian rhythms of invertebrates and nonmammalian vertebrates, almost all studies show that the mammalian circadian system can only be affected by light to the eyes. The exception is a recent study by Campbell and Murphy that reported phase shifts in humans to bright light applied with fiber-optic pads behind the knees (popliteal region). We tested whether this extraocular light stimulus could accelerate the entrainment of circadian rhythms to a shift of the sleep schedule, as occurs in shift work or jet lag. In experiment 1, the sleep/dark episodes were delayed 8h from baseline for 2 days, and 3h light exposures were timed to occur before the temperature minimum to help delay circadian rhythms. There were three groups: (1) bright (about 13,000 lux) extraocular light from fiber-optic pads, (2) control (dim light, 10-20 lux), and (3) medium-intensity (about 1000 lux) ocular light from light boxes. In experiment 2, the sleep/dark episodes were inverted, and extraocular light was applied either before the temperature minimum to help delay circadian rhythms or after the temperature minimum to help advance rhythms. Circadian phase markers were the salivary dim light melatonin onset (DLMO) and the rectal temperature minimum. There was no evidence that the popliteal extraocular light had a phase-shifting effect in either experiment. Possible reasons for phase shifts in the Campbell and Murphy study and not the current study include the many differences between the protocols. In the current study, there was substantial sleep deprivation before the extraocular light was applied. There was a large shift in the sleep/dark schedule, rather than allowing subjects to sleep each day from midnight to noon, as in the Campbell and Murphy study. Also, when extraocular light was applied in the current protocol, subjects did not experience a change from sleeping to awake, a change in posture (from lying in bed to sitting in a chair), or a change in ocular light (from dark to dim light). Further research is necessary to determine the conditions under which extraocular light might produce phase shifts in human circadian rhythms.

Individual differences in the phase and amplitude of the human circadian temperature rhythm: with an emphasis on morningness-eveningness.

We studied the relationship between the phase and the amplitude of the circadian temperature rhythm using questionnaires that measure individual differences in personality variables, variables that relate to circadian rhythms, age and sex. The ambulatory core body temperature of 101 young men and 71 young women was recorded continuously over 6 days. The temperature minimum (Tmin) and amplitude (Tamp) were derived by fitting a complex cosine curve to each day's data for each subject. Participants completed the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ), the Circadian Type Inventory (CTI) and the MMPI-2, scored for the Psychopathology-5 (PSY-5) personality variables. We found that the average Tmin occurred at 03.50 h for morning-types (M-types), 05.02 h for the neither-types and 06.01 h for evening-types (E-types). Figures were presented that could provide an estimate of Tmin given an individual's morningness-eveningness score or weekend wake time. The Tmin occurred at approximately the middle of the 8-h sleep period, but it occurred closer to wake in subjects with later Tmin values and increasing eveningness. In other words, E-types slept on an earlier part of their temperature cycle than M-types. This difference in the phase-relationship between temperature and sleep may explain why E-types are more alert at bedtime and sleepier after waking than M-types. The Tmin occurred about a half-hour later for men than women. Another interesting finding included an association between circadian rhythm temperature phase and amplitude, in that subjects with more delayed phases had larger amplitudes. The greater amplitude was due to lower nocturnal temperature.

Nocturnal melatonin secretion is not suppressed by light exposure behind the knee in humans.

Ocular light exposure can phase shift circadian rhythms and suppress nocturnal melatonin production. A recent finding suggests that extraocular light can also produce phase shifts in humans. We investigated whether extraocular light could also suppress melatonin secretion in humans. We assayed the salivary melatonin of 16 subjects during a baseline night and an experimental night in dim light (10-20 lux). The experimental night included either: (1) 3-h ocular light exposure (1000 lux, n = 6); (2) 3-h extraocular light exposure behind the knee (13,000 lux, n = 7) or (3) constant dim light exposure (10-20 lux, n = 3). Melatonin suppression occurred with ocular light but not with extraocular light or constant dim light.

Intermittent bright light and exercise to entrain human circadian rhythms to night work.

