Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light-dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep-wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep-wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders - Third Edition, including jet lag and shift work disorders, delayed and advanced sleep-wake phase rhythm disorders, non-24-h sleep-wake rhythm disorder, and irregular sleep-wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.

Effects of Light Treatment on Sleep, Cognition, Mood, and Behavior in Alzheimer's Disease: A Systematic Review.

BACKGROUND: Bright light treatment is a therapeutic intervention mainly used to treat sleep and circadian disturbances in Alzheimer's disease (AD) patients. Recently, a handful of studies also focused on the effect on cognition and behavior. Conflicting findings are reported in the literature, and no definite conclusions have been drawn about its specific therapeutic effect. SUMMARY: The aim of this review is to provide a critical evaluation of available evidence in this field, highlighting the specific characteristics of effective bright light treatment. Eligible studies were required to assess at least one of the following outcome measures: sleep, cognition, mood, and/or behavior (e.g., depression, agitation). A total of 32 articles were included in this systematic review and identified as research intervention studies about light treatment in AD. The quality of the papers was evaluated based on the US Preventive Service Task Force guidelines. Key Messages: Overall, the current literature suggests that the effects of light treatment in AD patients are mixed and may be influenced by several factors, but with a general trend toward a positive effect. Bright light seems to be a promising intervention treatment without significant adverse effects; therefore, further well-designed randomized controlled trials are needed taking into account the highlighted recommendations.

Depressive mood and circadian rhythms disturbances as outcomes of seasonal affective disorder treatment: A systematic review.

BACKGROUND: The present systematic review was aimed at critically summarizing the evidence about interventions focused on circadian rhythms and mood symptoms in seasonal affective disorder (SAD). METHODS: A systematic search of the electronic databases PUBMED, PsycINFO and Web of Science was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Original papers reporting data about the effects of treatments on both mood and circadian rhythms disturbances in SAD patients were considered for inclusion. The quality of the evidence provided by the eligible studies was assessed using the Revised Cochrane Risk of Bias Tool (RoB 2.0) and the Cochrane Risk of Bias in Non-Randomized Studies of Interventions Tool (ROBINS-I). RESULTS: Forty papers were deemed eligible for the systematic review. The evidence of treatment outcomes referring to circadian disturbances was not robust. Despite this, bright light therapy (BLT) demonstrates to phase-advance delayed rhythms and to improve sleep-wake disorders. As for mood symptoms, both BLT and selective serotonin reuptake inhibitors (SSRIs) show evidence of efficacy. The possible connection between improvements of mood symptoms and changes in circadian outcomes seems controversial. LIMITATIONS: The included studies presented considerable methodological heterogeneity, small sample sizes and non-optimal sample selection. CONCLUSIONS: The effectiveness of BLT in depressive symptoms and circadian disturbances of SAD was outlined by the present systematic review. The evidence about other biological and pharmacological treatments, although promising, should be replicated. A multifactorial etiopathogenesis could explain the heterogeneous clinical presentations of SAD and the complex link between mood and circadian symptoms.

Circadian disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention.

