Eye Movement Sleep Research Articles

Associations of Alzheimer’s disease Plasma Biomarkers' and slow wave sleep within Black and White Cognitively Normal Older‐Adults

AbstractBackgroundWe studied whether plasma levels of Aβ40, Aβ42, Aβ42/Aβ40, Tau, tau/Aβ42 and NfL are associated with slow wave sleep, and if this association varied within non‐Hispanic Whites and Blacks/African‐Americans.MethodThis was a cross‐sectional analysis of baseline data from 171 cognitively normal older‐adults, volunteering in active NYU studies on memory and sleep. Plasma Aβ40, Aβ42, Tau and NfL were measured using single molecule array (SIMOA). Non‐rapid eye movement sleep (NREM) slow wave sleep (SWS) duration was assessed from 2 nights of in‐lab NPSGs. Associations of NREM SWS duration and plasma AD biomarker levels were examined by applying adjusted generalized linear models and Pearson correlation analysis after data normalization. Analyses were adjusted for age, sex, BMI, race, and education.ResultOf the 171 subjects (128 Whites and 43 Blacks), 112 (65.5%) were females, and mean (SD) age was 68.6 (6.6) years, BMI was 27.6 (6.1) kg/m**2, and education was 16.9 (2.1). There were no racial differences in age, sex, and BMI, SWS and AHI4%. In comparison to whites, blacks had significantly lower years of education (14.2 vs. 17.2, p <.01). Black/African‐American subjects had significantly lower plasma Aβ40 (248.3 vs. 262.5 pg/ml) and NfL levels (11.4 vs. 15.2 pg/ml). p<.05 for both. There were no significant racial differences in levels of plasma Aβ42, Aβ42/Aβ40, Tau, Tau/Aβ40 and Tau/Aβ42. NREM SWS duration was not associated with plasma Aβ42, Aβ40 or tau in the overall sample. However, in Whites, SWS negatively correlated with plasma Aβ42 (r = ‐0.28, p< = 0.05). In Black/African‐Americans, SWS positively correlated with plasma Aβ42 (r = 0.48, p = 0.05). In Whites, SWS negatively correlated with plasma Aβ40 (r = ‐0.087, p = 0.72), though not significant. In Black/African‐Americans, SWS positively correlated with plasma Aβ40 levels (r = 0.32, p = 0.04). In Whites, SWS negatively correlated with plasma Tau (r = ‐0.153, p = 0.27), though not significant. In Black/African‐Americans, SWS positively correlated with plasma Tau levels (r = 0.52, p = 0.04). NREM SWS was not associated with plasma tau/Aβ42, plasma tau/Aβ40 or plasma NfL in the overall sample and across racial‐subgroups.ConclusionRace‐specific relationships between NREM SWS and plasma Aβ42, Aβ40 & Tau might propose differences in SDOH mechanisms that may affect sleep and AD‐risk in older‐adults.

Pathogenesis, clinical features and treatment of anti‐IgLON5 disease

AbstractAnti‐immunoglobulin‐like cell adhesion molecule 5 (IgLON5) disease is an autoimmune encephalitis that targets the cell adhesion molecule, IgLON5. The disease presents with various clinical features, including sleep disorders, bulbar palsy, movement disorders, cognitive dysfunction and neuromuscular manifestations. Sleep disorders are characterized by parasomnias and sleep‐disordered breathing (stridor and sleep apnea). Bulbar palsy includes dysarthria, dysphagia, vocal cord paralysis and stridor. Movement disorders include a variety of symptoms and signs, such as chorea, dystonia, rigidity, tremor, myoclonus and myorhythmia. Cognitive dysfunction includes executive dysfunction, impairment of attention, and verbal and visual memory dysfunction. Neuromuscular manifestations include fasciculations in the tongue and peripheral muscles, limb weakness, and muscle atrophy. Some patients resemble those with neurodegenerative diseases, such as progressive supranuclear palsy or amyotrophic lateral sclerosis. On video polysomnography, undifferentiated non‐rapid eye movement sleep and poorly structured N2 sleep are characteristic. Brain magnetic resonance imaging and cerebrospinal fluid studies are often normal or non‐specific. Human leukocyte antigen testing shows that HLA‐DRB1*10:01‐DQB1*05:01 is highly associated with the disease. Pathologically, neuronal deposition of both hyperphosphorylated 3‐repeat and 4‐repeat tau isoforms, neuronal loss, and gliosis in the hypothalamus, brainstem tegmentum, and upper cervical cord are observed. Some patients are responsive to immunotherapies, such as steroids, intravenous immunoglobulin, plasma exchange therapy and rituximab. Factors associated with a favorable response to immunotherapies include early initiation of treatment, cerebrospinal fluid inflammation and immunoglobulin G1 (IgG1) predominance of IgLON5 antibody compared with immunoglobulin G4 (IgG4). Anti‐IgLON5 disease should be suspected in patients with atypical movement disorders complicated by sleep disturbances.

