Circadian Rhythm Sleep-Wake Disorders.

OBJECTIVE: This article provides an overview of advances in the understanding of circadian rhythms and the health implications of circadian disruption. LATEST DEVELOPMENTS: Circadian medicine is a relatively new concept, with widespread overlap with many other areas of medicine. Circadian clocks rely on feedback loops that control the expression of many genes. Functional circadian oscillators exist at multiple physiologic levels and facilitate a multimodal clock mechanism. The suprachiasmatic nucleus is the central circadian pacemaker. Peripheral tissues can be entrained by other stimuli (such as food intake) and can uncouple from the suprachiasmatic nucleus pacemaker; this discovery may provide new therapeutic options for circadian rhythm disorders. Numerous modern developments have altered our circadian clocks and these changes are associated with poor health outcomes. ESSENTIAL POINTS: Circadian clocks are ubiquitous throughout our body and regulate multiple body functions. Several studies have highlighted that circadian disruption can result in significant negative mental and physical health consequences. A deeper understanding of the effects of misalignment between our circadian clocks and the external environment may ultimately have therapeutic implications for our health.

Circadian rhythm and disease: Relationship, new insights, and future perspectives.

The circadian system is responsible for internal functions and regulation of the organism according to environmental cues (zeitgebers). Circadian rhythm dysregulation or chronodisruption has been associated with several diseases, from mental to autoimmune diseases, and with life quality change. Following this, some therapies have been developed to correct circadian misalignments, such as light therapy and chronobiotics. In this manuscript, we describe the circadian-related diseases so far investigated, and studies reporting relevant data on this topic, evidencing this relationship, are included. Despite the actual limitations in published work, there is clear evidence of the correlation between circadian rhythm dysregulation and disease origin/development, and, in this way, clock-related therapies emerge as great progress in the clinical field. Future improvements in such interventions can lead to the development of successful chronotherapy strategies, deeply contributing to enhanced therapeutic outcomes.

Beneficial effects of voluntary wheel running on activity rhythms, metabolic state, and affect in a diurnal model of circadian disruption.

Emerging evidence suggests that disruption of circadian rhythmicity contributes to development of comorbid depression, cardiovascular diseases (CVD), and type 2 diabetes mellitus (T2DM). Physical exercise synchronizes the circadian system and has ameliorating effects on the depression- and anxiety-like phenotype induced by circadian disruption in mice and sand rats. We explored the beneficial effects of voluntary wheel running on daily rhythms, and the development of depression, T2DM, and CVD in a diurnal animal model, the fat sand rat (Psammomys obesus). Voluntary exercise strengthened general activity rhythms, improved memory and lowered anxiety- and depressive-like behaviors, enhanced oral glucose tolerance, and decreased plasma insulin levels and liver weight. Animals with access to a running wheel had larger heart weight and heart/body weight ratio, and thicker left ventricular wall. Our results demonstrate that exercising ameliorates pathological-like daily rhythms in activity and blood glucose levels, glucose tolerance and depressive- and anxiety-like behaviors in the sand rat model, supporting the important role of physical activity in modulating the "circadian syndrome" and circadian rhythm-related diseases. We suggest that the utilization of a diurnal rodent animal model may offer an effective way to further explore metabolic, cardiovascular, and affective-like behavioral changes related to chronodisruption and their underlying mechanisms.

[Chronobiology of Depression].

Seasonal fluctuations in mood, drive, energy, sleeping- and eating behavior, weight, as well as further important mental and physical functions, and the utilization of light as an effective treatment option were already described by Hippocrates of Kos and Araeteus, the Cappadocian. The concept of the so-called seasonal affective disorder (SAD) as a disruption of the circadian rhythm precipitated by a deficiency of environmental light during darker seasons was first described in the 1980s. Furthermore, chronobiological and hormonal dysregulation in SAD patients was repeatedly shown to be accompanied by alterations on a neuroreceptor and neurotransmitter level and to normalize after remission. Hence, SAD represents one of the most important models of a chronobiological disorder with over 1000 international publications on its aetiology and treatment options, whereby their underpinnings could be elucidated on a clinical as well as molecular level. The present article summarizes the current understanding of etiological mechanisms of SAD and provides an overview of diagnostic and therapeutic strategies, which are based on available international evidence including clinical trials, systematic reviews, and meta-analyses. According to current recommendations of international guidelines, promising treatment options as bright light therapy, psychopharmacotherapy, therapeutic sleep deprivation, and their underlying mechanisms of action are presented.

