Human Circadian Pacemaker Research Articles

Quantifying Human Circadian Pacemaker Response to Brief, Extended, and Repeated Light Stimuli over the Phototopic Range

The authors' previous models have been able to describe accurately the effects of extended (5 h) bright-light (>4000 lux) stimuli on the phase and amplitude of the human circadian pacemaker, but they are not sufficient to represent the surprising human sensitivity to both brief pulses of bright light and light of more moderate intensities. Therefore, the authors have devised a new model in which a dynamic stimulus processor ( Process L) intervenes between the light stimuli and the traditional representation of the circadian pacemaker as a self-sustaining limit-cycle oscillator ( Process P). The overall model incorporating Process L and Process P is intended to allow the prediction of phase shifts to photic stimuli of any temporal pattern (extended and brief light episodes) and any light intensity in the photopic range. Two time constants emerge in the Process Lmodel: the characteristic duration for necessary bright-light pulses to achieve their full effect (5-10 min) and the characteristic stimulus-free (dark) interval that can be tolerated without incurring an excessive penalty in phase shifting (30-80 min). The effect of reducing light intensity is incorporated in Process L as an extension of the time necessary for the light pulse to be fully realized (a power-law relation between time and intensity). This new model generates a number of new testable hypotheses, including the surprising prediction that 24-h cycles consisting of8hof darkness and 16 h of only 3.5 lux would be capable of entraining a large fraction of the adult population (45%). Experimental data on the response of the human circadian system to lower light intensities and briefer stimuli are needed to allow for further refinement and validation of the model proposed here.

Revised Limit Cycle Oscillator Model of Human Circadian Pacemaker

Revised Limit Cycle Oscillator Model of Human Circadian Pacemaker

Melatonin rhythm observed throughout a three-cycle bright-light stimulus designed to reset the human circadian pacemaker.

Exposure to light and darkness can rapidly induce phase shifts of the human circadian pacemaker. A type 0 phase response curve (PRC) to light that has been reported for humans was based on circadian phase data collected from constant routines performed before and after a three-cycle light stimulus, but resetting data observed throughout the entire resetting protocol have not been previously reported. Pineal melatonin secretion is governed by the hypothalamic circadian pacemaker via a well-defined neural pathway and is reportedly less subject to the masking effects of sleep and activity than body temperature. The authors reasoned that observation of the melatonin rhythm throughout the three-cycle light resetting trials could provide daily phase-resetting information, allowing a dynamic view of the resetting response of the circadian pacemaker to light. Subjects (n = 12) living in otherwise dim light (approximately 10-15 lux) were exposed to a noncritical stimulus of three cycles of bright light (approximately 9500 lux for 5 h per day) timed to phase advance or phase delay the human circadian pacemaker; control subjects (n = 11) were scheduled to the same protocols but exposed to three 5-h darkness cycles instead of light. Subjects underwent initial and final constant routine phase assessments; hourly melatonin samples and body temperature data were collected throughout the protocol. Average daily phase shifts of 1 to 3 h were observed in 11 of 12 subjects receiving the bright light, supporting predictions obtained using Kronauer's phase-amplitude model of the resetting response of the human circadian pacemaker. The melatonin rhythm in the 12th subject progressively attenuated in amplitude throughout the resetting trial, becoming undetectable for >32 hours preceding an abrupt reappearance of the rhythm at a shifted phase with a recovered amplitude. The data from control subjects who remained in dim lighting and darkness delayed on average -0.2 h per day, consistent with the daily delay expected due to the longer than 24-h intrinsic period of the human circadian pacemaker. Both temperature and melatonin rhythms shifted by equivalent amounts in both bright light-treated and control subjects (R = 0.968; p<0.0001; n = 23). Observation of the melatonin rhythm throughout a three-cycle resetting trial has provided a dynamic view of the daily phase-resetting response of the human circadian pacemaker. Taken together with the observation of strong type 0 resetting in humans in response to the same three-cycle stimulus applied at a critical phase, these data confirm the importance of considering both phase and amplitude when describing the resetting of the human circadian pacemaker by light.