Progress of mechanism research on the neurotransmitters in treatment of insomnia with acupuncture by regulating sleep architecture

Low-quality sleep in patients with insomnia is closely related to sleep architecture imbalance and neurotransmitter impairment. Acupuncture may reduce the duration of light sleep and its proportion, increase the time of deep sleep and rapid- eye-movement sleep as well as their proportions so as to modulate the sleep architecture for insomnia. The paper summarized the related studies of acupuncture for improving sleep architecture through regulating serotonin, norephinephrine, dopamine, γ-aminobutyric acid, acetylcholine and orexin; and explored the effects of acupuncture on the neurotransmitters and their specific performance in regulating sleep architecture. It is anticipated that the review may provide the literature evidences of acupuncture for improving sleep quality in patients with insomnia, and the approaches to the mechanism research of acupuncture for regulating sleep architecture.

Subclinical β‐amyloid peptides impair homeostatic synaptic potentiation in hippocampal neurons in 5XFAD mice

AbstractBackgroundAlzheimer’s disease (AD) patients exhibit early symptoms of non‐rapid eye movement sleep (NREM) reduction and relatively REM sleep increase, which influences homeostatic synaptic plasticity (HSP) in cortical and subcortical neurons. Meanwhile, β‐amyloid peptides can suppress synaptic plasticity in hippocampus to impair learning/memory in animal studies.MethodIn accordance with IACUC of Vanderbilt University Medical center, coronal brain slices were prepared from wt and hemi 5xFAD mice at postnatal days (P)30, 60‐90 and 120‐150. Whole‐cell patch‐clamp recordings were made from hippocampal CA1 pyramidal neurons to record spontaneous excitatory synaptic currents (sEPSCs) at 32°C (clamped at ‐55.8mV, chloride reversal potentials). Slow‐wave oscillations (SWOs, 0.5 Hz, 10 min) were induced by injecting sinusoidal currents into neurons to simulate neuronal activity (up/down state) during NREM sleep. 200 µM β‐amyloid peptides were used in ACSF for this study.ResultCompared with age‐matched wt littermates at P30 and P60‐90, sEPSCs in hippocampal neurons from hemi 5xFAD mice (n = 4 mice) exhibited larger amplitudes and higher frequency. However, at P120‐150, sEPSCs in neurons from hemi 5xFAD mice (n = 5 mice) became smaller than wt littermates (n = 4 mice), suggesting that excitatory synapses in hemi 5xFAD mice may be altered along the ageing course. Moreover, following SWO induction, HSP could be induced in neurons from wt littermates at all postnatal ages (n = 5 mice) and post‐SWO sEPSCs in neurons were increased. However, HSP could not be induced in neurons from hemi 5xFAD mice at P120‐150, except P30 and P60‐90. Moreover, 200 µM β‐amyloid peptides can suppress this synaptic potentiation in neurons from hemi 5XFAD mice at P90 (n = 4 mice).ConclusionReduced NREM sleep activity in hemi 5xFAD mice can impair sEPSCs and HSP in hippocampal CA1 neurons along the ageing course, and subclinical β‐amyloid peptides can suppress this sleep‐related homeostatic synaptic potentiation, which contributes to cognitive deficits in AD patients.

