Advanced Sleep Phase Syndrome Research Articles

Pattern of sleep disorders among children with autism spectrum disorder

BackgroundSleep disorders (SDs) are among many co-morbid medical conditions that affect children with autism spectrum disorder (ASD). Raising awareness and improving the standard of care for children diagnosed with ASD may result from identifying SDs among them. This study aims to evaluate patterns of SDs among Sudanese children diagnosed with ASD.MethodUsing the Childhood Sleep Habit Questionnaire (CSHQ) to gather data on sleep disorders and SPSS version 26.0 for data analysis, a descriptive cross-sectional study was carried out in the five main autistic centres in Khartoum state covering all registered patients with ASD between April and June 2022. Ninety-two children diagnosed with ASD were enrolled in this study after the purpose of the research was explained and consent was obtained from their guardians. A p-value < 0.05 was considered to indicate statistical significance.ResultsThe mean age was 6.90 (± 2.6) years with a boys-to-girls ratio of 2.17:1. The prevalence of SDs (at least one sleep condition almost daily) was 95.65%. Sleep onset 71 (77.2%), limit setting 32 (32.6%), resistant onset to sleep 48 (52.2%), and combined 52 (56.5%) insomnia affected the majority of children. Additionally, there were significant associations between sex and Limit-setting insomnia, advanced sleep phase disorder, and narcolepsy type 2 (P values = 0.033, 0.009, and 0.037, respectively). Additionally, there was a significant association between age and sleep-related breathing disorders-snoring (p value = 0.031).ConclusionThe frequency of SDs is significant among children diagnosed with ASD from Sudan, and certain SDs are associated with age and sex. Subsequent studies are required to develop national guidelines for the prevalence, presentation, screening, and treatment of SDs in children diagnosed with ASD.

Challenges and gaps in the treatment of advanced sleep phase disorder: A call for further research and understanding

Challenges and gaps in the treatment of advanced sleep phase disorder: A call for further research and understanding

Research on genetic regulation of sleep

Sleep is the most vital function of mammals to maintain energy homeostasis. For years, the mechanism behind how sleep is regulated has been studied, and several genetic pathways had been identified as the key to encoding the circadian rhythms to enable the mammalian sleep and wake cycles. This paper explains the mechanisms behind the PER, CRY, CLOCK, and BMAL1 pathways, which play a central role in manipulating the function of the circadian clock. Other pathways, such as the DEC1/2 genes, interact with the circadian clock genes to form negative feedback loops to further control the circadian rhythm pathway and directly regulate sleep through orexin. Mutations occurring in these pathways could potentially cause conditions such as narcolepsy, restless leg syndrome, insomnia, sleep apnea, delayed sleep phase syndrome (DSPS), and advanced sleep phase syndrome (ASPS). These conclusions are based on previous studies and experiments that identified these pathways. While recent studies have shed light on the mechanisms of the PER, CLOCK, BMAL1, and DEC genes in regulating sleep and circadian rhythms, there is still much to discover. The intricate interactions and genetic pathways involved in sleep regulation are not yet fully understood. Further research in this field may uncover new insights into the genetic basis of sleep and provide avenues for developing interventions to address sleep disorders.

Increased presynaptic excitability in a migraine with aura mutation.

Migraine is a common and disabling neurological disorder. The headache and sensory amplifications of migraine are attributed to hyperexcitable sensory circuits, but a detailed understanding remains elusive. A mutation in casein kinase 1 delta (CK1δ) was identified in non-hemiplegic familial migraine with aura and advanced sleep phase syndrome. Mice carrying the CK1δT44A mutation were more susceptible to spreading depolarization (the phenomenon that underlies migraine aura), but mechanisms underlying this migraine-relevant phenotype were not known. We used a combination of whole-cell electrophysiology and multiphoton imaging, in vivo and in brain slices, to compare CK1δT44A mice (adult males) to their wild-type littermates. We found that despite comparable synaptic activity at rest, CK1δT44A neurons were more excitable upon repetitive stimulation than wild-type, with a reduction in presynaptic adaptation at excitatory but not inhibitory synapses. The mechanism of this adaptation deficit was a calcium-dependent enhancement of the size of the readily releasable pool of synaptic vesicles, and a resultant increase in glutamate release, in CK1δT44A compared to wild-type synapses. Consistent with this mechanism, CK1δT44A neurons showed an increase in the cumulative amplitude of excitatory post-synaptic currents, and a higher excitation-to-inhibition ratio during sustained activity compared to wild-type. At a local circuit level, action potential bursts elicited in CK1δT44A neurons triggered an increase in recurrent excitation compared to wild-type, and at a network level, CK1δT44A mice showed a longer duration of 'up state' activity, which is dependent on recurrent excitation. Finally, we demonstrated that the spreading depolarization susceptibility of CK1δT44A mice could be returned to wild-type levels with the same intervention (reduced extracellular calcium) that normalized presynaptic adaptation. Taken together, these findings show a stimulus-dependent presynaptic gain of function at glutamatergic synapses in a genetic model of migraine, that accounts for the increased spreading depolarization susceptibility and may also explain the sensory amplifications that are associated with the disease.

