An Improved Method for Estimating Human Circadian Phase Derived From Multichannel Ambulatory Monitoring and Artificial Neural Networks

Recently, we developed a novel method for estimating human circadian phase with noninvasive ambulatory measurements combined with subject-independent multiple regression models and a curve-fitting approach. With this, we were able to estimate circadian phase under real-life conditions with low subject burden, i.e., without need of constant routine (CR) laboratory conditions, and without measuring standard circadian markers, such as core body temperature (CBT) or pineal hormone melatonin rhythms. The precision of ambulatory-derived estimated circadian phase was within an error of 12?±?41?min (mean?±?SD) in comparison to melatonin phase during a CR protocol. The physiological measures could be reduced to a triple combination: skin temperatures, irradiance in the blue spectral band of ambient light, and motion acceleration. Here, we present a nonlinear regression model approach based on artificial neural networks for a larger data set (25 healthy young males), including both the original data and additional data collected in the same protocol and using the same equipment. Throughout our validation study, subjects wore multichannel ambulatory monitoring devices and went about their daily routine for 1 wk. The devices collected a large number of physiological, behavioral, and environmental variables, including CBT, skin temperatures, cardiovascular and respiratory functions, movement/posture, ambient temperature, spectral composition and intensity of light perceived at eye level, and sleep logs. After the ambulatory phase, study volunteers underwent a 32-h CR protocol in the laboratory for measuring unmasked circadian phase (i.e., “midpoint” of the nighttime melatonin rhythm). To overcome the complex masking effects of many different confounding variables during ambulatory measurements, neural network–based nonlinear regression techniques were applied in combination with the cross-validation approach to subject-independent prediction of circadian phase. The most accurate estimate of circadian phase with a prediction error of ?3?±?23?min (mean?±?SD) was achieved using only two types of the measured variables: skin temperatures and irradiance for ambient light in the blue spectral band. Compared to our previous linear multiple regression modeling approach, motion acceleration data can be excluded and prediction accuracy, nevertheless, improved. Neural network regression showed statistically significant improvement of variance of prediction error over traditional approaches in determining circadian phase based on single predictors (CBT, motion acceleration, or sleep logs), even though none of these variables was included as predictor. We, therefore, have identified two sets of noninvasive measures that, combined with the prediction model, can provide researchers and clinicians with a precise measure of internal time, in spite of the masking effects of daily behavior. This method, here validated in healthy young men, requires testing in a clinical or shiftwork population suffering from circadian sleep-wake disorders. (Author correspondence: vitaliy.kolodyazhniy@sbg.ac.at)     

Estimation of human circadian phase via a multi-channel ambulatory monitoring system and a multiple regression model

Reliable detection of circadian phase in humans using noninvasive ambulatory measurements in real-life conditions is challenging and still an unsolved problem. The masking effects of everyday behavior and environmental input such as physical activity and light on the measured variables need to be considered critically. Here, we aimed at developing techniques for estimating circadian phase with the lowest subject burden possible, that is, without the need of constant routine (CR) laboratory conditions or without measuring the standard circadian markers, (rectal) core body temperature (CBT), and melatonin levels. In this validation study, subjects (N = 16) wore multi-channel ambulatory monitoring devices and went about their daily routine for 1 week. The devices measured a large number of physiological, behavioral, and environmental variables, including CBT, skin temperatures, cardiovascular and respiratory function, movement/posture, ambient temperature, and the spectral composition and intensity of light received at eye level. Sleep diaries were logged electronically. After the ambulatory phase, subjects underwent a 32-h CR procedure in the laboratory for measuring unmasked circadian phase based on the "midpoint" of the salivary melatonin profile. To overcome the complex masking effects of confounding variables during ambulatory measurements, multiple regression techniques were applied in combination with the cross-validation approach to subject-independent prediction of circadian phase. The most accurate estimate of circadian phase was achieved using skin temperatures, irradiance for ambient light in the blue spectral band, and motion acceleration as predictors with lags of up to 24 h. Multiple regression showed statistically significant improvement of variance of prediction error over the traditional approaches to determining circadian phase based on single predictors (motion acceleration or sleep log), although CBT was intentionally not included as the predictor. Compared to CBT alone, our method resulted in a 40% smaller range of prediction errors and a nonsignificant reduction of error variance. The proposed noninvasive measurement method could find applications in sleep medicine or in other domains where knowing the exact endogenous circadian phase is important (e.g., for the timing of light therapy).     

