REM Sleep Activity Research Articles

Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.

Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.

Incidental Detection of Anti-IgLON5: A Diagnostic and Therapeutic Dilemma (P5-5.021)

<h3>Objective:</h3> To report a patient in whom anti-IgLON5 was incidentally detected as part of work-up for possible autoimmune-associated epilepsy. <h3>Background:</h3> Anti-IgLON5 disease has recently been characterized. Core manifestations include sleep disturbances, bulbar dysfunction, gait instability, chorea and cognitive decline, while seizures are not typical. Response to immunotherapy is usually suboptimal and prognosis is frequently poor, although early treatment could improve outcomes. <h3>Design/Methods:</h3> Case report. <h3>Results:</h3> A 49-year-old woman had an 18-year-history of temporal lobe epilepsy that developed after cervical cancer. Brain MRI was unremarkable but EEG showed right temporal epileptiform discharges and PET showed right temporal hypometabolism, compatible with right temporal seizure origin. Due to seizure refractoriness and history of cancer, comprehensive neural antibody testing for possible autoimmune-associated epilepsy was pursued and revealed anti-IgLON5 in serum and cerebrospinal fluid. On directed history, the patient reported snoring and insomnia that had developed two years prior, which were symptoms she had not initially volunteered because she felt they were mild and stable. Neurologic examination was unremarkable. The patient received a six-week trial of corticosteroids, without improvement in seizure frequency or sleep disturbances. Polysomnography revealed minimal sleep disordered breathing, mild arousals from slow wave sleep, unusually prominent beta activity in REM sleep, and excessive fragmentary myoclonus, which may represent early anti-IgLON5 disease. <h3>Conclusions:</h3> Diagnostically, we hypothesize that anti-IgLON5 is unrelated to chronic temporal lobe epilepsy in our patient, which we suspect is idiopathic. However, this antibody may explain sleep findings, and the mildness of her symptoms referable to anti-IgLON5 disease creates a unique therapeutic dilemma. In discussion with the patient, we have opted to monitor clinically and with polysomnography, and to consider institution of further immunotherapy if there is demonstrable disease progression. Future study into the natural history of anti-IgLON5 disease is needed to determine the optimal management of patients with mild symptoms. <b>Disclosure:</b> Dr. Alkabie has nothing to disclose. The institution of Dr. Murray has received research support from Wake Up Narcolepsy. Dr. Murray has received publishing royalties from a publication relating to health care. Dr. Budhram has nothing to disclose.

Disruption of hippocampal neuronal circuit function depends upon behavioral state in the APP/PS1 mouse model of Alzheimer’s disease

The Alzheimer’s disease-associated peptide amyloid-beta (Aβ) has been associated with neuronal hyperactivity under anesthesia, but clinical trials of anticonvulsants or neural system suppressors have, so far, failed to improve symptoms in AD. Using simultaneous hippocampal calcium imaging and electrophysiology in freely moving mice expressing human Aβ, here we show that Aβ aggregates perturbed neural systems in a state-dependent fashion, driving neuronal hyperactivity in exploratory behavior and slow wave sleep (SWS), yet suppressing activity in quiet wakefulness (QW) and REM sleep. In exploratory behavior and REM sleep, Aβ impaired hippocampal theta–gamma phase-amplitude coupling and altered neuronal synchronization with theta. In SWS, Aβ reduced cortical slow oscillation (SO) power, the coordination of hippocampal sharp wave-ripples with both the SO and thalamocortical spindles, and the coordination of calcium transients with the sharp wave-ripple. Physostigmine improved Aβ-associated hyperactivity in exploratory behavior and hypoactivity in QW and expanded the range of gamma that coupled with theta phase, but exacerbated hypoactivity in exploratory behavior. Together, these findings show that the effects of Aβ alone on hippocampal circuit function are profoundly state dependent and suggest a reformulation of therapeutic strategies aimed at Aβ induced hyperexcitability.

