Acute REM sleep behaviour disorder associated with alcohol withdrawal: A case report and literature review.

INTRODUCTION: Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by the loss of REM sleep muscle atonia and the enactment of dreams. Acute RBD associated with alcohol withdrawal syndrome is known, but the studies are limited, particularly on its neurobiological underpinnings and management alongside the withdrawal state. This work attempts to address this using a case study and relevant literature review. CASE PRESENTATION: A 40-year-old male with alcohol dependence (for 20 years) reported new-onset terrifying nightmares and violent behaviours in his sleep precipitated by alcohol withdrawal states for the last 18 months. The polysomnographic finding of REM-without-atonia supported the diagnosis of RBD. He was treated with chlordiazepoxide 100 mg/day (gradually tapered and stopped) and thiamine supplements. Post-discharge, he remained abstinent and symptom-free during the three months of follow-up. DISCUSSION: RBD related to alcohol withdrawal syndrome has been previously described in a few anecdotal reports. Sudden withdrawal from central nervous system suppressants like alcohol is hypothesised to cause a homeostatic imbalance in gamma-aminobutyric acid (GABA) pathways and 'REM rebound', resulting in the clinical and polysomnographic picture of RBD. Benzodiazepines have been found to be useful in both RBD and alcohol withdrawal. CONCLUSIONS: Alcohol withdrawal syndrome may present with acute RBD, which can be treated with a short course of benzodiazepine. However, further studies are needed to explore the long-term course of RBD in these patients.

A case of prazosin in treatment of rapid eye movement sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream-enactment behaviors that emerge during a loss of REM sleep atonia. Untreated RBD carries risks for physical injury from falls or other traumatic events during dream enactment as well as risk of injury to the bed partner. Currently, melatonin and clonazepam are the mainstay pharmacological therapies for RBD. However, therapeutic response to these medications is variable. While older adults are most vulnerable to RBD, they are also particularly vulnerable to the adverse effects of benzodiazepines, including increased risk of falls, cognitive impairment, and increased risk of Alzheimer disease. Prazosin is a centrally active alpha-1 adrenergic receptor antagonist often prescribed for trauma nightmares characterized by REM sleep without atonia in patients with posttraumatic stress disorder. We report a case of successful RBD management with prazosin in a patient in whom high-dose melatonin was ineffective. Although there was no observable reduction in dream-enactment behaviors with high-dose melatonin, the possibility of a synergistic effect of prazosin combined with melatonin cannot be ruled out. This case report supports further evaluation of prazosin as a potential therapeutic for RBD. CITATION: Cho Y, Iliff JJ, Lim MM, Raskind M, Peskind E. A case of prazosin in treatment of rapid eye movement sleep behavior disorder. J Clin Sleep Med. 2024;20(2):319-321.

Photomodulatory effects in the hypothalamus of sleep-deprived young and aged rats.

Insufficient sleep is associated with impaired hypothalamic activity and declined attentional performance. In this study, alterations in the hypothalamus of REM sleep-deprived (SD) young and aged rats, and the modulatory effect of near-infrared (NIR) laser were investigated. Forty-eight male Wistar rats (24 young at 2 months and 24 senile at 14 months) were divided into three groups: the control, the SD group subjected to 72 hr of sleep deprivation, and the transcranial-NIR laser-treated (TLT) group subjected to SD for 72 hr and irradiated with 830 nm laser. The hypothalamic levels of oxidative stress, inflammatory biomarkers, antioxidant enzymes, mitochondrial cytochrome C oxidase (CCO), apoptotic markers (BAX, BCL-2), and neuronal survival-associated genes (BDNF, GLP-1) were evaluated. Furthermore, the hypothalamic tissue alterations were analyzed via histological examination. The results revealed that TLT treatment has enhanced the antioxidant status, prevented oxidative insults, suppressed neuroinflammation, regulated CCO activity, reduced apoptotic markers, and tuned the survival genes (BDNF & GLP-1) in hypothalamic tissue of SD young and aged rats. Microscopically, TLT treatment has ameliorated the SD-induced alterations and restored the normal histological features of hypothalamus tissue. Moreover, the obtained data showed that SD and NIR laser therapy are age-dependent. Altogether, our findings emphasize the age-dependent adverse effects of SD on the hypothalamus and suggest the use of low-laser NIR radiation as a potential non-invasive and therapeutic approach against SD-induced adverse effects in young and aged animals.