Older poor-sleeping women display a smaller evening increase in melatonin secretion and lower values of melatonin and core body temperature than good sleepers

Melatonin concentration and core body temperature (CBT) follow endogenous circadian biological rhythms. In the evening, melatonin level increases and CBT decreases. These changes are involved in the regulation of the sleep-wake cycle. Therefore, the authors hypothesized that age-related changes in these rhythms affect sleep quality in older people. In a cross-sectional study design, 11 older poor-sleeping women (aged 62-72 yrs) and 9 older good-sleeping women (60-82 yrs) were compared with 10 younger good-sleeping women (23-28 yrs). The older groups were matched by age and body mass index. Sleep quality was assessed by the Pittsburgh Sleep Quality Index questionnaire. As an indicator of CBT, oral temperature was measured at 1-h intervals from 17:00 to 24:00?h. At the same time points, saliva samples were collected for determining melatonin levels by enzyme-linked immunosorbent assay (ELISA). The dim light melatonin onset (DLMO), characterizing the onset of melatonin production, was calculated. Evening changes in melatonin and CBT levels were tested by the Friedman test. Group comparisons were performed with independent samples tests. Predictors of sleep-onset latency (SOL) were assessed by regression analysis. Results show that the mean CBT decreased in the evening from 17:00 to 24:00?h in both young women (from 36.57°C to 36.25°C, p < .001) and older women (from 36.58°C to 35.88°C, p < .001), being lowest in the older poor sleepers (p < .05). During the same time period, mean melatonin levels increased in young women (from 16.2 to 54.1 pg/mL, p < .001) and older women (from 10.0 to 23.5 pg/mL, p < .001), being lowest among the older poor sleepers (from 20:00 to 24:00?h, p < .05 vs. young women). Older poor sleepers also showed a smaller increase in melatonin level from 17:00 to 24:00?h than older good sleepers (mean?±?SD: 7.0?±?9.63 pg/mL vs. 15.6?±?24.1 pg/mL, p = .013). Accordingly, the DLMO occurred at similar times in young (20:10?h) and older (19:57?h) good-sleeping women, but was delayed ～50?min in older poor-sleeping women (20:47?h). Older poor sleepers showed a shorter phase angle between DLMO and sleep onset, but a longer phase angle between CBT peak and sleep onset than young good sleepers, whereas older good sleepers had intermediate phase angles (insignificant). Regression analysis showed that the DLMO was a significant predictor of SOL in the older women (R(2)?=?0.64, p < .001), but not in the younger women. This indicates that melatonin production started later in those older women who needed more time to fall asleep. In conclusion, changes in melatonin level and CBT were intact in older poor sleepers in that evening melatonin increased and CBT decreased. However, poor sleepers showed a weaker evening increase in melatonin level, and their DLMO was delayed compared with good sleepers, suggesting that it is not primarily the absolute level of endogenous melatonin, but rather the timing of the circadian rhythm in evening melatonin secretion that might be related to disturbances in the sleep-wake cycle in older people.     

Comparisons of the variability of three markers of the human circadian pacemaker

A circadian pacemaker within the central nervous system regulates the approximately 24-h physiologic rhythms in sleep cycles, hormone secretion, and other physiologic functions. Because the pacemaker cannot be examined directly in humans, markers of pacemaker function must be used to study the pacemaker and its response to environmental stimuli. Core body temperature (CBT), plasma cortisol, and plasma melatonin are three marker variables frequently used to estimate the phase of the human pacemaker. Measurements of circadian phase using markers can contain variability due to the circadian pacemaker itself, the intrinsic variability of the marker relative to the pacemaker, the method of analysis of the marker, and the marker assay. For this report, we compared the mathematical variability of a number of methods of identifying circadian phase from CBT, plasma cortisol, and plasma melatonin data collected in a protocol in which pacemaker variability was minimized using low light levels and regular timing of both the light pattern and the rest/activity schedule. We hoped to assess the relative variabilities of the different physiological markers and the analysis methods. Methods were based on the crossing of an absolute threshold, on the crossing of a relative threshold, or on fitting a curve to all data points. All methods of calculating circadian phase from plasma melatonin data were less variable than those calculated using CBT or cortisol data. The standard deviation for the phase estimates using CBT data was 0.78 h, using cortisol data was 0.65 h, and for the eight analysis methods using melatonin data was 0.23 to 0.35 h. While the variability for these markers might be different for other subject populations and/or less stringent study conditions, assessment of the intrinsic variability of the different calculations of circadian phase can be applied to allow inference of the statistical significance of phase and phase shift calculations, as well as estimation of sample size or statistical power for the number of subjects within an experimental protocol.     