Genetic Mechanisms of Migraine: Insights from Monogenic Migraine Mutations.

Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models, advancing appreciation of the extended clinical phenotype, and functional neuroimaging studies, we can further our understanding of the neurobiological basis of this highly disabling condition. Despite increasing understanding of the molecular and chemical architecture of migraine mechanisms, many areas require further investigation. Research over the last three decades has suggested that migraine has a strong genetic basis, based on the positive family history in most patients, and this has steered exploration into possibly implicated genes. In recent times, human genome-wide association studies and rodent genetic migraine models have facilitated our understanding, but most migraine seems polygenic, with the monogenic migraine mutations being considerably rarer, so further large-scale studies are required to elucidate fully the genetic underpinnings of migraine and the translation of these to clinical practice. The monogenic migraine mutations cause severe aura phenotypes, amongst other symptoms, and offer valuable insights into the biology of aura and the relationship between migraine and other conditions, such as vascular disease and sleep disorders. This review will provide an outlook of what is known about some monogenic migraine mutations, including familial hemiplegic migraine, familial advanced sleep-phase syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Circadian rhythm sleep-wake disorders and the risk of dyslipidemia among railway workers in southwest China: A cross-sectional study

ABSTRACT Railway workers are more likely to have an irregular work schedule, which had an effect on their circadian rhythm of sleep, and may lead to circadian rhythm sleep-wake disorders (CRSWDs). The association between CRSWDs and dyslipidemia in railway workers is poorly understood. The objective of this research is to study the association between CRSWDs and the risk of dyslipidemia. This cross-sectional study was conducted among railway workers in Southwest China. CRSWDs were assessed by the morningness-eveningness questionnaire self-assessment version (MEQ-SA). The blood samples were collected in the morning and the lipids of participants were measured. Associations of CRSWDs with dyslipidemia and its components were analyzed. A total of 8079 participants were enrolled in this study, and the results revealed that shift work sleep disorder (SWD) and advanced sleep-wake phase disorder (ASWPD) were associated with a higher risk of dyslipidemia (OR 1.17, 95%CI 1.06–1.29, P < 0.01; OR 1.68, 95%CI 1.09–2.64, P < 0.05) after adjusting for sociodemographic characteristics and lifestyles, in comparison with the control group. As for its components, the SWD group was associated with a higher risk of elevated total cholesterol, triglycerides, and low-density lipoprotein than the control group, while the ASWPD group was associated with a higher risk of elevated total cholesterol, and low-density lipoprotein (P < 0.05). In summary, SWD and ASWPD participants were associated with a higher risk of dyslipidemia in railway workers in Southwest China. Abbreviation: TG: triglyceride; TC: Total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; FPG: fasting plasma glucose. MEQ-SA: morningness-eveningness questionnaire self-assessment version; IPW: inverse-probability weighting; HDS: healthy diet scores; FFQ: food frequency; PA: physical activity; IQAP-SF: international physical activity questionnaire short form; MET-min/wk: metabolic equivalent task minutes per week; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HBP: hypertension; DM: diabetes; CVD: cerebrovascular disease; OR: odds ratios; CI: confidence intervals.

Human-centred design, disability and bioethics

Human-centred design methodologies provide a means to align bioethical advocacy with the needs and desires of disabled people. As a method, human-centred design seeks to locate points of friction in...