Enhancing imagery rehearsal therapy for nightmares with targeted memory reactivation.

Nightmare disorder (ND) is characterized by dreams with strong negative emotions occurring during rapid eye movement (REM) sleep. ND is mainly treated by imagery rehearsal therapy (IRT), where the patients are asked to change the negative story line of their nightmare to a more positive one. We here used targeted memory reactivation (TMR) during REM sleep to strengthen IRT-related memories and accelerate remission of ND. Thirty-six patients with ND were asked to perform an initial IRT session and, while they generated a positive outcome of their nightmare, half of the patients were exposed to a sound (TMR group), while no such pairing took place for the other half (control group). During the next 2 weeks, all patients performed IRT every evening at home and were exposed to the sound during REM sleep with a wireless headband, which automatically detected sleep stages. The frequency of nightmares per week at 2 weeks was used as the primary outcome measure. We found that the TMR group had less frequent nightmares and more positive dream emotions than the control group after 2 weeks of IRT and a sustained decrease of nightmares after 3 months. By demonstrating the effectiveness of TMR during sleep to potentiate therapy, these results have clinical implications for the management of ND, with relevance to other psychiatric disorders too. Additionally, these findings show that TMR applied during REM sleep can modulate emotions in dreams.

Predictive risk factors of phenoconversion in idiopathic REM sleep behavior disorder: the Italian study "FARPRESTO".

Most patients with idiopathic REM sleep behavior disorder (iRBD) will develop an overt α-synucleinopathy over time, with a rate of phenoconversion of 73.5% after 12 years from diagnosis. Several markers of phenoconversion were identified; however, most studies investigated biomarkers separately, with retrospective study designs, in small cohorts or without standardized data collection methods. The risk FActoRs PREdictive of phenoconversion in idiopathic REM sleep behavior disorder: the Italian STudy (FARPRESTO) is a multicentric longitudinal retrospective and prospective study with a cohort of incident (prospective recruitment) and prevalent (retrospective recruitment) iRBD patients, whose primary aim is to stratify the risk of phenoconversion, through the systematic collection by means of electronic case report forms of different biomarkers. Secondary aims are to (1) describe the sociodemographic and clinical characteristics of patients with iRBD; (2) collect longitudinal data about the development of α-synucleinopathies; (3) monitor the impact of iRBD on quality of life and sleep quality; (4) assess the correlation between phenoconversion, cognitive performance, and loss of normal muscle atony during REM sleep; (5) identify RBD phenotypes through evaluating clinical, biological, neurophysiological, neuropsychological, and imaging biomarkers; and (6) validate vPSG criteria for RBD diagnosis. The FARPRESTO study will collect a large and harmonized dataset, assessing the role of different biomarkers providing a unique opportunity for a holistic, multidimensional, and personalized approach to iRBD, with several possible application and impact at different levels, from basic to clinical research, and from prevention to management. The FARPRESTO has been registered at clinicaltrials.gov (NCT05262543).

NMDA Receptors in the Lateral Preoptic Hypothalamus Are Essential for Sustaining NREM and REM Sleep.

The lateral preoptic (LPO) hypothalamus is a center for NREM and REM sleep induction and NREM sleep homeostasis. Although LPO is needed for NREM sleep, we found that calcium signals were, surprisingly, highest in REM sleep. Furthermore, and equally surprising, NMDA receptors in LPO were the main drivers of excitation. Deleting the NMDA receptor GluN1 subunit from LPO abolished calcium signals in all cells and produced insomnia. Mice of both sexes had highly fragmented NREM sleep-wake patterns and could not generate conventionally classified REM sleep. The sleep phenotype produced by deleting NMDA receptors depended on where in the hypothalamus the receptors were deleted. Deleting receptors from the anterior hypothalamic area (AHA) did not influence sleep-wake states. The sleep fragmentation originated from NMDA receptors on GABA neurons in LPO. Sleep fragmentation could be transiently overcome with sleeping medication (zolpidem) or sedatives (dexmedetomidine; Dex). By contrast, fragmentation persisted under high sleep pressure produced by sleep deprivation (SD), mice had a high propensity to sleep but woke up. By analyzing changes in δ power, sleep homeostasis (also referred to as "sleep drive") remained intact after NMDA receptor ablation. We suggest NMDA glutamate receptor activation stabilizes firing of sleep-on neurons and that mechanisms of sleep maintenance differ from that of the sleep drive itself.SIGNIFICANCE STATEMENT Insomnia is a common affliction. Most insomniacs feel that they do not get enough sleep, but in fact, often have good amounts of sleep. Their sleep, however, is fragmented, and sufferers wake up feeling unrefreshed. It is unknown how sleep is maintained once initiated. We find that in mice, NMDA-type glutamate receptors in the hypothalamus are the main drivers of excitation and are required for a range of sleep properties: they are, in fact, needed for both sustained NREM sleep periods, and REM sleep generation. When NMDA receptors are selectively reduced from inhibitory preoptic (PO) neurons, mice have normal total amounts of sleep but high sleep-wake fragmentation, providing a model for studying intractable insomnia.

