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Adverse Effects of Modest Sleep Restriction on Sleepiness, Performance, and Inflammatory Cytokines

Sleep Research and Treatment Center, Department of Psychiatry (A.N.V., E.O.B., H.F., A.K.), and Health Evaluation Sciences (H.-M.L.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; and Pediatric and Reproductive Endocrinology Branch, National Institutes of Health (E.Z., G.P.C.), Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Alexandros N. Vgontzas, M.D., Department of Psychiatry, H073, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: axv3{at}psu.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Total sleep restriction in humans is associated with increased daytime sleepiness, decreased performance, and hormonal/metabolic disturbances. The effects of mild chronic sleep restriction that mimic real life are not known. To assess the effects of modest sleep restriction from 8 to 6 h/night for 1 wk, 25 young, healthy, normal sleepers (12 men and 13 women) were studied for 12 consecutive nights in the sleep laboratory. After 1 wk of sleep restriction, although subjects’ nighttime sleep was deeper, subjects were significantly sleepier (multiple sleep latency test) and performed worse in four primary variables of psychomotor vigilance test (both P < 0.01). Furthermore, 24-h secretion of IL-6 was increased by 0.8 ± 0.3 pg/ml (P < 0.05) in both sexes, whereas TNF was increased only in men. Also, the peak cortisol secretion was lower after sleep restriction than at baseline, and this difference was stronger in men (55.18 ± 24.83 nmol/liter; P < 0.05) than in women (35.87 ± 24.83 nmol/liter; P < 0.16). We conclude that in young men and women, modest sleep loss is associated with significant sleepiness, impairment of psychomotor performance, and increased secretion of proinflammatory cytokines. Given the potential association of these behavioral and physical alterations with health, well-being, and public safety, the idea that sleep or parts of it are optional should be regarded with caution.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ALTHOUGH TOTAL OR severe partial sleep deprivation is not commonly practiced in the general population, a modest reduction of sleep time on a chronic basis appears to be a characteristic of modern civilization. It has been estimated that although in the first half of the 20th century the average person used to sleep 9 h/d, today an individual sleeps, on the average, 7.5 h/d(1). The increasing pressure from work, family, and social changes have resulted in many people sleeping a total of 6 h/d or even less (2). Although some researchers have expressed concern about the effects of chronic sleep curtailment or chronic sleep debt (3, 4), others have argued that an individual’s body and mind can adapt to these changes without any detrimental effects (5). Thus, it was reported that acute deprivation of the last 3.5 h of sleep did not increase the delta (0–3 Hz) electroencephalograms (EEGs) in recovery sleep (6), suggesting that nondelta sleep might be unnecessary. These results supported the hypothetical division of sleep into core sleep, which consisted primarily of slow wave sleep (SWS), and optional stage 2 sleep, which might be "a time filler when the mammals have little else to do" (5).

However, significant daytime sleepiness has been reported after restricting sleep by 50% for 3 consecutive nights (6) or after reduction of habitual sleep by 33% for 1 wk (4) in young healthy adults. Furthermore, a recent study by Van Dongen et al. (7) showed that even a sleep restriction to 6 h in 13 healthy adults (10 men and three women) was associated with a deterioration of psychomotor performance. In our study we chose to restrict sleep from 8 to 6 h (25%) for 1 wk to mimic real-life situations and to test whether these 2 h of sleep are optional for healthy young men and women in terms of effects on daytime sleepiness, psychomotor performance, and physical health.

The potential impact of chronic sleep loss on human health, with the exception of the behavioral effects, has received little attention, and this only recently. In 1999, we published a study showing that in young men a night of total sleep loss was associated with sleepiness and fatigue, and a marked increase in the circulating concentrations of the proinflammatory cytokine IL-6 the next day (8). At about the same time, Van Cauter and her colleagues (9) reported that sleep restriction to 4 h/d for 6 d was associated with significant impairment of glucose metabolism. Thus, the aim of this study was to assess in young healthy men and women the impact of modest sleep loss not only on daytime sleepiness and performance, but also on plasma levels of the proinflammatory cytokines IL-6 and TNF and the end product of the stress axis, cortisol.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Twenty-five normal sleepers (12 men and 13 women), 19–34 yr of age (mean ± SD, 25.6 ± 4.1 for men; 24.8 ± 3.4 for women), with a body mass index of 23.8 ± 2.3 (24.6 ± 1.5 for men; 23.1 ± 2.7 for women), were recruited from the community and from the medical and technical staff and students of Milton S. Hershey Medical Center. They were in good general health, physically active but not excessively so, had no sleep complaints or circadian abnormalities, were not taking any medications, and were screened in the sleep laboratory for sleep disordered breathing, nocturnal myoclonus, or other primary sleep disorders. Also, a battery of clinical tests (including complete cell blood count, urinalysis, thyroid indexes, electrocardiogram, and urine screen for drug use) were negative for abnormal findings.

