Adapting to phase shifts, I. An experimental model for jet lag and shift work

Physiology & Behavior, Vol. 59. Nos. 4/5, pp. 665-673, 1996 Copyright © 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0031-9384/96515,00 + ,00

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Adapting to Phase Shifts, I. An Experimental Model for Jet Lag and Shift Work STEPHEN D E A C O N I A N D J O S E P H I N E A R E N D T

Chronobiology Laboratory, Endocrinology and Metabolism Group, School of Biological Sciences, University of Surrey, Guildford, Surrey, GU2 5XH, UK Received 8 January 95 DEACON, S. AND J. ARENDT. Adapting to phase shifts, 1. An experimental model to study jet lag and shift work. PHYSIOL BEHAV 59(4/5) 665-673, 1996.--An experimental model was developed to measure various behavioral and physiological parameters in a laboratory paradigm mimicking phase shifts that could occur in time-zone transitions and shift work rotas. Volunteers were exposed to 9-h pulses of bright light (1,200 lx) as follows: day (D) I: 1800-0300 h, D2:2100-0600 h, and D3, 4, 5:2400-0900 h, each period followed by 8 h darkness. Immediately following the last treatment, subjects resumed their baseline sleep/wake schedule in a normal environment, thus experiencing a rapid 9-h advance phase shift of local time cues. During the gradual delay shift, a progressive delay shift in the rhythms of urinary 6-sulphatoxymelatonin (aMT6s), temperature and alertness was evident (maximum shift: 9.13 -t- 0.83 h, 9.09 _+ 1.06, and 10.62 + 0.96 h, mean + SD, respectively). There were no important detrimental effects on behavioral variables. After the rapid 9-h phase advance, sleep patterns, temperature amplitude, aMT6s acrophase, alertness, and performance took at least 5 days to reestablish normal baseline patterns. This model provides an effective and inexpensive model to study adaptation strategies in real life. Melatonin Sleep

Bright light Circadian rhythms

Jet lag Shift work Phase shifting Psions

ON arrival at their destination, time-zone travellers encounter a pattern of light and darkness, activity, and social schedules shifted in time. The endogenous circadian timing system is slow to adapt to new time cues (or zeitgebers) and until the correct phase relationship between biological rhythms and external zeitgebers is established, a host of physiological and behavioral problems are manifest (20,34,43). Similar problems are encountered by shift workers operating to new work schedules out of phase with the normal light/dark cycles, other competing zeitgebers, and their endogenous body clock (1,2,9,21,25,36). Field studies to investigate the problems associated with jet lag and shift work are expensive and difficult to control. Laboratory simulations provide a more controlled environment with which to study these circadian rhythm disorders in detail. However, a critical feature of laboratory simulations is that the subjects are isolated from a normal environment, whereas field studies allow the subject to be exposed to a whole range of time cues that may be important in the normal adaptation process in every day life. Treatment strategies to facilitate adaptation to shift work or new time-zones must be effective in the presence of competing zeitgebers that are present in normal every day life.

Model

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Thus, to simulate conditions as true to life as possible, an experimental model was developed without complete environmental isolation allowing subjects to adapt to rapid shifts in local time cues in their normal environment. When suitably timed, bright light of sufficient intensity and duration will induce phase shifts in various biological rhythms such as those of core body temperature, cortisol, thyrotropin, and melatonin (6,7,10,14,15,26,30,33,37). In constant routine (unmasked) conditions, the magnitude and direction of shift of circadian rhythms is similar (12,33,37), strongly suggesting that light has a unique ability to phase-shift the human circadian pacemaking system governing many physiological circadian rhythms. The reported phase-response curve (PRC) to light enables predictions of the magnitude and direction of the shift based upon the timing of the light pulse. Exposure to bright light in the evening can delay circadian rhythms, and morning light exposure will produce advance shifts, with the greatest shifts achieved with light exposure close to the temperature minimum (12,30,37). Such a PRC for light may be applied to facilitate the adaptation of rhythms in circadian rhythm disorders such as jet lag and

1 TO whom requests for reprints should be addressed.

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maladaptation to shift work (11,13,16-19,22). It may also provide a means of simulating such disorders in a laboratory. This experiment formed part of a four-leg crossover study that investigated the effects of bright light and melatonin in facilitating the readaptation of the circadian system and alleviating the associated behavioral problems after a rapid 9-h advance shift in local time. Comparison of these treatment strategies will be discussed in the related article, Adapting to phase shifts, II. It is the purpose of this article to describe in detail an experimental model that gradually induces a synchronized 9-h delay phase shift in the circadian system under controlled environmental conditions (using a combination of bright light and darkness/sleep) and allows a rapid 9-h advance shift of external time cues to be induced when the subjects resume their baseline sleep/wake schedule in a normal environment. The readaptation of the subjects to their normal environment will be described under placebo treatment.

