Antisense oligonucleotide therapeutic approach for Timothy syndrome.

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.

Evaluation of the benefits of neutral bicarbonate ionized water baths in an open-label, randomized, crossover trial.

We previously demonstrated that neutral bicarbonate ionized water (NBIW) bathing enhances blood flow by bicarbonate ions and described the underlying mechanism. However, additional clinical investigation was warranted to investigate the efficacy of NBIW bathing. Hence, we performed a randomized, open-label, crossover trial to examine the effects of NBIW bathing on mental stress, sleep, and immune function. Participants who regularly felt stressed were randomly assigned to NBIW or regular bathing for 4 weeks. Mental stress was assessed with the Brief Job Stress Questionnaire (BJSQ) and the Profile of Mood States Second Edition; sleep quality, with the Pittsburgh Sleep Quality Index Japanese version (PSQI-J) and actigraphy; and immune function, with laboratory tests. PSQI-J scores and actigraphy sleep latency and bed out latency improved significantly more with NBIW bathing than with regular bathing (p < 0.05). Furthermore, NBIW bathing reduced both stress-induced fluctuations in CD4+ and CD8+ T cell counts and fluctuations in the naive to memory T cell ratio and neutrophil phagocytosis, indicating improved immune function. These findings suggest that daily NBIW bathing could improve mental stress, sleep quality, and immune function and bring about positive health effects in those who experience stress in their daily lives.

Eurycoma longifolia (Tongkat Ali) enhances wakefulness during active periods but facilitates sleep during resting periods in C57BL/6 mice.

The effects of the Eurycoma longifolia (also known as Tongkat Ali [TA]) on sleep and wakefulness was evaluated in C57BL/6 mice. While TA has been used as an aphrodisiac in males, it exhibits various pharmacological effects. The most notable effect observed with TA was wake-enhancement during the second half of the active period, accompanied by significant elevations in core body temperature (CBT). In contrast, sleep was enhanced during the resting period (i.e., increase in rapid eye movement [REM] sleep and delta electroencephalography [EEG] power in non-REM sleep) with significant declines in CBT. The transition of TA's effects between resting and active periods was rapid. The results of the experiments in constant darkness indicate that TA prolongs the circadian tau and that this transition is governed by circadian clock mechanisms rather than light exposure. TA did not demonstrate efficacy in aiding sleep in an acute stress-induced insomnia model; thus, TA may be more suitable as a wake-enhancing agent for daytime sleepiness, as sleep propensity tends to accumulate towards the end of active period. Since TA amplifies the rest-activity pattern, prolongs circadian tau and increases REM sleep, thereby reversing some common symptoms seen in elderly subjects, it may also hold promise as a rejuvenating medicine.

BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep.

Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.

Characteristics of hypersomnia due to inflammatory demyelinating diseases of the central nervous system.

Background: Neuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria for inflammatory demyelinating central nervous system diseases included symptomatic narcolepsy; however, no relevant case-control studies exist. We aimed to examine the relationship among cerebrospinal fluid orexin-A (CSF-OX) levels, cataplexy and diencephalic syndrome; determine risk factors for low-and-intermediate CSF-OX levels (≤200 pg/mL) and quantify hypothalamic intensity using MRI. Methods: This ancillary retrospective case-control study included 50 patients with hypersomnia and 68 controls (among 3000 patients) from Akita University, the University of Tsukuba and community hospitals (200 facilities). Outcomes were CSF-OX level and MRI hypothalamus-to-caudate-nucleus-intensity ratio. Risk factors were age, sex, hypersomnolence and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130%. Logistic regression was performed for the association between the risk factors and CSF-OX levels ≤200 pg/mL. Results: The hypersomnia group (n=50) had significantly more cases of NMOSD (p<0.001), diencephalic syndrome (p=0.006), corticosteroid use (p=0.011), hypothalamic lesions (p<0.023) and early treatment (p<0.001). No cataplexy occurred. In the hypersomnia group, the median CSF-OX level was 160.5 (IQR 108.4-236.5) pg/mL and median MRI hypothalamus-to-caudate-nucleus-intensity ratio was 127.6% (IQR 115.3-149.1). Significant risk factors were hypersomnolence (adjusted OR (AOR) 6.95; 95% CI 2.64 to 18.29; p<0.001) and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% (AOR 6.33; 95% CI 1.18 to 34.09; p=0.032). The latter was less sensitive in predicting CSF-OX levels ≤200 pg/mL. Cases with MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% had a higher rate of diencephalic syndrome (p<0.001, V=0.59). Conclusions: Considering orexin as reflected by CSF-OX levels and MRI hypothalamus-to-caudate-nucleus-intensity ratio may help diagnose hypersomnia with diencephalic syndrome.

