1 Division of Sleep Medicine, Department of Medicine, and 2 Center for Ophthalmic Research, Brigham and Women's Hospital, and 3 Harvard Medical School, Boston, Massachusetts 02115
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ABSTRACT |
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We tested the hypothesis that circadian adaptation to night work is best achieved by combining bright light during the night shift and scheduled sleep in darkness. Fifty-four subjects participated in a shift work simulation of 4 day and 3 night shifts followed by a 38-h constant routine (CR). Subjects received 2,500 lux (Bright Light) or 150 lux (Room Light) during night shifts and were scheduled to sleep (at home in darkened bedrooms) from 0800 to 1600 (Fixed Sleep) or ad libitum (Free Sleep). Dim light melatonin onset (DLMO) was measured before and after the night shifts. Both Fixed Sleep and Bright Light conditions significantly phase delayed DLMO. Treatments combined additively, with light leading to larger phase shifts. Free Sleep subjects who spontaneously adopted consistent sleep schedules adapted better than those who did not. Neither properly timed bright light nor fixed sleep schedules were consistently sufficient to shift the melatonin rhythm completely into the sleep episode. Scheduling of sleep/darkness should play a major role in prescriptions for overcoming shift work-related phase misalignment.
melatonin; phototherapy; wakefulness; shift work
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INTRODUCTION |
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MODERN SOCIETY REQUIRES that many people reverse their inherent diurnal activity pattern to ensure 24-h availability of services. There are roughly 8 million workers in the United States who regularly work at night (40). Many are employed in occupations in which peak functioning is critical (e.g., nurses and physicians, airline pilots, and operators of nuclear power plants and heavy machinery). However, night shift work exacts a substantial cost in terms of degraded health and disrupted performance. Night shift workers experience both sleep loss and misalignment of circadian phase. They suffer from greater risk of gastric and duodenal ulcers (51) and cardiovascular disease (7, 12). Night workers are particularly prone to vehicular accidents (2, 11, 32, 36, 43). Their decreased alertness, performance, and vigilance (16) are likely to blame for a substantially higher rate of industrial accidents and quality-control errors on the job (35), injuries (33, 47), and a general decline in work rate (46).
It is now well established that sleep, alertness, and cognitive functioning are determined by the interaction of two processes, the endogenous circadian pacemaker and a sleep homeostat (20, 31). The circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, generates an endogenous, near-24-h rhythm (15) that regulates subjective alertness, sleep propensity, and a wide variety of cognitive functions (24, 26), as well as core body temperature and melatonin secretion. The pacemaker is known to be highly sensitive to light, which is now considered to be the primary synchronizer of the circadian system (14).
The homeostat mediates a continual decline in performance and corresponding increase in sleepiness with time elapsed since awakening. Extended sleep deprivation experiments show a steady decay in alertness and cognitive functioning superimposed over the daily rhythm produced by the pacemaker (34).
Night workers, who are attempting to invert their normal sleep/wake schedule, suffer because the timing of their sleep/wake and work schedule remains permanently out of phase with the timing of environmental light, which probably accounts for the fact that the endogenous circadian rhythms of most permanent night shift workers fail to adapt completely (45). Ingestion of meals at an inappropriate circadian phase may be an important contributor to the gastrointestinal problems that shift workers suffer (51). Circadian misalignment leads to a substantial loss of sleep efficiency during the (daytime) sleep episode (1, 24), in addition to environmental obstacles to sleep (e.g., noise, light). Finally, night shift workers typically begin their workday 5-10 h after awakening, leaving them with more accumulated homeostatic sleep drive at the beginning of their night work shift compared with day workers (1).
Several strategies could mitigate the debilitating effects of shift work, including improved schedule design (18, 38), pharmacological agents to improve alertness on the job (3), and changes in diet, sleep scheduling, or the work environment itself (46). Appropriately timed bright light is effective in resetting the circadian rhythms of subjects undergoing simulated night work protocols (16, 21, 22, 29, 30, 48). For example, Czeisler et al. (16) demonstrated that physiological maladaptation to night work could be effectively treated by a regimen of exposure to bright light during night work and darkness during day sleep. This was accompanied by a significant improvement in alertness and performance during the night shift hours. However, it is not known how much of this effect was due to the bright light during work and how much was due to the scheduled daytime sleep in darkness (50).