Is sleep per se a zeitgeber in humans?

It is not clear whether shifting of sleep per se, without a concomitant change in the light-dark cycle, can induce a phase shift of the human circadian pacemaker. Two 9-day protocols (crossover, counterbalanced order) were completed by 4 men and 6 women (20-34 years) after adherence to a 2330 to 0800 h sleep episode at home for 2 weeks. Following a modified baseline constant routine (CR) protocol on day 2, they remained under continuous near-darkness (< 0.2 lux, including sleep) for 6 days. Four isocaloric meals were equally distributed during scheduled wakefulness, and their timing was held constant. Subjects remained supine inbed from 2100 to 0800 h on all days; sleep was fixed from 2330 to 0800 h in the control condition and was gradually advanced 20 min per day during the sleep advance condition until a 2-h difference had been attained. On day 9, a 25 to 27 h CR protocol (approximately 0.1 lux) was carried out. Phase markers were the evening decline time of the core body temperature (CBT) rhythm and salivary melatonin onset (3 pg/ml threshhold). In the fixed sleep condition, the phase drift over 7 days ranged from +1.62 to -2.56 h (for both CBT and melatonin rhythms, which drifted in parallel). The drifts were consistently advanced in the sleep advance schedule by +0.66 +/- 0.23 (SEM) h for CBT (p = 0.02) and by 0.27 +/- 0.14 h for melatonin rhythms (p = 0.09). However, this advance was small to medium according to effect size. Sleep per se may feed back onto the circadian pacemaker, but it appears to be a weak zeitgeber in humans.     

Nasal versus temporal illumination of the human retina: effects on core body temperature, melatonin, and circadian phase

The mammalian retina contains both visual and circadian photoreceptors. In humans, nocturnal stimulation of the latter receptors leads to melatonin suppression, which might cause reduced nighttime sleepiness. Melatonin suppression is maximal when the nasal part of the retina is illuminated. Whether circadian phase shifting in humans is due to the same photoreceptors is not known. The authors explore whether phase shifts and melatonin suppression depend on the same retinal area. Twelve healthy subjects participated in a within-subjects design and received all of 3 light conditions--1) 10 lux of dim light on the whole retina, 2) 100 lux of ocular light on the nasal part of the retina, and 3) 100 lux of ocular light on the temporal part of the retina--on separate nights in random order. In all 3 conditions, pupils were dilated before and during light exposure. The protocol consisted of an adaptation night followed by a 23-h period of sustained wakefulness, during which a 4-h light pulse was presented at a time when maximal phase delays were expected. Nasal illumination resulted in an immediate suppression of melatonin but had no effect on subjective sleepiness or core body temperature (CBT). Nasal illumination delayed the subsequent melatonin rhythm by 78 min, which is significantly (p= 0.016) more than the delay drift in the dim-light condition (38 min), but had no detectable phase-shifting effect on the CBT rhythm. Temporal illumination suppressed melatonin less than the nasal illumination and had no effect on subjective sleepiness and CBT. Temporal illumination delayed neither the melatonin rhythm nor the CBT rhythm. The data show that the suppression of melatonin does not necessarily result in a reduction of subjective sleepiness and an elevation ofCBT. In addition, 100 lux of bright white light is strong enough to affect the photoreceptors responsible for the suppression of melatonin but not strong enough to have a significant effect on sleepiness and CBT. This may be due to the larger variability of the latter variables.     

Linear demasking techniques are unreliable for estimating the circadian phase of ambulatory temperature data.