Corrections for vol. 274, p. 991

CORRIGENDACorrections for vol. 274, p. 991Published Online:01 Aug 1998https://doi.org/10.1152/ajpregu.1998.275.2.Ra1Original articleMoreSectionsPDF (15 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat Volume 274, April 1998 Volume 43, April 1998 Pages R991–R996: Elizabeth B. Klerman, David W. Rimmer, Derk-Jan Dijk, Richard E. Kronauer, Joseph F. Rizzo III, and Charles A. Czeisler. “Nonphotic entrainment of the human circadian pacemaker.” On page R995, the fifth sentence of thenote added in proof should read: His circadian rhythms of CBT and melatonin did not appear to be affected by the nonphotic protocol; they continued to oscillate with a 24.1-h period, notwithstanding an enforced 23.8-h sleep-wake schedule. This article has no references to display. Download PDF Previous Back to Top FiguresReferencesRelatedInformationRelated articlesNonphotic entrainment of the human circadian pacemaker 01 Apr 1998American Journal of Physiology-Regulatory, Integrative and Comparative Physiology More from this issue > Volume 275Issue 2August 1998Pages Ra1-Ra1 Copyright & PermissionsCopyright © 1998 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.1998.275.2.Ra1History Published online 1 August 1998 Published in print 1 August 1998 Metrics Downloaded 96 times

Refinement of Limit Cycle Oscillator Model of the Effects of Light on the Human Circadian Pacemaker

In 1990, Kronauer proposed a mathematical model of the effects of light on the human circadian pacemaker. Although this model predicted many general features of the response of the human circadian pacemaker to light exposure, additional data now available enable us to refine the original model. We first refined the original model by incorporating the results of a dose response curve to light into the model's predicted relationship between light intensity and the strength of the drive onto the pacemaker. Data from three bright light phase resetting experiments were then used to refine the amplitude recovery characteristics of the model. Finally, the model was tested and further refined using data from an extensive phase resetting experiment in which a 3-cycle bright light stimulus was presented against a background of dim light. In order to describe the results of the four resetting experiments, the following major refinements to the original model were necessary: (i) the relationship between light intensity (I) and drive onto the pacemaker was reduced fromI1.3toI0.23for light levels between 150 and 10000 lux; (ii) the van der Pol oscillator from the original model was replaced with a higher-order limit cycle oscillator so that amplitude recovery is slower near the singularity and faster near the limit cycle; (iii) a direct effect of light on circadian period (τx) was incorporated into the model such that asIincreases, τxdecreases, which is in accordance with “Aschoff's rule”.This refined model generates the following testable predictions: it should be difficult to enhance normal circadian amplitude via bright light; near the critical point of a type 0 phase response curve (PRC) the slope should be steeper than it is in a type 1 PRC; and circadian period measured during forced desynchrony should be directly affected by ambient light intensity.

Nonphotic entrainment of the human circadian pacemaker.

In organisms as diverse as single-celled algae and humans, light is the primary stimulus mediating entrainment of the circadian biological clock. Reports that some totally blind individuals appear entrained to the 24-h day have suggested that nonphotic stimuli may also be effective circadian synchronizers in humans, although the nonphotic stimuli are probably comparatively weak synchronizers, because the circadian rhythms of many totally blind individuals "free run" even when they maintain a 24-h activity-rest schedule. To investigate entrainment by nonphotic synchronizers, we studied the endogenous circadian melatonin and core body temperature rhythms of 15 totally blind subjects who lacked conscious light perception and exhibited no suppression of plasma melatonin in response to ocular bright-light exposure. Nine of these fifteen blind individuals were able to maintain synchronization to the 24-h day, albeit often at an atypical phase angle of entrainment. Nonphotic stimuli also synchronized the endogenous circadian rhythms of a totally blind individual to a non-24-h schedule while living in constant near darkness. We conclude that nonphotic stimuli can entrain the human circadian pacemaker in some individuals lacking ocular circadian photoreception.

Resetting the melatonin rhythm with light in humans.

