Circadian rhythms during gradually delaying and advancing sleep and light schedules

The circadian rhythms of the night shift worker show very little phase shift in response to the daytime sleep and night work schedule. One strategy for producing circadian adaptation may be to use appropriately timed exposure to high-intensity light. We attempted to shift the circadian temperature rhythms of seven normal subjects while they followed a sleep schedule that gradually delayed (2 h per day) until sleep occurred during the daytime, as is customary for workers during the night shift. After 5 days, the sleep schedule was gradually advanced back to baseline. High illuminance light (2 h per day) and the attenuation or avoidance of sunlight were timed to facilitate temperature rhythm phase shifts. In general, the temperature rhythm did not shift along with the sleep-wake schedule, but appeared either to free run or remain entrained to the natural 24-h zeitgebers. This study showed how difficult it can be to shift human circadian rhythms in the field, when subjects are exposed to competing 24-hr zeitgebers.     

Effect of redox conditions on the DNA-binding efficiency of the retinoic acid receptor zinc-finger

All 24-hour endocrine rhythms partially reflect the interaction of circadian rhythmicity with sleep-wake homeostasis but their relative contributions vary from one system to another. In older adults, many 24-hour rhythms are dampened and/or advanced, including those of cortisol and GH. Amplitude reduction and phase advance of 24-hour rhythms may represent age-related changes in the central nervous systems underlying circadian rhythmicity and sleep-wake homeostasis. Age-related alterations in circadian function could also reflect decreased exposure and/or responsivity to the synchronizing effects of both photic (e.g. light exposure) and nonphotic (e.g. social cues) inputs. There are pronounced age-related alterations in sleep quality in aging which consist primarily of a marked reduction of slow-wave sleep, a reduction in REM stages and a marked increase in the number and duration of awakenings interrupting sleep. Alterations in slow-wave sleep occur abruptly in young adulthood (30-40 years of age) whereas disturbances in amounts of REM and wake appear more gradually. This article reviews evidence indicating that deficits in characteristics of sleep-wake homeostasis and circadian function may mediate age-related alterations in somatotropic and corticotropic function. Because sleep loss in young subjects results in endocrine disturbances which mimic those observed in aging, it is conceivable that the decrease in sleep quality which characterizes aging may contribute to age-related alterations in hormonal function and their metabolic consequences.     

Effects of ageing on modulation of hormonal secretions by sleep and circadian rhythmicity

Circadian rhythmicity persists in healthy elderly subjects but a number of 24 hour rhythms are dampened and/or advanced in old age. The tendency for earlier sleep onset, earlier morning awakening and a more fragmented and more shallow sleep period is representative of these alterations. Other overt rhythms which have been shown to be of lower amplitude and/or phase-advanced are those of body temperature and of the peripheral levels of hormones such as cortisol, melatonin, TSH, testosterone, prolactin and GH. Mean hormonal levels are generally decreased, but overall cortisol secretion is increased with ageing. These modifications are likely to be partially due to alterations of the circadian central nervous system processes controlling circadian rhythmicity and sleep.     

Disturbances of sleep and cognitive functioning in patients with dementia

The relationship of sleep, circadian rhythms, and cognitive impairment in dementia patients is briefly reviewed. All-night sleep EEG data were collected in relatively young and relatively unimpaired patients with presumptive Alzheimer's disease and eight age-matched controls. Delta sleep time and Delta sleep % (Stages 3 and 4)--but not REM sleep measures--were significantly reduced in the patients. Implications of these findings are discussed.     

The role of melatonin in the human fetus (review)

Melatonin, an indole amine, primarily derived from the pineal gland is secreted during the hours of darkness. Melatonin acts as a hormonal transduction of photoperiod influencing the timing of seasonal and daily (circadian) physiological rhythms. Maternal melatonin crosses the placenta and enters the fetal circulation providing photoperiodic information to the fetus influencing the subsequent circadian and seasonal rhythms of the offspring. The function of melatonin in humans is more obscure. However, melatonin has attained prominence as a treatment for disturbed circadian rhythms and sleep patterns which occur as a result of transmeridian travel, shift work or blindness. The biological clock, the hypothalamic suprachiasmatic nuclei (SCN), possesses melatonin receptors, in both the adult and fetal human. This concurs with the reported influence of melatonin on human circadian rhythmicity and indicates that this influence may begin in utero. Melatonin receptors are widespread in the human fetus and occur in both central and peripheral tissue from early in fetal development. Thus, the influence of melatonin on the developing human fetus may not be limited to entraining circadian rhythmicity. Considering the transplacental availability of melatonin to the fetus the ingestion of melatonin by pregnant women may be inadvisable.     