P006 Case study: Dancing eyes post COVID-19 vaccination

Abstract INTRODUCTION We describe a case of rapid eye movements in NREM sleep in a patient who had Guillain-Barre Syndrome (GBS) post AstraZeneca ( AZ) COVID-19 vaccine. This has not been reported previously. METHOD An 81-year-old male with recent diagnosis of GBS secondary to AZ COVID-19 vaccination was referred of investigation of sleep disordered breathing. A Level 2 PSG showed rapid eye movements in the absence of atonia predominantly during N1 sleep. A second study one month later confirmed the persistence of the eye movements. RESULTS Study 1 revealed mild supine and REM-predominant obstructive sleep apnoea (AHI = 14.9/hr) with reduced REM latency (44.5 minutes) & slow wave sleep (1.6%). Study 2 showed normal REM latency (61.5 minutes). REM indices were 0.33 per minute of N1 sleep and 0.12 for N2 sleep. REM density was 3% during N1 and 0.55% in N2. DISCUSSION COVID-19 vaccinations have been associated with various side-effects, some of which have been attributed to autoimmune response. A previous study on GBS patients reported sleep architecture abnormalities including sleep onset REM periods and abnormal eye movements in NREM sleep, during acute phase attributed to autonomic dysfunction and transitory hypocretin-1 transmission reduction . Our patient had almost completely recovered from GBS when we performed Study 1. We believe this to be the first case of abnormal eye movements in sleep being identified on polysomnography in a patient with GBS following AZ Covid-19 vaccination

Effects of Alcohol Withdrawal on Sleep Macroarchitecture and Microarchitecture in Female and Male Rats.

The prevalence of sleep disruptions is higher among people with alcohol use disorder (AUD), particularly during alcohol withdrawal, compared to non-AUD individuals. Although women generally have a higher risk of developing sleep disorders, few studies have investigated sex differences in sleep disruptions following chronic alcohol exposure. The present study examined sleep macroarchitecture (time spent asleep or awake and sleep onset latency) and microarchitecture (bout rate and duration and sleep spindle characterization) prior to alcohol vapor exposure (baseline), during acute withdrawal, and through protracted abstinence in female and male rats. Females and males showed reduced time in rapid eye movement (REM) sleep during acute withdrawal, which returned to baseline levels during protracted abstinence. REM sleep onset latency was decreased during protracted abstinence in females only. Furthermore, there was a sex difference observed in overall REM sleep bout rate. Although there were no changes in non-REM sleep time, or to non-REM sleep bout rate or duration, there was an increase in non-REM sleep intra-spindle frequency during acute withdrawal in both females and males. Finally, there was increased wakefulness time and bout duration during acute withdrawal in both females and males. The results demonstrate both macroarchitectural and microarchitectural changes in sleep following chronic alcohol exposure, particularly during acute withdrawal, suggesting the need for therapeutic interventions for sleep disturbances during withdrawal in individuals with AUD. Furthermore, sex differences were observed in REM sleep, highlighting the importance of including both sexes in future alcohol-related sleep studies.

0640 North American Prodromal Synucleinopathy Consortium: Baseline characteristics in 251 patients with REM Sleep Behavior Disorder

Abstract Introduction Introduction: Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD) is characterized by a lack of muscle atonia during REM sleep with dream enactment. RBD is regarded as a prodromal synucleinopathy as a high proportion of patients eventually phenoconvert to Parkinson’s Disease and related synucleinopathies, suggesting RBD may be an early non-motor symptom of disease. Accordingly, patients with RBD are ideally situated to test potential therapeutic interventions to prevent phenoconversion to synucleinopathy. However, RBD itself, and associated patient registries, are rare. The North American Prodromal Synucleinopathy Consortium (NAPS) establishes a multisite registry of RBD patients with standardized neurological, neuropsychiatric, and neuropsychological assessments and biomarker collection. The present work reports baseline characteristics of this RBD patient database at its current state. Methods Methods: Participants >18 years of age with overnight polysomnogram-confirmed RBD by ICSD-3 criteria who did not meet criteria for the diagnosis of PD, dementia, MSA, or narcolepsy were enrolled from 10 sites across North America (8/2018 to 4/2021). Data collection included family and personal history of RBD and related symptoms, as well as standardized assessments related to cognitive, motor, sensory and autonomic function. Additionally, all subjects have contributed blood, and a subset of subjects have contributed cerebrospinal fluid samples to the National Centralized Repository for Alzheimer's Disease and Related Dementias for future analysis. Results Results: A total of n=251 participants were enrolled. Outcomes are reported based on sex (n=202 male, n=49 female). Data were further examined based on participants’ history of antidepressant use (n=142 with, n=103 without) and based on participants’ extent of synucleinopathy burden (n=70 defined as isolated RBD, n=181 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Any observed sex differences among the data did not persist after correction for antidepressant use. Conclusion Conclusions: This prospective, cross-sectional data on history, demographic, cognitive, motor, sensory, and autonomic function in n=251 participants with RBD highlight the lack of sex differences and the high preponderance of concomitant neurological abnormalities with RBD, and provide a valuable registry for future longitudinal studies and neuroprotective clinical trials. Support (If Any) NIH NIA R34 AG056639 (YJ, BB)

