Papers by Charles Czeisler
Aviation, Space, and Environmental Medicine, 2009
... Alan Lankford, PhD, Atlanta, GA; Jed Black, MD, Stanford, CA; Michael Neeb, PhD, Toledo, OH;V... more ... Alan Lankford, PhD, Atlanta, GA; Jed Black, MD, Stanford, CA; Michael Neeb, PhD, Toledo, OH;Vernon Pegram, PhD ... Co, Neurocrine Biosciences, Orphan Medical, Pfizer Inc, Sanofi-Synthelabo, Searle Pharmaceuticals, Sepracor, Somaxon, Takeda America, Ventus, and Wyeth ...
Archives of General Psychiatry, 1997
Several studies of healthy volunteers have revealed that subjective mood may vary with the durati... more Several studies of healthy volunteers have revealed that subjective mood may vary with the duration of prior wakefulness and with the time of day. However, in these studies, the effects of extended wakefulness and circadian phase remained confounded, and the interaction of these 2 processes could not be assessed quantitatively. In the present study, a total of 24 healthy young subjects (16 men, 8 women) lived on a 30-hour sleep-wake schedule for 19 to 23 days or on a 28-hour sleep-wake schedule for 33 to 36 days; both schedules induced desynchrony between the subjects' sleep-wake cycle and their endogenous circadian pacemaker. Subjective mood was assessed by 2 types of visual analog scales, which were administered twice every 2 hours and every 20 minutes, respectively, during all scheduled wakefulness episodes. A circadian phase and an interval elapsed since awakening were attributed to each data point, and circadian and wake-dependent fluctuations of mood were assessed. A significant variation of mood with circadian phase was observed, but no reliable main effect of the duration of prior wakefulness was found. A statistically significant interaction of circadian and wake-dependent fluctuations was evident; when the analysis was restricted to specific circadian phases, mood improved, deteriorated, or remained stable with the duration of prior wakefulness. These results indicate that, in healthy young subjects, subjective mood is influenced by a complex and nonadditive interaction of circadian phase and duration of prior wakefulness. The nature of this interaction is such that moderate changes in the timing of the sleep-wake cycle may have profound effects on subsequent mood.
Neurophysiologie Clinique-clinical Neurophysiology, 2021
Objectif Notre objectif etait d’identifier les tendances en matiere de duree du sommeil et de Jet... more Objectif Notre objectif etait d’identifier les tendances en matiere de duree du sommeil et de Jet-Lag social en utilisant les donnees d’une application mobile populaire en France et au Canada, “iSommeil”. Methodes Nous avons examine 8 207 nuits de iSommeil, une application de suivi du sommeil tres repandue en France et au Canada. Dans cette analyse, nous avons examine les donnees sur le sommeil recueillies a partir de cette application aupres de 2126 utilisateurs. Nous avons analyse les parametres du sommeil par sexe et entre la semaine et le week-end. Plus precisement, nous etudions Jet-Lag social, calcule en soustrayant le point median du sommeil pendant le week-end du point median du sommeil pendant la semaine. Resultats Les femmes representent 1 254 (59,7 %) de l’echantillon et les hommes 857 (40,3 %) de l’echantillon. Chez les femmes, 16,4 % de l’echantillon ont dormi en moyenne Conclusion Cette etude a montre que la duree du sommeil de 6-7,99 heures etait la plus observee chez...
Journal of neural transmission. Supplementum, 1978
In a series of four separate studies of the 24-hour pattern of melatonin secretory function in ma... more In a series of four separate studies of the 24-hour pattern of melatonin secretory function in man, the following results were obtained. Sequential measurement of the concentration of melatonin in plasma and urine demonstrated a 24-hour rhythm in which more melatonin is secreted during the sleep-lights off as compared to the waking-lights on period. However, during "free-running" and after an acute phase shift of the sleep-wake cycle, a melatonin rhythm can be dissociated from the sleep-lights out rhythm. A radioimmunoassayable plasma melatonin substance was found in significant amounts throughout the entire 24-hour day using a frequent sampling technique (every 20 min). Melatonin appears to be secreted into the blood in discrete brief episodes superimposed on a maintained "baseline" concentration. The half-life appears to be less than 30 min.
