The impact of Mendelian sleep and circadian genetic variants in a population setting

Rare variants in ten genes have been reported to cause Mendelian sleep conditions characterised by extreme sleep duration or timing. These include familial natural short sleep (ADRB1, DEC2/BHLHE41, GRM1 and NPSR1), advanced sleep phase (PER2, PER3, CRY2, CSNK1D and TIMELESS) and delayed sleep phase (CRY1). The association of variants of these genes with extreme sleep conditions were usually based on clinically ascertained families, and their effects when identified in the population are unknown. We aimed to determine the effects of these variants on sleep traits in large population-based cohorts. We performed genetic association analysis of variants previously reported to be causal for Mendelian sleep and circadian conditions. Analyses were performed using 191,929 individuals with data on sleep and whole-exome or genome-sequence data from 4 population-based studies: UK Biobank, FINRISK, Health-2000-2001, and the Multi-Ethnic Study of Atherosclerosis (MESA). We identified sleep disorders from self-report, hospital and primary care data. We estimated sleep duration and timing measures from self-report and accelerometery data. We identified carriers for 10 out of 12 previously reported pathogenic variants for 8 of the 10 genes. They ranged in frequency from 1 individual with the variant in CSNK1D to 1,574 individuals with a reported variant in the PER3 gene in the UK Biobank. We found no association of any of these variants with extreme sleep or circadian phenotypes. Using sleep timing as a proxy measure for sleep phase, only PER3 and CRY1 variants demonstrated association with earlier and later sleep timing, respectively; however, the magnitude of effect was smaller than previously reported (sleep midpoint ~7 mins earlier and ~5 mins later, respectively). We also performed burden tests of protein truncating (PTVs) or rare missense variants for the 10 genes. Only PTVs in PER2 and PER3 were associated with a relevant trait (for example, 64 individuals with a PTV in PER2 had an odds ratio of 4.4 for being "definitely a morning person", P=4x10-8; and had a 57-minute earlier midpoint sleep, P=5x10-7). Our results indicate that previously reported variants for Mendelian sleep and circadian conditions are often not highly penetrant when ascertained incidentally from the general population.

The connection of polymorphism and diurnal changes of the biological clock gene expression with the risk of progression of primary open-angle glaucoma

The purpose of this work is to study the connection betweengenetic factors (polymorphism and expression of key genes of the biological clock (KGBC), key genes controlled by KGBC, melatonin receptors) and the diurnal oscillation of melatonin in patients with stable and progressing primary open-angle glaucoma. Materials and methods. The study involved 115 patients aged 53–86 (averagely, 68.8 ± 7.9 years) with stable and progressive glaucoma. All patients underwent primary ophthalmological examination, tested for diurnal body temperature profile, intraocular pressure (IOP), melatonin (by the DLMO protocol) and were typed for key genes of the biological clock using the real-time polymerase chain reaction. We studied the sleep phase shift to later hours in carriers of the G-allele of the melatonin receptor gene during the progression of glaucoma. Results. The study of the clinical and genotypic features of the POAG course revealed phasal shifts of the circadian rhythms of body temperature, IOP, salivary melatonin levels and sleep phases which contributed to the progression of glaucomatous optic neuropathy. Certain polymorphic variants of genes contribute to individual frequent manifestations of desynchronosis. The clock rs1801260 and MTNR1B rs10830963 gene polymorphism was found to be related to disturbances in melatonin production and sleep phase. Conclusion. Complex manifestations of circadian desynchronization accompanying the progressive course of glaucoma are the late phase of rhythms and a decrease in sleep duration, body temperature, salivary melatonin and IOP, internal desynchronization between IOP and body temperature, IOP and sleep, evening dyslipidemia. The revealed patterns open up prospects for future studies of the relationship between polymorphism and daily changes of the expression of key genes in the biological clock with the risk of progression of primary open angle glaucoma.