Sleep and circadian rhythms in four orbiting astronauts

This experiment measured the sleep and circadian rhythms of four male astronauts aboard a space shuttle (STS-78) orbiting the Earth for 17 days. The space mission was specially scheduled to minimize disruptions in circadian rhythms and sleep so that the effects of space flight and microgravity per se could be studied. Data were collected in 72-h measurement blocks: one block 7 days before launch, one early within the mission (3 days after launch), one late in the mission (12 days after launch), and one 18 days after landing. Within each measurement block, all sleep was recorded both polysomnographically and by sleep diary. Core body temperature was sampled every 6 mins. Actillumes were worn continuously. All urine samples were collected separately. Performance was assessed by a computerized test battery (3/day) and by end-of-shift questionnaires (1/day); mood and alertness were measured by visual analogue scales (5/day). Circadian rhythms in orbit appeared to be very similar in phase and amplitude to those on the ground, and were appropriately aligned for the required work/rest schedule. There was no change from early flight to late flight. This was also reflected in mood, alertness, and performance scores, which were satisfactory at both in-flight time points. However, in-flight sleep showed a decreased amount of sleep obtained (mean = 6.1 h), and all four astronauts showed a decrease in delta sleep. No further degradation in sleep was seen when early flight was compared to late flight, and no other sleep parameters showed reliable trends.     

Polysomnography and other methods for the assessment of sleep disorders

Polysomnography is an essential tool in the assessment of sleep disorders. However, PSG alone not always sufficient to evaluate various sleep disorders patients. For instance, in patients with suspected inadequate sleep hygiene, sleep logs or questionnaires on sleep habits may, be helpful in making the diagnosis. Patients who complain of excessive daytime sleepiness as a result of insomnia should be evaluated with the Epworth sleepiness scale and/or polysomnographic nap studies such as the multiple sleep latency test. In patients with suspected circadian rhythm sleep disorder, continuous temperature monitoring together with sleep log and actigraphy may establish the phase relationship between sleep-wake rhythms and other biological rhythms. Because polysomnographic measurements are cumbersome and expensive, it is necessary to select the suitable methods for the assessment of sleep disorders by the careful examination of the patients' complain.     

Immunological requirements for a subunit vaccine against tuberculosis

Although the causes are different, totally blind people (without light perception) and night shift workers have in common recurrent bouts of insomnia and wake-time sleepiness that occur when their preferred (or mandated) sleep and wake times are out of synchrony with their endogenous circadian rhythms. In this article, the patterns of circadian desynchrony in these two populations are briefly reviewed with special emphasis on longitudinal studies in individual subjects that used the timing of melatonin secretion as a circadian marker. In totally blind people, the most commonly observed pattern is a free-running rhythm with a stable non-24-h circadian period (24.2-24.5 h), although some subjectively blind people are normally entrained, perhaps by residually intact retinoypothalamic photic pathways. Experiments at the cellular and behavioral levels have shown that melatonin can produce time dependent circadian phase shifts. With this in mind, melatonin has been administered to blind people in an attempt to entrain abnormal circadian rhythms, and substantial phase shifts have been accomplished; however, it remains to be demonstrated unequivocally that normal long-term entrainment can be produced. In untreated night shift workers, the degree and direction of phase shifting in response to an inverted sleep-wake schedule appears to be quite variable. When given at the optimal circadian time, melatonin treatment appears to facilitate phase shifting in the desired direction. Melatonin given prior to a night worker's daytime sleep also may attenuate interference from the circadian alerting process. Because melatonin has both phase-shifting and sleep-promoting actions, night shift workers, who number in the millions, may be the most likely group to benefit from treatment.     

Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms

This study demonstrates the involvement of the MT2 (Mel1b) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin. In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes revealed for the first time the expression of mt1 and MT2 melatonin receptor mRNA within the suprachiasmatic nucleus of the C3H/HeN mouse. Melatonin (0.9 to 30 microg/mouse, s.c.) administration during 3 days at the end of the subjective day (CT 10) to C3H/HeN mice kept in constant dark phase advanced circadian rhythms of wheel running activity in a dose-dependent manner [EC50=0.72 microg/mouse; 0.98+/-0.08 h (n=15) maximal advance at 9 microg/mouse]. Neither the selective MT2 melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 microg/mouse, s.c.) nor luzindole (300 microg/mouse, s.c.), which shows 25-fold higher affinity for the MT2 than the mt1 subtype, affected the phase of circadian activity rhythms when given alone at CT 10. All three antagonists, however, shifted to the right the dose-response curve to melatonin, as they significantly reduced the phase shifting effects of 0.9 and 3 microg melatonin. This is the first study to demonstrate that melatonin phase advances circadian rhythms by activation of a membrane-bound melatonin receptor and strongly suggests that this effect is mediated through the MT2 melatonin receptor subtype within the circadian timing system. We conclude that the MT2 melatonin receptor subtype is a novel therapeutic target for the development of subtype-selective analogs for the treatment of circadian sleep and mood-related disorders.     

