Circadian control of the sleep-wake cycle

It is beyond doubt that the timing of sleep is under control of the circadian pacemaker. Humans are a diurnal species; they sleep mostly at night, and they do so at approximately 24-h intervals. If they do not adhere to this general pattern, for instance when working night shifts or when travelling across time zones, they experience the stubborn influence of their circadian clock. In recent years much has been discovered about the organisation of the circadian clock. New photoreceptor cells in the retina have been found to influence the input to the clock, and much of the molecular machinery of the clock has been unravelled. It is now known that the circadian rhythm of sleep and wakefulness is only loosely coupled to the circadian rhythm of the pacemaker. New theories have been proposed for the functions of sleep and the sites at which those functions are executed. In spite of this rapid increase in knowledge of the circadian clock and of sleep regulatory processes, much remains to be discovered concerning the precise interaction between the biological clock and sleep timing. This is particularly unfortunate in view of the 24-h demands of our society for 7 days a week. Too little is known about the negative consequences of the societal pressures on well-being and performance.     

Daytime sleep-wake cycle in the rat.

The daytime sleep-wake cycle of 20 male, albino rats was observed for a 8:00 a.m. to 8:00 p.m. period. EEG, EMG, gross body movement and eyelid position were continuously monitored throughout the 12 hr observation period. Based on percent of total time the results indicate that the rat's sleep-wake activities during the day are: awake, 24% (active, 17%; restings, 7%); SWS, 67% (light SWS, 13%; deep SWS, 54%); PS, 9%; and total sleep, 76%. The rats had a mean of 396 wake-ups from either SWS and PS per day. Visual observations revealed a sleep phenomenon not previously reported for the rat and termed “paradoxical awake”; an animal would generate typical light and deep SWS, EEG waves with either one or both eyes opened. The present results compared to previous findings revealed significant variability in estimates of the rat's sleep-wake activities which may be a function of illumination cycles, sleep observation times or duration of the adaptation periods.     

Hypothalamic contribution to sleep-wake cycle development

Infant mammals cycle rapidly between sleep and wakefulness and only gradually does a more consolidated sleep pattern develop. The neural substrates responsible for this consolidation are unknown. To establish a reliable measure of sleep-wake cyclicity in infant rats, nuchal muscle tone was measured in 2-, 5-, and 8-day-old rats, as were motor behaviors associated with sleep (i.e. myoclonic twitching) and wakefulness (e.g. kicking, stretching). Sleep-wake cycles of 2-day-old rats were characterized by short periods of muscle atonia followed by equally short periods of high tone. In 8-day-olds, sleep periods lengthened significantly and disproportionately in relation to awake periods. Next, locus coeruleus (LC) lesions in 8-day-olds resulted in rapid sleep-wake cycling similar to that exhibited by 2-day-olds; in addition, LC lesions had no effect on the duration of awake periods. Finally, transections caudal, but not rostral, to the anterior hypothalamus also reinstated rapid cycling in 8-day-olds, again without affecting the duration of awake periods. This last finding implicates neural structures within the anterior hypothalamus (e.g. ventrolateral preoptic area) in the modulation of sleep-wake cyclicity. The temporal coherence of atonia and myoclonic twitching was not disrupted by any of the manipulations.These results suggest the presence of a bistable mesopontine circuit governing rapid sleep-wake cycling that does not include the LC and that comes increasingly under hypothalamic control during the first postnatal week. This circuit may represent a basic building block with which other sleep components become integrated during ontogeny.     

The sleep-wake cycle and sleeping pills

Sleeping pills are drugs which are used world-wide to combat sleep disturbances, and to prevent symptoms due to maladjustment to shiftwork or jet-lag. Today, benzodiazepines and the so-called "non-benzodiazepines", such as zolpidem, which both act on benzodiazepine receptors, are drugs of first choice and they are substitutes for barbiturates. Their use as sleeping pills in insomniacs is established after appropriate medical diagnosis. Symptoms from shiftwork or jet-lag are due to an internal desynchronisation of biological rhythms, and there is ample evidence that benzodiazepines are not effective in preventing these symptoms. Cabin crews in particular should never take sleeping pills, in order not to impair cognitive functions or to reduce the reactivity needed to fly an aircraft safely. The biological clock(s) cannot be reset instantaneously by any drug.     

