The mechanism of polycystic ovarian syndrome induced by circadian rhythm disturbance and the therapeutic effect of melatonin

The activation of inflammasomes plays an important role in the pathogenesis of spinal cord injury (SCI). In addition, the administration of melatonin (MT) has been shown to suppress the activation of inflammasomes. In this study, we aimed to investigate the molecular mechanisms underlying the therapeutic effect of MT in the treatment of SCI. Basso-Beattie-Bresnahan (BBB) locomotion scaling was conducted to evaluate the therapeutic effect of MT on post-SCI locomotion recovery. In addition, the measurement of spinal cord water content was performed together with Nissl staining to evaluate the protective effect of MT against SCI. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry (IHC) assay, Western blot analysis, and real-time polymerase chain reaction (PCR) were also conducted to clarify the molecular mechanisms underlying the therapeutic effect of MT in the treatment of SCI. BBB scores of SCI + MT rats were increased compared with the BBB scores of SCI rats, thus confirming the beneficial role of MT treatment in post-SCI functional recovery. Meanwhile, the administration of MT could alleviate SCI by reducing spinal cord water content and by exerting a neuroprotective effect on motor neurons. Furthermore, in the treatment of SCI, MT also attenuated cell apoptosis. Moreover, the relative expression of NLRP3, interleukin-1β (IL-1β), and caspase-1 were markedly elevated in the SCI group compared with that in the sham group, while the administration of MT reduced the expression of NLRP3 in SCI rats. MT treatment accelerated the recovery of SCI by suppressing the activation of inflammasomes.

Circadian rhythm (CR) disturbances are among the most commonly observed symptoms during major depressive disorder, mostly in the form of disrupted sleeping patterns. However, several other measurable parameters, such as plasma hormone rhythms and differential expression of circadian clock genes (ccgs), are also present, often referred to as circadian phase markers. In the recent years, CR disturbances have been recognized as an essential aspect of depression; however, most of the known animal models of depression have yet to be evaluated for their eligibility to model CR disturbances. In this study, we investigate the potential of adrenocorticotropic hormone (ACTH)-treated animals as a disease model for research in CR disturbances in treatment-resistant depression. For this purpose, we evaluate the changes in several circadian phase markers, including plasma concentrations of corticosterone, ACTH, and melatonin, as well as gene expression patterns of 13 selected ccgs at 3 different time points, in both peripheral and central tissues. We observed no impact on plasma corticosterone and melatonin concentrations in the ACTH rats compared to vehicle. However, the expression pattern of several ccgs was affected in the ACTH rats compared to vehicle. In the hippocampus, 10 ccgs were affected by ACTH treatment, whereas in the adrenal glands, 5 ccgs were affected and in the prefrontal cortex, hypothalamus and liver 4 ccgs were regulated. In the blood, only 1 gene was affected. Individual tissues showed changes in different ccgs, but the expression of Bmal1, Per1, and Per2 were most generally affected. Collectively, the results presented here indicate that the ACTH animal model displays dysregulation of a number of phase markers suggesting the model may be appropriate for future studies into CR disturbances.

Hospital-Acquired Morbidity and Circadian Rhythms in Patients in the ICU

Dementia severity and Lewy bodies affect circadian rhythms in Alzheimer disease

Lack of change in average age and MMSE in newly diagnosed AD patients over the last 10 years

Disrupted circadian rhythm commonly reported in cancer survivors is closely associated with cancer related fatigue, sleep disturbances and compromised quality of life. As more cancer survivors request non-pharmacological treatment strategies for the management of their chronic sleep-related symptoms, there is a need for meta-analyses of various interventions such as exercise on sleep and circadian rhythm disturbances. A search for RCT's was conducted in April 2020 and updated in July 2023 using relevant keywords for cancer, sleep, circadian rhythm and exercise interventions on PubMed, Scopus, Web of Science, PEDro and CINAHL. Thirty-six studies were included for qualitative analysis and 26, for meta-analysis. Thirty-five studies analyzed sleep outcomes, while five analyzed circadian rhythm. RCT's studying the effect of aerobic exercise, resistance exercise, combined aerobic and resistance exercise, physical activity, yoga, or tai chi were included. Meta-analysis results showed significant exercise-related improvements on sleep quality assessed by Pittsburgh Sleep Quality index (PSQI) (SMD = -0.50 [-0.87, -0.13], p=0.008), wake after sleep onset (WASO) (SMD = -0.29 [-0.53, -0.05], p=0.02) and circadian rhythm, assessed by salivary cortisol levels (MD = -0.09 (95% CI [-0.13 to -0.06]) mg/dL, p<0.001). Results of the meta-analysis indicated that exercise had no significant effect on sleep efficiency, sleep onset latency, total sleep time and circadian rhythm assessed by accelerometry values. While some sleep and circadian rhythm outcomes (PSQI, WASO and salivary cortisol) exhibited significant improvements, it is still somewhat unclear what exercise prescriptions would optimize different sleep and circadian rhythm outcomes across a variety of groups of cancer survivors. As exercise does not exacerbate cancer-related circadian rhythm and sleep disturbances, and may actually produce some significant benefits, this meta-analysis provides further evidence for cancer survivors to perform regular exercise.