Clinical investigators often use ambulatory temperature monitoring to assess the endogenous phase and amplitude of an individual's circadian pacemaker for diagnostic and research purposes. However, an individual's daily schedule includes changes in levels of activity, in posture, and in sleep-wake state, all of which are known to have masking or evoked effects on core body temperature (CBT) data. To compensate for or to correct these masking effects, many investigators have developed "demasking" techniques to extract the underlying circadian phase and amplitude data. However, the validity of these methods is uncertain. Therefore, the authors tested a variety of analytic methods on two different ambulatory data sets from two different studies in which the endogenous circadian pacemaker was not synchronized to the sleep-wake schedule. In both studies, circadian phase estimates calculated from CBT collected when each subject was ambulatory (i.e., free to perform usual daily activities) were compared to those calculated during the same study when the same subject's activities were controlled. In the first study, 24 sighted young and older subjects living on a 28-h scheduled "day" protocol were studied for approximately 21 to 25 cycles of 28-h each. In the second study, a blind man whose endogenous circadian rhythms were not synchronized to the 24-h day despite his maintenance of a regular 24-h sleep-wake schedule was studied for more than 80 consecutive 24-h days. During both studies, the relative phase of the endogenous (circadian) and evoked (scheduled activity-rest) components of the ambulatory temperature data changed progressively and relatively slowly, enabling analysis of the CBT rhythm at nearly all phase relationships between the two components. The analyses of the ambulatory temperature data demonstrate that the masking of the CBT rhythm evoked by changes in activity levels, posture, or sleep-wake state associated with the evoked schedule of activity and rest can significantly obscure the endogenous circadian component of the signal, the object of study. In addition, the masking effect of these evoked responses on temperature depends on the circadian phase at which they occur. These nonlinear interactions between circadian phase and sleep-wake schedule render ambulatory temperature data unreliable for the assessment of endogenous circadian phase. Even when proposed algebraic demasking techniques are used in an attempt to reveal the endogenous temperature rhythm, the phase estimates remain severely compromised.     

Circadian periods of sensitivity for ramelteon on the onset of running-wheel activity and the peak of suprachiasmatic nucleus neuronal firing rhythms in C3H/HeN mice

Ramelteon, an MT(1)/MT(2) melatonin receptor agonist, is used for the treatment of sleep-onset insomnia and circadian sleep disorders. Ramelteon phase shifts circadian rhythms in rodents and humans when given at the end of the subjective day; however, its efficacy at other circadian times is not known. Here, the authors determined in C3H/HeN mice the maximal circadian sensitivity for ramelteon in vivo on the onset of circadian running-wheel activity rhythms, and in vitro on the peak of circadian rhythm of neuronal firing in suprachiasmatic nucleus (SCN) brain slices. The phase response curve (PRC) for ramelteon (90?μg/mouse, subcutaneous [sc]) on circadian wheel-activity rhythms shows maximal sensitivity during the late mid to end of the subjective day, between CT8 and CT12 (phase advance), and late subjective night and early subjective day, between CT20 and CT2 (phase delay), using a 3-day-pulse treatment regimen in C3H/HeN mice. The PRC for ramelteon resembles that for melatonin in C3H/HeN mice, showing the same magnitude of maximal shifts at CT10 and CT2, except that the range of sensitivity for ramelteon (CT8-CT12) during the subjective day is broader. Furthermore, in SCN brain slices in vitro, ramelteon (10 pM) administered at CT10 phase advances (5.6?±?0.29?h, n?=?3) and at CT2 phase delays (-3.2?±?0.12?h, n?=?6) the peak of circadian rhythm of neuronal firing, with the shifts being significantly larger than those induced by melatonin (10 pM) at the same circadian times (CT10: 2.7?±?0.15?h, n?=?4, p?相似文献   

Mood and the circadian system: investigation of a circadian component in positive affect

The aim of this study was to test if the pattern of human mood variation across the day is consistent with the hypothesis that self-reports of positive affect (PA) have a circadian component, and self-reports of negative affect (NA) do not. Data were collected under two protocols: normal ambulatory conditions of activity and rest and during a 27 h constant routine (CR) procedure. Mood data were collected every 3 h during the wake span of the ambulatory protocol and hourly during the 27 h CR. In both protocols, rectal temperature data were continuously recorded. In the ambulatory protocol, activity data were also collected to enable estimation of the unmasked (purified) temperature rhythm. Participants were 14 healthy females aged 18-25 yr in the follicular phase of the menstrual cycle. Under both protocols, PA exhibited significant 24 h temporal variation [CR: F(23, 161) = 2.12, p < 0.01; ambulatory: F(5,55) = 2.44, p < 0.05] with a significant sinusoidal component [CR: F(2, 21) = 7.51, p < 0.01; ambulatory: F(2,3) = 20.49, p < .05] of the same form as the circadian temperature rhythm. In contrast, NA exhibited an increasing linear trend over time under the ambulatory protocol [F(1, 11) = 5.74, p < 0.05] but nonsignificant temporal variation under the CR protocol. The findings support the hypothesis of a circadian component in PA variation.     