Hypernychthemeral sleep-wake cycle: some hidden regularities

A patient with a sleep-wake cycle greater than 24 h recorded his sleep-onset and wake times for 4 years. During this time the patient found himself unable to maintain a 24-h sleep-wake schedule. The lengths of his sleep-wake periods (subjective days) and his sleep periods were highly variable. Nonetheless, there were certain unexpected regularities in his sleep-wake data, corresponding to fixed clock hours. Across the 4-year period, there were certain clock hours during which sleep onset and waking were likely to occur and certain clock hours that may be considered forbidden zones for sleep, during which the patient rarely either began or ended a sleep period. It is possible that the unexpected regularities resulted from partial entrainment to external cues or from some residual influence of an endogenous ultradian-regulating mechanism.     

Disrupting life events and the sleep-wake cycle in depression

BACKGROUND: Social rhythm disruption life events are significant predictors of mood relapse in bipolar patients. However, no research has examined the relationship between these events and their hypothesized mechanism of action: disrupted sleep-wake patterns. The goal of this study was to test whether participants with major depressive disorder have a greater disruption of daily sleep and motor activity following disrupting life events when compared to normal controls. METHOD: Over the course of 2 weeks, 39 normal controls and 39 individuals with major depressive disorder completed life events interviews and wore actigraphs to obtain estimates of sleep/wake activity. RESULTS: Statistically significant interactions indicated that the presence of at least one disrupting life event in the previous 4 months correlated with elevations in the amount of time spent awake after sleep onset [beta=0.45, deltaF(1,73)=4.80, p<0.05], and decreases in the percentage of time spent asleep [beta=-0.53, deltaF(1,73)=6.57, p<0.05], in depressed individuals but not in normal controls. CONCLUSIONS: The results indicated that depressed individuals may be more susceptible to the effects of life events on sleep than normal controls. This is the first study to date to correlate life events with objective measures of sleep. However, prospective longitudinal research is necessary to clarify the temporal relationship among these variables.     

中缝背核在睡眠-觉醒中的作用

中缝背核(DRN)是调控睡眠-觉醒的重要核团,在脑内有着广泛的神经投射区域。DRN位于中脑导水管腹侧,主要由5-羟色胺(5-HT)、γ-氨基丁酸(GABA)、多巴胺(DA)和谷氨酸(Glu)能4类神经元构成。本文主要介绍了DRN的各类神经元在睡眠-觉醒中相关作用的最新研究进展。     

Kindling stimuli delivered at different times in the sleep-wake cycle

STUDY OBJECTIVES: Clinical and experimental observations argue that sleep disturbances are common and coexist in patients with epilepsy. Our previous observations have suggested that neural-immune interactions between corticotropin-releasing hormone (CRH) and interleukin-1 (IL-1) are involved in the regulation of physiological sleep-wake behavior. In the present study, we determined the involvement of CRH and IL-1 in the alteration of sleep-wake activities in rats when amygdala kindling was given either at the beginning of the light period (light-onset kindling) or at the beginning of the dark period (dark-onset kindling). DESIGN: The analysis of sleep-wake activities was performed before and after full-blown kindling, and the actions of CRH and IL-1 were tested by pharmacological blockade. SETTING: Neuroscience Laboratory at China Medical University Hospital. PARTICIPANT AND INTERVENTIONS: Male Sprague-Dawley rats were implanted with electroencephalogram (EEG) electrodes and an intracerebroventricular (ICV) guide cannula. Kindling stimuli delivered via a bipolar electrode placing in the right central nucleus of the amygdala. MEASUREMENT AND RESULTS: Amygdala kindling induced diverse effects on sleep. Slow-wave sleep (SWS) and rapid eye movement (REM) sleep decreased during the first 12-hour light period when rats were kindled at light onset. When dark-onset kindling was given, SWS increased but REM sleep was not altered during the first 12-hour dark period. After light-onset kindling, the circulating corticosterone concentrations increased and were blocked by ICV administration of the CRH receptor antagonist, astressin or alpha-hCRH. The ICV administration of the CRH antagonist blocked the light-onset kindling-induced decrease of SWS in a dose-dependent manner. After dark-onset kindling, IL-1 mRNA expression in the hippocampus and cortex increased. The dark-onset kindling-induced SWS was blocked in a dose-dependent manner by ICV administration of IL-1 receptor antagonist (IL-1 ra). The slow-wave activity during SWS was enhanced regardless of when kindling occurred, but both CRH antagonists and IL-1 ra had little effect on the alteration of slow-wave activity. CONCLUSION: These observations argue that amygdala-kindling-induced sleep-wake alterations are modulated by central increases in CRH or IL-1.     