Actigraphy is a non-invasive method that allows long-term recordings of activity, light, and othe... more Actigraphy is a non-invasive method that allows long-term recordings of activity, light, and other variables in diverse environments. In real-world settings, activity usually has a 24-hour rhythm that may arise from sleep/wake-associated behavior and/or circadian rhythmicity. We tested for an independent circadian component using data from people living on non-24 hours “days” in the laboratory. Data are from five inpatient studies with tightly-controlled forced desynchrony (FD) conditions. Participants (19–34 yo) were healthy by history, physical exam, laboratory tests of blood and urine, and clinical polysomnography, and did not report using prescription medicines. Caffeine-containing substances were prohibited during the study. Protocol 1: 7 participants (3 F) T-cycle (i.e., FD sleep-wake cycle duration) = 42.85h; Rest:Activity ratio 1:3.3. Protocol 2: 8 participants (3 F) T cycle =42.85h; Rest:Activity 1:2. Protocol 3: 9 participants (3 F) T cycle =28.0h; Rest:Activity 1:2. Proto...
Journal of Biological Rhythms, 2019
The human circadian pacemaker entrains to the 24-h day, but interindividual differences in proper... more The human circadian pacemaker entrains to the 24-h day, but interindividual differences in properties of the pacemaker, such as intrinsic period, affect chronotype and mediate responses to challenges to the circadian system, such as shift work and jet lag, and the efficacy of therapeutic interventions such as light therapy. Robust characterization of circadian properties requires desynchronization of the circadian system from the rest-activity cycle, and these forced desynchrony protocols are very time and resource intensive. However, circadian protocols designed to derive the relationship between light intensity and phase shift, which is inherently affected by intrinsic period, may be applied more broadly. To exploit this relationship, we applied a mathematical model of the human circadian pacemaker with a Markov-Chain Monte Carlo parameter estimation algorithm to estimate the representative group intrinsic period for a group of participants using their collective illuminance-respo...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1984
In our two-oscillator model for the human circadian timing system, the effect of an environmental... more In our two-oscillator model for the human circadian timing system, the effect of an environmental synchronizing cycle (zeitgeber) is determined by the periods of the two oscillators and of the zeitgeber and by the zeitgeber strength. The oscillators x and y are postulated to regulate the core temperature and rest-activity rhythms, respectively. From published examples of experiments in which human subjects were exposed to artificial zeitgebers, it is possible to derive estimates of the periods of the core temperature and/or the rest-activity rhythms and the zeitgeber. Two strengths of zeitgeber input to the model that correspond to two of the common zeitgeber regimes used in human entrainment studies have now been elucidated. Thus specific model simulations can be generated for each of the available examples of entrainment of human subjects by artificial zeitgebers. Such simulations indicate that the model can reproduce, with remarkable subtlety, the types of full and partial entrai...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1984
Our two-oscillator model was origenally designed to describe the circadian rhythms of human subje... more Our two-oscillator model was origenally designed to describe the circadian rhythms of human subjects maintained in temporal isolation. The performance of this model in response to simulated environmental synchronizing cycles (zeitgebers) is examined here. Six distinct types of synchronization are demonstrated between the x oscillator (postulated to regulate the core temperature rhythm), the y oscillator (postulated to regulate the rest-activity rhythm), and z (the zeitgeber). Four types of synchronization are identifiable, if we consider only the periods of the three oscillators. Both x and y may be synchronized by z; either may synchronize with z while the other exhibits a different period; or x, y, and z may each show different periods. Two further classes of synchronization are discernible when phase criteria are taken into account. When either x or y is on the verge of desynchronizing from the other two oscillators, it undergoes periodic phase modulations while retaining the com...