0408 A Narcolepsy Detection Paradigm: Automated Nocturnal Detection and Notification of Sleep Onset Rapid Eye Movement Periods

Abstract Introduction Rapid eye movement (REM) sleep detected by polysomnography (PSG) occurring within 15 minutes of nocturnal sleep (sleep onset REM period; SOREMP) is a known biomarker for hypocretin-deficient narcolepsy. However, the SOREMP is often underappreciated when observed in patients undergoing routine diagnostic sleep testing, evidenced by the paucity of further evaluation for hypersomnia in these individuals. To enhance identification of SOREMP episodes, we developed an automated process to detect and advise sleep clinicians of sleep onset REMs. This study aimed to evaluate the impact of automated SOREMP notification on clinician recommendations for narcolepsy diagnostic evaluation and multiple sleep latency test (MSLT) outcomes. Methods The automated SOREMP notification program was offered to all sleep clinicians within a large multicenter sleep clinic network. De-identified sleep studies were uploaded to a secure data cloud for real-time automated SOREMP detection. Algorithmic-determined SOREMPs underwent human adjudication by a team of expert registered sleep scorers. Clinicians were advised of the presence of SOREMPs within the interpretation platform via a visual banner. Clinician recommendations and future testing (including MSLTs) were naturalistically tracked. Results Of 17,447 sleep studies processed over 3 years, 145 exhibited a SOREMP (0.8%). Five studies were excluded from primary analyses because of a prescheduled MSLT (n=2 narcolepsy; n=2 idiopathic hypersomnia; n=1 “normal”). Of the remaining 140 patients, 19 (14%) were recommended for further narcolepsy evaluation/MSLT; to date, 4 patients have had an MSLT (n=3 narcolepsy; n=1 “normal”). Excluding the PSG SOREMP, MSLT outcomes were #1: 2 SOREMPs and MSL=4.7 min; #2: 3 SOREMPs and MSL=3.0 min; #3: 5 SOREMPs and MSL=4.6 min; #4: 0 SOREMPs and MSL=11.7 min. Conclusion This study implemented enhanced identification and subsequent clinician notification of nocturnal SOREMPs using a novel sensitive SOREMP detection paradigm. This methodology resulted in recommendation of 19 patients, who otherwise may have gone undetected, for further narcolepsy evaluation. When conducted, MSLTs most often supported a narcolepsy diagnosis. This is a call to action for medical providers to critically evaluate patients who exhibit a PSG SOREMP, as it may provide a unique opportunity to identify and treat narcolepsy. Further research is needed to better understand the low referral rate. Support (If Any) Jazz Pharmaceuticals.