Protocol

Each subject participated in a sleep restriction experiment that lasted 12 d. Adequate sleep time and regular sleep schedules were verified with a sleep log and actigraphy for 2 wk before the study. During the first 4 consecutive nights in the sleep laboratory, the subjects were allowed to sleep for 8 h (2230–0630 h). During the subsequent 8 nights, the subjects were awakened 2 h earlier (0430 h). After staying in the laboratory for 2 h, they were dismissed to their daily activities. They were instructed not to nap, to stay on the same diet including caffeinated beverages, and not to deviate from their normal daily routines throughout the experiment. To assess the compliance of the subjects with the no nap instructions, the subjects were monitored with actigraphy attached to the wrist of the nondominant hand throughout the experiment. Blood sampling was performed for 24 h (0800–0730 h the next day) every 30 min on the fourth day (the last day before the sleep-restricted schedule) and the 12th day after the completion of 1 wk of sleep restriction (8, 10, 11). In women, both periods of blood sampling took place during the follicular phase, as evidenced by progesterone levels obtained on the 4th and 12th days of the experiment. Throughout sampling, the subjects were ambulatory and allowed to watch television, play computer and table games, go to the bathroom, etc. Also, they were instructed not to change their diet, and their three daily meals were at about 0700, 1200, and 1800 h. The subjects remained in a lying or sitting position for the rest of the experiment when awakened early with the room lights on. The brightness of the light in the room in which the blood drawing took place was, on the average, about 800 lux, ranging from a minimum of 200 to 1400 lux (Minolta III F digital light meter Konica, Minolta, Tokyo, Japan). The protocol was approved by the institutional review board, and each subject signed a written consent form.

Sleep recordings

Assessment of nighttime sleep. Each subject was monitored with EEG, electrooculograph, and electromyograph recordings continuously for 8-h (2230–0630 h) during the first 4 nights and for 6 h (2230–0430 h) of the remaining 8 nights. The sleep schedule in the sleep laboratory at baseline was similar to the subjects’ normal sleep schedule. Polysomnographic recordings were obtained and scored in accordance with standard methods (12). Sleep parameters were assessed as previously described (8, 10, 11).

Assessment of daytime sleepiness and performance. Multiple sleep latency test (MSLT):
During the 4th and the 12th days (days of blood sampling), the subjects’ levels of sleepiness and alertness were evaluated using MSLT (13). In our study, we allowed six 20-min opportunities to sleep at 0900, 1200, 1500, 1700, 1900, and 2100 h to sample sleepiness throughout the day, including evening and presleep periods. The onset of sleep was established in two different ways: the first, which is the standard MSLT definition (13), requires the presence of any sleep stage for a duration of one epoch (30 sec) or longer, and the second requires that if the initial stage of sleep is stage 1, it must be followed, without any intervening wakefulness, by 60 sec of stage 2, 3, 4, or rapid eye movement (REM) sleep (10). Also, before each nap opportunity, subjective levels of sleepiness were assessed using a visual analog scale that ranged from 0 (not sleepy at all) to 10 (extremely sleepy) and a seven-point question: "how sleepy do you feel right now?"

Psychomotor vigilance task (PVT):
The PVT is a test of behavioral alertness, and it involves a simple (as opposed to choice) reaction time (RT) test designed to evaluate the ability to sustain attention and respond in a timely manner to salient signals (7, 14). The primary variables assessed in our study are: 1) frequency of lapses, which refer to the number of times the subject fails to respond to the signal or fails to respond in a timely manner; 2) duration of lapse domain, which refers to shifts in lapse duration calculated from the 10% slowest RTs, a metric that reflects vigilance response slowing; 3) optimum response times, which are the average of the 10% fastest RTs per trial, and reflect the very best performance an operator is capable of producing; and 4) the median RT in the trial. In this study PVT was administered every hour during the 4th and 12th days. Also, the number of women who completed the PVT was lower than that of men because we obtained the PVT after the start of this experiment.