0675 Vagal Activity in REM Sleep Is Associated With Extinction Recall in Trauma Exposed Individuals but Not in Individuals With Post-Traumatic Stress Disorder

Abstract Introduction Post-traumatic stress disorder (PTSD) is characterized by impaired fear extinction memory. Sleep, and especially REM sleep, facilitates consolidation of fear extinction. Therefore, it is postulated that abnormal sleep physiology in PTSD may contribute to its persistence. Recent studies suggest that vagal activity may support the memory benefit of sleep. In addition, a separate line of studies shows reduced vagal activity during sleep in PTSD. However, the link between extinction memory and vagal activity during sleep has not been investigated in PTSD. We examined the association of extinction recall with vagal activity, measured as heart rate variability (HRV), during REM sleep, in PTSD and matched controls. Methods Participants included individuals with PTSD (n=70) and trauma exposed controls (TEC; n=69). All participants completed 3 nights of ambulatory polysomnography that included ECG. After acclimation and baseline PSG nights, fear conditioning and extinction learning were carried out in the evening after which they completed a third ("consolidation") PSG night. Extinction recall was tested 24h later. During fear conditioning, partial reinforcement with a mild electric shock produced a conditioned skin conductance response (SCR) to the image of a colored lamp, which was immediately extinguished by un-reinforced presentations in a different room. Extinction recall was indexed by the degree to which SCR remained suppressed 24h later. HRV indices were calculated using Kubios software. Results Preliminary analyses included 20 individuals with PTSD and 37 TEC participants. In the TEC group, extinction recall was significantly correlated with REM sleep HRV measures that reflect vagal activity, including high frequency (HF) absolute power (Rs=0.51, p =0.009), HF normalized units (Rs=0.54, p =0.005) and RMSSD (Rs=0.40, p =0.046). In hierarchical regression models which included extinction recall as the dependent variable, HF absolute power accounted for a significant proportion of the variance, over and above a model that included %REM sleep, %N3 sleep, REM density and average duration of REM epochs (R2=0.50, F=5.06, p=0.04). These associations were not present in the PTSD group Conclusion Our preliminary results suggest that vagal activity during REM sleep is involved in the consolidation of extinction memory and that this mechanism may be impaired in PTSD. Support (If Any) R01MH109638 K23MH119322

Journal Digest: Post-COVID Depression; Locus Coeruleus and Alzheimer’s; CY-BOCS Reliability; and More

Journal Digest: Post-COVID Depression; Locus Coeruleus and Alzheimer’s; CY-BOCS Reliability; and More

Sleep and longitudinal cognitive performance in preclinical and early symptomatic Alzheimer's disease.

Sleep monitoring may provide markers for future Alzheimer's disease; however, the relationship between sleep and cognitive function in preclinical and early symptomatic Alzheimer's disease is not well understood. Multiple studies have associated short and long sleep times with future cognitive impairment. Since sleep and the risk of Alzheimer's disease change with age, a greater understanding of how the relationship between sleep and cognition changes over time is needed. In this study, we hypothesized that longitudinal changes in cognitive function will have a non-linear relationship with total sleep time, time spent in non-REM and REM sleep, sleep efficiency and non-REM slow wave activity. To test this hypothesis, we monitored sleep-wake activity over 4-6 nights in 100 participants who underwent standardized cognitive testing longitudinally, APOE genotyping, and measurement of Alzheimer's disease biomarkers, total tau and amyloid-β42 in the CSF. To assess cognitive function, individuals completed a neuropsychological testing battery at each clinical visit that included the Free and Cued Selective Reminding test, the Logical Memory Delayed Recall assessment, the Digit Symbol Substitution test and the Mini-Mental State Examination. Performance on each of these four tests was Z-scored within the cohort and averaged to calculate a preclinical Alzheimer cognitive composite score. We estimated the effect of cross-sectional sleep parameters on longitudinal cognitive performance using generalized additive mixed effects models. Generalized additive models allow for non-parametric and non-linear model fitting and are simply generalized linear mixed effects models; however, the linear predictors are not constant values but rather a sum of spline fits. We found that longitudinal changes in cognitive function measured by the cognitive composite decreased at low and high values of total sleep time (P < 0.001), time in non-REM (P < 0.001) and REM sleep (P < 0.001), sleep efficiency (P < 0.01) and <1 Hz and 1-4.5 Hz non-REM slow wave activity (P < 0.001) even after adjusting for age, CSF total tau/amyloid-β42 ratio, APOE ε4 carrier status, years of education and sex. Cognitive function was stable over time within a middle range of total sleep time, time in non-REM and REM sleep and <1 Hz slow wave activity, suggesting that certain levels of sleep are important for maintaining cognitive function. Although longitudinal and interventional studies are needed, diagnosing and treating sleep disturbances to optimize sleep time and slow wave activity may have a stabilizing effect on cognition in preclinical or early symptomatic Alzheimer's disease.