0197 Increased Brain Kynurenic Acid Elicits Sex-Dependent Abnormalities in NREM Sleep Spindle Dynamics

Abstract Introduction Sleep spindles are thalamocortical oscillations which occur during non-rapid eye movement (NREM) sleep. NREM sleep spindle aberrations are a consistent clinical sleep deficiency associated with psychotic disorders and exacerbation of cognitive symptoms. Kynurenic acid (KYNA), a tryptophan metabolite synthesized from kynurenine via kynurenine aminotransferases (KATs) and modulator of glutamatergic and cholinergic neurotransmission, is elevated in the brain of patients with psychotic disorders, including schizophrenia and bipolar disorder. Currently, we sought to understand the neurodevelopmental and transient impacts of brain KYNA elevation on sleep spindle dynamics. Methods In Experiment #1, sleep spindles were evaluated in adult offspring, postnatal day (PD) 56 from embryonic kynurenine (EKyn) treated rat dams (Rentschler et al., 2021 Sz Bull) (N=7-9 per group). EKyn KYNA male, but not female, offspring have elevated KYNA during the light phase (Wright et al., 2021 Frontiers in Psychiatry). In Experiment #2, sleep spindles were evaluated in adult rats injected with kynurenine (100 mg/kg; i.p.) to acutely elevate brain KYNA levels at zeitgeber time 0 (N=8-12 per group). Polysomnography was recorded via EEG/EMG telemetry. Sleep spindles were evaluated using a custom-made manual scoring system during the first 4 hr of the light cycle. Results Male EKyn, but not female, exhibited a decrease in spindle density compared to ECon (2-wayANOVA: ***P<0.001). FFT spectral power for peak spindle frequency (10-15 Hz) was reduced for all EKyn offspring (3-way ANOVA; frequency x treatment interaction: ****P<0.0001; treatment: *P<0.05). Kynurenine challenge reduced spindle density for both sexes (2-way ANOVA: ***P<0.001; M: **P<0.01; F: *P<0.05). Frequency x treatment interaction for males (2-way ANOVA: ***P<0.001) was observed with lower FFT spectral power for 10-10.5 Hz (*P<0.05) and greater power for 14-14.5 Hz (*P<0.05). Conclusion We determined conspicuous sex differences in spindle dynamics in the EKyn paradigm that may be related to brain KYNA levels; only males exhibited a decrease in spindle density, however all EKyn offspring had reduced FFT spectral power. Kynurenine challenge reduced spindle density in both sexes, however only males had changes in FFT spectral power. Future work will consider the efficacy of KYNA synthesis inhibition to prevent NREM sleep spindle abnormalities induced by KYNA elevation. Support (If Any) Funding Source: National Institute of Health Grants: NIH RO1 NS102209 & P50 MH103222.

0085 SleepInceptionNet: A Deep Learning Algorithm for Real-Time Sleep Stages Scoring Using Single-channel EEG

Abstract Introduction Most of the current automatic polysomnography sleep staging methods use multi-signal data and require a sequence of preceding and following epochs to score the stage of a specific epoch, which may not be desirable for analysis in real-time and/or in free-living conditions. We developed a deep learning-based sleep staging algorithm, namely SleepInceptionNet, that is designed to score each epoch using only single-channel electroencephalogram (EEG) data within that specific epoch. Methods Polysomnography data of 883 participants (937,975 thirty-second epochs) in the Multi-Ethnic Study of Atherosclerosis (MESA) obtained from the National Sleep Research Resource (NSRR) were randomly divided into a separate training/validation set of 194 participants and a test set of 689 participants. Each 30-second raw central EEG channel signal was transformed to time-frequency domain images using continuous wavelet transform method. Sleep stage in each epoch was obtained using SleepInceptionNet, in which the InceptionV3 convolutional neural network structure was trained and tuned on the time-frequency images of the training set to classify each epoch into one of the five stages of Wake, N1, N2, N3, or rapid eye movement (REM) sleep. Results Compared to the ground truth manually scored polysomnography sleep stages, SleepInceptionNet achieved an overall kappa agreement of 0.690 and overall weighted accuracy of 0.897. The model showed accuracy (mean±SD across the test set participants) of 0.940±0.067 in detecting Wake, 0.883±0.047 in detecting N1, 0.845±0.055 in detecting N2, 0.939±0.038 in detecting N3, and 0.930±0.038 in detecting REM epochs, in reference to manually scored polysomnography. Conclusion SleepInceptionNet showed a high agreement with manually scored polysomnography in epoch-by-epoch classification of sleep stages. This study demonstrates the viability of real-time, accurate sleep staging using a single-channel EEG, which could have a variety of applications such as delivery of on-demand interventions during specific sleep stages in free-living conditions. Support (If Any) MESA Sleep Ancillary study was funded by NIH-NHLBI Association of Sleep Disorders with Cardiovascular Health Across Ethnic Groups (RO1 HL098433). MESA is supported by NHLBI (HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01- HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169) and NCATS (UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420). NSRR was supported by NHLBI (R24 HL114473, 75N92019R002).

