Loss Of Circadian Rhythm Research Articles

Sleep in children with neoplasms of the central nervous system: case review of 14 children.

Sleep is a complex neurologic process that is generated by and primarily benefits the brain. Sleep can be disrupted by a wide range of brain injuries, many of which may occur in children with neoplasms of the central nervous system (CNS). The specific sleep problems that have been associated with brain injuries include sleepiness, apnea, insomnia, and loss of circadian rhythmicity. The objective of this study was to characterize the sleep problems seen in children with neoplasms of the CNS through a comprehensive clinical and objective sleep evaluation. A retrospective case series review was conducted of all children with neoplasms of the CNS referred to the sleep clinic for a clinical evaluation between 1994 and 2002. The sleep evaluation of the 14 children in this report included a sleep history, a sleep log, and a polysomnogram. In the 12 children with complaints of daytime sleepiness and/or fatigue, a multiple sleep latency test was performed the day after the polysomnogram. Three children also had a 2-week actigraphic study. The most common sleep complaint in this group of children was excessive daytime sleepiness (EDS), present in 9 of the 14 children. In these children, the sleepiness was manifest by 1 or more of the following symptoms: 1) an increase in total sleep time per 24 hours; 2) the resumption of daytime naps that had been previously discontinued at a younger age; 3) an inability to awaken in the morning to begin the days activities; or 4) the inability to remain awake during activities of daily living, such as school. Of the 9 children with daytime sleepiness, 8 had brain tumors requiring neurosurgical procedures at the time of their diagnosis, 6 of whom required ventricular shunting. The children with the most severe sleepiness had evidence of hypothalamic/pituitary injury with deficiencies in both anterior and posterior pituitary hormones. Five of the children with EDS had polysomnographic evidence of symptomatic narcolepsy with rapid eye movement sleep present on 2 or more of the daytime naps. The symptoms of EDS were effectively controlled with modest doses of daytime stimulant medication and/or scheduled naps. Central apnea leading to respiratory insufficiency and requiring mechanical ventilation to correct was present in 2 children with tumors involving the medulla. Although snoring with possible obstructive sleep apnea was the reason for referral to the sleep clinic in 5 children, none of the children in this series had polysomnographic evidence of significant obstructive sleep apnea. The other sleep problems seen in these children were hypoxia in 2 children, fatigue in 3 children, and seizures during sleep in 1 child. The interval between tumor diagnosis and sleep evaluation varied from 0 months to 9 years (mean: 42 months). The treatment of the sleep problems of this group of children took many forms, including stimulants, scheduled naps, mechanical ventilation, supplemental oxygen, and anticonvulsants. Brain injuries, which invariably are present in children with neoplasms of the CNS, may result in a variety of diagnosable and treatable sleep disorders. The sleep symptoms did not appear to be directly related to the specific therapy the child received, nor the presence of residual tumor. Rather, the primary determinant of the sleep symptoms was the area of the brain that was damaged, regardless of how the damage occurred. Children who sustained damage to the hypothalamic/pituitary region developed EDS regardless of whether the damage was the result of the tumor, surgery, hydrocephalus, or radiation to the whole brain or localized to the suprasellar area. The only children who developed respiratory insufficiency had an injury to the medulla. This observation is consistent with the view that sleep is a specific, albeit complex, neurologic process that is controlled by specific brain regions. EDS and respiratory insufficiency were the most commonly diagnosed severe sleep disorders in these children. The sleep problems of children with brain tumors may develop before, but more often soon after, their tumor diagnosis and treatment. However, the sleep symptoms may not be appreciated by medical providers until years after their onset, which may delay the beginning of effective interventions.