Characterization of sleep in six patients with pantothenate kinase-associated neurodegeneration

BackgroundPantothenate kinase-associated neurodegeneration (PKAN) is a rare neurologic disorder included in the group of neurodegeneration with brain iron accumulation diseases (NBIA). Information regarding sleep in patients with PKAN is limited. ObjectivesTo describe the clinical and polysomnographic characteristics of sleep in six patients with genetically confirmed PKAN. MethodsThe evaluation included a clinical interview, sleep questionnaires -Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS)- and a video-polysomnography (VPSG). In addition to standard sleep measures we manually quantified sleep spindle density in stage N2 and rapid eye movements in REM sleep comparing the results with matched controls. Quantification of EMG activity in REM sleep was performed following standard criteria. ResultsAll the patients reported at least one sleep complaint, most commonly sleep fragmentation (4/6) and sleep onset insomnia (3/6). ESS and PSQI were abnormal in 3/6 and 4/6, respectively. VPSG showed in 4/6 decreased ocular movements during REM sleep, an increase in sleep spindles in 3/6 (all of them with deep brain pallidal stimulation), an absence of slow wave sleep in 2 and undifferentiated NREM sleep and delayed sleep phase in one. Three patients had an abnormal sleep apnea/hypopnea index, and 2 periodic limb movements of sleep. REM sleep muscular atonia was preserved in all. ConclusionsSleep disorders are common in patients with PKAN. Although our sample is small and heterogeneous, with different symptomatic treatments possibly influencing the results, it suggests that evaluation of sleep should be considered in their management.

Unaltered EEG spectral power and functional connectivity in REM microstates in frequent nightmare recallers: are nightmares really a REM parasomnia?

BackgroundFrequent nightmares show signs of hyperarousal in NREM sleep. Nevertheless, idiopathic nightmare disorder is considered a REM parasomnia, but the pathophysiology of REM sleep in relation to frequent nightmares is controversial. Cortical oscillatory activity in REM sleep is largely modulated by phasic and tonic REM periods and seems to be linked to different functions and dysfunctions of REM sleep. Here, we examined cortical activity and functional synchronization in frequent nightmare recallers and healthy controls, during phasic and tonic REM. MethodsFrequent nightmare recallers (N = 22) and healthy controls (N = 22) matched for high dream recall spent two nights in the laboratory. Phasic and tonic REM periods from the second nights' recordings were selected to examine differences in EEG spectral power and weighted phase lag index (WPLI) across groups and REM states. ResultsPhasic REM showed increased power and synchronization in delta and gamma frequency bands, whereas tonic REM featured increased power and synchronization in the alpha and beta bands. In the theta band, power was higher during tonic, and synchronization was higher during phasic REM sleep. No differences across nightmare and control participants or patterns representing interactions between the groups and REM microstates emerged. ConclusionsOur findings do not support the idea that abnormal REM sleep power and synchronization play a role in the pathophysiology of frequent nightmares. Altered REM sleep in nightmare disorder could have been confounded with comorbid pathologies and increased dream recall, or might be linked to more specific state factors (nightmare episodes).

