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Decreased Human Circadian Pacemaker Influence After 100 Days in Space: A Case Study

From the Clinical Neuroscience Research Center (T.H.M., K.S.K., L.R.R.), Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA; and Linenger Communications (J.M.L.), Suttons Bay, MI.

Address reprint requests to: Timothy H. Monk, DSc, WPIC Room E1123, 3811 O’Hara St., Pittsburgh, PA 15213. Email: monkth{at}msx.upmc.edu

	ABSTRACT

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OBJECTIVE: The objectives of this study were (1) to assess the circadian rhythms and sleep of a healthy, 42-year-old male astronaut experiencing microgravity (weightlessness) for nearly 5 months while living aboard Space Station Mir as it orbited Earth and (2) to determine the effects of prolonged space flight on the endogenous circadian pacemaker, as indicated by oral temperature and subjective alertness rhythms, and their ramifications for sleep, alertness, and performance.

METHODS: For three 12- to 14-day blocks of time (spread throughout the mission), oral temperatures were taken and subjective alertness was self-rated five times per day. Sleep diaries and performance tests were also completed daily during each block.

RESULTS: Examination of the subject’s circadian alertness and oral temperature rhythms suggested that the endogenous circadian pacemaker seemed to function quite well up to 90 days in space. Thereafter (on days 110–122), the influence of the endogenous circadian pacemaker on oral temperature and subjective alertness circadian rhythms was considerably weakened, with consequent disruptions in sleep.

CONCLUSIONS: Space missions lasting more than 3 months might result in diminished circadian pacemaker influence in astronauts, leading to eventual sleep problems.

Key Words: sleep, • circadian rhythms, • alertness, • performance, • microgravity, • space travel.

Abbreviations: ANOVA = analysis of variance;; CI = confidence interval;; ECP = endogenous circadian pacemaker.

	INTRODUCTION

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Human beings seem to be unique in their ability to temporarily remove a few of their kind from their planet, orbiting in a weightless environment with no natural light/darkness cycle. This raises the question of whether the human endogenous circadian pacemaker (ECP), which evolved on a planet with a 24-hour rotation, still functions well when removed from all of the natural time cues of Earth. In our previous study of astronauts aboard an orbiting Space Shuttle for 17 days, we showed that the ECP seems to retain an appropriate phase and amplitude (1), thus partially confirming a contemporaneous German-Russian study aboard Space Station Mir reported by Gundel et al. (2), although in the latter study there was some evidence of a slight (2-hour) delay in ECP phase. Studies of lower animals orbiting in microgravity have suggested that entrainment mechanisms might be weakened in space (3, 4). However, the Gundel et al. study (2) showed no evidence of free-running in human circadian temperature rhythms. The present study concerns data from an astronaut who lived aboard Mir for nearly 5 months, testing the hypothesis that the behavior and/or influence of his ECP would change as the mission progressed and that these changes would have an impact on sleep, alertness, and performance.

	METHODS

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This experiment concerns an extremely fit and healthy male astronaut (J.M.L.), aged 42 years, who lived aboard Mir from January 15, 1997, to May 22, 1997. During this time, three measurement blocks were recorded, each almost 2 weeks in duration: block 1 consisted of days 37 to 50; block 2, days 79 to 91; and block 3, days 110 to 122. The crew’s activities were scheduled according to Moscow Time, and the subject of this study habitually went to bed and arose at fairly standard times (bedtime: mean = 23:25, SD = 29 minutes; wake time: mean = 08:06, SD = 49 minutes). Four other subjects completed some measures for this experiment, but their data were insufficient to be included.

During each measurement block the subject was required to measure his oral temperature and rate his subjective alertness five times per day (approximate times: 09:20, 12:30, 15:30, 18:30, and 21:20 hours), recording his results on a laptop computer. Oral temperatures were measured using a Becton Dickinson model 2860 digital thermometer (Becton Dickinson, Inc., Franklin Lakes, New Jersey), the tip of which was placed under the tongue for a timed 60 seconds. Subjective alertness was assessed using four visual analog scales, yielding a single "global vigor" score between 0 and 100 (5). For each of the three measurement blocks, this resulted in between 57 and 63 data points for each of the two variables (oral temperature and subjective alertness). Because only sparse and unequal sampling of temperature and alertness rhythms was available, we adopted a cosine curve-fitting technique to characterize the two rhythms at each measurement block. A single sinusoid was fitted by least-squares to the entire time series iteratively at period lengths ranging from 22 to 27 hours in steps of 0.1 hour (6). This yielded estimates of acrophase (clock time of peak fitted value) and amplitude (fitted maximum value minus mean level) at each period length, together with a statistical test of goodness of fit. An alternative statistical approach making no assumptions about rhythm shape was also used (see below).