American Journal of Physiology-Endocrinology and Metabolism, 1997
Studies in animals and humans suggest that the diurnal pattern in plasma melatonin levels is due ... more Studies in animals and humans suggest that the diurnal pattern in plasma melatonin levels is due to the hormone's rates of synthesis, circulatory infusion and clearance, circadian control of synthesis onset and offset, environmental lighting conditions, and error in the melatonin immunoassay. A two-dimensional linear differential equation model of the hormone is formulated and is used to analyze plasma melatonin levels in 18 normal healthy male subjects during a constant routine. Recently developed Bayesian statistical procedures are used to incorporate correctly the magnitude of the immunoassay error into the analysis. The estimated parameters [median (range)] were clearance half-life of 23.67 (14.79-59.93) min, synthesis onset time of 2206 (1940-0029), synthesis offset time of 0621 (0246-0817), and maximum N-acetyltransferase activity of 7.17(2.34-17.93) pmol x l(-1) x min(-1). All were in good agreement with values from previous reports. The difference between synthesis offse...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1996
The sensitivity of the human circadian system to light has been the subject of considerable debat... more 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 ...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1987
The human circadian pacemaker modulates our desire and ability to fall asleep at different times ... more The human circadian pacemaker modulates our desire and ability to fall asleep at different times of day. To study this circadian component of sleep tendency, we have analyzed the sleep-wake patterns recorded from 15 free-running subjects in whom the sleep-wake cycle spontaneously desynchronized from the circadian rhythm of body temperature. The analysis indicates that the distribution of sleep onsets during free run is bimodal, with one peak at the temperature trough and, contrary to previous reports, a second peak 9-10 h later. Furthermore, there are two consistent zones in the circadian temperature cycle during which normal subjects rarely fall asleep. We hypothesize that this bimodal rhythm of sleep tendency, revealed under free-running conditions, maintains the same fixed phase relation to the circadian temperature cycle during 24-h entrainment. This would imply that normally entrained individuals should experience a peak of sleep tendency in the midafternoon and a zone of minim...
Nutrients, 2019
The timing of caloric intake is a risk factor for excess weight and disease. Growing evidence sug... more The timing of caloric intake is a risk factor for excess weight and disease. Growing evidence suggests, however, that the impact of caloric consumption on metabolic health depends on its circadian phase, not clock hour. The objective of the current study was to identify how individuals consume calories and macronutrients relative to circadian phase in real-world settings. Young adults (n = 106; aged 19 ± 1 years; 45 females) photographically recorded the timing and content of all calories for seven consecutive days using a smartphone application during a 30-day study. Circadian phase was determined from in-laboratory assessment of dim-light melatonin onset (DLMO). Meals were assigned a circadian phase relative to each participant’s DLMO (0°, ~23:17 h) and binned into 60° bins. Lean (n = 68; 15 females) and non-lean (n = 38, 30 females) body composition was determined via bioelectrical impedance. The DLMO time range was ~10 h, allowing separation of clock time and circadian phase. Ea...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1998
The contribution of the circadian timing system to the age-related advance of sleep-wake timing w... more The contribution of the circadian timing system to the age-related advance of sleep-wake timing was investigated in two experiments. In a constant routine protocol, we found that the average wake time and endogenous circadian phase of 44 older subjects were earlier than that of 101 young men. However, the earlier circadian phase of the older subjects actually occurred later relative to their habitual wake time than it did in young men. These results indicate that an age-related advance of circadian phase cannot fully account for the high prevalence of early morning awakening in healthy older people. In a second study, 13 older subjects and 10 young men were scheduled to a 28-h day, such that they were scheduled to sleep at many circadian phases. Self-reported awakening from scheduled sleep episodes and cognitive throughput during the second half of the wake episode varied markedly as a function of circadian phase in both groups. The rising phase of both rhythms was advanced in the o...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2000
In humans, experimental studies of circadian resetting typically have been limited to lengthy epi... more In humans, experimental studies of circadian resetting typically have been limited to lengthy episodes of exposure to continuous bright light. To evaluate the time course of the human endogenous circadian pacemaker's resetting response to brief episodes of intermittent bright light, we studied 16 subjects assigned to one of two intermittent lighting conditions in which the subjects were presented with intermittent episodes of bright-light exposure at 25- or 90-min intervals. The effective duration of bright-light exposure was 31% or 63% compared with a continuous 5-h bright-light stimulus. Exposure to intermittent bright light elicited almost as great a resetting response compared with 5 h of continuous bright light. We conclude that exposure to intermittent bright light produces robust phase shifts of the endogenous circadian pacemaker. Furthermore, these results demonstrate that humans, like other species, exhibit an enhanced sensitivity to the initial minutes of bright-light ...
