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Original Studies |
Department of Medicine, University of Chicago (R.L., E.F.C., E.V.C.), Chicago, Illinois 60637; and Laboratoire de Médecine Expérimentale and Centre d’Etude des Rythmes Biologiques, Université Libre de Bruxelles (R.L., M.L.-B., E.V.C.), B-1070, Brussels, Belgium
Address all correspondence and requests for reprints to: Eve Van Cauter, Ph.D., Department of Medicine, MC 1027, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: evcauter{at}medicine.bsd.uchicago.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is evidence to indicate that exposure to bright light, compared with dim light, has general central nervous system-activating effects. A number of studies have shown that increasing light intensity reduces subjective sleepiness and limits decrements in cognitive performance, particularly during overnight sleep deprivation (11, 12, 13, 14). Bright light exposure has, therefore, been proposed as a strategy to promote alertness in nightworkers (15, 16, 17). The time course of subjective sleepiness and/or alertness during prolonged wakefulness has been clearly defined in a number of well controlled studies (18, 19, 20). Increased sleepiness becomes apparent after 14–16 h of continuous wakefulness, i.e. usually during the late evening hours, at a time when the concentrations of both melatonin and TSH are increasing. In the absence of sleep, sleepiness peaks in the early morning, around the usual wake-up time, when cortisol concentrations are maximal. Sleepiness is then partly alleviated despite the increased length of wakefulness. This improvement in alertness coincides with a decline in TSH and melatonin concentrations toward lower daytime values (20).
It has been suggested that the "alerting" effects of bright light during overnight sleep deprivation may be partly exerted via the suppression of the nocturnal secretion of melatonin, a hormone with putative hypnotic properties (12). The involvement of other hormones in nocturnal decrements of alertness and their attenuation by bright light, however, cannot be excluded. It is conceivable that the alerting effects of bright light involve a stimulation of the hypothalamo-pituitary-adrenal (HPA) axis, consistent with the involvement of this axis in behavioral activation. It is also conceivable that the pronounced increase in TSH levels during overnight sleep deprivation (4, 21) plays a role in subjective fatigue and that alleviation of sleepiness by bright light exposure might be associated with changes in TSH levels.
The present study was designed to determine whether exposure to bright light, compared with dim light, has alerting effects in subjects kept continuously awake for 36 h, and whether these activating effects are related to concomitant changes in melatonin, cortisol, and TSH secretion. The experimental conditions allowed for the examination of the impact of changes in light intensity per se,in the absence of sleep-wake transitions and changes in activity levels, posture, and caloric intake. The subjects were exposed to bright light on two separate occasions, once in the early morning, after more than 20 h of wakefulness, when sleepiness is maximum, and once in the afternoon, after approximately 30 h of wakefulness, when a secondary peak of sleepiness consistent with the usual timing of the "postlunch dip" has been hypothesized (22).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eight healthy normal male subjects (24 ± 1 yr old; body mass index, 24.1 ± 1.4 kg/m2) participated in this study. None of the subjects had a personal history of psychiatric illness, endocrine illness, or sleep disorder. Positive criteria for selection included regular life habits with a habitual total sleep time of approximately 8 h. Shift workers and subjects having experienced a transmeridian flight less than 6 weeks before the beginning of the study were excluded.
Experimental protocol
The protocol, shown in Fig. 1
, was
approved by the institutional review board of the University of
Chicago, and the volunteers gave written informed consent.
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For 7 days before each study, the volunteers were asked to comply with a standardized schedule of sleep in total darkness: going to bed between 2300–2400 h and getting up between 0700–0800 h. Continuous recordings of wrist activity (Gähwiler Electronics, Hombrechtikon, Switzerland; or Minilogger, Minimitter Co., Inc., Sunriver, OR) were used to verify compliance.
For each study, the volunteers were admitted to the Clinical Research Center of the University of Chicago around 0830 h and received breakfast. Starting at 1000 h, they were maintained on a regimen of bedrest with enforced wakefulness in dim indoor light (<150 lux). The subjects completed at hourly intervals a visual analog scale for mood and vigor (23). Scores recorded during usual waking hours on the summary scale "overall, how do you feel?" (0 = very bad, 10 = very good) averaged 7.2 ± 1.8 in the baseline study, 7.2 ± 1.7 in the early morning study, and 7.7 ± 1.2 in the afternoon study. These scores are in the normal range for healthy nondepressed subjects. Heart rate was recorded via a Mini-Logger (Mini-Mitter Co., Inc.) throughout the study period. Two catheters were inserted, one for glucose infusion and one for blood sampling. At noon, the subjects received lunch, which constituted their last meal until the end of the study, i.e. until 1800 h the next day. Starting at 1400 h, caloric intake was exclusively in the form of a glucose infusion at a constant rate of 5 g/kg·24 h. At 1800 h, blood sampling at 15-min intervals for 24 h was initiated. The iv line was kept patent with a slow drip of heparinized saline.