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Subjecls Eight healthy volunteers (4M:4F), aged 22-26, under no medication, and all nonsmokers, were recruited from research students of the University of Surrey who followed similar sleep/wake schedules and lifestyles. All subjects gave informed and written consent and the study protocol was approved by the Advisory Committee on Ethics of the University of Surrey. The female subjects were questioned for the regularity of their menstrual cycle before recruitment into the study. For these volunteers, each leg of the study took place within the first 2 weeks of their menstrual cycle. Using the Home and 0stberg questionnaire (1976) to determine morning or evening type individuals, no definite morning or evening types were detected (scores > 70 or < 31). The subjects refrained from heavy exercise and restricted their alcohol consumption (maximum 2 units per day) throughout the experiment.

Study Design The study was performed as four legs during winter (November 1992-March 1993) at 52°N. Each leg consisted of a gradual, forced, 9-h delay phase shift followed by an abrupt 9-h advance phase shift to reestablish local time cues. Subjects were then treated with timed exposure to either placebo, melatonin, bright light plus placebo, bright light plus melatonin in a randomized, double blind, crossover design. The placebo leg is described here. Baseline. For 3 days prior to the phase shift (days (D) - 2 to 0), the subjects were required to maintain a regular sleep/wake schedule, retiring to bed at approximately 2330 h and waking at 0800 h, remaining in the dark ( < 1 Ix) between these times. Gradual 9-h delay phase shift. Immediately following the baseline days, the subjects were exposed to 9-h pulses of moderately bright full spectrum light (average 1,200 lx at eye level; Tru-Lite, Duro-Test Corporation, Fairfield, N J, obtained through Full Spectrum Lighting, High Wycombe, Buckinghamshire, UK), at progressively 3 h later times during 3 27-h days (D1-D3) and then at the same times on 2 24-h clays (D4-D5) as for D3. Bright light exposure was administered in a controlled environment in the Clinical Investigation Unit, University of Surrey. The periods of light exposure were as follows--Dl: 1800-0300 h, D2: 2100-0600 h, D3, 4 , 5 : 2 4 0 0 - 0 9 0 0 h. Each period of light treatment was followed by 8 h of imposed darkness ( < 1 Ix, in subjects' own bedroom on campus with windows blackened) when they slept. During the remaining hours of each day subjects were in dim light ( < 300 Ix, indoors)

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FIG. 1. Diagrammatic design of the study showing patterns of exposure to bright light (open column, = 1,200 Ix), darkness/sleep (filled column), and natural ambient light (dotted column). After a 3-day baseline (D2DO), a gradual 9-h delay phase shift was induced over 3 27-h days (DI-D3) and then the 9-h shift was maintained for the following 2 24-h days (D4-D5). On day 6, subjects resumed their baseline sleep/wake schedule in a normal environment, thus experiencing a rapid 9-h advance phase shift of local time cues.

or moderately bright light ( < 1,000 Ix, outdoors with sunglasses) until dusk (1630-1700 h). From dusk until the light treatment period, subjects remained in domestic intensity light (50-300 lx at eye level). During the phase shift (D1-D5) meal times were shifted progressively by 3 h on days 1-3 and then maintained at the same times on D4-D5 as for D3, in line with the imposed light/dark and sleep/wake cycles. Subjects were allowed to choose their activity (e.g., reading, writing, watching videos) as long as they glanced regularly (at least every 5 m/n) at the light source. The subjects were continuously supervised throughout these periods. The patterns of exposure to bright light, natural ambient light, and darkness are summarized in Fig. 1. 9-h rapid advance phase shift. Immediately following the last light/dark treatment on day 6, subjects were required to assume the baseline sleep/wake schedule in their normal environment, inducing a rapid 9-h advance phase shift in extemal time cues, i.e., retiring to bed at 2330 h and waking at 0800 h for 6 days (D6-D1 I). The subsequent readaptation of the subjects in their normal environment was then observed. Subjects took a placebo pill (lactose-gelatin capsule) just before the desired bedtime at 2300 h on D6-D8. In addition, from 0800-1200 h on D7 and D8 subjects were exposed to controlled lighting of between 50-300 Ix. Subjects were asked to avoid bright sunlight and wore sunglasses when outdoors (filtering out > 90% of the light; assessed by holding a digital light meter (Full Spectrum Lighting, UK) behind the glasses and directing towards varying light intensities from 50-10 000 Ix). At dusk, they were required to remain in ordinary domestic lighting (50-300 Ix) until bedtime (and darkness). Each subjects ambient lighting at work and home was monitored using a hand-held digital light meter on 2 different days (1 baseline day and 1 day after the rapid advance phase shift). Subjects were only allowed to sleep during the periods of darkness throughout this study.

AN EXPERIMENTAL MODEL TO STUDY JET LAG

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Sampling Urine. Sequential 4-h urine samples (8 h when asleep) were collected throughout the study. All urine was collected throughout each 4-h period and the bladder completely emptied at the end of that collection period. The volume of each sample was noted and a 5 ml aliquot from each sample was collected into a labeled vial and frozen at - 2 0 ° C until analysis. Temperature. Rectal temperature was recorded continuously every 6 min throughout the trial using Squirrel Minilogger devices (Grant Instruments, Cambridge, UK).