Is There a Place for Medicinal Cannabis in Treating Patients with Sleep Disorders? What We Know so Far.

The legalization of cannabis for medicinal, and in some countries, recreational, purposes in addition to growth in the cannabis industry has meant that cannabis use and interest in the area has increased rapidly over the past 20 years. Treatment of poor sleep and sleep disorders are two of the most common reasons for the current use of medicinal cannabis. However, evidence for the role of medical cannabis in the treatment of sleep disorders has not been clearly established, thus making it challenging for clinicians to make evidence-based decisions regarding efficacy and safety. This narrative review summarizes the highest quality clinical evidence currently available in relation to the use of medicinal cannabis for the treatment of sleep disorders including insomnia, obstructive sleep apnea, restless legs syndrome, rapid eye movement sleep behavior disorder, nightmare disorder and narcolepsy. A summary of the effect of cannabis on sleep quality and architecture is also presented. Currently, there is insufficient evidence to support the routine use of medicinal cannabis as an effective and safe treatment option for any sleep disorder. Nevertheless, emerging evidence is promising and warrants further investigation using standardized cannabinoid products and validated quantitative measurement techniques.

[Sleep disorders in patients with a neurocognitive disorder]. / Les troubles du sommeil chez les patients atteints d'un trouble neurocognitif.

INTRODUCTION: Sleep disorders are prevalent in patients with a neurocognitive disorder, and diagnosis and treatment in these patients remain challenging in clinical practice. METHODS: This narrative review offers a systematic approach to diagnose and treat sleep disorders in neurocognitive disorders. RESULTS: Alzheimer's disease is often associated with circadian rhythm disorders, chronic insomnia, and sleep apnea-hypopnea syndrome. Alpha-synucleinopathies (e.g., Parkinson's disease and Lewy body dementia) are often associated with a rapid eye movement sleep behavior disorder, restless legs syndrome, chronic insomnia, and sleep apnea-hypopnea syndrome. A focused history allows to diagnose most sleep disorders. Clinicians should ensure to gather the following information in all patients with a neurocognitive disorder: (1) the presence of difficulties falling asleep or staying asleep, (2) the impact of sleep disturbances on daily functioning (fatigue, sleepiness and other daytime consequences), and (3) abnormal movements in sleep. Sleep diaries and questionnaires can assist clinicians in screening for specific sleep disorders. Polysomnography is recommended if a rapid eye movement sleep behavior disorder or a sleep apnea-hypopnea syndrome are suspected. Sleep complaints should prompt clinicians to ensure that comorbidities interfering with sleep are properly managed. The main treatment for moderate to severe obstructive sleep apnea-hypopnea syndrome remains continuous positive airway pressure, as its efficacy has been demonstrated in patients with neurocognitive disorders. Medications should also be reviewed, and time of administration should be optimized (diuretics and stimulating medications in the morning, sedating medications in the evening). Importantly, cholinesterase inhibitors (especially donepezil) may trigger insomnia. Switching to morning dosing or to an alternative drug may help. Cognitive-behavioral therapy for insomnia is indicated to treat chronic insomnia in neurocognitive disorders. False beliefs regarding sleep should be addressed with the patient and their caregiver. The sleep environment should be optimized (decrease light exposure at night, minimize noise, avoid taking vital signs, etc.). Sleep restriction can be considered as patients with a neurocognitive disorder often spend too much time in bed. The need for naps should be assessed case by case as naps may contribute to insomnia in some patients but allow others to complete their diurnal activities. Trazodone (50mg) may also be used under certain circumstances in chronic insomnia. Recent evidence does not support a role for exogenous melatonin in patients with a neucognitive disorder and insomnia. Patients in long-term care facilities are often deprived of an adequate diurnal exposure to light. Increasing daytime exposure to light may improve sleep and mood. Patients with circadian rhythm disorders can also benefit from light therapy (morning bright light therapy in case of phase delay and evening bright light therapy in case of phase advance). Rapid eye movement sleep behavior disorder can lead to violent behaviors, and the sleeping environment should be secured (e.g., mattress on the floor, remove surrounding objects). Medication exacerbating this disorder should be stopped if possible. High dose melatonin (6 to 18mg) or low dose clonazepam (0.125-0.25mg) at bedtime may be used to reduce symptoms. Melatonin is preferred in first-line as it is generally well tolerated with few side effects. Patients with restless legs syndrome should be investigated for iron deficiency. Medication decreasing dopaminergic activity should be reduced or stopped if possible. Behavioral strategies such as exercise and leg massages may be beneficial. Low-dose dopamine agonists (such as pramipexole 0.125mg two hours before bedtime) can be used to treat the condition, but a prolonged treatment may paradoxically worsen the symptoms. Alpha-2-delta calcium channel ligands can also be used while monitoring for the risk of falls. CONCLUSION: Multiple and sustained nonpharmacological approaches are recommended for the treatment of sleep disturbances in patients with neurocognitive disorder. Pharmacological indications remain limited, and further randomized clinical trials integrating a multimodal approach are warranted to evaluate the treatment of sleep disorders in specific neurocognitive disorders.

