The response of the human circadian pacemaker to light was measured in 45 resetting trials. Each trial consisted of an initial endogenous circadian phase assessment, a three-cycle stimulus which included 5 hours of bright light per cycle, and a final phase assessment. The stimulus induced strong (type 0) resetting, with responses highly dependent on the initial circadian phase of light exposure. The magnitude and direction of the phase shifts were modulated by the timing of exposure to ordinary room light, previously thought to be undetectable by the human pacemaker. The data indicate that the sensitivity of the human circadian pacemaker to light is far greater than previously recognized and have important implications for the therapeutic use of light in the management of disorders of circadian regulation.

https://science.sciencemag.org/content/sci/244/4910/1328.full.pdf

Bright light induction of strong (type 0) resetting of the human circadian pacemaker.

The circadian pacemaker is differentially sensitive to the resetting effects of retinal light exposure, depending upon the circadian phase at which the light exposure occurs. Previously reported human phase response curves (PRCs) to single bright light exposures have employed small sample sizes, and were often based on relatively imprecise estimates of circadian phase and phase resetting. In the present study, 21 healthy, entrained subjects underwent pre- and post-stimulus constant routines (CRs) in dim light (approximately 2-7 lx) with maintained wakefulness in a semi-recumbent posture. The 6.7 h bright light exposure stimulus consisted of alternating 6 min fixed gaze (approximately 10 000 lx) and free gaze (approximately 5000-9000 lx) exposures. Light exposures were scheduled across the circadian cycle in different subjects so as to derive a PRC. Plasma melatonin was used to determine the phase of the onset, offset, and midpoint of the melatonin profiles during the CRs. Phase shifts were calculated as the difference in phase between the pre- and post-stimulus CRs. The resultant PRC of the midpoint of the melatonin rhythm revealed a characteristic type 1 PRC with a significant peak-to-trough amplitude of 5.02 h. Phase delays occurred when the light stimulus was centred prior to the critical phase at the core body temperature minimum, phase advances occurred when the light stimulus was centred after the critical phase, and no phase shift occurred at the critical phase. During the subjective day, no prolonged 'dead zone' of photic insensitivity was apparent. Phase shifts derived using the melatonin onsets showed larger magnitudes than those derived from the melatonin offsets. These data provide a comprehensive characterization of the human PRC under highly controlled laboratory conditions.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2003.040477

A Phase Response Curve to Single Bright Light Pulses in Human Subjects

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.

Melatonin: Nature's most versatile biological signal?

The basic physiology and pathophysiology of melatonin

Human circadian rhythms were once thought to be insensitive to light, with synchronization to the 24-hour day accomplished either through social contacts or the sleep-wake schedule. Yet the demonstration of an intensity-dependent neuroendocrine response to bright light has led to renewed consideration of light as a possible synchronizer of the human circadian pacemaker. In a laboratory study, the output of the circadian pacemaker of an elderly woman was monitored before and after exposure to 4 hours of bright light for seven consecutive evenings, and before and after a control study in ordinary room light while her sleep-wake schedule and social contacts remained unchanged. The exposure to bright light in the evening induced a 6-hour delay shift of her circadian pacemaker, as indicated by recordings of body temperature and cortisol secretion. The unexpected magnitude, rapidity, and stability of the shift challenge existing concepts regarding circadian phase-resetting capacity in man and suggest that exposure to bright light can indeed reset the human circadian pacemaker, which controls daily variations in physiologic, behavioral, and cognitive function.

https://science.sciencemag.org/content/sci/233/4764/667.full.pdf

Bright light resets the human circadian pacemaker independent of the timing of the sleep-wake cycle.

The relative effectiveness of external zeitgebers synchronizing circadian rhythms can be evaluated by mesuring 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 100 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 (∼400 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.

Bright light affects human circadian rhythms.

Circadian rhythms are known to exist in many measures of human performance efficiency as well as in physiological processes1. The demands of a task, and in particular its ‘working memory’2 load, play a large part in determining the time of day at which it is best performed3. 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 transitions4. These differences in rate of adjustment may be explained by a similar multi-oscillatory model to those proposed for physiological rhythms5–10. 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 h11. 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.

Multi-oscillatory control of circadian rhythms in human performance

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.

Some effects of melatonin and the control of its secretion in humans.

a very high value of biosynthesis was found which corresponded approximately to the biosynthetic production of AA, ascertained by the same laboratory method in healthy young rats. Both the high content of vitamin C in body tissues and its formation in vitro prove the presence and a physiologically adequate activity of L-gulonolactone oxidase in the liver microsomes of the animal. At the present stage, obtaining statistically substantiated proofs of the virtual cause of dependency upon the natural sources of vitamin C in the vast majority of the population has proved difficult owing to the very low incidence of registered individuals among the guinea pigs that synthesize AA. Another open question is whether it would be possible to select a strain of guinea pigs synthesizing vitamin C; the contradictory results obtained in the case of the gravid guinea pig No. 9 and its three fetuses suggest the difficulty of this problem. A striking coincidence of gravidity and biosynthesis in our guinea pig does not have any argumentative value, since another two gravid females of the same group did not synthesize vitamin C. The finding of a relatively large body pool of vitamin C in another animal (No. 5) is remarkable; however, the enzymatic test for biosynthesis was negative. This implies a different individual rate of catabolism and desaturation of vitamin C from the animal's body pool which may also be the cause of a prolonged survival time when kept on the ascorbic acid-free regimen.

Christina M. Wildgruber

Papers

Bright light affects human circadian rhythms.

Multi-oscillatory control of circadian rhythms in human performance

Some effects of melatonin and the control of its secretion in humans.

Circadian control of meal timing during temporal isolation.