Analysis of the Effects of Known Sleep-Support Supplements in Relation to Life Habits, Sleep Conditions, and Sleep Problems.

Sleep is a crucial component of health, and insomnia is among the most common and vexing of life-habit-related disorders. While dietary sleep-support supplements can improve sleep, choosing an effective dietary supplement can be challenging for users due to the wide variety of options available and the varying effects experienced by different individuals. In this study, to identify new criteria for estimating the effects of dietary supplements, we examined the relationships among the dietary supplements, the pre-conditions (PCs; defined as the life habits and sleep conditions before supplementation), and the sleep problems of subjects before supplementation. An open, randomized, cross-over intervention trial enrolling 160 subjects was conducted to test the efficacy of each dietary supplement (Analysis 1) and the relationships among dietary supplements, the PCs, and sleep problems (Analysis 2). To this end, l-theanine (200 mg/day), γ-aminobutyric acid (GABA) (111.1 mg/day), Apocynum venetum leaf extract (AVLE) (50 mg/day), and l-serine (300 mg/day) were administered to subjects. Before the first intervention period, life habits and sleep conditions were surveyed to identify each subject's PCs. For each combination of supplements and sleep problems, PCs were compared between subjects whose sleep problems were improved and subjects whose sleep problems were not improved via supplementation. All the tested supplements were found to ameliorate sleep problems significantly (Analysis 1). In Analysis 2, the PCs specific to improved subjects were found to differ depending on the dietary supplements and sleep problems. In addition, subjects who consumed dairy products often showed improvement in their sleep problems with all the tested supplements. This study suggests the possibility of personalizing sleep-support supplementation based on personal life habits, sleep conditions, and sleep problems, in addition to the known efficacy of dietary supplements.

Changes in sleep profile on exposure to sodium chloride and artificially carbonated springs: a pilot study.

[Purpose] Herein, we aimed to investigate the effects of bathing in a sodium chloride spring and an artificially carbonated spring on core body temperature and electroencephalograms, to assess whether the springs facilitate sleep. [Participants and Methods] This randomized, controlled, crossover study evaluated the effects of a sodium chloride spring, an artificially carbonated spring, a plain hot bath, and no bath on sleep. The subjective evaluations and recording of temperature were performed before/after bathing at 40 °C for 15 min at 22:00 h, before nocturnal sleep (0:00-7:00 h), and after the participants (n=8) woke up in the morning. [Results] Bathing significantly increased the core body temperature, with significant subsequent declines observed until bedtime. Participants in the sodium chloride spring group had the highest average core body temperature, while participants in the no-bath group had the lowest average core body temperature before bedtime (23:00-0:00 h). During bedtime (1:00-2:00 h), the participants in the no bath group had the highest average core body temperature, while participants in the artificially carbonated spring group had the lowest average core body temperature. The amount of delta power/min in the first sleep cycle significantly increased in the bathing groups, with the highest value during bedtime being recorded in the artificially carbonated spring group, followed by the sodium chloride spring, plain hot bath, and no-bath groups. These sleep changes were associated with significant declines in the elevated core body temperature. Increased heat dissipation and decreased core body temperature were observed in the artificially carbonated spring and sodium chloride spring groups, which increased the delta power during the first sleep cycle compared with that observed in the plain hot bath group, followed by the no-bath group. [Conclusion] An artificially carbonated spring would be the most appropriate given each circumstance because it did not cause fatigue, as observed with the sodium chloride spring.

Comparison of Solriamfetol and Modafinil on Arousal and Anxiety-Related Behaviors in Narcoleptic Mice.