A school-based health and mindfulness curriculum improves children's objectively measured sleep: a prospective observational cohort study.

STUDY OBJECTIVES: Poor sleep impedes children's cognitive, emotional, and psychosocial development. Pediatric sleep dysregulation is common, and children who live in communities of low socioeconomic status experience additional risk factors for short sleep duration and poor sleep quality. School-based training in mindfulness and yoga-informed practices can improve children's behavior and well-being, but effects on objectively measured sleep are unknown. METHODS: Effects of a school-based health and mindfulness curriculum, which taught practices such as paced breathing, on sleep and stress were examined in 115 children (49 girls, ages 8 to 11 at baseline). Fifty-eight children in a community of low socioeconomic status received the curriculum twice weekly for 2 years. Fifty-seven children in a socioeconomic status-matched community engaged in their usual physical education class instead. In-home ambulatory polysomnography and perceived social stress were measured in all children at 3 time points: at baseline (ie, prior to curriculum exposure) and at 2 yearly follow-ups. RESULTS: Children receiving the curriculum gained an average of 74 minutes of total sleep time, and 24 minutes of rapid eye movement sleep, per night over the 2-year study period. Children not receiving the curriculum experienced a decrease in total sleep time averaging 64 minutes per night, with no changes in rapid eye movement sleep. Sleep improved within the first 3 months of curriculum exposure, in a dose-dependent fashion. Higher curriculum engagement (eg, using the breathing exercises outside of class) was associated with larger gains in total and rapid eye movement sleep duration. Aggregate within-group changes in social stress were not significant. However, among children receiving the curriculum, those who experienced larger gains in total and rapid eye movement sleep duration also experienced larger increases in perceived social stress. CONCLUSIONS: A school-based health and mindfulness curriculum improved children's objectively measured sleep over 2 years. Social stress did not mediate these effects; instead, mindfulness training may have increased awareness of environmental stressors, while developing tools to reduce stress vulnerability. CITATION: Chick CF, Singh A, Anker LA, et al. A school-based health and mindfulness curriculum improves children's objectively measured sleep: a prospective observational cohort study. J Clin Sleep Med. 2022;18(9):2261-2271.

Effective Treatment of Adult Parasomnias with Keishikaryukotsuboreito in Four Cases.

Parasomnias are undesirable behaviors or experiences during sleep that manifest clinically as abnormal behavior, emotions, and nightmares. We herein report four elderly parasomnia patients who were successfully treated for abnormal nocturnal behaviors, including rapid eye movement (REM) sleep behavior disorders, with Keishikaryukotsuboreito (KRB), a Japanese traditional herbal medicine. KRB resolved nocturnal violent behaviors and sleep walking without any adverse effects. In one patient, occipital dominant spike-wave complexes induced by 3-Hz photic stimulation were reduced after KRB treatment, suggesting that KRB has inhibitory effects on brain irritability. KRB may represent a safe therapeutic option for treating parasomnias in the elderly.