Biological processes are organized in time as innate rhythms defined by the period (τ), phase (peak [Φ] and trough time), amplitude (A, peak-trough difference) and mean level. The human time structure in its entirety is comprised of ultradian (τ < 20 h), circadian (20 h > τ < 28 h) and infradian (τ > 28 h) bioperiodicities. The circadian time structure (CTS) of human beings, which is more complicated than in lower animals, is orchestrated and staged by a brain central multioscillator system that includes a prominent pacemaker - the suprachiasmatic nuclei of the hypothalamus. Additional pacemaker activities are provided by the pineal hormone melatonin, which circulates during the nighttime, and the left and right cerebral cortices. Under ordinary circumstances this system coordinates the τ and Φ of rhythms driven by subservient peripheral cell, tissue and organ clock networks. Cyclic environmental, feeding and social time cues synchronize the endogenous 24 h clocks and rhythms. Accordingly, processes and functions of the internal environment are integrated in time for maximum biological efficiency, and they are also organized and synchronized in time to the external environment to ensure optimal performance and response to challenge. Artificial light at night (ALAN) exposure can alter the CTS as can night work, which, like rapid transmeridian displacement by air travel, necessitates realignment of the Φ of the multitude of 24 h rhythms. In 2001, Stevens and Rea coined the phrase "circadian disruption" (CD) to label the CTS misalignment induced by ALAN and shift work (SW) as a potential pathologic mechanism of the increased risk for cancer and other medical conditions. Current concerns relating to the effects of ALAN exposure on the CTS motivated us to renew our long-standing interest in the possible role of CD in the etiopathology of common human diseases and patient care. A surprisingly large number of medical conditions involve CD: adrenal insufficiency; nocturia; sleep-time non-dipping and rising blood pressure 24 h patterns (nocturnal hypertension); delayed sleep phase syndrome, non-24 h sleep/wake disorder; recurrent hypersomnia; SW intolerance; delirium; peptic ulcer disease; kidney failure; depression; mania; bipolar disorder; Parkinson's disease; Smith-Magenis syndrome; fatal familial insomnia syndrome; autism spectrum disorder; asthma; byssinosis; cancers; hand, foot and mouth disease; post-operative state; and ICU outcome. Poorly conceived medical interventions, for example nighttime dosing of synthetic corticosteroids and certain ß-antagonists and cyclic nocturnal enteral or parenteral nutrition, plus lifestyle habits, including atypical eating times and chronic alcohol consumption, also can be causal of CD. Just as surprisingly are the many proven chronotherapeutic strategies available today to manage the CD of several of these medical conditions. In clinical medicine, CD seems to be a common, yet mostly unrecognized, pathologic mechanism of human disease as are the many effective chronotherapeutic interventions to remedy it.

[Temporal order deterioration and circadian disruption with age. 2. Systemic mechanisms and correction].

Part 2 of the present review highlights the impact of aging on mechanisms involved in response of the circadian system to different photic and non-photic factors, especially zeitgebers. Promising strategies to prevent age-dependent circadian disruption using internal and external factors that may entrain circadian rhythms are presented. In particular, benefits of bright light, melatonin and other chronobiotics, the circadian body temperature rhythm, physical activity and regular feeding schedules to preserve the temporal order of aged organisms are discussed, emphasizing especially a personalized approach based on the assessment of individual overt rhythms parameters.

Rats with minimal hepatic encephalopathy show reduced cGMP-dependent protein kinase activity in hypothalamus correlating with circadian rhythms alterations.

Patients with liver cirrhosis show disturbances in sleep and in its circadian rhythms which are an early sign of minimal hepatic encephalopathy (MHE). The mechanisms of these disturbances are poorly understood. Rats with porta-caval shunt (PCS), a model of MHE, show sleep disturbances reproducing those of cirrhotic patients. The aims of this work were to characterize the alterations in circadian rhythms in PCS rats and analyze the underlying mechanisms. To reach these aims, we analyzed in control and PCS rats: (a) daily rhythms of spontaneous and rewarding activity and of temperature, (b) timing of the onset of activity following turning-off the light, (c) synchronization to light after a phase advance and (d) the molecular mechanisms contributing to these alterations in circadian rhythms. PCS rats show altered circadian rhythms of spontaneous and rewarding activities (wheel running). PCS rats show more rest bouts during the active phase, more errors in the onset of motor activity and need less time to re-synchronize after a phase advance than control rats. Circadian rhythm of body temperature is also slightly altered in PCS rats. The internal period length (tau) of circadian rhythm of motor activity is longer in PCS rats. We analyzed some mechanisms by which hypothalamus modulate circadian rhythms. PCS rats show increased content of cGMP in hypothalamus while the activity of cGMP-dependent protein kinase was reduced by 41% compared to control rats. Altered cGMP-PKG pathway in hypothalamus would contribute to altered circadian rhythms and synchronization to light.

Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder.

INTRODUCTION: Disruptions in sleep and circadian rhythms are observed in individuals with bipolar disorders (BD), both during acute mood episodes and remission. Such abnormalities may relate to dysfunction of the molecular circadian clock and could offer a target for new drugs. AREAS COVERED: This review focuses on clinical, actigraphic, biochemical and genetic biomarkers of BDs, as well as animal and cellular models, and highlights that sleep and circadian rhythm disturbances are closely linked to the susceptibility to BDs and vulnerability to mood relapses. As lithium is likely to act as a synchronizer and stabilizer of circadian rhythms, we will review pharmacogenetic studies testing circadian gene polymorphisms and prophylactic response to lithium. Interventions such as sleep deprivation, light therapy and psychological therapies may also target sleep and circadian disruptions in BDs efficiently for treatment and prevention of bipolar depression. EXPERT OPINION: We suggest that future research should clarify the associations between sleep and circadian rhythm disturbances and alterations of the molecular clock in order to identify critical targets within the circadian pathway. The investigation of such targets using human cellular models or animal models combined with 'omics' approaches are crucial steps for new drug development.

Circadian use of glucocorticoids in rheumatoid arthritis.

A clear temporal relationship exists in rheumatoid arthritis (RA) patients between increased nocturnal levels of pro-inflammatory cytokines, such as TNF-α and interleukin (IL)-6, pro-inflammatory hormones (i.e. melatonin, prolactin) and insufficient night production of the anti-inflammatory cortisol (circadian rhythm). Under long-standing chronic stress of disease, insufficient cortisol is available to inhibit an ongoing nocturnal immune/inflammatory reaction. Clinical RA symptoms follow the same circadian rhythm with highest morning severity. Chronotherapy with nighttime glucocorticoid (GC) availability optimizes the treatment of RA patients with low-dose GCs through more efficient targeting of mediators of the immune/inflammatory reaction during the night to be available on arising. Circadian use of low-dose, long-term prednisone, by using night-release formulations (ingested at 10 to 11 p.m.) especially in early RA patients, appears characterized by a significantly superior efficacy on decreasing morning stiffness and IL-6 serum levels, compared to conventional daytime immediate-release prednisone. Shift from medium-dose, immediate-release prednisone (over 7.5-10 mg/day) to night-release formulations GC low-dose, long-term chronotherapy requires a gradual passage, since the hypothalamic-pituitary-adrenal axis of the treated RA patients, potentially altered by a negative feedback induced by the medium/high daily exogenous GC administration, needs time to re-synchronize control of endogenous GC production into a circadian and more physiological nocturnal hormone availability/optimized efficacy.

Chronic consumption of dietary proanthocyanidins modulates peripheral clocks in healthy and obese rats.

Circadian rhythm plays an important role in maintaining homeostasis, and its disruption increases the risk of developing metabolic syndrome. Circadian rhythm is maintained by a central clock in the hypothalamus that is entrained by light, but circadian clocks are also present in peripheral tissues. These peripheral clocks are trained by other cues, such as diet. The aim of this study was to determine whether proanthocyanidins, the most abundant polyphenols in the human diet, modulate the expression of clock and clock-controlled genes in the liver, gut and mesenteric white adipose tissue (mWAT) in healthy and obese rats. Grape seed proanthocyanidin extracts (GSPEs) were administered for 21 days at 5, 25 or 50 mg GSPE/kg body weight in healthy rats and 25 mg GSPE/kg body weight in rats with diet-induced obesity. In healthy animals, GSPE administration led to the overexpression of core clock genes in a positive dose-dependent manner. Moreover, the acetylated BMAL1 protein ratio increased with the same pattern in the liver and mWAT. With regards to clock-controlled genes, Per2 was also overexpressed, whereas Rev-erbα and RORα were repressed in a negative dose-dependent manner. Diet-induced obesity always resulted in the overexpression of some core clock and clock-related genes, although the particular gene affected was tissue specific. GSPE administration counteracted disturbances in the clock genes in the liver and gut but was less effective in normalizing the clock gene disruption in WAT. In conclusion, proanthocyanidins have the capacity to modulate peripheral molecular clocks in both healthy and obese states.

