Four congenitally blind children with circadian sleep-wake rhythm disorder

Four congenitally blind children aged 4-12 years, with severe or moderate mental retardation, were chronobiologically studied. Three of them showed a free-running rhythm of sleep-wake, and the fourth showed an irregular sleep-wake rhythm. To entrain their sleep-wake rhythm to a 24-h rhythm, several trials based on chronotherapy were performed. The free-running rhythms in the three children were considered their own endogenous rhythms, revealed through some disorder in the mechanism synchronizing the endogenous rhythm to the normal 24-h environmental rhythm. The irregular sleep-wake rhythm in the fourth child may have been the result of immaturity or failure of the pacemaker of the circadian rhythm. Because of their severe mental retardation, all the children were lacking in social time cues, which are the most potent "Zeitgebers" for human biological clocks.     

Vitamin B12 treatment for sleep-wake rhythm disorders

Vitamin B12 (VB12) was administered to two patients suffering for many years from different sleep-wake rhythm disorders. One patient was a 15-year-old blind girl suffering from a free-running sleep-wake rhythm (hypernychthemeral syndrome) with a period of about 25 h. In spite of repeated trials to entrain her sleep-wake cycle to the environmental 24-h rhythm, her free-running rhythm persisted for about 13 years. When she was 14 years old, administration of VB12 per os was started at the daily dose of 1.5 mg t.i.d. Shortly thereafter, her sleep-wake rhythm was entrained to the environmental 24-h rhythm, and her 24-h sleep-wake rhythm was maintained while she was on the medication. Within 2 months of the withholding of VB12, her free-running sleep-wake rhythm reappeared. The VB12 level in the serum was within the normal range both before and after treatment. The other patient was a 55-year-old man suffering from delayed sleep phase syndrome since 18 years of age. After administration of VB12 at the daily doses of 1.5 mg, his sleep-wake rhythm disorder was improved. The good therapeutic effect lasted for more than 6 months while he was on the medication.     

Entrainment of circadian rhythm to a photoperiod reversal shows retinal dystrophy in RPE65(-/-) mice

Light entrainment of circadian rhythms is mediated by classical "visual" photoreceptors (rods and cones) as well as "nonvisual" photoreceptive elements (light-detecting cells that do not contribute to classical "vision"). This paper aimed to assess whether light entrainment of locomotor circadian rhythms in mice with impaired rods and cones differs from normal controls and whether this technique, alongside existing techniques, could be used to assess visual function. The study was primarily interested in differences between the entrainment of circadian rhythms of normal-sighted C57Bl/6J mouse and the C57Bl/RPE65 knockout mouse (RPE65(-/-)), although C3H/HeJ (rd/rd) mice were included as a preexisting model of retinal degeneration. Circadian rhythms of motor activity before and after a 12-h light reversal were assessed in custom-built cages that continuously monitored movement. The controls showed a significantly higher mesor and amplitude when compared to the RPE65(-/-) and rd/rd mice. Despite the loss of rods and cones, the RPE65(-/-) and rd/rd maintained a 24-h circadian rhythm entrained to light similar to controls and were capable of circadian reentrainment to a 12-h light reversal. Importantly, this light reentrainment of the circadian phase occurred at a significantly slower rate in the retinal degenerate models than in the controls. The RPE65(-/-) model demonstrates a retinal degenerate reentrainment phenotype when compared to the rd/rd model. It is suggested that these retinal degenerate mice retain the ability to detect light for the purposes of circadian rhythm entrainment. However, alterations of specific parameters of the circadian rhythm with loss of rods and cones may provide measures of loss of visual function (sight).     

Circadian rhythm in rat brain opiate receptor

To investigate diurnal variations in opiate receptor binding, the amount of specifically bound [3H]naloxone was measured at 4-h intervals across a 24-h period in the forebrains of rats that had been housed under a controlled light--dark cycle (lights on from 07.00 to 19.00 h) for 3 weeks. A significant rhythm with a peak at 22.00 h was found, the amplitude was 46--78%. In the absence of time cues, this circadian rhythm persisted with a peak at 02.00--06.00 h and an amplitude of 88%. Scatchard analysis indicated that the differences in binding throughout the day were due not to changes in affinity, but to changes in the number of binding sites.     