The subjects had access to external time cues (wristwatch, radio and television programs, social contacts). Water ad libitum and a maximum of three diet decaffeinated sodas per day were allowed. At the end of the study, i.e. at 1800 h, the glucose infusion was tapered, dinner was served, and the subjects were discharged.
Procedures for light exposure
Mobile panels of mounted fluorescent tubes, providing a light intensity of 16,000 lux at a distance of 0.30 m, were placed in front of the subjects at about a distance of 1.5 m. In addition, light boxes, providing a light intensity of 14,000 lux at a distance of 0.30 m, were placed on each side of the bed. Illumination levels at the subject’s eye were regularly checked using a digital light meter (Research Products International Corp., Mount Prospect, IL). Each 3-h period of exposure to bright light included successively 15 min of illumination at 2000–2500 lux, 45 min of illumination at 3000–4000 lux, 1 h of illumination at 4500 lux, 45 min of illumination at 3000–4000 lux, and 15 min of illumination at 2000–2500 lux.
Hormonal assays
Plasma melatonin levels were measured with a double antibody RIA using commercially available reagents (Stockgrand, Guilford, Surrey, UK) as previously described (24). The lower limit of sensitivity of the assay was 11 pmol/L. The intraassay coefficient of variation averaged 17.5% for values less than 43 pmol/L and 8.6% for values greater than 43 pmol/L.
Plasma cortisol levels were measured by a chemiluminescent enzyme immunometric assay (Immulite, Diagnostic Products Corporation, Los Angeles, CA) with a lower limit of sensitivity of 28 nmol/L. The intraassay coefficient of variation averaged 6%.
Plasma TSH levels were measured by a chemiluminescent enzyme immunometric assay (Immulite Third Generation TSH, Diagnostic Products Corp, Los Angeles, CA). The sensitivity of the assay was 0.002 µU/mL. The intraassay coefficient of variation averaged 2% in the physiological range. For all hormonal determinations, samples from the same subject were measured in the same assay run.
Estimation of vigilance
Two cognitive performance tasks, a perceptual cueing task and a vigilance task that are part of the Harvard Cognitive Performance Battery (Department of Psychology, Harvard University, Boston, MA), were administered hourly on portable computers. Four versions of each task were created to avoid learning effects. Each task took approximately 2 min to complete.
The perceptual cueing task measures both the strength of a subject’s attention and the ease with which that attention can be shifted. This task included 40 trials for which the subject has to press the space bar as fast as possible in response to each trial. The vigilance task measures the ability of a subject to sustain attention in the absence of salient signals. This task contains 48 trials. For both tasks, the reaction time is measured for each trial.
For each subject and for each task, lapses were defined as reaction times that exceeded the 99th percentile of the distribution of reaction times measured in each study during the normal waking period, i.e. the time interval 1000–2300 h. For each individual and for each study, the total number of lapses on each task was determined, and an objective hourly measure of sleepiness was obtained by adding the number of lapses on the two tasks.
Statistical tests
All group values were expressed as the mean ± SEM. All statistical calculations were performed using nonparametric tests (Friedman procedure for three repeated measures and Wilcoxon test for two repeated measures) with the StatView SE+ software (Abacus Concepts, Inc., Berkeley, CA) for Macintosh computers. Correlations were calculated using the Spearman rank coefficient of correlation (rS).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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shows the TSH, melatonin,
and cortisol profiles for the three studies. Under baseline conditions,
the profiles of the three hormones conformed with previous observations
in normal subjects undergoing 1 night of total sleep deprivation
(20).
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TSH profiles (left panels of Fig. 2
) were similar in
the three study conditions, and in particular, there were no
significant effects of exposure to bright light either in the morning
or in the afternoon.
