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Original Studies |
Department of Neuropsychiatry (K.M., T.S., Y.H.), Akita University School of Medicine, Akita City 010-8543; and Division of Psychophysiology (M.O.), National Institute of Mental Health, National Center of Neurology and Psychiatry, Ichikawa 272-0827, Japan
Address all correspondence and requests for reprints to: Kazuo Mishima, M.D., Department of Neuropsychiatry, Akita University School of Medicine, 1-1-1 Hondo, Akita City 010-8543, Japan. E-mail: mishima{at}psy.med.akita-u.ac.jp
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Abstract |
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Introduction |
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Aging is often associated with sleep-waking disorders (15, 16). Insomnia in the elderly is presumed to be based, in part, on changes in the circadian time-keeping system. Previous reports have indicated age-related decreases in melatonin levels (17, 18, 19, 20, 21, 22, 23), especially in elderly insomniacs (EIs) (24) and elderly persons with dementia who often show various types of sleep problems (25, 26, 27, 28). These findings let us assume that reduction in melatonin secretion with aging may be a causal or exacerbating factor in sleep disturbances observed in this age group. Thus, supplementary administration of exogenous melatonin has been tried for sleep disorders in elderly persons with (29, 30, 31) and without (32, 33) dementia. However, the underlying mechanism of age-related decreases in melatonin secretion remains unclear, and use of supplementary exogenous melatonin tends to be long-term, despite the fact that potential side effects are not well-defined. In addition, one recent well-controlled study demonstrated no significant change in melatonin secretion in normal elderly persons. Zeitzer and co-workers (34) examined the amplitudes of plasma melatonin levels during a constant routine in 34 healthy drug-free elderly subjects and were unable to detect any significant age-related changes in mean 24-h average melatonin levels or any other nocturnal melatonin secretion profile parameters.
We demonstrate here that resident elderly persons can suffer from insufficient environmental light and that supplementation with bright light at levels similar to those in the young living at home can improve melatonin secretion and sleep quality, suggesting that the discrepancies in previously reported studies could be attributable, at least in part, to the exposure of the experimental subjects to varying degrees of environmental light.
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Subjects and Methods |
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Study subjects were 10 elderly residents of a nursing home with psychophysiological insomnia [EI group; males/females (M/F) = 4/6; 66–82 yr old, average age = 74.2 yr], 10 healthy residents of the same home [elderly control (EC) group; M/F = 5/5; 65–80 yr old, average age = 70.7 yr], and 10 healthy college students [young control (YC) group; M/F = 10/0; 19–23 yr old, average age = 20.9] living at home. Subjects in the EI group were required to satisfy Lushington et al. criteria (35) based on the International Classification of Sleep Disorders criteria for psychophysiological insomnia (36) and criteria for sleep maintenance insomnia by Waters et al. (37). That is, according to The Pittsburgh Sleep Quality Index (38) and 7-day sleep diary, EIs were selected if they reported a mean wake time after sleep onset (WASO, the accumulated time awake after the sleep onset) more than 30 min, total sleep time (TST) less than 6 h, and sleep efficacy (the total time asleep as a percentage of the total time in bed) less than 85%. All subjects gave informed consent. With the exception of 4 elderly subjects in the EI group who were using short-acting benzodiazepines, no subject took any medication, such as ß-blocker or antiphlogistic, that might modify sleep states or melatonin secretion levels. The 4 patients who took benzodiazepines (7.5 mg zopiclone for 2 subjects, 0.5 mg etizolam for 1 subject, and 0.125 mg triazolam for 1 subject) had been on medication continuously at fixed dosages for at least 6 weeks before participating in our study, and continued the treatment during the study. All elderly subjects underwent brain magnetic resonance imaging and/or computed tomography, as well as Mini Mental State (MMS) examinations, and subjects with moderate-to-severe ischemic and/or atrophic changes in the brain, and MMS scores of 20 or less, were excluded from the study. Average ± SEM of MMS scores for the EI and EC groups were 23.6 ± 0.83 (range, 21–30) and 24.4 ± 0.64 (range, 22 to 30), respectively.