The endogenous circadian rhythm of melatonin in humans provides information regarding the resetting response of the human circadian timing system to changes in the light-dark (LD) cycle. Alterations in the LD cycle have both acute and chronic effects on the observed melatonin rhythm. Investigations to date have firmly established that the melatonin rhythm can be reentrained following an inversion of the LD cycle. Exposure to bright light and darkness given over a series of days can rapidly induce large-magnitude phase shifts of the melatonin rhythm. Even single pulses of bright light can shift the timing of the melatonin rhythm. Recent data have demonstrated that lower light intensities than originally believed are capable of resetting the melatonin rhythm and that stimulation of photopically sensitive photoreceptors (i.e., cones) is sufficient to reset the endogenous circadian melatonin rhythm. In addition to phase resetting, exposure to light of critical timing, strength, and duration can attenuate the amplitude of the endogenous circadian rhythm of melatonin. Measurement of melatonin throughout resetting trials provides a dynamic view of the resetting response of the human circadian pacemaker to light. Future studies of the melatonin rhythm in humans may further characterize the resetting response of the human circadian timing system to light.

Photopic transduction implicated in human circadian entrainment

Despite the preeminence of light as the synchronizer of the circadian timing system, the phototransductive machinery in mammals which transmits photic information from the retina to the hypothalamic circadian pacemaker remains largely undefined. To determine the class of photopigments which this phototransductive system uses, we exposed a group ( n=7) of human subjects to red light below the sensitivity threshold of a scotopic (i.e. rhodopsin/rod-based) system, yet of sufficient strength to activate a photopic (i.e. cone-based) system. Exposure to this light stimulus was sufficient to reset significantly the human circadian pacemaker, indicating that the cone pigments which mediate color vision can also mediate circadian vision.

Light and plasma melatonin rhythm in humans.

Plasma melatonin rhythm in humans was investigated: its stability, relationship to the sleep-wake rhythm, and response to light. The so-called day-to-day variation of reference phases of plasma melatonin rhythm was within 1.4 h when blood was sampled at 1-hour intervals. Therefore, a change in phase beyond this value is regarded as a phase shift of melatonin rhythm in individuals. Plasma melatonin rhythm was spontaneously desynchronized from the sleep-wake rhythm and probably regulated by the common circadian pacemaker which drives the rhythm in rectal temperature. When a bright-light pulse was applied, the melatonin rhythm produced a phase shift, but the amount of phase shift seems to be different for the ascending and descending phases of nocturnal melatonin rise. Finally, a partial entrainment was observed in a subject who developed a non-24-hour sleep-wake syndrome later, in which the plasma melatonin rhythm was free-running whereas the sleep-wake rhythm was apparently entrained by a 24-hour day-night alternation. It is concluded that the plasma melatonin rhythm is the best marker of the human circadian pacemaker so far available.

Phase-shifting human circadian rhythms: influence of sleep timing, social contact and light exposure.

1. Both the timing of behavioural events (activity, sleep and social interactions) and the environmental light-dark cycle have been reported to contribute to entrainment of human circadian rhythms to the 24 h day. Yet, the relative contribution of those putative behavioural synchronizers to that of light exposure remains unclear. 2. To investigate this, we inverted the schedule of rest, sedentary activity and social contact of thirty-two young men either with or without exposure to bright light. 3. On this inverted schedule, the endogenous component of the core temperature rhythm of subjects who were exposed to bright light showed a significant phase shift, demonstrating that they were adapting to the new schedule. In contrast, the core temperature rhythm of subjects who were not exposed to bright light moved on average 0.2 h later per day and after 10 days had not significantly adapted to the new schedule. 4. The direction of phase shift in the groups exposed to bright light was dependent on the time of bright light exposure, while control subjects drifted to a later hour regardless of the timing of their schedule of sleep timing, social contact and meals. 5. These results support the concept that the light-dark cycle is the most important synchronizer of the human circadian system. They suggest that inversion of the sleep-wake, rest-activity and social contact cycles provides relatively minimal drive for resetting the human circadian pacemaker. 6. These data indicate that interventions designed to phase shift human circadian rhythms for adjustment to time zone changes or altered work schedules should focus on properly timed light exposure.

Simulations of light effects on the human circadian pacemaker: implications for assessment of intrinsic period.

