Crosstalk between central and peripheral biological clocks

Mammalian circadian system is multi-oscillator system. Clock gene expression analysis revealed that central clock, suprachiasmatic nucleus, organizes and synchronizes the peripheral oscillators in the whole body cells. Similarly, human circadian system is considered to be dual oscillation system because of internal desynchronization between melatonin, body temperature rhythms(driven by oscillator I) and sleep-wake rhythm (driven by oscillator II) under temporal isolation of dim light conditions. These oscillators control their periods mutually which means there is crosstalk of oscillators. Although the effect from oscillator II to oscillator I is weak under experimental dim light conditions, sleep-wake behavior controls light input to light sensitive oscillator I and feedbacks to sleep-wake driving oscillator II under lighting condition we live. To understand these mechanisms is important for prevention of circadian rhythm related diseases.     

Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics.

The light-entrainable circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus regulates the timing and consolidation of sleep by generating a paradoxical rhythm of sleep propensity; the circadian drive for wakefulness peaks at the end of the day spent awake, ie close to the onset of melatonin secretion at 21.00-22.00 h and the circadian drive for sleep crests shortly before habitual waking-up time. With advancing age, ie after early adulthood, sleep consolidation declines, and time of awakening and the rhythms of body temperature, plasma melatonin and cortisol shift to an earlier clock hour. The variability of the phase relationship between the sleep-wake cycle and circadian rhythms increases, and in old age sleep is more susceptible to internal arousing stimuli associated with circadian misalignment. The propensity to awaken from sleep advances relative to the body temperature nadir in older people, a change that is opposite to the phase delay of awakening relative to internal circadian rhythms associated with morningness in young people. Age-related changes do not appear to be associated with a shortening of the circadian period or a reduction of the circadian drive for wake maintenance. These changes may be related to changes in the sleep process itself, such as reductions in slow-wave sleep and sleep spindles as well as a reduced strength of the circadian signal promoting sleep in the early morning hours. Putative mediators and modulators of circadian sleep regulation are discussed.     

Relationship of endogenous circadian melatonin and temperature rhythms to self-reported preference for morning or evening activity in young and older people.

BACKGROUND: Morningness-eveningness refers to interindividual differences in preferred timing of behavior (i.e., bed and wake times). Older people have earlier wake times and rate themselves as more morning-like than young adults. It has been reported that the phase of circadian rhythms is earlier in morning-types than in evening types, and that older people have earlier phases than young adults. These changes in phase have been considered to be the chronobiological basis of differences in preferred bed and wake times and age-related changes therein. Whether such differences in phase are associated with changes in the phase relationship between endogenous circadian rhythms and the sleep-wake cycle has not been investigated previously. METHODS: We investigated the association between circadian phase, the phase relationship between the sleep-wake cycle and circadian rhythms, and morningness-eveningness, and their interaction with aging. In this circadian rhythm study, 68 young and 40 older subjects participated. RESULTS: Among the young subjects, the phase of the melatonin and core temperature rhythms occurred earlier in morning than in evening types and the interval between circadian phase and usual wake time was longer in morning types. Thus, while evening types woke at a later clock hour than morning types, morning types actually woke at a later circadian phase. Comparing young and older morning types we found that older morning types had an earlier circadian phase and a shorter phase-wake time interval. The shorter phase-waketime interval in older "morning types" is opposite to the change associated with morningness in young people, and is more similar to young evening types. CONCLUSIONS: These findings demonstrate an association between circadian phase, the relationship between the sleep-wake cycle and circadian phase, and morningness-eveningness in young adults. Furthermore, they demonstrate that age-related changes in phase angle cannot be attributed fully to an age-related shift toward morningness. These findings have important implications for understanding individual preferences in sleep-wake timing and age-related changes in the timing of sleep.     

Circadian rhythm sleep disorders

Individuals who have circadian rhythm sleep disorders present with symptoms of insomnia or excessive sleepiness and complain of an inability to sleep at their desired time. Although the primary etiology of these disorders is a misalignment between the endogenous circadian clock and the external environment, social and behavioral factors can also play important roles in perpetuating or exacerbating these disorders. Currently, the management of circadian rhythm disorders is limited to the use of bright light and melatonin to realign the circadian clock with the desired sleep time.However, as the understanding of the physiologic and genetic basis of sleep and circadian rhythm regulation advances, even more practical and effective treatments should become available.     