Protocol
The study was performed in Akita City (39° 42' N) located in the northern part of Japan. The study comprised a 2-week baseline period (day 1 to day 14) for the three groups, followed immediately by a 4-week light exposure period (day 15 to day 42) for the EI group. The EI group was exposed to bright light for 4 h each day, from 1000 h to 1200 h and from 1400 h to 1600 h, in a light room where full-spectrum fluorescent tubes were placed across the entire ceiling so that subjects were exposed to light without behavioral restriction, at an intensity of approximately 2500 lux at eye level when seated anywhere in the room. Throughout the study, all elderly subjects followed self-determined schedules, with the exception of some common daily events such as meals at 0700 h, 1200 h, and 1730 h and bathing between 1600 h and 1700 h. All subjects in the YC group followed self-determined schedules at home. Light during the time in bed was kept below 25 lux; 0 lux was used during sleeping times, as identified by wrist actigraph data. To maintain consistency between the three groups, with respect to the influences of weather on rhythm properties and light conditions, monitoring was performed simultaneously in three subjects from each group.
Evaluation of environmental light condition
Light exposure was simultaneously monitored, at 1-min intervals, in each subject, from day 6 to day 12 in the baseline period and during the last 7 days in the light-exposure period, using a thin patch-type photosensor (Matsushita Electric Works, Ltd., Osaka, Japan) that was calibrated to measure light intensities from 1–10,000 lux (r = 0.99999) and that was applied to each subject’s forehead or to glass frames connected to a small ambulatory illuminorecorder (Gram Ltd., Tokyo, Japan). This device allowed us to evaluate entry of incidental environmental light into the retina. Parameters for light condition were defined as follows: total light exposure (Ltotal), the area under the light intensity curve calculated for each subject by summing the total light intensity values during wake time; bright light exposure time (L > 1000), the number of minutes of light exposure above 1,000 lux during wake time.
Evaluation of sleep quality calculated by actigraph data
Throughout the study period, wrist activity was monitored with an actigraph (AMI Inc., Ardsley, NY) around the nondominant wrist of each subject. Actigraph data were analyzed for computer-calculated sleep-wake determinations (39). Nighttime sleep parameters for each subject were defined as follows: sleep onset time (SOT), clock time of the onset of sleep; sleep efficacy (SE), the total time asleep as a percentage of the total time in bed; awake time (AT), the total number of waking episodes that continued for at least 10 min during the sleep period; WASO (accumulated time); and sleep latency (SL), the time between bedtime and the sleep onset.
Evaluation of melatonin secretion rhythm
Blood sampling for RIA of serum melatonin was performed on the days 13–14 and on days 42–43. Blood was collected every hour for 24 h, starting from 8 h before the average SOT determined for days 6–12 in the baseline period for 3 groups (, and for days 35–41 in the light-exposure period for the EI group) via iv catheter that had been placed in a forearm vein under dim light (<25 lux) to avoid masking effect on melatonin levels. The blood sample was immediately centrifuged (3000 rpm for 15 min), and serum was separated and frozen (below -75 C) for later RIA. Parameters for melatonin rhythm were defined as follows: rhythm amplitude (AMP), the difference between peak and low values; nocturnal melatonin secretion volume (AUCn), the area under the melatonin time-concentration curve calculated for each subject by summing the total melatonin levels from 4 h before to 8 h after bedtime; daytime melatonin secretion volume (AUCd), the area under the melatonin time-concentration curve with the exception of AUCn; dim light melatonin onset time (DLMOn), the evening time at which serum melatonin concentrations reached 8.1 pg/mL, which was 3 times the detection limit of the RIA kit used in this study; dim light melatonin offset time (DLMOff), the morning time at which serum melatonin concentrations decreased below 8.1 pg/mL; the duration of nocturnal rise (Duration), the duration during which serum melatonin concentration was kept higher than 8.1 pg/mL; and the midtime of nocturnal rise (Midtime), the midtime between DLMOn and Off time). The DLMOn, DLMOff, and Midtime were expressed as a time relative to 0000 h, defined as average SOT determined for day 6–12 (day 35–41) in the baseline period (in the light-exposure period).
Statistics
For statistical analysis, we used the Kruskal-Wallis test, followed by the Mann-Whitney U or Wilcoxon test, to identify the significant intergroup differences in light, sleep, and melatonin parameters among three groups. Pearson correlation analysis was used to examine association between changes in melatonin and sleep parameters induced by midday light exposure. Results were evaluated at the P < 0.05 significance level and are shown as the mean and SEM values.
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Results |
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Sleep parameters and their values for the last 7 days of the
baseline period (excluding the last day for melatonin sampling) are
shown in Table 1
. The EI group showed
significantly lower values of TST and SE, as well as significantly
higher values of AT, WASO, and SL, compared with the corresponding
values in the YC group. The EC group also showed significantly lower
values of TST and SE, as well as significantly higher values of AT and
WASO, compared with the corresponding values in the YC group.