Bright light can phase shift human circadian rhythms, and recent studies have suggested that exercise can also produce phase shifts in humans. However, few studies have examined the phase-shifting effects of intermittent bright light, exercise, or the combination. This simulated night work field study included eight consecutive night shifts followed by daytime sleep/dark periods (delayed 9 h from baseline). There were 33 subjects in a 2 x 2 design that compared 1) intermittent bright light (6 pulses, 40-min long each, at 5,000 lx) versus dim light and 2) intermittent exercise (6 bouts, 15-min long each, at 50-60% of maximum heart rate) versus no exercise. Bright light and exercise occurred during the first 6 h of the first three night shifts. The circadian phase marker was the demasked rectal temperature minimum. Intermittent bright-light groups had significantly larger phase delays than dim-light groups, and 94% of subjects who received bright light had phase shifts large enough for the temperature minimum to reach daytime sleep. Exercise did not affect phase shifts; neither facilitating nor inhibiting phase shifts produced by bright light.

How to use light and dark to produce circadian adaptation to night shift work.

The circadian rhythms of night shift workers do not usually adjust to their unusual work and sleep schedules, reducing their quality of life and producing potentially dangerous health and safety problems. This paper reviews field studies of simulated night work in which shifted light-dark cycles were constructed with artificial bright or medium-intensity light to produce circadian adaptation, ie the shifting of circadian rhythms to align with night work and day sleep schedules. By using these studies we describe fundamental principles of human circadian rhythms relevant to producing circadian adaptation to night shift work at a level designed for the reader with only a basic knowledge of circadian rhythms. These principles should enable the reader to start designing work/sleep-light/dark schedules for producing circadian adaptation in night shift workers. One specific schedule is presented as an example. Finally, we discuss phase-response curves to light and clarify common misconceptions about the production of circadian rhythm phase shifts.

Bright light treatment of winter depression: a placebo-controlled trial.

BACKGROUND: Bright light therapy is the recommended treatment for winter seasonal affective disorder (SAD). However, the studies with the best placebo controls have not been able to demonstrate that light treatment has a benefit beyond its placebo effect. METHODS: Ninety-six patients with SAD completed the study. Patients were randomly assigned to 1 of 3 treatments for 4 weeks, each 1.5 hours per day: morning light (average start time about 6 AM), evening light (average start about 9 PM), or morning placebo (average start about 6 AM). The bright light (approximately 6000 lux) was produced by light boxes, and the placebos were sham negative-ion generators. Depression ratings using the Structured Interview Guide for the Hamilton Depression Rating Scale, SAD version (SIGH-SAD) were performed weekly. RESULTS: There were no differences among the 3 groups in expectation ratings or mean depression scores after 4 weeks of treatment. However, strict response criteria revealed statistically significant differences; after 3 weeks of treatment morning light produced more of the complete or almost complete remissions than placebo. By 1 criterion (24-item SIGH-SAD score <50% of baseline and < or =8), 61% of the patients responded to morning light, 50% to evening light, and 32% to placebo after 4 weeks of treatment. CONCLUSIONS: Bright light therapy had a specific antidepressant effect beyond its placebo effect, but it took at least 3 weeks for a significant effect to develop. The benefit of light over placebo was in producing more of the full remissions.

Medium-intensity light produces circadian rhythm adaptation to simulated night-shift work.

STUDY OBJECTIVES: To assess the effect of nocturnal light intensity on circadian adaptation to simulated night work. SETTING AND PARTICIPANTS: Normal young men and women, simulated night work, home sleep. DESIGN AND MEASUREMENTS: We compared temperature rhythm phase shifts following timed exposure to high (approximately 5700 lux 3 hours/day), medium (approximately 1230 lux 3 hours/day) or constant low-intensity (< 250 lux) light during consecutive night shifts. Subjects (n = 35) followed a schedule of 7 days baseline, 6 days of 8-hour night shifts (with day sleep delayed 10 hours from baseline sleep), and 4 days of recovery. Subjects wore dark sunglasses while outdoors during daylight. Sleep logs were completed after each 8-hour sleep/dark period. Night work fatigue was rated by questionnaire. RESULTS: During the 3rd through 5th days of night work, most subjects in the high and medium groups (100% and 85%) exhibited phase delays large enough that their body temperature minima occurred within the daytime sleep/dark period. Only 42% of subjects in the low group exhibited phase delays large enough to meet this criterion of circadian adaptation. The phase shifts of the high and medium groups were not significantly different, and were significantly different from the low group. Larger phase shifts were correlated with more sleep and less fatigue. CONCLUSIONS: Extremely "bright" light may not be necessary for circadian adaptation in shift work situations similar to our study protocol (e.g., regular daytime sleep/dark periods, sunglasses).

