Entrainment of human circadian rhythms by artificial bright light cycles

Summary Artificial bright light cycles (LD 816) of about 5000 lux during the light period were applied to two subjects in a temporal isolation unit, who had shown free-running circadian rhythms in sleep-wakefulness and rectal temperature. The circadian rhythms were successfully entrained by the artificial light cycle, but the phase relation of the rhythms to the light cycle was substantially different between the two subjects. The result indicated that the artificial bright lights are able to reset human circadian rhythms.     

Phase-dependent shift of free-running human circadian rhythms in response to a single bright light pulse

Responsiveness of free-running human circadian rhythms to a single pulse of bright light was examined in a temporal isolation unit. Bright light (5000 lx) of either 3 or 6 h duration, applied during the early subjective day, produced phase-advance shifts in both the sleep-wake cycle and the rhythm of rectal temperature; the light pulse had essentially no effect on the phase of the circadian rhythms, when it was introduced during the late subjective day or the early subjective night. The results indicate that bright light can reset the human circadian pacemaker.     

Chronobiology of sleep in humans

Periodic circadian (24-h) cycles play an important role in daily hormonal and behavioural rhythms. Usually our sleep/wake cycle, temperature and melatonin rhythms are internally synchronized with a stable phase relationship. When there is a desynchrony between the sleep/wake cycle and circadian rhythm, sleep disorders such as advanced and delayed sleep phase syndrome can arise as well as transient chronobiologic disturbances, for example from jet lag and shift work. Appropriately timed bright light is effective in re-timing the circadian rhythm and sleep pattern to a more desired time, ameliorating these disturbances. Other less potent retiming effects may also be obtained from the judicious use of melatonin and exercise.     

Circabidian rhythm: its appearance and disappearance in association with a bright light pulse

A shift from circadian to circabidian periods or vice versa was observed in the rhythm of sleep and wakefulness under temporal isolation. The shift occurred in two subjects, 3 times in association with a single bright light pulse applied, 4 times in all. The finding suggests that the bright light pulse has an additional effect to the phase shift on the human circadian system.     

Single-cell recordings from chick pineal glands in vitro reveal ultradian and circadian oscillations

Evidence is clear that each melatonin-producing cell in the chick pineal gland contains a circadian oscillator that continues to function in vitro, resulting in a prominent day/night rhythm of melatonin secretion. The aim of the present investigation was to examine whether the circadian organization of the gland has an electrophysiological correlate. To this end, single-cell recordings were made from isolated chick pineal glands kept in vitro under a light/dark cycle of 12:12 h, identical to that of the donors, or under continuous light or darkness. In all the glands investigated, a very small percentage of cells exhibited sodium-dependent spontaneous spike activity with a mean frequency below 10 Hz. The cells revealed rhythms with periods in the 15- to 60-min range and, additionally, exhibited ultradian and circadian rhythms in firing, with periods of 10.75+/-1.06 h and 26.25+/-1.26 h (mean +/- standard deviation), respectively. Most of the cells exhibited circadian rhythms with higher activity during daytime than at night, showing that the electrical activity and melatonin rhythm were out of phase. Under constant light or darkness, the circadian rhythm persisted. When the light/dark cycle of the donors was phase-advanced by 5 h, the cells revealed complete entrainment. We discuss whether the cells, albeit small in number, could function as a secondary ultradian/circadian oscillator contributing to the ultradian/circadian organization of the gland.     

Effects of vitamin B12 on plasma melatonin rhythm in humans: Increased light sensitivity phase-advances the circadian clock?

Vitamin B12 (methylcobalamine) was administered orally (3 mg/day) to 9 healthy subjects for 4 weeks. Nocturnal melatonin levels after exposure to bright light (ca. 2500 lx) were determined, as well as the levels of plasma melatonin over 24 h. The timing of sleep was also recorded. Vitamin B12 was given blind to the subjects and crossed over with placebo. We found that the 24-h melatlonin rhythm was significantly phase-advanced (1.1. h) in the vitamin B12 trial as compared with that in the placebo trial. In addition, the 24-h mean of plasma melatonin level was much lower in the vitamin B12 traial than with the placebo. Furthermore, the nocturnal melatonin levels during bright light exposure were significantly lower in the vitamin B12 trial than with the placebo. On the other hand, vitamin B12 did not affect the timing of sleep. These findings raise the possibility that vitamin B12 phase-advances the human circadian rhythm by increasing the light sensitivity of the circadian clock.     

