Forced Desynchrony Research Articles

Circadian rhythms in cognitive performance: Methodological constraints, protocols, theoretical underpinnings

The investigation of time-of-day effects on cognitive performance began in the early days of psychophysiological performance assessments. Since then, standardised, highly controlled protocols (constant routine and forced desynchrony) and a standard performance task (psychomotor vigilance task) have been developed to quantify sleep–wake homeostatic and internal circadian time-dependent effects on human cognitive performance. However, performance assessment in this field depends on a plethora of factors. The roles of task difficulty, task duration and complexity, the performance measure per se, practice effects, inter-individual differences, and ageing are all relevant aspects. Therefore, well-defined theoretical approaches and standard procedures are needed for tasks pinpointing higher cortical functions along with more information about time-dependent changes in the neural basis of task performance. This promises a fascinating challenge for future research on sleep–wake related and circadian aspects of different cognitive domains.

The relationship between the rate of melatonin excretion and sleep consolidation for locomotive engineers in natural sleep settings

BackgroundThe aim of the study was to examine the role that melatonin production plays in the regulation of sleep consolidation in a population of shiftworkers working and sleeping in their natural environments.Methods253 locomotive engineers (249 male, 4 female, mean age = 39.7 years) participated in the study for a 2-week period whilst working their normal roster patterns. Participants recorded details for all sleep periods in a sleep diary and collected urine samples during each day's main sleep period. The samples were subsequently assayed for the metabolite of melatonin in urine, 6-sulphatoxymelatonin (aMT6s), and the rate of excretion during main sleep periods was calculated.ResultsSeparate one-way factorial ANOVAs revealed a significant effect of time of sleep onset on aMT6s excretion rate, sleep duration, and subjective sleep quality. Generally, the rate of aMT6s excretion was lower, sleep duration was shorter, and sleep quality was lower for sleeps initiated during the daytime than for sleeps initiated at night.ConclusionCombined with previous studies linking melatonin production and sleep propensity, and others demonstrating the relationship between sleep consolidation and melatonin production in forced desynchrony protocols, the current results indicate that low production of melatonin may play a role in the poor consolidation of daytime sleep in natural sleep settings.

Intrinsic Period and Light Intensity Determine the Phase Relationship between Melatonin and Sleep in Humans

The internal circadian clock and sleep-wake homeostasis regulate the timing of human brain function, physiology, and behavior so that wakefulness and its associated functions are optimal during the solar day and that sleep and its related functions are optimal at night. The maintenance of a normal phase relationship between the internal circadian clock, sleep-wake homeostasis, and the light-dark cycle is crucial for optimal neurobehavioral and physiological function. Here, the authors show that the phase relationship between these factors-the phase angle of entrainment (psi)-is strongly determined by the intrinsic period (tau) of the master circadian clock and the strength of the circadian synchronizer. Melatonin was used as a marker of internal biological time, and circadian period was estimated during a forced desynchrony protocol. The authors observed relationships between the phase angle of entrainment and intrinsic period after exposure to scheduled habitual wakefulness-sleep light-dark cycle conditions inside and outside of the laboratory. Individuals with shorter circadian periods initiated sleep and awakened at a later biological time than did individuals with longer circadian periods. The authors also observed that light exposure history influenced the phase angle of entrainment such that phase angle was shorter following exposure to a moderate bright light (approximately 450 lux)-dark/wakefulness-sleep schedule for 5 days than exposure to the equivalent of an indoor daytime light (approximately 150 lux)-dark/wakefulness-sleep schedule for 2 days. These findings demonstrate that neurobiological and environmental factors interact to regulate the phase angle of entrainment in humans. This finding has important implications for understanding physiological organization by the brain's master circadian clock and may have implications for understanding mechanisms underlying circadian sleep disorders.

Older people awaken more frequently but fall back asleep at the same rate as younger people.