Which environmental variables are related to the onset of seasonal affective disorder?

The regular fall-winter onset of seasonal affective disorder is believed to be related to seasonal changes in the environment. However, the high correlation among various environmental variables has made it difficult to distinguish which ones may play a causal role. Photoperiod should explain variations in onset risk across both latitude and day of the year because it varies as a function of only these 2 factors. In Study 1, the authors found this to be the case using data from 5 locations. Environmental factors that vary from year to year should explain variations in onset risk across both time of year and actual year. In Study 2, the authors examined data from 7 years at 1 location and failed to find evidence of this effect for daily hours of sunshine, mean daily temperature, and total daily radiation. Findings support photoperiod as being related to the onset of seasonal affective disorder.

Conflicting bright light exposure during night shifts impedes circadian adaptation.

This simulated night shift field study compared high-intensity ("bright") light exposures designed to either facilitate or conflict with adaptation to a 9-h phase shift of the sleep/dark schedule. There were 7 days of baseline with night sleep followed by 8 night shifts with day sleep in a 2 x 2 design with factors bright light (facilitating vs. conflicting) and direction of shifted sleep/dark (delayed vs. advanced). A total of 32 subjects (8 in each group) were exposed to 3 h of bright light (about 5,000 lux) and 5 h of ordinary indoor room light of "dim" light (< 500 lux) during each 8-h night shift. The bright light was timed according to the light phase-response curve (PRC) to delay or advance rhythms; it was timed to occur either before or after the baseline body temperature minimum, which served as an estimate of the PRC crossover point between delays and advances. Core body temperature was measured continuously and demasked to determine daily temperature minima. Significantly more subjects showed large temperature rhythm phase shifts (> or = 6 h during the last 4 night shifts relative to baseline) with facilitating bright light compared to conflicting bright light as well as with delayed sleep/dark compared to advanced sleep/dark. The combination of facilitating bright light and delayed sleep/dark produced large phase delay shifts in all subjects tested. By contrast, the combination of conflicting bright light and advanced sleep/dark resulted in very small phase shifts in most subjects. Because bright light timed to delay usually was not able to phase shift rhythms when sleep/dark was advanced, it appears that the timing of sleep/dark was as important as the timing of the bright light. There was a relationship between the amount of phase shift and the individual's baseline phase when sleep/dark was delayed. Larger phase delays were achieved by subjects with later baseline temperature minima and greater eveningness on the Morningness-Eveningness Questionnaire. These results show that it is important to time bright light appropriately to achieve circadian adaptation to the night shift and that individual differences play an important role in the ability of the circadian system to phase shift.

Phase-shifting human circadian rhythms with exercise during the night shift.

Appropriately timed exercise can phase shift the circadian rhythms of rodents. The purpose of this study was to determine whether exercise during the night shift could phase delay the temperature rhythm of humans to align with a daytime sleep schedule. Exercise subjects (N = 8) rode a stationary cycle ergometer for 15 min every h during the first 3 of 8 consecutive night shifts, whereas control subjects (N = 8) remained sedentary. All subjects wore dark welder's goggles when outside after the night shift until bedtime, and then slept in dark bedrooms. Sleep was delayed 9 h from baseline. Rectal temperature was continuously measured. There were fewer evening-types and more morning-types in the exercise group than in the control group, which should have made phase delay shifts more difficult for the exercise group. Nevertheless, a majority of the exercise subjects (63%) had large temperature rhythm phase delay shifts ( > 6 h in the last 4 days relative to baseline), whereas only 38% of the control subjects had large shifts. An ANCOVA showed that, when morningness-eveningness was accounted for (as the covariate), the exercise group had a significantly larger temperature rhythm phase shift than the control group. As expected, there was a correlation between the temperature rhythm phase shift and morningness-eveningness in the control group, with greater eveningness resulting in larger phase shifts. However, there was no such relationship in the exercise group; exercise facilitated temperature rhythm phase shifts regardless of circadian type. These results suggest that exercise might be used to promote circadian adaptation to night shift work.

Circadian rhythm adaptation to simulated night shift work: effect of nocturnal bright-light duration.