Microbial Reconstitution Improves Aging-Driven Lacrimal Gland Circadian Dysfunction.

Lacrimal glands are highly susceptible to aging and exhibit age-related structural and functional alterations. However, the mechanisms by which aging affects the lacrimal glands are not well-established. The current study explores the crosstalk between the aging process, gut microbiota, and circadian rhythm in age-associated lacrimal gland dysfunction. C57BL/6J mice were divided into young, old, and fecal microbiota transplant (FMT)-treated old groups. The gut bacterial community diversity was analyzed by 16S rRNA sequencing. Exorbital lacrimal glands (ELGs) were collected at 3-hour intervals over a 24-hour circadian cycle, and total RNA was subjected to high-throughput sequencing. Rhythmic transcriptional data were analyzed using the Jonckheere-Terpstra-Kendall algorithm and bioinformatics analysis technology. Immunostaining was used to identify lymphocytic infiltration, lipid deposition, and nerve innervation in the ELGs. Compared with young mice, old mice underwent a significant gut microbial community shift. The rhythmically transcriptomic profile was significantly reprogrammed over a 24-hour cycle in the old ELG group. Intervention with serial FMT from young donors for 1 month rejuvinated the gut microbial community of the old mice. Most alterations in rhythmic transcriptomic profiling were improved. Furthermore, chronic inflammation, lipid deposition, and aberrant neural response of the aging lacrimal glands were significantly reduced. Thus, the study shows that reconstitution of age-associated gut dysbiosis with FMTs from young donors improves aging-driven lacrimal gland circadian dysfunction.

Association between circadian disruption and diseases: A narrative review.

Circadian rhythms play an important role in a wide range of human physiology and pathology. Individuals increasingly experience situations such as night-shift work schedules, likely leading to circadian disruption. Recent studies have also demonstrated that patients with other diseases often show symptoms of circadian disruption as manifested by the sleep-wake cycle and other biological rhythms. Circadian disruption often results in changes to the phase, period, and amplitude of the sleep-wake cycle, melatonin rhythm, and core body temperature. Several cardiometabolic, psychiatric, and neurodegenerative diseases are closely related to circadian disruption. Several interventions are also available, including phototherapy, exogenous melatonin, and exercise. The cumulative findings suggest that circadian disruption can increase risk for some cardiometabolic diseases. Circadian disruption also acts as a concomitant symptom of several psychiatric and neurodegenerative diseases. More attention should be paid to evaluating the impact of circadian disruption on these related diseases, as well as the benefits of the mitigation interventions for both circadian disruption and related diseases.

The relationship between diurnal blood pressure abnormalities and target organ damage in normotensive subjects. Which is more important? Increased blood pressure levels or circadian blood pressure abnormalities.

Objective: Circadian blood pressure (CBP) abnormalities are well-known risk factors for many diseases such as cardiovascular, cerebrovascular, and chronic kidney disease. The object of this study was to evaluate the relationship between abnormalities in CBP rhythm and target organ damage (TOD) in normotensive non-dipper (non-DP) subjects.Methods: The 24-h ambulatory BP monitoring (ABPM) and echocardiography were performed and urinary albumin excretion (UAE) was measured in 127 normotensive dipper (DP) (42 males, 85 females) and 337 (89 males, 248 females) normotensive non-DP subjects.Results: When we compared DP and non-DP subjects; Pulse wave velocity (PWV) (7.12 ± 1.72 vs 7.57 ± 1.87 m/s, p = 0.02), the percentile of corrected PWV (cPWV) (7.1 vs. 20.2, p= 0.001) and the percentile of corrected augmentation index (cAIx) (23.5 vs. 33.9, p = 0.03), left ventricle mass index (LVMI) (78.00 ± 23.27 vs. 95.59 ± 18.29 g/m2, p = 0.01), relative wall thickness (RWT)(0.36 ± 0.13 vs 0.46 ± 0.09, p = 0.01), percentile of proteinuria (8.6 vs 29.2%, p = 0.00) were higher in non-DP group. In the correlation analyses, the PWV, LVMI, RWT were negatively correlated with the rate of systolic fall in nighttime (%)(-0.15, p = 0.01 vs. -0.23, p = 0.02 vs. -0.27, p = 0.00). It was observed that cPWV, cAIx, and UAE were independently associated with age and non-DP status (NDS), in logistic regression analysis.Conclusions: Our results suggested that normotensive persons with CBP abnormalities had TOD. In light of the data of this article, non-dipper status is detected in the early period and if the provision of diurnal blood pressure rhythm may reduce the incidence of future adverse events in nondipper normotensive subjects.

