Sex Differences in Insomnia and Circadian Rhythm Disorders: A Systematic Review.

Insomnia and circadian rhythm disorders are increasingly common in modern society and lead to significant challenges for people's health and well-being. Some studies suggests that men and women differ in neurohormonal secretion, biological processes, and brain morphology. Thus, such differences may affect the etiology, manifestation, and course of sleep disorders, including insomnia and circadian rhythm. This systematic review aims to synthesize the existing literature on sex differences in insomnia and circadian rhythm disorders. PubMed, MEDLINE, Epistemonikos, and Cochrane databases were searched for articles published from inception until 5 September 2023, not older than five years. We performed a systematic search using MESH and non-MESH queries: (sex differences) or (male and female differences) or (men and women differences) or (men and women) AND (insomnia) or (sleep wake disorder*) or (sleep wake rhythm disorder*) or (circadian rhythm disorder*) or (sleep cycle disruption) or (sleep cycle disorder*). Out off 2833 articles screened, 11 studies were included. The prevalence of insomnia is higher among women, and their sleep is more regular and stable compared to men. Studies evaluating the impact of the stressful situation associated with the lockdown on women's and men's insomnia present discordant results concerning sex differences. Women's circadian rhythm was found to be more stable and less fragmented than men's. However, the progression of peak activity time with age was more pronounced in men. The current literature suggests that risk factors for insomnia and circadian rhythm disorders affect men and women differently. These include cerebrovascular and cardiometabolic factors, shift work, and infections. The long-term effects of insomnia seem to be more relevant for the male sex, shortening lifespan more than in women. By summarizing and analyzing existing studies, we highlight the need for further research to improve understanding of the interaction between sex and sleep.

Melatonin attenuates fentanyl - induced behavioral sensitization and circadian rhythm disorders in mice.

Melatonin is a neurohormone synthesized by the pineal gland to regulate the circadian rhythms and has proven to be effective in treating drug addiction and dependence. However, the effects of melatonin to modulate the drug-seeking behavior of fentanyl and its underlying molecular mechanism is elusive. This study was designed to investigate the effects of melatonin on fentanyl - induced behavioral sensitization and circadian rhythm disorders in mice. The accompanying changes in the expression of Brain and Muscle Arnt-Like (BMAL1), tyrosine hydroxylase (TH), and monoamine oxidase A (MAO-A) in relevant brain regions including the suprachiasmatic nucleus (SCN), nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus (Hip) were investigated by western blot assays to dissect the mechanism by which melatonin modulates fentanyl - induced behavioral sensitization and circadian rhythm disorders. The present study suggest that fentanyl (0.05, 0.1 and 0.2 mg/kg) could induce behavioral sensitization and melatonin (30.0 mg/kg) could attenuate the behavioral sensitization and circadian rhythm disorders in mice. Fentanyl treatment reduced the expression of BMAL1 and MAO-A and increased that of TH in relevant brain regions. Furthermore, melatonin treatment could reverse the expression levels of BMAL1, MAO-A, and TH. In conclusion, our study demonstrate for the first time that melatonin has therapeutic potential for fentanyl addiction.

Latest advances in the study of non-coding RNA-mediated circadian rhythm disorders causing endometrial cancer.

Endometrial cancer (EC) is one of the most common gynecological cancers, and its risk factors include obesity and metabolic, genetic, and other factors. Recently, the circadian rhythm has also been shown to be associated with EC, as the severity of EC was found to be related to night work and rhythm disorders. Therefore, circadian rhythm disorders (CRDs) may be one of the metabolic diseases underlying EC. Changes in the circadian rhythm are regulated by clock genes (CGs), which in turn are regulated by non-coding RNAs (ncRNAs). More importantly, the mechanism of EC caused by ncRNA-mediated CRDs is gradually being unraveled. Here, we review existing studies and reports and explore the relationship between EC, CRDs, and ncRNAs.

July 14th 2016 Nice Terrorist Attack Court Trial: A Protocol on Sleep Quality and Somatic Symptoms as Markers of Risk for Traumatic Reactivation in Adolescents Exposed to This Attack.