Current Treatment Options for REM Sleep Behaviour Disorder.

The symptomatic treatment of REM sleep behaviour disorder (RBD) is very important to prevent sleep-related falls and/or injuries. Though clonazepam and melatonin are usually considered the first-line symptomatic therapy for RBD, their efficiency has not been proven by randomized clinical trials. The role of dopamine agonists in improving RBD symptoms is controversial, and rivastigmine, memantine, 5-hydroxytryptophan, and the herbal medicine yokukansan have shown some degree of efficacy in short- and medium-term randomized clinical trials involving a low number of patients. The development of potential preventive therapies against the phenoconversion of isolated RBD to synucleinopathies should be another important aim of RBD therapy. The design of long-term, multicentre, randomized, placebo-controlled clinical trials involving a large number of patients diagnosed with isolated RBD with polysomnographic confirmation, directed towards both symptomatic and preventive therapy for RBD, is warranted.

Neurobiology of cataplexy.

Cataplexy is the pathognomonic and the most striking symptom of narcolepsy. It has originally been, and still is now, widely considered as an abnormal manifestation of rapid eye movement (REM) sleep during wakefulness due to the typical muscle atonia. The neurocircuits of cataplexy, originally confined to the brainstem as those of REM sleep atonia, now include the hypothalamus, dorsal raphe (DR), amygdala and frontal cortex, and its neurochemistry originally focused on catecholamines and acetylcholine now extend to hypocretin (HCRT) and other neuromodulators. Here, we review the neuroanatomy and neurochemistry of cataplexy and propose that cataplexy is a distinct brain state that, despite similarities with REM sleep, involves cataplexy-specific features.

Sleep disorders and the hypothalamus.

As early as the 1920s, pathological studies of encephalitis lethargica allowed Von Economo to correctly identify hypothalamic damage as crucial for the profound associated sleep-related symptoms that helped define the condition. Only over the last 3 decades, however, has the key role of the hypothalamus in sleep-wake regulation become increasingly recognized. As a consequence, a close relation between abnormal sleep symptomatology and hypothalamic pathology is now widely accepted for a variety of medical disorders. Narcolepsy is discussed in some detail as the cardinal primary sleep disorder that is caused directly and specifically by hypothalamic pathology, most notably destruction of hypocretin (orexin)-containing neurons. Thereafter, various conditions are described that most likely result from hypothalamic damage, in part at least, producing a clinical picture resembling (symptomatic) narcolepsy. Kleine-Levin syndrome is a rare primary sleep disorder with intermittent symptoms, highly suggestive of hypothalamic involvement but probably reflecting a wider pathophysiology. ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) and Prader-Willi syndrome are also covered as hypothalamic syndromes with prominent sleep-related symptoms. Finally, sleep issues in several endocrine disorders are briefly discussed.

Nightmare Disorder and Isolated Sleep Paralysis.

Nightmare disorder and recurrent isolated sleep paralysis are rapid eye movement (REM) parasomnias that cause significant distress to those who suffer from them. Nightmare disorder can cause insomnia due to fear of falling asleep through dread of nightmare occurrence. Hyperarousal and impaired fear extinction are involved in nightmare generation, as well as brain areas involved in emotion regulation. Nightmare disorder is particularly frequent in psychiatric disorders and posttraumatic stress disorder. Nonmedication treatment, in particular imagery rehearsal therapy, is especially effective. Isolated sleep paralysis is experienced at least once by up to 40% of the general population, whereas recurrence is less frequent. Isolated sleep paralysis can be accompanied by very intense and vivid hallucinations. Sleep paralysis represents a dissociated state, with persistence of REM atonia into wakefulness. Variations in circadian rhythm genes might be involved in their pathogenesis. Predisposing factors include sleep deprivation, irregular sleep-wake schedules, and jetlag. The most effective therapy consists of avoiding those factors.

Melatonin (MEL) and its use in neurological diseases and insomnia: Recommendations of the French Medical and Research Sleep Society (SFRMS).