Furthermore, the EI group showed significantly lower values of TST and
SE, as well as significantly higher values of AT and WASO, compared
with the corresponding values in the EC group.
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The melatonin secretion rhythm parameters in the baseline period
are also shown in Table 1
. AMP and AUCn in the EI group and AMP in the
EC group were significantly reduced, compared with the corresponding
values in the YC group. AUCn in the EC group shows a decreasing
tendency, compared with that in the YC group (P =
0.082), as well as a increasing tendency, compared with that in the EI
group and compared with the EC group (P = 0.080). There
were no significant differences in AMP between the EC and EI groups.
There were no significant differences in AUCd, DLMOn, DLMOff, Duration,
and Midtime among the three groups. Four subjects in the EI group
who took benzodiazepines showed no significant difference in either AMP
or AUCn, compared with the corresponding value in the other six
subjects in the EI group (34.5 ± 5.7 vs. 35.2 ±
5.2 pg/mL, and 226.2 ± 33.3 vs. 230.68 ± 30.39
pg/mL·h, respectively).
Luminous condition in the baseline period
Values of parameters of light condition in the baseline period are
also shown in Table 1. Average Ltotal values, measured at eye level
during wake time in both the EI and EC groups, were significantly lower
than that measured in the YC group. There was also significant
difference in Ltotal between the EI and EC groups. Average L > 1000
values, measured at eye level during wake time in both the EI
and EC groups, were significantly lower than that measured in the YC
group. There was no significant difference in L > 1000 between the EI
and EC groups.
Midday exposure to bright light
During the light exposure time in the light room, the light
intensity at eye level was controlled for each EI subject (range,
2205–2501; mean, 2406 ± 30.2 lux). Average Ltotal during the
light exposure period was not significantly different from that in the
YC group during the baseline period (P = 0.596). Midday
bright light exposure for 4 weeks significantly decreased AT, increased
SE (P = 0.083), and decreased WASO (P =
0.066) in the EI group (Table 1). The midday bright light exposure also
increased the AMP and AUCn without any significant changes in DLMOn,
DLMOff, and Midtime in the EI group (Table 1, Fig. 1). There was a tendency for increased
AMP to be associated with increased SE (r = 0.56,
P = 0.096) and for increased AMP to be associated with
decreased AT (r = 0.60, P = 0.066) induced by
light exposure (Fig. 2). There was also a
tendency for increased AUCn to be associated with decreased AT
(r = 0.57, P = 0.086) induced by light
exposure.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We also found that these resident elderly persons were exposed to significantly lower levels of environmental light, compared with the YCs. It is noteworthy that supplementary exposure of bright light at midday for EIs induced significant increases in AMP and nocturnal melatonin secretion, resulting in levels of melatonin secretion similar to those in YCs. Based on these data, we suggest that the diminished secretion of melatonin in the elderly subjects in this study was attributable, at least in part, to their poor environmental illumination. In addition, the improvement in sleep maintenance, as represented by decreased AT and WASO and increased SE induced by midday exposure to bright light, tended to parallel the improvement in nocturnal melatonin secretion but without significant circadian phase-shifting as represented by DLMOn, DLMOff, and Midtime. These findings indicate that reduced secretion of melatonin observed in poor light conditions may cause sleep maintenance disturbances. In experimental and/or therapeutic trials, melatonin has been given in doses ranging from 0.1–10 mg (45), which often yields nonphysiological profiles of serum melatonin concentration (6). Some previous studies have demonstrated that melatonin supplementation at night significantly improved sleep problems in EIs (32, 33). However, considering possible side effects of long-term melatonin administration, exposure to midday light may provide a more desirable, potent, safe, and self-directed therapeutic tool for EIs with diminished melatonin secretion.