To determine whether the increased wake within a bedrest episode in healthy older people is due to an increased number and/or increased duration of awakenings by evaluating the rates of transition between sleep and wake bouts within a bedrest episode. Analysis of previously reported polysomnographic data from 13 older and 11 younger healthy individuals scheduled to sleep at many different phases of the endogenous circadian cycle during conditions of forced desynchrony (18.7 hours wake: 9.3 hours bedrest) of the circadian and wake-bedrest cycles. General clinical research center None. None. Older subjects had an approximately 2.7-fold increased rate of awakening from sleep but the same rate of falling back asleep as younger subjects. These differences between young and older individuals were observed at most circadian phases and throughout the bedrest episodes. In addition, the circadian variation in transition rates was greater in younger than older subjects. These results suggest that the reduced consolidation of sleep within a bedrest episode is due to difficulties remaining asleep, rather than falling asleep once awake, and is a primary change in sleep with aging.

Measuring Period of Human Biological Clock: Infill Asymptotic Analysis of Harmonic Regression Parameter Estimates

Publisher Summary This chapter examines the infill asymptotic behavior of the maximum likelihood estimates of a harmonic regression plus continuous first-order autoregressive noise model in order to determine the precision with which the intrinsic period of the human biological clock can be estimated. It is found that the intrinsic period of the human biological clock is closer to 24 h instead of 25 h and that it can be estimated with a standard error of 1.4 to 2.1 min. It is shown that for the forced de-synchrony (FD) protocol, the intrinsic period of the clock can be estimated in a computationally efficient manner with near-maximal precision from a sampled series containing less than 2% of the original temperature data. The relation of the results to the classic formulas for the asymptotic covariance matrix of the harmonic regression parameter estimates is elaborated. The implications of these results for determining the precision with which the period of the human biological clock may be estimated are studied in an analysis of core temperature data from five male subjects monitored under FD.

Chronobiology and mood disorders

The clinical observations of diurnal variation of mood and early morning awakening in depression have been incorporated into established diagnostic systems, as has the seasonal modifier defining winter depression (seasonal affective disorder, SAD). Many circadian rhythms measured in depressive patients are abnormal: earlier in timing, diminished in amplitude, or of greater variability. Whether these disturbances are of etiological significance for the role of circadian rhythms in mood disorders, or a consequence of altered behavior can only be dissected out with stringent protocols (eg, constant routine or forced desynchrony). These protocols quantify contributions of the circadian pacemaker and a homeostatic sleep process impacting on mood, energy, appetite, and sleep. Future studies will elucidate any allelic mutations in "circadian clock" -related or "sleep"-related genes in depression. With respect to treatment, antidepressants and mood stabilizers have no consistent effect on circadian rhythmicity. The most rapid antidepressant modality known so far is nonpharmacological: total or partial sleep deprivation in the second half of the night. The disadvantage of sleep deprivation, that most patients relapse after recovery sleep, can be prevented by coadministration of lithium, pindolol, serotonin (5-HT) reuptake inhibitors, bright light, or a subsequent phase-advance procedure. Phase advance of the sleep-wake cycle alone also has rapid effects on depressed mood, which lasts longer than sleep deprivation. Light is the treatment of choice for SAD and may prove to be useful for nonseasonal depression, alone or as an adjunct to medication. Chronobiological concepts emphasize the important role of zeitgebers to stabilize phase, light being the most important, but dark (and rest) periods, regularity of social schedules and meal times, and use of melatonin or its analogues should also be considered. Advances in chronobiology continue to contribute novel treatments for affective disorders.