The role of scheduled sleep in darkness as a circadian synchronizer in humans is unclear. Absence of light during the sleep episode may function as a photic synchronizer by changing the timing and distribution of light; the sleep itself may function as a behavioral, nonphotic synchronizer (37, 41); or the darkness may act as a synchronizer in its own right (a "dark pulse") (10, 49). Whatever the underlying mechanism, it is important to know how bright light treatments are affected by sleep schedule when designing a treatment regimen to alleviate circadian maladaptation to night work. It is possible that bright light may be sufficiently powerful to overcome all other synchronizers, and that shift workers' sleep habits are largely irrelevant in determining the effectiveness of bright light intervention. Alternatively, the powerful phase-shifting effect observed by Czeisler et al. (16) might have been due entirely to fixing the treatment subjects' sleep schedules, with the bright light playing only an incidental role. Accordingly, we designed an experiment to independently manipulate these two factors.
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METHOD |
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Subjects
Twenty-seven men and 27 women aged 20-40 [mean 26.99 ± 6.22 (SD) yr] were included in the study after extensive clinical evaluation. Medical screening included a complete physical examination, clinical biomedical tests on blood and urine, electrocardiogram, psychological screening tests (Minnesota Multiphasic Personality Inventory and the Beck Depression inventory), and a Sleep Disorders Questionnaire (27).Subjects were instructed to abstain from caffeine, nicotine, alcohol, and medication use for 3 wk before the study. On admission, and at the start of the constant routine, a comprehensive toxicological urinalysis verified subjects to be drug free. Subjects who reported travel greater than two time zones in the 3 mo before study, or a history of night work during the prior 3 yr or for >2 yr, were excluded.
Subjects wore a wrist activity monitor and called in sleep and wake times for 1 wk before study but were not required to maintain a regular sleep/wake schedule.
Experimental Protocol
Day shift.
On days 1-4, subjects practiced the battery of
computerized tests for 4 h per day, 0700-1100. The purposes
of this segment were to reduce practice effects during the night shift
and Constant Routine (see Constant routine) segments of the
study and to ensure that subjects began the night shifts with their
endogenous circadian phases similar both to each other and to workers
on a typical shift rotation. From day 1 on, activity was
monitored continuously with a wrist actigraph equipped with a light
sensor (Actiwatch-L, MiniMitter, Sun River, OR). After testing was
completed (1100), subjects left the laboratory and assumed normal
activity and sleep cycles (see Fig. 1).
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Constant posture. On day 5, subjects returned to the laboratory at 1700. Subjects were seated in dim light (<8 lux) from 1700 to 2300 and provided hourly saliva samples (SaliSaver, ALPCO). Compliance with the protocol was ensured by having a technician remain with the subject throughout the constant posture (CP) regimen.
Night shift. Beginning on day 5, subjects worked three consecutive 8-h night shifts from 2300 to 0700. Subjects performed four iterations of a cognitive performance battery, including a visual analog scale measure of subjective alertness.1 There were short breaks between individual tasks in the battery and 30-min breaks between batteries. During long breaks, subjects were instructed not to lie down, nap, or leave the suite, with video monitoring for compliance.
Constant routine. Final endogenous circadian phase was measured during a 38-h constant routine (CR). The CR, described in detail in Refs. 8, 9, 16, 17, and 28, is designed to minimize or distribute evenly across the circadian cycle factors known to mask the endogenous component of core body temperature rhythm. Subjects were restricted to semirecumbent wakeful bed rest in dim light conditions (<8 lux). Food was distributed in hourly snacks. A technician was present at all times during the CR to ensure compliance with the protocol and to help the subject maintain wakefulness. Saliva samples were acquired and a 30-min test battery was administered hourly. Core body temperature (CBT) was monitored via a rectal thermistor (Yellow Springs Instruments, Yellow Springs, OH). Subjects were allowed 8 h of recovery sleep in the laboratory after the CR. The CR began at 1700 on day 8 and ended at 0700 on day 10.
Experimental Conditions
During the night shift, there were two experimental manipulations: light, and sleep schedule. Bright Light subjects were exposed toSubjects' sleep schedule at home was the second experimental variable. Starting on day 6, Fixed Sleep subjects were given opaque material to cover their windows and instructed to be in bed with the lights off, trying to sleep from 0800 to 1600 (±30 min) each day. Subjects thus had a maximum of 1.5 h to travel home and prepare for bed.2 Subjects were not given goggles or sunglasses for the trip home. Compliance was monitored via actigraphy. Free Sleep subjects were told that they could sleep whenever they wanted to.
This design yields four groups of subjects: Bright Light & Fixed Sleep (hereafter Bright Fixed; Fig. 1A; n = 13, 2 women), Room Light & Fixed Sleep (Room Fixed; Fig. 1B; n = 14, 6 women), Bright Light & Free Sleep (Bright Free; Fig. 1C; n = 13, 8 women), and Room Light & Free Sleep (Room Free; Fig. 1D; n = 14, 12 women). Subjects were randomly assigned to groups. All subjects were treated identically until the first night shift. Subjects were informed of their sleep schedules at the end of the first night shift.
