Light effects on human circadian rhythms: a review of recent Andechs experiments.
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Acoustic Stimulation↗
Biomedical subjects
R A Wever
Publications and source records attributed to R A Wever.
Meal timing in humans during isolation without time cues.
In an underground isolation unit, 46 subjects lived singly without time cues under conditions of self-selected light-dark (LDs) cycles or constant illumination (LL). They all developed free-running circadian rhythms that either remained internally synchronized (i.e., with equal periods in all functions; n = 24) or became desynchronized by a sudden lengthening (n = 14) or shortening (n = 8) of the sleep-wake cycle. Six further subjects were synchronized to 24 hr by an externally controlled LD cycle. All subjects had to prepare their own meals. Signals were given by the subjects when they woke up, had a meal, and retired. Of the 52 subjects, 43 consistently had three meals per "day," and 9 had two meals, irrespective of the length of the circadian cycle and despite the fact that, due to desynchronization, wakefulness varied from over 30 hr to less than 12 hr. The intervals between meals, between wake-up time and breakfast, and between last meal and bedtime were "stretched" or "compressed" in strong proportionality to the duration of wakefulness.
Adult↗
Characteristics of circadian rhythms in human functions.
Circadian rhythms are of endogenous origin, in humans as in all organisms. Under temporal isolation, i.e., after exclusion of all environmental time cues, circadian rhythmicity persists but with a period slightly deviating from 24 hours; in human, freerunning circadian rhythms always show periods close to 25 hours. In a minority of experiments, overt rhythms of different variables do not run in mutual synchrony but internally desynchronized in the steady state. This means that, indeed, most physiological rhythms, and particularly that of body temperature, hold a period close to 25 hours; it is mainly the sleep-wake rhythm (but also the overt rhythms of several more variables) which shows freerunning periods being considerably longer or shorter than 25 hours. This state of the rhythm is not concerned by the presence or absence of naps; rather, this state is characterized by a considerable stretching or compressing of the entire sleep-wake cycle. The period and other parameters of freerunning rhythms can be modified by continuously operating stimuli. Also the tendency toward the spontaneous occurrence of internal desynchronization does not depend only on personality data (e.g., neuroticism, or age) but also on the external conditions. Whereas constant light in the normal range of artificial illumination (intensities between 0 and 1500 lux) does not affect freerunning human circadian rhythms, the period is longer and the tendency toward internal desynchronization is higher under constant bright light (intensity greater than 3000 lux) than under constant light of normal intensity (or total darkness). This result has been confirmed with various physiological functions, e.g. the rhythms of deep body temperature and melatonin excretion. Social contacts (when subjects do not live singly isolated but in groups) or behavioral stress operates in the same direction as bright light. On the other hand, physical workload does not affect freerunning rhythms. Under natural conditions, the endogenously generated rhythms are synchronized to the 24-hour day. Under laboratory conditions (i.e., under temporal isolation), also artificial zeitgebers can be effective but only within limited ranges of periods; the width of such a range of entrainment is an indicator of the strength of the zeitgeber under consideration.(ABSTRACT TRUNCATED AT 400 WORDS)
Body Temperature↗
Purification and determination of the modifying protein responsible for the post-synthetic modification of creatine kinase (EC 2.7.3.2) and enolase (EC 4.2.1.11).
The purification of a serum protein, responsible for the postsynthetic modification of CK and enolase, is described. A purification of about 1300-fold could be reached after subsequent chromatography of human serum on DEAE cellulose and Sephacryl S-200 Superfine followed by affinity chromatography using antibodies against human serum albumin, C3 and C4 and against total human serum proteins. A recovery of 160% of modifying activity was found. The molecular mass and the isoelectric point of the modifying protein have been determined. It is concluded that the concentration of the modifying protein in human serum is less than 210 mg/l.
Blood Protein Electrophoresis↗
Internal interactions within the human circadian system: the masking effect.