Challenging the sleep homeostat does not influence the thermoregulatory system in men: evidence from a nap vs. sleep-deprivation study

The purpose of our study was to understand the relationship between the components of the three-process model of sleepiness regulation (homeostatic, circadian, and sleep inertia) and the thermoregulatory system. This was achieved by comparing the impact of a 40-h sleep deprivation vs. a 40-h multiple nap paradigm (10 cycles with 150/75 min wakefulness/sleep episodes) on distal and proximal skin temperatures, core body temperature (CBT), melatonin secretion, subjective sleepiness, and nocturnal sleep EEG slow-wave activity in eight healthy young men in a "controlled posture" protocol. The main finding of the study was that accumulation of sleep pressure increased subjective sleepiness and slow-wave activity during the succeeding recovery night but did not influence the thermoregulatory system as measured by distal, proximal, and CBT. The circadian rhythm of sleepiness (and proximal temperature) was significantly correlated and phase locked with CBT, whereas distal temperature and melatonin secretion were phase advanced (by 113 +/- 28 and 130 +/- 30 min, respectively; both P < 0.005). This provides evidence for a primary role of distal vasodilatation in the circadian regulation of CBT and its relationship with sleepiness. Specific thermoregulatory changes occur at lights off and on. After lights off, skin temperatures increased and were most pronounced for distal; after lights on, the converse occurred. The decay in distal temperature (vasoconstriction) was significantly correlated with the disappearance of sleep inertia. These effects showed minor and nonsignificant circadian modulation. In summary, the thermoregulatory system seems to be independent of the sleep homeostat, but the circadian modulation of sleepiness and sleep inertia is clearly associated with thermoregulatory changes.     

Alteration of internal circadian phase relationships after morning versus evening carbohydrate-rich meals in humans

The effects of a single morning and evening carbohydrate-rich meal for 3 consecutive days on circadian phase of core body temperature (CBT), heart rate, and salivary melatonin rhythms were compared under controlled constant routine conditions. In 10 healthy young men entrained to a natural light-dark cycle with regular sleep timing, CBT and heart rate were significantly elevated for approximately 8 h after the last evening carbohydrate-rich meal (EM), and nocturnal melatonin secretion (as measured by salivary melatonin and urinary 6-sulphatoxymelatonin levels) was reduced, compared to the morning carbohydrate-rich meal (MM) condition. Thus, circadian phase could not be measured until the following day due to this acute masking effect. The day after the last meal intervention, MM showed a significant advanced circadian phase position in CBT (+59+/-12 min) and heart rate (+43+/-18 min) compared to EM. However, dim-light melatonin onset was not significantly changed (+15+/-13 min). The results are discussed with respect to central (light-entrainable) and peripheral (food-entrainable) oscillators. Food may be a zeitgeber in humans for the food-entrainable peripheral oscillators, but melatonin data do not support such a conclusion for the light-entrainable oscillator in the suprachiasmatic nucleus.     

Older Poor-Sleeping Women Display a Smaller Evening Increase in Melatonin Secretion and Lower Values of Melatonin and Core Body Temperature Than Good Sleepers

Melatonin concentration and core body temperature (CBT) follow endogenous circadian biological rhythms. In the evening, melatonin level increases and CBT decreases. These changes are involved in the regulation of the sleep-wake cycle. Therefore, the authors hypothesized that age-related changes in these rhythms affect sleep quality in older people. In a cross-sectional study design, 11 older poor-sleeping women (aged 62–72 yrs) and 9 older good-sleeping women (60–82 yrs) were compared with 10 younger good-sleeping women (23–28 yrs). The older groups were matched by age and body mass index. Sleep quality was assessed by the Pittsburgh Sleep Quality Index questionnaire. As an indicator of CBT, oral temperature was measured at 1-h intervals from 17:00 to 24:00?h. At the same time points, saliva samples were collected for determining melatonin levels by enzyme-linked immunosorbent assay (ELISA). The dim light melatonin onset (DLMO), characterizing the onset of melatonin production, was calculated. Evening changes in melatonin and CBT levels were tested by the Friedman test. Group comparisons were performed with independent samples tests. Predictors of sleep-onset latency (SOL) were assessed by regression analysis. Results show that the mean CBT decreased in the evening from 17:00 to 24:00?h in both young women (from 36.57°C to 36.25°C, p < .001) and older women (from 36.58°C to 35.88°C, p < .001), being lowest in the older poor sleepers (p < .05). During the same time period, mean melatonin levels increased in young women (from 16.2 to 54.1 pg/mL, p < .001) and older women (from 10.0 to 23.5 pg/mL, p < .001), being lowest among the older poor sleepers (from 20:00 to 24:00?h, p < .05 vs. young women). Older poor sleepers also showed a smaller increase in melatonin level from 17:00 to 24:00?h than older good sleepers (mean?±?SD: 7.0?±?9.63 pg/mL vs. 15.6?±?24.1 pg/mL, p = .013). Accordingly, the DLMO occurred at similar times in young (20:10?h) and older (19:57?h) good-sleeping women, but was delayed ～50?min in older poor-sleeping women (20:47?h). Older poor sleepers showed a shorter phase angle between DLMO and sleep onset, but a longer phase angle between CBT peak and sleep onset than young good sleepers, whereas older good sleepers had intermediate phase angles (insignificant). Regression analysis showed that the DLMO was a significant predictor of SOL in the older women (R²?=?0.64, p < .001), but not in the younger women. This indicates that melatonin production started later in those older women who needed more time to fall asleep. In conclusion, changes in melatonin level and CBT were intact in older poor sleepers in that evening melatonin increased and CBT decreased. However, poor sleepers showed a weaker evening increase in melatonin level, and their DLMO was delayed compared with good sleepers, suggesting that it is not primarily the absolute level of endogenous melatonin, but rather the timing of the circadian rhythm in evening melatonin secretion that might be related to disturbances in the sleep-wake cycle in older people. (Author correspondence: mdittmar@zoologie.uni-kiel.de)     