Wake-promoting agents are used for the management of excessive daytime sleepiness caused by narcolepsy. Clinical and preclinical data suggests that solriamfetol, a novel dopamine and norepinephrine reuptake inhibitor, is a promising therapeutic option for excessive daytime sleepiness. We provide the first head-to-head comparison of in vivo efficacy between modafinil and solriamfetol in narcoleptic mice. Both compounds induced potent wake-promoting effects in littermate wild-type and orexin-tTA; TetO-DTA mice when dosed at active and resting phases. However, neither modafinil nor solriamfetol alleviated cataplexy. Remarkably, modafinil significantly induced locomotor activity but solriamfetol had small effects. Awake electroencephalogram profiles revealed that modafinil augmented theta oscillation in a dose-dependent manner, but, on the contrary, the response to solriamfetol was blunted, reflecting the differences in their neurochemical properties and anxiogenic effects. Drug-induced anxiety-related behaviors were evaluated at equipotent wake-promoting doses in WT and DTA mice using the elevated plus maze and forced swim tests. Importantly, 100 mg/kg of modafinil significantly produced anxiety-related behaviors in WT mice, whereas 150 mg/kg of solriamfetol did not have anxiogenic effects. On the other hand, DTA mice exhibited trait anxiety and altered drug responses. Our results suggest that solriamfetol potently promotes wakefulness without psychomotor effects and without inducing anxiety-related behaviors.

Influences of sleep and lifestyle factors on the risk for covid-19 infections, from internet survey of 10,000 Japanese business workers.

We conducted an internet survey to assess sociodemographic variables, lifestyle factors, sleep problems, and comorbidities for sleep apnea syndrome (SAS) in COVID-19 and influenza (FLU) infections. Data from 10,323 workers (50.0% male) were analyzed. COVID-19 was diagnosed in 144 subjects (COVID-19+), and 8,693 were classified as not suspected to be infected (COVID-19-). SAS had been diagnosed in 35.4% of the COVID-19+ subjects, but only 231 (2.7%) of the 8,693 COVID-19- subjects. COVID-19+ subjects were more susceptible to FLU (35.4%) compared to COVID-19- subjects (3.0%). A multivariate analysis revealed that higher risks of COVID-19+ were linked to the following factors: going out without a face mask (OR 7.05, 95% CI 4.53-11.00), FLU+ (OR 6.33, 95% CI 3.80-10.54), excessive exercise before going to sleep (OR 2.10, 95% CI 1.63-2.70), SAS+ (OR 5.08, 95% CI 2.88-8.94), younger age (OR 1.05, 95% CI 1.03-1.07), falling sleep while sitting or talking with someone (OR 3.70, 95% CI 2.30-5.95), and use of hypnotics (OR 2.28, 95% CI 1.20-4.30). Since sleep impairment played a relatively small role in COVID-19+/SAS- subjects, we assume that SAS itself was a more significant risk factor for COVID-19 infection rather than sleep impairment. A better understanding of the mechanisms that result in increased susceptibility to COVID-19 in SAS is vital for helping prevent COVID-19.

Social stress alters sleep in FGF21-deficient mice.

Although several previous studies have suggested a relationship between sleep and the stress response, the mechanism underlying this relationship remains largely unknown. Here, we show that fibroblast growth factor 21 (FGF21), a lipid metabolism-related hormone, may play a role in this relationship. In this study, we examined differences in the stress response between FGF21 knockout (KO) mice and wild-type (WT) mice after social defeat stress (SDS). When the amount of non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep and wakefulness were averaged over the dark period after SDS, only KO mice showed significant differences in NREM sleep and wakefulness. In the social interaction test, KO mice seemed to be more prone to social avoidance. Our real-time (RT) -PCR results revealed that the mRNA expression of the stress- and sleep-related gene gamma-aminobutyric acid A receptor subunit alpha 2 was significantly lower in WT mice than in KO mice. Moreover, KO mice showed lower plasma levels of ketone bodies, which also affect sleep/wake regulation, than WT mice. These results suggested that FGF21 might influence sleep/wake regulation by inducing production of an anti-stress agent and/or ketone bodies, which may result in resilience to social stress.

Maturation and circuit integration of transplanted human cortical organoids.

Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1-5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.

Pharmacologic Management of Excessive Daytime Sleepiness.

Excessive daytime sleepiness (EDS) is defined as "irresistible sleepiness in a situation when an individual would be expected to be awake, and alert." EDS has been a big concern not only from a medical but also from a public health point of view. Patients with EDS have the possibility of falling asleep even when they should wake up and concentrate, for example, when they drive, play sports, or walk outside. In this article, clinical characteristics of common hypersomnia and pharmacologic treatments of each hypersomnia are described.

Residual effects of low dose of suvorexant, zolpidem, and ramelteon in healthy elderly subjects: A randomized double-blind study.