The sensitivity of the human circadian system to light has been the subject of considerable debate. Using computer simulations of a recent quantitative model for the effects of light on the human circadian system, we investigated these effects of light during different experimental protocols. The results of the simulations indicate that the nonuniform distribution over the circadian cycle of exposure to ordinary room light seen in classical free-run studies, in which subjects select their exposure to light and darkness, can result in an observed period of approximately 25 h, even when the intrinsic period of the subject's endogenous circadian pacemaker is much closer to 24 h. Other simulation results suggest that accurate assessment of the true intrinsic period of the human circadian pacemaker requires low ambient light intensities (approximately 10-15 lx) during scheduled wake episodes, desynchrony of the imposed light-dark cycle from the endogenous circadian oscillator, and a study length of at least 20 days. Although these simulations await further experimental substantiation, they highlight the sensitivity to light of the human circadian system and the potential confounding influence of light on the assessment of the intrinsic period of the circadian pacemaker.

Chapter 14 The role of melatonin and light in the human circadian system

This chapter focuses on the role of melatonin and light in the human circadian system. Unique to melatonin is that its production can be acutely suppressed by exposure to light during the night. Consequently, it was concluded that humans, unlike other primates, lacked the neural pathways that mediated light input to the human circadian pacemaker. These pathways have been well defined in animals and are delineated in the chapter. Humans may have seasonal rhythms that respond to the change in natural day length—indoor light in the winter evenings does not lengthen the photoperiod. Similarly, turning on room lights briefly in the middle of the night should not have much effect on the circadian rhythms. The second implication was that one could substitute bright artificial light for sunlight to experimentally, or perhaps therapeutically, manipulate biological rhythms in humans. Studies showed that melatonin could potentially shift some circadian rhythms, particularly the rhythm of sleepiness.

Influence of Exercise on Human Sleep

Several research paradigms have been used to examine the influence of exercise on sleep. Epidemiological studies show that exercise is perceived as helpful in promoting sleep and suggest that regular physical activity may be useful in improving sleep quality and reducing daytime sleepiness. Additional epidemiological inquiry is clearly warranted based on the available evidence. Acute exercise experiments that have measured sleep physiology directly from subjects who either performed, or refrained from, daytime exercise indicate that exercise is associated with a small, but reliable increase in Stage 2 and slow wave sleep. The mechanism(s) that underlie exercise-associated increases in SWS is unknown. However, there is evidence that links elevations in daytime core body temperature to increases in SWS. Acute exercise experiments were found to be associated with a reduction in REM sleep and a delay in REM onset latency that were larger in magnitude than the effects observed for Stage 2 and SWS. These REM sleep observations highlight the need for continued study of the consequences of exercise on both circadian and homeostatic aspects of sleep. The delay in REM onset latency observed in the naturalistic acute exercise studies was consistent with the results of experiments in which environmental factors were more rigorously controlled and showed that physical exercise, or a concomitant, can induce a phase delay in markers of the human circadian pacemaker. It is worth pointing out that the most sophisticated and rigorous experiments from a standpoint of understanding sleep, such as those involving constant routines, bed rest, and temporal isolation, have for the most part used exercise in a crude manner. Because exercise is a stressor with diverse psychophysiological consequences that depends in part upon the interaction of multiple factors (e.g., the setting; degree of environmental heat stress; the activity history and fitness of the subject; the duration, intensity, and timing of the exercise bout; body position, etc.), understanding the influence of exercise on sleep will be stymied until carefully designed sleep studies also use exercise in an equally sophisticated and systematic way. Exercise is widely believed to have large effects on sleep. However, the scientific evidence does not strongly support this common belief. This incongruity may well be explained in part by considering the paradigms that have been used to study exercise and sleep.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase-amplitude resetting of the human circadian pacemaker via bright light: a further analysis.