Effects of valerian extract on the sleep-wake cycle in sleep-disturbed rats

The present study was performed to investigate the effects of valerian extract on the sleep-wake cycle using sleep-disturbed model rats. A significant shortening in sleep latency was observed with valerian extract at doses of 1000 and 3000 mg/kg. On the other hand, valerian extract had no significant effects on total times of wakefulness, non-rapid eye movement (non-REM) sleep, or REM sleep, even at a dose of 3000 mg/kg. Valerian extract at doses of 1000 and 3000 mg/kg showed a significant increase in the delta activity during non-REM sleep. In conclusion, valerian extract may be useful as an herbal medicine having not only sleep-inducing effects but also sleep quality-enhancement effects.     

Neonatal monosodium glutamate dosing alters the sleep-wake cycle of the mature rat

Alterations of the sleep-wake cycle have been studied in male adult rats after neonatal administration of monosodium glutamate (MSG; 4 X 4 mg/g body wt.). Results indicated that MSG treatment caused: an almost complete disappearance of ACTH and alpha-MSH immunoreactive (IR) perikarya in the rostral part of the arcuate nucleus; an increase in total sleep duration with a more pronounced effect on paradoxical sleep. Regarding circadian rhythmicity there was a trend to a decomposition of the 24 h period into ultradian components (12 h, 8 h, 6 h harmonics). The participation of pro-opiomelanocortin peptides in sleep regulation is discussed.     

Effect of chronic manganese intoxication on the sleep-wake cycle in the rat

Chronic manganese intoxication elicits in the rat an increase in slow wave sleep and a decrease in paradoxical sleep by modification of the length of the phases. The similarities between this observation and the sleep disturbances observed in man in Parkinson's disease and chronic manganese poisoning are discussed.     

High frequency activities in the human orbitofrontal cortex in sleep-wake cycle

We recorded human orbitofrontal electrocorticogram during wakefulness and sleep in epileptic patients using subdural electrodes. During wakefulness and rapid eye movement (REM) sleep, we observed beta activity in the raw orbitofrontal signals. Power spectral analysis demonstrated beta enhancement during wakefulness and REM sleep when compared to slow wave sleep (SWS). During the phasic REM periods, the beta power was significantly lower than during the tonic REM periods. Gamma enhancement manifested itself in four out of six subjects during the phasic periods. This study is the first that has focused on electrical activity in the human orbitofrontal cortex. Although the role of the orbitofrontal cortex during sleep still remains unclear, high frequency activities give us important suggestions in elucidating the human sleep mechanism.     

Endogenous and exogenous factors on sleep-wake cycle regulation.

A number of theories have proposed the involvement of different brain structures and neurotransmitters in order to explain the regulation of the sleep wake cycle. However, there is no clear consensus as to the mechanisms through which the brain structures and their various neurotransmitters interact to produce theses phases. Perhaps the problem is related to the fact sleep is a very fragile state, easily modified or influenced by a variety of substances or experimental manipulations. In this paper, we describe the evidence of two different groups of factors that induce important changes on the sleep wake cycle. The endogenous factors: neurotransmitters; hormone; peptides; and some substances of lipidic nature and exogenous factors: stress, food intake, learning, sleep deprivation, sensorial stimulation, exercise and temperature on the regulation the sleep-wake cycle. Likewise, we propose a hypothesis which attempts to reconcile the fact that endogenous and exogenous factors have similar effects.     