Behavioral Measurements Every 2 h throughout the whole trial during waking hours, alertness was rated on visual analogue scales (VAS: Drowsy Alert) and performance tasks (low- and high-load search and memory tests: SAM-1 and SAM-5, respectively) were carried out. In addition, daily sleep logs were recorded on waking to estimate sleep onset, offset, and the number and duration of night awakenings. Sleep quality was rated on a VAS (Worst ever Best ever). Activity diaries were also kept. For 3 - 4 days prior to the trial subjects practiced the performance tests regularly. All behavioral measurements were performed using hand-held computers, Psion Organisers (Psion UK, Greenford, UK). Programs for the Psions were written and generously donated by P. Totterdell (University of Sheffield, UK) and Prof. S. Folkard (University of Wales, Swansea, UK).

Urinary 6-Sulphatoxymelatonin (aMT6s) Assays Urinary aMT6s was determined using the method of Aldhous and Arendt (3) with antiserum (No. A B / S / 0 5 ) from Stockgrand Ltd. (School of Biological Sciences, University of Surrey, Guildford, Surrey, UK). The interassay coefficients of variation (COV) were 7, 4, and 3.3% at 2.9, 22.3, and 42.7 n g / m l (n ~ 37). The minimum level of detection was 0.4 _ 0.22 ng/ml (n = 37). All samples from one subject from one leg were analyzed in the same assay. The intraassay COVs were < 4%.

Test) were applied to raw aMT6s and temperature data, and the cosinor-derived parameters of acrophase and amplitude for 24 h temperature and aMT6s profiles, over the baseline, gradual phase-delay shift, and readaptation periods (under placebo treatment). Subjects were used as their own controls for the analysis of the cosinor-derived parameters: acrophases were calculated as a difference from individual's own mean baseline value. For analysis by ANOVA, the temperature data were averaged over each hour. Twenty-four-hour profiles for each mood parameter were analyzed by cosinor analysis over 3-day windows for more reliable estimates of acrophase and amplitude (baseline: D2-D0, changing phase shift: D1-D3, stable phase shift: D3-D5, readaptation periods: D7-D9 and D9-D11) followed by ANOVA (for repeated measures). Degrees of shift were determined by comparison with the individual's mean baseline.

Sleep Data and Daily Means for Mood and Performance Daily means for every mood and performance parameter were determined. All sleep, mood, and performance data were then calculated as a percentage of, or difference from, individuals own baseline, followed by repeated measures ANOVA over nights 6-11 for sleep and D 7 - D l l for mood and performance. The values quoting an increase or reduction in these parameters are the average per day over the periods just described. The performance parameters accuracy, response time, and efficiency were defined as the percentage of correct responses, time taken to complete the task, and accuracy/response time, respectively. Response time data were normalized by square root determination. Initial statistical comparisons for the baseline and the gradual 9-h delay shift indicated that there were no significant differences in any parameter between the four legs. Thus each individual's data for each parameter was averaged over the four legs of the study, and the mean values used for grouped statistics (n = 7).

STATISTICAL ANALYSIS

Temperature, Alertness, and aMT6s Rhythms Repeated measures ANOVA (factors: day of study and time of day) followed by post hoc analysis (Duncan's Multiple Range 1800 1600 1400 1200 1000 800 6OO 400 2OO 0 12:00 D-2

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RESULTS There were no significant differences between the four legs of the trial during the baseline and forced delay phase shift. Data presented for the baseline and forced delay phase shift days are averaged over all legs of the study. For daily mean parameters, daily means for each individual for each leg were determined and then overall mean calculated. One subject did not conform to the protocol and was, therefore, excluded from all analysis.

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Clock time/Day of study FIG. 2. Circadian profiles of urinary aMT6s over a 3-day baseline (D2-D0) and gradual 9-h delay phase shift (D1-D5). A significantdecline in amplitude was observed over the phase shift (p < 0.0001) with return to baselinevalues by D4-D5. Open column,bright light exposure (1,200 lx); filled column, darkness (< 1 lx); dotted column,normal ambientlight. Valuesrepresent mean 5: SEM (n = 7) and are plotted with reference to the midpointof the urine collectionperiod.

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FIG. 3. Circadian profiles for core body temperature over a 3-day baseline (D2-D0) and a gradual 9-h delay phase shift (Dl-D5). A significant phase-delay was indicated by ANOVA for repeated measures (time of day by day of study interaction, p < 0.001). A decline in amplitude was observed over the phase shift with return to baseline values on D5. Bars show patterns of exposure to bright light (1,200 Ix, open column), darkness ( < 1 Ix, filled column), and natural ambient light (dotted column). Temperature was recorded continuously every 6 min, then averaged and plotted as the mean of seven subjects ( + SEM).