As expected, early morning bright light exposure resulted in an
immediate inhibition of melatonin secretion (lower middle
panel of Fig. 2). Melatonin levels averaged 292 ± 43 pmol/L
in the sample preceding the increase in light intensity and decreased
to 215 ± 30 pmol/L within 15 min and to 151 ± 17 pmol/L
within 30 min of turning on the light banks (P <
0.005). After this initial rapid inhibition, melatonin levels continued
to decrease at a slower rate during the next 2 h. Melatonin levels
from 0515 until 0800 h, i.e. during the period of
exposure to bright light in the early morning study, averaged 95
± 17 pmol/L in the early morning study compared with 280 ± 56
pmol/L in the baseline study and 245 ± 60 pmol/L in the afternoon
study (P < 0.02). For all three study conditions,
consistent with the known characteristics of the circadian rhythm of
pineal secretion, melatonin levels were low in the afternoon and were
not affected by bright light exposure at this time of day (middle
panels of Fig. 2). Melatonin levels from 1315 until 1600 h,
i.e. during the period of exposure to bright light in the
afternoon study, averaged 13 ± 4 pmol/L in the early morning
study, compared with 17 ± 4 pmol/L in the baseline study and
17 ± 4 pmol/L in the early morning study.
A robust effect of bright light exposure was observed in the
cortisol profiles in the early morning, but not in the afternoon
(right panels of Fig. 2). The time course of changes in
cortisol levels associated with early morning changes in light
intensity compared with constant dim light is further illustrated in
the left panels of Fig. 3.
Within 15 min of the transition from dim light to bright light, a
robust elevation of plasma cortisol was detected in all individual
profiles. On the average, cortisol levels increased from 223 ± 33
nmol/L at 0500 h, i.e. just before the increase in
light intensity, to 348 ± 47 nmol/L at 0515 h
(P < 0.02). The elevation in cortisol levels from
0500–0515 h averaged 121 ± 19 nmol/L and was larger than
increases occurring at the same clock time in the baseline (17 ±
19 nmol/L; P < 0.01) or the afternoon studies (66
± 41 nmol/L; P = 0.12). The fact that the difference
between the early morning and the afternoon studies failed to reach
significance reflects the presence of a large afternoon cortisol
elevation (342 nmol/L) in a single subject. If this subject is excluded
from that comparison (n = 7 instead of n = 8), the elevation
of cortisol levels from 0500–0515 h averaged 113 ± 19 nmol/L in
the early morning study and was larger than increases occurring in the
same clock time in the baseline (28 ± 19 nmol/L;
P < 0.02) or the afternoon (25 ± 14 nmol/L;
P < 0.02) studies. After this initial rise associated
with the transition from dim to bright light, cortisol levels decreased
slowly throughout the period of bright light exposure (Fig. 3) and
averaged 295 ± 19 nmol/L during the time interval 0800–0830 h,
following the end of bright light exposure. A consistent rebound of
cortisol concentrations followed, with levels reaching 403 ± 33
nmol/L (P < 0.02) during the time interval 0900–0945
h. Interindividual synchronization of short-term increases and
decreases in cortisol levels did not occur at the same clock times in
either the baseline study or the afternoon study. In the afternoon
study, changes in light intensity had no detectable effect on cortisol
profiles (Fig. 2).
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). Effects of bright light exposure on cognitive performance
Figure 4 shows the mean profiles of
the number of lapses on performance tasks for the three studies.
Performance showed no major changes from morning until the early part
of the usual sleep period. Indeed, from 1000 until 0200 h, the
number of lapses remained low at 1.0 ± 0.1 in all three studies.
The number of lapses then started to increase, indicating a
deterioration of performance.
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; P <
0.05). The level of peak sleepiness, as estimated by the maximum number
of lapses, did not differ significantly across the three study
conditions (16.1 ± 2.2 lapses in the baseline study, 18.2 ±
3.0 in the afternoon study, and 14.8 ± 3.5 in the early morning
study). In all three studies, performance steadily improved in the late morning and afternoon despite the persistence of total sleep deprivation. There was no immediate effect of afternoon exposure to bright light on cognitive performance.
Correlations of hormonal and performance changes after early morning bright light
During the first 15 min of bright light exposure, the sharp increases in cortisol levels were not significantly correlated with the concomitant decreases in melatonin levels (rS = -0.47; P = 0.22). However, the decreases in melatonin after 30 min of bright light were significantly correlated with the increase in cortisol levels observed during the first 15 min (rS = -0.80; P = 0.03).
We also sought to determine whether alleviation of performance
deterioration during bright light exposure (as estimated by the slope
of the number of lapses) was correlated with the magnitude of melatonin
suppression or/and the magnitude of the cortisol elevation. There were
no significant correlations between performance changes and initial
melatonin decreases. In contrast, a trend for a negative correlation
between the slope of the number of lapses and the magnitude of the
acute cortisol response to light was apparent (rS
= -0.62; P = 0.10). Thus, the subjects who maintained
the best performance levels (i.e. had the lowest rate of
increase in number of lapses) during the period of bright light
exposure were those who had the largest acute cortisol responses after
the transition from dim to bright light. The left panels of
Fig. 3 show the simultaneous profiles of plasma cortisol and number of
performance lapses for the baseline study and the study with early
morning bright light.