The French Medicine and Research Sleep Society had organized a consensus conference about sleep/wake circadian rhythms and their disorders. During this conference a subgroup of 11 sleep doctors/researchers looked specifically at the use of MEL in different pathologies. This article gives a summary of the main results of MEL therapy in some neurological diseases and insomnia approved by this consensus group. Exogenous MEL, which crosses the blood-brain barrier, has been used as a treatment in its two available forms: an immediate release form that principally shows a chronobiotic action and a long release form that mimics the physiological MEL secretion rhythm and is used to replace reduced physiological secretion. MEL secretion decreases frequently with age, mostly in elderly insomniacs and dementia patients. Results of level A studies show that MEL therapy, used as an add-on treatment, has beneficial effects in mild cognitive impairment (MCI) and Alzheimer patients with sleep disorders in improving sleep quality and in regulating the sleep/wake rhythm. MEL has to be prescribed as early as possible and for a long period, at a dose of 2 to 5 or 10 mg. It may have a beneficial effect on cognitive function in MCI but shows no effect in moderate to severe Alzheimer's disease. It should be emphasized that there are no serious side effects with MEL treatment. In these diseases, light therapy used 12 hours before melatonin treatment has a positive synergic effect. In REM sleep behavior disorder, immediate release MEL should be prescribed first as its side effect profile is much better than clonazepam shortly before bedtime. MEL has a good efficacy on clinical symptoms and PSG REM sleep without atonia episodes and is well tolerated. In Parkinson disease with sleep disorders and without REM sleep behavior disorder, MEL seems to improve subjective sleep quality but no conclusions can be drawn. There is insufficient scientific proof for using MEL as a prophylactic treatment in primary headache, migraine and cluster headache. In epileptic patients, MEL can be safely used to regulate the sleep/wake rhythm and to improve insomnia but more randomized controlled studies are necessary. In primary or no-comorbid insomnia, only a 2 mg dose of slow release MEL, 1 to 2 hours before bedtime, over a period of 3 to 12 weeks, is recommended. It decreases sleep onset latency, improves quality of sleep, morning alertness and quality of life without serious side effects and without withdrawal symptoms.

Enhancing innate immunity against virus in times of COVID-19: Trying to untangle facts from fictions.

INTRODUCTION: In light of the current COVID-19 pandemic, during which the world is confronted with a new, highly contagious virus that suppresses innate immunity as one of its initial virulence mechanisms, thus escaping from first-line human defense mechanisms, enhancing innate immunity seems a good preventive strategy. METHODS: Without the intention to write an official systematic review, but more to give an overview of possible strategies, in this review article we discuss several interventions that might stimulate innate immunity and thus our defense against (viral) respiratory tract infections. Some of these interventions can also stimulate the adaptive T- and B-cell responses, but our main focus is on the innate part of immunity. We divide the reviewed interventions into: 1) lifestyle related (exercise, >7 h sleep, forest walking, meditation/mindfulness, vitamin supplementation); 2) Non-specific immune stimulants (letting fever advance, bacterial vaccines, probiotics, dialyzable leukocyte extract, pidotimod), and 3) specific vaccines with heterologous effect (BCG vaccine, mumps-measles-rubeola vaccine, etc). RESULTS: For each of these interventions we briefly comment on their definition, possible mechanisms and evidence of clinical efficacy or lack of it, especially focusing on respiratory tract infections, viral infections, and eventually a reduced mortality in severe respiratory infections in the intensive care unit. At the end, a summary table demonstrates the best trials supporting (or not) clinical evidence. CONCLUSION: Several interventions have some degree of evidence for enhancing the innate immune response and thus conveying possible benefit, but specific trials in COVID-19 should be conducted to support solid recommendations.

A Preliminary Trial in the Efficacy of Yokukansankachimpihange on REM Sleep Behavior Disorder in Dementia With Lewy Bodies.

Background: Clonazepam (CNZP) is effective in ~90% of patients with rapid eye movement sleep behavior disorder (RBD) but has risks of oversedation, muscular relaxation, and adverse effects on cognitive function when used to treat RBD associated with dementia with Lewy bodies (DLB). Yokukansankachimpihange (YKSCH), a traditional herbal medicine, decreases sleep latency and increases sleep stage 2, like benzodiazepines (BZPs), but does not cause adverse events such as oversedation, muscular relaxation, and adverse effects on cognitive function. Given these pharmacological properties, YKSCH was studied as a potential alternative to CNZP. Methods: Of patients who were diagnosed with DLB according to the criteria for the clinical diagnosis of DLB established by the Consortium on Dementia with Lewy Bodies (CDLB) in 2017, 13 consecutive patients with the cutoff score (5 points) or more in a REM sleep behavior disorder screening questionnaire and polysomnographic evidence of REM without atonia were observed using the Neuropsychiatric Inventory (NPI) night-time behavior disturbance, visual analog scale (VAS) frequency, and VAS severity as the co-primary endpoints. Data from 11 patients who completed the study were statistically analyzed. Results: Statistically significant improvements were observed in the NPI night-time behavior disturbance, VAS frequency, and VAS severity. No notable adverse events were reported. Conclusion: The results indicated that YKSCH, which does not cause oversedation, muscular relaxation, or adverse effects on cognitive function, may provide a new therapeutic option for RBD associated with DLB as an alternative to CNZP.