0118 Improved Working Memory is Related to Non-REM Delta Activity in Control but Not PTSD Participants

Abstract Introduction Individuals with post-traumatic stress disorder (PTSD) experience altered sleep and daytime function, including deficits in working memory (WM), the ability to store and manipulate information over short timeframes. As sleep contributes to WM, understanding how sleep parameters influence changes in WM may provide insight into potential intervention targets to improve or restore daytime function. Here, we investigated the relationship between sleep and WM improvement in Veterans with and without PTSD. Methods Forty-eight post-911 Veterans without PTSD (Control) and 37 with PTSD (PTSD) completed a 48-hour lab stay during which WM was assessed using a n-back task. Nighttime polysomnography, using high-density (64-channels) electroencephalography, quantified time spent in non-REM and REM sleep and log-transformed spectral activity for non-REM sleep in delta (.5-4Hz), theta (4-8Hz), alpha (8-12Hz), sigma (12-16Hz), and beta (16-32Hz) bands. Pearson’s correlations were used to assess associations between baseline sleep and baseline WM on 1-back trials. Within control and PTSD groups, independent samples t-tests were used to compare changes in sleep across nights between improvers and non-improvers categorized by 1-back accuracy changes across days. Results Proportions of improvers and non-improvers were similar between groups (χ 2 = .023, p = .880). Within either group, baseline sleep did not relate to baseline WM and changes in time spent in each sleep stage did not differ between improvers and non-improvers. Within the control group, improvers (n = 15; 3.67 ± 3.56) had a greater increase (t = -2.826, p = .007) in delta activity than non-improvers (n = 33; .77 ± 3.20), but this relationship was not observed in the PTSD group (11 improvers, 26 non-improvers). Conclusion Increased delta activity related to improved WM in the Control but not PTSD group. This suggests individuals with PTSD do not improve WM through non-REM sleep but that it may be a useful intervention target. Support USAMRMC MOMRP PT-130572 (PI: Reifman)

GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice

Sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed mechanism is far from understood. Here, we found that glutamic acid decarboxylase 67-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTAGad67+ project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH). Chemogenetic activation of VTAGad67+ promoted NREM sleep with higher delta power whereas optogenetic inhibition of these induced prompt arousal from NREM sleep, even under highly somnolescent conditions, but not from REM sleep. VTAGad67+ showed the highest activity in NREM sleep and the lowest activity in REM sleep. Moreover, VTAGad67+ directly innervated and inhibited wake-promoting orexin/hypocretin neurons by releasing GABA. As such, optogenetic activation of VTAGad67+ terminals in the LH promoted NREM sleep. Taken together, we revealed that VTAGad67+ play an important role in the regulation of NREM sleep.

Dynamic Contributions of Slow Wave Sleep and REM Sleep to Cognitive Longevity.

The purpose of this paper was to address how sleep changes with aging, with the broader goal of informing how REM sleep and slow wave activity mechanisms interact to promote cognitive longevity. We conducted novel analyses based on the National Sleep Research Resource database. Over approximately five years, middle-to-older aged adults, on average, showed dramatically worse sleep fragmentation, a steady decrease in slow wave sleep, and yet a small increase in REM sleep. Averaging across participants, however, masked a major theme: Individuals differ substantially in their longitudinal trajectories for specific components of sleep. We considered this individual variability in light of recent theoretical and empirical work that has shown disrupted sleep and decreased slow wave activity to impair frontal lobe restoration, glymphatic system functioning, and memory consolidation. Based on multiple recent longitudinal studies, we contend that preserved or enhanced REM sleep may compensate for otherwise disrupted sleep in advancing age. The scientific community has often debated whether slow wave activity or REM sleep mechanisms are more important to cognitive aging. We propose that a more fruitful approach for future work will be to investigate how REM and slow wave processes dynamically interact to affect cognitive longevity.

The REM sleep circuit and how its impairment leads to REM sleep behavior disorder.

REM sleep is characterized by rapid eye movements, desynchronized electroencephalographic activity, dreams and muscle paralysis that preclude the individual from acting out the action of dreams. REM sleep is generated and modulated by a complex and still poorly understood, neuronal network that involves multiple nuclei and neurotransmission systems. The key structures that generate REM sleep muscle paralysis are the subcoeruleus nucleus in the mesopontine tegmentum and the reticular formation of the ventral medial medulla. Using glutamatergic, GABAergic and glycinergic inputs, direct and indirect projections from these two areas inhibit the motoneurons of the spinal cord resulting in skeletal paralysis in REM sleep. Experimental studies in cats and rodents where the subcoeruleus nucleus and ventral medial medulla were impaired by electrolytic, pharmacological and genetic manipulations have repeatedly produced increased electromyography activity during REM sleep associated with abnormal motor behaviors (e.g., prominent twitching, attack-like behaviors). These animal models represent the pathophysiological substrate of REM sleep behavior disorder, a parasomnia in humans characterized by nightmares and abnormal vigorous behaviors (e.g., prominent jerking, shouting, kicking) linked to excessive phasic and/or tonic electromyographic activity in REM sleep. The extraordinary observation that a sleep disorder is often the first manifestation of a devastating neurodegenerative disease such as Parkinson disease carries important diagnostic implications and opens a window for neuroprotection. This review addresses the neuronal substrates of REM sleep generation and modulation and how its impairment may lead to REM sleep behavior disorder.