Acute and phase-shifting effects of ocular and extraocular light in human circadian physiology

Light can influence physiology and performance of humans in two distinct ways. It can acutely change the level of physiological and behavioral parameters, and it can induce a phase shift in the circadian oscillators underlying variations in these levels. Until recently, both effects were thought to require retinal light perception. This view was challenged by Campbell and Murphy, who showed significant phase shifts in core body temperature and melatonin using an extraocular stimulus. Their study employed popliteal skin illumination and exclusively considered phase-shifting effects. In this paper, the authors explore both acute effects and phase-shifting effects of ocular as well as extraocular light. Twelve healthy males participated in a within-subject design and received all of three light conditions--(1) dim ocular light/no light to the knee, (2) dim ocular light/bright extraocular light to the knee, and (3) bright ocular light/no light to the knee--on separate nights in random order. The protocol consisted of an adaptation night followed by a 26-h period of sustained wakefulness, during which a 4-h light pulse was presented at a time when maximal phase delays were expected. The authors found neither immediate nor phase-shifting effects of extraocular light exposure on melatonin, core body temperature (CBT), or sleepiness. Ocular bright-light exposure reduced the nocturnal circadian drop in CBT, suppressed melatonin, and reduced sleepiness significantly. In addition, the 4-h ocular light pulse delayed the CBT rhythm by -55 min compared to the drift of the CBT rhythm in dim light. The melatonin rhythm shifted by -113 min, which differed significantly from the drift in the melatonin rhythm in the dim-light condition (-26 min). The failure to find immediate or phase-shifting effects in response to extraocular light in a within-subjects design in which effects of ocular bright light are confirmed strengthens the doubts raised by other labs of the impact of extraocular light on the human circadian system.     

MOOD AND THE CIRCADIAN SYSTEM: INVESTIGATION OF A CIRCADIAN COMPONENT IN POSITIVE AFFECT

The aim of this study was to test if the pattern of human mood variation across the day is consistent with the hypothesis that self-reports of positive affect (PA) have a circadian component, and self-reports of negative affect (NA) do not. Data were collected under two protocols: normal ambulatory conditions of activity and rest and during a 27h constant routine (CR) procedure. Mood data were collected every 3 h during the wake span of the ambulatory protocol and hourly during the 27h CR. In both protocols, rectal temperature data were continuously recorded. In the ambulatory protocol, activity data were also collected to enable estimation of the unmasked (purified) temperature rhythm. Participants were 14 healthy females aged 18–25 yr in the follicular phase of the menstrual cycle. Under both protocols, PA exhibited significant 24h temporal variation [CR: F(23,161)=2.12, p<0.01; ambulatory: F(5,55)=2.44, p<0.05] with a significant sinusoidal component [CR: F(2,21)=7.51, p<0.01; ambulatory: F(2,3)=20.49, p<.05] of the same form as the circadian temperature rhythm. In contrast, NA exhibited an increasing linear trend over time under the ambulatory protocol [F(1,11)=5.74, p<0.05] but nonsignificant temporal variation under the CR protocol. The findings support the hypothesis of a circadian component in PA variation.     

