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.     

The bright-nights and dim-days of the urban photoperiod: Implications for circadian rhythmicity,metabolism and obesity

Abstract

Artificial light decreases the amplitude of daily rhythms in human lifestyle principally by permitting activity and food intake to occur during hours of darkness, and allowing day-time activity to occur in dim light, indoors. Endogenous circadian timing mechanisms that oscillate with a period of 24 h have evolved to ensure physiology is synchronized with the daily variations in light, food, and social cues of the environment. Artificial light affects the synchronization between these oscillators, and metabolic disruption may be one consequence of this. By dampening the amplitude of environmental timing cues and disrupting circadian rhythmicity, artificial lighting might initiate metabolic disruption and contribute to the association between global urbanization and obesity. The aim of this review is to explore the historical, physiological, and epidemiological relationships between artificial light and circadian and metabolic dysfunction.     

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.     

Circadian phase resetting in older people by ocular bright light exposure.

BACKGROUND: Aging is associated with frequent complaints about earlier bedtimes and waketimes. These changes in sleep timing are associated with an earlier timing of multiple endogenous rhythms, including core body temperature (CBT) and plasma melatonin, driven by the circadian pacemaker. One possible cause of the age-related shift of endogenous circadian rhythms and the timing of sleep relative to clock time is a change in the phase-shifting capacity of the circadian pacemaker in response to the environmental light-dark cycle, the principal synchronizer of the human circadian system. METHODS: We studied the response of the circadian system of 24 older men and women and 23 young men to scheduled exposure to ocular bright light stimuli. Light stimuli were 5 hours in duration, administered for 3 consecutive days at an illuminance of approximately 10,000 lux. Light stimuli were scheduled 1.5 or 3.5 hours after the CBT nadir to induce shifts of endogenous circadian pacemaker to an earlier hour (phase advances) or were scheduled 1.5 hours before the CBT nadir to induce shifts to a later hour (phase delays). The rhythms of CBT and plasma melatonin assessed under constant conditions served as markers of circadian phase. RESULTS: Bright light stimuli elicited robust responses of the circadian timing system in older people; both phase advances and phase delays were induced. The magnitude of the phase delays did not differ significantly between older and younger individuals, but the phase advances were significantly attenuated in older people. CONCLUSIONS: The attenuated response to light stimuli that induce phase advances does not explain the advanced phase of the circadian pacemaker in older people. The maintained responsiveness of the circadian pacemaker to light implies that scheduled bright light exposure can be used to treat circadian phase disturbances in older people.     

Neuroendocrine rhythms

Hormones are secreted with circhoral, circadian and seasonal periodicities. Circhoral pulsatility is a temporal code, many chronic and acute changes in neuroendocrine status being mediated by changes in the frequency of circhoral release. The identity of the neuronal circuits controlling circhoral release is not known. Circadian release of hormones occurs with a precise temporal order entrained to the light-dark cycle, synchronized to the activity/rest rhythm and generated by circadian oscillators, of which the suprachiasmatic nuclei are the most important. Seasonal rhythms are driven either by an endogenous circannual clock mechanism or by a process of photoperiodic time measurement which is dependent upon the duration of the nocturnal peak of the pineal hormone melatonin.     

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.     

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.     

Ambulatory blood pressure monitoring and cardiovascular function tests in multiple system atrophy

Summary— Cardiovascular tests (CT) of autonomic function and non-invasive ambulatory blood pressure (BP) and heart rate (HR) monitoring were performed in 17 patients with multiple system atrophy (MSA) (mean age 61 ± 9 years) and in 12 healthy subjects matched for sex and age. CT showed severe autonomic dysfunction with orthostatic hypotension (OH) in eight patients with MSA (47%) (Group I). The remaining nine out of the 17 patients didn't show BP abnormalities during CT but an impaired HR reflex response was found (Group II). BP monitoring showed a reversed circadian BP rhythm in Group I with higher night-time than day-time values, a blunted circadian BP pattern in Group II and a normal day-night BP reduction in controls. Day-night HR reduction was poor in Group II and absent in Group I. Post-prandial hypotension was evaluated after a standard meal. In Group I systolic/diastolic BP fell within 30 minutes after meal (from 135 ± 16/89 ± 13 to 118 ± 17/73 ± 12 mmHg; p < 0.05) and after two hours had not returned to basal levels. In Group II a reduction of only systolic BP was found within 45 minutes after meal and persisted for one hour. OH clinically identifies a subgroup of MSA patients with a more severe BP dysregulation characterized by severe post-prandial hypotension and reversed circadian BP rhythm. CT and ambulatory BP monitoring are useful tools in identifying early stage of cardiovascular autonomic impairment.     