Hormone assays

Blood collected from the indwelling catheter was transferred to an EDTA-containing tube and refrigerated until centrifugation (within 3 h). The plasma was frozen at –70 C until assay. Cortisol levels were measured by specific immunoassay techniques, and plasma TNF and IL-6 were measured by ELISA (R&D Systems, Minneapolis, MN) as previously described (10, 11).

Statistical analyses

To assess the effects of sleep deprivation on hormone variables as a function of time of day, differences in the 24-h TNF, IL-6, and cortisol levels before and after intervention were analyzed using a mixed effects multivariate ANOVA, which takes into account the intra- and intersubject correlations. The intervention effect (e.g. sleep restriction) and group (e.g. gender) were treated as fixed effects. The subjects were treated as random effect, and the repeated measurements (e.g. 24-h blood samples) were nested within subjects (15). Time, gender, and their interaction effects were tested for significance. Similar approaches using multivariate ANOVA were used to analyze the effects of sleep deprivation on daytime sleepiness (MSLT) and performance (PVT). MSLT data are presented, with sleep onset defined as the presence of either any stage of sleep for 30 sec or at least 60 sec of stage 2 sleep. PVT data were analyzed as described previously (14). To compare the trends (quadratic vs. linear) of the MSLT data and the PVT data, random coefficient models were used. To assess the effects of sleep restriction on sleep, we compared averaged data from nights 10 and 11 to averaged data from nights 2 and 3 (baseline). Correlations of sleep variables with MSLT and hormone data were calculated using the Pearson product-moment correlation while adjusting for baseline MSLT or hormone values. Data are presented as the mean ± SE, except for demographic data (age and body mass index), for which we used SD to describe variance.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Sleep at baseline and after 1 wk of partial sleep restriction

After 1 wk of partial sleep restriction, subjects demonstrated significantly shorter sleep latencies, increased percentage of total sleep time, and decreased percentage of wake time after sleep onset (Table 1). In terms of sleep stages, subjects spent more time in SWS (deep sleep) and less time in stage 1 sleep (light sleep). Also, REM latency was significantly decreased compared with baseline. Interestingly, the above-described responses of sleep latency, percent sleep time (ST), and percent SWS to sleep restriction were significant in women, but not in men, who showed similar nonsignificant trends. Also, women at baseline had a higher amount of SWS than men (in terms of both percentages and absolute amounts; 17.7 ± 2.0% vs. 11.0 ± 1.7%, and 75.2 ± 7.9 vs. 47.9 ± 7.1 min, respectively; both P < 0.05).

MSLT. After 1 wk of sleep restriction, both the average daily sleep latency as well as sleep latencies at each time point of the MSLT (0900, 1200, 1500, 1700, 1900, and 2100 h) were significantly shorter compared with baseline (Fig. 1). The differences were significant when we used the standard MSLT criterion of 30 sec of any stage of sleep (12.4 ± 1.2 vs. 5.8 ± 1.4, 11.2 ± 1.2 vs. 6.9 ± 1.2, 8.9 ± 0.9 vs. 4.7 ± 0.5, 10.9 ± 1.4 vs. 6.3 ± 0.9, 13.8 ± 1.3 vs. 10.4 ± 0.9, and 16.0 ± 1.2 vs.10.4 ± 1.0; all P < 0.05) or the criterion of 1 min of stage 2 sleep (15.0 ± 1.2 vs. 6.8 ± 1.3, 12.3 ± 1.4 vs. 7.3 ± 1.2, 10.7 ± 1.3 vs. 7.3 ± 1.1, 11.7 ± 1.4 vs. 7.1 ± 1.1, 15.9 ± 1.7 vs. 11.5 ± 1.3, and 17.6 ± 1.1 vs. 12.4 ± 1.5; all P < 0.05). The stronger responses were observed at 0900 and 2100 h, when sleep latency was decreased by 6.6 ± 1.3 and 5.6 ± 1.1 min, respectively (both P < 0.01). There were no gender differences. A concave quadratic curve was fitted both at baseline (P < 0.01) and after sleep restriction (P = 0.03). Subjective data also indicated that after 1 wk of sleep restriction, subjects were sleepier than at baseline (P < 0.05). Also, after adjusting for baseline MSLT values, the increase in percent ST and nocturnal SWS (minutes) after 1 wk of sleep restriction (nights 10 and 11 minus nights 2 and 3) was associated with decreased objective sleepiness (r_xy = 0.43; P < 0.05 and r_xy = 0.38; P = 0.06, respectively).