Hormonal Assay
Saliva samples were immediately centrifuged and frozen. They were assayed for melatonin concentration by radioimmunoassay (assay sensitivity of 22 pmol/l, intra-assay coefficient of variability of 8%, interassay coefficient of variation of 13%; DiagnosTech, Osceola, WI).Data Analysis
Final melatonin phase was defined as the midpoint of the melatonin secretion episode (MMSE). Mean melatonin concentration during the first 24 h of the CR was calculated, and the MMSE was computed as the midpoint of the upward and downward mean crossings (53, 54). The dim light melatonin onset [DLMO (23, 39)] was defined as the time that the melatonin levels during the CP reached 20% of the maximum melatonin level observed during the CR. A DLMO was also calculated for the CR.Final CBT phase was computed by a two-harmonic fit to the temperature data (9). The phase was defined as the average of the nadir of the fundamental and of the composite fit (CBTmin).
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RESULTS |
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Circadian Phase
Two subjects (one in the Bright Fixed group and one in the Room Fixed group) were excluded from the melatonin analyses because of data collection problems. The mean MMSE is plotted by group in Fig. 2A. The data clearly show that the combination of bright light and scheduled sleep in darkness produced the greatest adaptation to night work. The mean MMSE of this group, 0806, has moved into the sleep episode. Data were submitted to a 2 (Bright Light vs. Room Light) × 2 (Fixed Sleep vs. Free Sleep) ANOVA. The Bright Light group's phase was significantly delayed with respect to the Room Light group [F(1,48) = 28.72, P < 0.0001], and a fixed sleep schedule significantly delayed MMSE phase compared with a free sleep schedule [F(1,48) = 17.23, P < 0.0005]. There was no interaction [F(1,48) <1].
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The CBT phase analysis (shown in Fig. 2B) was consistent with analysis of the melatonin data. Bright light significantly delayed the CBT nadir [F(1,50) = 25.32, P < 0.0001], as did a fixed sleep schedule [F(1, 50) = 16.97, P < 0.0005]; again the two factors did not interact [F(1,50) <1].
Initial phase was computed from the CP data. Nine subjects either did not exhibit a DLMO during the CP, according to the criterion, or had insufficient data during the CP. Data from the remaining subjects were analyzed via ANOVA. There was no effect of light treatment [F(1,39) <1]. The Fixed Sleep subjects' DLMO was 44.2 min later than that of the Free Sleep group [F(1,39) = 5.76, P < 0.05]. There was no interaction [F(1,39) <1]. We do not know why the initial DLMO, measured before subjects were given a sleep schedule, should have differed as a function of sleep schedule. To ensure that this initial difference in phase was not responsible for producing our observed distribution of final phases, we reanalyzed both the final MMSE phase data and the CBTmin data by ANCOVA by use of the CP DLMO as a covariate.3 The ANCOVAs produced nearly identical results to the original ANOVAs. For the MMSE analysis, the main effect of light was significant [F(1, 38) = 31.25, P < 0.0001], as was the main effect of sleep schedule [F(1,38) = 17.05, P < 0.0005], with no interaction [F(1,38) <1]. Similarly, for the CBTmin analysis, the main effect of light was significant [F(1,38) = 30.36, P < 0.0001], as was the main effect of sleep schedule [F(1,38) = 13.58, P < 0.001], with no interaction [F(1,38) <1].
We determined the phase shift from CP to CR by computing the first DLMO during the CR and subtracting this from the CP DLMO. Figure 2C plots the mean phase shift as a function of group. An ANOVA on the phase shifts showed a main effect of light [F(1,39) = 19.64, P < 0.0001], with larger delays for the Bright Light subjects, and a main effect of sleep [F(1,39) = 6.60, P < 0.05], with Fixed Sleep subjects' final phase delayed more than that of the Free Sleep subjects. These results confirm that the pattern of final phases observed in the MMSE data was due to the phase-shifting effects of bright light and scheduled sleep in darkness, rather than to preexisting group differences.
Subjective Alertness
We analyzed the subjective alertness data from the part of the CR corresponding to the hours of the night shifts, from 2300 to 700 on days 8 and 9. We selected these data, instead of data from the actual night work shifts, because all subjects are under exactly the same conditions during the CR, so the data were not contaminated by the acute effects of light (52). Because the study schedule required all subjects, regardless of sleep schedule group, to sleep between the end of the third night shift at 0700 and the start of the CR at 1700 on day 8, differences in homeostatic sleep pressure should also be minimized. The eight hourly measurements per day were averaged and then entered into a 2 (Bright vs. Room Light) × 2 (Fixed vs. Free Sleep schedule) × 2 (day 8 vs. day 9) mixed ANOVA. There were significant main effects of all three factors. Bright Light subjects were more alert than Room Light subjects [F(1,50) = 7.72, P < 0.01], and Fixed Sleep subjects were more alert than Free Sleep subjects [F(1, 50) = 12.19, P < 0.005]. Finally, alertness was substantially lower on the 2nd day of the CR [F(1,50) = 103.25, P < 0.0001], because subjects had been awake for 24 h longer by this time. There were no interactions (all P < 0.10). Data are shown in Fig. 3 as a function of group. Figure 3A plots the data on the 1st day of the CR, and Fig. 3B shows data from the 2nd day.