Functional relationship between circadian rhythm and control of food intake

Living things on the earth including bacteria, plants and animals show circadian rhythms in their behaviors and physiological phenomena, and these circadian rhythms are usually synchronized with environmental changes having the period of 24 h on the earth. In mammals including human beings, the hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian oscillator, and generates a circadian rhythm of food intake. Sometimes the circadian oscillation of the SCN is disturbed with physical and psychological stressors. This review describes the functional relationship in respect to connections between the circadian oscillator in the SCN and food regulatory centers and neurons in the brain focusing on its mechanism in human beings, and a possible involvement of the circadian oscillator of the SCN in the abnormality of the appetite control.     

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.     

Circadian rhythmicity and homeostatic stability in thermoregulation

Stability and circadian variation in core body temperature (Tc) were believed to be homeostatic responses until well into the 20th century. Defense of a narrow thermoneutral range was well documented, whereas circadian oscillations were attributed to episodic biochemical and environmental stimuli or chronological stressors in life routines. Research in thermal physiology has illuminated several of the "black boxes" in the understanding of temperature regulation, and advances in chronobiology have shattered old paradigms. While these discoveries are still evolving, existing information provides valuable clues about physiological responses to heat loss or over-heating that could improve clinical assessment and intervention. Discoveries that circadian rhythm of Tc is regulated by an endogenous "clock" and is remarkably stable have helped to make it the most widely used circadian indicator. More recently, Tc was found to exert its own cyclic rhythm under free-running conditions. While some investigators claim that circadian and homeostatic processes are independent, there are conditions in which clinical distinctions are less clear. This overview reviews contemporary scientific findings about circadian and homeostatic processes in thermoregulation. Examples are drawn from human and animal research. Physiological responses and mechanisms are explained in relation to their relevance to clinical treatment or health care. Gaps in existing research and application 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.     

Effects of oral contraceptive therapy on the circadian patterns of cortisol and thyrotropin (TSH).

The daily variation of serum cortisol and thyrotropin (TSH) has been simultaneously recorded every 30-min. in 4 women taking the same oral contraceptive containing oestrogens and progestogens and in 4 control women. The circadian rhythm of cortisol persisted under contraceptive therapy with about a 2.5 fold elevation of the mean level and amplitude of the basal rhythm. Theoretical equilibrium calculations of the circadian variations of the free, transcortin-bound and albumin-bound cortisol fractions showed that these elevations are explained qualitatively and quantitatively by an oestrogen-induced increase of the same order of the transcortin cortisol-binding sites. As a consequence of the already high saturation of transcortin in normal conditions, the magnitude of the variation of free cortisol level resulting from a burst in cortisol secretion varies with the time of day. The role of albumin as a buffer is thereby emphasized. The early morning maximum, characterizing the normal TSH daily pattern, appeared to be considerably enhanced in women under contraceptive therapy. If the circadian variations of TSH are driven by thyrotropin releasing hormone (TRH), these higher morning peaks probably reflect a higher burst of TRH secretion rather than an increased responsiveness of the pituitary to TRH secretion induced by contraceptive therapy. Finally these results do not support the hypothesis of a regulation of TSH circadian variations by an inhibiotry action of cortisol. Contraceptive therapy does not appear to play a role at the level of the central clock or on the resetting mechanism.     

Serotonin and the regulation of mammalian circadian rhythmicity

The suprachiasmatic nucleus (SCN), the site of the primary mammalian circadian clock, contains one of the densest serotonergic terminal plexes in the brain. Although this fact has been appreciated for some time, only in the last decade has there been substantial approach toward the understanding of the function of serotonin in the circadian rhythm system. The intergeniculate leaflet, which projects to the SCN via the geniculohypothalamic tract, receives serotonergic innervation from the dorsal raphe nucleus, and the SCN receives its serotonergic input from the median raphe nucleus. This separation of serotonergic origins provides the opportunity to investigate the function of the two projections. Loss of serotonergic neurones of the median raphe yields earlier onset and later offset of the nocturnal activity phase, longer duration of the activity phase, and increased sensitivity of circadian rhythm response to light. Despite the simplicity of the origins of serotonergic anatomy with respect to the circadian rhythm system, the actual involvement of serotonin in rhythm modulation is not so obvious. A variety of pharmacological studies have clearly implicated serotonin as a direct regulator of circadian rhythm phase, but others employing different methods suggest that simple elevation of SCN serotonin concentrations does not modify rhythm phase. The most convincing role of serotonin is its apparent ability to modulate sensitivity of the circadian rhythm to light. The putative method for such modulation is via a presynaptic 5-HT1B receptor on the retinohypothalamic tract, the activation of which attenuates photic input to the SCN thereby reducing phase response to light. Serotonin may modulate phase response to benzodiazepines, but does not appear to modify such response to environmentally induced locomotor activity. Current interest in serotonergic modulation of circadian rhythmicity is strong and the research is vigorous. There is an abundance of information about serotonin and circadian rhythm function that lacks a satisfactory framework for its interpretation. The next decade is likely to see the gradual evolution of this framework as the role of serotonin in circadian rhythm regulation is further elucidated.     