Vasopressin deficiency provides evidence for separate circadian oscillators of activity and temperature

Vasopressin-containing Long–Evans and vasopressin-deficient Brattleboro rats were maintained in individual cages while telemetered activity (AC) and body temperature (BT) data were collected. Rats were initially exposed to a 12 h/12-h light/dark cycle (photic zeitgeber) and were allowed ad-libitum access to food and water. Daily feeding, care, and handling (nonphotic zeitgebers) occurred at the beginning of the second hour of the dark cycle. After a 14-day habituation period, rats were subjected to continuous light (LL) or dark (DD) and nonphotic cues were presented irregularly. During the habituation period, both strains exhibited clear 24-h circadian rhythms of AC and BT. In LL or DD, photic cues were removed and nonphotic cues were presented irregularly. There was a shift in the rhythm for Long–Evans animals to 26 h for both AC and BT in LL and 24.6 h in DD. Feeding, care, and handling were seen as minor artifact. In Brattleboro rats, although there were robust 26-h and 24.6-h circadian rhythms of AC in the LL and DD, respectively, BT data were inconsistent and showed sporadic fluctuations. In the BT rhythm of Brattleboro animals, strong peaks were associated with feeding, care, and handling times and trough periods were characterized by a dramatic drop in temperature. This experiment demonstrates that AC and BT are controlled by separate oscillators. In addition, the importance of vasopressinergic fibers in the control of circadian rhythms of BT is evidenced by the loss of circadian rhythms in animals lacking these functional fibers when exposed to free-running paradigms where there is no entrainment of photic or nonphotic oscillators.

Decreased RR interval complexity and loss of circadian rhythm in patients with congestive heart failure.

The present study investigated how the RR interval complexity and variability and their circadian rhythms alter for patients with congestive heart failure (CHF). Sixteen patients aged between 41 and 72 years with CHF and 20 control subjects were included. 24-h ambulatory electrocardiographic recordings were analyzed, and digitized data was partitioned into sections of 30-min duration. For each section, time- and frequency-domain indices, and complexity indices of heart rate variability were calculated. For CHF patients, 24-h average values of all indices were significantly decreased. The circadian rhythms of mean RR intervals were preserved and resembled the abnormal circadian rhythms of the low-frequency power. The circadian rhythms of high-frequency power and all complexity indices shown in the normal control were lost. Conclusively, the patients with CHF showed decreased RR interval complexity and loss of its circadian rhythm, in addition to decreased frequency-domain RR interval variability and its abnormal circadian rhythm.

The mPer2 gene encodes a functional component of the mammalian circadian clock.

Circadian rhythms are driven by endogenous biological clocks that regulate many biochemical, physiological and behavioural processes in a wide range of life forms. In mammals, there is a master circadian clock in the suprachiasmatic nucleus of the anterior hypothalamus. Three putative mammalian homologues (mPer1, mPer2 and mPer3) of the Drosophila circadian clock gene period (per) have been identified. The mPer genes share a conserved PAS domain (a dimerization domain found in Per, Arnt and Sim) and show a circadian expression pattern in the suprachiasmatic nucleus. To assess the in vivo function of mPer2, we generated and characterized a deletion mutation in the PAS domain of the mouse mPer2 gene. Here we show that mice homozygous for this mutation display a shorter circadian period followed by a loss of circadian rhythmicity in constant darkness. The mutation also diminishes the oscillating expression of both mPer1 and mPer2 in the suprachiasmatic nucleus, indicating that mPer2 may regulate mPer1 in vivo. These data provide evidence that an mPer gene functions in the circadian clock, and define mPer2 as a component of the mammalian circadian oscillator.

Melatonin Entrains the Restored Circadian Activity Rhythms of Syrian Hamsters Bearing Fetal Suprachiasmatic Nucleus Grafts

A circadian pacemaker consists of at least three essential features: the ability to generate circadian oscillations, an output signal, and the ability to be entrained by external signals. In rodents, ablation of the suprachiasmatic nucleus (SCN) results in the loss of circadian rhythms in activity. Rhythmicity can be restored by transplanting fetal SCN into the brain of the lesioned animal, demonstrating the first two of the essential pacemaker features within the grafts. External signals, such as the light/dark cycle, have not, however, been shown to entrain the restored rhythms. Melatonin injections are an effective entraining stimulus in fetal and neonatal Syrian hamsters of the same developmental ages used to provide donor tissue for transplantation. Therefore, melatonin was used to test the hypothesis that SCN grafts contain an entrainable pacemaker. Daily injections of melatonin were given to SCN-lesioned hosts beginning on the day after transplantation of fetal SCN. Two groups that received melatonin at different times of day 12 hr apart each showed significantly clustered phases but with average phases that differed by 8.67 hr. Thus melatonin was able to entrain the restored circadian activity rhythms. In contrast to these initial injections, injections given 6 weeks after transplantation were unable to entrain or phase shift the rhythms. The results demonstrate that SCN grafts contain an entrainable circadian pacemaker. In addition, the results also indicate that the fetal SCN is directly sensitive to melatonin and, as with intact hamsters, sensitivity to melatonin is lost during SCN development.