We compared bright-light durations of 6, 3 and 0 hours (i.e. dim light) during simulated night shifts for phase shifting the circadian rectal temperature rhythm to align with a 12-hour shift of the sleep schedule. After 10 baseline days there were 8 consecutive night-work, day-sleep days, with 8-hour sleep (dark) periods. The bright light (about 5,000 lux, around the baseline temperature minimum) was used during all 8 night shifts, and dim light was < 500 lux. This was a field study in which subjects (n = 46) went outside after the night shifts and slept at home. Substantial circadian adaptation (i.e. a large cumulative temperature rhythm phase shift) was produced in many subjects in the bright light groups, but not in the dim light group. Six and 3 hours of bright light were each significantly better than dim light for phase shifting the temperature rhythm, but there was no significant difference between 6 and 3 hours. Thus, durations > 3 hours are probably not necessary in similar shift-work situations. Larger temperature rhythm phase shifts were associated with better subjective daytime sleep, less subjective fatigue and better overall mood.

Light treatment for sleep disorders: consensus report. I. Chronology of seminal studies in humans.

Examination of the influence of the light-dark cycle on circadian rhythmicity has been a fundamental aspect of chronobiology since its inception as a scientific discipline. Beginning with Bünning's hypothetical phase response curve in 1936, the impact of timed light exposure on circadian rhythms of literally hundreds of species has been described. The view that the light-dark cycle was an important zeitgeber for the human circadian system, as well, seemed to be supported by early studies of blind and sighted subjects. Yet, by the early 1970s, based primarily on a series of studies conducted at Erling-Andechs, Germany, the notion became widely accepted that the light-dark cycle had only a weak influence on the human circadian system and that social cues played a more important role in entrainment. In 1980, investigators at the National Institute of Mental Health reported that bright light could suppress melatonin production in humans, thereby demonstrating unequivocally the powerful effects of light on the human central nervous system. This finding led directly to the use of timed bright light exposure as a tool for the study and treatment of human circadian rhythms disorders.

Light treatment for sleep disorders: consensus report. II. Basic properties of circadian physiology and sleep regulation.

The rationale for the treatment of sleep disorders by scheduled exposure to bright light in seasonal affective disorder, jet lag, shift work, delayed sleep phase syndrome, and the elderly is, in part, based on a conceptual framework developed by nonclinical circadian rhythm researchers working with humans and other species. Some of the behavioral and physiological data that contributed to these concepts are reviewed, and some pitfalls related to their application to bright light treatment of sleep disorders are discussed. In humans and other mammals the daily light-dark (LD) cycle is a major synchronizer responsible for entrainment of circadian rhythms to the 24-h day, and phase response curves (PRCs) to light have been obtained. In humans, phase delays can be induced by light exposure scheduled before the minimum of the endogenous circadian rhythm of core body temperature (CBT), whereas phase advances are induced when light exposure is scheduled after the minimum of CBT. Since in healthy young subjects the minimum of CBT is located approximately 1 to 2 h before the habitual time of awakening, the most sensitive phase of the PRC to light coincides with sleep, and the timing of the monophasic sleep-wake cycle itself is a major determinant of light input to the pacemaker. The effects of light are mediated by the retinohypothalamic tract, and excitatory amino acids play a key role in the transduction of light information to the suprachiasmatic nuclei. LD cycles have direct "masking" effects on many variables, including sleep, which complicates the assessment of endogenous circadian phase and the interpretation of the effects of light treatment on sleep disorders. In some rodents motor activity has been shown to affect circadian phase, but in humans the evidence for such a feedback of activity on the pacemaker is still preliminary. The endogenous circadian pacemaker is a major determinant of sleep propensity and sleep structure; these, however, are also strongly influenced by the prior history of sleep and wakefulness. In healthy young subjects, light exposure schedules that do not curtail sleep but induce moderate shifts of endogenous circadian phase have been shown to influence the timing of sleep and wakefulness without markedly affecting sleep structure.

Light treatment for sleep disorders: consensus report. III. Alerting and activating effects.

In addition to the well-established phase-shifting properties of timed exposure to bright light, some investigators have reported an acute alerting, or activating, effect of bright light exposure. To the extent that bright light interventions for sleep disturbance may cause subjective and/or central nervous system activation, such a property may adversely affect the efficacy of treatment. Data obtained from patient samples and from healthy subjects generally support the notion that exposure to bright light may be associated with enhanced subjective alertness, and there is limited evidence of objective changes (EEG, skin conductance levels) that are consistent with true physiological arousal. Such activation appears to be quite transient, and there is little evidence to suggest that bright light-induced activation interferes with subsequent sleep onset. Some depressed patients, however, have experienced insomnia and hypomanic activation following bright-light exposure.