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Actigraphy
For each subject, we separately analyzed four activity measures: the average sleep start time, the average wake time, and the standard deviations of sleep start time and wake time. These values were computed using the SleepWatch software (MiniMitter). Data were incomplete for the night shift days for 9 subjects (3 each in the Free Sleep groups, 1 in the Bright Fixed group, and 2 in the Room Fixed group). For the remaining subjects, the mean sleep start time (hours of the day ± SD) was 0807 (±07) for the Bright Fixed group, 0935 (±41) for the Bright Free group, 0818 (±06) for the Room Fixed group, and 0842 (±22) for the Room Free group. Mean wake times (SD) were 1548 (±06) for the Bright Fixed group, 1530 (±29) for the Bright Free group, 1556 (±05) for the Room Fixed group, and 1533 (±37) for the Room Free group. The SD of sleep start time over the 3 days were 17 (±02) min for the Bright Fixed group, 1 h 23 (±33) min for the Bright Free group, 15 (±02) min for the Room Fixed group, and 29 (±13) min for the Room Free group. The SD of wake times over the 3 days were 31 (±10) for the Bright Fixed group, 1 h 43 (±21) min for the Bright Free group, 31 (±04) min for the Room Fixed group, and 1 h 37 (±21) min for the Room Free group.ANOVA showed that Free Sleep subjects went to sleep later than Fixed Sleep subjects [F(1,41) = 6.39, P < 0.05]. Light had no effect on sleep start times [F(1, 41) <1], and there was no interaction [F(1,41) = 2.08, P > 0.10]. Wake time did not differ significantly among groups [all F(1,41) <1]. The Free Sleep subjects were also more variable in their behavior. The standard deviation of sleep start time was higher for the Free Sleep group [F(1,41) = 6.28, P < 0.05]. There was a trend toward more variable sleep onset times in the Bright Light condition [F(1,41) = 2.91, P = 0.096], but there was no interaction [F(1,41) = 2.68, P > 0.10]. Variability in the wake time was substantially higher for the Free Sleep group [F(1,41) = 21.84, P < 0.0001]. Again, there was no effect of light or any interaction [both F(1,41) <1].
In the Free Sleep conditions, there was wide variability in
the final (MMSE) phase. Figure 4
illustrates that this measure is negatively correlated with variability
in wake time. The more variable the subjects' sleep patterns, the less
likely they were to adapt to the night shift schedule. Across groups,
variability in wake times is negatively correlated with final phase
[r = 0.546; t(43) = 4.28, P < 0.0001]. Mean wake time itself did not
predict final phase [r =
0.136,
t(43) <1]. The mean time that subjects went
to sleep was also negatively correlated with final phase, although not
as strongly as the standard deviation of wake time [r =
0.426, t(43) = 3.09, P < 0.005]. Variability in sleep onset time was not significantly
related to final phase [r =
0.235, t(43) = 1.58, P > 0.10].
Of course, all four of these variables are strongly correlated with one
another. Sleep onset time naturally determines wake time
(r = 0.858, P < 0.0001). More
importantly, mean sleep and wake times will determine the variability
because of the study schedule. On day 8, subjects have only
10 h between the end of the final night shift at 0700 and the
start of the CR at 1700, so all sleep episodes on day 8 take
place within this window. Therefore, subjects who go to sleep later on
days 6 and 7 will have high variability, as well
as later mean sleep and wake times. We focus on the standard deviation
of wake time, because it is the best predictor of final phase in the
Free Sleep groups. The four panels in Fig. 4 scatter plot
final MMSE phase against the standard deviation of wake time for each
group. It is clear from Fig. 4 that the overall correlation between
waketime variablity and phase is generated by the Free Sleep
schedule subjects (Fig. 4, C and D). There is
little variability in the wake times of subjects in the Fixed
Sleep groups (Fig. 4, A and B), indicating that subjects followed instructions. For the Bright Fixed
subjects, the correlation with final phase is
0.136
[t(10) <1], and for the Room
Fixed subjects, the correlation is close to zero
[r = 0.059, t(10) <1]. For
the Room Free subjects, however, wake time variability was
strongly negatively correlated with final phase [r =
0.634, t(9) = 2.46 < 0.05]. The
relationship is strongest for the Bright Free subjects
[r =
0.750, t(8) = 3.21, P < 0.05].