Twenty-four-hour structure of sleepiness in morning and evening persons investigated by ultrashort sleep-wake cycle

"Morning" and "evening" persons, defined according to a modified version of the Horne and Ostberg questionnaire, performed the 7/13 min sleep-waking schedule under attempting sleep condition after sleeping for one night in the laboratory, and under the resisting sleep condition after one night of sleep deprivation. Morning types slept significantly more under the attempting sleep condition and showed an earlier rise in nocturnal sleepiness. After sleep deprivation, morning types had a more distinct sleep propensity pattern with well-defined midafternoon and nocturnal sleep gates. In this condition there was a significant interaction between type and time of day with respect to amount of sleep: morning types slept more during the night, and evening types slept more during the day. Based on their amounts of sleep, subjects were also divided into "sleepy" and "alert" types, which were independent from the chronotypology.     

Interleukin-6 serum levels in healthy persons correspond to the sleep-wake cycle

Dedicated to Prof. Dr. Dr. h. c. W. Gerok on the occasion of his 68th birthday     

Effects of a short light-dark cycle on the sleep-wake patterns of the cat.

The purpose of this study was to measure the effect of a short, 106 min, light-dark (LD) cycle on the sleep-wake (SW) patterns of the cat. Eight cats prepared for chronic sleep studies were observed with electrographic tracings for 48 hr on a regular 12:12 hr LD schedule and again after 2 weeks of adaptation to a 27 min light and 79 min dark schedule. Each 1 min of data was scored as either alert, drowsy, slow wave sleep (SWS) or REM sleep. The parameters studied were percent electrographic state, state epoch length, polycyclic SW cycle, and mean vigilance. The short LD cycle caused a significant increase in alert state accompanied by reductions in drowsy, SWS, and REM sleep states. Although the effect was more pronounced during lights-on intervals, the trend was also present in dark intervals. Alert episodes of about all lengths increased. There were decreases in longer episodes of the other three states and a tendency for shorter episodes to increase in number. Episodes of the polycyclic SW cycle did not tend to follow the short LD cycle. The mean length of both sleep and wake episodes increased rather than decreased. However, mean vigilance values increased toward wakefulness at or near the light interval. Analyses showed that both the amplitude and phase relationship of this increase was significantly related to the 27 min light interval in comparison to base-line data. It was hypothesized that both light-dark and dark-light transitions represent alerting cues to the cat. Differences between the SW response of the cat and the rat to LD cycles are discussed.     

儿童癫痫发作与睡眠觉醒周期的关系

目的：研究儿童癫痫发作与睡眠觉醒周期的关系。方法：经同步录像脑电图（V—EEG）监测,对142例儿童癫痫发作期的临床表现与V-EEG进行同步分析。结果：142例患儿中94例（66．2％）患儿的发作与睡眠觉醒周期相关。此94例患儿的154次发作中,思睡期36次（23．4％）,睡眠I-Ⅱ期64次（41．6％）,睡眠Ⅲ-Ⅳ期10次（6．5％）,REM期1次（0．6％）,觉醒后43次（27．9％）;发作类型中,部分性发作或伴泛化全面性发作81次（52．6％）,痉挛发作27次（17．5％）,肌阵挛25次（16．2％）,强直发作11次（7．1％）,失神发作7次（4．6％）,强直阵挛发作3次（2．0％）。结论：儿童癫痫发作与睡眠觉醒周期密切相关,了解发作与睡眠觉醒周期的关系,既有助于更好地管理和治疗癫痫患儿,又有助于合理安排EEG检查的方式和时机,提高检查阳性率,确定发作类型。     