During each "morning" of a measurement block, within 1 hour of waking, the subject completed a computer-based version of the Pittsburgh Sleep Diary (7), yielding measures of the times of bedtime and waking, the estimated duration of unwanted wakefulness, and the amount and rated quality of the sleep obtained the preceding "night." There were two instances for which the subject deviated markedly from his normal pattern of bedtimes and wake times: first, because of a fire aboard the space station, which led to his being up all night, and second, a split sleep period (early evening and late morning), which occurred because he was required to be awake for a night operation aboard the space station. Both deviations occurred in block 1 and were omitted from the analysis of sleep diary data, including the recovery sleep after the missed night of sleep. Thus, 10 nights of sleep diary data were analyzed for block 1 and 12 nights of data were analyzed for blocks 2 and 3. These were analyzed by repeated-measures ANOVA.

There was also one performance battery completed each day at around midday (average time was 12:41, although occasionally it was as early as 09:54 or as late as 17:11). The battery consisted of a simple serial search test (32 trials of searching for an E in 30 random letters) and 32 trials of a modified Baddeley verbal reasoning test (8). Both tasks were presented on a laptop computer and yielded speed and accuracy scores. Daily values were subjected to repeated-measures ANOVA.

	RESULTS

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Using the results of the iterative cosine curve-fitting procedure described above, the value of estimated squared amplitude was taken as a measure of rhythmic power at that period length, and that measure was then plotted against period to give an approximation of a power frequency spectrum separately for temperature and alertness time series at each measurement block. These "spectra" are plotted in Figure 1.

View larger version (17K): [in this window] [in a new window]   Fig. 1. Power frequency spectra for oral temperature and subjective alertness circadian rhythms. Plotted separately for block 1 (days 37–50), block 2 (days 79–91), and block 3 (days 110–122) is the square of the amplitude of the best-fitting sinusoid at each period length.

As suggested by the power frequency "spectra" shown in Figure 1, amplitude estimates at 24 hours were lower in block 3 for both temperature (0.43 ± 0.21, 0.32 ± 0.13, and 0.18 ± 0.11°C) and alertness (15.7 ± 6.1, 18.1 ± 5.2, and 6.6 ± 4.6 arbitrary units). In both measures, the block 3 amplitude was outside the 95% CI for the amplitude estimates from both blocks 1 and 2.

As an alternative analytic technique that made no assumptions about the shape of the underlying rhythm, each datum was cast into a 3-hour time-of-day "bin," with bins centered at 07:30, 10:30, 13:30, 16:30, 19:30, and 22:30. Each bin had between 6 and 14 data points (mean = 10), and average time-of-day functions were then plotted for temperature and alertness (Figure 2). These graphs reveal an apparent flattening in time-of-day function over the mission. Most notably, the alertness rhythm on block 3 failed to show the usual inverted U shape with drops near wake time and bedtime (10), instead showing a relatively flat function over the day. These findings coincided with the subjective impressions of the subject who, in block 3, often forced himself to go to bed "by the clock" without feeling sleepy, this being part of a deliberate strategy to keep to a rigid routine (ie, to enhance 24-hour behavioral time cues) and to lessen the feeling of being dissociated from 24-hour time. These data were subjected to analysis of variance using days as the random variable. For temperature, there was a significant main effect of time of day (F(5,160) = 8.97, p < .0001) and a significant main effect of block number (F(2,160) = 12.89, p < .0001), indicating a reliable lowering of daytime temperatures during block 3. However, the apparent time of day by block number interaction failed to achieve significance (F(10,160) < 1). Likewise, for alertness there were significant main effects of time of day (F(5,162) = 18.81, p < .0001) and block number (F(2,162) = 8.45, p < .0003), but no significant time of day by block number interaction (F(10,162) = 1.37, p = .20). Paradoxically, the significant effect of block number was manifest as an increase in daily alertness level over the mission (block 1, 42.6; block 2, 49.1; and block 3, 51.7 arbitrary units).

View larger version (20K): [in this window] [in a new window]   Fig. 2. Time-of-day functions for oral temperature and subjective alertness. Plotted separately for block 1 (days 37–50), block 2 (days 79–91), and block 3 (days 110–122) is the mean value per 3-hour time-of-day bin. Each mean is derived from 6 to 14 data points.

	DISCUSSION

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Recent research (11) has indicated that typical value for free-running human ECP may be 24.2 hours rather than the 25 hours figure quoted in earlier literature (12). It is noteworthy that the block 3 temperature value of our subject was indeed 24.2 hours in the present experiment, although the study was clearly not sufficiently powerful to differentiate between 24.0 and 24.2 hours and thus to determine whether free-running of the subject’s ECP had truly occurred. It was unfortunate that around-the-clock sampling of circadian variables was not available because such sampling would have provided a much more powerful test for the occurrence of free-running. In our previous published work, however, we confirmed that meaningful circadian rhythm end points can be gleaned from the data even with sparse and irregular sampling. We used laboratory data obtained by frequent around-the-clock temperature recording and compared it with data obtained by sparse and irregular sampling, which we analyzed with the iterative cosine curve-fitting procedure described here, and showed that acceptable estimates of best-fitting period and rhythm phase and amplitude could be made using such a technique (13, 14). Indeed, because they omit any sampling during sleep (when temperatures are lower because of the sleep and inactivity per se), these estimates are less dominated by the exogenous effects of the 24-hour rest-activity cycle.