Supramammillary glutamate neurons are a key node of the arousal system

Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuMvglut2) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuMvglut2 neurons. Inhibition of SuMvglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuMvglut2 neurons include a subpopulation containing both glutamate and GABA (SuMvgat/vglut2) and another also expressing nitric oxide synthase (SuMNos1/Vglut2). Activation of SuMvgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuMvgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuMNos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuMvglut2 neurons as a key node of the wake−sleep regulatory system.

Activation of the Hypoglossal to Tongue Musculature Motor Pathway by Remote Control

Reduced tongue muscle tone precipitates obstructive sleep apnea (OSA), and activation of the tongue musculature can lessen OSA. The hypoglossal motor nucleus (HMN) innervates the tongue muscles but there is no pharmacological agent currently able to selectively manipulate a channel (e.g., Kir2.4) that is highly restricted in its expression to cranial motor pools such as the HMN. To model the effect of manipulating such a restricted target, we introduced a “designer” receptor into the HMN and selectively modulated it with a “designer” drug. We used cre-dependent viral vectors (AAV8-hSyn-DIO-hM3Dq-mCherry) to transduce hypoglossal motoneurons of ChAT-Cre+ mice with hM3Dq (activating) receptors. We measured sleep and breathing in three conditions: (i) sham, (ii) after systemic administration of clozapine-N-oxide (CNO; 1 mg/kg) or (iii) vehicle. CNO activates hM3Dq receptors but is otherwise biologically inert. Systemic administration of CNO caused significant and sustained increases in tongue muscle activity in non-REM (261 ± 33% for 10 hrs) and REM sleep (217 ± 21% for 8 hrs), both P < 0.01 versus controls. Responses were specific and selective for the tongue with no effects on diaphragm or postural muscle activities, or sleep-wake states. These results support targeting a selective and restricted “druggable” target at the HMN (e.g., Kir2.4) to activate tongue motor activity during sleep.

SP 5. Poor modulation of event related local field potentials in the subthalamic nucleus during nocturnal movements in Parkinson’s patients – Are subthalamic neurons sleeping?

Introduction The modulating effect of subthalamic beta oscillations on motor control in patients with Parkinson’s disease (PD) is a well-established observation: beta oscillations are enhanced in PD, and are reduced by voluntary movements, dopaminergic treatment or deep brain stimulation (DBS). PD patients with REM sleep behavior disorder (RBD) reveal mostly unimpaired motor behavior during REM sleep, despite lack of dopaminergic treatment during the night. However, it is unknown whether normalized neuronal signaling in the subthalamic nucleus during REM sleep is linked to this phenomenon which contrasts strongly to coexistent nocturnal bradykinesia in PD. Objectives We aim at investigating the dynamic electrophysiological properties of basal ganglia motor networks during nocturnal movements in PD patients by measuring event related potentials of limb movements in both REM and non-REM sleep. Specifically, we set out to determine whether phenotypically normal REM sleep-related movements are mirrored by reduced subthalamic beta oscillations. Patients and methods After implantation of deep brain stimulation (DBS) electrodes, we recorded local field potentials in the subthalamic nucleus (STN) and scalp EEG (modified 10/20 montage) during sleep in 5 PD patients with clinically manifest REM sleep behavioral disorder (12 h recording, 8 pm–8 am). Nocturnal movements were assessed by video-EEG monitoring and EMG recordings. Time-locked event-related beta band oscillations were then calculated to assess the relative and absolute beta (de-)synchronization during movements in REM (206 events) and non-REM sleep (112 events). Results Spectral analysis of local field potentials in the STN revealed elevated beta band power during REM sleep as compared to NREM sleep and tonic beta activity in REM sleep reached levels similar as in the waking state. Despite the continuously elevated beta band activity, event related analysis showed no significant beta desynchronization prior to or during movements in REM sleep. In other words, we observed unimpaired movements in REM sleep and recorded continuously elevated beta activity in the STN. Beta band power in NREM sleep was limited to the lower beta band (13–20 Hz), whereas in REM sleep beta power was more prominent in the high beta range (20–35 Hz). Conclusion In contrast to voluntary motor control in wakefulness, subthalamic beta oscillations are poorly modulated during movements in REM and NREM sleep, indicating that nocturnal movements are not processed by the same cortico-basal ganglia networks as in the waking state. In this line, we propose that motor performance during REM sleep in PD patients with RBD is significantly improved because alternative motor networks for movement initiation might be activated. By this mechanism, the pathological movement-inhibiting basal ganglia networks in PD patients could be bypassed during REM sleep.