Longitudinal study of daily variation of rats' behavior in the elevated plus-maze

We conducted a longitudinal study about daily variation of Wistar male rats' behavior in the elevated plus-maze (EPM) evaluated in the 1st, 2nd, 3rd, 6th, 12th, and 18th months of life. Animals were submitted to the plus-maze in 12 sessions at 2-h intervals (n=72, 6 per time point). Spontaneous rest-activity rhythm of four animals was assessed by observation of 24-h videotape records. Time series were analyzed by Cosinor method. Behavioral rates on the six occasions and in light and dark phases were compared by means of two-way ANOVA with repeated measures. Exploratory behavior in EPM was smaller in the light phase and in older animals. Higher values of open and closed arms exploration were observed in the first and third months of the dark phase, and in the first month of the light phase. Adjustment to the 24-h period was significant at all stages for rest-activity data, number of entries in closed arms, and time on center, and for three to five stages for open-arm exploration. In general, 24 h variability was more pronounced in younger animals compared with older ones. The present study showed that: (1). a significant amount of total variability of the behavioral indexes analyzed could be attributed to 24 h variation, (2). light/dark phases differences in EPM exploration were present at all developmental stages, (3). older Wistar rats explored less the EPM and were less active in their home cage compared with younger ones, and (4). behavioral indexes (EPM) decrease was phase related and partially related to a reorganization of rest-activity rhythm.     

Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod

Heart rate (HR) and heart rate variability (HRV) undergo marked fluctuations over the 24-h day. Although controversial, this 24-h rhythm is thought to be driven by the sleep-wake/rest-activity cycle as well as by endogenous circadian rhythmicity. We quantified the endogenous circadian rhythm of HR and HRV and investigated whether this rhythm can be shifted by repeated melatonin administration while exposed to an altered photoperiod. Eight healthy males (age 24.4 +/- 4.4 years) participated in a double-blind cross-over design study. In both conditions, volunteers were scheduled to 16 h-8 h rest : wake and dark : light cycles for nine consecutive days preceded and followed by 29-h constant routines (CR) for assessment of endogenous circadian rhythmicity. Melatonin (1.5 mg) or placebo was administered at the beginning of the extended sleep opportunities. For all polysomnographically verified wakefulness periods of the CR, we calculated the high- (HF) and low- (LF) frequency bands of the power spectrum of the R-R interval, the standard deviation of the normal-to-normal (NN) intervals (SDNN) and the square root of the mean-squared difference of successive NN intervals (rMSSD). HR and HRV variables revealed robust endogenous circadian rhythms with fitted maxima, respectively, in the afternoon (16:36 hours) and in the early morning (between 05:00 and 06:59 hours). Melatonin treatment phase-advanced HR, HF, SDNN and rMSSD, and these shifts were significantly greater than after placebo treatment. We conclude that endogenous circadian rhythmicity influences autonomic control of HR and that the timing of these endogenous rhythms can be altered by extended sleep/rest episodes and associated changes in photoperiod as well as by melatonin treatment.     

Circadian rhythm abnormalities of deep body temperature in depressive disorders.

We investigated circadian rhythms of body temperature in 62 inpatients with major depressive episodes, by monitoring the deep body temperature through the abdominal skin every two hours for a consecutive 48-h period. The data were analyzed by both the least-squares method and the maximum entropy spectral analysis (MEM) and were compared with those in 29 normal volunteers who apparently had a regular 24-h sleep-wake schedule. Circadian rhythm phase disturbances in the depressed patients were likely to be manifested in a phase normal or a phase delay pattern rather than in a phase advance pattern. The amplitude of body temperature was significantly smaller and the mesor was higher in the depressed patients than in the normal subjects. Analysis by MEM revealed that the periods of circadian rhythm of body temperature tended to be longer in the depressed patients than in the normal subjects, though there was no significant difference. The power spectral density by MEM was significantly lower, and there were significantly more ultradian rhythm components in the depressed patients than in the normal subjects. These findings suggest that the fundamental rhythm disturbance in depression may be a weakening of the coupling processes between internal pacemakers and an abnormal sensitivity to environmental information.     