Circadian locomotor activity and core-body temperature rhythms in Alzheimer's disease

Sleep-wake cycle disturbances suggest that circadian rhythms may be disrupted in patients with Alzheimer's disease (AD). In this study, we examined the circadian rhythms of core-body temperature and locomotor activity in 28 patients with probable AD and 10 healthy controls. AD patients had higher percent nocturnal activity than controls, corresponding to the clinical picture of fragmented sleep. The amplitude of the activity cycle in the AD patients was lower than that of controls and the acrophase of this cycle in AD patients was 4.5 h later. There was no difference in the amplitude of the core-body temperature circadian rhythm, but AD patients had delayed temperature acrophases. A subgroup of AD patients with large mean time differences between the acrophases of their activity and temperature cycles had lower temperature amplitudes and greater activity during the night. These findings suggest that a subgroup of AD patients with impaired endogenous pacemaker function may have a diminished capacity to synchronize the rhythm of core-body temperature with the circadian cycle of rest-activity. This circadian rhythm dysfunction may partly explain the fragmented nocturnal sleep exhibited by these patients.     

Ocular bubble formation as a method of assessing decompression stress

Human well-being depends on the entrainment of endogenous circadian rhythms of biological functions and the sleep-wake rhythm. Although the incidence of otherwise healthy subjects with chronically altered sleep-wake rhythms is rather low, the investigation of these patients provides new sights into circadian entrainment mechanisms. We therefore examined the circadian rhythm of circulating melatonin and the sleep-wake rhythm in five patients with chronic sleep-wake rhythm disorders and ten age-matched healthy controls. All patients showed altered circadian melatonin rhythm parameters in relation to their sleep-wake cycle compared to age-matched controls. These alterations were random, i.e., independent of the type, the duration, and the age of onset of the disorder. The melatonin onset to sleep onset interval varied between the patients and the melatonin acrophase to sleep offset interval was prolonged in four patients. These findings indicate individual phase relations between the circadian melatonin rhythm and the sleep-wake cycle in patients with chronic sleep-wake rhythm disorders. Since the prolonged melatonin acrophase to sleep offset interval was the most consistent finding independent of aetiological origins, this abnormality may be one possible maintaining factor in chronic sleep-wake rhythm disorders due to reduced phase-resetting properties of the circadian pacemaker. Furthermore, rather low circadian melatonin amplitudes and a subsensitivity to daylight may maintain the disorder in at least some patients.     

Melatonin, its receptors, and relationships with biological rhythm disorders

Melatonin is a neurohormone produced during the night by the pineal gland. Its secretion is regulated by circadian and seasonal variations in daylength, transmitted via visual projections to the suprachiasmatic nucleus which functions as a circadian clock in mammals. Melatonin has been proposed to act as an internal synchronizer of circadian rhythms generated at different levels of the organism. The chronobiotic effects of melatonin in humans have been mainly studied in circadian rhythm sleep disorders related to jet lag, shift work, blindness or aging. Alterations of the melatonin profiles have also been reported in other biological rhythm disorders.     

Rhythms in the central nervous system and 1/f fluctuations of the heart rate

We have developed a system to analyze heart rate variability (HRV) (power spectral array of the HRV) during 24 h ambulatory electrocardiographic monitoring. Several rhythms (circadian and several ultradian rhythms) were observed in the power spectral array of the heart rates and 1/f-like fluctuations in the log-log scaled heart rate power spectrum. The circadian change of the heart rate is closely related to the body temperature rhythm. The 90 min rhythm of HRV during sleep was suspected to be produced by the sleep cycle (REM/NREM) and the lower frequency peak of the HRV was coherent with oscillation in amplitude modulated respiration. These circadian and ultradian rhythm as assessed by heart rate variability exist both in normal subjects and in patients with autonomic failure. The power of the high frequency band decreases in subjects with autonomic failure. The power of low frequency components increases during periodic breathing or Cheyne-Stokes respiration. Log-log scaled analysis of the power spectrum of HRV disclosed that the slope of the HRV is markedly modulated by the range of the frequency applied for the least square regression line analysis. The increased power that might be produced by periodic breathing and decreased power in patients with autonomic failure might strongly modulate the slope of the log-log scaled HRV. It is concluded that the power spectral array of the HRV during 24 h period is useful in the detection of circadian and ultradian rhythm, and log-log scaled power spectra might be useful in the overall integration of the heart rate dynamics produced by the central nervous system. The several rhythm factors that might be produced by the central nervous system might modulate 1/f fluctuations of the HRV.     