FIG. 4. Daily profiles for self-rated alermess over a 3-day baseline (D2-D0) and a gradual 9-h delay phase shift (DI-D5). Using cosinor acrophase estimates, over 3-day windows, there was a significant phase delay of 10.62+0.96 (mean_+SD, D3-D5 compared to D2-D0, p < 0.0001, ANOVA). Bars show patterns of exposure to bright light exposure (1,200 Ix, open column), darkness ( < 1 Ix, filled column), and normal ambient light (dotted column). Values represent mean (+ SEM, n = 7) alertness, rated every 2 h during wakefulness.

Cosinor analysis gave most significant fits for 24 h temperature data (100% at p < 0.005) followed by alertness (96% at p < 0.05; using 3-day windows) and urinary aMT6s (84% at p < 0.05). However, the percentage variance accounted for by a cosine curve was > 80% in all the 24h aMT6s profiles.

D 3 - D 5 compared to baseline: 10.62 + 0.96 h). A delay phase shift was also indicated by A N O V A on the raw aMT6s and temperature data (Figs. 2 and 3) (time of day by day of study interaction, p < 0.0001). Significant suppression of the temperature and aMT6s rhythm amplitudes was observed over the forced phase shift (ANOVA, p < 0.0001) with return to baseline values

Ambient Light Monitoring At home in the evening, light intensity did not exceed t80 lx (average 110 lx). Maximum natural bright light exposure (up to 10,000 lx) commonly occurred around 0800-0900 and 17001900 h, corresponding to travel to work and home, respectively (during baseline). However, the light intensity always remained less than 1,000 ix with sunglasses when outside and, more commonly, < 500 lx. In the work environment, the average light intensity was 490 lx (range 55-1,000 lx). These values were obtained from an average of eight readings throughout the subject's spatial environment. While working (and looking) at the laboratory bench or at the computers, the average light intensity was reduced to 170 lx (range 55-500 lx).

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Baseline No day to day differences for any sleep, mood, aMT6s, or temperature parameters were evident. A significant time of day effect was established by ANOVA (repeated measures, p < 0.0005) for aMT6s, temperature, alertness (Figs. 2, 3, and 4, respectively).

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Gradual, Forced 9-h Delay Phase Shift Using moderately bright light combined with darkness (sleep) it was possible to force a progressively larger delay phase shift in the temperature and aMT6s rhythms (max. degree of shift, D5 compared to mean baseline: 9.09 + 1.06 h and 9 . 1 3 _ 0.83 h, mean + SD, respectively) (Fig. 5). A comparable shift in the alertness rhythm was also evident (Fig. 4) (degree of shift,

FIG. 5. Acrophase estimates for aMT6s ( • ) and core body temperature (cir;, masked) over a 3-day baseline (D2-D0) and during a slow 9-h delay phase shift (DI-D5). A highly significant phase delay was indicated by ANOVA (for repeated measures, p < 0.0001). Degree of shift (D5 compared to individuals' mean baseline) for aMT6s was 9.13 +__0.83 h, and for temperature was 9.09 + 1.06 h (mean 4-SD). Values represent mean + SEM, n = 7.

AN EXPERIMENTAL MODEL TO STUDY JET LAG

on D4-D5 for aMT6s and D5 for temperature (Figs. 2 and 3). No important detrimental effects on alertness, performance efficiency, or sleep were evident (Figs. 6 and 7). However, a small but significant increase in sleep latency ( p = 0.025) and corresponding fall in sleep duration ( p ~ 0.0017) was observed during the phase shift (mean + SD: 8.1 + 13.1 rain, increase in sleep latency). This was mainly attributable to the first 2 nights of the phase shift. Daily mean alertness increased by 3.0 _ 1.0% during the shift (D1-D5) with the greatest improvement associated with the latter end of the shift. Overall performance efficiency improved for SAM-1 (2.9 + 0.3%, p = 0.0007) and remained unchanged for SAM-5 (Fig. 6).

Adaptation to a Rapid 9-h Advance Phase Shift (Placebo Treatment) After the rapid 9-h advance shift of external time cues on day 6, the temperature acrophase was delayed from baseline on D7 only in six out of seven subjects (Fig. 8; group analysis indicated apparent reentrainment by D7), although the rhythm amplitude remained significantly lower on D6-D10 ( p < 0.05, n = 7) (Fig. I0). ANOVA on the group mean acrophase indicated reentrainment by D7. aMT6s acrophase remained significantly delayed from baseline ( p < 0.01, n = 7) on days 6-11 (Fig. 9). This was also indicated with ANOVA on the raw aMT6s data where a time

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of day by day of study interaction was still significant on DI 1 compared to DO ( p < 0.0001, n = 7). The direction of the subjects' natural entrainment of the aMT6s rhythm varied. At least two subjects were reentraining by phase-delay and at least two subjects were phase advancing (Fig. 9). The alertness rhythm did not reestablish a normal baseline pattern until day 11 (Fig. 11). Daily mean alertness and performance efficiency deteriorated by a daily average over D7-D11 of 11.5_ 2.7% ( p < 0.001, Fig. 12), 4.2 + 1.17% (SAM-l, p < 0.0005, Fig. 12), 11.12_+ 1.2% (SAM-5, p < 0.0005, Fig. 12), respectively. A large and highly significant ( p p < 0.0001) reduction in sleep duration (SLD), quality (SQ), and increase in the duration of night awakenings (DA) was apparent (daily average over nights 6 - 1 1 = S L D : -1.6___0.36 h, SQ: - 2 4 - 4 - 5 % , DA: - 5 2 . 6 + 14.7 rain) (Fig. 13). Sleep latency (Fig. 13) and the number of night awakenings remained virtually unchanged.