In Silico Analysis of BMAL1 and CLOCK SNPs in the Ensembl Database

Objective: A circadian rhythm in mammals controls the sleep-wake cycle, blood pressure, hormone secretion, metabolism and many other physiological processes. The circadian clock mechanism is regulated by four genes: Bmal1, Clock, Cry, and Per. Mutations in these regulatory genes are associated with sleep and mood disorders, obesity, and cancer. Several PER2 and CRY2 SNPs are associated with advanced sleep phase syndrome. It is, therefore, critical to understand the effect of clock genes’ SNPs on the circadian clock. In this study, we determined “pathogenic” BMAL1 and CLOCK SNPs in the Ensembl database for biochemical characterization. Materials and Methods: BMAL1 and CLOCK SNPs in the Ensemble database were filtered out for only missense mutations. Among the missense mutations, pathogenic ones were determined according to SIFT, PolyPhen, and CADD scores, REVEL, MetalR, Mutation Assessor, I-Mutant, PROVEAN, and FireDock programs. BMAL1 and CLOCK SNPs were visualized by using PyMol. Results: Thousands of BMAL1 and CLOCK missense SNP mutations were reported in the Ensembl database. After the classification of those SNPs according to their SIFT, PolyPhen, and CADD pathogenicity, twelve SNPs for each protein remained as pathogenic. A further analysis with all in silico tools revealed that BMAL1 SNPs causing Ala154Val, Arg166Gln, and Val440Gly mutations; and CLOCK SNPs causing Gly120Val, Asp119Val, Gly120Ser, Ala117Val, and Cys371Gly mutations were predicted as the most “pathogenic” ones. Conclusion: Overall, by using in silico tools, we provided a starting point for experimental studies for determining the effect of pathogenic BMAL1 and CLOCK SNPs on the circadian clock mechanism.

Circadian Rhythm Sleep Disorders: Genetics, Mechanisms, and Adverse Effects on Health.

Nearly all living organisms, from cyanobacteria to humans, have an internal circadian oscillation with a periodicity of approximately 24 h. In mammals, circadian rhythms regulate diverse physiological processes including the body temperature, energy metabolism, immunity, hormone secretion, and daily sleep-wake cycle. Sleep is tightly regulated by circadian rhythms, whereas a misalignment between the circadian rhythms and external environment may lead to circadian rhythm sleep disorders (CRSD). CRSD includes four main kinds of disorders: the advanced sleep-wake phase disorder (ASPD), the delayed sleep-wake phase disorder (DSPD), the irregular sleep-wake rhythm disorder and the non-24-h sleep-wake rhythm disorder. Recent studies have begun to shed light on the genetic basis of CRSD. Deciphering the genetic codes for ASPD and DSPD has so far been more successful than the other CRSDs, which allow for the development of animal models and understanding of the pathological mechanisms for these disorders. And studies from humans or animal models implicate CRSDs are associated with adverse health consequences, such as cancer and mental disorders. In this review, we will summarize the recent advances in the genetics, underlying mechanisms and the adverse effects on health of ASPD and DSPD.

Setting Objective Clinical Assessment Tools for Circadian Rhythm Sleep-Wake Disorders - A Community-Based Cross-Sectional Epidemiological Study.

IntroductionCircadian rhythm sleep-wake disorder (CRSWD) is an often-misdiagnosed group of sleep disturbances with limited data concerning diagnostic and therapeutic algorithms in the general population. Therefore, reported prevalence varies in the literature due to different case definitions, methodological, and environmental factors.ObjectivesThe purpose of our cross-sectional study was to estimate the prevalence of CRSWD in the general population of Cyprus and to suggest clinical parameters for the assessment of atypical sleep schedules. The estimation was carried out by introducing normal preset sleep time limits, according to the imposed local environment and by administering well-established questionnaires for symptoms and consequence dysfunction, as objective evaluation tools.MethodsIn a nationwide epidemiological survey, 4118 Cypriot adult participants, selected and stratified to represent the general population, were interviewed on sleep habits and complaints by computer-assisted telephone interviewing (CATI). In the second stage, 250 adults were randomly selected from the initial representative sample, for a CRSWD assessment. According to the proposed diagnostic criteria, patients were interviewed about sleepiness and/or insomnia, and daytime dysfunction (fatigue, anxiety, and depression). They were also assessed by a weekly sleep diary for sleep schedules. Finally, all participants underwent a Type III Sleep Study, to rule out obstructive sleep apnea.ResultsFrom 195 enrolled participants (response rate 78%), 25 individuals (12.8%) met the criteria for CRSWD. The two most prevalent disorders were delayed sleep-wake phase disorder (DSWPD) (10pts, 5.1%) and shift work sleep disorder (SWD) (13, 6.7%). Less prevalent disorders included irregular sleep-wake rhythm disorder (ISWRD) (1, 0.5%) and advanced sleep-wake phase disorder (ASWPD) (1, 0.5%).ConclusionsAccording to our data, CRSWDs are common in the general population of Cyprus, especially DSWPD and SWD. Affected individuals usually suffer from sleep deprivation and complain about insomnia, sleepiness and depression.