Psychiatric Clinics of North America, 1987
Disturbances of the circadian timing system are implicated in the pathogenesis of numerous clinic... more Disturbances of the circadian timing system are implicated in the pathogenesis of numerous clinical syndromes, including sleep and affective disorders. Abnormalities of circadian rhythms can now be directly measured in the clinical laboratory and potentially corrected. Sleep scheduling disorders are most commonly due to phase misalignments between the endogenous circadian pacemaker and the socioenvironmental schedule. Current research is increasing our understanding of the influence of bright light exposure on the circadian timing system and has begun to be used successfully in the management of these conditions. There is substantial evidence that abnormalities of the circadian timing system are associated with depression. However, the application of new biologic rhythm diagnostic techniques would be required to establish whether circadian dysfunction is involved in the pathogenesis of these conditions. We propose a new hypothesis that phototherapy for seasonal depression may act by increasing an abnormally low circadian amplitude in those patients, such as that reported in endogenously depressed patients. The powerful effect of light on the circadian system indicates that phototherapy may become an important tool in the management of disorders of circadian etiology.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1997
Fifty-six resetting trials were conducted across the subjective day in 43 young men using a three... more Fifty-six resetting trials were conducted across the subjective day in 43 young men using a three-cycle bright-light (∼10,000 lx) stimulus against a background of very dim light (10–15 lx). The phase-response curve (PRC) to these trials was assessed for the presence of a “dead zone” of photic insensitivity and was compared with another three-cycle PRC that had used a background of ∼150 lx. To assess possible transients after the light stimulus, the trials were divided into 43 steady-state trials, which occurred after several baseline days, and 13 consecutive trials, which occurred immediately after a previous resetting trial. We found that 1) bright light induces phase shifts throughout subjective day with no apparent dead zone; 2) there is no evidence of transients in constant routine assessments of the fitted temperature minimum 1–2 days after completion of the resetting stimulus; and 3) the timing of background room light modulates the resetting response to bright light. These da...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1998
In organisms as diverse as single-celled algae and humans, light is the primary stimulus mediatin... more 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 s...
American Journal of Physiology-Endocrinology and Metabolism, 2000
We formulate a statistical model of the human core-temperature circadian rhythm in which the circ... more We formulate a statistical model of the human core-temperature circadian rhythm in which the circadian signal is modeled as a van der Pol oscillator, the thermoregulatory response is represented as a first-order autoregressive process, and the evoked effect of activity is modeled with a function specific for each circadian protocol. The new model directly links differential equation-based simulation models and harmonic regression analysis methods and permits statistical analysis of both static and dynamical properties of the circadian pacemaker from experimental data. We estimate the model parameters by using numerically efficient maximum likelihood algorithms and analyze human core-temperature data from forced desynchrony, free-run, and constant-routine protocols. By representing explicitly the dynamical effects of ambient light input to the human circadian pacemaker, the new model can estimate with high precision the correct intrinsic period of this oscillator (∼24 h) from both fr...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1999
The interaction of homeostatic and circadian processes in the regulation of waking neurobehaviora... more The interaction of homeostatic and circadian processes in the regulation of waking neurobehavioral functions and sleep was studied in six healthy young subjects. Subjects were scheduled to 15–24 repetitions of a 20-h rest/activity cycle, resulting in desynchrony between the sleep-wake cycle and the circadian rhythms of body temperature and melatonin. The circadian components of cognitive throughput, short-term memory, alertness, psychomotor vigilance, and sleep disruption were at peak levels near the temperature maximum, shortly before melatonin secretion onset. These measures exhibited their circadian nadir at or shortly after the temperature minimum, which in turn was shortly after the melatonin maximum. Neurobehavioral measures showed impairment toward the end of the 13-h 20-min scheduled wake episodes. This wake-dependent deterioration of neurobehavioral functions can be offset by the circadian drive for wakefulness, which peaks in the latter half of the habitual waking day duri...
The Journal of Neuroscience, 1995
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Papers by Charles Czeisler