Body-temperature circadian rhythm in 67 patients after heart valve replacement surgery secondary to valvular heart disease

PurposePatient body temperature was monitored after cardiac valve replacement, in order to explore the characteristics of body-temperature circadian rhythm and the factors influencing that rhythm.MethodsA cohort of 67 patients who received cardiac valve replacement in a Fuzhou, Fujian province, China, general hospital underwent temperature measurements and analysis (by cosine curve) of their body-temperature circadian rhythm. A biological rhythm model was established through principal component analysis and evaluation of biological rhythm features. Multiple circadian parameters were included through linear regression analysis.ResultsPatients' temperature after cardiac valve replacement exhibited circadian characteristics (p < 0.05), among which the scores of temperature mesor, amplitude, and acrophase were respectively (37.61 ± 0.08), (0.10 ± 0.09), and −33 (–355, –119). Body-temperature rhythms were influenced by both gender and cardiopulmonary bypass time (p < 0.05).ConclusionAlthough some patients' circadian characteristics disappeared after cardiac valve replacement, circadian rhythms remained intact for most patients. Measures that were found to mitigate body-temperature circadian rhythm disruption included building a natural rhythm of light/darkness and decreasing cardiopulmonary bypass time.     

Presence of angiotensin peptides in human urine.

Immunoreactive angiotensin I and angiotensin II were found in human urine that was purified on octadecasilylsilica cartridges. The daily excretion of angiotensin I and II in healthy volunteers was 189.00 (SE 38.36) and 17.54 (SE 3.07) pmol/24 h or 148.09 (SE 32.22) and 12.82 (SE 2.34) pmol/L, respectively (n = 12). No circadian rhythm was observed in the excretion patterns of angiotensin I and II. In vitro degradation of angiotensin I or II could not be detected in acidified urine samples. A marked increase in the excretion of angiotensin I and II could be demonstrated in patients with anaphylactoid reactions to drugs and food additives after oral challenge. Immunoreactive angiotensin I and II could be characterized by HPLC as Ile5-angiotensin I, Ile5-angiotensin II, and angiotensin II metabolites.     

Fatigue and disrupted sleep-wake patterns in patients with cancer: a shared mechanism

The strong and potentially reciprocal relationship between cancer-related fatigue (CRF) and disrupted sleep-wake patterns suggests a possible shared physiologic pathway. A growing body of evidence supports this and shows that abnormalities in the 24-hour rhythm of stress-related hormones may be related to chronic fatigue and sleep disturbances. Aberrations in the hypothalamic-pituitary-adrenal (HPA) axis, the primary neuroendocrine interface responding to stress, induce important biologic and behavioral consequences. HPA aberrations have long been associated with chronic fatigue syndrome. Many overlapping symptoms exist between chronic fatigue syndrome and CRF, including sleep disruption. Therefore, in the absence of knowledge about CRF mechanisms, emerging biologic models from chronic fatigue syndrome may assist in understanding the cause of CRF. Cancer-associated stressors also may alter the circadian functions of HPA-associated neuroendocrine activities, which result in the symptoms of fatigue and disrupted sleep-wake patterns in patients with cancer. Exploring promising physiologic models furthers the knowledge about CRF and disrupted sleep and may foster hypothesis-based studies of mechanisms that underlie apparent overlapping symptoms, providing the basis for new management to improve sleep and lessen fatigue.     

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.     

Effects of Oral Contraceptive Therapy on the Orcadian Patterns of Cortisol and Thyrotropin (TSH)

Abstract. The daily variation of serum Cortisol and thyrotropin (TSH) has been simultaneously recorded every 30-min. in 4 women taking the same oral contraceptive containing oestrogens and progestogens and in 4 control women. The circadian rhythm of Cortisol persisted under contraceptive therapy with about a 2. 5 fold elevat ion of the mean level and amplitude of the basal rhythm. Theoretical equilibrium calculations of the circadian variations of the free, transcortin-bound and albumin-bound Cortisol fractions showed that these elevations are explained qualitatively and quantitatively by an oestrogen-induced increase of the same order of the transcortin cortisol-binding sites. As a consequence of the already high saturation of transcortin in normal conditions, the magnitude of the variation of free Cortisol level resulting from a burst in Cortisol secretion varies with the time of day. The role of albumin as a buffer is thereby emphasized. The early morning maximum, characterizing the normal TSH daily pattern, appeared to be considerably enhanced in women under contraceptive therapy. If the circadian variations of TSH are driven by thyrotropin releasing hormone (TRH), these higher morning peaks probably reflect a higher burst of TRH secretion rather than an increased responsiveness of the pituitary to TRH secretion induced by contraceptive therapy. Finally these results do not support the hypothesis of a regulation of TSH circadian variations by an inhibiotry action of Cortisol. Contraceptive therapy does not appear to play a role at the level of the central clock or on the resetting mechanism.