Light treatment for sleep disorders: consensus report. IV. Sleep phase and duration disturbances.

Advanced and delayed sleep phase disorders, and the hypersomnia that can accompany winter depression, have been treated successfully by appropriately timed artificial bright light exposure. Under entrainment to the 24-h day-night cycle, the sleep-wake pattern may assume various phase relationships to the circadian pacemaker, as indexed, for example, by abnormally long or short intervals between the onset of melatonin production or the core body temperature minimum and wake-up time. Advanced and delayed sleep phase syndromes and non-24-h sleep-wake syndrome have been variously ascribed to abnormal intrinsic circadian periodicity, deficiency of the entrainment mechanism, or--most simply--patterns of daily light exposure insufficient for adequate phase resetting. The timing of sleep is influenced by underlying circadian phase, but psychosocial constraints also play a major role. Exposure to light early or late in the subjective night has been used therapeutically to produce corrective phase delays or advances, respectively, in both the sleep pattern and circadian rhythms. Supplemental light exposure in fall and winter can reduce the hypersomnia of winter depression, although the therapeutic effect may be less dependent on timing.

Light treatment for sleep disorders: consensus report. V. Age-related disturbances.

Sleep maintenance insomnia is a major complaint among the elderly. As a result, an inordinate proportion of sleeping pill prescriptions go to individuals over 65 y of age. Because of the substantial problems associated with use of hypnotics in older populations, efforts have been made to develop nondrug treatments for age-related sleep disturbance, including timed exposure to bright light. Such bright light treatments are based on the assumption that age-related sleep disturbance is the consequence of alterations in the usual temporal relationship between body temperature and sleep. Although studies are limited, results strongly suggest that evening bright light exposure is beneficial in alleviating sleep maintenance insomnia in healthy elderly subjects. Less consistent, but generally positive, findings have been reported with regard to bright light treatment of sleep and behavioral disturbance in demented patients. For both groups, it is likely that homeostatic factors also contribute to sleep disturbance, and these may be less influenced by bright light interventions.

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.

Light treatment for sleep disorders: consensus report. VII. Jet lag.

Sleep disturbances are an all-too-familiar symptom of jet lag and a prime source of complaints for transmeridian travelers and flight crews alike. They are the result of a temporary loss of synchrony between an abruptly shifted sleep period, timed in accordance with the new local day-night cycle, and a gradually reentraining circadian system. Scheduled exposure to bright light can, in principle, alleviate the symptoms of jet lag by accelerating circadian reentrainment to new time zones. Laboratory simulations, in which sleep time is advanced by 6 to 8 h and the subjects exposed to bright light for 3 to 4 h during late subjective night on 2 to 4 successive days, have not all been successful. The few field studies conducted to date have had encouraging results, but their applicability to the population at large remains uncertain due to very limited sample sizes. Unresolved issues include optimal times for light exposure on the first as well as on subsequent treatment days, whether a given, fixed, light exposure time is likely to benefit a majority of travelers or whether light treatment should be scheduled instead according to some individual circadian phase marker, and if so, can such a phase marker be found that is both practical and reliable.

Light treatment for NASA shiftworkers.

Intense artificial light can phase-shift circadian rhythms and improve performance, sleep, and well-being during shiftwork simulations. In real shiftworkers, however, exposure to sunlight and other time cues may decrease the efficacy of light treatment, and occupational and family responsibilities may make it impractical. With these considerations in mind, we designed and tested light-treatment protocols for NASA personnel who worked on shifted schedules during two Space Shuttle missions. During the prelaunch week, treatment subjects self-administered light of approximately 10,000 lux at times of day that phase-delay circadian rhythms. Treatment continued during the missions and for several days afterward. No treatment was administered to subjects in the control group. Treatment subjects reported better sleep, performance, and physical and emotional well-being than control subjects and rated the treatment as highly effective for promoting adjustment to their work schedules. Light treatment is both feasible and beneficial for NASA personnel who must work on shifted schedules during Space Shuttle missions.