Racial Differences in the Human Endogenous Circadian Period

The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study, subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays, relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep phase disorder.     

Molecular genetics of timing in intrinsic circadian rhythm sleep disorders

Recent advances in circadian biology are identifying key genes and the molecular clockworks they command. These biochemical systems provide new tools for evaluating clinically observed, intrinsic circadian rhythm sleep disorders. A striking example was last year's discovery of a point mutation in a human clock gene that produces a sleep phase syndrome. This finding suggested that other intrinsic sleep disorders may have genetic underpinnings, and that less debilitating variations in sleep/wake behavior may be revealed by molecular screening of known clock genes in broader human populations.     

Molecular genetics of timing in intrinsic circadian rhythm sleep disorders

Recent advances in circadian biology are identifying key genes and the molecular clockworks they command. These biochemical systems provide new tools for evaluating clinically observed, intrinsic circadian rhythm sleep disorders. A striking example was last year's discovery of a point mutation in a human clock gene that produces a sleep phase syndrome. This finding suggested that other intrinsic sleep disorders may have genetic underpinnings, and that less debilitating variations in sleep/wake behavior may be revealed by molecular screening of known clock genes in broader human populations.     

Desynchronization of daily rest-activity rhythm in the days following light propofol anesthesia for colonoscopy

Anesthesia and surgery are associated with fatigue and sleep disorders, suggestive of disturbance of the circadian rest-activity rhythm. Previous studies on circadian rhythm disturbance were focused on patients undergoing general anesthesia associated with surgery. This does not permit one to draw valid conclusions about the effects of general anesthesia per se on circadian rhythms. Our study was set up to determine the impact of a hypnotic dose of propofol on the circadian rest-activity rhythm in humans under real-life conditions. Seventeen healthy subjects scheduled to receive light propofol anesthesia for ambulatory colonoscopy were investigated. Their rest-activity rhythms were assessed using actigraphic monitoring. Diurnal rest was increased, whereas nocturnal sleep was unchanged in the days following anesthesia. Nonparametric analyses showed a decrease in the strength of coupling of the rhythm to stable environmental zeitgebers and increase of fragmentation of the rhythm after anesthesia. Light general anesthesia itself impairs synchronization of the circadian rest-activity rhythm to local time in patients by acting directly on the circadian clock.     

New hypnotics ramelteon for the treatment of insomniacs with circadian rhythm disturbance

Ramelteon is a new class of sleep agent that selectively binds to the melatonin type 1 (MT1) and type 2 (MT2) receptors in the suprachiasmatic nucleus (SCN), instead of binding to GABA-A receptors such as with traditional hypnotics benzodiazepines. Ramelteon exhibits not only acute sleep-promoting effect but also circadian phase-shifting effect via MT1 and MT2 receptors respectively, and has been revealed to contribute to the treatment of acute and chronic insomnia in patients with circadian rhythm sleep disorders(sleep-wake rhythm disorders) or with inappropriate timing of sleep habits. Optimal administration plan for insomniac patients to induce these characteristic sleep-modulating effects by ramelteon was discussed.     

Entrainment of the diurnal rhythm of plasma leptin to meal timing.

To identify the physiologic factor(s) that entrain the diurnal rhythm of plasma leptin, leptin levels were measured hourly after changes in light/dark cycle, sleep/wake cycle, and meal timing. Four young male subjects were studied during each of two protocols, those being a simulated 12-h time zone shift and a 6.5-h meal shift. During the baseline day, plasma leptin demonstrated a strong diurnal rhythm with an amplitude of 21%, zenith at 2400 h, and nadir between 0900 and 1200 h. Acute sleep deprivation did not alter plasma leptin, but day/night reversal (time zone shift) caused a 12+/-2 h shift (P < 0.01) in the timing of the zenith and nadir. When meals were shifted 6.5 h without changing the light or sleep cycles, the plasma leptin rhythm was shifted by 5-7 h (P < 0.01). The phase change occurred rapidly when compared with changes in the diurnal rhythm of cortisol, suggesting that leptin levels are not acutely entrained to the circadian clock. The leptin rhythm was altered by meal timing in a manner very similar to the rhythm of de novo cholesterol synthesis. We conclude that the diurnal rhythm of plasma leptin in young males is entrained to meal timing.     