The 24-h growth hormone rhythm in men: sleep and circadian influences questioned

The 24-h rhythm of growth hormone (GH) is thought to be controlled primarily by sleep processes with a weak circadian component. This concept has been recently questioned in sleep-deprived persons. To test the notion of a high sleep-dependency of GH release, we established simultaneous 24-h rhythms of GH and melatonin, a circadian marker, in night workers who form a model for challenging sleep and circadian processes. Ten day-active subjects and 11 night workers were studied during their usual sleep-wake schedule, with sleep from 23:00 to 07:00 hours and 07:00 to 15:00 hours, respectively. Experiments were conducted in sleep rooms under continuous nutrition, bed rest, and dim light. Melatonin and GH were measured every 10 min over 24 h. In day-active subjects, melatonin and GH showed the well-known 24-h profiles, with a major sleep-related GH pulse accounting for 52.8 +/- 3.5% of the 24-h GH production and the onset of the melatonin surge occurring at 21:53 hours +/- 18 min. In night workers, melatonin showed variable circadian adaptation, with the onset of secretion varying between 21:45 and 05:05 hours. The sleep-related GH pulse was lowered, but the reduction was compensated for by the emergence of large individual pulses occurring unpredictably during waking periods, so that the total amount of GH secreted during the 24 h was constant. One cannot predict the degree of GH adaptation from the highly variable melatonin shift. These results argue against the concept that sleep processes exert a predominant influence on GH release whatever the conditions. When sleep and circadian processes are misaligned, the blunting of the sleep-related GH pulse is counteracted, as in sleep-deprived persons, by a compensatory mechanism promoting GH pulses during wakefulness.     

Alertness, mood and performance rhythm disturbances associated with circadian sleep disorders in the blind

Blind people report disturbances in alertness, mood and performance. In laboratory studies, these waking functions can only be maintained when the wake-dependent deterioration is opposed by appropriately-timed endogenous circadian rhythms. We aimed to quantify whether variations in waking function experienced by blind people living in society were dependent on the phase relationship between the sleep-wake cycle and the circadian pacemaker. The time course of alertness, mood and performance was assessed in 52 blind subjects with and without circadian rhythm disorders every 2 h for 2 days per week for 4 weeks. Sleep-wake timing and circadian phase were assessed from diaries and weekly measurements of urinary 6-sulphatoxymelatonin rhythms, respectively. In those subjects who woke at either a normal circadian phase (n = 26) or abnormally early (n = 5), alertness, mood and performance deteriorated significantly with increased time awake (P < 0.05). In 17 non-entrained ('free-running') subjects, waking function varied significantly with circadian phase such that subjects rated themselves most sleepy (P = 0.03) and most miserable (P = 0.02) when they were awake during the time of peak melatonin production. The internal phase relationship between sleep-wake behaviour and the circadian melatonin rhythm in entrained subjects contributed to predictable differences in the daily profile of alertness, mood and performance. Disruption of this phase relationship in non-entrained blind individuals with circadian rhythm sleep disorders resulted in impaired waking function during the day equivalent to that usually only experienced when awake during the night. Treatment for circadian rhythm disorders should be targeted in normalizing these phase relationships.     

The rhythms of human sleep propensity and core body temperature

Evidence from human free-running studies has suggested a close relationship between the timing of the circadian rhythm of core body temperature and the rhythm of sleep propensity. However, this relationship may be questioned by variations of sleep and wakeful activity which could have masked the endogenous temperature rhythm. A constant routine was used here to «unmask>> the endogenous temperature rhythm in addition to frequent sleep trials across a 24-h period to confirm the relationship between temperature and sleep propensity rhythms. Of the 14 healthy, good sleeping subjects 13 had significant 24-h cosine rhythms of sleep propensity. Eight of these also had a significant 12-h cosine rhythm. The eight subjects with both 24-h and 12-h rhythms showed a minor peak of sleep propensity in the early afternoon followed by a trough in the early evening (20.00 hours). Sleep propensity then rose rapidly at about midnight to a major peak in the early morning. This was followed by a second trough of sleep propensity in the late morning. The average times of the sleep propensity phases relative to the circadian temperature rhythm were very similar to the earlier free-running studies. Furthermore, the times of the sleep propensity phases were highly correlated with the body temperature minimum. These results suggested the possibility that a common oscillator determines the timing of both the body temperature rhythm and the phases of the sleep propensity rhythm.     

Circadian rhythm of objectively recorded hot flashes in postmenopausal breast cancer survivors