The human sleep-wake cycle reconsidered from a thermoregulatory point of view

Sleep is typically initiated on the declining portion of the circadian rhythm of core body temperature (CBT) when its rate of change, and body heat loss, is maximal. Distal vasodilatation plays a primary role in the circadian regulation of body heat loss and is strongly associated with sleepiness and sleep induction. In contrast, sleep (i.e. non-REM sleep and slow-wave activity, SWA) has no or only a minor thermoregulatory function. Two lines of evidence support this statement. First, detailed analyses of thermoregulatory changes before and after lights off show clearly that they start before stage 2 sleep begins. Second, accumulation of sleep pressure with increasing time awake, increases subjective sleepiness and SWA during the succeeding recovery night, but does not influence the thermoregulatory system. Taken together, the circadian modulation of sleepiness and sleep induction is clearly associated with thermoregulatory changes, but the thermoregulatory system seems to be independent of the sleepiness/sleep regulatory system. A simplified model is presented which attempts to explain the relationship between these two systems. It is based on the main hypothesis that all thermoregulatory effects which lead to an increase in the core/shell ratio (e.g. a reduced shell by increased distal skin temperature) lead to increased sleepiness and, as a consequence, to increased sleep propensity. However, the sleepiness/sleep regulatory system feeds back onto the thermoregulatory system only indirectly via sleep-related behaviors (e.g. relaxation, lying down).     

Correlation of high-frequency oscillations with the sleep-wake cycle and cognitive activity in humans

While several authors have suggested that high-frequency electroencephalogram activity (gamma, >30 Hz) correlates with conscious thought, others have suggested that electroencephalogram activity >30 Hz shows the same relationships to cognitive activity and sleep as activity in the conventional beta frequency band. The existence of coherence of gamma over large distances also remains controversial. We studied quantitatively the relationship of gamma activity to the sleep-wake cycle and cognitive tasks during wakefulness in humans using intracranial electroencephalogram. Gamma activity made up less than 1% of the total power spectrum. A significant relationship was observed between gamma activity and the sleep-wake cycle such that gamma was highest during wakefulness, intermediate during light and rapid eye movement sleep, and lowest during slow-wave sleep. As well, gamma was higher during rapid eye movement sleep with eye movements than during rapid eye movement sleep without eye movements. During a cognitive task experiment, while lower frequencies, including beta, showed a stepwise reduction with increasing task difficulty, gamma was observed to increase during cognitive tasks as compared to the resting state. The relationship between gamma and the sleep-wake cycle and cognitive tasks was independent of brain region and hemisphere. Coherence of gamma activity at distances of 5 mm and greater was not observed. Our data support previously reported findings that gamma activity has a significant relationship to the sleep-wake cycle. The findings of differences in gamma during REM sleep with and without eye movements suggest that the presence or absence of eye movements may reflect two different states of brain activity. Our findings of differences in the relationships of the beta and gamma bands to both the sleep-wake cycle and cognitive tasks demonstrate that various components of the high-frequency spectrum behave differently in some situations.     

Effects of sex differences and regulation of the sleep-wake cycle on aversive memory encoding

Formation of aversive memories sometimes involves a pathogenic cognitive process that could lead to the development of posttraumatic stress disorder (PTSD). Here, we explore chronobiological aspects of shifts in aversive memory encoding abilities around habitual sleep onset periods (SOPs). Thirty university students, who were randomly assigned to one of two groups, watched a suspenseful movie for 2 h, beginning either 3h prior to their habitual sleep onset periods (pre-SOP group) or 1h after their habitual sleep onset periods (post-SOP group). Recognition accuracy was tested 15 min after the movie finished and again 10h after the movie finished, after a sleep period. Overall recognition accuracy was higher in the post-SOP women than in the pre-SOP women, while that in the pre-SOP men was higher than that in the post-SOP men. The recognition accuracy gap (aversive-neutral) was significantly greater in the post-SOP women than in the pre-SOP women throughout both recognition sessions, while there was a non-significant group difference for men. These findings suggest that habitual SOP is a watershed in women's ability to learn to identify aversive events. Women more correctly encode aversive episodes post-SOP than pre-SOP, which could contribute to high PTSD prevalence in women.