The Prevalence and Characteristics of REM Sleep without Atonia (RSWA) in Patients Taking Antidepressants.

The association of REM sleep without atonia (RSWA) as well as REM sleep behavior disorder (RBD) with the intake of selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI) is well established. Our study objective was to determine the prevalence of RSWA and RBD among a group of sleep center patients taking SSRI and SNRI. A retrospective chart review was done at our tertiary sleep center, and 10,746 consecutive records from October 1, 2007, through October 31, 2013, were searched for SSRI and SNRI names using the Sleep Cataloguer Software. The search resulted in 1,444 records, which were then reviewed for keywords of RSWA and RBD. The AASM scoring criteria were used to determine RSWA. Reports of 41 patients with known narcolepsy or α-synucleinopathies were excluded. The remaining records were mined for age, sex, presence of obstructive sleep apnea (OSA), type of antidepressant (SSRI or SNRI), and diagnosis for which antidepressant was prescribed. We used logistic regression analysis to adjust for age, OSA, and sex. Of the 1,444 participants on antidepressants, 176 (12.2%) had RSWA (all confirmed by the investigators) compared to 226 of the entire sleep lab population of 10,746 (2.1%), risk ratio (95% CI) 9.978 (8.149, 12.22). Seven of the 176 patients on antidepressants had RBD (0.48%) compared to 108 of 10,746 (1%), p = 0.005. SSRI and SNRI are associated with a higher prevalence of RSWA but not of RBD. This is independent of medication type.

Chronic escitalopram treatment caused dissociative adaptation in serotonin (5-HT) 2C receptor antagonist-induced effects in REM sleep, wake and theta wave activity

Several multi-target drugs used in treating psychiatric disorders, such as antidepressants (e.g. agomelatine, trazodone, nefazodone, amitriptyline, mirtazapine, mianserin, fluoxetine) or most atypical antipsychotics, have 5-hydroxytryptamine 2C (5-HT2C) receptor-blocking property. Adaptive changes in 5-HT2C receptor-mediated functions are suggested to contribute to therapeutic effects of selective serotonin reuptake inhibitor (SSRI) antidepressants after weeks of treatment, at least in part. Beyond the mediation of anxiety and other functions, 5-HT2C receptors are involved in sleep regulation. Anxiety-related adaptive changes caused by antidepressants have been studied extensively, although sleep- and electroencephalography (EEG)-related functional studies are still lacking. The aim of this study was to investigate the effects of chronic SSRI treatment on 5-HT2C receptor antagonist-induced functions in different vigilance stages and on quantitative EEG (Q-EEG) spectra. Rats were treated with a single dose of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg, i.p.) or vehicle at the beginning of passive phase following a 20-day-long SSRI (escitalopram; 10 mg/kg/day, osmotic minipump) or VEHICLE pretreatment. Fronto-parietal electroencephalogram, electromyogram and motility were recorded during the first 3 h of passive phase. We found that the chronic escitalopram pretreatment attenuated the SB-242084-caused suppression in rapid eye movement sleep (REMS). On the contrary, the 5-HT2C receptor antagonist-induced elevations in passive wake and theta (5-9 Hz) power density during active wake and REMS were not affected by the SSRI. In conclusion, attenuation in certain, but not all vigilance- and Q-EEG-related functions induced by the 5-HT2C receptor antagonist, suggests dissociation in 5-HT2C receptor adaptation.