Investigating the interaction between the homeostatic and circadian processes of sleep–wake regulation for the prediction of waking neurobehavioural performance

The two-process model of sleep regulation has been applied successfully to describe, predict, and understand sleep-wake regulation in a variety of experimental protocols such as sleep deprivation and forced desynchrony. A non-linear interaction between the homeostatic and circadian processes was reported when the model was applied to describe alertness and performance data obtained during forced desynchrony. This non-linear interaction could also be due to intrinsic non-linearity in the metrics used to measure alertness and performance, however. Distinguishing these possibilities would be of theoretical interest, but could also have important implications for the design and interpretation of experiments placing sleep at different circadian phases or varying the duration of sleep and/or wakefulness. Although to date no resolution to this controversy has been found, here we show that the issue can be addressed with existing data sets. The interaction between the homeostatic and circadian processes of sleep-wake regulation was investigated using neurobehavioural performance data from a laboratory experiment involving total sleep deprivation. The results provided evidence of an actual non-linear interaction between the homeostatic and circadian processes of sleep-wake regulation for the prediction of waking neurobehavioural performance.

The role of chronobiology in sleep disorders medicine.

This review is concerned with circadian (approximately 24 h) aspects of chronobiology, and how they relate to sleep disorders medicine. We begin with an introduction to the key concepts and paradigms of circadian rhythms research in general, including a description of homeostatic and circadian determinants of sleep timing. This is followed by a brief history of chronobiology in relation to sleep disorders medicine. Both animal and human circadian rhythm studies are considered. We trace historical changes in the relative emphasis placed on social contacts, light, and melatonin in human circadian rhythms research. Special attention is given to free-running, forced desynchrony, and ultra-short sleep/wake cycle findings of particular relevance to sleep disorders medicine. The latter part of the review comprises a description of the circadian rhythm sleep disorders, highlighting insights derived from basic circadian rhythms research, including recent advances in molecular genetics. We conclude that the role of chronobiology in sleep disorders medicine is profound and pervasive, and that the two disciplines will move ever closer as a natural function of important new insights into sleep and sleep disorders provided by basic circadian rhythms research.

Mood regulation in seasonal affective disorder patients and healthy controls studied in forced desynchrony

In healthy subjects, both the duration of wakefulness and the circadian pacemaker have been demonstrated to be involved in the regulation of mood. Some features of affective disorders suggest that these two factors also play a role in the dysregulation of mood. In particular, disturbances of the circadian pacemaker have been proposed to be a pathogenetic factor in Seasonal Affective Disorder, winter type (SAD). This report presents a test of this proposition. To this end seven SAD patients and matched controls were subjected to a 120-h forced desynchrony protocol, in which they were exposed to six 20-h days. This protocol enables us to discriminate the extent to which the course of mood is determined by the imposed 20-h sleep–wake cycle from the influence of the circadian pacemaker on that course. Patients participated during a depressive episode, after recovery upon light therapy and in summer. Controls were studied in winter and in summer. Between SAD patients and controls no significant differences were observed in the period length nor in the timing of the endogenous circadian temperature minimum. In both groups, sleep–wake cycle- and pacemaker-related components were observed in the variations of mood, which were not significantly different between conditions.

Sleep in seasonal affective disorder patients in forced desynchrony: an explorative study.

The majority of winter-type seasonal affective disorder (SAD) patients complain of hypersomnia and daytime drowsiness. As human sleep is regulated by the interaction of circadian, ultradian and homeostatic processes, sleep disturbances may be caused by either one of these factors. The present study focuses on homeostatic and ultradian aspects of sleep regulation in SAD. Sleep was recorded polysomnographically in seven SAD patients and matched controls subjected to a 120-h forced desynchrony protocol. In time isolation, subjects were exposed to six 20-h days, each comprising a 6.5-h period for sleep. Patients participated while being depressed, while remitted after light therapy and in summer. Controls were studied in winter and in summer. In each condition, the data of each subject were averaged across all recordings. Thus, the influence of the effects of the circadian pacemaker on sleep was excluded mathematically. The comparison of patients with controls and with themselves in the various conditions revealed no abnormalities in homeostatic parameters: sleep stage variables, relative power spectra and time courses of power in various frequency bands across the first three non-rapid eye movement-rapid eye movement (NREM-REM) cycles showed no differences. The data suggest that homeostatic processes are not involved in the disturbance of sleep in SAD.