Hypoleptinemia in patients with anorexia nervosa: loss of circadian rhythm and unresponsiveness to short-term refeeding.

Leptin is a protein encoded by the ob gene that is expressed in adipocytes and regulates eating behavior via neuroendocrine mechanisms. Plasma leptin levels have been shown to correlate with weight and body fat in normal, obese and anorexic subjects. In the last of these populations, the dynamic profile of plasma leptin levels during short-term refeeding has never been assessed. We thus investigated basal plasma leptin levels in 29 female patients with anorexia nervosa (AN) (age 21.9 +/- 1.4 years, body mass index (BMI) 15.2 +/- 0.3 kg/m2) and in 80 normal female controls (age 21.2 +/- 0.2 years, BMI 20.3 +/- 0.3 kg/m2, mean +/- S.E.M.). Basal plasma leptin levels in AN were decreased by 77% compared with controls (2.5 +/- 0.2 vs 11.1 +/- 0.7 ng/ml, P < 0.0001). In both AN subjects and controls, plasma leptin levels correlated significantly with BMI (r2 = 0.448, P < 0.0001 and r2 = 0.339, P < 0.0001 respectively). Five AN patients (four female, one male, age 22.0 +/- 4.7 years, BMI 14.2 +/- 0.4 kg/m2, body fat 4.3 +/- 0.9 kg or 11.0 +/- 1.9% of body weight, basal metabolic rate (BMR) 958 +/- 122 kcal/day) were studied during a 3-day refeeding period and compared with eight control subjects (two male, six female, age 25.7 +/- 1.2 years, BMI 21.3 +/- 0.8 kg/m2, body fat 15.1 +/- 0.9 kg or 24.6 +/- 1.7%, BMR 1455 +/- 78 kcal/day) submitted to 36-h fasting. The amount of calories administered was based on BMR + 20% (carbohydrate 60%, protein 17%, fat 23%). In contrast to the rise in leptin levels that occurred during refeeding after a prolonged fast period in normal subjects, plasma leptin levels remained low and unchanged throughout the 3 days of renutrition in AN patients. The circadian rhythm of leptin was also completely abolished. This contrasted with the preserved circadian variations of cortisol, whose mean levels were increased. In conclusion, we confirmed that plasma leptin levels are low in AN and correlate with body weight. We further demonstrated that plasma leptin levels do not respond to short-term refeeding in anorexic patients in whom circadian variations are not restored, which suggests that the acute regulation of leptin by positive changes in energy balance is not preserved under a critical threshold of body fat.

Effects of selective vagotomy on circadian rhythms of plasma glucose, insulin and food intake in control and ventromedial hypothalamic (VMH) lesioned rats.

Effects of hepatic and celiac vagotomy on circadian rhythms of plasma glucose, insulin, and food intake were examined in sham-operated (control) and ventromedial hypothalamic (VMH) lesioned rats. Rats were acclimated to the condition with a 12-hour light-dark cycle for 1 week before surgery. One week after VMH lesions, control and VMH lesioned rats were divided into three groups: sham vagotomy, hepatic vagotomy, and celiac vagotomy. Three days after vagotomy, food intake was measured at 6-hour intervals. Seven days after vagotomy, plasma glucose and insulin were measured at the midpoint of each feeding period. In control rats, hepatic vagotomy destroyed circadian rhythms of plasma glucose and insulin probably due to removal of afferent function. In VMH lesioned rats, celiac vagotomy destroyed circadian rhythm of food intake due to the reduction of plasma insulin by removal of efferent function without affecting the loss of circadian rhythms of plasma glucose and insulin.