We present here an analysis of strong, weak, and critical bright-light resetting trials in humans, and report not only phase but also amplitude data for the first time. For this analysis, an appropriate iterative smoothing procedure for phase transition curves is introduced, in which the data are sequenced so as to minimize the perpendicular distance from the data to the smoothed fit. From these smoothed data, we create polar phase-amplitude resetting maps (PARMs) in order to fully illustrate the effects of the resetting stimuli on both circadian amplitude and phase, and thereby to determine whether these resetting results can be described by a phase-only model or whether a phase-amplitude model is required. Our results indicate that a single 5-hr episode of bright light induces weak type 1 resetting of the human circadian pacemaker. Two cycles of exposure to the same stimulus on consecutive days induce critical resetting, in which significant amplitude reduction may be observed. A three-cycle stimulus induces strong type 0 resetting with different effects on circadian amplitude, depending on the initial phase of the stimulus application. When a three-cycle stimulus is centered near the nadir of the temperature cycle, large phase shifts are achieved via amplitude suppression. However, when this stimulus is centered away from the temperature nadir, smaller phase shifts are achieved in which both small increases and small decreases in circadian amplitude are observed. These data indicate that the human circadian pacemaker is not a simple, phase-only oscillator. Instead, a full description of human circadian resetting responses to light requires analysis of both phase and amplitude data--a finding that is consistent with a phase-amplitude model of the circadian resetting mechanism.

Persistence of the circadian thyrotropin rhythm under constant conditions and after light-induced shifts of circadian phase.

TSH levels in human, which normally peak in the late evening, are augmented by sleep deprivation. Based on prior research, we postulated that TSH secretion is governed by both sleep and circadian processes. However, environmental and behavioral factors known to affect each of those processes were not controlled in prior investigations. Therefore, we evaluated TSH secretory patterns in three different conditions: 1) entrainment to the 24-h day, 2) a constant routine designed to unmask the endogenous component of circadian rhythmicity, and 3) before and after a light-induced phase shift of the circadian timing system. We found that TSH levels rose over the 4-5 h preceding sleep during entrainment, followed by a precipitous drop at sleep onset. When subjects remained awake on a constant routine, TSH levels remained elevated throughout the nighttime hours. Subjects kept awake for 2 consecutive nights on constant routine showed two distinct cycles of nocturnal TSH secretion, despite increasing sleep deprivation. Both the TSH and body temperature rhythms were substantially shifted, by an equivalent amount, in response to three consecutive nightly exposures to bright light. These data demonstrate that both the output of the human circadian pacemaker and the inhibitory effect of sleep contribute to the regulation of TSH secretion. Under normal conditions, the inhibitory effect of sleep on TSH secretion opposes the nocturnal peak in the circadian TSH drive.

Nocturnal exercise phase delays circadian rhythms of melatonin and thyrotropin secretion in normal men.

To determine whether a single episode of physical activity is capable of inducing rapid phase shifts in human circadian rhythms, 17 subjects were studied two times under constant routine conditions, once in the absence of stimulus and once with a 3-h nighttime pulse of exercise interrupting the constant routine conditions. The profiles of plasma cortisol, thyrotropin (TSH), and melatonin and of body temperature were monitored continuously to derive estimations of circadian phase position. The phase shifts were measured on the 1st day after exercise exposure. The timing of the exercise period ranged from -5 h to +4 h around the time of the minimum body temperature rhythm. Nighttime exercise was associated with 1- to 2-h phase delays of both the melatonin and TSH rhythms, with the size of the delays tending to be smaller when the exercise was presented in the latter part of the nighttime period and in the early morning. These data demonstrate that nonphotic stimuli may exert phase-shifting effects on the human circadian pacemaker.

Phase resetting of the human circadian pacemaker with use of a single pulse of bright light.

Since the initial studies reporting that light can alter the phase position of the human circadian system, there has been increasing interest in the use of bright light as a tool for manipulating the phase position of the circadian pacemaker. Exposure protocols typically require subjects to receive 2-5 h of exposure over several circadian cycles. As a consequence, bright light treatment can involve a considerable time investment. However, recent studies indicate that a single pulse of bright light can produce significant phase shifts in the circadian pacemaker. If a single pulse of bright light can produce significant phase-shifting effects, multiple-pulse designs may be unnecessary. This study examined the phase-shifting effects of a single 4-h pulse of bright light (12,000 lux) in 14 male and one female subject aged between 19-45 years. With use of a "constant routine" to estimate circadian phase, a single 4-h pulse of light produced significant shifts in the phase of the core temperature rhythm. The timing of the exposure, relative to the core temperature rhythm, determined the degree and direction of the phase shift. Exposure immediately prior to habitual bedtime produced a mean phase delay in the core temperature of 2.39 h (SD = 1.37 h). In contrast, exposure immediately following habitual wake-up produced a mean phase advance of 1.49 h (SD = 2.06 h). In addition, the magnitude of the shift increased the closer the light pulse was to the individual's estimated endogenous core temperature minimum. There was, however, considerable interindividual variability in this relationship.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of sleep-wake habits in older people with changes in output of circadian pacemaker