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DISCUSSION |
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The ability of bright light to induce precise phase shifts under controlled laboratory conditions is now well known (14, 14, 19). Controlled simulations of shift work schedules have convincingly demonstrated the potential value of applying circadian principles to the problem of night work (13, 30). Our data demonstrate that scheduling of sleep/darkness should play a major role in prescriptions for overcoming shift work-related phase misalignment. Both bright light and a fixed sleep/dark schedule significantly delayed melatonin phase, and the effects of these two factors were additive. Neither factor alone was sufficient to induce consistently adequate phase shifts. In fact, we found that a fixed sleep/wake schedule accounted for 3.17 h of phase delay, compared with 4.10 h for 2,500 lux of light; together, they yielded 7.28 h, sufficient to induce complete physiological adaptation to night shift work. Of course, Fig. 4 indicates that our manipulation was complicated by the fact that seven subjects in the Free Sleep condition voluntarily adopted schedules that were less variable than the most variable Fixed Sleep subject, so we may be underestimating the contribution of a fixed sleep schedule to circadian adaptation to night work.
The Bright Fixed subjects (Fig. 4A) are all clustered in the upper left of the plot. This is the outcome of a typical controlled laboratory study: subjects are on consistent, experimenter-selected schedules and receive the full benefit of properly timed bright light treatment. The midpoint of the melatonin episode moved into their sleep episodes (0800-1600). Figure 4D depicts subjects who behaved most like night shift workers in the real world, in that they manifested a variety of sleep/wake schedules, generally did not have lightproof bedrooms, and were exposed to room light only at work. This group fares quite poorly.
In Fig. 4B, the Room Fixed subjects generally did not shift, although some did achieve a phase near 0800 at the start of the sleep episode. It is important to remember that even normal room light can elicit a significant phase-shifting effect in the laboratory (6). Measurements of the human circadian pacemaker's dose-response curve to light suggest that one-half of the maximal type I resetting response is achieved at ~100 lux (5, 55). The presence of competing synchronizers, to which these subjects were exposed outside of the laboratory, probably accounts for why most of our Room Light subjects failed to adapt. Actual night shift workers face a similar situation, in which the light exposure they receive at work may be insufficient to overcome the effects of the bright light they encounter on the drive home or while running errands.
Figure 4C shows the subjects who received bright indoor light treatment sufficient to overcome the competing environmental synchronizers, but who were not required to keep a fixed sleep schedule in a darkened bedroom. The outcome for these subjects strongly depended on whether they chose to maintain a consistent sleep/wake schedule. Those who did adapted as well as the Bright Fixed subjects; indeed, the latest midpoint, near 1100, is from this group. But according to the slope of the regression line (not shown), increasing the variability of wake time by one standard deviation entailed the sacrifice of 2 h 36 min of phase delay, so that subjects with highly variable sleep/wake schedules were as poorly adapted to night work as the worst-off subjects in the Room Light conditions; the earliest midpoint, near 2300, is also from this group.
It is important to recognize that we cannot, from these experiments, determine what it is about the scheduled sleep in darkness that promotes adaptation. There are several (not mutually exclusive) possibilities. A fixed period of darkness changes the distribution of light throughout the day, therefore changing the photic effects on the pacemaker. Alternatively, the timing of sleep itself may act as a synchronizer. Finally, a sleep episode in a darkened bedroom may act as a "dark pulse" on the pacemaker (10, 49). Whatever the underlying mechanism (and more than one mechanism may be acting in concert), a consistent sleep/wake schedule should minimize competition from the natural schedule of synchronizers.
Of course, generalizing from laboratory studies to actual shift work situations can be challenging. Our goal was to create a "high-fidelity" laboratory simulation of night shift work. Except for the CR and CP episodes, subjects left the laboratory when not working their shifts. They were thus exposed to typical, uncontrolled patterns of natural light and social interaction experienced by people working the night shift. We are thus more confident about the generalizability of our results than we would have been if our subjects had spent the entire experimental protocol isolated in controlled conditions in the laboratory. However, one caveat is that our subjects were not allowed to use psychopharmacological agents. Use of drugs such as alcohol, nicotine, and caffeine, as well as over-the-counter sleep medications, is quite common among shift workers (42). All of these agents can affect sleep quality, and there is some evidence that alcohol (4) and nicotine (44) can directly alter circadian rhythms. We have no evidence from this study on how light or scheduled sleep may interact with drug use to affect circadian adaptation to, or performance on, the night shift.