Although the issue of free-running remains unresolved in this study, our previous ground-based studies of sparse and irregular sampling during forced desynchrony confirm (13) that even if free-running had occurred, it could not explain the present findings, because in that case there would still be spectral power at , which would be evidenced in Figure 1 by a strong peak somewhere between 24.0 and 25.0 hours. The absence of such a peak in block 3 suggests that the effect of prolonged removal from the natural time cues and gravity of Earth resulted in an attenuation of the circadian signal irrespective of whether free-running had occurred. This effect is similar to the attenuation in ECP signal that we have observed in the healthy elderly in their circadian alertness rhythms, although not in their circadian temperature rhythms (10).

The effects of time into mission on the timing of the circadian temperature and alertness rhythms were interesting and to some extent unexpected. The delay in acrophase by 2 hours of the block 3 temperature rhythm compared with that from block 1 echoed an earlier finding by Gundel et al. (2), who found precisely such a phase delay, although in their experiments it occurred earlier in the mission. The mechanism for such a delay remains open to investigation, but it might be a natural consequence of reduced ECP influence. Less expected was the dissociation between temperature and alertness rhythm effects, with the former showing a delay in phase, the latter an advance. Conventional wisdom holds that temperature and alertness rhythms invariably run parallel (15), but it should be remembered that circadian alertness rhythms are under the influence of both homeostatic (time since waking) and rhythmic (ECP) processes (16, 17). When ECP influence is reduced, then homeostatic processes will dominate, and these processes may tend to push the alertness rhythm into an earlier-peaking phase position because the pressure for sleep ("Process S"; Ref. 18) will be increasing monotonically throughout the day. Such mechanisms might also explain the increase in block 3 daily levels of alertness. As the lower panel of Figure 2 reveals, the only points of the alertness time-of-day function showing non-overlapping error bars were the first (07:30) and last (22:30) of the day. One could argue that these would be the time points most influenced by a failure of the ECP to "drag down" alertness levels at either end of the sleep episode. Clearly, though, further experimentation is needed to explore this hypothesis.

The performance findings were unexpected and belied any simple explanation based on sleep disruption. In the search task, performance simply improved in block 3, whereas in verbal reasoning the increase in speed seemed to be won at the expense of a decrease in accuracy. It is quite possible that there were a number of different factors leading to these observed changes in performance. Thus, changes in ECP influence, practice level, and prior sleep may all have had an influence on the information-processing strategy adopted by the subject. As reported by the subject himself, another factor was that he was able to overcome the fatigue he felt during the final month aboard Mir and to muster his resources for the relatively brief (<10 minutes) performance tests, overcoming any performance decrements that might otherwise have occurred. Had time been available for a longer "vigilance" type of task, the performance tests may have instead reflected a deterioration in performance during block 3.

In addition to weightlessness, cramped conditions, and the absence of natural time cues, space travel also involves elements of personal danger. It is worth noting that the present mission was an extremely eventful one that did not run exactly as planned, as is fully described in a recent book authored by the subject (19). Block 1 included a time for which there were six rather than three people on board and the almost catastrophic oxygen generator fire (night 43), which led to a totally missed night of sleep and the need to wear filter masks for several study nights thereafter. In block 2 ambient temperatures on Mir rose into the uncomfortable range (30–38°C), and coolant leaks led to an unpleasant ethylene glycol smell and concerns about toxicity. These problems persisted throughout the mission and undoubtedly increased the level of stress experienced by the subject, although the present experiment had no way of quantifying such effects. It is an empirical question as to whether the ECP would have retained its influence for a somewhat longer period of time had the mission been less eventful. Clearly there is a need for further experimentation on human sleep and circadian rhythms in long-duration space missions to determine whether these findings from a single case study can be generalized to other missions and to other astronauts.

	CONCLUSIONS

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After about 3 months in space there may be a failure of the human ECP to strongly drive a 24-hour circadian rhythm. This lack of ECP influence could lead to sleep problems in those attempting to live on a rigid 24-hour work/rest routine.

	ACKNOWLEDGMENTS

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Supported by NASA Contract NAS9-19407, NASA Grants NAG9-1036 and NAG9-1234, and National Institute on Aging Grants AG 13396 and AG 15136.

Received for publication September 12, 2000.

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