The court trial of the 14th of July 2016 terrorist attack in Nice (France) opened in September 2022 and ended in December 2022. Engaging in court proceedings, whether as a victim or a witness, can lead to a significant risk of traumatic reactivation (i.e., the re-emergence of post-traumatic stress symptoms). The present protocol aimed to improve knowledge of the pathophysiology of traumatic reactivation due to the media coverage of the trial by assessing sleep disturbances and somatic symptoms that could reappear if there is a traumatic reactivation. Method and Analysis: This is a monocentric longitudinal study, with recruitment solely planned at the Nice Pediatric Psychotrauma Center (NPPC). We intended to include 100 adolescents aged 12 to 17 years who were directly or indirectly exposed to the attack and included in the "14-7" program). Assessments began one month before the trial, in August 2022, and were scheduled once a month until the end of the trial. A smartwatch recorded sleep activity. Somatic and PTSD symptoms and sleep were assessed through validated questionnaires. The main analyses comprised the variance and regression analyses of predictors of clinical evolution over time. Ethics and Dissemination: The National Ethics Committee "NORD OUEST III" approved the "14-7" program protocol (number 2017-A02212-51). The specific amendment for this research was approved in April 2022 by the same national ethical committee. Inclusions started in August 2022.

Case report: A patient with Delayed Sleep-Wake Phase Disorder and Optic Nerve Hypoplasia treated with tasimelteon: a case study.

We present a case of an adult female diagnosed with Delayed Sleep-Wake Phase Disorder (DSWPD) and Optic Nerve Hypoplasia (ONH), with a confirmed delayed Dim Light Melatonin Onset (DLMO), who reports the inability to fall asleep at their desired bedtime and obtain adequate sleep nightly, despite the ability to have a full night's sleep when not required to be up at a specific time for societal requirements. The participant was enrolled in an 11-month Open-Label Extension (OLE) following the randomized portion of a clinical study and was successfully treated with tasimelteon. DSWPD symptoms were resolved, and their previously delayed sleep-wake cycle was advanced. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04652882, identifier NCT04652882.

A Novel Home-Based Study of Circadian Rhythms: Design, Rationale, and Methods for the Circadia Study.

The Circadia Study (Circadia) is a novel "direct-to-participant" research study investigating the genetics of circadian rhythm disorders of advanced and delayed sleep phase and non-24 hour rhythms. The goals of the Circadia Study are twofold: (i) to create an easy-to-use toolkit for at-home circadian phase assessment for patients with circadian rhythm disorders through the use of novel in-home based surveys, tests, and collection kits; and (ii) create a richly phenotyped patient resource for genetic studies that will lead to new genetic loci associated with circadian rhythm disorders revealing possible loci of interest to target in the development of therapeutics for circadian rhythm disorders. Through these goals, we aim to broaden our understanding and elucidate the genetics of circadian rhythm disorders across a diverse patient population while increasing accessibility to circadian rhythm disorder diagnostics reducing health disparities through self-directed at-home dim light melatonin onset (DLMO) collections.

Recent advances in the study of circadian rhythm disorders that induce diabetic retinopathy.

Diabetic retinopathy (DR) is a severe microvascular complication of diabetes mellitus and a major cause of blindness in young adults. Multiple potential factors influence DR; however, the exact mechanisms are poorly understood. Advanced treatments for DR, including laser therapy, vitrectomy, and intraocular drug injections, slow the disease's progression but fail to cure or reverse visual impairment. Therefore, additional effective methods to prevent and treat DR are required. The biological clock plays a crucial role in maintaining balance in the circadian rhythm of the body. Poor lifestyle habits, such as irregular routines and high-fat diets, may disrupt central and limbic circadian rhythms. Disrupted circadian rhythms can result in altered glucose metabolism and obesity. Misaligned central and peripheral clocks lead to a disorder of the rhythm of glucose metabolism, and chronically high sugar levels lead to the development of DR. We observed a disturbance in clock function in patients with diabetes, and a misaligned clock could accelerate the development of DR. In the current study, we examine the relationship between circadian rhythm disorders, diabetes, and DR. We conclude that: 1) abnormal function of the central clock and peripheral clock leads to abnormal glucose metabolism, further causing DR and 2) diabetes causes abnormal circadian rhythms, further exacerbating DR. Thus, our study presents new insights into the prevention and treatment of DR.

Light-induced circadian rhythm disorder leads to microvascular dysfunction via up-regulating NETs.