Alexithymia associated with nightmare distress in idiopathic REM sleep behavior disorder.

Idiopathic REM sleep behavior disorder (iRBD) is characterized by atypical REM sleep motor activity, vivid dreams and nightmares, and dream-enacting behaviors that can result in injuries to the patient and bed partner. It is also a known predictor of Parkinson disease (PD). Alexithymia has been associated with disturbances in sleep and dreaming (e.g., nightmares) and is a non-motor symptom of PD. We assessed alexithymia and disturbed dreaming in iRBD patients with the aim of determining if these two factors are elevated and interrelated among this population. Questionnaire study of clinically diagnosed patients. Clinical sleep disorders center. Thirty-two iRBD patients and 30 healthy age- and sex-matched control participants. Participants completed the 20-item Toronto Alexithymia Scale (TAS-20), the Dream Questionnaire, and the Beck Depression Inventory. iRBD patients obtained higher TAS-20 total scores (62.16 ± 13.90) than did controls (52.84 ± 7.62; F 1,59 = 10.44, P < 0.01), even when controlling for depressive symptoms, and more frequently attained the suggested cutoff for alexithymia than did controls (P < 0.01). iRBD patients obtained higher scores on the Difficulty Identifying Feelings alexithymia subscale. For both iRBD and control groups, the Difficulty Indentifying Feelings subscale correlated positively with the Nightmare Distress scale of the Dream Questionnaire. Elevated alexithymia scores among idiopathic rapid eye movement sleep behavior disorder patients, and especially a difficulty in identifying feelings, parallels evidence of dysautonomia in this population. The higher incidence of distressing nightmares and the association of nightmares with alexithymia further extend similar findings for both clinical and non-clinical samples and suggest that an affect regulation disturbance may be common to the two sets of symptoms.

Assessment of REM Sleep Behavior Disorder in Veterans With Posttraumatic Stress Disorder

PURPOSE: The American Academy of Sleep Medicine (AASM) Manual for the Scoring of Sleep and Associated Events defines RBD PSG features as sustained muscle activity or excessive transient muscle activity in REM sleep. These scoring rules have not yet been validated in combat veterans with both PTSD and RBD.

Phasic Motor Activity of Respiratory and Non-Respiratory Muscles in REM Sleep

In this study, we quantified the profiles of phasic activity in respiratory muscles (diaphragm, genioglossus and external intercostal) and non-respiratory muscles (neck and extensor digitorum) across REM sleep. We hypothesized that if there is a unique pontine structure that controls all REM sleep phasic events, the profiles of the phasic twitches of different muscle groups should be identical. Furthermore, we described how respiratory parameters (e.g., frequency, amplitude, and effort) vary across REM sleep to determine if phasic processes affect breathing. Electrodes were implanted in Wistar rats to record brain activity and muscle activity of neck, extensor digitorum, diaphragm, external intercostal, and genioglossal muscles. Ten rats were studied to obtain 313 REM periods over 73 recording days. Data were analyzed offline and REM sleep activity profiles were built for each muscle. In 6 animals, respiratory frequency, effort, amplitude, and inspiratory peak were also analyzed during 192 REM sleep periods. Respiratory muscle phasic activity increased in the second part of the REM period. For example, genioglossal activity increased in the second part of the REM period by 63.8% compared to the average level during NREM sleep. This profile was consistent between animals and REM periods (η(2)=0.58). This increased activity seen in respiratory muscles appeared as irregular bursts and trains of activity that could affect rythmo-genesis. Indeed, the increased integrated activity seen in the second part of the REM period in the diaphragm was associated with an increase in the number (28.3%) and amplitude (30%) of breaths. Non-respiratory muscle phasic activity in REM sleep did not have a profile like the phasic activity of respiratory muscles. Time in REM sleep did not have an effect on nuchal activity (P=0.59). We conclude that the concept of a common pontine center controlling all REM phasic events is not supported by our data. There is a drive in REM sleep that affects specifically respiratory muscles. The characteristic increase in respiratory frequency during REM sleep is induced by this drive.