Our results suggest that shift workers should be strongly encouraged to adopt a consistent sleep schedule, avoiding the common practice of changing their sleep/wake schedules during the work week. Further research involving multiple light levels will be required, so that appropriately higher light intensities may be recommended in situations in which fixed sleep/dark schedules are impractical. Conversely, given the expense of installing bright light systems, it is important to know the minimal amount of light to recommend when workers can maintain an optimal fixed sleep schedule. Although controlled laboratory studies suggest that the phase-shifting effects of light saturate ~600 lux of the phase-shifting effects of light (5, 55), this finding requires recalibration in a shift work situation in which there are competing synchronizers. Nevertheless, the implications of our findings are clear: use of both bright light exposure and scheduled darkness/sleep is required to achieve a reliable treatment for circadian maladaptation to night work.
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ACKNOWLEDGEMENTS |
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We thank the subject volunteers, the recruiters (Conor O'Brien, Naomi Gonzalez, and Serena Ma), and the research technicians.
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FOOTNOTES |
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This work was supported by National Institutes of Health (NIH) Grant HL-52992 and the Air Force Office of Scientific Research Grant F49620-95-1-0388, and an NIH Division of Research Resources General Clinical Research Center Grant GCRC-2-MO1-RR-02635.
Address for reprint requests and other correspondence: C. A. Czeisler, Division of Sleep Medicine, Dept. of Medicine, Brigham and Women's Hospital, 221 Longwood Ave., Boston, MA 02115 (E-mail: caczeisler{at}gcrc.bwh.harvard.edu).
1 Other data from this battery will be published in a separate paper.
2 Subjects who lived more than an hour's travel from the laboratory (by car or public transit) were excluded during the screening process.
3 We are grateful to an anonymous reviewer for this suggestion.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 16 August 2000; accepted in final form 4 April 2001.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Åkerstedt, T.
Sleepiness as a consequence of shift work.
Sleep
11:
17-34,
1988[ISI][Medline].
2.
Åkerstedt, T,
Czeisler CA,
Dinges DF,
and
Horne JA.
Accidents and sleepiness: a consensus statement from the International Conference on Work Hours, Sleep and Accidents, Stockholm, 8-10 September 1994.
J Sleep Res
3:
195,
1994[ISI].
3.
Åkerstedt, T,
and
Ficca G.
Alertness-enhancing drugs as a countermeasure to fatigue in irregular work hours.
Chronobiol Int
14:
145-158,
1997[ISI][Medline].
4.
Baird, TJ,
Briscoe RJ,
Vallett M,
Vanecek SA,
Holloway FA,
and
Gauvin DV.
Phase-response curve for ethanol: alterations in circadian rhythms of temperature and activity in rats.
Pharmacol Biochem Behav
61:
303-315,
1998[ISI][Medline].
5.
Boivin, DB,
Duffy JF,
Kronauer RE,
and
Czeisler CA.
Dose-response relationships for resetting of human circadian clock by light.
Nature
379:
540-542,
1996[ISI][Medline].
6.
Boivin, DB,
Zeitzer JM,
and
Czeisler CA.
Resetting of the endogenous circadian rhythm of plasma melatonin and body temperature by ordinary room light in humans.
J Sleep Res
5:
S20-S20,
1995.
7.
Bøggild, H,
and
Knutsson A.
Shift work, risk factors, and cardiovascular disease.
Scand J Work Environ Health
25:
85-99,
1999[ISI][Medline].
8.
Brown, EN,
Choe Y,
Shanahan TL,
and
Czeisler CA.
A mathematical model of diurnal variations in human plasma melatonin levels.
Am J Physiol Endocrinol Metab
272:
E506-E516,
1997
9.
Brown, EN,
and
Czeisler CA.
The statistical analysis of circadian phase and amplitude in constant-routine core-temperature data.
J Biol Rhythms
7:
177-202,
1992[ISI][Medline].
10.
Buxton, OM,
L'Hermite-Balériaux M,
Turek FW,
and
van Cauter E.
Daytime naps in darkness phase shift the human circadian rhythms of melatonin and thyrotropin secretion.
Am J Physiol Regulatory Integrative Comp Physiol
278:
R373-R382,
2000
11.
Cluydts, R,
De Roeck J,
Cosyns P,
and
Lacante P.
Antagonizing the effects of experimentally induced sleep disturbance in healthy volunteers by lormetazepam and zolpidem.
J Clin Psychopharmacol
15:
132-137,
1995[ISI][Medline].
12.
Costa, G.
The problem: shiftwork.
Chronobiol Int
14:
89-98,
1997[ISI][Medline].
13.
Czeisler, CA,
and
Dijk DJ.
Use of bright light to treat maladaption to night shift work and circadian rhythm sleep disorders.
J Sleep Res
4:
70-73,
1995[ISI][Medline].