Patterns of urine flow and electrolyte excretion in patients following traumatic brain injury

This study was conducted to determine how commonly, following a traumatic brain injury (TBI), patients might lose their circadian rhythm of urine production and to explore possible causes. In health, an adult would be expected to have a daytime rate of urine production twice that of the night. Seven patients, all more than three months post-TBI, who were either continent or in whom continence could be achieved by use of an external device (convene) were investigated. For each patient, over a five-day period, the mean daytime and night-time rates of urine production were measured. These values were expressed as a ratio. In three of the seven patients this ratio did not differ significantly from 1, suggesting that they had lost their normal circadian rhythm of urine production. Screening of pituitary function implicated hypothalamic dysfunction in six of the seven patients, offering a possible explanation for the loss of circadian rhythm seen.

Loss of circadian rhythm in luminal acidity of canine stomach by implantation of a gastric fistula.

One to four months after implantation of a gastric fistula, a circadian rhythm in gastric acidity could be demonstrated by use of the intragastric 24-hour pH-metry in dogs with the gastric fistula protruding on the left side of the upper abdomen. This circadian rhythm was found to be fully developed within 3 years, and it remained unchanged up to 5 years after implantation. It is characterized by a daytime intragastric median pH of about 2 and a nocturnal intragastric median pH of about 7. In contrast, a circadian rhythm did not develop within 5 months after instrumentation of the dogs with a gastric fistula protruding on the right side of the upper abdomen. Only 2 years after implantation of the fistula, an intragastric daytime median pH of about 2 and a nocturnal median pH of about 4 appeared. Four years after implantation, the circadian rhythm had evolved. The results show a delayed postoperative restoration of circadian rhythm in canine gastric acidity if a gastropexy occurs at an untolerated position. This may lead to unphysiological distensions in the gastric wall with subsequent continuous stimulation of acid secretion.

Cardiovascular neural regulation during and after prolonged high altitude exposure.

Eight young healthy male subjects, members of a Himalayan expedition, underwent 24 h Holter monitoring before departure, after 1 and 4 weeks at high altitude (5000 m) and after return to sea level. At high altitude, the circadian reciprocal changes in low and high frequency (LF, HF) were absent, with no significant reduction in the LF to HF ratio over the 24 h; moreover, the proportion of adjacent R-R intervals that differed by more than 50 ms (pNN50) decreased significantly and remained lower after return to sea level. Urine catecholamines increased at high altitude, but only norepinephrine, after 1 week of exposure, rose significantly. Upon return to sea level the density, but not the affinity, of [alpha]2-adrenergic receptors on platelets decreased significantly compared to pre-expedition values. At high altitude increased sympathetic activity was indicated by elevation of urine norepinephrine and by the loss of circadian rhythm in spectral components. The simultaneous reduction of HF and pNN50 demonstrated decreased vagal tone. The persistence of increased sympathetic activity could explain the downregulation of adrenergic receptors after prolonged high altitude exposure.

Paroxysmal activity increased in subjects under habitual eating of MSG

Cellular and organismal iron storage depends on the function of the ferritin protein complex in insects and mammals alike. In the central nervous system of insects, the distribution and relevance of ferritin remain unclear, though ferritin has been implicated in Drosophila models of Alzheimers' and Parkinsons' disease and in Aluminum-induced neurodegeneration. Here we show that transgene-derived expression of ferritin subunits in glial cells of Drosophila melanogaster causes a late-onset behavioral decline, characterized by loss of circadian rhythms in constant darkness and impairment of elicited locomotor responses. Anatomical analysis of the affected brains revealed crystalline inclusions of iron-loaded ferritin in a subpopulation of glial cells but not significant neurodegeneration. Although transgene-induced glial ferritin expression was well tolerated throughout development and in young flies, it turned disadvantageous at older age. The flies we characterize in this report contribute to the study of ferritin in the Drosophila brain and can be used to assess the contribution of glial iron metabolism in neurodegenerative models of disease.

Chronic activation of the hypothalamo-pituitary-adrenal axis and loss of circadian rhythm during adjuvant-induced arthritis in the rat.