0280 Orexins play a dual role in immobility episodes on taiep rats a model of H-ABC

Abstract Introduction Leukodystrophies are a heterogenous group of congenital myelin alterations with more than 30 classified diseases was described until now. Among them there are several mutations in the a and b tubulins the so called tubulinophaties, that affect the central nervous system. The hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is due to a mutation in the tubulin b 4a (TUBB4A) and the taiep rats is the only available model of this human disease with similar magnetic resonance changes and a punctual mutation in the TUBB4A. Taiep rats had immobility episodes (IEs) with a peak between at 9 months of age. Importantly, electroencephalographic recordings shown that IEs had a rapid eye movement (REM) sleep characteristic pattern supporting that are equal to human cataplexy episodes that are key sign of narcolepsy. It is possible to induced IEs when taiep rats are manipulated from the tail or the thorax. Narcolepsy in humans and narcoleptic dogs had a significant decreased in orexin levels in the cerebrospinal fluid (CSF) and a concomitantly decreased of orexin neurons in the lateral hypothalamus. Methods We used 21 male rats from taiep at 9 months of age. All rats were kept in standard conditions and were implanted for EEG, EMG and EOG recordings to characterize IEs. We administered orexin A and B agonists and characterized the sleep-wake cycle and frequency of IEs, the peptides were administered by a intracerebroventricular (i.c.v.) injections diluted in artificial CSF. We also measured the number or positive orexin neurons in the lateral hypothalamus through immunohistochemistry. Results The i.c.v. administration of [Ala11, D-Leu 15] orexin B agonist significantly decrease the frequency of IEs with 3 and 10 nM doses (P≤0.05 and P≤0.03, respectively), without affecting the sleep-wake pattern. However, the i.c.v. administration of Orexin A (17-33) an agonist did not affect the sleep-wake pattern or the frequency of IEs. It is relevant that the number of orexins neurons did not differ between taiep and control Sprague-Dawley (SD) male rats. Conclusion Our results showed that IEs had a REM sleep EEG characteristic pattern with cataplexic-like atonia, there are sensible to orexin B agonist, but the number of orexin positive neurons do not differ with respect to SD male rats. In conclusion taiep rats a model of H-ABC is an adequate model of cataplexy-like episodes due to myelin disease. Support (If Any) Partially supported by PRONACES-CONACYT grant 194171, and VIEP-BUAP 2021 to CA in Neuroendocrinología. KGE is fellowship from CONACYT No. 772626.

0536 Association of a Novel EEG Biomarker of Sleep Depth with Sleep Disordered Breathing in Adolescents

Abstract Introduction The odds ratio product (ORP) provides a standardized, continuous measure of sleep depth that ranges from 0 (deep sleep) to 2.5 (full wakefulness). ORP has been shown to increase during adolescence, representing the decline in sleep depth that occurs during this developmental period. In adults, higher ORP has been associated with sleep disordered breathing (SDB), including obstructive sleep apnea (OSA), while there have been no studies in youth. We aimed to determine the association of ORP with SDB in adolescents. Methods We extracted ORP from the sleep EEG of 261 typically developing adolescents aged 12-23y (median 16y) from the Penn State Child Cohort. Higher ORP during rapid eye movement (REM) and non-REM sleep indicates less deep sleep, while higher ORP-9 (i.e., average ORP in the 9-seconds following non-REM cortical arousals) indicates greater arousability. We used general linear models, adjusted for sex, age and race/ethnicity, to examine mean differences in ORP metrics among clinically meaningful groups of SDB based on the apnea/hypopnea index (AHI) consisting of no SDB (AHI<2 and no snoring, n=100), primary snoring (AHI<2 and snoring, n=75), 2≤AHI<5 (n=64), and AHI≥5 (n=22). Results Adolescents with primary snoring or 2≤AHI<5 did not significantly differ in ORP metrics from those without SDB (all p≥0.12). Adolescents with AHI≥5 had higher ORP-NREM compared to those without SDB, with primary snoring or with 2≤AHI<5 (all p≤0.01), while ORP-REM was significantly higher compared to those without SDB (p=0.02). ORP-9 was significantly greater in adolescents with AHI≥5 compared to those with no SDB (p<0.01) and those with primary snoring (p=0.02), but not when compared to those with 2≤AHI<5 (p=0.07). Conclusion Our data suggest that adolescents with OSA experience lower REM and non-REM sleep depth/intensity (higher ORP) compared to those without SDB. In addition, these adolescents experience a slower progression back to deep sleep following cortical arousals (higher ORP-9), which suggests they remain in a high arousability state and, thus, are more likely to repeat arousals. Commensurate with previous studies in adults, our data show that ORP is a useful sleep EEG biomarker able to capture decreased sleep depth in adolescents with OSA. Support (If Any) National Institutes of Health (R01MH118308, UL1TR000127)