Individual differences in circadian rhythm parameters and short-term tolerance to shiftwork: a follow-up study

The relationship between individual differences in the phase and amplitude of circadian rhythms and tolerance to shiftwork has been the subject of several studies. Those studies recorded circadian rhythms and shiftwork tolerance at approximately the same time. The present study aimed to examine the predictive relationships between the amplitude, phase, and mesor of 24 h rhythms obtained before exposure to shiftwork, and subsequent indices of tolerance measured after one and three years of shiftwork. The results revealed some stable relations between the various rhythm parameters and subsequent tolerance measures. Workers who had a higher mesor of positive moods, and a lower mesor of negative moods and fatigue, before entering shiftwork tended to tolerate shiftwork better. Further, those whose heart rate rhythm showed an earlier acrophase had better subsequent sleep quality scores, while those with a smaller amplitude of their temperature, negative mood and fatigue rhythms showed better night-shift tolerance.     

Circadian rhythm in susceptibility of mice to the anti-tumor drug carboplatin

The platinum-containing compounds has become a major chemical agent in the treatment of cancer. A circadian rhythm in the susceptibility of rodents and human being to cisplatin has been demonstrated, the maximal tolerance being found in the animal's active phase. Carboplatin is a second generation analog. Two studies were performed on mice with carboplatin under 12:12 light dark cycle to study its chronotoxicity and chronoeffectiveness. In study I, single intraperitoneal injection of 192mg/kg (LD50) carboplatin was given to four groups of mice at four different circadian stage. It was found that at 50% the overall mortality of mice, there was a mortality difference of 28% for mice receiving the drug at 9 a.m. to 71% for mice receiving drug at 9 p.m. It demonstrated that carboplatin was better tolerated in the animal's early sleep phase. In study II, S180 tumor-bearing mice were treated with 50mg/kg of carboplatin. The longest mean survival time and the lowest marrow toxicity occurred in the group which received the drug at the beginning of the sleep phase. It showed that the susceptibility of mice to carboplatin is circadian stage dependent. These data clearly demonstrate that, by timing the administration of drugs according to body rhythms, such as the host susceptibility-resistance rhythm to a drug, one can gain a therapeutic advantage over an approach which ignores such rhythms.     

When the human circadian system is caught napping: evidence for endogenous rhythms close to 24 hours

It is now well acknowledged that napping constitutes an inherent component of the human circadian system. To date, however, few studies have examined the effects of spontaneous napping on human free-running rhythms. This study investigated the free-running circadian periods of rest/activity and body core temperature in a group of young subjects who were permitted to nap during their time in isolation. Based on the frequency of self-reported sleep bouts, subjects were classified as Nappers or Nonnappers. Nappers exhibited free-running rhythms in both rest/activity and body core temperature that were not significantly different from 24 hours. Nappers showed a tendency for shorter free-running periods in both variables, when compared with Nonnappers. These findings emphasize the need for careful reassessment of data obtained from traditional free-run protocols.     

An improved sample packing device for rapid freeze-trap electron paramagnetic resonance spectroscopy kinetic measurements

Circadian rhythms are generated by the suprachiasmatic nuclei (SCN) and synchronized (entrained) to environmental light-dark cycles by the retinohypothalamic tract (RHT), a direct pathway from the retina to the suprachiasmatic nuclei. In anophthalmic mice, the optic primordia are resorbed between embryonic days 11.5 and 13, before retinal ganglion cells emerge. Thus the retinohypothalamic tract, which is the primary "zeitgeber" for circadian rhythms in sighted animals, never forms, and there is no retinal or photic input to the circadian system. We have used wheel running activity, a highly consistent and reliable measure of circadian rhythmicity in rodents, to establish the properties of endogenous locomotor rhythms of anophthalmic mice. We have identified three subpopulations of anophthalmic mice: a) rhythmic with strong stable circadian period but significantly increased period length; b) rhythmic with unstable circadian period; and c) arrhythmic. Future correlation of locomotor rhythms with properties of the suprachiasmatic nuclei in these mice will clarify the relationship between generation and properties of circadian rhythms and the neuroanatomical, neurochemical, and molecular organization of the circadian clock.     

Polysomnographie, chronobiologie et approche cognitive dans le traitement de la dépression majeure.