Late-night presentation of an auditory stimulus phase delays human circadian rhythms

Although light is considered the primary entrainer of circadian rhythms in humans, nonphotic stimuli, including exercise and melatonin also phase shift the biological clock. Furthermore, in birds and nonhuman mammals, auditory stimuli are effective zeitgebers. This study investigated whether a nonphotic auditory stimulus phase shifts human circadian rhythms. Ten subjects (5 men and 5 women, ages 18-72, mean age +/- SD, 44.7 +/- 21.4 yr) completed two 4-day laboratory sessions in constant dim light (<20 lux). They received two consecutive presentations of either a 2-h auditory or control stimulus from 0100 to 0300 on the second and third nights (presentation order of the stimulus and control was counterbalanced). Core body temperature (CBT) was collected and stored in 2-min bins throughout the study and salivary melatonin was obtained every 30 min from 1900 to 2330 on the baseline and poststimulus/postcontrol nights. Circadian phase of dim light melatonin onset (DLMO) and of CBT minimum, before and after auditory or control presentation was assessed. The auditory stimulus produced significantly larger phase delays of the circadian melatonin (mean +/- SD, -0.89 +/- 0.40 h vs. -0.27 +/- 0.16 h) and CBT (-1.16 +/- 0.69 h vs. -0.44 +/- 0.27 h) rhythms than the control. Phase changes for the two circadian rhythms also positively correlated, indicating direct effects on the biological clock. In addition, the auditory stimulus significantly decreased fatigue compared with the control. This study is the first demonstration of an auditory stimulus phase-shifting circadian rhythms in humans, with shifts similar in size and direction to those of other nonphotic stimuli presented during the early subjective night. This novel stimulus may be a useful countermeasure to facilitate circadian adaptation after transmeridian travel or shift work.     

An arousing, musically enhanced bird song stimulus mediates circadian rhythm phase advances in dim light

A musically enhanced bird song stimulus presented in the early subjective night phase delays human circadian rhythms. This study determined the phase-shifting effects of the same stimulus in the early subjective day. Eleven subjects (ages 18-63 yr; mean +/- SD: 28.0 +/- 16.6 yr) completed two 4-day laboratory sessions in constant dim light (<20 lux). They received two consecutive presentations of either a 2-h musically enhanced bird song or control stimulus from 0600 to 0800 on the second and third mornings while awake. The 4-day sessions employing either the stimulus or control were counterbalanced. Core body temperature (CBT) was collected throughout the study, and salivary melatonin was obtained every 30 min from 1900 to 2330 on the baseline and poststimulus/postcontrol nights. Dim light melatonin onset and CBT minimum circadian phase before and after stimulus or control presentation was assessed. The musically enhanced bird song stimulus produced significantly larger phase advances of the circadian melatonin (mean +/- SD: 0.87 +/- 0.36 vs. 0.24 +/- 0.22 h) and CBT (1.08 +/- 0.50 vs. 0.43 +/- 0.37 h) rhythms than the control. The stimulus also decreased fatigue and total mood disturbance, suggesting arousing effects. This study shows that a musically enhanced bird song stimulus presented during the early subjective day phase advances circadian rhythms. However, it remains unclear whether the phase shifts are due directly to effects of the stimulus on the clock or are arousal- or dim light-mediated effects. This nonphotic stimulus mediates circadian resynchronization in either the phase advance or delay direction.     

The benefits of four weeks of melatonin treatment on circadian patterns in resistance-trained athletes

Exercise can induce circadian phase shifts depending on the duration, intensity and frequency. These modifications are of special meaning in athletes during training and competition. Melatonin, which is produced by the pineal gland in a circadian manner, behaves as an endogenous rhythms synchronizer, and it is used as a supplement to promote resynchronization of altered circadian rhythms. In this study, we tested the effect of melatonin administration on the circadian system in athletes. Two groups of athletes were treated with 100?mg?day^?1 of melatonin or placebo 30?min before bed for four weeks. Daily rhythm of salivary melatonin was measured before and after melatonin administration. Moreover, circadian variables, including wrist temperature (WT), motor activity and body position rhythmicity, were recorded during seven days before and seven days after melatonin or placebo treatment with the aid of specific sensors placed in the wrist and arm of each athlete. Before treatment, the athletes showed a phase-shift delay of the melatonin circadian rhythm, with an acrophase at 05:00?h. Exercise induced a phase advance of the melatonin rhythm, restoring its acrophase accordingly to the chronotype of the athletes. Melatonin, but not placebo treatment, changed daily waveforms of WT, activity and position. These changes included a one-hour phase advance in the WT rhythm before bedtime, with a longer nocturnal steady state and a smaller reduction when arising at morning than the placebo group. Melatonin, but not placebo, also reduced the nocturnal activity and the activity and position during lunch/nap time. Together, these data reflect the beneficial effect of melatonin to modulate the circadian components of the sleep–wake cycle, improving sleep efficiency.     