EFFECT OF MELATONIN ON PAIN SYNDROME IN DELAYED SLEEP PHASE DISORDER IN PATIENTS WITH PARKINSON'S DISEASE

Parkinson’s disease is characterized mainly by damage to the neurons of the substantia nigra and other brain structures and manifested by motor and non-motor symptoms. In patients with Parkinson’s disease receiving dopaminergic therapy, a later onset of sleep has been identified that is associated with the development of the delayed sleep phase disorder. The delayed sleep phase disorder is characterized by a persistent delay in the circadian rhythm that causes a delay in the desired time of falling asleep and waking up. According to clinical guidelines for the treatment of delayed sleep phase disorder, exogenous melatonin is recommended. Along with this, its analgesic properties have been reported. At the same time circadian regulation of fluctuations of painful sensations transmission by either peripheral or central alarm system has been reported. In particular, the two-way connection between the nociceptive system and the circadian rhythm in the human body determines the possibility of mutual influence between these systems. However, the question of the therapeutic effect of melatonin in the presence of concomitant pathology on the circadian rhythm disorders, and, in particular, delayed sleep phase disorder that is a topical issue for patients with Parkinson's disease, is still remaining unexplored. The aim of the study is to compare the changes in subjective perception of pain in patients with Parkinson's disease, who received melatonin therapy and who did not, in delayed sleep phase disorder. We conducted a prospective study that included 48 patients with Parkinson's disease. Circadian rhythm disorders were diagnosed according to the criteria of the International Classification of Sleep Disorders-3. The diagnosis of delayed sleep phase disorder was made on the basis of a clinical interview, filling in a sleep diary and daily thermometry for 7 days. The examined patients were divided into 2 groups according to the chosen method of treatment: group 1 - patients with Parkinson's disease and delayed sleep phase disorder receiving melatonin; group 2 - patients with Parkinson's disease and delayed sleep phase disorder receiving only general recommendations for improving sleep quality and daily functioning without medical intervention. The Unified Parkinson's Disease Rating Scale was used to assess the severity of patients’ clinical condition. The intensity of the pain syndrome was assessed on a visual-analogue scale. The McGill Questionnaire was used to analyze subjective experiences of pain. The patients of group 1 were prescribed to take melatonin, 1 tablet in a dose of 3 mg at 22:00. Individuals in group 2 received general recommendations on the schedule of sleep-wake cycles, light regime and sleep hygiene. Patients with Parkinson's disease and delayed sleep phase disorder have been diagnosed with mild to moderate pain. Treatment of delayed sleep phase disorder in patients with Parkinson's disease reduces the intensity and modality of the pain syndrome, which may be due to improved functioning of the descending pain modulation system and restoration of rhythmic expression of internal clock genes. The administration of melatonin as part of a comprehensive approach to the treatment of circadian rhythm disorders helps to reduce sensory sensations and affective experiences caused by pain that indicates the potential antinociceptive effect of melatonin in the treatment of circadian disorders.

Circadian Disorders, Insomnia, and Parasomnias

Circadian rhythm disorders have misalignment between the desired sleep schedule and the circadian (24-hour) sleep-wake rhythm. Many persons experience this misalignment with jet lag. Other common circadian rhythm disorders include delayed sleep-phase disorder, advanced sleep-phase disorder, and shift-work sleep disorder. Insomnia is one of the most common medical concerns, and its prevalence increases with age. Patients may have difficulty initiating sleep or maintaining sleep and generally have a poor quality of sleep. Causes of insomnia are multifactorial.