A forced desynchrony study of circadian pacemaker characteristics in seasonal affective disorder.

The circadian pacemaker is an endogenous clock that regulates oscillations in most physiological and psychological processes with a near 24-h period. In many species, this pacemaker triggers seasonal changes in behavior. The seasonality of symptoms and the efficacy of light therapy suggest involvement of the circadian pacemaker in seasonal affective disorder (SAD), winter type. In this study, circadian pacemaker characteristics of SAD patients were compared with those of controls. Seven SAD patients and matched controls were subjected to a 120-h forced desynchrony protocol, in which core body temperature and melatonin secretion profiles were measured for the characterization of circadian pacemaker parameters. During this protocol, which enables the study of unmasked circadian pacemaker characteristics, subjects were exposed to six 20-h days in time isolation. Patients participated twice in winter (while depressed and while remitted after light therapy) and once in summer. Controls participated once in winter and once in summer. Between the SAD patients and controls, no significant differences were observed in the melatonin-derived period or in the phase of the endogenous circadian temperature rhythm. The amplitude of this rhythm was significantly smaller in depressed and remitted SAD patients than in controls. No abnormalities of the circadian pacemaker were observed in SAD patients. A disturbance in thermoregulatory processes might explain the smaller circadian temperature amplitude in SAD patients during winter.

Relationship between alertness, performance, and body temperature in humans.

Body temperature has been reported to influence human performance. Performance is reported to be better when body temperature is high/near its circadian peak and worse when body temperature is low/near its circadian minimum. We assessed whether this relationship between performance and body temperature reflects the regulation of both the internal biological timekeeping system and/or the influence of body temperature on performance independent of circadian phase. Fourteen subjects participated in a forced desynchrony protocol allowing assessment of the relationship between body temperature and performance while controlling for circadian phase and hours awake. Most neurobehavioral measures varied as a function of internal biological time and duration of wakefulness. A number of performance measures were better when body temperature was elevated, including working memory, subjective alertness, visual attention, and the slowest 10% of reaction times. These findings demonstrate that an increased body temperature, associated with and independent of internal biological time, is correlated with improved performance and alertness. These results support the hypothesis that body temperature modulates neurobehavioral function in humans.

Sleep- and circadian-dependent modulation of REM density.

Rapid eye movement (REM) density, a measure of the frequency of rapid eye movements during REM sleep, is known to increase over the course of the sleep episode. However, the circadian modulation of REM density has not been thoroughly evaluated. Data from a forced desynchrony protocol, in which 20 consecutive sleep opportunities were systematically scheduled over the entire circadian cycle, were analysed. The REM density was evaluated from polysomnographically recorded REM sleep episodes, and analyzed as a function of time in the sleep opportunity and as a function of phase in the circadian cycle. The REM density showed a robust increase over the course of the sleep episode. This sleep-dependent increase was observed regardless of circadian phase, because data analyzed from different thirds of the circadian cycle exhibited a similar pattern. The REM density did not show a significant circadian-dependent modulation for data from the entire sleep opportunity. However, analysis of circadian modulation from separate thirds of the sleep opportunity revealed a significant circadian modulation in the last third of the sleep episode. Maximum REM densities were observed when the last third of the sleep episode coincided with the wake-maintenance zone, i.e.;8-10 h before the crest of the circadian rhythm of REM sleep propensity. These results confirm the dominant sleep-dependent modulation of REM density, and indicate that the density of REMs is greatest when sleep pressure is low, such as in the latter part of the sleep episode, at which time the circadian modulation of REM density is also appreciable.

Measuring circadian temperature rhythm.