The pathophysiological basis for chronic fatigue syndrome (CFS) remains poorly understood. Certain symptoms of CFS, namely fatigue, neurocognitive symptoms and sleep disturbance, are similar to those of acute jet lag and shift work syndromes thus raising the possibility that CFS might be a condition associated with disturbances in endogenous circadian rhythms. In this study, we tested this hypothesis by examining the circadian rhythm of core body temperature (CBT) in CFS and control subjects. Continuous recordings of CBT were obtained every 5 min over 48 h in a group of 10 subjects who met the Center for Disease Control (CDC) definition of CFS and 10 normal control subjects. Subjects in the two groups were age, sex and weight-matched and were known to have normal basal metabolic rates and thyroid function. CBT recordings were performed under ambulatory conditions in a clinical research centre with the use of an ingestible radio frequency transmitter pill and a belt-worn receiver-logger. CBT time series were analysed by a cosinor analysis and by a harmonic-regression-plus-correlated-noise model to estimate the mean, amplitude and phase angle of the rhythm. The goodness of fit of each model was also compared using the Akaike Information Criterion (AIC) and sigma2. Average parameters for each group were compared by Student's t-test. By cosinor analysis, the only significant difference between CFS and control groups was in the phase angle of the third harmonic (P=0.02). The optimal harmonic-regression-plus-correlated-noise models selected were ARMA(1,1): control 7, CFS 6; ARMA(2,0): control 1, CFS 4; and ARMA(2,1): control 2 subjects. The optimal fit ARMA model contained two harmonics in eight of 10 control subjects but was more variable in the CFS subjects (1 harmonic: 5 subjects; 2 harmonics: 1 subject; 3 harmonics: 4 subjects). The goodness of fit measures for the optimal ARMA model were also better in the control than the CFS group, but the differences were not statistically significant. We conclude that, measured under ambulatory conditions, the circadian rhythm of CBT in CFS is nearly indistinguishable from that of normal control subjects although there was a tendency for greater variability in the rhythm. Hence, it is unlikely that the symptoms of CFS are because of disturbance in the circadian rhythm of CBT.

Circadian rhythms are cycles in physiological, behavioural, psychological and other domains that recur approximately every 24 h. Such rhythms are driven by an endogenous circadian timekeeping system, whose molecular basis consists of the interlocking transcription and translation of a panel of ‘‘clock’’ genes, the expression of which then regulates gene expression and cellular function in a tissuespecific manner. Such rhythmic expression of clock genes is observed in most tissues, including the master circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus, other CNS sites and peripheral organs. Therefore, the circadian system exerts considerable control over physiology and behaviour, and equally dysfunction of this circadian system may result in detrimental pathophysiological and psychopathological consequences. It has been observed for many years that a number of neuropsychiatric conditions, most markedly mood disorders, are associated with circadian rhythm and sleep disturbances, with the implications that such disturbances are important in the aetiology and/or the clinical phenomenology of such conditions. In this special issue of the Journal of Neural Transmission, the contributing authors provide a comprehensive collection of reviews and original investigations that cover the field of circadian rhythm and sleep investigations across a broad range of neuropsychiatric disorders. The evidence for circadian rhythm disturbance in schizophrenia (Pritchett et al.), obsessive– compulsive disorder (Lange et al.), depression (Lall et al.), childhood and adolescent psychiatric disorders (Dueck et al.), borderline personality disorder (Fleischer et al.) and alcoholism are reviewed (Wong and Schumann), as are the links between shift work (which results in circadian disruption) and mood disorders (Braungart et al.). These reviews illustrate a notable fact that some measure of circadian rhythm disturbance is observed across a spectrum of psychiatric disorders. Genetic evidence that implicates polymorphisms in clock genes with mood disorders is also overviewed (Partonen) and such evidence may point to circadian roles in disease aetiology. Given that the circadian system is complex and pervasive, there are many potential pathways through which circadian dysfunction might ultimately affect affective and cognitive as well as psychomotor, volatile and perceptive processes. This is highlighted in a review focussing on links between the circadian and immune systems, and the implications arising for major depression (Eyre and Baune). The therapeutic opportunities offered by addressing abnormal circadian rhythm is highlighted in a review on the use of light therapy in childhood, adolescent and postpartum depression, as well as in eating disorders (Krysta et al.). Original investigations address circadian rhythmicity and sleep in those with, and those at elevated risk of, bipolar disorder (Ritter et al.), assessing skin temperature rhythms in Alzheimer’s disease (van Someren et al.), the links between sleep and diurnal preference and ADHD in adults (Voinescu et al.), changes of subjective time estimation in mentally traumatised patients (Kowalski et al.), alterations of time-dependent psychological processes in migraine patients (Kropp et al.), associations between salivary oxytocin and cortisol and sleep stage (Blagrove et al.), the role of circadian rhythms and sleep in cognitive function in healthy older adults (Cochrane et al.) and how circadian A. N. Coogan (&) National University of Ireland, Maynooth, Republic of Ireland e-mail: Andrew.Coogan@nuim.ie