Clock desynchronisation: why and how?

The internal clock located in the suprachiasmatic nuclei of the anterior hypothalamus is controlled by external (environment and social life) and genetic factors. Desynchronisation of the organism occurs when the clock does no longer work in harmony with the environ- mentalfactors. Rhythm desynchronization can be related to a conflict between the clock and environmentalfactors (shift work, night shift, transmeridianflight), to inefficient synchro- nizers (aging, psychiatric diseases..), to badly received synchronizers (circadian rhythm sleep disorders with e.g delayed or advanced sleep phase syndromes), or to the use of some drugs (lithium, propofol, alcohol...). In the long term rhythm desynchronisation can result in serious illnesses and the use of resynchronizing agents like melatonin or bright light are useful to the clock resynchronization.

Behavioral therapy reverses circadian deficits in a transgenic mouse model of Huntington's disease.

Progressive disruption of circadian rhythmicity associated with disturbance of the sleep-wake cycle is one of the most insidious symptoms of Huntington's disease (HD) and represents a critical management issue for both patients and their care takers. The R6/2 mouse model of HD shows a progressive disruption of the circadian rhythmicity at both behavioral and molecular levels, although the intrinsic cellular machinery that drives circadian rhythmicity in individual cells appears to be fundamentally intact. Circadian rhythms are controlled by a master clock located in the suprachiasmatic nuclei (SCN) and can be synchronized by light and non-photic factors such as exercise. Here, we aimed to test whether or not stimulating the SCN directly could prevent the loss of circadian rhythmicity in R6/2 mice. We used combinations of bright light therapy and voluntary exercise as our treatment regimes. We found that all treatments had some beneficial effects, as measured by delayed disintegration of the rest-activity rhythm and improved behavioral synchronization to the light-dark cycle. The best effects were observed in mice treated with a combination of bright light therapy and restricted periods of voluntary exercise. Neither the cause nor the consequence of deteriorating sleep-wake activity in HD patients is known. Nevertheless, our findings can be translated immediately to human patients with little cost or risk, since both light therapy and restricted exercise regimes are non-pharmacological interventions that are relatively easy to schedule. Improved circadian rhythmicity is likely to have beneficial knock-on effects on mood and general health in HD patients. Until effective treatments are found for HD, strategies that reduce deleterious effects of disordered physiology should be part of HD patient treatment programs.

[Sleep problems in dementia].

Sleep disturbance is common in patients with dementia. Circadian rhythm sleep disorders are caused by the disturbance of sleep-wake regulation in the central nervous system, disturbed input into the sensory organs, and decreased social activities. Diurnal change of serum melatonin level in Alzheimer's disease showed decreased amplitude and shifted peak secretion. Age related sleep disturbances and sleep disorders due to the neurodegeneration including REM sleep behavior disorder also increase in dementia. Identifying and treating underlying sleep disorders along with therapeutic approach to circadian mechanism is effective. Treatment of circadian abnormality in dementia require light therapy and increased daytime activity. Use of oral melatonin is also effective for the improvement of nocturnal sleep. Treatment of sleep problems in dementia also contribute to the better management of dementia.

Sundowning syndrome: a possible marker of frailty in Alzheimer's disease?

The term "sundowning" describes a clinical phenomenon characterized by late afternoon exacerbation of behavioural symptoms in dementia. Beyond this clinical definition, the debate around this concept is not properly solved, because many authors define it in different ways, mentioning various hypothetical etiological explanations. It represents a concrete problem, which is difficult to manage for physicians and caregivers, and is probably linked to various biological, psychological and social aspects. As recently reported, the sundowning phenomenon is a predictor of faster cognitive decline in Alzheimer's disease, and as such can represent a possible marker of frailty in this illness. This article presents an overview of the biological understanding and possible pharmacological and non-pharmacological treatment of this condition.