Experimental control and mathematical techniques increase confidence that results of circadian temperature rhythm studies reflect true changes in the circadian timing system versus coupling with exogenous synchronizers. Masking effects represent confounding influences in studies that are concerned with the endogenous temperature rhythm. Because it is technically difficult to measure directly the behavior of the endogenous timing system, marker rhythms are used as proxy measures. However in addition to entraining, the external environment exerts a direct masking effect on the monitored rhythm. Methods for measuring circadian temperature rhythm are reviewed in this article. Constant routine, forced desynchrony, and purification methods represent attempts, at an experimental or mathematical level, to remove masking effects and more accurately capture the endogenous circadian temperature rhythm. Exogenous factors have not been subjected to the same scrutiny as the endogenous features of circadian temperature rhythm. But it is the environmental context, the extent to which the endogenous features are adaptively modified by the field environment, that will ultimately determine the biological value of circadian temperature rhythm to the organism. Thus, nurse investigators are encouraged to use rigorous methods to study both endogenous circadian temperature rhythm and exogenous rhythms.

Is There an Intrinsic Period of the Circadian Clock?

In their report “Stability, precision, and near-24-hour period of the human circadian pacemaker” (25 June 1999, p. [2177][1]), C. A. Czeisler et al. describe that under the experimental conditions of “forced desynchrony,” the human endogenous pacemaker exhibits a period averaging 24.18 hours

Body temperature and mood variations during forced desynchronization in winter depression: a preliminary report

Background: It has been suggested that certain abnormalities (e.g., in phase or amplitude) of the circadian pacemaker underlie seasonal affective disorder. Methods: One male seasonal affective disorder patient (blind to the study design) participated in two 120-hour forced desynchrony experiments and was subjected to six 20-hour days, once during a depressive episode and once after recovery. Core body temperature was continuously measured. During wakefulness, the Adjective Mood Scale was completed at 2-hour intervals. Results: Sleep–wake as well as pacemaker-related variations of mood were found, both when the subject was depressed and when he was euthymic. Compared with recovery, during the depressive episode the circadian temperature minimum and the circadian mood variation showed phase delays of approximately 1 and 2 hours, respectively. Conclusions: The data of this first seasonal affective disorder patient, participating in forced desynchrony experiments, may indicate a phase delay of the circadian pacemaker during a seasonal affective disorder episode.

CONTRIBUTION OF CIRCADIAN PHYSIOLOGY AND SLEEP HOMEOSTASIS TO AGE-RELATED CHANGES IN HUMAN SLEEP

The circadian pacemaker and sleep homeostasis play pivotal roles in vigilance state control. It has been hypothesized that age-related changes in the human circadian pacemaker, as well as sleep homeostatic mechanisms, contribute to the hallmarks of age-related changes in sleep, that is, earlier wake time and reduced sleep consolidation. Assessments of circadian parameters in healthy young (∼20–30 years old) and older people (∼65–75 years old)—in the absence of the confounding effects of sleep, changes in posture, and light exposure—have demonstrated that an earlier wake time in older people is accompanied by about a 1h advance of the rhythms of core body temperature and melatonin. In addition, older people wake up at an earlier circadian phase of the body temperature and plasma melatonin rhythm. The amplitude of the endogenous circadian component of the core body temperature rhythm assessed during constant routine and forced desynchrony protocols is reduced by 20–30% in older people. Recent assessments of the intrinsic period of the human circadian pacemaker in the absence of the confounding effects of light revealed no age-related reduction of this parameter in both sighted and blind individuals. Wake maintenance and sleep initiation are not markedly affected by age except that sleep latencies are longer in older people when sleep initiation is attempted in the early morning. In contrast, major age-related reductions in the consolidation and duration of sleep occur at all circadian phases. Sleep of older people is particularly disrupted when scheduled on the rising limb of the temperature rhythm, indicating that the sleep of older people is more susceptible to arousal signals genernpated by the circadian pacemaker. Sleep-homeostatic mechanisms, as assayed by the sleep-deprivation–induced increase of EEG slow-wave activity (SWA), are operative in older people, although during both baseline sleep and recovery sleep SWA in older people remains at lower levels. The internal circadian phase advance of awakening, as well as the age-related reduction in sleep consolidation, appears related to an age-related reduction in the promotion of sleep by the circadian pacemaker during the biological night in combination with a reduced homeostatic pressure for sleep. Early morning light exposure associated with this advance of awakening in older people could reinforce the advanced circadian phase. Quantification of the interaction between sleep homeostasis and circadian rhythmicity contributes to understanding age-related changes in sleep timing and quality. (Chronobiology International, 17(3), 285–311, 2000)

Sleep homeostasis and models of sleep regulation.