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DISCUSSION

Gradual 9-h Delay Phase Shift The light/dark schedule was chosen to enhance the natural tendency of the circadian system to delay, because most humans

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FIG. 10. Adaptation of the circadian rhythm of core body temperature after a rapid 9-h advance phase shift [on day (D) 6] in a normal environment. Although the calculated peak time of the rhythm indicates reentrainment by D7 (see Fig. 8), the rhythm amplitude remained significantly reduced ( p < 0.001, DT-D11, ANOVA). Normal baseline patterns were not established until at least D 10. Bars show patterns of exposure to darkness ( < 1 Ix, filled column), natural ambient light (dotted column), and bright light (1,200 Ix, open column). Temperature was recorded continuously every 6 min, then averaged and plotted every hour as the mean of seven subjects ( + SEM).

have a free-running period greater than 24 h. However, bright light can enhance the entrainment of the biological clock to longer days (41,42). In the present study, using a 27-h sleep/wake schedule over 3 days, with bedtime and waketime 3 h later each day, the evening light treatment was aimed to hit the delay portion of the PRC each day. Using a controlled environment, an approximate 9-h delay phase shift was induced in the core body temperature and urinary aMT6s rhythms, two commonly used physiological rhythm markers of the biological clock. A similar degree of shift was also

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FIG. 9. Acrophase estimates for aMT6s showing individual adaptation to a rapid 9-h advance phase shift (on day 6) in a normal environment. At least two subjects showed an antidromic effect where they reentrained to the 9-h advance shift by delay. Mean aMT6s acrophase remained significantly delayed compared to baseline (ANOVA, p < 0.01, D7-DI1, n= 7).

FIG. 11. Adaptation of the self-rated alertness rhythm in a normal vironment after a rapid 9-h advance phase shift on day (D) 6. The alertness rhythm took at least 5 days to reestablish normal baseline patterns. Bars show patterns of exposure to darkness ( < l lx, filled column) and natural ambient light (dotted column). Alertness was rated every 2 h while awake and was plotted as the mean of seven subjects ( + SEM).

AN EXPERIMENTAL MODEL TO STUDY JET LAG

identified with the behavioral rhythm of self-rated alertness. The contemporary shift in the sleep/wake cycle clearly influenced the calculated estimates of acrophase for alertness because this data was only collected during wakefulness. In addition, exogenous influences, such as activity and sleep, may have modified cosinor estimates of the temperature rhythm (29). However, comparable shifts were seen with the aMT6s rhythm, which is minimally influenced by exogenous factors apart from the acute suppressant effects of bright light (27). The maximum degree of shift induced (approx. 9 h) was seen on the last day of the gradual delay phase shift under bright light conditions (D5). However, the aMT6s rhythm had reestablished the normal baseline amplitude and shape on D4-D5 and visual inspection of the aMT6s raw data confirms the magnitude of the maximum shift. A mean delay shift of 7.5 h (_+ 1.5 h, mean + SD) was obtained on day 6, when subjects returned to the normal environment in conditions of darkness and dim light with no masking influences. The gradual delay shift in environmental and social (e.g., meal) time cues, together with the suitably timed bright light/darkness, were effective in promoting the adaptation of sleep, mood, and performance efficiency to the 9-h delay shift. No important detrimental effects on sleep, mood, and performance were apparent. This method may, therefore, provide a means of facilitating adaptation to new time zones or shift work. For example, by using this paradigm for night shift workers

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FIG. 13. Subjective measures of (a) sleep quality, (b) duration of night awakenings, (c) sleep duration, and (d) sleep latency showing adaptation to a rapid 9-h advance phase shift (on day 6) in a normal environment. Significant deleterious effects on sleep quality, sleep duration, and duration of night awakenings were evident (p < 0.0001, ANOVA for repeated measures, nights 6-11 compared to baseline) with no significant effect on sleep latency. Values represent mean _+SEM, n = 7.