OBJECTIVE: Similar to the circadian rhythm of core body temperature, hot flashes have been found to exhibit a circadian rhythm in healthy, naturally postmenopausal women, with a peak in frequency at 18:25 h. However, to date, no studies have evaluated whether this same pattern is found among breast cancer survivors reporting hot flashes. DESIGN: Daily hot flash frequencies were measured among 21 postmenopausal breast cancer survivors using validated 24-h sternal skin conductance monitoring. RESULTS: Hot flashes were noted in all women, ranging in frequency from 1 to 30 per 24-h period. A majority of the sample (86%) experienced > or = 1 nighttime hot flash, with 48% exhibiting > or = 3 but < or = 7 nighttime hot flashes. For the total sample, a modest circadian rhythm was noted with a peak in hot flash frequency occurring at 16:10 h. However, significant variability was observed across individual women, and, as a whole, breast cancer survivors demonstrated distorted to obliterated rhythms. CONCLUSIONS: Data suggest that hot flashes in postmenopausal breast cancer survivors do not follow the same circadian pattern as previously seen in healthy, naturally postmenopausal women. Findings have implications for (1) understanding the potential for sleep disturbances and fatigue in breast cancer survivors experiencing hot flashes, and (2) future research examining circadian rhythms of core body temperature and hot flashes in breast cancer survivors.     

Ultradian rhythm of 100 min in the dark phase EEG of the rat

Using the "variance in statistics" as an index of electroencephalogram (EEG) parameters, we observed the cortico-hippocampal EEG rhythm under a 12:12-h light-dark condition in the rat with chronically implanted electrodes for EEG recording. The above EEG variance was simply measured in real time and on line through a personal computer. It corresponded to EEG slow wave activity and expressed the process of slow wave sleep as described in the two-process model by Borbély et al. Only in the dark phase, mean power spectral density of the EEG variance had a significant peak at about 1/100 cycles/min. This 100-min rhythmicity similar to the basic rest-activity cycle in human beings was observed in rats, particularly in the dark (active) phase for nocturnal animals. We propose that this ultradian 100-min rhythm is essential for the rat to maintain the waking state dominantly over the 12-h dark period.     

Allomaternal vocal behavior in squirrel monkeys.

Three groups of squirrel monkeys, containing 1-3 infants (N = 7) and 4 adult females each, were observed weekly for the first 12 weeks of the infants' lives. Infants received approximately 100 vocalizations, mostly "caregiver" calls, per waking hour from their mothers and the other adult females with whom they were housed (allomothers). Mothers vocalized very little to their own infants during the first few weeks of life, when infants remain on the mother's back full-time. Instead, allomothers (who were often carrying their own dependent infants) vocalized copiously to others' very young infants. Infants responded vocally to these allomaternal caregiver calls as early as Day 1 but were less responsive to mothers. When infants began leaving the mothers' backs, mothers' rates of calling increased five-fold as they used caregiver calls to retrieve separated infants. Early vocalizing to infants involves them in their first social exchanges and is probably performed by allomothers rather than mothers because the infant rides dorsally in this genus.     

The circadian rhythm of temperature in humans during a 26-hr sleep-wake schedule

The effect of non-24-hr zeitgebers on human circadian rhythms is usually studied in temporal isolation units. In this study, subjects tried to adhere to a 26-hr sleep-wake schedule while living at home exposed to the conflicting natural 24-hr zeitgebers. Temperature was continuously measured with a rectal probe. Daily sleep logs provided subjective estimates of sleep and wake times. After a baseline period on a 24-hr schedule, the subjects followed the 26-hr schedule for 12-13 consecutive days. The circadian rhythm of temperature appeared entrained to the 26-hr schedule for two of the subjects (the adapters), but was definitely not entrained for the other two subjects (the non-adapters). For the non-adapters a 24-hr component persisted in the temperature rhythm. Sleep time conformed more closely to the planned schedule for the adapters than for the non-adapters. These results show that a 26-hr sleep-wake schedule can be a more powerful zeitgeber than the natural 24-hr zeitgebers. Factors that might determine whether an individual will entrain to the 26-hr schedule are discussed.     

Circadian rhythm of biliary excretion and its control mechanisms in rats with chronic biliary drainage.

Rats with chronic biliary drainage under a rigid lighting schedule (light on at 6 A.M. and off at 6 P.M.) exhibited a remarkable circadian rhythm of bile flow, biliary concentrations and excretory rates of bile salts, cholesterol, and phospholipid. The peak was attained at midnight and nadir at noon except for the peak concentrations of cholesterol and phospholipid occurring at 8 P.M. Cholesterol feeding abolished the circadian rhythm of biliary cholesterol and phospholipid concentrations but not their excretory rates because the daily fluctuation of the bile flow remained unchanged. Bilateral vagotomy enhanced the bile flow rate and shifted the peak of circadian rhythm of all parameters except bile salt 4 h earlier. Bilateral adrenalectomy abolished the circadian variation of the concentration of cholesterol and phospholipid and minimized that of bile salt, but the daily fluctuation of their excretory rates persisted in a lower amplitude. The studies suggested that such circadian rhythm might be controlled simultaneously by multiple factors and could not be entirely abolished by any single special treatment.     