INTRODUCTION: Current hypnotic agents have next-day residual effects. The new orexin antagonist, suvorexant, has little muscle relaxation effect on the physical and cognitive function in the following morning and daytime. In this study, the effects of suvorexant, zolpidem, ramelteon and placebo in elderly subjects were evaluated. METHODS: Six men and eight women aged 63-75 years received a single tablet and lights were then turned off. Subjects were instructed to sleep from 23:00-6:00 with an interruption from 4:00-4:30 for evaluations. Suvorexant 10 mg, zolpidem 5 mg, ramelteon 4 mg or placebo was administered single time in a randomized, double-blind and crossover design with a one-week drug holiday in between each drug. Measures of objective parameters and subjective ratings were obtained every 2 h from 4:00 to 16:00. RESULT: No subjects showed serious side effects from physical observations and vital sign checks before and after hypnotics were taken. During the first sleep period, the REM sleep time with suvorexant was especially longer than that with zolpidem. During the second sleep period, suvorexant had shorter sleep latency and longer stage2 sleep time than ramelteon and zolpidem, respectively. During the whole entire sleep, the REM sleep time with suvorexant was longer than zolpidem and placebo. For the body sway test with closed eye, the main effects of the medicines and zolpidem were significantly better than suvorexant and ramelteon. CONCLUSION: The changes of physical and cognitive functions in healthy elderly after taking hypnotics were not remarkable. Therefore, these three hypnotics maybe appropriate for the elderly people with insomnia for single-time low dose administration.

Brain Mast Cells in Sleep and Behavioral Regulation.

The function of mast cells in the brain for the mediation of neurobehavior is largely unknown. Mast cells are a heterogeneous population of granulocytic cells in the immune system. Mast cells contain numerous mediators, such as histamine, serotonin, cytokines, chemokines, and lipid-derived factors. Mast cells localize not only in the periphery but are also resident in the brain of mammalians. Mast cells in the brain are constitutively active, releasing their contents gradually or rapidly by anaphylactic degranulation. Their activity is also increased by a wide range of stimuli including both immune and non-immune signals. Brain mast cell neuromodulation may thus be involved in various neurobehavior in health and diseases.Using Kit mutant mast cell deficient mice (KitW/KitW-v), we obtained results indicating that brain mast cells regulate sleep/wake and other behavioral phenotypes and that histamine from brain mast cells promotes wakefulness. These findings were also confirmed using a newer inducible and Kit-independent mast cell deficient Mas-TRECK (toxin receptor knockout) mouse. Injections of diphtheria toxin (DT) selectively deplete mast cells and reduce wakefulness during the periods of mast cell depletion.We recently introduced a mouse model for chronic sleep loss associated with diabetes. The mice reared on the wire net for 3 weeks (i.e., mild stress [MS]) showed decreased amount of non-rapid eye movement (NREM) sleep, increased sleep fragmentation, and abnormal glucose tolerance test [GTT] and insulin tolerance test [ITT], phenotypes which mirror human chronic insomnia. Interestingly, these mice with insomnia showed an increased number of mast cells in both the brain and adipose tissue. Mast cell deficient mice (KitW/KitW-v) and inhibition of mast cell functions with cromolyn or a histamine H1 receptor antagonist administration ameliorated both insomnia and abnormal glycometabolism. Mast cells may therefore represent an important pathophysiological mediator in sleep impairments and abnormal glycometabolism associated with chronic insomnia.

A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.

Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10-8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.

Sake yeast induces the sleep-promoting effects under the stress-induced acute insomnia in mice.

Sleep deprivation induces adverse effects on the health, productivity, and performance. The individuals who could not get enough sleep temporarily experience the symptoms of an induced acute insomnia. This study investigated the efficacy of sake yeast in treatment of acute insomnia in mice. The results of this study showed that sake yeast induced a significant dose-dependent wake reduction, a rapid eye movement (REM) and a non-REM (NREM) sleep enhancement during the first 6 h after the oral administration of sake yeast with locomotor activity and core body temperature decreases under the stressful environment in a new cage. In fact, the wake amounts at 3 h and 6 h were significantly reduced after the oral administration of sake yeast compared with the vehicle. The NREM sleep amounts at 3 h and 6 h significantly increased after the administration of sake yeast compared with the vehicle. The REM amount at 6 h significantly increased after the administration of sake yeast compared with the vehicle, but not at 3 h. The previous study suggested that the sleep-promoting effects of sake yeast could be referred from the activating effect of adenosine A2A receptor (A2AR). In summary, the sake yeast is an A2AR agonist and may induce sleep due to its stress-reducing and anti-anxiety properties. Further verification of the involvement of adenosine in the pathophysiology of insomnia is needed.

