Chronobiological characterization of women with primary vasospastic syndrome: body heat loss capacity in relation to sleep initiation and phase of entrainment

Women with primary vasospastic syndrome (VS), but otherwise healthy, exhibit a functional disorder of vascular regulation (main symptom: cold extremities) and often suffer from difficulties initiating sleep (DIS). Diverse studies have shown a close association between distal vasodilatation before lights off and a rapid onset of sleep. Therefore, we hypothesized that DIS in women with VS could be due to a reduced heat loss capacity in the evening, i.e., subjects are physiologically not ready for sleep. The aim of the study was to elucidate whether women having both VS and DIS (WVD) or not (controls) show different circadian characteristics (e.g., phase delay of the circadian thermoregulatory system with respect to the sleep-wake cycle). Healthy young women (n = 9 WVD and n = 9 control) completed a 40-h constant routine protocol (adjusted to habitual bedtime) before and after an 8-h sleep episode. Skin temperatures [off-line calculated as distal-proximal skin temperature gradient (DPG)] and core body temperature (CBT; rectal) were continuously recorded. Half-hourly saliva samples were collected for melatonin assay and subjective sleepiness was assessed on the Karolinska Sleepiness Scale (KSS). Compared with control, WVD showed no differences in habitual bed times, but a 1-h circadian phase delay of dim light-melatonin onset (hours after lights on: WVD 14.6 +/- 0.3 h; control 13.5 +/- 0.2 h; P = 0.01). Similar phase shifts were observed in CBT, DPG, and KSS ratings. In conclusion, WVD exhibit a phase delay of the endogenous circadian system with respect to their habitual sleep-wake cycle, which could be a cause of DIS.     

Predominance of distal skin temperature changes at sleep onset across menstrual and circadian phases

Menstrual cycle-associated changes in reproductive hormones affect body temperature in women. We aimed to characterize the interaction between the menstrual, circadian, and scheduled sleep-wake cycles on body temperature regulation. Eight females entered the laboratory during the midfollicular (MF) and midluteal (ML) phases of their menstrual cycle for an ultradian sleep-wake cycle procedure, consisting of 36 cycles of 60-minute wake episodes alternating with 60-minute nap opportunities, in constant bed-rest conditions. Core body temperature (CBT) and distal skin temperature (DT) were recorded and used to calculate a distal-core gradient (DCG). Melatonin, sleep, and subjective sleepiness were also recorded. The circadian variation of DT and DCG was not affected by menstrual phase. DT and DCG showed rapid, large nap episode-dependent increases, whereas CBT showed slower, smaller nap episode-dependent decreases. DCG values were significantly reduced for most of the wake episode in an overall 60-minute wake/60-minute nap cycle during ML compared to MF, but these differences were eliminated at the wake-to-nap lights-out transition. Nap episode-dependent decreases in CBT were further modulated as a function of both circadian and menstrual factors, with nap episode-dependent deceases occurring more prominently during the late afternoon/evening in ML, whereas nap episode-dependent DT and DCG increases were not significantly affected by menstrual phase but only circadian phase. Circadian rhythms of melatonin secretion, DT, and DCG were significantly phase-advanced relative to CBT and sleep propensity rhythms. This study explored how the thermoregulatory system is influenced by an interaction between circadian phase and vigilance state and how this is further modulated by the menstrual cycle. Current results agree with the thermophysiological cascade model of sleep and indicate that despite increased CBT during ML, heat loss mechanisms are maintained at a similar level during nap episodes, which may allow for comparable circadian sleep propensity rhythms between menstrual phases.     

Thermoregulatory effects of melatonin in relation to sleepiness

Thermoregulatory processes have long been implicated in the initiation of human sleep. In this paper, we review our own studies conducted over the last decade showing a crucial role for melatonin as a mediator between the thermoregulatory and arousal system in humans. Distal heat loss, via increased skin temperature, seems to be intimately coupled with increased sleepiness and sleep induction. Exogenous melatonin administration during the day when melatonin is essentially absent mimics the endogenous thermophysiological processes occurring in the evening and induces sleepiness. Using a cold thermic challenge test, it was shown that melatonin-induced sleepiness occurs in parallel with reduction in the thermoregulatory set-point (threshold); thus, melatonin may act as a circadian modulator of the thermoregulatory set-point. In addition, an orthostatic challenge can partially block the melatonin-induced effects, suggesting an important role of the sympathetic nervous system as a link between the thermoregulatory and arousal systems. A topographical analysis of finger skin temperature with infrared thermometry revealed that the most distal parts of the fingers, i.e., fingertips, represent the important skin regions for heat loss regulation, most probably via opening the arteriovenous anastomoses, and this is clearly potentiated by melatonin. Taken together, melatonin is involved in the fine-tuning of vascular tone in selective vascular beds, as circulating melatonin levels rise and fall throughout the night. Besides the role of melatonin as "nature's soporific", it can also serve as nature's nocturnal vascular modulator.     