Circadian rhythm is a physical, mental, and behavioral pattern over the course of 24-hour cycle, and its disturbance is associated with increased risk of cardiovascular diseases. Microvascular dysfunction serves as an important cause of cardiovascular disease, but the relationship between rhythm disturbances and microcirculation remains elusive. Herein, we constructed the mice model of circadian rhythm disturbance and investigated the alterations of microvascular conditions. It was revealed that coronary microcirculatory function and cardiac diastolic function were significantly reduced, along with endothelium-dependent diastolic function of microvessels remarkably impaired in the rhythm-disordered group of mice compared to the control group. Notably, rhythm disturbance led to a significant upregulation of neutrophil extracellular traps (NETs) levels in mice, which cause endothelial dysfunction by inhibiting microvascular endothelial cell activity and migration capacity as well as inducing apoptosis. Additionally, intraperitoneal injection of Cl-amidine suppressed the production of NETs, which further improved coronary microcirculatory function and endothelium-dependent diastolic function. In conclusion, this study demonstrated that circadian rhythm disorders could induce the development of coronary microvascular dysfunction (CMD) through the up-regulation of NETs, providing a potential therapeutic direction for the treatment of CMD.

Sleep medicine provider perceptions and attitudes regarding consumer sleep technology.

STUDY OBJECTIVES: This study assessed perceptions and attitudes of sleep medicine providers regarding consumer sleep technology (CST). METHODS: A convenience sample of n = 176 practicing sleep medicine and behavioral sleep medicine experts was obtained using social media and the American Academy of Sleep Medicine directory. Providers completed a questionnaire that assessed perceptions and attitudes about patient use of CST in the clinical setting. RESULTS: The sample included both adult and pediatric psychologists, physicians, and advanced practice providers from a variety of health settings. Providers reported 36% (3%-95%) of patients used CST, and the most common devices seen by providers were wrist-worn devices followed by smartphone apps. The most common perceived patient motivations for frequent use were to measure sleep and self-discovery. Across sleep disorders, clinicians did not endorse frequent CST use; the highest reported use was for assisting patients in the completion of sleep diaries. Overall devices were rated as somewhat accurate and neutral regarding helpfulness. In qualitative responses, providers associated CST use with increased patient engagement but increased orthosomnia and misperceptions about sleep. CONCLUSIONS: CST is frequently encountered in the sleep medicine clinic, and providers view CST as somewhat accurate but neither helpful nor unhelpful in clinical practice. Although providers viewed these devices as useful to drive patient engagement/awareness and track sleep patterns, providers also viewed them as a contributor to orthosomnia and misperceptions about sleep. CITATION: Addison C, Grandner MA, Baron KG. Sleep medicine provider perceptions and attitudes regarding consumer sleep technology. J Clin Sleep Med. 2023;19(8):1457-1463.

Pediatric sleep: current knowledge, gaps, and opportunities for the future.

This White Paper addresses the current gaps in knowledge, as well as opportunities for future studies in pediatric sleep. The Sleep Research Society's Pipeline Development Committee assembled a panel of experts tasked to provide information to those interested in learning more about the field of pediatric sleep, including trainees. We cover the scope of pediatric sleep, including epidemiological studies and the development of sleep and circadian rhythms in early childhood and adolescence. Additionally, we discuss current knowledge of insufficient sleep and circadian disruption, addressing the neuropsychological impact (affective functioning) and cardiometabolic consequences. A significant portion of this White Paper explores pediatric sleep disorders (including circadian rhythm disorders, insomnia, restless leg and periodic limb movement disorder, narcolepsy, and sleep apnea), as well as sleep and neurodevelopment disorders (e.g. autism and attention deficit hyperactivity disorder). Finally, we end with a discussion on sleep and public health policy. Although we have made strides in our knowledge of pediatric sleep, it is imperative that we address the gaps to the best of our knowledge and the pitfalls of our methodologies. For example, more work needs to be done to assess pediatric sleep using objective methodologies (i.e. actigraphy and polysomnography), to explore sleep disparities, to improve accessibility to evidence-based treatments, and to identify potential risks and protective markers of disorders in children. Expanding trainee exposure to pediatric sleep and elucidating future directions for study will significantly improve the future of the field.

Tea combats circadian rhythm disorder syndrome via the gut-liver-brain axis: potential mechanisms speculated.