Effects of vitamin B12 on plasma melatonin rhythm in humans: increased light sensitivity phase-advances the circadian clock?

Vitamin B12 (methylcobalamin) was administered orally (3 mg/day) to 9 healthy subjects for 4 weeks. Nocturnal melatonin levels after exposure to bright light (ca. 2500 lx) were determined, as well as the levels of plasma melatonin over 24 h. The timing of sleep was also recorded. Vitamin B12 was given blind to the subjects and crossed over with placebo. We found that the 24-h melatonin rhythm was significantly phase-advanced (1.1 h) in the vitamin B12 trial as compared with that in the placebo trial. In addition, the 24-h mean of plasma melatonin level was much lower in the vitamin B12 trial than with the placebo. Furthermore, the nocturnal melatonin levels during bright light exposure were significantly lower in the vitamin B12 trial than with the placebo. On the other hand, vitamin B12 did not affect the timing of sleep. These findings raise the possibility that vitamin B12 phase-advances the human circadian rhythm by increasing the light sensitivity of the circadian clock.     

Persistent 24-h variations of urinary 6-hydroxy melatonin sulphate and cortisol in Antarctica

Bright light (2000-3000 lux) of sufficient intensity to suppress human melatonin secretion, acts as a strong zeitgeber in the entrainment of circadian rhythms in man. In polar conditions, light of this intensity is not experienced for several weeks during the winter. The entrainment of human circadian rhythms, in particular that of melatonin, is clearly of interest in these circumstances. Urinary 6-hydroxy melatonin sulphate (aMT6s) is a good index of melatonin secretion in man. In a limited study of seven male volunteers living on an Antarctic base the overall 24-h rhythm of aMT6s excretion was maintained at four different times of year (spring, summer, autumn and winter) and no significant seasonal effects were noted. Cortisol excretion, appeared to be markedly affected by the season although other factors such as social and environmental stress cannot be discounted. These observations suggest that in the absence of a strong light-dark cycle melatonin production may be entrained by other factors.     

Persistent 24-h variations of urinary 6-hydroxy melatonin sulphate and cortisol in Antarctica

Summary Bright light (2000–3000 lux) of sufficient intensity to suppress human melatonin secretion, acts as a strong zeitgeber in the entrainment of circadian rhythms in man. In polar conditions, light of this intensity is not experienced for several weeks during the winter. The entrainment of human circadian rhythms, in particular that of melatonin, is clearly of interest in these circumstances. Urinary 6-hydroxy melatonin sulphate (aMT6s) is a good index of melatonin secretion in man. In a limited study of seven male volunteers living on an Antarctic base the overall 24-h rhythm of aMT6s excretion was maintained at four different times of year (spring, summer, autumn and winter) and no significant seasonal effects were noted. Cortisol excretion, appeared to be markedly affected by the season although other factors such as social and environmental stress cannot be discounted. These observations suggest that in the absence of a strong light-dark cycle melatonin production may be entrained by other factors.     

Aging alters resynchronization of the circadian system in rats after a shift of the light-dark cycle

Four days following an 8-h advance of the light-dark cycle, the circadian rhythms in the pineal N-acetyltransferase activity and melatonin content reappeared in 7-week-old rats, but were still abolished in 24-month-old animals.     

Aging alters resynchronization of the circadian system in rats after a shift of the light-dark cycle

Summary Four days following an 8-h advance of the light-dark cycle, the circadian rhythms in the pineal N-acetyltransferase activity and melatonin content reappeared in 7-week-old rats, but were still abolished in 24-month-old animals.     

Functional absence of brain photoreceptors mediating entrainment of circadian rhythms in the adult rat

Summary The photic energy penetrating into the brain was increased in adult rats sustaining craniotomies sealed with transparent plastic. After blinding, these animals failed to entrain their circadian food intake rhythm to light-dark cycles. Short pulses of light did not phase-shift the freerunning rhythm. We conclude that adult rats lack brain photoreceptors mediating entrainment of circadian rhythms.     