Altered responses of end-expiratory lung volume and upper airway patency to body posture in diet-induced obese mice.

OBJECTIVE: Although both obesity and body posture are important factors affecting end-expiratory lung volume (EELV) and upper airway patency, the influence of those factors on EELV and the association between EELV and upper airway calibers are still unknown in mice. This study examined such interaction effects in obese mice to test the hypothesis that obese mice have decreased EELV accompanied by structural alterations of the upper airway. METHODS: A high-resolution in vivo micro-computed tomography was utilized to scan anesthetized lean and diet-induced obese mice in the prone and supine positions, followed by quantifying lung volume and analyzing upper airway morphology. RESULTS: There was a statistically significant interaction between the effects of body weight and posture on both EELV (p = 0.0049, η 2  = 0.1041) and upper airway calibers (p = 0.0215, η 2  = 0.6304). In lean mice, EELV in the prone position was significantly larger than in the supine position (prone EELV = 193.22 ± 9.10 µl vs. supine EELV = 176.01 ± 10.91 µl; p = 0.0072), whereas obese mice did not have such an improvement in EELV in the prone position (prone EELV = 174.37 ± 20.23 µl vs. supine EELV = 183.39 ± 17.49 µl; p = 0.0981) and tended to have a smaller upper airway when EELV was low based on Spearman's correlation analysis. CONCLUSIONS: These data indicate that obesity is an important factor compromising both EELV and upper airway calibers in a posture-dependent manner even in mice, which should be taken into consideration in future studies regarding upper airway collapse and lung mechanical properties using mice.

Genetic and demographic predisposing factors associated with pediatric sleepwalking in the Philadelphia Neurodevelopmental Cohort.

OBJECTIVES: Sleepwalking is a parasomnia associated with non-rapid eye movement (NREM) sleep and is formally diagnosed using polysomnography (PSG). However, PSG are difficult to perform on children or adolescents due to needed compliance. To understand this condition in youth, few studies have been conducted on a large cohort of youths with a diverse distribution of ages and races to characterize it better in the absence of PSG. The present study aimed to evaluate the prevalence of sleepwalking in youth, as well as associated demographic and genetic characteristics, using questionnaires in a large pediatric cohort. METHODS: Data from the Philadelphia Neurodevelopmental Cohort (PNC) of 7515 youths aged between 8 and 22 years were used in analyses. Demographic and clinical data, including age, sex, and race, and genetic data from 2753 African American (AA) and 4762 European American (EA) subjects were investigated. The age-wise prevalence of sleepwalking in AA and EA subjects was evaluated. Finally, race-specific genome-wide association (GWAS) analyses of sleepwalking were also performed (N = 155 AA cases and 2598 AA controls; N = 512 EA cases and 4250 EA controls). RESULTS: Lifetime history of sleepwalking correlated with male sex and EA race. A genetic risk locus that reached genome-wide significance was detected at rs73450744 on chromosome 18 in AA, but not EA youth. CONCLUSION: The present results suggest that male sex, EA race, and genetic factors may be associated with higher rates of sleepwalking among youth. Future studies should consider these variables to advance understanding of the complex pathogenesis of sleepwalking.

Advances in the pharmacological management of non-24-h sleep-wake disorder.

Introduction: Melatonin, a hormone that regulates circadian rhythms and the sleep-wake cycle, is produced mainly during the dark period in the pineal gland and is suppressed by light exposure. Patients with non-24-h sleep-wake disorder (non-24) fail to entrain the master clock with the 24-h light-dark cycle due to the lack of light perception to the suprachiasmatic nucleus typically in totally blind individuals or other organic disorders in sighted individuals, causing a progressive delay in the sleep-wake cycle and periodic insomnia and daytime sleepiness.Areas covered: Herein, the authors review the pharmacological therapies including exogenous melatonin and melatonin receptor agonists for the management of non-24. They introduce a historical report about the effects of melatonin on the phase shift and entrainment for blind individuals with the free-running circadian rhythm.Expert opinion: Orally administered melatonin entrains the endogenous circadian rhythm and improves nighttime sleep and daytime alertness for non-24. Currently, tasimelteon is the only approved medication for non-24 by the US Food and Drug Administration and the European Medicines Agency. Treatments that focus only on sleep problems are insufficient for the treatment of non-24, and aids to entrain the free-running rhythm with the light-dark cycle are needed.