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.

0005 Cataplexy Triggered by Social Cues: A Role for Oxytocin in the Amygdala

Introduction People with narcolepsy type 1 report that cataplexy is triggered most often by positive social experiences such as laughing with friends, yet the mechanisms through which social interaction promotes cataplexy are unknown. We hypothesize a subpopulation of central amygdala neurons that are sensitive to the prosocial neuropeptide, oxytocin (CeAOTR), respond to positive valence and trigger cataplexy. Methods We have used in vivo calcium imaging, chemogenetic and optogenetic approaches to characterize the activity pattern of these neurons and to manipulate their activity state. Results Cre-dependent anterograde tracing of the CeAOTR neurons of the central amygdala indicate a moderate to dense projection to the REM sleep-regulatory region of the ventral lateral periaqueductal gray (vlPAG). Additionally, Channel Rhodopsin Assisted Circuit Mapping (CRACM) experiments show that CeAOTR neurons inhibit vlPAG neurons that innervate the REM atonia-promoting region, the sublaterodorsal nucleus. Targeted photostimulation (15Hz (10ms) for 20sec every hour) of the CeAOTR fibers in the vlPAG doubled the amount of cataplexy. Preliminary in vivo calcium imaging indicates that the CeAOTR are active just prior to the onset of cataplexy. Chemogenetic and optogenetic activation of CeAOTR neurons increased cataplexy. Conclusion We conclude that the CeAOTR subpopulation is sufficient to promote cataplexy. Our future directions include determining the necessity of these oxytocin sensitive neurons in cataplexy under different conditions of positive valence. Support R01 NS106032 and WakeUp Narcolepsy.

REM sleep atonia loss distinguishes synucleinopathy in older adults with cognitive impairment

ObjectiveTo determine whether quantitative polysomnographic REM sleep without atonia (RSWA) distinguishes between cognitive impairment phenotypes.BackgroundNeurodegenerative cognitive impairment in older adults predominantly correlates with tauopathy or synucleinopathy. Accurate antemortem phenotypic diagnosis has important prognostic and treatment implications; additional clinical tools might distinguish between dementia syndromes.MethodsWe quantitatively analyzed RSWA in 61 older adults who underwent polysomnography including 46 with cognitive impairment (20 probable synucleinopathy), 26 probable non-synucleinopathy (15 probable Alzheimer disease, 11 frontotemporal lobar dementia), and 15 age- and sex-matched controls. Submentalis and anterior tibialis RSWA metrics and automated REM atonia index were calculated. Group statistical comparisons and regression were performed, and receiver operating characteristic curves determined diagnostic RSWA thresholds that best distinguished synucleinopathy phenotype.ResultsSubmentalis—but not anterior tibialis RSWA—was greater in synucleinopathy than nonsynucleinopathy; several RSWA diagnostic thresholds distinguished synucleinopathy with excellent specificity including submentalis tonic, 5.6% (area under the curve [AUC] 0.791); submentalis any, 15.0% (AUC 0.871); submentalis phasic, 10.8% (AUC 0.863); and anterior tibialis phasic, 31.4% (AUC 0.694). In the subset of patients without dream enactment behaviors, submentalis RSWA was also greater in patients with synucleinopathy than in those without synucleinopathy. RSWA was detected more frequently by quantitative than qualitative methods (p = 0.0001).ConclusionElevated submentalis RSWA distinguishes probable synucleinopathy from probable nonsynucleinopathy in cognitively impaired older adults, even in the absence of clinical dream enactment symptoms.Classification of evidenceThis study provides Class III evidence that quantitative RSWA analysis is useful for distinguishing cognitive impairment phenotypes. Further studies with pathologic confirmation of dementia diagnoses are needed to confirm the diagnostic utility of RSWA in dementia.