View larger version (8K): [in this window] [in a new window]   FIG. 1. Mean sleep latency during six daytime naps (MSLT) before () and after () partial sleep restriction. Sleep onset was defined as the presence of any stage of sleep for 30 sec or more. Bar indicates SE. *, P < 0.05.

Effects of sleep restriction on cortisol, IL-6, and TNF secretion

24-h cortisol secretion. Overall, sleep restriction did not significantly affect 24-h cortisol secretion in either men or women. However, there was a significant effect in terms of the circadian secretory pattern of the hormone, as indicated by the significant time effect and the time and gender interaction effect. Specifically, the peak cortisol secretion in the morning was lower after sleep restriction than at baseline (difference between pre- and postsleep restriction, 44.14 ± 16.55 nmol/liter; P < 0.05), and this difference was stronger in men (55.18 ± 24.83 nmol/liter; P < 0.05) than in women (35.87 ± 24.83 nmol/liter; P = 0.16; Fig. 2). Also, cortisol secretion during the morning hours after the early awakening (0430–1130) was significantly lower than baseline, and this difference was stronger in men (57.94 ± 11.04 nmol/liter; P < 0.01) than in women (22.07 ± 13.80 nmol/liter; P = 0.08). In both genders, the peak of cortisol secretion was shifted by 2 h earlier than baseline (0800 vs. 0600 h; P < 0.05).

View larger version (17K): [in this window] [in a new window]   FIG. 2. Twenty-four-hour circadian secretory pattern of cortisol before () and after () partial sleep restriction in women (top) and men (bottom). Bar indicates SE. The thick black bar on the abscissa represents the sleep recording period during baseline. The open bar on the abscissa represents the sleep recording period during partial sleep restriction. *, P < 0.05.

24-h IL-6 secretion. Sleep restriction was associated with a significant overall increase in 24-h secretion of IL-6 (post minus pre, 0.8 ± 0.3 pg/ml; P < 0.05; Fig. 3). No effects of gender, time, or their interaction were detected. Postsleep restriction IL-6 secretion peaked in the morning immediately after early awakening and in the evening before the sleep period. The strongest differences for both genders were detected between 0430–0630 h (1.4 ± 0.5 pg/ml; P < 0.01) and 1830–2230 h (1.3 ± 0.5 pg/ml; P < 0.01). The drop in IL-6 levels from the presleep period to early sleep was sharper in the postrestriction condition than at baseline.

View larger version (19K): [in this window] [in a new window]   FIG. 3. Twenty-four-hour circadian secretory pattern of IL-6 before () and after () partial sleep restriction. Bar indicates SE. The thick black bar on the abscissa represents the sleep recording period during baseline. The open bar on the abscissa represents the sleep recording period during partial sleep restriction. *, P < 0.05.

24-h TNF secretion.

View larger version (26K): [in this window] [in a new window]   FIG. 4. Twenty-four-hour circadian secretory pattern of TNF before () and after () partial sleep restriction in women (top) and men (bottom). The thick black bar on the abscissa represents the sleep recording period during baseline. The open bar on the abscissa represents the sleep recording period during partial sleep restriction. *, P < 0.05.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Sleepiness and fatigue are not only troubling to the individual, but are also a major risk factor for public safety, including transportation accidents (16) and accidents in the workplace, especially under critical circumstances such as emergency room workers or physicians on call (17), workers in nuclear reactors, etc. Our study refutes views that sleep is optional or a waste of time, views that have become increasingly popular among groups of the population, particularly those who are young and in their productive years.