Thermoregulatory effects of melatonin in relation to sleepiness

Thermoregulatory processes have long been implicated in the initiation of human sleep. In this paper, we review our own studies conducted over the last decade showing a crucial role for melatonin as a mediator between the thermoregulatory and arousal system in humans. Distal heat loss, via increased skin temperature, seems to be intimately coupled with increased sleepiness and sleep induction. Exogenous melatonin administration during the day when melatonin is essentially absent mimics the endogenous thermophysiological processes occurring in the evening and induces sleepiness. Using a cold thermic challenge test, it was shown that melatonin‐induced sleepiness occurs in parallel with reduction in the thermoregulatory set‐point (threshold); thus, melatonin may act as a circadian modulator of the thermoregulatory set‐point. In addition, an orthostatic challenge can partially block the melatonin‐induced effects, suggesting an important role of the sympathetic nervous system as a link between the thermoregulatory and arousal systems. A topographical analysis of finger skin temperature with infrared thermometry revealed that the most distal parts of the fingers, i.e., fingertips, represent the important skin regions for heat loss regulation, most probably via opening the arteriovenous anastomoses, and this is clearly potentiated by melatonin. Taken together, melatonin is involved in the fine‐tuning of vascular tone in selective vascular beds, as circulating melatonin levels rise and fall throughout the night. Besides the role of melatonin as “nature's soporific”, it can also serve as nature's nocturnal vascular modulator.     

Relationships between the circadian rhythms of finger temperature, core temperature, sleep latency, and subjective sleepiness

Skin temperature circadian rhythms have been explored relatively recently. It has been suggested that distal and proximal skin temperature changes play a role in the regulation of the core temperature circadian rhythm and sleepiness. The authors investigated the circadian finger and core temperature rhythms in conjunction with the circadian rhythms of subjective and objective sleepiness. Fourteen healthy, young, good sleepers participated in a modified constant-routine procedure in which palmar finger temperature, rectal temperature, subjective sleepiness, and objective sleep latency were measured half-hourly across a 48-h period of enforced wakeful bed rest. Individual curves were adjusted to the group mean temperature minimum time of 0500 h and averaged to create the 4 mean curves. The 5 possible cross-correlation curves between these 4 measures were calculated for half-hourly phase lags from 12 h before to 12 h after the group mean core temperature minimum time. Maximum cross-correlations for each curve suggested that finger temperature preceded core temperature by 3 h (r = -0.22), and subjective sleepiness followed core temperature by 0.5 h (r = -0.33) and objective sleepiness by 2 h (r = 0.29). Although these data are correlational, they are consistent with the notion that finger temperature changes drive core temperature changes, which determine changes of subjective and objective sleepiness.     

Young women with major depression live on higher homeostatic sleep pressure than healthy controls

There is mounting evidence for the involvement of the sleep-wake cycle and the circadian system in the pathogenesis of major depression. However, only a few studies so far focused on sleep and circadian rhythms under controlled experimental conditions. Thus, it remains unclear whether homeostatic sleep pressure or circadian rhythms, or both, are altered in depression. Here, the authors aimed at quantifying homeostatic and circadian sleep-wake regulatory mechanisms in young women suffering from major depressive disorder and healthy controls during a multiple nap paradigm under constant routine conditions. After an 8-h baseline night, 9 depressed women, 8 healthy young women, and 8 healthy older women underwent a 40-h multiple nap protocol (10 short sleep-wake cycles) followed by an 8-h recovery night. Polysomnographic recordings were done continuously, and subjective sleepiness was assessed. In order to measure circadian output, salivary melatonin samples were collected during scheduled wakefulness, and the circadian modulation of sleep spindles was analyzed with reference to the timing of melatonin secretion. Sleep parameters as well as non-rapid eye movement (NREM) sleep electroencephalographic (EEG) spectra were determined for collapsed left, central, and right frontal, central, parietal, and occipital derivations for the night and nap-sleep episodes in the frequency range .75-25 Hz. Young depressed women showed higher frontal EEG delta activity, as a marker of homeostatic sleep pressure, compared to healthy young and older women across both night sleep episodes together with significantly higher subjective sleepiness. Higher delta sleep EEG activity in the naps during the biological day were observed in young depressed women along with reduced nighttime melatonin secretion as compared to healthy young volunteers. The circadian modulation of sleep spindles between the biological night and day was virtually absent in healthy older women and partially impaired in young depressed women. These data provide strong evidence for higher homeostatic sleep pressure in young moderately depressed women, along with some indications for impairment of the strength of the endogenous circadian output signal involved in sleep-wake regulation. This finding may have important repercussions on the treatment of the illness as such that a selective suppression of EEG slow-wave activity could promote acute mood improvement.     