Normative and isolated rapid eye movement sleep without atonia in adults without REM sleep behavior disorder

Study Objectives Values for normative REM sleep without atonia (RSWA) remain unclear. Older age and male sex are associated with greater RSWA, and isolated elevated RSWA has been reported. We aimed to describe normative RSWA and characterize isolated RSWA frequency in adults without REM sleep behavior disorder (RBD). Methods We visually quantified phasic, “any,” and tonic RSWA in the submentalis (SM) and anterior tibialis (AT) muscles, and the automated Ferri REM Atonia Index during polysomnography in adults without RBD aged 21–88. We calculated RSWA percentiles across age and sex deciles and compared RSWA in older (≥ 65) versus younger (<65) men and women. Isolated RSWA (exceeding diagnostic RBD cutoffs, or >95th percentile) frequency was also determined. Results Overall, 95th percentile RSWA percentages were SM phasic, any, tonic = 8.6%, 9.1%, 0.99%; AT phasic and “any” = 17.0%; combined SM/AT phasic, “any” = 22.3%, 25.5%; and RAI = 0.85. Most phasic RSWA burst durations were ≤1.0 s (85th percentiles: SM = 1.07, AT = 0.86 seconds). Older men had significantly higher AT RSWA than older women and younger patients (all p < 0.04). Twenty-nine (25%, 18 men) had RSWA exceeding the cohort 95th percentile, while 17 (14%, 12 men) fulfilled diagnostic cutoffs for phasic or automated RBD RSWA thresholds. Conclusions RSWA levels are highest in older men, mirroring the demographic characteristics of RBD, suggesting that older men frequently have altered REM sleep atonia control. These data establish normative adult RSWA values and thresholds for determination of isolated RSWA elevation, potentially aiding RBD diagnosis and discussions concerning incidental RSWA in clinical sleep medicine practice.

REM sleep muscle activity in idiopathic REM sleep behavior disorder predicts phenoconversion

ObjectiveTo determine whether REM sleep without atonia (RSWA) during polysomnography (PSG) predicts phenoconversion in patients with idiopathic REM sleep behavior disorder (iRBD), a prodromal feature of a neurodegenerative disease.MethodsWe analyzed RSWA in 60 patients with iRBD, including manual phasic, tonic, and any muscle activity in the submentalis and anterior tibialis muscles and the automated REM atonia index in the submentals. We identified patients who developed parkinsonism or mild cognitive impairment (MCI) during at least 3 years of follow-up after PSG. Kaplan-Meier analysis was performed and receiver operator curves were calculated to determine RSWA cutoffs predicting faster phenoconversion.ResultsTwenty-six (43%) patients developed parkinsonism (n = 17) or MCI (n = 9). Phenoconverters were older at iRBD diagnosis (p = 0.02). Median time to phenoconversion was 3.9 ± 2.5 years. iRBD phenoconverters had significantly more RSWA at diagnosis. Phenoconversion risk from iRBD diagnosis was 20% and 35% at 3 and 5 years, respectively, with greater risk in patients with iRBD with >46.4% any combined RSWA, which increased further to 30% and 55% at 3 and 5 years for patients >65 years of age at diagnosis.ConclusionsPatients with iRBD with higher amounts of polysomnographic RSWA had a greater risk of developing Parkinson disease or MCI. Patients with older age and higher RSWA amounts had more rapid phenoconversion than younger patients with RBD. Our study suggests that RSWA is a potential biomarker for risk stratification of iRBD phenoconversion that could facilitate prognostication for patients with iRBD.Classification of evidenceThis study provides Class II evidence that for patients with iRBD, increased RSWA correlates with increased risk for developing parkinsonism or MCI.

REM sleep behavior disorder

A diagnosis of REM sleep behavior disorder (RBD), a disorder characterized by “acting out” of dreams during REM sleep, has critical implications for a patient’s future. Aside from being a treatable parasomnia, usually managed with melatonin or clonazepam, RBD is the most powerful risk factor for Parkinson disease and dementia with Lewy bodies yet discovered. Over 70% of patients with idiopathic RBD will develop a neurodegenerative synucleinopathy. Moreover, the disease course is more severe in patients with RBD than those without. Numerous screens have been developed to aid detection, and clinical history can help distinguish RBD from NREM parasomnia. However, final diagnosis relies on polysomnographic documentation of REM atonia loss. Given the profound implications of idiopathic RBD, patients need careful counseling and the offer of neurological follow-up to detect and treat prodromal disease symptoms. Recognition of RBD is also a means to discover and test protective therapies against neurodegenerative disease.