Diagnosis and treatment in circadian rhythm sleep disorders

Circadian rhythm sleep disorders (CRSD) are characterized by misalignment between major sleep episode and desired sleep phase, or symptoms associated with internal desynchronization between endogenous circadian rhythm and overt sleep-wake rhythm. Endogenous circadian rhythm is mainly regulated by master circadian clock located in the suprachiasmatic nucleus. Light entrains the circadian clock according to a phase-response curve. Furthermore, social time cue affects human sleep-wake rhythm. Instructions concerning sleep hygiene including light environment play fundamental role for the treatment in CRSD. In addition, light therapy and oral melatonin administration have application to delayed sleep phase type. Diagnostic classification and treatment in each types of CRSD are reviewed in this article.     

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.     

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.     

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.     

Melatonin as a regulator of human sleep and circadian systems

Melatonin(N-acetyl-5-methoxytryptamine) is synthesized from tryptophan and is intensively secreted into the blood only in darkness (nighttime) by the pineal gland. Melatonin is not only the most reliable marker of internal circadian phase but also a potent sleep-promoting and circadian phase regulatory agent in humans. There is evidence that daytime administered melatonin is able to exhibit short-acting hypnagogic effect and phase-shifting of the circadian rhythms such that sleep timing and associated various physiological functions realign at a new desired phase. Under favor of these properties, melatonin and melatonin receptor agonists have been shown to be potent therapeutic agents for the treatment of circadian rhythm sleep disorders and some type of insomnia.     

Circadian genes, rhythms and the biology of mood disorders

For many years, researchers have suggested that abnormalities in circadian rhythms may underlie the development of mood disorders such as bipolar disorder (BPD), major depression and seasonal affective disorder (SAD). Furthermore, some of the treatments that are currently employed to treat mood disorders are thought to act by shifting or "resetting" the circadian clock, including total sleep deprivation (TSD) and bright light therapy. There is also reason to suspect that many of the mood stabilizers and antidepressants used to treat these disorders may derive at least some of their therapeutic efficacy by affecting the circadian clock. Recent genetic, molecular and behavioral studies implicate individual genes that make up the clock in mood regulation. As well, important functions of these genes in brain regions and neurotransmitter systems associated with mood regulation are becoming apparent. In this review, the evidence linking circadian rhythms and mood disorders, and what is known about the underlying biology of this association, is presented.     

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.     

Sleep disorders and the eye

During the past decade, associations between sleep disorders and certain ophthalmologic disorders have been increasingly recognized. To review the literature on these important associations, we conducted a PubMed search using combinations of the following terms: sleep disorders, sleep apnea, circadian rhythm disorder, continuous positive airway pressure, eye disease, floppy eyelid syndrome, glaucoma, ischemic optic neuropathy, papilledema, nocturnal lagophthalmos, and vision loss. We limited our search to articles published in English that involved human participants. All available dates were included. One of the most common sleep disorders, obstructive sleep apnea, has been associated with a variety of eye diseases, including glaucoma, nonarteritic anterior ischemic optic neuropathy, floppy eyelid syndrome, papilledema, and continuous positive airway pressure-associated eye complications. Nocturnal lagophthalmos manifests during sleep and is defined as the failure to fully close the eyelids at night. Finally, blindness is associated with increased risk of circadian rhythm disorders. On the basis of the existing published literature, we discuss these rarely recognized associations, potential pathophysiologic mechanisms, and the effect these associations have on the clinical management of patients. The knowledge of these associations is important for the primary care physician, ophthalmologist, and sleep physician so that underlying sleep disorders or ophthalmologic disorders can be detected.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Is shift work making your patient sick? Emerging theories and therapies for treating shift work disorder

"Shift work" is a term that applies to a wide array of nontraditional work schedules. Shift work disorder (SWD) is a circadian rhythm sleep disorder experienced by a subset of shift workers that is characterized by excessive sleepiness during work and/or insomnia during scheduled sleep times. It is estimated to affect up to 2 million Americans, and is associated with increased morbidity and mortality from metabolic risk factors, cardiovascular and gastrointestinal diseases, depression, accidents, and some kinds of cancers. Patient history is all that is needed to make a diagnosis with the International Classification of Sleep Disorders-Second Edition criteria as described herein. Circadian rhythm disorders, in which an underlying misalignment of circadian rhythm with the sleep-wake cycle occurs, may be treated by behavioral and pharmacologic approaches, including the use of hypnotics to improve the duration of sleep. However, evidence is limited with these approaches in patients diagnosed with SWD. Other treatment options may include pharmacologic interventions such as modafinil and armodafinil, which have shown efficacy in this population. Combined therapy can reduce insomnia and excessive sleepiness, and improve attention and alertness during work shifts and the subsequent commute home.     

Regulation of adipose functions by molecular clocks

Adipocytes play essential metabolic roles, not only serving as massive energy reserves but also secreting hormones and cytokines that regulate metabolic activities. The link between metabolic activity in adipocytes and circadian rhythm has long been studied, e.g., glucose and lipid homeostasis are well known to exhibit circadian variation. Therefore, molecular clock may play important roles in regulation of metabolic activity in adipocytes. In a previous study, we reported that white adipose tissue contains functional molecular clock and expression of several adipocytokines including leptin and plasminogen activator inhibitor-1 displays circadian rhythm. The diurnal rhythm in the level of these molecules suggests that molecular clock is, at least partly, associated with the onset of metabolic syndrome.     

Is Shift work Making Your Patient Sick? Emerging Theories and Therapies for Treating Shift Work Disorder

Abstract

“Shift work” is a term that applies to a wide array of nontraditional work schedules. Shift work disorder (SWD) is a circadian rhythm sleep disorder experienced by a subset of shift workers that is characterized by excessive sleepiness during work and/or insomnia during scheduled sleep times. It is estimated to affect up to 2 million Americans, and is associated with increased morbidity and mortality from metabolic risk factors, cardiovascular and gastrointestinal diseases, depression, accidents, and some kinds of cancers. Patient history is all that is needed to make a diagnosis with the International Classification of Sleep Disorders–Second Edition criteria as described herein. Circadian rhythm disorders, in which an underlying misalignment of circadian rhythm with the sleep–wake cycle occurs, may be treated by behavioral and pharmacologic approaches, including the use of hypnotics to improve the duration of sleep. However, evidence is limited with these approaches in patients diagnosed with SWD. Other treatment options may include pharmacologic interventions such as modafinil and armodafinil, which have shown efficacy in this population. Combined therapy can reduce insomnia and excessive sleepiness, and improve attention and alertness during work shifts and the subsequent commute home.