睡眠干预对提高睡眠——觉醒节律紊乱老年患者睡眠质量的影响

目的探讨睡眠干预对提高睡眠—觉醒节律紊乱老年患者睡眠质量的影响。方法对39例睡眠—觉醒节律紊乱老年患者实施睡眠干预。干预前后采用阿森斯(athens,AIS)失眠量表、爱泼沃斯思睡量表(epworth sleepiness scale,ESS)对患者睡眠—觉醒节律紊乱程度进行测评。结果干预后3个月,患者睡眠—觉醒紊乱程度较干预前改善,干预前后比较,Z=13.560,P<0.05,差异具有统计学意义。结论对睡眠—觉醒节律紊乱老年患者实施日间及夜间睡眠干预,可使其逐步建立正常睡眠—觉醒节律,从而提高患者睡眠质量,促进疾病的康复。     

Sleep and circadian schedule disorders

The timing and synchronization of human circadian rhythms is important for health and well-being. Some individuals, for reasons that remain unclear, display less resilience or flexibility in their ability to synchronize to the 24-hour world and are thus diagnosed with a circadian schedule disorder. The objective of this article is to briefly introduce concepts about human circadian timing and to review what is known about chronic, long-term circadian schedule disorders such as delayed sleep phase syndrome, advanced sleep phase syndrome, irregular sleep-wake patterns, and non-24-hour sleep-wake disorder. Practical considerations for the clinician caring for these individuals are discussed.     

Definitions and clinical classifications of sleep disorders

Sleep disorders are defined as disorders which symptoms or pathophysiology are related with sleep regardless of comorbid physical and/or mental disorders. Sleep disorders are classified into 6 major categories: sleep related breathing disorders which exhibit abnormal breathing during sleep, sleep related movement disorders which show involuntary movements and/or abnormal sensations during sleep and/or nighttime, hypersomnia of central origin not due to other sleep disorders, circadian rhythm sleep disorders due to desynchronization between sleep-wake pattern and required social schedule, parasomnia which exhibit abnormal behavior during sleep and/or around sleep, and insomnia not due to other sleep disorders.     

Methodological issues for studying the rest-activity cycle and sleep disturbances: a chronobiological approach using actigraphy data

Shift work schedules, intensive physical exercise late in the day, psychological stress, or a busy lifestyle might induce disorders of the circadian structure, which can affect health on both the physiological and neurobehavioral levels. Rest-activity rhythm is strongly connected with an organism's circadian structure, and irregular sleep-wake patterns can lead to a disruption of entrainment, resulting in physiological and neurobehavioral dysfunction. Shift nurses are often subject to disturbances in the quality and duration of their sleep, raising the possibility of negative impacts on their health and their patients' safety. Researchers have used actigraphy in a number of studies to assess sleep patterns. Because of the close connection between sleep and circadian structure, it may be useful to extend the evaluation of actigraphy data to the analysis of the rest-activity rhythm with rhythmometric procedures to provide a better understanding of possible sleep disorders in relation to entrainment. Actigraphy is an easy and reliable way to study these rhythms and identify possible circadian-rhythm disorders. In this article, the authors discuss methodological issues concerning the evaluation of the rest-activity rhythm, with a focus on actigraphy.     

Effects of phototherapy in neonates on circadian sleep-wake and saliva cortisol level rhythms

The influence of phototherapy treatment during the neonatal period on sleep-wake rhythm, and its long-term effects on biological rhythms, was evaluated in preterm and full-term infants. Forty-three infants treated with phototherapy during the neonatal period and 47 untreated infants were examined for entrainment of sleep-wake rhythms between 16 and 52 weeks and for sleep-wake and saliva cortisol rhythms at 2.5 years of age. The age of sleep-wake rhythm entrainment was not significantly different between the 2 groups. No correlations between duration of exposure to phototherapy and corrected age of entrainment of sleep-wake rhythm were observed. At follow-up, no significant differences in sleep-wake and saliva cortisol rhythms were observed between the 2 groups, indicating that circadian variations were similar to those in adults.     

Biological rhythms and sleep

Sleep is regulated by dual oscillatory processes, one is the hierarchical multi oscillatory circadian system and the other is the ultradian rest-activity cycle. The circadian system is composed of the central clock located in the suprachiasmatic nucleus and the peripheral clocks in a variety of tissues which express overt rhythms. The peripheral clock(s) for sleep and wakefulness in nocturnal rodents are strongly regulated by the central clock. By contract, the peripheral clock(s) in humans is more independent of and easily desynchronized from the central clock. Nocturnal sleep is characterized by REM and nonREM cycles which appear alternatively at 1.5 to 2 hour intervals. The origin of ultradian rhythm is not known. We propose an integrated model for the regulation of sleep and wakefulness by two different oscillatory systems.     