830 Combined Phototherapy and Melatonin for treatment of Circadian Rhythm Disorder in a Patient with Cornelia de Lange Syndrome

Abstract Introduction Cornelia de Lange syndrome (CdLS) is a rare genetic disorder characterized by variable physical, cognitive, and behavioral characteristics. Sleep disturbances have been frequently reported in CdLS including insomnia, sleep-disordered breathing, intrinsic sleep disorders, and circadian rhythm disorders (CRDs). The characterization and prevalence of CRDs in CdLS remain ill- defined. We report a case of a 13-year-old female with CdLS presenting with advanced sleep wake phase disorder (ASWPD). Report of case(s) A 13-year-old female with a past medical history of CdLS, developmental delay, bilateral cleft palate status post repair presents with inability to fall asleep at night and excessive daytime sleepiness.(EDS) Her sleep history consists of going to bed at 4 pm with no delayed sleep onset. She wakes at 2:30 am which has occurred since infancy. Mother reports the patient will remain awake from 2:30 am until she goes to school at 7:30 am. History is consistent with EDS and sleeping during the day while at school. Total sleep time of approximately 11–12 hours was reported in 24-hour period. History of obstructive sleep apnea, parasomnias, insomnia, restless leg syndrome, and psychotropic medications were not reported. Patient was treated with timed low dose melatonin therapy 0.5 mg at 4 pm and bright light therapy using 10,000 lux for 30 minutes at 7 am and 4 pm. Dim lights starting at 7:30 pm with structured scheduled sleep hygiene ensuring consistent bedtime at 9:30 pm. A consistent wake time at 7 am and no naps during the day was recommended. Follow up visits report successful response to therapy with attainment of desired sleep wake rhythm (bedtime at 9:30 pm and wake time at 7 am) and resolution of sleepiness during the day. Our patient was able to be weaned off of melatonin and light therapy and her circadian rhythm remained entrained. Conclusion Patients with disorder such as CdLS are at risk for circadian rhythm disorders. Our patient responded well to treatment with combined timed phototherapy and low dose melatonin therapy. Better knowledge and characterization of typology of CRDs in CdLS patients could permit a more specific therapeutic approach to sleep disorders in this population. Support (if any) None

841 PAP Therapy Data Provides Clues To Comorbid Sleep Disorders

Abstract Introduction Obstructive sleep apnea (OSA) is a common condition and positive airway pressure (PAP) therapy is the treatment of choice. Treatment guidelines recommend monitoring objective PAP usage data to track treatment efficacy. A typical report includes the percentage of days/month and cumulative hours/day a PAP device was used. In addition, PAP therapy timing can be graphically viewed with use plotted by time/day. This latter presentation reveals patterns of usage that can identify comorbid sleep disorders. Report of case(s) Case 1: A 65-year-old male with OSA presented with sleep inertia despite compliance with PAP therapy. Therapy timing data revealed a delayed circadian phase, with bedtime of 4 am and wake time of 1 pm. Circadian phase advancement therapy was added. Case 2: An 86-year-old male with OSA presented with daytime sleepiness after years of excellent PAP usage. Two years earlier, he was diagnosed with Parkinson’s disease and developed increasing afternoon sleepiness. Compliance data showed a mild reduction in PAP usage. However, therapy timing data revealed an irregular sleep-wake rhythm disorder with sleep scattered around the clock, consistent with neurodegenerative disease. Case 3: A 70 year-old-female with PTSD and OSA presented with persistent tiredness and difficulty initiating and maintaining sleep despite good compliance with PAP therapy. Her timing data showed irregular sleep times with long gaps in usage suggestive of sleep maintenance insomnia. After starting a behavioral treatment regimen her pattern regularized and awakenings reduced, seen by consistent PAP use. Case 4: An 80-year-old female with OSA complained of early morning awakenings despite PAP use with good compliance. Review of PAP therapy timing revealed a pattern suggestive of advanced sleep-wake phase disorder. Circadian phase delay therapy was started. Conclusion Patients with OSA on PAP therapy may have comorbid sleep disorders impacting sleep quality. PAP therapy data can provide information on sleep-wake behavior similar to actigraphy to help diagnose these conditions and track treatment response. Support (if any) None

Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene.

The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep-phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian-relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2-related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration.

CK2 Inhibits TIMELESS Nuclear Export and Modulates CLOCK Transcriptional Activity to Regulate Circadian Rhythms

SUMMARYCircadian clocks orchestrate daily rhythms in organismal physiology and behavior to promote optimal performance and fitness. In Drosophila, key pacemaker proteins PERIOD (PER) and TIMELESS (TIM) are progressively phosphorylated to perform phase-specific functions. Whereas PER phosphorylation has been extensively studied, systematic analysis of site-specific TIM phosphorylation is lacking. Here, we identified phosphorylation sites of PER-bound TIM by mass spectrometry, given the importance of TIM as a modulator of PER function in the pacemaker. Among the 12 TIM phosphorylation sites we identified, at least two of them are critical for circadian timekeeping as mutants expressing non-phosphorylatable mutations exhibit altered behavioral rhythms. In particular, we observed that CK2-dependent phosphorylation of TIM(S1404) promotes nuclear accumulation of PER-TIM heterodimers by inhibiting the interaction of TIM and nuclear export component, Exportin 1 (XPO1). We propose that proper level of nuclear PER-TIM accumulation is necessary to facilitate kinase recruitment for the regulation of daily phosphorylation rhythm and phase-specific transcriptional activity of CLOCK (CLK). Our results highlight the contribution of phosphorylation-dependent nuclear export of PER-TIM heterodimers to the maintenance of circadian periodicity and identify a new mechanism by which the negative elements of the circadian clock (PER-TIM) regulate the positive elements (CLK-CYC). Finally, because the molecular phenotype of tim(S1404A) non-phosphorylatable mutant exhibits remarkable similarity to that of a mutation in human timeless that underlies familial advanced sleep phase syndrome (FASPS), our results revealed an unexpected parallel between the functions of Drosophila and human TIM and may provide new insights into the molecular mechanisms underlying human FASPS.

Recent Advances in the Development of Casein Kinase 1 Inhibitors.

The casein kinase 1 (CK1) family is involved in regulating many cellular processes, including membrane trafficking, DNA damage repair, cytoskeleton dynamics, cytoskeleton maintenance and apoptosis. CK1 isoforms, especially CK1δ and CK1ε have emerged as important therapeutic targets for severe disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), familial advanced sleep phase syndrome and cancer. Due to the importance of CK1 for the pathogenesis of disorders, there are great interests in the development of CK1 inhibitors. Using SciFinder® as a tool, the publications about the biology of CK1 and the recent developments of CK1 inhibitors were surveyed with an exclusion of those published as patents. This review presents the current state of knowledge on the development of CK1 inhibitors, including both synthetic small molecular inhibitors that were divided into 7 categories according to structural features, and the natural compounds. An overview of the advancement of CK1 inhibitors was given, with the introduction of various existing CK1 inhibitors, their inhibitory activities, and the structure-activity relationships. Through physicochemical characterization and biological investigations, it is possible to understand the structure-activity relationship of CK1 inhibitors, which will contribute to better design and discovery of potent and selective CK1 inhibitors as potential agents for severe disorders such as AD, ALS and cancer.

NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging

Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.

Sleep, Sleep Disturbances among Medical Students and their Academic Performance and Health: A Global Issue

Sleep disorders, medical students, ICSD-3 classification, advanced sleep phase syndrome, excessive daytime sleepiness, burnout, sleep debt, nonrefreshing sleep, and academic performance.International Journal of Human and Health Sciences Vol. 03 No. 04 October’19 Page : 181-185

Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep-wake phase disorder in a sleep clinic population.