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Day of study

FIG. 12. Daily means for (a) SAM-I performance efficiency, (b) SAM-5 performance efficiency, and (c) subjective alertness during adaptation to a rapid 9-h advance phase shift (on day 6) in a normal environment. Significant deleterious effects on all parameters were evident compared to baseline (p < 0.001, ANOVA for repeated measures, D7-D11 compared to baseline). Values represent mean + SEM, n = 7.

starting a new shift from midnight to 0900 h, individuals could be shifted or nudged progressively later by 3 h a day for 3 days before the first night shift, with further light treatment during the night shift to reinforce the 9 h phase shift. This nudging technique has previously been employed by Eastman and colleagues (16-19,22) using a 26 h light/dark schedule (i.e., daylength progressively lengthened by 2 h/day) with bright light to phase-shift circadian rhythms to the desired time. In one such study, bright light (1,770-2,800 Ix) facilitated the entrainment of the temperature rhythm in 74% of the subjects and promoted better sleep (19). It is important to note that in the studies conducted by Eastman and colleagues, strict light control of natural ambient light after sleep was necessary to achieve this effect. Both these techniques may be impractical for individuals not wishing to undergo such an elaborate sleep/wake and light/dark

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schedule prior to the new shift or time-zone. An alternative method involves the use of much brighter intensity light (approx. 10,000 Ix) centered over the temperature minimum; a time at which the circadian system is most sensitive to large phase shifts (12). This technique has been employed in a shift work study by Czeisler colleagues (11) using bright light during the night shift together with darkness during the day and with no treatment administered or altered sleep/wake cycle prior to the new shift. Complete adaptation of circadian variables and improvements in alertness and performance were evident within 6 days. In a preliminary study comparing the bright light nudge technique with the rapid shift method in two different subjects, Eastman (17) found that although the latter technique induced a faster phase shift, alertness was compromised during the first few days of the shift. Clearly, further research is needed to evaluate the most effective and practical method of promoting adaptation to new time schedules.

Rapid 9-h Advance Phase Shift The major and significant deleterious effects on behavior occurred after subjects resumed their baseline sleep pattern in their normal environment. This rapid 9-h advance shift of external time cues can be related to a night shift worker returning to a day shift or a 9-h eastward transmeridian flight. Trying to sleep at inappropriate circadian phases resulted in sleep disruption as expected. Travel fatigue and sleep loss while flying may compound these problems in real life. Sleep patterns, mood, and performance variables and the endogenous aMT6s rhythm took at least 5 days to reestablish normal baseline patterns in agreement with field based studies (4,20,24,38) and laboratory simulations (32). The temperature rhythm apparently took 2 days reentrain. However, environmental and behavioral masking were likely to be responsible for this effect (29). Because the natural reentrainment of circadian rhythms after rapid and large phase shifts can take many days or weeks (5,24,38), and because the zeitgeber strength of natural light exposure was controlled, it was unlikely that in every individual the rhythm shifted by 9 h in one day. The significant reduction in rhythm amplitude suggests that core body temperature had not reentrained properly even after 5 days. The direction of shift in the urinary aMT6s rhythm to the rapid 9-h advance change of external time cues varied in different individuals even with similar environmental zeitgebers. Unfortunately, it was not possible to properly assess the direction of entrainment for some subjects and the time taken for complete reentrainment to occur due to the limited number of days studied. However, some individuals showed a definite tendency to reentrain to the rapid 9-h advance shift by delay, a so-called antidromic effect (24), where individuals delay the circadian system by 15 h to complete the 24-h cycle of entrainment. This effect

has been observed in field studies over 8 - 1 0 time zones flying east (8,23,24,28,35) and in laboratory based studies after phase advances of 6 h (31,40). The natural tendency for circadian rhythms to delay may explain the fact that some individuals apparently reentrained by phase delay after a rapid and large phase advance. Reasons for the antidromic effect remain unknown. Individual differences in urinary aMT6s acrophase or morning/evening type personality scores did not correlate with the direction of natural reentrainment. However, the small sample size precludes the determination of any reliable relationship. The advantage of field studies on travellers and shift workers is the exposure to a whole range of external time cues and psychological influences. However, there are important disadvantages. Susceptibility to jet lag is highly individual; therefore, crossover experiments afford the best design. However, field studies are expensive and difficult to control because standardizing social and environmental stimuli over each stage is virtually impossible. There are also difficulties in the collection of biochemical data. Laboratory studies provide a means of measuring a whole range of physiological and behavioral variables in detail and in a controlled environment. But the laboratory environment may not give a true reflection of the normal readaptation process in real life. For example, Wegmann et al. (39) described how sleep quality improved in the quieter isolated environment of the laboratory in comparison to real life. Allowing subjects to readapt in a normal environment overcomes this problem. This experimental model, therefore, acts as a compromise between field studies and studies in complete environmental isolation. Using a controlled environment it was possible to force a progressively larger delay phase shift in circadian rhythms with no significant detrimental effect on sleep, mood, and performance efficiency. The subsequent and rapid 9-h advance shift of external time cues induced major and significant problems related to behavior and physiology. This model, therefore, provides an effective and inexpensive method of simulating aspects of jet lag and shift work so that the effectiveness of various treatment strategies can be assessed in real life. The related article (Adapting to phase shifts II) describes the effects of melatonin and bright light on adaptation to a rapid 9-h advance phase shift using the model just described. ACKNOWLEDGEMENTS These results were presented at the Society for Research on Biological Rhythms, Florida, May 1994. S. Deacon was supported by a PhD studentship from the MRC with further support from Stockgrand Ltd. (University of Surrey, Guildford, UK). We are grateful to all our volunteer subjects, Lara Blann, Sandra Hill, Nicola Wootton, David Hall, Tim Marczylo, Simon Gamble, and Judie English for help, and Prof. Simon Folkard and Peter Totterdell for advice.