Adjuvant-induced arthritis (AA) in Sprague-Dawley rats resulted in a chronic increase in plasma levels of ACTH and corticosterone (B). Joint inflammation became clinically apparent between days 12-15 after injection of adjuvant and reached a peak on day 21, after which time it subsided. In AA animals, plasma ACTH and B levels in the morning (0800-0900 h) on days 7, 8, 9, and 21 were significantly higher than those in control animals (day 0). The corresponding evening ACTH and B levels in AA animals were not significantly different from evening levels in the control animals. Adrenal weight in AA animals was increased on day 21, while thymic weight diminished gradually from days 7-21 postinjection. Development of AA was associated with activation of the hypothalamo-pituitary-adrenal axis, with increased morning ACTH and B levels and abolition of normal diurnal ACTH and B rhythms. This model of chronic inflammatory stress clearly activates the ACTH drive despite increased corticosteroid feedback in the morning, resulting overall in chronically increased B secretion.

Chronic activation of the hypothalamo-pituitary-adrenal axis and loss of circadian rhythm during adjuvant-induced arthritis in the rat

Chronic activation of the hypothalamo-pituitary-adrenal axis and loss of circadian rhythm during adjuvant-induced arthritis in the rat

Circadian Locomotor Rhythms, but Not Photoperiodic Responses, Survive Surgical Isolation of the SCN in Hamsters

Surgical isolation of the suprachiasmatic nuclei (SCN) within a hypothalamic island is reported to produce loss of circadian rhythmicity. The results have been interpreted to indicate that SCN efferents are necessary for the expression of circadian rhythms. It is not clear, however, whether the loss of circadian rhythms in behavioral responses following SCN isolation is attributable to transection of efferents, to loss of cells within the island, or to gliosis produced by the knife cut. To explore this issue, we examined locomotor activity and gonadal state of male golden hamsters housed in constant darkness (DD, with a dim red light for maintenance) for at least 10 weeks following isolation of the SCN from the rest of the brain by cuts by means of a Halasz wire microknife. Brain sections were immunocytochemically stained for the peptides vasoactive intestinal polypeptide (VIP), vasopressin (VP) or neurophysin II (NP II), and neuropeptide Y (NPY) to localize the SCN and to assess its viability, and for glial fibrillary acidic protein (GFAP) to delimit the border of the knife cut. Experimental animals with VIP and VP/NP II immunoreactivity in the SCN within the island retained free-running locomotor rhythms following transection of SCN efferents. Animals with cuts that failed to sever SCN efferents, and sham-operated animals (in which the Halasz knife was lowered but not rotated), also maintained circadian rhythmicity. Hamsters sustaining severe damage to the SCN showed disrupted locomotor activity. In those hamsters that retained circadian locomotor rhythmicity following SCN isolation, gonads failed to regress in DD, demonstrating the absence of an appropriate photoperiodic response. The results suggest a multiplicity of SCN coupling mechanisms in the control of circadian rhythms.

哺乳動物の脳内神経機構とサーカディアンリズム

It is now widely accepted that the suprachiasmatic nucleus (SCN) of the hypothalamus is a circadian pacemaker in the mammalians. This conclusion is based on three principal lines of the following evidence. First, ablation of the SCN results in a loss of circadian rhythms in rodents. Second, the SCN exhibits rhythms in neuronal activity and glucose metabolism both in vivo and in vitro experiments. Third, the transplantation of fetal SCN to the third ventricle of animals rendered arrhythmic++ by SCN ablation restores circadian function. In this review the anatomical, physiological and pharmacological characteristics of SCN neurons in vitro are discussed by focusing especially upon the roles of various neurotransmitters and modulators in the circadian system of mammals, in relation to the function of SCN.

