Neurophysiological Aspects of REM Sleep Behavior Disorder (RBD): A Narrative Review

REM sleep without atonia (RSWA) is the polysomnographic (PSG) hallmark of rapid eye movement (REM) sleep behavior disorder (RBD), a feature essential for the diagnosis of this condition. Several additional neurophysiological aspects of this complex disorder have also recently been investigated in depth, which constitute the focus of this narrative review, together with RSWA. First, we describe the complex neural network underlying REM sleep and its muscle atonia, focusing on the disordered mechanisms leading to RSWA. RSWA is then described in terms of its polysomnographic features, and the methods (visual and automatic) currently available for its scoring and quantification are exposed and discussed. Subsequently, more recent and advanced neurophysiological features of RBD are described, such as electroencephalography during wakefulness and sleep, transcranial magnetic stimulation, and vestibular evoked myogenic potentials. The role of the assessment of neurophysiological features in the study of RBD is then carefully discussed, highlighting their usefulness and sensitivity in detecting neurodegeneration in the early or prodromal stages of RBD, as well as their relationship with other proposed biomarkers for the diagnosis, prognosis, and monitoring of this condition. Finally, a future research agenda is proposed to help clarify the many still unclear aspects of RBD.

Can Corticomuscular Coherence Differentiate between REM Sleep Behavior Disorder with or without Parkinsonism?

REM sleep behavior disorder (RBD) could be a predictor of Parkinsonism even before development of typical motor symptoms. This study aims to characterize clinical features and corticomuscular and corticocortical coherence (CMC and CCC, respectively) during sleep in RBD patients with or without Parkinsonism. We enrolled a total of 105 subjects, including 20 controls, 54 iRBD, and 31 RBD+P patients, patients who were diagnosed as idiopathic RBD (iRBD) and RBD with Parkinsonism (RBD+P) in our neurology department. We analyzed muscle atonia index (MAI) and CMC between EEG and chin/limb muscle electromyography (EMG) and CCC during different sleep stages. Although differences in the CMC of iRBD group were observed only during REM sleep, MAI differences between groups were noted during both REM and NREM N2 stage sleep. During REM sleep, CMC was higher and MAI was reduced in iRBD patients compared to controls (p = 0.001, p < 0.001, respectively). Interestingly, MAI was more reduced in RBD+P compared to iRBD patients. In comparison, CCC was higher in iRBD patients compared to controls whereas CCC was lower in RBD+P groups compared to control and iRBD groups in various frequency bands during both NREM N2 and REM sleep stages. Among them, increased CMC during REM sleep revealed correlation between clinical severities of RBD symptoms. Our findings indicate that MAI, CMC, and CCC showed distinctive features in iRBD and RBD+P patients compared to controls, suggesting potential usefulness to understand possible links between these diseases.

006 The effect of sodium oxybate on cataplexy in orexin knockout mice

Introduction Narcolepsy is a neurological disorder that is characterized by the loss of orexin neurons in the lateral hypothalamus. Cataplexy is a symptom of narcolepsy and is identified by a sudden loss of muscle tone during wakefulness. Cataplexy abruptly interrupts day-to-day activities, and makes activities like driving dangerous and potentially fatal. It is hypothesized that cataplexy occurs due to the intrusion of REM sleep muscle atonia during wakefulness. It has been demonstrated that a GABAergic mechanism is responsible for silencing the REM sleep atonia circuit and preventing REM sleep muscle atonia from occurring during wakefulness. Sodium oxybate (SXB), a low affinity agonist of GABAB receptors, is currently an approved treatment for narcolepsy; however, its mechanism of action in the brain remains unknown. Here, we investigate the hypothesis that SXB prevents cataplexy through a GABAB mediated mechanism by potentially suppressing the REM sleep atonia circuit. Methods We intraperitoneally (IP) injected orexin-/- mice with one of five treatments; either Lactated Ringers Solution, SXB at 50, 100, or 200 mg/kg, or Phaclophen at 10 mg/kg followed by SXB at 100 mg/kg. Cataplexy was assessed by video recordings. We gathered and analyzed data at three distinct chronological time points (i.e, at baseline, after three consecutive weeks of daily dosing with a treatment, and after one week of no treatment). These experiments were designed and conducted to determine whether; 1) SXB reduces cataplexy, 2) the cessation of SXB administration has an effect on cataplexy, 3) SXB is mediated through a GABAB mechanism. Results We first confirmed that mice used were indeed orexin-/- using immunohistochemical analysis to show that no orexin-a expressing neurons were located in the lateral hypothalamus. Then, we determined that: 1) SXB reduces cataplexy compared to time matched controls (unpaired t-test, p=0.0027, n=18); 2) When we stopped administering SXB IP injections, cataplexy levels increased towards control levels (paired t-test, p=0.0024, n=18); 3) it remains unclear if SXB’s effect is solely mediated through a GABAB mechanism. Conclusion Our findings demonstrate that SXB effectively reduces cataplexy in orexin-/- mice. Support (if any) This research was funded by Jazz Pharmaceuticals

Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep

SUMMARYThe preoptic hypothalamus regulates both NREM and REM sleep. We found that calcium levels in mouse lateral preoptic (LPO) neurons were highest during REM. Deleting the core GluN1 subunit of NMDA receptors from LPO neurons abolished calcium signals during all vigilance states, and the excitatory drive onto LPO neurons was reduced. Mice had less NREM sleep and were incapable of generating conventionally classified REM sleep episodes: cortical theta oscillations were greatly reduced but muscle atonia was maintained. Additionally, mice lacking NMDA receptors in LPO neurons had highly fragmented sleep-wake patterns. The fragmentation persisted even under high sleep pressure produced by sleep deprivation. Nevertheless, the sleep homeostasis process remained intact, with an increase in EEG delta power. The sedative dexmedetomidine and sleeping medication zolpidem could transiently restore consolidated sleep. High sleep-wake fragmentation, but not sleep loss, was also produced by selective GluN1 knock-down in GABAergic LPO neurons. We suggest that NMDA glutamate receptor signalling stabilizes the firing of “GABAergic NREM sleep-on” neurons and is also essential for the theta rhythm in REM sleep.

Orexin signaling modulates synchronized excitation in the sublaterodorsal tegmental nucleus to stabilize REM sleep

The relationship between orexin/hypocretin and rapid eye movement (REM) sleep remains elusive. Here, we find that a proportion of orexin neurons project to the sublaterodorsal tegmental nucleus (SLD) and exhibit REM sleep-related activation. In SLD, orexin directly excites orexin receptor-positive neurons (occupying ~3/4 of total-population) and increases gap junction conductance among neurons. Their interaction spreads the orexin-elicited partial-excitation to activate SLD network globally. Besides, the activated SLD network exhibits increased probability of synchronized firings. This synchronized excitation promotes the correspondence between SLD and its downstream target to enhance SLD output. Using optogenetics and fiber-photometry, we consequently find that orexin-enhanced SLD output prolongs REM sleep episodes through consolidating brain state activation/muscle tone inhibition. After chemogenetic silencing of SLD orexin signaling, a ~17% reduction of REM sleep amounts and disruptions of REM sleep muscle atonia are observed. These findings reveal a stabilization role of orexin in REM sleep.

1266 Primary Central apnea and loss of muscle atonia during REM

Introduction Central sleep apnea (CSA) syndrome is defined when five or more central apneas and/or hypopneas are present per hour of sleep, more than 50% of all respiratory events. CSA usually occur during NREM stage and rarely during REM. CSA is important to recognize because of complications ranging from frequent nighttime awakenings,sleepiness to adverse cardiovascular outcomes. We present a 40 year old female patient with rare CSA during REM sleep and dream enactment. Report of Case 40yo African American female with history of loud snoring, witnessed sleep apnea, and daytime fatigue. She reported nightmares, sleep talking, and acting out her dreams without injury. Epworth sleepiness score was 5 /24. Her past medical history is significant for depression and anxiety. She has no history of head trauma, no neurologic or cardiovascular disorders. Her medications include fluoxetine and,quetiapine. She denied substance use, narcotic use, or alcohol use. Her level 1 sleep study showed predominantly REM-associated central sleep apneas which is rare. She also was observed to have loss of REM sleep muscle atonia suggestive of REM Behavior disorder. Her sleep architecture was atypical with decreased N3 sleep stage. REM sleep duration was adequate. She was noted to have loss of REM muscle atonia based on AASM guidelins elevated chin EMG, excessive transient muscle activity, and witnessed movement during REM stage via video monitoring. During the study, she had an apnea/hypopnea index (AHI) of 13.1 per hour of sleep, Central apneas were predominantly noted during REM stage, 10 per hour, comprised of 50% of her respiratory events. The minimum SpO2 value with CSA was 94%. She had normal sinus rhythm. Her sleep was fragmented. A total arousals were 28.4/hour,and 7.9/hour were respiratory arousals, and the rest were spontaneous arousals. An echocardiogram showed normal left ventricular ejection fraction of 55 to 60 %. Her room air arterial blood gas was normal with PaC02 of 37 mmHg. MRI of the brain/brainstem was ordered given her atypical REM sleep. She had no acute intracranial abnormalities. There is a non specific finding of a low lying cerebellar tonsils without evidence of Chiari I malformation. Conclusion Our patient has rare idiopathic central apnea in REM stage and is third case reported. She also has loss of muscle atonia during REM with dream enactment which is also rare in her age group. Injury precaution advised.

Case Report: Rapid Eye Movement Sleep Behavior Disorder as the First Manifestation of Multiple Sclerosis

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by brief recurrent episodes of loss of muscle atonia during rapid eye movement sleep, with enacted dreams that cause sleep disruption. Patients with multiple sclerosis (MS) have an increased risk compared with the general population to be affected by a sleep disturbance, including RBD. Patients affected, however, uncommonly can present RBD as the first clinical manifestation of MS without other neurologic deficits. These clinical presentations have usually been attributed to inflammatory lesions in the pedunculopontine nuclei, located in the dorsal pons. We present a case of RBD in a 38-year-old woman who was later diagnosed as having MS due to imaging findings and development of focal neurologic deficits. MS should be considered among the differential diagnoses in patients who present with symptoms of RBD, particularly if they are young and female.