Melatonin: possible implications for the postoperative and critically ill patient

There is increasing interest in the hormone melatonin in postoperative and critically ill patients. The roles of melatonin in the regulation of the sleep-wake cycle, resetting of circadian rhythm disturbances and its extensive antioxidant activity have potential applications in these patient groups. The interaction between melatonin and the stresses of surgery and critical illness are explored in the context of circadian rhythms, sleep disorders and delirium. The antioxidant activity is discussed in terms of the reduction of ischaemic reperfusion injury, prevention of multi-organ failure and treatment of sepsis. Unfortunately, there is currently insufficient evidence that exogenous melatonin is effective in preventing or treating postoperative delirium. Similarly, in the critically ill patient, sleep disorders are associated with disrupted melatonin circadian secretion, but there is a paucity of data to support routine exogenous melatonin supplementation. More clinical evidence to confirm the potential benefits of melatonin therapy is required before it can be routinely used in the postoperative or critically ill patient.     

经皮穴位电刺激对轮班制失眠护士睡眠质量及昼夜节律的影响

目的研究经皮穴位电刺激(transcutaneous electrical acupoint stimulation,TEAS)治疗对轮班制失眠护士睡眠质量及昼夜节律的影响作用。方法在200名轮班护士中,筛选出30例失眠护士,对其进行14 d的TEAS干预治疗,采用腕式睡眠健康记录仪对受试者的睡眠质量进行监测,并检测其唾液褪黑素和皮质醇的变化,采用余弦法分析其昼夜节律的周期、相位、中值、振幅的变化。结果受试者治疗前的平均入睡潜伏期为37.72 min,平均睡眠效率79.48%,唾液褪黑素节律中值(626.98±157.47)nmol/L,峰值相位时间(24.03±0.83)h,唾液皮质醇节律中值(1 088.39±297.43)nmol/L,峰值相位时间(9.04±0.64)h;而治疗14 d后,平均入睡潜伏期缩短至13.44 min,平均睡眠效率达到86.37%,唾液褪黑素节律中值升高至(835.36±160.23)nmol/L,峰值相位时间提前至(23.35±0.56)h,唾液皮质醇节律中值降低至(902.65±208.50)nmol/L,峰值相位时间提前至(8.10±1.20)h...     

Seasonal affective disorder. Shedding light on a dark subject

Seasonal affective disorder (SAD) appears to be a disturbance of circadian rhythm caused by desynchronization between the solar clock and the human biologic clock during seasons of short photoperiods. The supplemental bright light of phototherapy resynchronizes the disturbed rhythm; however, a comprehensive theory to explain the mechanism of phototherapy is lacking. Future research on the action of melatonin and serotonin and the photochemical effect of light in relation to possible circadian rhythm disorders should help us to better understand and treat not only SAD but other conditions such as jet lag, premenstrual syndrome, eating disorder, and carbohydrate-craving obesity.     

Circadian regulation of cardiac metabolism

Circadian rhythm evolved to allow organisms to coordinate intrinsic physiological functions in anticipation of recurring environmental changes. The importance of this coordination is exemplified by the tight temporal control of cardiac metabolism. Levels of metabolites, metabolic flux, and response to nutrients all oscillate in a time-of-day–dependent fashion. While these rhythms are affected by oscillatory behavior (feeding/fasting, wake/sleep) and neurohormonal changes, recent data have unequivocally demonstrated an intrinsic circadian regulation at the tissue and cellular level. The circadian clock — through a network of a core clock, slave clock, and effectors — exerts intricate temporal control of cardiac metabolism, which is also integrated with environmental cues. The combined anticipation and adaptability that the circadian clock enables provide maximum advantage to cardiac function. Disruption of the circadian rhythm, or dyssynchrony, leads to cardiometabolic disorders seen not only in shift workers but in most individuals in modern society. In this Review, we describe current findings on rhythmic cardiac metabolism and discuss the intricate regulation of circadian rhythm and the consequences of rhythm disruption. An in-depth understanding of the circadian biology in cardiac metabolism is critical in translating preclinical findings from nocturnal-animal models as well as in developing novel chronotherapeutic strategies.