Report the first prevalence estimates of advanced sleep phase (ASP), familial advanced sleep phase (FASP), and advanced sleep-wake phase disorder (ASWPD). This can guide clinicians on the utility of screening for extreme chronotypes both for clinical decision-making and to flag prospective participants in the study of the genetics and biology of FASP. Data on morning or evening sleep schedule preference (chronotype) were collected from 2422 new patients presenting to a North American sleep center over 9.8 years. FASP was determined using a severity criterion that has previously identified dominant circadian mutations in humans. All patients were personally seen and evaluated by one of the authors (C.R.J.). Our results demonstrate an ASP prevalence of 0.33%, an FASP prevalence of 0.21%, and an ASWPD prevalence of at least 0.04%. Most cases of young-onset ASP were familial. Among patients presenting to a sleep clinic, conservatively 1 out of every 300 patients will have ASP, 1 out of every 475 will have FASP, and 1 out of every 2500 will have ASWPD. This supports obtaining a routine circadian history and, for those with extreme chronotypes, obtaining a family history of circadian preference. This can optimize treatment for evening sleepiness and early morning awakening and lead to additional circadian gene discovery. We hope these findings will lead to improved treatment options for a wide range of sleep and medical disorders in the future.

Melatonin in the treatment of Circadian Rhythm Sleep-Wake Disorders – the principles of choosing the right time and dose of administration

Aim. Circadian Rhythm Sleep-Wake Disorders (CRSWD) are a common group of sleep disorders. The aim of this article is to present the principles for treatment of CRSWD with melatonin. Methods. Review of data from randomised, placebo-controlled clinical trials. Results. The main indication for the use of melatonin is a treatment of Delayed Sleep-Wake Phase Disorder (DSWPD). Melatonin is also recommended for the treatment of Irregular Sleep-Wake Rhythm Disorder and Non-24-Hour Sleep-Wake Rhythm Disorder. However, in the treatment of Advanced Sleep-Wake Phase Disorder melatonin plays a secondary role. The therapeutic effect of melatonin primarily depends on the appropriate time of its administration. In DSWPD it should be administered even 6–8 hours before the scheduled sleep time. The available data does not indicate that the melatonin’s therapeutic effect is strongly correlated with the used dose and the recommended doses fall within a wide range of 0.5 to 10 mg. However, usually higher doses, e.g. 5 mg, are beneficial in the first 3–6 weeks of treatment. In neuropsychiatric disorders in children, dosage even up to 10 mg is recommended. Melatonin is also an effective form for relieving symptoms of exogenous CRSWD: shift work disorder and jet lag disorder. Prolonged-release formulation of melatonin in a 2 mg dose is registered for the treatment of insomnia patients aged 55 years and older. Conclusions. Treatment of CRSWD is based primarily on chronotherapeutic interventions. They include phototherapy, light avoidance, melatonin treatment and behavioural interventions that influence, among other things, the rhythm of meals, physical and social activity.

Chapter 24 - Clinical neurophysiology of circadian rhythm sleep–wake disorders

Circadian rhythms are the endogenous near-24-h oscillations in physiologic processes. In mammals the suprachiasmatic nucleus serves as the primary circadian pacemaker, and it maintains rhythmicity at a genetic level through a complex transcription-translation feedback loop of core circadian clock genes. The circadian clock is entrained to the environment through daily exposure to light and melatonin. Disruption of these endogenous rhythms or the ability to entrain to the surrounding environment results in the circadian rhythm sleep-wake disorders (CRSWDs). Patients with CRSWDs can present with either late sleep/wake times (delayed sleep-wake phase disorder), early sleep/wake times (advanced sleep-wake phase disorder), inconsistent sleep/wake times (irregular sleep-wake rhythm disorder) or sleep-wake times that move progressively later each day (non-24-h sleep-wake rhythm disorder). Diagnosis of these disorders relies on the use of sleep logs and/or actigraphy to demonstrate the daily patterns of rest and activity. Treatment of the CRSWDs focuses on sleep hygiene and strategically timed light and melatonin.