The role of melatonin treatment in chronic kidney disease.

The pineal hormone melatonin plays a major role in circadian sleep-wake rhythm. Patients with Chronic Kidney Disease (CKD), especially those who are on hemodialysis, frequently suffer from sleep disturbances. In this review an overview is given of the classification of stages of chronic kidney disease, followed by a presentation of the circadian rhythm disorders in renal disease involving sleep disturbances in relation to melatonin deficiency. The therapeutic benefit of melatonin treatment in sleep disorders related to chronic kidney disease including the controlled trials solving this topic, is described. Furthermore, the beneficial effect of melatonin on blood pressure alterations in CKD states and the protection of melatonin in oxidative stress and inflammation in renal disorders are explored. Finally a hypothetic model is described for the relation between circadian rhythm disorders and CKD.

Circadian rhythms in obsessive-compulsive disorder.

The etiopathology and neurobiology of obsessive-compulsive disorder (OCD) are not fully understood. As for altered circadian rhythms associated with OCD, hormonal dysregulation and a delayed sleep phase have come into the focus of research. The novel antidepressant agomelatine is able to resynchronize circadian rhythms and the augmentative administration of this compound has been shown to be of benefit in some OCD patients who are refractory to common forms of pharmacotherapy. Adjunctive chronotherapy might also enhance the outcome in treatment-refractory OCD. The present review summarises the findings regarding circadian abnormalities in OCD.

Circadian clock manipulation for cancer prevention and control and the relief of cancer symptoms.

Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that of its species. The first whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations. Single nucleotide polymorphisms within the genes of clock, clock-controlled, and melatonin pathways have been found to confer excess cancer risk or protection from cancer. Experimental studies have shown that specific core clock genes (Per2 and Per1) are tumor suppressors because their genetic absence doubles tumor numbers, and decreasing their expression in cancer cells doubles cancer growth rate, whereas their overexpression decreases cancer growth rate and diminishes tumor numbers. Experimental interference with circadian clock function increases cancer growth rate, and clinical circadian disruption is associated with higher cancer incidence, faster cancer progression, and shorter cancer patient survival. Patients with advanced lung cancer suffering greater circadian activity/sleep cycle disruption suffer greater interference with function, greater anxiety and depression, poorer nighttime sleep, greater daytime fatigue, and poorer quality of life than comparable patients who maintain good circadian integration. We must now determine whether strategies known to help synchronize the circadian clocks of normal individuals can do so in advanced cancer patients and whether doing so allows cancer patients to feel better and/or live longer. Several academic laboratories and at least 2 large pharmaceutical firms are screening for small molecules targeting the circadian clock to stabilize its phase and enhance its amplitude and thereby consolidate and coordinate circadian organization, which in turn is likely to help prevent and control human cancer. These drugs and strategies can, in turn, be used to make cancer patients with advanced disease feel and function more normally.

Analysis of the hypothalamus in a case of X-linked lissencephaly with abnormal genitalia (XLAG).

X-linked lissencephaly with abnormal genitalia (XLAG) is characterized by lissencephaly, absent corpus callosum and ambiguous genitalia. We examined hypothalamic dysfunctions in a XLAG case with a novel mutation of the ARX gene, and performed immunohistochemical evaluation of the diencephalons in autopsy brain. A 1-year-old boy showed intractable epilepsy, persistent diarrhea and disturbed temperature regulation. This case had abnormalities in circadian rhythms and pituitary hormone reserve test. He died of pneumonia. The globus pallidus and subthalamic nucleus was not identified, and the putamen and thalamus were dysplasic. The suprachiasmatic nucleus was absent. A few neurons immunoreactive for vasopressin seemed to form the ectopic supraoptic-like nucleus. The diencephalons were disturbed differently in each sub-region, and the changes may be related to various hypothalamic dysfunctions.