Apart from pharmacotherapy and biological conceptualisations, the cognitive theory and its therapeutic approach are likely the most used in the conceptualization and the treatment of major depression. The cognitive model attempts to explain how certain factors activate a dysfunctional cognitive structure. As such, the cognitive therapy focuses on the modification of negative and depressive cognitive distortions. Despite a success rate of approximately 66%, a significant proportion of patients (30%) suffer a relapse within one year of treatment. This suggests that the cognitive approach is not sufficient to explain the development, maintenance, remission and relapse of a major depressive episode. It is proposed here that sleep and chronobiological factors should be taken into consideration in order to improve the understanding of major depression and to maximize the chances of complete remission in those who suffer from this disorder. Indeed, both research and clinical reports have revealed that major depression is accompanied by sleep disruptions. More specifically, three types of problems have been identified: (1) Sleep discontinuity (reduced total sleep time, increased sleep latency, increased awakenings, reduced sleep efficiency); (2) decreases in slow wave sleep (SWS); (3) changes in rapid eye movement (REM) sleep characteristics (decreased REM latency, increased REM density, increase in the length of the first REM period and in the quantity of REM sleep). Of particular interest is the observation that, when the depressive symptoms disappear, sleep improves. Recent research, however reveals that certain sleep abnormalities, namely short REM latency and reduced SWS, are more robust or trait-like and are indicators of an increased risk of relapse. Furthermore, other studies suggest that the presence of these sleep abnormalities may facilitate the onset of depression. Models of sleep-wake regulation which have attempted to explain the sleep characteristics of depression are reviewed. These point to underlying chronobiological factors such as phase advances of circadian rhythms and suggest that such factors are responsible for the manifestation of the sleep disturbances observed in major depression. Fortunately, techniques that improve sleep quality and resynchronize the biological rhythms are available. Sleep hygiene maximizes sleep habits that facilitate normal sleep, particularly sleep initiation, sleep continuity and length of sleep. On the chronobiological side, bright light exposure and sleep schedule manipulations can resynchronize sleep periods with the appropriate circadian phase. It is thus proposed that sleep recordings, namely polysomnography, which have recently become more readily available (particularly with ambulatory devices), be used to select adequate treatment, and to support decisions regarding treatment duration. Similarly, sleep hygiene and chronobiological treatments should be integrated in the treatment of major depression. This article concludes by proposing a hierarchical model of interventions that combine polysomnography and chronobiological techniques with the classic cognitive approach to major depression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronopharmacological effects on nicotine repeated administration on heart rate, body temperature and locomotor activity circadian rhythms in rats

The aim of this study was to compare morning and evening repeated nicotine administration on the circadian rhythms of heart rate (H), body temperature (T) and locomotor activity (A) in unrestrained rats by using implanted radio-telemetry transmitters. The study was divided into three 7-day periods: a control period (P1), a treatment period (P2) and a recovery period (P3). During P2, four rats received nicotine (1mg.kg(-1)) subcutaneously at 09.00 h and four rats received nicotine in the same conditions at 21.00 h. For P1, P2 and P3, a power spectrum analysis was applied in order to determine the dominant period of rhythmicity. If H, T and A circadian rhythms were detected, the characteristics of these rhythms were determined by cosinor analysis, expressed as means+/-SEM and compared by ANOVA. Our results indicated: (1) a lack of detection of A circadian rhythm during P2 for the morning group while H and T circadian rhythms were detected for the morning and evening group whatever the period. (2) alterations of mesors, amplitudes and acrophases of H and T circadian rhythms for the morning and evening group during P2 and alterations of mesor, amplitude and acrophase of A circadian rhythm for the evening group. Furthermore these alterations were significantly different for the morning and evening group during P2. These results showed that the time of administration of nicotine differently affect H, T and A rhythms. The authors suggest that these effects can be mediated by central cholinergic and/or monoaminergic mechanisms.     

Beneficial effect of risperidone on sleep disturbance and psychosis following traumatic brain injury

Severe disturbances of sleep architecture and circadian rhythms are common in traumatic brain injured patients; however, complete absence of the rapid eye movement sleep stage is very rare. We describe a brain injured patient with cognitive disturbances who developed severe alterations of sleep architecture, accompanied by paranoid and jealousy delusions. Following several trials with conventional antipsychotics his psychotic state stabilized but he continued to complain of insomnia and daytime fatigue. When treated with risperidone 2 mg/day, both his sleep and the delusional thoughts improved markedly and his daytime alertness increased. Severe deterioration of his support system brought about discontinuation of treatment with re-emergence of all symptoms.