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.     

Young Women With Major Depression Live on Higher Homeostatic Sleep Pressure Than Healthy Controls

There is mounting evidence for the involvement of the sleep-wake cycle and the circadian system in the pathogenesis of major depression. However, only a few studies so far focused on sleep and circadian rhythms under controlled experimental conditions. Thus, it remains unclear whether homeostatic sleep pressure or circadian rhythms, or both, are altered in depression. Here, the authors aimed at quantifying homeostatic and circadian sleep-wake regulatory mechanisms in young women suffering from major depressive disorder and healthy controls during a multiple nap paradigm under constant routine conditions. After an 8-h baseline night, 9 depressed women, 8 healthy young women, and 8 healthy older women underwent a 40-h multiple nap protocol (10 short sleep-wake cycles) followed by an 8-h recovery night. Polysomnographic recordings were done continuously, and subjective sleepiness was assessed. In order to measure circadian output, salivary melatonin samples were collected during scheduled wakefulness, and the circadian modulation of sleep spindles was analyzed with reference to the timing of melatonin secretion. Sleep parameters as well as non-rapid eye movement (NREM) sleep electroencephalographic (EEG) spectra were determined for collapsed left, central, and right frontal, central, parietal, and occipital derivations for the night and nap-sleep episodes in the frequency range .75–25?Hz. Young depressed women showed higher frontal EEG delta activity, as a marker of homeostatic sleep pressure, compared to healthy young and older women across both night sleep episodes together with significantly higher subjective sleepiness. Higher delta sleep EEG activity in the naps during the biological day were observed in young depressed women along with reduced nighttime melatonin secretion as compared to healthy young volunteers. The circadian modulation of sleep spindles between the biological night and day was virtually absent in healthy older women and partially impaired in young depressed women. These data provide strong evidence for higher homeostatic sleep pressure in young moderately depressed women, along with some indications for impairment of the strength of the endogenous circadian output signal involved in sleep-wake regulation. This finding may have important repercussions on the treatment of the illness as such that a selective suppression of EEG slow-wave activity could promote acute mood improvement. (Author correspondence: Christian.cajochen@upkbs.ch)     

Masking effects of posture and sleep onset on core body temperature have distinct circadian rhythms: results from a 90-min/day protocol

Both recumbency and sleep affect core body temperature (CBT). To characterize their circadian effects and interactions, the authors examined the bedtime temperature drops (TDs) of nine men and eight women (aged 20 to 30) who repeated 90-min sleep-wake cycles over 2.5 days. While awake, subjects were exposed to 50 to 250 lux; while asleep, lights were off. Electroencephalogram-monitored time inbed lasted 30 min during each cycle. Cosinor nonlinear mixed-effects regressions modeled the circadian rhythm of TDs. The circadian maximum of TDs occurred approximately 4 h before the time of circadian CBT minimum, in a model that included the effects of baseline expected CBT, deviations from baseline CBT, time in study, and gender-dependent 24- and 12-h adjustments. Rates of temperature drops were faster during initial periods of lying awake than during periods of initially sleeping. Both rates followed separate circadian rhythms. The circadian maximum of TDs was located near customary nocturnal bedtimes, suggesting its role in fostering sleep during a normal bedtime routine. The apparent deceleration of temperature dropping at sleep onset supports the notion that the sleep onset period has complicated circadian neuroregulatory dynamics. These findings confirm the need for nonlinear models of temperature responses to postural changes and sleep that incorporate circadian variability in these masking effects.     