The present findings pose some important issues concerning environmental light conditions and the related physiological and/or chronobiological significance. First, we need to note elderly individuals who suffer from poor light conditions during both phase-shifting (morning and evening) and nonphase-shifting periods, which result in disorganized circadian rhythms, including the sleep-wake cycle. Timed exposure to bright light ranging from 2500 lux to 13000 lux has been revealed to induce marked suppression of melatonin secretion (46) and strong circadian phase-resetting effect (47, 48, 49) in humans. Dimmer light exposure of 1000 lux or less could also induce similar effects; however, their magnitude have been shown to distinctly decrease in intensity-dependent manners (50, 51). In addition, light intensity of 1000 lux, defined as a cutoff point of bright vs. dim light in the present study, is thought to reflect exposure to sunlight both in the summer and winter, and it is rare to record light intensity of 1000 lux or more under indoor light conditions (52). These findings let us assume that elderly persons, especially EIs, spending most of their daily life under room light, could receive insufficient light intensity to adjust their circadian timing system. Actually, the inadequate exposure to environmental light that affected the resident elderly persons in this study were thought to result from the high incident angle of sunlight (decreased sunlight intensities through windows), withdrawal of residents into their rooms, and/or little time spent outdoors. Such conditions may exist for inactive elderly persons residing at home.
Second, we need to recognize the physiological significance of environmental midday light. Sufficient and well-timed morning and evening exposure to light according to the human phase-response curve is essential for maintaining proper mutual phase position (47, 48, 49). However, the physiological significance of midday light exposure without significant circadian phase-shifting is unclear. Hashimoto et al. (53) found that midday exposure to bright light for 3 consecutive days had a phase-resetting effect on melatonin rhythm without changing the AMP, under isolated conditions in young subjects. In the present study, more long-term exposure to midday bright light induced remarkable increases in circadian AMPs in elderly persons despite lack of circadian phase-shifting, even under entrained conditions. In future studies, these amplitude-modifying effects should be confirmed, with respect to other physiological markers of circadian rhythms, such as core body temperature.
Third, the present study may help to explain the contradictory data regarding age-related decreases in melatonin secretion. The discrepancy between previous studies concerning melatonin secretion properties in elderly persons may be attributable, at least in part, to the environmental light condition surrounding the experimental subjects. Twenty older women and 14 older men participating in a well-controlled study by Zeitzer et al. (34) showed no age-related changes in melatonin secretion. The subjects in that study were not institutionalized, and they underwent extensive medical screening to assess physical and mental health, including sleep patterns and medications. It is possible that these super-healthy elderly subjects spend their daily lives under light conditions sufficient to maintain melatonin secretion at levels similar to those of young persons. Although serum melatonin secretion rhythm is often used as a stable marker of circadian output, the present findings suggest that we need to consider the environmental light conditions of the experimental subjects when evaluating their melatonin rhythms as a circadian marker.
The mechanism behind increased nocturnal melatonin secretion after midday exposure to bright light is unclear. One explanation is that repeated light stimuli could enhance the oscillatory amplitude of the circadian clock (54) via the suprachiasmatic nucleus. Bright light was shown to modify both the phase and the amplitude of the circadian system. In young subjects, a 3-cycle light stimulus induced strong circadian phase shifting, with different effects on circadian amplitude that depended on the initial phase of the stimulus application (54). The effect of long-term exposure to midday light stimulus in elderly persons remains unclear. However, a previous study revealed that a 2-week exposure to bright light daily from 0900 h to 1100 h could induce significant increases in the AMP of core body temperature in EIs (55).
One possible explanation is that midday bright light modifies brain serotonergic function, resulting in increased secretion of melatonin, which is a major metabolite of serotonin (5-HT) in the pineal gland. Some data from rodent (56) and human (57) studies have suggested that light can alter the processing of brain 5-HT signals. Penev et al. (56) showed that exposure of hamsters to light during their subjective midday significantly attenuated the phase-shifting effect caused by a 5-HT1a agonist. Lam et al. (57) showed, in humans, that rapid depletion of the 5-HT precursor tryptophan reversed the antidepressant effect of bright light therapy in patients with seasonal affective disorder, suggesting that the therapeutic effect of bright light may involve a serotonergic mechanism. It is possible that the significant increase in melatonin synthesis, observed in the present study, is caused by altered 5-HT metabolism induced by long-term exposure to bright light.
Environmental light not only acts as a mediator of visual perception, but it also influences the phase/amplitude of circadian rhythms, which tend to run at a period of about (but not exactly) 24 h (48, 58). Generally, environmental light is thought to be sufficient to maintain the circadian time-keeping system, except in special situations such as physiological blindness, experimental isolation, or space flight. However, findings of the present and some previous studies (28, 59, 60, 61) suggest that many elderly people spend less time in bright light because of living arrangements or seasonal factors. For elderly persons who live with few social time cues, the possibility that poor daytime conditions could affect various brain functions, including circadian and serotonergic systems, should be evaluated.
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Footnotes |
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Received July 20, 2000.
Revised September 7, 2000.
Accepted September 10, 2000.
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References |
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