In the realm of human circadian rhythms, the masking effect is defined as the change in the course of deep body temperature induced by changes in the degree of physical activity, or by the alteration between sleep and wake. This effect is particularly obvious during internal desynchronization where the rhythms of deep body temperature, and the sleep-wake sleep cycle - i.e. one of the masking factors - run with different periods. Every sleep onset is accompanied by a rapid drop, and wake onset by a rapid rise in deep body temperature, each one with an overshoot of about 50% of the steady state variations. When rhythms are calculated, with the dominant temperature period as the screening period, exclusively from data obtained during sleep episodes, on the one hand, and from those obtained exclusively during wake, on the other, two average cycles emerge: the 'sleep temperature curve' and the 'wake temperature curve'. Both run in parallel but are separated by the 'masking effect'. As derived from many experiments, the mean masking effect amounts to 0.28 +/- 0.06 degree C. The masking effect also depends to some extent on the phase of the temperature rhythm; it is larger than average around the temperature maximum and during the descending phase of the temperature cycle, where the alertness commonly is highest and the probability to sleep, in general, and the REM sleep propensity, in particular, are smaller than average. This also can be interpreted to indicate that the sleep temperature curve is phase advanced relative to the wake temperature curve; this, on the average, by 0.9 +/- 0.3 h. If the individually determined amount of masking is added to the temperature data obtained during sleep, or subtracted from the temperature data obtained during wake, a temperature curve emerges that can be thought of as being 'purified' of the masking effect. Analyses of this artificial curve allow estimation of that part of the internal interactions uninfluenced by the masking effect. On the average, about half of the amount of interaction between the rhythm of sleep-wake and that of deep body temperature is explained by the masking effect, whereas the other half is 'oscillatory interaction'. Both types of interaction are inherent and inseparable parts of the circadian clock mechanism, as can be deduced from model considerations.
Body Temperature↗
Some effects of melatonin and the control of its secretion in humans.
Whether or not the pineal gland has a significant physiological role in humans is not known. There has nevertheless been speculation about the potential therapeutic use of melatonin (in view of its hypnotic and possible zeitgeber properties) in conditions such as insomnia and jet lag, and in shift-workers. Our work concerns the effects of melatonin administration in humans and the interactions between melatonin and other circadian variables. Chronic (one month), timed (1700 h), low-dose (2 mg daily) melatonin administration to normal subjects without environmental control consistently increased evening fatigue and slightly modified the 24 h prolactin rhythm without effect on cortisol, growth hormone, luteinizing hormone, thyroxine, testosterone or self-rated mood. In five out of 11 subjects the endogenous melatonin rhythm was advanced by one to three hours. During fractional desynchronization of circadian rhythms by increasing imposed 'day' length (26-29 h, 24 days, 500 lux), 5 mg melatonin per os at lights-out in two subjects resulted in better entrainment of the fatigue rhythm to the zeitgeber than in five out of six control subjects, without major consistent effects on other measured circadian variables. Using a new radioimmunoassay for 6-hydroxymelatonin sulphate (aMT6s), the major melatonin metabolite, we have shown that the urinary aMT6s rhythm is closely correlated to that of melatonin in plasma and is completely suppressed by an acute dose of atenolol (100 mg per os), a peripheral beta-adrenergic antagonist. During fractional desynchronization by increasing imposed 'day' length in one subject and decreasing imposed 'day' length in two subjects, the urinary aMT6s rhythm behaved similarly to that of core temperature. The results suggest that fatigue (or alertness) may be entrained by melatonin, but whether critical performance rhythms can be suitably manipulated remains to be clarified. It is likely that melatonin production is linked to the so-called 'strong' circadian oscillator.
Circadian Rhythm↗
Use of light to treat jet lag: differential effects of normal and bright artificial light on human circadian rhythms.
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Behavior↗
Sex differences in human circadian rhythms: intrinsic periods and sleep fractions.
The period of freerunning circadian rhythms is significantly shorter and the fraction of sleep is significantly larger in human females than in males, as long as the rhythms run internally synchronized. The sex difference in the period could be a property either of the whole circadian system or of only one of the oscillators in a multi-oscillator system. The sex difference in the sleep fraction could be a fixed property of the sleep-wake rhythm or could depend on interactions in the multi-oscillator system. To investigate these questions, a sample of 33 long-term experiments, in which the rhythms ran internally synchronized in one section and internally desynchronized in another section, were analyzed. The periods of rhythms in rectal temperature were different in females and males during internal synchronization, but became identical during internal desynchronization. In contrast, sex differences in sleep-wake periods were more pronounced when the rhythms were desynchronized than when they were internally synchronized. This result provides evidence that the sex difference in periodicity is a property only of the sleep-wake rhythm; the intrinsic periods of temperature rhythms are identical in females and males, whereas those of sleep-wake rhythms are distinctly shorter in females than in males. In the state of internal synchronization, the joint period is a compromise between the intrinsic periods of the rhythms involved, and therefore it shows a small but significant sex difference. Moreover, the transition from internally synchronized to desynchronized rhythms is combined with a highly significant reduction in the sleep fraction, which is considerably greater in females than in males. These results suggest that the occurrence of internal desynchronization strongly affects the sleep-wake rhythm, and that the influence of rhythm disorders is considerably greater in females than in males.
Body Temperature↗
Seasonality in freerunning circadian rhythms in man.