A Role for Astroglial Calcium in Mammalian Sleep and Sleep Regulation.

Mammalian sleep expression and regulation have historically been thought to reflect the activity of neurons. Changes in other brain cells (glia) across the sleep-wake cycle and their role in sleep regulation are comparatively unexplored. We show that sleep and wakefulness are accompanied by state-dependent changes in astroglial activity. Using a miniature microscope in freely behaving mice and a two-photon microscope in head-fixed, unanesthetized mice, we show that astroglial calcium signals are highest in wake and lowest in sleep and are most pronounced in astroglial processes. We also find that astroglial calcium signals during non-rapid eye movement sleep change in proportion to sleep need. In contrast to neurons, astrocytes become less synchronized during non-rapid eye movement sleep after sleep deprivation at the network and single-cell level. Finally, we show that conditionally reducing intracellular calcium in astrocytes impairs the homeostatic response to sleep deprivation. Thus, astroglial calcium activity changes dynamically across vigilance states, is proportional to sleep need, and is a component of the sleep homeostat.

Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder - A PET study.

INTRODUCTION: Noradrenergic denervation is thought to aggravate motor dysfunction in Parkinson's disease (PD). In a previous PET study with the norepinephrine transporter (NART) ligand 11C-MeNER, we detected reduced NART binding in primary sensorimotor cortex (M1S1) of PD patients. Idiopathic rapid-eye-movement sleep behaviour disorder (iRBD) is a phenotype of prodromal PD. Using 11C-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether 11C-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with 18F-DOPA PET were correlated. METHODS: 17 iRBD patients, 16 PD patients with (PDRBD+) and 14 without RBD (PDRBD-), and 25 control subjects underwent 11C-MeNER PET. iRBD patients also had 18F-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed. RESULTS: Partial-volume corrected 11C-MeNER binding potential (BPND) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PDRBD+ groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PDRBD+P = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 11C-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal 18F-DOPA uptake and thalamic 11C-MeNER binding in iRBD patients (r2 = 0.343, P = 0.013). CONCLUSIONS: This study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 11C-MeNER binding in iRBD may represent noradrenergic terminal degeneration or physiological down-regulation of NARTs in this prodromal phenotype of PD. The correlation between thalamic 11C-MeNER binding and putaminal 18F-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD.

Altered resting-state thalamo-occipital functional connectivity is associated with cognition in isolated rapid eye movement sleep behavior disorder.

OBJECTIVE: Isolated rapid eye movement sleep behavior disorder (iRBD) patients are at risk of cognitive impairments, however the underlying mechanism is still unclear. This study aimed to evaluate thalamo-cortical functional connectivity (FC) using resting-state functional magnetic resonance imaging (fMRI) and its correlation with cognitive dysfunction in patients with iRBD. METHODS: A total 37 polysomnographies (PSGs) confirmed iRBD patients and 15 age-sex matched controls underwent resting-state fMRI and comprehensive neuropsychological assessment. Thalamo-cortical FC was evaluated by using seed-to voxel analysis and was compared between the iRBD and controls. Correlation between the average value of significant clusters and cognitive function scores in iRBD were calculated. RESULTS: Compared to the control subjects, patients with iRBD patients showed cognitive decline in word list recognition (p = 0.016), and constructional recall (p = 0.044). The FC analysis showed increased FC between the left thalamus and occipital regions including the right cuneal cortex, left fusiform gyrus and lingual gyrus (cluster level p < 0.05, corrected for false discovery rate). The averaged thalamo-fusiform FC value positively correlated with word list recognition after adjusting for age and sex (adjusted r = 0.347, p = 0.041). CONCLUSION: Thalamic resting state FC is altered in iRBD patients and is associated with the cognitive function. Enhancement of the thalamo-occipital FC may reflect a compensatory mechanism for cognitive impairment in iRBD.