14.
Czeisler CA and Dijk DJ. Human circadian physiology and sleep-wake
regulation. In: Handbook of Behavioral Neurobiology: Circadian
Clocks, edited by JS Takahashi, FW Turek, and RY Moore. New York:
Plenum. In press.
15.
Czeisler, CA,
Duffy JF,
Shanahan TL,
Brown EN,
Mitchell JF,
Rimmer DW,
Ronda JM,
Silva EJ,
Allan JS,
Emens JS,
Dijk DJ,
and
Kronauer RE.
Stability, precision, and near-24-hour period of the human circadian pacemaker.
Science
284:
2177-2181,
1999
16.
Czeisler, CA,
Johnson MP,
Duffy JF,
Brown EN,
Ronda JM,
and
Kronauer RE.
Exposure to bright light and darkness to treat physiologic maladaptation to night work.
N Engl J Med
322:
1253-1259,
1990[Abstract].
17.
Czeisler, CA,
Kronauer RE,
Allan JS,
Duffy JF,
Jewett ME,
Brown EN,
and
Ronda JM.
Bright light induction of strong (type 0) resetting of the human circadian pacemaker.
Science
244:
1328-1333,
1989[ISI][Medline].
18.
Czeisler, CA,
Moore-Ede MC,
and
Coleman RM.
Rotating shift work schedules that disrupt sleep are improved by applying circadian principles.
Science
217:
460-463,
1982[ISI][Medline].
19.
Czeisler, CA,
and
Wright KP, Jr.
Influence of light on circadian rhythmicity in humans.
In: Regulation of Sleep and Circadian Rhythms, edited by Turek FW,
and Zee PC. New York: Dekker, 1999, p. 149-180.
20.
Daan, S,
Beersma DGM,
and
Borbély AA.
Timing of human sleep: recovery process gated by a circadian pacemaker.
Am J Physiol Regulatory Integrative Comp Physiol
246:
R161-R178,
1984
21.
Dawson, D,
and
Campbell SS.
Timed exposure to bright light improves sleep and alertness during simulated night shifts.
Sleep
14:
511-516,
1991[ISI][Medline].
22.
Dawson, D,
Encel N,
and
Lushington K.
Improving adaptation to simulated night shift: timed exposure to bright light versus daytime melatonin administration.
Sleep
18:
11-21,
1995[ISI][Medline].
23.
Deacon, S,
and
Arendt J.
Posture influences melatonin concentrations in plasma and saliva in humans.
Neurosci Lett
167:
191-194,
1994[ISI][Medline].
24.
Dijk, DJ,
and
Czeisler CA.
Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves and sleep spindle activity in humans.
J Neurosci
15:
3526-3538,
1995[Abstract].
26.
Dinges, DF,
Orne MT,
Whitehouse WG,
and
Orne EC.
Temporal placement of a nap for alertness: contributions of circadian phase and prior wakefulness.
Sleep
10:
313-329,
1987[ISI][Medline].
27.
Douglass, A,
Bornstein R,
Nino-Murcia G,
and
Keenan S.
Creation of the "ASDC Sleep Disorders Questionnaire" (Abstract).
Sleep Res
15:
117,
1986.
28.
Duffy, JF.
Constant routine.
In: Encyclopedia of Sleep and Dreaming, edited by Carskadon MA. New York: Macmillan, 1993, p. 134-136.
29.
Eastman, CI.
High-intensity light for circadian adaptation to a 12-h shift of the sleep schedule.
Am J Physiol Regulatory Integrative Comp Physiol
263:
R428-R436,
1992
30.
Eastman, CI,
Boulos Z,
Terman M,
Campbell SS,
Dijk DJ,
and
Lewy AJ.
Light treatment for sleep disorders: Consensus Report. VI. Shift work.
J Biol Rhythms
10:
157-164,
1995[ISI][Medline].
31.
Edgar, DM,
Dement WC,
and
Fuller CA.
Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation.
J Neurosci
13:
1065-1079,
1993[Abstract].
32.
Folkard, S.
Black times: temporal determinants of transport safety.
Accid Anal Prev
29:
417-430,
1997[ISI][Medline].
33.
Frank, AL.
Injuries related to shiftwork.
Am J Prev Med
18:
33-36,
2000[ISI][Medline].
34.
Fröberg, JE,
Karlsson CG,
Levi L,
and
Lidberg L.
Circadian rhythms of catecholamine excretion, shooting range performance and self-ratings of fatigue during sleep deprivation.
Biol Psychol
2:
175-188,
1975[ISI][Medline].
35.
Gold, DR,
Rogacz S,
Bock N,
Tosteson TD,
Baum TM,
Speizer FE,
and
Czeisler CA.