Retrospective analysis of data collected over 15 years in normal subjects isolated from time cures showed seasonal rhythms in the circadian period of the core temperature rhythm, in the amount of sleep (both shorter in spring and longer in autumn), and in the incidence of internal desynchronisation (most often in summer). Women slept longer than men at all times of year.
Body Temperature↗
Properties of human sleep-wake cycles: parameters of internally synchronized free-running rhythms.
Sleep-wake alternations are governed by circadian regularities. In order to evaluate these regularities without interference from social constraints or behavioral influences, we conducted experiments under constant conditions, excluding all external time references. The experiments were conducted for approximately 1 month to ensure that the rhythms were at a steady state. A homogeneous sample of 27 human subjects with free-running and internally synchronized rhythms was analyzed with regard to numerous sleep-wake parameters. There was no temporal trend during the entire period or in individual wake or sleep episodes. The onset of sleep was consistently and by far the most variable reference phase within the sleep-wake cycle. The results of negative serial correlations within the sleep-wake rhythm were relevant. Essentially, every distortion in the duration of a cycle is followed, with high probability, by a deviation in the duration of the following cycles in the opposite direction; i.e., any chance variation in the duration of a cycle is corrected with the next, and to a smaller amount with the next but one, cycle. Hence, an intrinsic stabilizing mechanism of the underlying pacemaker is in effect. Secondarily, there are negative serial correlations among adjacent wake and sleep episodes. Every deviation of an episode from the long-term mean results in an opposite deviation of the following episode. In other words, a wake episode determines the duration of the following sleep, and a sleep episode determines the duration of the following wake. All these negative serial correlations are highly significant interindividually. Another relevant result concerns the difference between females and males. The mean sleep-wake cycle is significantly shorter in females than in males, on the average by 28 min. Even more significant is the sex difference in the fraction of sleep. On the average, the wake episode is shorter by 1 h 49 min and the sleep episode is longer by 1 h 21 min in females than in males; i.e., the fraction of sleep is larger for 18% in females than males. There are indications that the established sex difference concerns, within the human multioscillator system, only that oscillator which is predominantly responsible for sleep-wake rhythm, but not the other oscillator, which is predominantly responsible, for instance, for deep body temperature. On the other hand, no parameter describing variabilities for the period or the separate episodes shows a sex difference, either in amount or in the temporal sequence of the variations as expressed in the serial correlations.
Adult↗
Bright light affects human circadian rhythms.
The relative effectiveness of external zeitgebers synchronizing circadian rhythms can be evaluated by measuring the size of the range of entrainment. The experimental approach to measure entrainment limits is the application of an artificial zeitgeber with slowly and steadily changing period. In human circadian rhythms, an absolute light-dark (LD) cycle with a light intensity during L of 1000 lux or less, results in an upper entrainment limit of 26.91 +/- 0.24 hours. The same limit is reached in constant illumination when only informations are given to the subjects. Consequently, the LD cycle is effective mainly with its behavioral component characterized by the request of the light-dark alternation to go to rest. In experiments with the same experimental protocol but higher intensity of illumination during L (approximately 4000 lux, i.e., exceeding the threshold beyond which melatonin excretion is suppressed in humans), human circadian rhythms can be synchronized within a much larger range; the upper entrainment limit is, with all overt rhythms measured, beyond 29 hours. This means that bright light has an effect on the human circadian system which is qualitatively different from that of dim light, and which is similar to the effect of light in most animal experiments. This finding has theoretical and practical implications.
Body Temperature↗
Fractional desynchronization of human circadian rhythms. A method for evaluating entrainment limits and functional interdependencies.
Under the influence of artificial zeitgebers, human circadian rhythms can be entrained only within limited ranges of periods; different overt rhythms may show different entrainment limits. When the period of a zeitgeber is varied slowly but continuously, entrainment limits can be evaluated precisely. An overt rhythm is synchronized to the zeitgeber only up to a certain day, or period respectively, until it breaks away from the zeitgeber and starts to freerun. The interindividual comparison among different subjects shows that the range of entrainment is positioned nearly symmetrically around the freerunning period. Its width depends strongly on the freerunning period; it increases with lengthening freerunning period. As the consequence, subjects with a freerunning period only slightly shorter than 23 h would fail to become synchronized to the natural 24-h day, whereas subjects with a freerunning period even slightly longer 28 h would become synchronized. In the intraindividual comparison, overt rhythms of different variables show different entrainment limits. For instance, rhythms in urinary excretion of different electrolytes can be dissociated for several days; the same is true with the rhythms of deep body temperature and performance. This temporal separation excludes the possibility of functional interdependencies between the variables under consideration. Consequently, results obtained with this method of fractional desynchronization do not only assist in evaluating properties of the circadian system, but also assist in the search for physiological interconnections between different variables.