Circadian rhythm is an intrinsic mechanism developed by organisms to adapt to external environmental signals. Nowadays, owing to the job and after-work entertainment, staying up late - Circadian rhythm disorders (CRD) are common. CRD is linked to the development of fatty liver, type 2 diabetes, and chronic gastroenteritis, which affecting the body's metabolic and inflammatory responses via multi-organ crosstalk (gut-liver-brain axis, etc.). However, studies on the mechanisms of multi-organ interactions by CRD are still weak. Current studies on therapeutic agents for CRD remain inadequate, and phytochemicals have been shown to alleviate CRD-induced syndromes that may be used for CRD-therapy in the future. Tea, a popular phytochemical-rich beverage, reduces glucolipid metabolism and inflammation. But it is immature and unclear in the mechanisms of alleviation of CRD-mediated syndrome. Here, we have analyzed the threat of CRD to hosts and their offspring' health from the perspective of the "gut-liver-brain" axis. The potential mechanisms of tea in alleviating CRD were further explored. It might be by interfering with bile acid metabolism, tryptophan metabolism, and G protein-coupled receptors, with FXR, AHR, and GPCR as potential targets. We hope to provide new perspectives on the role of tea in the prevention and mitigation of CRD.HighlightsThe review highlights the health challenges of CRD via the gut-liver-brain axis.CRD research should focus on the health effects on healthy models and its offspring.Tea may prevent CRD by regulating bile acid, tryptophan, and GPCR.Potential targets for tea prevention and mitigation of CRD include FXR, AHR and GPCR.A comprehensive assessment mechanism for tea in improving CRD should be established.

Delayed circadian rhythms in older Africans living with human immunodeficiency virus (HIV).

The increasing number of people living with human immunodeficiency virus, HIV, (PLWH) have an elevated incidence of risk for noncommunicable comorbidities, the aetiology of which remains incompletely understood. While sleep disturbances are often reported in PLWH, it is unknown to what extent they relate to changes in the circadian and/or sleep homeostatic processes. We studied the relationship between sleep characteristics, circadian phase, and HIV status in older adults from the HAALSI (Health and Ageing in Africa: a Longitudinal Study of an INDEPTH Community in South Africa) subsample of the Agincourt Health and Demographic Surveillance System in South Africa (n = 187, 36 human immunodeficiency virus positive [HIV+], age: 66.7 ± 11.5 years, range 45-93 years), where HIV prevalence is high and (in contrast to the global north) does not associate significantly with potentially confounding behavioural differences. In participants with valid actigraphy data (n = 172), regression analyses adjusted for age and sex indicated that HIV+ participants had slightly later sleep onset (ß = .16, p = .039), earlier sleep offset times (ß = -.16, p = .049) and shorter total sleep times (ß = -.20, p = .009) compared to the HIV negative (HIV-) participants. In a subset of participants (n = 51, 11 HIV+), we observed a later dim light melatonin onset (DLMO) in HIV+ (21:16 ± 01:47) than in HIV- (20:06 ± 00:58) participants (p = .006). This substantial difference remained when adjusted for age and sex (ß = 1.21; p = .006). In 36 participants (6 HIV+) with DLMO and actigraphy data, median phase angle of entrainment was -6 min in the HIV+ group and +1 h 25 min in the HIV- group. DLMO time correlated with sleep offset (ρ = 0.47, p = .005) but not sleep onset (ρ = -0.086, p = .623). Collectively, our data suggest that the sleep phase occurred earlier than what would be biologically optimal among the HIV+ participants. This is the first report of a mistimed circadian phase in PLWH, which has important potential implications for their health and well-being, especially given the well-established relationships between circadian asynchrony and sleep deprivation with poorer health outcomes.

Corrigendum: Case report: A patient with Delayed Sleep-Wake Phase Disorder and Optic Nerve Hypoplasia treated with tasimelteon: a case study.

[This corrects the article DOI: 10.3389/fnins.2023.1287514.].

Changes in Circadian Variations in Blood Pressure, Pain Pressure Threshold and the Elasticity of Tissue after a Whole-Body Photobiomodulation Treatment in Patients with Fibromyalgia: A Tripled-Blinded Randomized Clinical Trial.