Behavioural entrainment of circadian rhythms

Summary This paper reviews the discovery and characterization of a behavioural system for entrainment of circadian rhythms. This behavioural system depends on non-photic inputs but interacts with the light-entrainment system. Non-photic stimuli can be powerful quantitatively: behavioural events can shift rhythms by several hours. Nonphotic entrainment offers scope for rephasing biological rhythms in circumstances where light input from the environment is inadequate.     

Behavioural entrainment of circadian rhythms

This paper reviews the discovery and characterization of a behavioural system for entrainment of circadian rhythms. This behavioural system depends on non-photic inputs but interacts with the light-entrainment system. Non-photic stimuli can be powerful quantitatively: behavioural events can shift rhythms by several hours. Non-photic entrainment offers scope for rephasing biological rhythms in circumstances where light input from the environment is inadequate.     

Antidepressant drugs can slow or dissociate circadian rhythms

Summary The circadian rest-activity cycle of female hamsters was lengthened by chronic administration of the monoamineoxidase inhibitor antidepressant drug clorgyline. Chronic treatment with clorgyline or the tricyclic antidepressant drug imipramine also induced dissociation of circadian activity rhythm components. Thus these drugs may be added to the very small group of substances (including the prophylactic antidepressant and antimanic drug lithium) that modify circadian frequency and/or coupling between circadian rhythms.A preliminary analysis of these results was presented at the 18th Annual Meeting of the American College of Neuropsychopharmacology, Puerto Rico 1979²⁸.Neuropharmacology Branch, National Institute of Mental Health.     

Structures and molecules involved in generation and regulation of biological rhythms in vertebrates and invertebrates

Melatonin from the retina and the pineal gland functions in neuroendocrine hierarchies. Photoreceptors — eyes and extraretinal — detect light. Oscillators — pineal and suprachiasmatic nuclei — act as pacemakers. Driven neuroendocrine rhythms carry temporal hormone signals throughout the body. Light controls melatonin: light sets the phase of the melatonin rhythm and determines the duration of melatonin synthesis. By these means, circadian rhythms (e.g. in locomotor activity and body temperature) and seasonal rhythms (e.g. in reproduction) are controlled.     

Effects of the light-dark cycle and scheduled feeding on behavioral and reproductive rhythms of the cyprinodont fish, Medaka, Oryzias latipes

Medaka were maintained on a 16:8 light-dark cycle and fed once daily on one of 5 different feeding schedules. The daily rhythm of agonistic behavior rapidly entrained to the scheduled feeding time and maintained this entrainment during a 3-day starvation period. In contrast the daily rhythms of egg laying and courtship stayed entrained to the L:D cycle regardless of the feeding schedule. Thus, temporal integration of this fish with its daily environment can involve multistimuli which concurrently and differentially entrain externally expressed circadian systems.     

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.     

Altered circadian rhythm of catecholamines in patients with apallic syndrome

Summary Circadian rhythms of catecholamines were investigated in 4 healthy subjects and in 6 patients suffering from an apallic syndrome. The clinical picture of this syndrome is characterized by disturbed consciousness (coma vigile), by suspension of the sleeping and waking rhythm, by lack of emotional reactions and by appearance of primitive motor patterns. 5 of the 6 apallic patients showed an abolished rhythmicity compared with the control group. These results were interpreted as an indication that endogenous, centrally controlled processes are the cause of circadian rhythms.Acknowledgments. This study was supported by the Robert-Bosch-Stiftung, Stuttgart. The authors wish to thank P. Schaff of Max Planck-Institute for Psychiatry, Munich, for statistical analysis.     

Interdependence between locomotor activity and duration of wakefulness in humans during isolation

Locomotor activity was recorded in 14 subjects who lived singly in an isolation unit for 16 to 88 days. Their free-running circadian rhythms had a mean period of 25.9 h, with individual means in the duration of wakefulness (alpha) ranging from 12.1 to 22.9 h. Intraindividually, the hourly means of activity were negatively correlated with alpha to such a degree that the total amount of activity per 'day' remained constant irrespective of large variations in alpha.