Disturbed circadian core body temperature rhythm and sleep disturbance in school refusal children and adolescents

Circadian rhythm disturbances, like sundowning, are seen in dementia. Because the circadian rhythm is regulated by the biological clock, melatonin might be effective in the treatment of these disturbances. We systematically studied the effect of melatonin treatment in patients with dementia. In addition, we elaborate on the possible effects one might expect of melatonin treatment in patients with delirium, since dementia and delirium are strongly related. Moreover, some evidence exists that sundowning in patients with dementia and the alterations in the sleep/wake cycle, seen in patients with delirium both originate from circadian rhythm disturbances. A systematic search of the literature, published between 1985 and April 2009, was performed using PubMed and other databases. All papers on melatonin treatment in dementia were retrieved. Effects of melatonin on circadian rhythm disturbances were scored by means of scoring sundowning/agitated behaviour, sleep quality and daytime functioning. Nine papers, including four randomised controlled trials (RCTs) (n = 243), and five case series (n = 87) were reviewed. Two of the RCTs found a significant improvement on sundowning/agitated behaviour. All five case series found an improvement. The results on sleep quality and daytime functioning were inconclusive. Sundowning/agitated behaviour improves with melatonin treatment in patients with dementia. There are several arguments that sundowning in patients with dementia and the alterations in the sleep/wake cycle in patients with delirium have a common background, namely a disturbance of the circadian rhythm. This suggests that melatonin treatment could also have the same positive effects in patients with delirium.

Background/Objectives: College student athletes can experience sleep and circadian rhythm disturbances. Methods: A PRISMA-based systematic review about young adult athletes' sleep and circadian rhythms was conducted, with 41 published studies analyzed. Results: Studies suggest that extending sleep duration could enhance athletic performance and support mental health. Risk factors for sleep and circadian rhythm disturbances include early morning practice sessions, late night games, jet lag, and female sex. Consequences of inadequate sleep include reduced reaction times and mental health problems, such as depressive symptoms and anxiety. Across the studies, numerous research design limitations reduced scientific rigor and hindered the ability to test hypotheses about sleep, circadian rhythms, athletic performance, and mental health outcomes. For example, most studies were underpowered due to small sample sizes and missing data. Many studies lacked randomization, control groups, and objective measures of sleep. Researchers commonly failed to control for variables that could confound results (e.g., caffeine, diet, and menstrual cycle hormones). Conclusions: Recommendations for future directions include conducting randomized clinical trials to test interventions related to sleep patterns, nutrition, light exposure, training schedules, and cognitive behavioral therapies to enhance sleep quality. Evidence-based education programs about healthy sleep are essential for coaches and athletes.

Sleep and circadian rhythm disturbances are less-known risk factors for the development and suboptimal outcomes of diabetes. The goal of this narrative review is to highlight the importance of sleep and circadian rhythm disturbances in the development and outcomes of type 1 diabetes (T1D) and type 2 diabetes (T2D), assess current treatment options and the possible mediating mechanisms. We performed a literature search using PubMed and selected relevant English and Dutch papers. Disturbances of sleep and circadian rhythm are common in people with diabetes. They are associated with an increased risk of developing T2D as well as with suboptimal diabetes outcomes (including higher HbA1c levels and reduced quality of life) for T1D and T2D. Preliminary data suggest that treatment of sleep and circadian rhythm disturbances could improve diabetes outcomes in people with T1D and T2D. Finally, the association with medical parameters appears to be mediated by disturbance in hormones, and by suboptimal self-care including forgetting or postponing glucose monitoring or medication use as well as higher consumption of high fat/high sugary foods. Diabetes may also disturb sleep, for example through nocturnal hypoglycemia and nocturia. We concluded that sleep and circadian rhythm disturbances are closely linked with diabetes. More attention to sleep in regular diabetes care is warranted, while further research is needed on treatment of sleep and circadian rhythm disturbances in the prevention of diabetes and its suboptimal outcomes.