Circadian rhythms and the molecular clock in cardiovascular biology and disease.

The Earth turns on its axis every 24 h; almost all life on the planet has a mechanism - circadian rhythmicity - to anticipate the daily changes caused by this rotation. The molecular clocks that control circadian rhythms are being revealed as important regulators of physiology and disease. In humans, circadian rhythms have been studied extensively in the cardiovascular system. Many cardiovascular functions, such as endothelial function, thrombus formation, blood pressure and heart rate, are now known to be regulated by the circadian clock. Additionally, the onset of acute myocardial infarction, stroke, arrhythmias and other adverse cardiovascular events show circadian rhythmicity. In this Review, we summarize the role of the circadian clock in all major cardiovascular cell types and organs. Second, we discuss the role of circadian rhythms in cardiovascular physiology and disease. Finally, we postulate how circadian rhythms can serve as a therapeutic target by exploiting or altering molecular time to improve existing therapies and develop novel ones.

Sleep Disorders.

Sleep disorders are frequent and can have serious consequences on patients' health and quality of life. While some sleep disorders are more challenging to treat, most can be easily managed with adequate interventions. We review the main diagnostic features of 6 major sleep disorders (insomnia, circadian rhythm disorders, sleep-disordered breathing, hypersomnia/narcolepsy, parasomnias, and restless legs syndrome/periodic limb movement disorder) to aid medical practitioners in screening and treating sleep disorders as part of clinical practice.

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.

Circadian rhythm in bipolar disorder: A review of the literature.

Sleep disturbances and circadian rhythm dysfunction have been widely demonstrated in patients with bipolar disorder (BD). Irregularity of the sleep-wake rhythm, eveningness chronotype, abnormality of melatonin secretion, vulnerability of clock genes, and the irregularity of social time cues have also been well-documented in BD. Circadian rhythm dysfunction is prominent in BD compared with that in major depressive disorders, implying that circadian rhythm dysfunction is a trait marker of BD. In the clinical course of BD, the circadian rhythm dysfunctions may act as predictors for the first onset of BD and the relapse of mood episodes. Treatments focusing on sleep disturbances and circadian rhythm dysfunction in combination with pharmacological, psychosocial, and chronobiological treatments are believed to be useful for relapse prevention. Further studies are therefore warranted to clarify the relation between circadian rhythm dysfunction and the pathophysiology of BD to develop treatment strategies for achieving recovery in BD patients.

[Circadian rhythms and depression]. / Störung zirkadianer Rhythmen im Kontext depressiver Erkrankungen.

Depressive disorders are associated with various neurobiological alterations like hyperactivity of the hypothalamic-pituitary-adrenal axis, altered neuroplasticity and altered circadian rhythms. Relating to the circadian symptoms, a process is adopted in which individual genetic factors together with social, psychological and physical stressors may lead to a decompensation of the circadian system. The causal connections between depressive disorders and disturbed circadian rhythms have not been completely clarified. Chronobiological therapy is based on these disturbed processes. For the treatment of the circadian symptoms, various scientifically tested chronotherapeutics are available with however different effectiveness and evidence like light therapy or sleep deprivation. The successful treatment of depression also frequently leads to a improvement in altered circadian rhythm.

Are sleep disturbances causally linked to the presence and severity of psychotic-like, dissociative and hypomanic experiences in non-clinical populations? A systematic review.