REFERENCES 1. Akerstedt, T. Inversion of sleep wakefulness pattern: Effects on circadian variations in psychophysiological activation. Ergonomics 20:459-474; 1977. 2. Akerstedt, T. Sleepiness as a consequence of shift work. Sleep 11:17-34; 1988. 3. Aldhous, M. E.; Arendt, J. Radioimmunoassay for 6-sulphatoxymelatonin in urine using an iodinated tracer. Ann. Clin. Biochem. 25:298-303; 1988. 4. Arendt, J.; Aldhous, M.; English, J.; Marks, V.; Marks, M.; Folkard,

S. Some effects of jet lag and their alleviation by melatonin. Ergonomics 30:1379-1393; 1987. 5. Aschoff, J.; Hoffman, K.; Pohl, H.; Wever, R. Reentrainment of circadian rhythms after phase-shifts of the zeitgeber. Chronobiologia 2:23-78; 1975. 6. Broadway, J.; Arendt, J.; Folkard, S. Bright light phase shifts the human melatonln rhythm during the Antarctic winter. Neurosci. Lett. 79:185-189; 1987. 7. Buresov~t, M.; Dvor~kov~t, M.; Zvolsky, P.; illnerova, H. Early

AN E X P E R I M E N T A L M O D E L TO S T U D Y J E T L A G

8.

9.

t0.

I 1.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21. 22.

23.

24.

morning bright light phase advances the human circadian pacemaker within one day. Neurosci. Lett. 121:47-50; 1991. Colquhoun, W. P. Phase shift in temperature rhythm after transmeridJan flight, as related to preflight phase angle. Int. Arch. Occup. Environ. Health 42:149-157; 1979. Colquhoun, W. P.; Blake, M. J. F.; Edwards, R. S. Experimental studies of shift-work II1: Stabilized 12-hour shift systems. Ergonomics 12:865-882; 1969. Czeisler, C. A.; Allan, J. S.; Strogatz, S. H.; Ronda, J. M.; S~inchez, R.; Rios, C. D.; Freitag, W. O.; Richardson, G. S.; Kronauer, R. E. Bright light resets the human circadian pacemaker independent of the timing of the sleep/wake cycle. Science 233:667-671; 1986. Czeisler, C, A.; Johnson, M. P.; Duffy, J. F.; Brown, E. N.; Ronda, J. M.; Kronauer, R. E. Exposure to bright light and darkness to treat physiologic maladaptation to night work. N. Engl. J. Med. 322:1253-1259; 1990. Czeisler, C, A.; Kronauer, R. E.; Strogatz, S. H.; Allan, J. S.; Duffy, J. F.; Jewett, M. E.; Brown, E. N.; Ronda, J. M. Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science 244:1328-1333; 1989. Daan, S.; Lewy, A. J. Scheduled exposure to daylight: A potential strategy to reduce "'jet lag" following transmeridian flight. Psychopharmacol. Bull. 20:566-568; 1984. Dijk, D.-J.; Beersma, D. G. M.; Daan, S.; Lewy, A. J. Bright morning light advances the human circadian system without affecting NREM sleep homeostasis. Am. J. Physiol. 256:R106-RII1; 1989. Dijk, D.-J.; Cajochen, C.; Borbrly, A. A. Effect of a single 3-hour exposure to bright light on core body temperature and sleep in humans. Neurosci. Lett. 121:59-62; 1991. Eastman, C. I. Bright light in work-sleep schedules for shift workers: Application of circadian rhythm principles. In: Rensing, L ; an der Heiden, U.; Mackey, M. C., eds. Temporal disorders in human oscillatory systems. New York: Springer Verlag; 1987:176-185. Eastman, C. I. Squashing vs. nudging circadian rhythms with artificial bright light: Solutions for shift work? Perspect. Biol. Med. 34:181-195; 1991. Eastman, C, I. High-intensity light for circadian adaptation to a 12-h shift of the sleep schedule. Am. J. Physiol. 263(32):R428-R436; 1992. Eastman, C. I.; Miescke, K.-J. Entrainment of circadian rhythms with 26-h bright light and sleep/wake schedules. Am. J. Physiol. 259(28):R1189-R1197; 1990. Fb~vre-Montange, M.; Van Canter, E ; Refetoff, S.; D6sir, D.; Tourniaire, J.; Copinschi, G. Effects of "jet lag" on hormonal patterns, I1. Adaptation of melatonin circadian periodicity. J. Clin. Endocrinoh Metab. 52:642-649; 1981. Folkard, S.; Monk, T. H. Hours of work: Temporal factors in workscheduling. New York: Wiley & Sons; 1985. Gallo, L. C.; Eastman, C. I. Circadian rhythms during gradually delaying and advancing sleep and light schedules. Physiol. Behav. 53:119-126; 1993. Gander, P. H.; Myhre, G.; Graeber, C.; Anderson, H. T.; Lauber, J. K. Adjustment of sleep and the circadian temperature rhythm after flights across nine time zones. Aviat. Space Environ. Med. 60:733743; 1989. Klein, K. E.; Wegmann, H.-M. Significance of circadian rhythms in aerospace operations. AGARDograph No. 247, Advisory Group for Aerospace Research and Development, NATO, Technical Editing and Reproduction Ltd., London; 1980:1-60.