Sound disrupts sleep-associated brain oscillations in rodents according to its meaning

SummarySleep is essential but poses a risk to the animal. Filtering acoustic information according to its relevance, a process generally known as sensory gating, is crucial during sleep to ensure a balance between rest and danger detection. The mechanisms of this sensory gating and its specificity are not understood. Here, we tested the effect that sounds of different meaning had on sleep-associated ongoing oscillations. We recorded EEG and EMG from mice during rapid-eye movement (REM) and non-REM (NREM) sleep while presenting sounds with or without behavioural relevance. We found that sound presentation per se, in the form of an unfamiliar neutral sound, elicited a weak or no change in the sleep-dependent EEG power during NREM and REM sleep. In contrast, the presentation of a sound previously conditioned in an aversive task, elicited a clear and fast decrease in the sleep-dependent EEG power during both sleep phases, suggesting a transition to lighter sleep without awakening. The observed changes generally weakened over training days and were not present in animals that failed to learn. Interestingly, the effect could be generalized to unfamiliar neutral sounds if presented following conditioned training, an effect that depended on sleep phase and sound type. The data demonstrate that sounds are differentially gated during sleep depending on their meaning and that this process is reflected in disruption of sleep-associated brain oscillations without an effect on behavioural arousal.

Nightmares in Migraine: A Focused Review

Nightmares usually occur during the sleep phase of rapid eye movement (REM) and are associated with some physical symptoms, including sweating, shortness of breath, and lower limb movements. Emotions of fear, anger, shame, and sadness may also accompany nightmares. These symptoms can occur during dreaming, upon awakening, or later when the dream experience is recollected. Nightmares may sporadically occur for everyone, but nightmare disorders are associated with features of impaired mental and physical health and require professional medical treatment. The occurrence of nightmares with several disorders has been reported in the literature, but in migraines it has only been investigated in a small number of studies. Considering the existing relationship between sleep disorders and migraine, the occurrence of nightmares in migraine can negatively affect this association and elevate the risk of depression and anxiety. This, in turn, further reduces the quality of life of affected individuals. Hence, expanding the knowledge on the link between nightmares and migraine, promoting an acceptable quantity and quality of sleep through pharmacological and nonpharmacological interventions in the management of nightmares in migraine, and further scientific investigation of the biopsychosocial mechanisms underlying the link, will be highly valuable for optimal care. This focused review, therefore, gives a brief overview of the current understanding of nightmares in migraine to highlight the open questions and value of further research. The ultimate goal is to contribute to timely recognition and sufficient action to offer beneficial outcomes for affected patients.

Use of Actigraphy for a Rat Behavioural Sleep Study

Previous studies of animal behavioural sleep is mainly divided into two study types, observation by video recording or counts by sensor, both of which require a complex environment and procedure. An actigraph unit is a commercially available product which can provide non-invasive monitoring human rest/activity cycles. The goal of this study was to evaluate whether actigraphy can be applied for analysing behavioural sleep in rats, since no reports have described utilization of the actigraphy unit for monitoring sleep of small animals. The actigraph unit was held on the chest of eight male rats by a loose elastic belt. The rats spent two days in a normal condition, followed by two days of sleep deprivation. Total counts measured by the actigraph could be clearly divided into two phases, sleep phase and awake phase, when the rats were kept in the normal cage. Next, the rats were moved into the sleep-deviation cage, and the total counts were significantly higher during daytime, indicating the successful induction of sleep deprivation. These results showed that the actigraphy unit monitored rest/activity cycles of rats, which will contribute to making sleep behaviour experiments easier.

Integration of sleep homeostasis and navigation in Drosophila

During sleep, the brain undergoes dynamic and structural changes. In Drosophila, such changes have been observed in the central complex, a brain area important for sleep control and navigation. The connectivity of the central complex raises the question about how navigation, and specifically the head direction system, can operate in the face of sleep related plasticity. To address this question, we develop a model that integrates sleep homeostasis and head direction. We show that by introducing plasticity, the head direction system can function in a stable way by balancing plasticity in connected circuits that encode sleep pressure. With increasing sleep pressure, the head direction system nevertheless becomes unstable and a sleep phase with a different plasticity mechanism is introduced to reset network connectivity. The proposed integration of sleep homeostasis and head direction circuits captures features of their neural dynamics observed in flies and mice.