This study analysed circadian variation changes in blood pressure (BP), the pain pressure threshold (PPT) and the elasticity of tissue in patients with fibromyalgia (FM) after a whole-body photobiomodulation (PBM) treatment. This was a tripled-blinded randomized clinical trial including forty participants with FM. Participants using validated self-measurement BP devices attained readings that were used to calculate the circadian variation. Additionally, a standard pressure algometer of 1cm2 was used to assess 13 tender points by exerting a pressure of up to 4 kg, and strain elastography assessed the elasticity of tissue. Circadian variations in BP showed significant differences after the PBM intervention (p = 0.036). When comparing PPT between groups, statistically significant differences were found in the occiput (p = 0.039), low cervical (p = 0.035), trapezius (p = 0.037), second rib (p < 0.001) and medial epicondyle points (p = 0.006). Furthermore, there were statistically significant differences in both the trapezius and the forearm at the distal dorsal third SEL values (p ≤ 0.001) when comparing groups. Whole-body PBM produces changes in circadian blood pressure, the pain pressure threshold and the elasticity of tissue after a treatment program was carried out. However, more studies are needed to corroborate our findings as well as to better understand the underlying mechanisms.

Dynamic molecular choreography of circadian rhythm disorders (DMCRD): a prospective cohort study protocol.

BACKGROUND: Circadian rhythm disorders (CRDs) are closely associated with the occurrence and development of various diseases, such as inflammatory and cardiovascular diseases, as well as tumors. The impact of a CRD on bodily health is a complex and comprehensive process, and its molecular mechanisms and signaling pathways are still unclear. We therefore aimed to investigate the molecular mechanism variation and adverse outcomes associated with CRDs in a prospective cohort of CRD cases and controls at term using multiomics data. The study has been tasked with developing a precise health promotion model for the prevention and management of CRDs. METHODS: This will be a 5-year prospective cohort study centered on the health management of individuals with CRDs. One hundred volunteers were recruited and had undergone baseline specimen collection, health examination, and health assessment. All of them will be followed up every year using the same protocol, and their biological specimens will be subjected to multiomics analysis after standardized processing. DISCUSSION: Longitudinal health examination, health assessment, and multiomics data will be analyzed to study the impact of CRDs on the volunteers' health status. The results of this study will promote the development of targeted health management programs based on precision medicine. TRIAL REGISTRATION: The clinical study registration has been completed (Trial Registration No. ChiCTR2100047242 ).

Central disorders of hypersomnolence: diagnostic discrepancies between military and civilian sleep centers.

STUDY OBJECTIVES: The majority of active-duty service members obtain insufficient sleep, which can influence diagnostic evaluations for sleep disorders, including disorders of hypersomnolence. An incorrect diagnosis of hypersomnia may be career ending for military service or lead to inappropriate medical care. This study was conducted to assess the rates at which narcolepsy (Nc) and idiopathic hypersomnia (IH) are diagnosed by military vs civilian sleep disorders centers. METHODS: This retrospective study utilized claims data from the Military Health System Data Repository. The analyses compared diagnostic rates of military personnel by provider type-either civilian provider or military provider-from January 1, 2016 to December 31, 2019. Three diagnostic categories for Nc and IH: Nc or IH, Nc only, and IH only, were assessed with multivariate logistic regression models. RESULTS: We found that among service members evaluated for a sleep disorder, the odds ratios of a positive diagnosis at a civilian facility vs a military facility for Nc or IH was 2.1, for Nc only was 2.1, and IH only was 2.0 over the 4-year period. CONCLUSIONS: Civilian sleep specialists were twice as likely to diagnose central disorders of hypersomnolence compared to military specialists. Raising awareness about this discrepancy is critical given the occupational and patient care-related implications of misdiagnoses. CITATION: Thomas CL, Vattikuti S, Shaha D, et al. Central disorders of hypersomnolence: diagnostic discrepancies between military and civilian sleep centers. J Clin Sleep Med. 2022;18(10):2433-2441.

Circadian Variation of Blood Pressure in Patients with Chronic Musculoskeletal Pain: A Cross-Sectional Study.

The aim of this study was to analyze the impact of circadian variation of blood pressure (BP) in patients with chronic musculoskeletal pain (CPM). A further purpose was to study differences in circadian variation of BP between genders and the correlation between BP circadian variation and pain. We performed a cross-sectional, observational study in which seventy-five participants with CMP participated. Circadian variation in BP was calculated using the diurnal/nocturnal BP ratio, and all participants used validated self-measurement BP devices. The Numeric Pain Rating Scale was used to assess pain perception. All circadian BP values from participants who suffered from CPM followed pathologic cardiovascular parameters (BP ratio < 10%). When comparing BP ratios between genders, statistically significant differences were found (p = 0.011). BP itself did not correlate with pain in any subgroup. Circadian variations of BP in those suffering from CMP are shown and new possibilities of research and treatment are proposed.