Previous findings from our group (8) and other investigators (18) have shown that total sleep loss is associated with an increased secretion of IL-6 and TNF the next day. Our study suggests that even modest sleep loss is associated with an increased secretion of these proinflammatory cytokines. It should be noted that the increase in daytime secretion of IL-6 for this study is similar to that observed after 1 night of total sleep loss (0.75 ± 0.3 vs. 0.95 ± 0.6 pg/ml; P = nonsignificant).

Both IL-6 and TNF are markers of systemic inflammation that may lead to insulin resistance, cardiovascular disease, and osteoporosis (19, 20). This suggests that mild sleep loss, besides its immediate behavioral effects, i.e. sleepiness and decrements in performance, may also be associated with long-term risks of significant morbidity and mortality. Our study cannot address the issue of whether the effects on hormones/cytokines depend on the cumulative number of hours lost, which would have required an interim assessment. An important question arises: are the reported elevations of plasma cytokines of any clinical or biological relevance? Although there is no direct answer to this question from this study, it should be noted that the increases in plasma levels of IL-6 and TNF that we observed in our study are similar to the increases associated with conditions such as obesity (21) or aging (10) that are associated with increased morbidity and mortality. Also, elevations of IL-6 and its surrogate marker C-reactive protein similar to those reported in our study have been associated with an increased risk for cardiovascular morbidity and mortality (22, 23, 24).

The response of cortisol to sleep restriction in this study is consistent with our previous study of total sleep loss (25), but it is different from other studies that reported increased cortisol secretion, particularly in the evening after total or partial sleep loss (9, 26). Methodological differences between these studies, such as delayed bedtime vs. advanced wake time, constant recumbent condition during sleep loss vs. ambulatory, calories given iv in the form of glucose vs. regular meals, may explain the variance in terms of cortisol response. Also, it has been shown that upright position (27) or the transition from dim light to bright light (28) in the morning induces an elevation of the cortisol level. In our study the subjects when awakened early remained in a lying or sitting position, whereas the light that they were exposed to was that of a regular sleep laboratory bedroom, which is much less bright compared with that in the study cited (28). Thus, it is unlikely that hormonal measures in our study were affected by posture or lighting.

Sleepiness affected to a lesser degree those subjects who demonstrated a stronger build-up of nocturnal SWS (deep sleep) during restriction, suggesting that individuals with the greatest build-up of slow wave activity during chronic sleep loss can tolerate sleep loss with the least increase in sleepiness (29).

An interesting finding of our study is that women appear to be more resilient to some extent than men to the effects of sleep loss. Potential gender differences in the response to sleep loss have not been assessed or reported previously. In our study after sleep restriction, the elevation in plasma TNF and the drop in the maximum cortisol value were significant only in men. Furthermore, women at baseline had more SWS than age-matched men by about 30 min. Several studies have reported that men compared with age-matched women tend to lose SWS faster (30, 31) and that they have lower power density on sleep EEG in delta and theta frequency (32). Also, a recent analysis of men and women from large general population samples showed that women had a better quantity (total sleep time) and quality (SWS and REM sleep) of sleep (33, 34). In addition, women had a stronger homeostatic response to sleep loss and were more resistant to the sleep-disturbing effects of blood drawing (35). Collectively, these data suggest that healthy women appear not only to sleep better, but that they also can cope better with sleep loss/sleep disturbance in terms of inflammation markers, which, in part, may contribute to women’s lower cardiovascular risks and greater longevity.

In summary, modest chronic sleep loss is associated with significant sleepiness, impairment of psychomotor performance, increased secretion of IL-6 and/or TNF, and a significant drop of maximum values of cortisol. These changes occurred despite the fact that the quality of the restricted nocturnal sleep improved as a result of increased homeostatic pressure. The effects of sleep loss on TNF and cortisol were stronger in men than in women. Given the potential association of these behavioral and physical alterations with health, well-being, and public safety, the idea that sleep or parts of it are optional should be regarded with caution.

	Footnotes

 
This work was supported by National Institutes of Health Grant HL-64415.

Abbreviations: EEG, Electroencephalogram; MSLT, multiple sleep latency test; PVT, psychomotor vigilance task; REM, rapid eye movement; RT, reaction time; SWS, slow wave sleep.

Received September 5, 2003.

Accepted February 1, 2004.

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