Rotating shift work, sleep, and accidents related to sleepiness in hospital nurses.
Am J Public Health
82:
1011-1014,
1992[Abstract].
36.
Harris, W.
Fatigue, circadian rhythm, and truck accidents.
In: Vigilance Theory, Operational Performance, and Physiological Correlates, edited by Mackie R. New York: Plenum, 1977, p. 133-146.
37.
Klerman, EB,
Rimmer DW,
Dijk DJ,
Kronauer RE,
Rizzo JF, III,
and
Czeisler CA.
Nonphotic entrainment of the human circadian pacemaker.
Am J Physiol Regulatory Integrative Comp Physiol
274:
R991-R996,
1998
38.
Kogi, K,
and
Thurman JE.
Trends in approaches to night and shiftwork and new international standards.
Ergonomics
36:
3-13,
1993[ISI][Medline].
39.
Lewy, AJ,
and
Sack RL.
The dim light melatonin onset as a marker for circadian phase position.
Chronobiol Int
6:
93-102,
1989[ISI][Medline].
40.
Mellor EF. Shift work and flexitime: how prevalent are they?
Monthly Labor Rev: 14-21, 1986.
41.
Nakamura, K.
Non-photic entrainment of human circadian clockeffects of forced sleep-wake schedule on the circadian rhythm in plasma melatonin.
Hokkaido Igaku Zasshi
71:
403-422,
1996[Medline].
42.
Niedhammer, I,
Lert F,
and
Marne MJ.
Psychotropic drug use and shift work among French nurses (1980-1990).
Psychol Med
25:
329-338,
1995[ISI][Medline].
43.
Novak, RD,
and
Auvil-Novak SE.
Focus group evaluation of night nurse shiftwork difficulties and coping strategies.
Chronobiol Int
13:
457-463,
1996[ISI][Medline].
44.
O'Hara, BF,
Edgar DM,
Cao VH,
Wiler SW,
Heller HC,
Kilduff TS,
and
Miller JF.
Nicotine and nicotinic receptors in the circadian system.
Psychoneuroendocrinology
23:
161-173,
1998[ISI][Medline].
45.
Patkai, P,
Åkerstedt T,
and
Pettersson K.
Field studies of shiftwork: I. Temporal patterns in psychophysiological activation in permanent night workers.
Ergonomics
20:
611-619,
1977[ISI][Medline].
46.
Rosa, RR,
Bonnet MH,
Bootzin RR,
Eastman CI,
Monk T,
and
Penn PE.
Intervention factors for promoting adjustment to nightwork and shiftwork.
Occup Med
5:
391-414,
1995.
47.
Smith, L,
Folkard S,
and
Poole CJM
Increased injuries on night shift.
Lancet
344:
1137-1139,
1994[ISI][Medline].
48.
Thessing, VC,
Anch AM,
Muehlbach MJ,
Schweitzer PK,
and
Walsh JK.
Two- and 4-hour bright-light exposures differentially effect sleepiness and performance the subsequent night.
Sleep
17:
140-145,
1994[ISI][Medline].
49.
Van Cauter, E,
Moreno-Reyes R,
Akseki E,
L'Hermite-Balériaux M,
Hirschfeld U,
Leproult R,
and
Copinschi G.
Rapid phase advance of the 24-h melatonin profile in response to afternoon dark exposure.
Am J Physiol Endocrinol Metab
275:
E48-E54,
1998
50.
Van Cauter, E,
and
Turek FW.
Strategies for resetting the human circadian clock.
N Engl J Med
322:
1306-1308,
1990[ISI][Medline].
51.
Vener, KJ,
Szabo S,
and
Moore JG.
The effect of shift work on gastrointestinal (GI) function: a review.
Chronobiologia
16:
421-439,
1989[ISI][Medline].
52.
Wright, KP, Jr,
Badia P,
Myers BL,
Plenzler SC,
and
Hakel M.
Caffeine and light effects on nighttime melatonin and temperature levels in sleep-deprived humans.
Brain Res
747:
78-84,
1997[ISI][Medline].
53.
Zeitzer, JM,
and
Czeisler CA.
Red light induces shifts in the human circadian rhythm of plasma melatonin (Abstract).
Soc Res Biol Rhythms
5:
108,
1996.
54.
Zeitzer, JM,
Daniels JE,
Duffy JF,
Klerman EB,
Shanahan TL,
Dijk DJ,
and
Czeisler CA.
Do plasma melatonin concentrations decline with age?
Am J Med
107:
432-436,
1999[ISI][Medline].
55.
Zeitzer, JM,
Dijk DJ,
Kronauer RE,
Brown EN,
and
Czeisler CA.
Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression.
J Physiol (Lond)
526:
695-702,
2000