According to the two-process model of sleep regulation, the timing and structure of sleep are determined by the interaction of a homeostatic and a circadian process. The original qualitative model was elaborated to quantitative versions that included the ultradian dynamics of sleep in relation to the non-REM-REM sleep cycle. The time course of EEG slow-wave activity, the major marker of non-REM sleep homeostasis, as well as daytime alertness were simulated successfully for a considerable number of experimental protocols. They include sleep after partial sleep deprivation and daytime napping, sleep in habitual short and long sleepers, and alertness in a forced desynchrony protocol or during an extended photoperiod. Simulations revealed that internal desynchronization can be obtained for different shapes of the thresholds. New developments include the analysis of the waking EEG to delineate homeostatic and circadian processes, studies of REM sleep homeostasis, and recent evidence for local, use-dependent sleep processes. Moreover, nonlinear interactions between homeostatic and circadian processes were identified. In the past two decades, models have contributed considerably to conceptualizing and analyzing the major processes underlying sleep regulation, and they are likely to play an important role in future advances in the field.

Interactive Mathematical Models of Subjective Alertness and Cognitive Throughput in Humans

The authors present here mathematical models in which levels of subjective alertness and cognitive throughput are predicted by three components that interact with one another in a nonlinear manner. These components are (1) a homeostatic component (H) that falls in a sigmoidal manner during wake and rises in a saturating exponential manner at a rate that is determined by circadian phase during sleep; (2) a circadian component (C) that is a function of the output of our mathematical model of the effect of light on the circadian pacemaker, with the amplitude further regulated by the level of H; and (3) a sleep inertia component (W) that rises in a saturating exponential manner after waketime. The authors first construct initial models of subjective alertness and cognitive throughput based on the results of sleep inertia studies, sleep deprivation studies initiated across all circadian phases, 28-h forced desynchrony studies, and alertness and performance dose response curves to sleep. These initial models are then refined using data from nearly one hundred fifty 30- to 50-h sleep deprivation studies in which subjects woke at their habitual times. The interactive three-component models presented here are able to predict even the fine details of neurobehavioral data from sleep deprivation studies and, after further validation, may provide a powerful tool for the design of safe shift work and travel schedules, including those in which people are exposed to unusual patterns of light.

Nonentrained circadian rhythms of melatonin in submariners scheduled to an 18-hour day.

The human circadian timing system has previously been shown to free run with a period slightly longer than 24 h in subjects living in the laboratory under conditions of forced desynchrony. In forced desynchrony, subjects are shielded from bright light and periodic time cues and are required to live on a day length outside the range of circadian entrainment. The work schedule used for most personnel aboard American submarines is 6 h on duty alternating with 12 h off duty. This imposed 18-h cycle is too short for human circadian synchronization, especially given that there is no bright-light exposure aboard submarines. However, crew members are exposed to 24-h stimuli that could mediate synchronization, such as clocks and social contacts with personnel who are living on a 24-h schedule. The authors investigated circadian rhythms of salivary melatonin in 20 crew members during a prolonged voyage on a Trident nuclear submarine. The authors found that in crew members living on the 18-h duty cycle, the endogenous rhythm of melatonin showed an average period of 24.35 h (n = 12, SD = 0.18 h). These data indicate that social contacts and knowledge of clock time are insufficient for entrainment to a 24-h period in personnel living by an 18-h rest-activity cycle aboard a submarine.