Circadian rhythm dissociation in an environment with conflicting temporal information.

The relative contributions of light-dark (LD) cycles and feeding (EF) cycles in providing temporal information to the circadian time-keeping system were examined in chair-acclimatized squirrel monkeys (Saimiri sciureus). The circadian rhythms of drinking, colonic temperature, urine volume, and urinary potassium excretion were measured with the LD and EF cycles providing either conflicting phases or periods. In conflicting phase experiments, animals were exposed to 24-h LD cycles consisting of 12 h of 600 lx followed by 12 h of less than 1 ls and concurrent 24-h EF cycles in which the animals ate for 3 h and then fasted for 21 h. One group had food available at the beginning and a second group at the end of the light period. In conflicting period experiments, monkeys were exposed to 23-h LD cycles (LD 11.5:11.5) and 24-h EF cycles (EF 3:21). Analysis of the rhythms showed that both phase and period information were conveyed to the drinking and urinary rhythms by the EF cycle, and to the temperature rhythm by the LD cycle.     

Fragmentation of the rest-activity rhythm correlates with age-related cognitive deficits

Aging affects both cognitive performance and the sleep-wake rhythm. The recent surge of studies that support a role of sleep for cognitive performance in healthy young adults suggests that disturbed sleep-wake rhythms may contribute to 'age-related' cognitive decline. This relationship has however not previously been extensively investigated. The present correlational study integrated a battery of standardized cognitive tests to investigate the association of mental speed, memory, and executive function with actigraphically recorded sleep-wake rhythms in 144 home-dwelling elderly participants aged 69.5 ± 8.5 (mean ± SD). Multiple regression analyses showed that the partial correlations of the fragmentation of the sleep-wake rhythm with each of the three cognitive domains ( r  = −0.16, −0.19, and −0.16 respectively) were significant. These associations were independent from main effects of age, implying that a unique relationship between the rest-activity rhythm and cognitive performance is present in elderly people.     

Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome

Post-exertional exacerbation of symptoms is one of the major characteristics of chronic fatigue syndrome (CFS). In this study, we evaluated the hypothesis that disturbances in circadian chronobiological regulation may play a role in generating this phenomenon. We recorded physical activity for 6-day periods in 16 women (10 CFS and 6 sedentary healthy controls, CON) before and after performing a maximal treadmill test. We calculated activity rhythms by computing autocorrelation coefficients by cutting 1 day apart from the data as a template and sliding it sequentially through each of the other days; all of 6 days were used as the templates. The peak value of autocorrelation coefficient (R) and the time between peak R's (circadian period, CP) were calculated. CFS patients had a lengthening (P < .05) of mean circadian period (MCP) that was longer than 24 h (P < .05), while MCP in CON remained unchanged. No difference was found in the standard error of each subject's MCP (circadian period variability, CPV) before and after exercise for both groups. We interpret this increase in circadian rest-activity period seen in CFS patients following exercise to indicate that exhaustive exercise interferes with normal entrainment to 24-h zeitgeber(s). This effect may be associated in part with the common patient complaint of symptom worsening following exertion.     

Effect of a short photoperiod on circadian rhythms of body temperature and motor activity in old rats

Circadian rhythms of body temperature and motor activity were documented in young and old rats (four 8-week-old and five 22-month-old male Wistars, implanted with telemetric probes and housed in a chronobiological facility) under two different photoperiod conditions. The animals were maintained in a light:dark (LD) cycle of 12 h each (LD 12:12) for 4 weeks and then exposed to a LD 6:18 cycle for 7 weeks to assess the effect of age on the desynchronization of the temporal structure of the rhythms. In old rats under LD 12:12, the power of the 24-h component and the circadian amplitude of body temperature and motor activity were markedly lower than in the young and both rhythms were phase-advanced. After the shift to LD 6:18, the circadian rhythmicity was maintained for both variables and the same phase delay (+5+/-1 h) was observed in both age groups, as was a gradual expansion of the patterns of both functions with the longer night. The photoperiod reduction (6 weeks under LD 6:18) did not modify the power of the 24-h component of body temperature and motor activity in old rats. In young rats, however, the power and amplitude of the 24-h component of motor activity rhythm fell to the levels of those in old rats, while the power of the 24-h component of body temperature rhythm and the amplitude did not change. Our data show that the circadian rhythm of motor activity, but not of body temperature, responds age dependently to a photoperiod reduction.