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Discussion |
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During the past decade, a number of studies have indicated that morning awakening is consistently followed by a short-term increase in cortisol levels (25, 26). Recently, Scheer et al. showed that this morning postawakening cortisol elevation, which occurs even in continuous darkness, can be enhanced by increasing light intensity. Available evidence from studies in night workers and from analyses of awakenings interrupting sleep indicates that a pulse in cortisol secretion consistently follows the sleep-wake transition regardless of time of day (27, 28). In contrast, the present data and limited evidence from a recent study (10) indicate that the impact of increased light intensity on cortisol levels is dependent on time of day. The present study further demonstrates that the stimulatory effect of early morning bright light on cortisol levels may occur in the absence of a sleep-wake transition. Thus, under normal conditions of nocturnal bedtimes, both sleep-wake and dark-light transitions contribute to amplify the morning acrophase of the circadian rhythm of cortisol secretion.
In mammalian species, the 24-h rhythms of cortisol and melatonin secretions are dependent on an endogenous circadian periodicity generated in the suprachiasmatic nuclei (SCN) of the hypothalamus. Light is the major environmental factor responsible for the synchronization of circadian rhythms. Light information is transmitted from the eyes to the SCN via a specific neuroanatomical pathway, the retino-hypothalamic tract (29). Efferent projections from the SCN to CRF-containing neurons in the paraventricular nucleus are thought to be involved in the entrainment of the 24-h rhythm in HPA activity and its photic synchronization. The melatonin rhythm is regulated by the SCN through a multisynaptic projection to the pineal gland that begins with a projection from the SCN to the paraventricular nucleus. Melatonin suppression is maintained as long as light signals are transmitted from the retina to the SCN and to the pineal gland. In contrast, the present data suggest that activation of the HPA axis is an acute response to the increase in light intensity. Although the anatomical and neurochemical mechanisms by which light via the SCN suppresses melatonin production are well understood, nothing is known about the mechanisms by which light can directly affect the HPA axis. In the human, exposure to light in the early morning results in advances of circadian phase, whereas exposure to light during the afternoon does not cause detectable shifts in circadian phase (4, 30, 31, 32, 33, 34, 35). The fact that the effects of light on cortisol levels and cognitive performance observed in the present study were also dependent on the timing of exposure suggests that these short-term effects of light could be mediated by the SCN. Alternatively, direct retinal projections to other areas of the hypothalamus have been evidenced (29) and could mediate the acute effect of light on cortisol levels observed in the present study (36).
After the increase in light intensity in the early morning, melatonin levels decreased sharply during the first 30 min and then continued to decline slowly, whereas cortisol levels augmented sharply and then steadily decreased. The magnitudes of the rapid cortisol and melatonin changes associated with the dim to bright light transition were negatively correlated, suggesting that common mechanisms, possibly mediated by the SCN, may have been involved in the initial, but not the sustained, effects of increased light intensity.
Our study also provides limited evidence for a relationship between improved performance and bright light-induced cortisol elevations, but not melatonin declines. Although the present analyses do not permit the exclusion of a role for melatonin suppression in the alerting effects of nocturnal bright light, they suggest that an activation of the HPA axis could also be involved, at least when exposure occurs in the early morning hours.
No effect of light exposure on TSH levels could be detected either in the early morning or in the afternoon. The fact that early morning bright light attenuated vigilance deficits in the absence of detectable effects on TSH levels suggests that the large TSH increase normally associated with nocturnal sleep deprivation does not play a major role in causing fatigue. The lack of effect of light on TSH in the present study also suggests that the sharp increases in TSH levels seen after an afternoon dark-light transition in a previous study (9) involved nonphotic factors, e.g. postural changes, sleep-wake transition, and social stimulation.
In conclusion, the present study demonstrates that in healthy young men, cortisol secretion can be stimulated by photic inputs in the morning, but not in the later part of the day, and suggests that the impact of light on HPA activity is mediated by the central circadian pacemaker located in the SCN. Further studies are needed to determine whether similar effects of morning light on cortisol levels occur in women and older adults.
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Acknowledgments |
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Footnotes |
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Received March 2, 2000.
Revised July 13, 2000.
Revised September 6, 2000.
Accepted September 13, 2000.
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