Differential Elimination of Circadian and Ultradian Rhythmicity by Hypothalamic Lesions in the Common Vole, Microtus arvalis

Effects of hypothalamic lesions on the ultradian and circadian organization of wheel running and feeding were studied in the common vole, Microtus arvalis. Circadian organization broke down within 30 days in continuous darkness in 24% of intact voles (n = 135). Ultradian rhythmicity of feeding (period 2-3 hr) persisted in constant conditions in all intact voles. Following lesions of the suprachiasmatic nuclei (SCN), circadian rhythmicity disappeared when lesions were complete (n = 8) or more extensive than 25% of the total SCN volume (n = 5). Absence of circadian rhythmicity was also found in animals with substantial lesions in the diencephalic paraventricular area (PVA) and in the retrochiasmatic area (RCA) and/or adjacent arcuate nucleus (Arc). Complete loss of ultradian and circadian organization occurred in eight voles with damage to the RCA and/or Arc. In three of these, the SCN was intact. The SCN is a likely candidate for a circadian pacemaker in voles (as in other rodents), while the loss of circadian rhythmicity following PVA and RCA/Arc lesions may be due to destruction of efferent pathways from the SCN. The RCA/Arc area is apparently necessary for the expression of ultradian rhythms. The intact SCN is neither necessary nor sufficient for the generation of ultradian rhythmicity.

Autologous transplantation of the superior cervical ganglion into the brain of parkinsonian monkeys

The effect of autologous transplantation of the superior cervical ganglion (SCG) into the brain of parkinsonian monkeys was studied through quantitative measurement of animal behavior. The motor activity of the monkey was measured with a telemetry system during the experiment. After experimental parkinsonism was induced by repeated intravenous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), three monkeys were treated with autologous transplantation of the SCG into both caudate nuclei. One monkey served as a control without SCG transplantation after MPTP treatment. Three SCG-transplanted monkeys showed biphasic (acute and chronic) behavioral amelioration of parkinsonism after transplantation. In the acute stage, the animals showed transient hyperkinesia with aggressive behavior and loss of circadian rhythm. In the chronic stage following acute hyperkinesia, the animals regained normal behavior and circadian rhythm without aggressiveness. In contrast with the transplanted monkeys, the control monkey failed to show recovery of the bradykinesia and muscle rigidity.

Circadian rhythm of acid phosphatase activity in rat liver microsomes and dependence of NADH 5 alpha-reductase on phosphatase activity.

The specific activity of acid phosphatase in male and female rats follows a circadian rhythm. Preincubation of liver microsomes with testosterone led to an increase of phosphatase activity and a loss of circadian rhythm. NADH 5 alpha-reductase was inactivated by several animal and bacterial acid and alkaline phosphatases while the acid phosphatase from potatoes was ineffective. The extent of inhibition depends on the course of circadian rhythm of NADH 5 alpha-reductase activity. Preincubation of microsomes in the presence of testosterone inhibited the NADH 5 alpha-reduction of testosterone. No such inhibition was observed after preincubation of microsomes with progesterone.

Concurrent Infections of Hymenolepis diminuta and Trichinella spiralis in the Rat Intestine

The intestinal distribution of Trichinella spiralis and Hymenolepis diminuta in rats was studied in single and concurrent infections. Results showed that the location of T. spiralis was not significantly changed in concurrent infections, but higher populations of T. spiralis in single and concurrent infections resulted in a posterior shift in position. Trichinella spiralis affected H. diminuta distribution significantly by causing a posterior shift in the position of scoleces and biomass and a loss of circadian rhythm. Infection with 4,000 T. spiralis larvae resulted in decreased tapeworm weight and fecundity, and destrobilation of H. diminuta from day 8 to 18 of the T. spiralis intestinal stage. Hymenolepis diminuta moved anteriorly to its preferred microhabitat as the T. spiralis intestinal stage decreased.

An analysis of circadian rhythmicity of heart rate in tetraplegic human subjects

Eight tetraplegic human volunteer subjects from the Veterans Administration Hospital in Houston, Texas, had their heart rates monitored at half-hour intervals for 24 hours. Autocovariance analysis demonstrated circadian rhythms of heart rate in four chronic tetraplegic subjects and one acute tetraplegic subject. The remaining three subacute tetraplegic subjects demonstrated no circadian rhythmicity of heart rate. It is postulated that central denervation of the heart from the sympathetic division of the autonomic nervous system in cervical cord injury results in loss of circadian rhythmicity in heart rate until the vagus of the parasympathetic division obtains control, sympathetic spinal cord centres re-establish control, or an orderly interaction of both occurs. Further study appears indicated.