Comparison of amplitude recovery dynamics of two limit cycle oscillator models of the human circadian pacemaker

At an organism level, the mammalian circadian pacemaker is a two-dimensional system. For these two dimensions, phase (relative timing) and amplitude of the circadian pacemaker are commonly used. Both the phase and the amplitude (A) of the human circadian pacemaker can be observed within multiple physiological measures--including plasma cortisol, plasma melatonin, and core body temperature (CBT)--all of which are also used as markers of the circadian system. Although most previous work has concentrated on changes in phase of the circadian system, critically timed light exposure can significantly reduce the amplitude of the pacemaker. The rate at which the amplitude recovers to its equilibrium level after reduction can have physiological significance. Two mathematical models that describe the phase and amplitude dynamics of the pacemaker have been reported. These models are essentially equivalent in predictions of phase and in predictions of amplitude recovery for small changes from an equilibrium value (A = 1), but are markedly different in the prediction of recovery rates when A < 0.6. To determine which dynamic model best describes the amplitude recovery observed in experimental data; both models were fit to CBT data using a maximum likelihood procedure and compared using Akaike's Information Criterion (AIC). For all subjects, the model with the lower recovery rate provided a better fit to data in terms of AIC, supporting evidence that the amplitude recovery of the endogenous pacemaker is slow at low amplitudes. Experiments derived from model predictions are proposed to test the influence of low amplitude recovery on the physiological and neurobehavioral functions.     

Phase relationship between skin temperature and sleep-wake rhythms in women with vascular dysregulation and controls under real-life conditions

The aim of the study was to investigate whether women with primary vascular dysregulation (VD; main symptoms of thermal discomfort with cold extremities) and difficulties initiating sleep (DIS) exhibit a disturbed phase of entrainment (Ψ) under everyday life conditions. The authors predicted a phase delay of the distal-proximal skin temperature gradient and salivary melatonin rhythms with respect to the sleep-wake cycle in women with VD and DIS (WVD) compared to controls (CON), similar to that found in their previous constant-routine laboratory data. A total of 41 young healthy women, 20 with WVD and 21 matched CON without VD and normal sleep onset latency (SOL), were investigated under ambulatory conditions (following their habitual bedtimes) during 7 days of continuous recording of skin temperatures, sleep-wake cycles monitored by actimetry and sleep-wake diaries, and single evening saliva collections for determining the circadian marker of dim light melatonin onset (DLMO). Compared to CON, WVD showed increased distal vasoconstriction at midday and in the evening, as indicated by lower distal (DIST; hands and feet) and foot-calf skin temperatures, and distal-proximal skin temperature gradients (p相似文献   

Partial sleep deprivation reduces phase advances to light in humans

Partial sleep deprivation is increasingly common in modern society. This study examined for the first time if partial sleep deprivation alters circadian phase shifts to bright light in humans. Thirteen young healthy subjects participated in a repeated-measures counterbalanced design with 2 conditions. Each condition had baseline sleep, a dim-light circadian phase assessment, a 3-day phase-advancing protocol with morning bright light, then another phase assessment. In one condition (no sleep deprivation), subjects had an 8-h sleep opportunity per night during the advancing protocol. In the other condition (partial sleep deprivation), subjects were kept awake for 4 h in near darkness (<0.25 lux), immediately followed by a 4-h sleep opportunity per night during the advancing protocol. The morning bright light stimulus was four 30-min pulses of bright light (~5000 lux), separated by 30-min intervals of room light. The light always began at the same circadian phase, 8 h after the baseline dim-light melatonin onset (DLMO). The average phase advance without sleep deprivation was 1.8 ± 0.6 (SD) h, which reduced to 1.4 ± 0.6 h with partial sleep deprivation (p < 0.05). Ten of the 13 subjects showed reductions in phase advances with partial sleep deprivation, ranging from 0.2 to 1.2 h. These results indicate that short-term partial sleep deprivation can moderately reduce circadian phase shifts to bright light in humans. This may have significant implications for the sleep-deprived general population and for the bright light treatment of circadian rhythm sleep disorders such as delayed sleep phase disorder.