The present review aimed to 1) identify what sleep disturbances co-occur alongside psychotic-like, dissociative and hypomanic experiences; 2) assess the strength of potential associations between the severity of sleep disturbances and of the experiences studied; and 3) appraise evidence for a causal link. MedLine and PsycInfo were searched and 44 studies were deemed eligible. Results showed that insomnia was associated with all individual psychotic-like, dissociative and hypomanic experiences reviewed (effect size range: small-to-large). Parasomnias were associated with all psychotic-like experiences; however, there was evidence of variation in magnitude between individual experiences. An eveningness chronotype was associated with dissociative and hypomanic experiences, and circadian dysrhythmia was found alongside hypomania but not the other experiences reviewed. Finally, experimental sleep manipulation studies revealed a potential causal link between sleep loss and psychotic-like and dissociative experiences, although size and consistency of effects varied by specific experience. Future research, using experimental manipulations of sleep to address putative mechanisms, will enable questions of causality to be answered with more confidence.

Sleep and Circadian Hygiene and Inflammatory Bowel Disease.

There is increasing evidence that sleep and circadian disruption can worsen the disease course in inflammatory bowel disease (IBD). Sleep and circadian disruption are prevalent in society and are associated with worse outcomes in IBD. Emerging research suggests sleep and circadian disruption can impact key components in IBD disease flares, including intestinal permeability, translocation of bacterial endotoxins, intestinal dysbiosis, and proinflammatory cytokines. Much of this research has been conducted in animal models. There is a clear need for large randomized controlled trials in human patients with IBD, where the potential for chronotherapeutic strategies to improve disease course can be tested.

Alpha-synuclein, epigenetics, mitochondria, metabolism, calcium traffic, & circadian dysfunction in Parkinson's disease. An integrated strategy for management.

The motor deficits which characterise the sporadic form of Parkinson's disease arise from age-related loss of a subset of dopamine neurons in the substantia nigra. Although motor symptoms respond to dopamine replacement therapies, the underlying disease process remains. This review details some features of the progressive molecular pathology and proposes deployment of a combination of nutrients: R-lipoic acid, acetyl-l-carnitine, ubiquinol, melatonin (or receptor agonists) and vitamin D3, with the collective potential to slow progression of these features. The main nutrient targets include impaired mitochondria and the associated oxidative/nitrosative stress, calcium stress and impaired gene transcription induced by pathogenic forms of alpha- synuclein. Benefits may be achieved via nutrient influence on epigenetic signaling pathways governing transcription factors for mitochondrial biogenesis, antioxidant defences and the autophagy-lysosomal pathway, via regulation of the metabolic energy sensor AMP activated protein kinase (AMPK) and the mammalian target of rapamycin mTOR. Nutrients also benefit expression of the transcription factor for neuronal survival (NR4A2), trophic factors GDNF and BDNF, and age-related calcium signals. In addition a number of non-motor related dysfunctions in circadian control, clock genes and associated metabolic, endocrine and sleep-wake activity are briefly addressed, as are late-stage complications in respect of cognitive decline and osteoporosis. Analysis of the network of nutrient effects reveals how beneficial synergies may counter the accumulation and promote clearance of pathogenic alpha-synuclein.

Chronic Insomnia Disorder.

PURPOSE OF REVIEW: Neurologists, along with all health care providers, commonly encounter patients with insomnia, which is a condition that impacts patients' underlying neurologic conditions in a bidirectional manner. While chronic insomnia is one of the most common sleep disturbances, only a small proportion of individuals with this condition discuss their sleep problems with their providers. When insomnia is described, it is more often in relationship to another medical problem, as opposed to an independent condition. In neurology practice, multiple factors including pain, movement disorders, sleep apnea, and medications that act on the central nervous system often contribute to insomnia. An all-inclusive approach is necessary when evaluating sleep problems in patients with insomnia. RECENT FINDINGS: The US Food and Drug Administration (FDA) has approved several medications for the treatment of insomnia that target specific receptor systems in the brain and incorporate several unique pharmacodynamic and pharmacokinetic profiles that can represent customized therapy for specific insomnia phenotypes. FDA-approved medications for insomnia include γ-aminobutyric acid (GABA)-modulating benzodiazepine receptor agonists, a melatonin receptor agonist, a histamine receptor antagonist, and the newest approved option, a hypocretin (orexin) receptor antagonist. SUMMARY: This article provides an evidence-based multidisciplinary approach to the treatment of insomnia, highlighting the rationale and utility of cognitive-behavioral therapy and pharmacologic interventions. Neurologists should be proactive in assessing the impact of underlying comorbidities on insomnia, particularly in the setting of psychiatric conditions such as depression, sleep disorders such as circadian rhythm disorders, and medical problems such as nocturia.