Many elderly people complain of disturbed sleep patterns but there is no evidence that the need to sleep decreases with age; it seems rather that the timing and consolidation of sleep change. We tried to find out whether there is a concurrent change in the output of the circadian pacemaker with age. The phase and amplitude of the pacemaker's output were assessed by continuous measurement of the core body temperature during 40 h of sustained wakefulness under constant behavioural and environmental conditions. 27 young men (18-31 years) were compared with 21 older people (65-85 years; 11 men, 10 women); all were healthy and without sleep complaints. The mean amplitude of the endogenous circadian temperature oscillation (ECA) was 40% greater in young men than in the older group. Older men had a lower mean temperature ECA than older women. The minimum of the endogenous phase of the circadian temperature oscillation (ECP) occurred 1 h 52 min earlier in the older than in the young group. Customary bedtimes and waketimes were also earlier in the older group, as was their daily alertness peak. There was a close correlation between habitual waketime and temperature ECP in young men, which may lose precision with age, especially among women. These findings provide evidence for systematic age-related changes in the output of the human circadian pacemaker. We suggest that these changes may underlie the common complaints of sleep disturbance among elderly people. These changes could reflect the observed age-related deterioration of the hypothalmic nuclei that drive mammalian circadian rhythms.

Short‐term memory, alertness and performance: a reappraisal of their relationship to body temperature

Previous studies have led to the beliefs: (1) that short-term memory is best during the night when the body temperature is at its nadir, and (2) that the circadian rhythms of short-term memory and subjective alertness are driven by oscillators independent from each other and from the body temperature cycle. Unfortunately, these conclusions, which would have major implications for understanding the organization of the human circadian timing system, are largely based on field and laboratory studies, which in many cases sampled data infrequently and/or limited data collection to normal waking hours. In order to investigate these points further, we have monitored behavioural variables in two different protocols under controlled laboratory conditions: (1) during a period of 36-60 h of sustained wakefulness; and (2) during forced desynchrony between the body temperature and sleep/wake cycles, allowing testing of non-sleep-deprived subjects at all circadian phases. Contrary to earlier findings, we report here that the circadian rhythm of short-term memory varies in parallel with the circadian rhythms of subjective alertness, calculation performance, and core body temperature under both these experimental conditions. These results challenge the notion that short-term memory is inversely linked to the body temperature cycle and suggest that the human circadian pacemaker, which drives the body temperature cycle, is the primary determinant of endogenous circadian variations in subjective alertness and calculation performance as well as in the immediate recall of meaningful material.

Light-induced suppression of endogenous circadian amplitude in humans

Winfree reported 20 years ago the intriguing finding that a light stimulus of a critical strength applied at a critical circadian phase could essentially stop the circadian clock in Drosophila pseudo-obscura by resetting the circadian oscillator close to its singularity (a phaseless position at which the amplitude of circadian oscillation is zero). Since then, similar observations of attenuated circadian amplitude in response to critical stimuli have been limited to unicells, insects and plants. Our recent demonstration that the phase of the human circadian pacemaker could be inverted using an unconventional three-cycle stimulus led us to investigate whether critically timed exposure to a more moderate stimulus could drive that oscillator towards its singularity. Here we report that exposure of humans to fewer cycles of bright light, centred around the time at which the human circadian pacemaker is most sensitive to light-induced phase shifts, can markedly attenuate endogenous circadian amplitude. In some cases this results in an apparent loss of rhythmicity, as expected to occur in the region of singularity.