673

25. Knauth, P.; Emde, E.; Rutenfranz, J.; Kiesswetter, E.; Smith, P. Reentrainment of body temperature in field studies of shiftwork. Int. Arch. Occup. Environ. Health 49:137-149; 1981. 26. Lewy, A. J.; Sack, R. L.; Muller, S.; Hobart, T. M. Antidepressant and circadian phase shifting effects of light. Science 235:352-354; 1987. 27. Lewy, A. J.; Wehr, T. A.; Goodwin, F. K.; Newsome, D. A,; Markey, S. P. Light suppresses melatonin secretion in humans. Science 2 t 0:1267-1269; 1980. 28. Mills, J. N.; Minors, D. S.; Waterhouse, J. M. Adaptation to abrupt time shifts of the oscillator(s) controlling human circadian rhythms. J. Physiol. (Lond.) 285:455-470; 1978. 29. Minors, D. S.; Waterhouse, J. M. Masking in humans and some attempts to solve it. Chronobioh Int. 6:29-53; 1989. 30. Minors, D. S.; Waterhouse, J. M.; Wirz-Justice, A. A human phase-response curve to light. Neurosci. Lett. 133:36-40; 1991. 31. Moline, M. L.; Pollak, C. P.; Monk, T. H.; Lester, L. S.; Wagner, D. R.; Zendell, S. M.; Graeber, C.; Salter, C. A.; Hirsch, E. Age-related differences in recovery from simulated jet lag. Sleep 15:28-40; 1992. 32. Samel, A.; Wegmann, H.-M.; Vejvoda, M.; MaaB, H.; Gundel, A.; Schlitz, M. Influence of melatonin treatment on human circadian rhythmicity before and after a simulated 9-hr time shift. J. Biol. Rhythms 6:235-248; 1991. 33. Shanahan, T. L.; Czeisler, C. A. Light exposure induces equivalent phase shifts of the endogenous circadian rhythms of circulating plasma melatonin and core body temperature in men. J. Clin. Endocrinol. Metab. 73:227-235; 1991. 34. Seigel, P. V.; Gerathewohl, S. J.; Mohler, S. R. Time zone effects. Science 164:1249-1255; 1969. 35. Spencer, M. B.; Nicholson, A. N.; Pascoe, P. A.; Rogers, A. S. Adaptation of the temperature rhythm to a 10 hour eastward time zone change. Abstract 17, Fourth Meeting, Soc. Res. Biol. Rhythms, Florida; May 1994. 36. Touitou, Y.; Motohashi, Y.; Reinberg, A.; Touitou, C.; Bordeleau, P. A. Auzeby, A. Effect of shift work on the night-time secretory patterns of melatonin, prolactin, cortisol and testosterone. Eur. J. Appl. Physiol. 60:288-292; 1990. 37. Van Canter, E.; Studs, J.; Byme, M. M.; et al. Demonstration of rapid light-induced advances and delays of the human circadian clock using hormonal phase markers. Am. J. Physiol. 266:E953-E963; 1994. 38. Wegmann, H.-M.; Klein, K. E.; Conrad, B.; Esser, P. A model for prediction of resynchronization after time-zone flights. Aviat. Space Environ. Med. 54:524-527; 1983. 39. Wegmann, H.-M.; Gundel, A.; Naumann, M.; Sameh A.; Schwartz, E.; Vejvoda, M. Sleep, sleepiness, and circadian rhythmicity in aircrews operating on transatlantic routes. Aviat. Space Environ. Med. 57(Suppl. 12):B53-64; 1986. 40. Wever, R. A. Phase shifts of human circadian rhythms due to shifts of artificial zeigebers. Chronobiologia 7:303-327; 1980. 41. Wever, R. A. Light effects on human circadian rhythms: A review of recent Andechs experiments. J. Biol. Rhythms 4:161-185; 1989. 42. Wever, R. A.; Polasek, J.; Wildgruber, C. M. Bright light effects human circadian rhythms. Pflugers Arch. 396:85-87; 1983. 43. Winget, C. M.; DeRoshia, C. W.; Markley, C. L.; Holley, D. C. A review of human physiological and performance changes associated with desynchronosis of biological rhythms. Aviat. Space Environ. Med. 55:1085-1096; 1984.