Is a SIMPLe smartphone application capable of improving biological rhythms in bipolar disorder?

BACKGROUND: Biological rhythms (BR) disturbance has been suggested as a potential mediator of mood episodes in Bipolar Disorder (BD). The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) was designed as an assessment tool to evaluate BR domains comprehensively. In the context of a trial evaluating a smartphone application delivering personalized psychoeducational contents for BD (SIMPLe 1.0), the main aim of this study is to evaluate the potential impact of SIMPLe 1.0 in BR regulation using the BRIAN scale. METHODS: 51 remitted BD patients were asked to use the application for 3 months. Paired t-test analyses were employed to compare baseline and follow-up BRIAN´s total and domains scores. The sample was divided into completers and non-completers of the study to evaluate differences between groups regarding BRIAN scores using ANCOVA analyses. RESULTS: The BRIAN's mean total score of the whole sample significantly decreased from baseline to post-intervention (35.89 (SD 6.64) vs. 31.18 (SD 6.33), t = 4.29, p = 0.001). At post-intervention, there was a significant difference between groups regarding the total BRIAN mean score (29.47 (SD 6.21) completers vs. 35.92 (SD 3.90) non-completers, t = 2.50, p = 0.02). This difference was maintained after conducting a one-way ANCOVA controlling for pre-intervention BRIAN scores, F (1, 46) = 10.545, p=0.002. LIMITATIONS: A limited sample, pre-post measures, and a short study timeframe could have affected the results. Additional factors affecting BR, such as medication, could not be ruled out. CONCLUSION: Our results suggest that there are potential positive effects of a psychoeducational smartphone application as an adjunctive to treatment as usual on BD patients' BR.

Management of sleep disorders in Parkinson's disease and multiple system atrophy.

Parkinson's disease (PD) and multiple system atrophy (MSA) are disorders associated with α synuclein-related neurodegeneration. Nonmotor symptoms are common hallmarks of these disorders, and disturbances of the sleep-wake cycle are among the most common nonmotor symptoms. It is only recently that sleep disturbances have received the attention of the medical and research community. Significant progress has been made in understanding the pathophysiology of sleep and wake disruption in alphasynucleinopathies during the past few decades. Despite these advancements, treatment options are limited and frequently associated with problematic side effects. Further studies that center on the development of novel treatment approaches are very much needed. In this article, the author discusses the current state of the management of disturbed sleep and alertness in PD and MSA. © 2017 International Parkinson and Movement Disorder Society.

White Adipose Tissue and Circadian Rhythm Dysfunctions in Obesity: Pathogenesis and Available Therapies.

A combined neuroendocrine, metabolic, and chronobiological view can help to better understand the multiple and complex mechanisms involved in obesity development and maintenance, as well as to provide new effective approaches for its control and treatment. Indeed, we have currently updated data on the whole adipogenic process involved in white adipose tissue (WAT) mass expansion, namely due to a mechanism whereby WAT cells become hypertrophic, thus inducing a serious local (WAT) inflammatory condition that in turn, will impair not only the cross-talk between the hypothalamus and the WAT, but also favoring the development of deep and widespread neuroendocrine-metabolic dysfunction. Moreover, we also have revisited the circadian clock genes involved in dysfunctional WAT mass expansion and the mechanisms that may lead to obesity development, including early metabolic dysfunctions, enhanced oxidative stress and distorted energy homeostasis. The epigenetic changes of clock genes driving metabolic disease and obesity development have also been included in this review. Finally, we have also underlined the relevance of metabolic homeostasis regulation by central and peripheral organ clocks, sleep disturbances, nutrients, and feeding time, as key factors in obesity development as well as both, classical and chronotherapeutic approaches for its prevention and treatment.