The therapeutic effect of melatonin on acute liver injury was examined in rats intoxicated with carbon tetrachloride (CCl4). Melatonin (10, 50, or 100 mg/kg body weight [BW]) was intraperitoneally administered to male Wistar rats 6 hr after intraperitoneal injection of CCl4 (1.6 g/kg BW) at which time an apparent liver injury occurred. This post-melatonin administration dose dependently prevented the progression of liver injury at 24 hr after CCl4 injection, judging from the levels of serum transaminases, indices of liver cell damage. Rats injected with CCl4 alone showed an increase in liver lipid peroxide (LPO) content and a decrease in liver reduced glutathione content at 6 and 24 hr after the injection. The post-melatonin administration dose dependently ameliorated both changes found at 24 hr after CCl4 injection. Rats injected with CCl4 alone showed an increase in liver triglyceride (TG) content and decreases in serum TG concentration and liver tryptophan 2,3-dioxygenase (TDO) activity, a marker of the inhibition of liver protein synthesis by CCl4, at 6 and 24 hr after the injection, and also a decrease in serum albumin concentration at 24 hr. The changes in serum TG, albumin concentration, liver TG content, and TDO activity found at 24 hr after CCl4 injection were not ameliorated by the post-administration of melatonin. The same administration of melatonin dose dependently reduced liver LPO content in CCl4-untreated rats. These results indicate that melatonin exerts a therapeutic effect on CCl4-induced acute liver injury in rats, possibly through its antioxidant action.

Pregnant women in poverty may be especially likely to experience sleep and circadian rhythm disturbances, which may have downstream effects on fetal neurodevelopment. However, the associations between sleep and circadian rhythm disturbances, social disadvantage during pregnancy, and neonatal brain structure remains poorly understood. The current study explored the association between maternal sleep and circadian rhythm disturbances during pregnancy and neonatal brain outcomes, examining sleep and circadian rhythm disturbances as a mediator of the effect of social disadvantage during pregnancy on infant structural brain outcomes. The study included 148 mother-infant dyads, recruited during early pregnancy, who had both actigraphy and neuroimaging data. Mothers' sleep was assessed throughout their pregnancy using actigraphy, and neonates underwent brain magnetic resonance imaging in the first weeks of life. Neonatal structural brain outcomes included cortical gray matter, subcortical gray matter, and white matter volumes along with a measure of the total surface area of the cortex. Neonates of mothers who experienced greater inter-daily deviations in sleep duration had smaller total cortical gray and white matter volumes and reduced cortical surface areas. Neonates of mothers who had higher levels of circadian misalignment and later sleep timing during pregnancy showed smaller subcortical gray matter volumes. Inter-daily deviations in sleep duration during pregnancy mediated the association between maternal social disadvantage and neonatal structural brain outcomes. Findings highlight the importance of regularity and rhythmicity in sleep schedules during pregnancy and bring to light the role of chronodisruption as a potential mechanism underlying the deleterious neurodevelopmental effects of prenatal adversity. RESEARCH HIGHLIGHTS: Social disadvantage was associated with sleep and circadian rhythm disturbances during pregnancy, including later sleep schedules, increased variability in sleep duration, circadian misalignment, and a higher proportion of the sleep period spent awake. Maternal sleep and circadian rhythm disturbances during pregnancy were associated with decreased brain volume and reduced cortical surface area in neonates. Maternal inter-daily deviations in sleep duration during pregnancy mediated the association between social disadvantage and neonatal brain volume and cortical surface area.

The purpose of this review is to summarize recent developments linking disturbances of sleep and circadian rhythms to an increased risk for obesity, and to review novel research on potential countermeasures. Effective treatments for obesity are limited, with long-term adherence to lifestyle changes proving difficult to maintain. Identifying new preventive strategies based on modifiable risk factors is therefore imperative in the fight against obesity. Disturbances of sleep and circadian rhythms have an adverse impact on food choices, hunger and appetite, and have lifelong deleterious metabolic consequences when they occur during childhood and early adulthood. The upregulation of the endocannabinoid system and abnormalities in the temporal distribution of caloric intake were recently implicated in the link between sleep loss and obesity risk. In addition, alterations in circadian variation in the composition and functionality of the gut microbiome have been identified as potential contributors to metabolic dysfunction during jet lag and shift work. Insufficient sleep and circadian misalignment are thus new modifiable risk factors for obesity. Emerging evidence suggests that novel countermeasures, such as manipulations of the timing of food intake, may be effective strategies in the prevention of obesity. Four important findings are briefly reviewed: disturbances of sleep and circadian rhythms in children and young adults are risk factors for the development of lifelong obesity; circadian misalignment, as occurs in shift work, has an adverse impact on energy balance and increases the risk of weight gain; the endocannabinoid system, an important regulator of hedonic feeding, could be a potential link between sleep, circadian rhythms, and feeding behavior; and disturbances of the circadian variation in composition of the gut microbiome may be involved in the increased risk of obesity associated with insufficient sleep and circadian misalignment.