Body Temperature↗
[The 25-hour man. Results of a study on circadian rhythms in man].
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Aging↗
Influence of physical workload on freerunning circadian rhythms of man.
While living under constant conditions and complete isolation from environmental time cues for about 4 weeks, 9 male subjects exercised on a bicycle ergometer seven times per 'day' during two weeks and refrained from physical activities during the other 2 weeks. The freerunning circadian rhythms of wakefulness and sleep and of rectal temperature showed, on the average, no difference between the two sections with regard to the autonomous period and the tendency towards internal desynchronization. Even in the one experiment in which the two rhythms became internally desynchronized, the periods of the rhythms remained unchanged during the time the subject worked on the bicycle. Only in one out of the nine subjects, the autonomous period was considerably longer under the influence of work than without it. The hypothesis is advanced that the period of an autonomous rhythm becomes normally independent of physical workload by way of a compensation mechanism.
Adult↗
Multi-oscillatory control of circadian rhythms in human performance.
Circadian rhythms are known to exist in many measures of human performance efficiency as well as in physiological processes. The demands of a task, and in particular its 'working memory' load, play a large part in determining the time of day at which it is best performed. Furthermore, task demands may affect the speed with which performance rhythms adjust to the altered sleep/wake schedules occasioned by shift-work and rapid time-zone transitions. These differences in rate of adjustment may be explained by a similar multi-oscillatory model to those proposed for physiological rhythms. These assume any given circadian rhythm to be jointly controlled by two endogenous oscillators. The first is thought to be relatively immune to exogenous factors and to control the temperature rhythm, while the second is thought to be more influenced by exogenous factors and to have the major role in governing the sleep/wake cycle. Normally, the pronounced 24-h time cues, or 'zeitgebers', in our environment result in both oscillators, and hence all circadian rhythms, running with a period of 24 h. However, under altered sleep/wake schedules, and in conditions of temporal isolation, the temperature rhythm and sleep/wake cycle may separate from one another and run with distinctly different periods. When such 'internal desynchronization' occurs, other physiological rhythms have been found to run in synchrony with one or other of these two functions. This finding forms the basis of current multi-oscillatory models. However, studies of abnormal sleep/wake schedules suggest that the rhythm in working memory performance may sometimes separate from both the sleep/wake cycle and temperature rhythm by running with a period of less than 24 h. We have investigated this possibility here and our results indicate control of working memory performance rhythms by a previously unidentified oscillator with an autonomous period of about 21 h.
Adult↗
Phase shifts of human circadian rhythms due to shifts of artificial Zeitgebers.
In special isolation units, circadian rhythms of human subjects have been investigated under the influence of artificial 24-h Zeitgebers, with 6-h advance and 6-h delay shifts of the Zeitgeber simulating time zone shifts. In most cases, the biological rhythms follow the Zeitgeber shifts in the course of several days: in rare cases, advancing Zeitgeber shifts are followed by delaying shifts of the biological rhythms, either of all variables or, partitioning, of only some of the variables. The rhythm of activity is re-entrained after both Zeitgeber shifts within a few days, independent of the shift direction. The rhythm of rectal temperature needs more time for re-entrainment than the activity rhythm; the rate of re-entrainment is consistently higher after advance than after delay shifts ('direction asymmetry'). Mean value and amplitude of the rectal temperature rhythm are, for some days, reduced after the advance but not after the delay Zeitgeber shift; among the different subjects, the reduction in amplitude is significantly correlated with the direction asymmetry. The rhythm of psychomotor performance (computation speed) re-entrains in parallel to that of rectal temperature; i.e. the performance level is decreased after advance but not after delay shifts. The direction asymmetry in the re-entrainment rates seems to contradict findings in flight experiments where this rate is mostly higher after westward than after eastward flights. Careful considerations, however, show that differences in the re-entrainment behavior after real and simulated time zone shifts disappear when the experimental designs are approximated and when identical procedures of analyzing the data are applied. The results of the time shift experiments are, in all respects tested, in agreement with theoretical postulations; hence, they confirm once more properties of the circadian system deduced earlier. On the other hand, the results are of practical importance since they state significant correlations between the re-entrainment behavior and rhythm parameters measured before the Zeitgeber shifts; this behavior, therefore, can be predicted from data obtained already before the Zeitgeber has been changed in any way: The duration of re-entrainment is correlated with the amplitude, and the decrement in performance with the phase of the rectal temperature rhythm. These practical implications may also apply to shift work.
Adaptation, Physiological↗