Time course of neurobehavioral alertness during extended wakefulness in morning- and evening-type healthy sleepers

The aim of the study was to evaluate the influence of chronotype (morning-type versus evening-type) living in a fixed sleep-wake schedule different from one's preferred sleep schedules on the time course of neurobehavioral performance during controlled extended wakefulness. The authors studied 9 morning-type and 9 evening-type healthy male subjects (21.4 ± 1.9 yrs). Before the experiment, all participants underwent a fixed sleep-wake schedule mimicking a regular working day (bedtime: 23:30 h; wake time: 07:30 h). Then, following two nights in the laboratory, both chronotypes underwent a 36-h constant routine, performing a cognitive test of sustained attention every hour. Core body temperature, salivary melatonin secretion, objective alertness (maintenance of wakefulness test), and subjective sleepiness (visual analog scale) were also assessed. Evening-types expressed a higher level of subjective sleepiness than morning types, whereas their objective levels of alertness were not different. Cognitive performance in the lapse domain remained stable during the normal waking day and then declined during the biological night, with a similar time course for both chronotypes. Evening types maintained optimal alertness (i.e., 10% fastest reaction time) throughout the night, whereas morning types did not. For both chronotypes, the circadian performance profile was correlated with the circadian subjective somnolence profile and was slightly phase-delayed with melatonin secretion. Circadian performance was less correlated with circadian core body temperature. Lapse domain was phase-delayed with body temperature (2-4 h), whereas optimal alertness was slightly phase-delayed with body temperature (1 h). These results indicate evening types living in a fixed sleep-wake schedule mimicking a regular working day (different from their preferred sleep schedules) express higher subjective sleepiness but can maintain the same level of objective alertness during a normal waking day as morning types. Furthermore, evening types were found to maintain optimal alertness throughout their nighttime, whereas morning types could not. The authors suggest that evening-type subjects have a higher voluntary engagement of wake-maintenance mechanisms during extended wakefulness due to adaptation of their sleep-wake schedule to social constraints.     

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.     

A relationship between heat loss and sleepiness: effects of postural change and melatonin administration

Kräuchi, Kurt, Christian Cajochen, and AnnaWirz-Justice. A relationship between heat loss and sleepiness:effects of postural change and melatonin administration.J. Appl. Physiol. 83(1): 134-139, 1997.Both the pineal hormone melatonin (Mel) and postural changeshave thermoregulatory sequelae. The purpose of the study was toevaluate their relationship to subjective sleepiness. Eight healthyyoung men were investigated under the unmasking conditions of aconstant routine protocol. Heart rate, rectal temperature(T_re), skin temperatures (foot,T_fo; and stomach), and subjectivesleepiness ratings were continuously recorded from 1000 to 1700. Mel (5 mg po) was administered at 1300, a time when Mel should not phaseshift the circadian system. Both the postural change at1000 from upright to a supine position (lying down in bed) and Meladministration at 1300 reduced T_reand increased T_fo in parallel withincreased sleepiness. These findings suggest that under comfortableambient temperature conditions, heat loss via the distal skin regions(e.g., feet) is a key mechanism for induction of sleepiness as corebody temperature declines.

     

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).     

Time Course of Neurobehavioral Alertness During Extended Wakefulness in Morning- and Evening-Type Healthy Sleepers

The aim of the study was to evaluate the influence of chronotype (morning-type versus evening-type) living in a fixed sleep-wake schedule different from one's preferred sleep schedules on the time course of neurobehavioral performance during controlled extended wakefulness. The authors studied 9 morning-type and 9 evening-type healthy male subjects (21.4?±?1.9 yrs). Before the experiment, all participants underwent a fixed sleep-wake schedule mimicking a regular working day (bedtime: 23:30?h; wake time: 07:30?h). Then, following two nights in the laboratory, both chronotypes underwent a 36-h constant routine, performing a cognitive test of sustained attention every hour. Core body temperature, salivary melatonin secretion, objective alertness (maintenance of wakefulness test), and subjective sleepiness (visual analog scale) were also assessed. Evening-types expressed a higher level of subjective sleepiness than morning types, whereas their objective levels of alertness were not different. Cognitive performance in the lapse domain remained stable during the normal waking day and then declined during the biological night, with a similar time course for both chronotypes. Evening types maintained optimal alertness (i.e., 10% fastest reaction time) throughout the night, whereas morning types did not. For both chronotypes, the circadian performance profile was correlated with the circadian subjective somnolence profile and was slightly phase-delayed with melatonin secretion. Circadian performance was less correlated with circadian core body temperature. Lapse domain was phase-delayed with body temperature (2–4?h), whereas optimal alertness was slightly phase-delayed with body temperature (1?h). These results indicate evening types living in a fixed sleep-wake schedule mimicking a regular working day (different from their preferred sleep schedules) express higher subjective sleepiness but can maintain the same level of objective alertness during a normal waking day as morning types. Furthermore, evening types were found to maintain optimal alertness throughout their nighttime, whereas morning types could not. The authors suggest that evening-type subjects have a higher voluntary engagement of wake-maintenance mechanisms during extended wakefulness due to adaptation of their sleep-wake schedule to social constraints. (Author correspondence: jack.taillard@gmail.com)     

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 ).     

Repeated exposures to daytime bright light increase nocturnal melatonin rise and maintain circadian phase in young subjects under fixed sleep schedule

Effects of two different light intensities during daytime were examined on human circadian rhythms in plasma melatonin, core body temperature, and wrist activity under a fixed sleep schedule. Sleep qualities as indicated by polysomnography and subjective sleepiness were also measured. In the first week, under dim light conditions ( approximately 10 lx), the onset and peak of nocturnal melatonin rise were significantly delayed, whereas the end of melatonin rise was not changed. The peak level of melatonin rise was not affected. As a result, the width of nocturnal melatonin rise was significantly shortened. In the second week, under bright light conditions ( approximately 5,000 lx), the phases of nocturnal melatonin rise were not changed further, but the peak level was significantly increased. Core body temperature at the initial sleep phase was progressively elevated during the course of dim light exposure and reached the maximum level at the first night of bright light conditions. Subjective sleepiness gradually declined in the course of dim light exposure and reached the minimum level at the first day of bright light. These findings indicate that repeated exposures to daytime bright light are effective in controlling the circadian phase and increasing the peak level of nocturnal melatonin rise in plasma and suggest a close correlation between phase-delay shifts of the onset of nocturnal melatonin rise or body temperature rhythm and daytime sleepiness.     

Functional link between distal vasodilation and sleep-onset latency?

Thermoregulatory processes have long been implicated in initiation of human sleep. The purpose of this study was to evaluate the role of heat loss in sleep initiation, under the controlled conditions of a constant-routine protocol modified to permit nocturnal sleep. Heat loss was indirectly measured by means of the distal-to-proximal skin temperature gradient (DPG). A stepwise regression analysis revealed that the DPG was the best predictor variable for sleep-onset latency (compared with core body temperature or its rate of change, heart rate, melatonin onset, and subjective sleepiness ratings). This study provides evidence that selective vasodilation of distal skin regions (and hence heat loss) promotes the rapid onset of sleep.     

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.     

Cutaneous warming promotes sleep onset

Sleep occurs in close relation to changes in body temperature. Both the monophasic sleep period in humans and the polyphasic sleep periods in rodents tend to be initiated when core body temperature is declining. This decline is mainly due to an increase in skin blood flow and consequently skin warming and heat loss. We have proposed that these intrinsically occurring changes in core and skin temperatures could modulate neuronal activity in sleep-regulating brain areas (Van Someren EJW, Chronobiol Int 17: 313-54, 2000). We here provide results compatible with this hypothesis. We obtained 144 sleep-onset latencies while directly manipulating core and skin temperatures within the comfortable range in eight healthy subjects under controlled conditions. The induction of a proximal skin temperature difference of only 0.78 +/- 0.03 degrees C (mean +/- SE) around a mean of 35.13 +/- 0.11 degrees C changed sleep-onset latency by 26%, i.e., by 3.09 minutes [95% confidence interval (CI), 1.91 to 4.28] around a mean of 11.85 min (CI, 9.74 to 14.41), with faster sleep onsets when the proximal skin was warmed. The reduction in sleep-onset latency occurred despite a small but significant decrease in subjective comfort during proximal skin warming. The induction of changes in core temperature (delta = 0.20 +/- 0.02 degrees C) and distal skin temperature (delta = 0.74 +/- 0.05 degrees C) were ineffective. Previous studies have demonstrated correlations between skin temperature and sleep-onset latency. Also, sleep disruption by ambient temperatures that activate thermoregulatory defense mechanisms has been shown. The present study is the first to experimentally demonstrate a causal contribution to sleep-onset latency of skin temperature manipulations within the normal nocturnal fluctuation range. Circadian and sleep-appetitive behavior-induced variations in skin temperature might act as an input signal to sleep-regulating systems.     

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)