0602 Rapid Eye Movement (REM) Sleep Duration Is Inversely Related To Daytime Pruritus Severity: Preliminary Findings in Posttraumatic Stress Disorder (PTSD) Patients

Abstract Introduction Pruritus (itching) is one of the most distressing symptoms of dermatologic disease. There can be a bidirectional relationship between pruritus severity and sleep. Pruritus during sleep is most frequently encountered during stages N1 and N2 and sleep fragmentation can exacerbate pruritus. Often there are limited effective treatments available for pruritus. In this study we examined REM sleep data obtained from PTSD patients who reported somatic complaints including daytime pruritus. To our knowledge there are no studies of REM sleep and pruritus during wakefulness. Methods Seventy-five consenting patients with mild-to-moderate PTSD (all female; mean ±SD age 48.89 ±13.50 years) completed a battery of psychiatric and sleep ratings and underwent ≥ 1 home sleep apnea test (Watch PAT200; Itamar) which provided measures of %REM and REM duration. Exclusion criteria were use of benzodiazepines or narcotics. Pruritus was measured using Item 2 of the Pennebaker Inventory of Limbic Languidness (PILL), which assesses the frequency of common physical symptoms. For PILL Item 2 patients self-rated the frequency with which they experienced “Itchy eyes or skin” with a rating of “1” = “”never or almost never”, “2”=”less than 3 or 4 times per year”, “3”=”every month or so”, “4”=”every week or so’, and”5”=”more than once every week”. Results The mean±SD % REM was 21.78 ±7.64 (range 1.76% to 40.69%); and overall duration of REM sleep (mean ±SD) was 91.37±38.20 minutes (range 5.01 to 194.47 minutes). The frequency of pruritus ratings were as follows:: 39.5% endorsed a rating of “5” . The remainder self-endorsed the following frequencies: “4” (15.8%), “3” (21.1%), “2” (15.8%), and “1” (7.9%).. Pearson product moment correlation between the pruritus rating (item 2 of PILL) and REM sleep parameters were as follows: % REM (Pearson r= -0.172; p=0.144) and REM duration (Pearson r= -0.247; p=0.035). Conclusion Daytime pruritus was inversely related to the duration of REM sleep in a sample of PTSD patients. Pruritus can be a difficult condition to manage. Optimization of REM sleep may have a role in the management of pruritus. Support (If Any) None

Prevalence and Risk Factors for Rapid Eye Movement-Related Obstructive Sleep Apnea in Children.

ObjectivesDifferent pathophysiological mechanisms and the distribution of respiratory events among rapid eye movement (REM) and non-rapid eye movement (NREM) sleep modulate the effect of obstructive sleep apnea (OSA). We aimed to study the prevalence and risk factors for REM-related OSA in children.Study DesignRetrospective, cross-sectional study.MethodsWe recruited 366 children with OSA confirmed by polysomnography (PSG) over a 5-year period. REM-related OSA is defined by an obstructive apnea-hypopnea index (OAHI) in the REM sleep ≥2× than during NREM sleep.ResultsThe prevalence of REM-related OSA in children was 50.3%. Children with REM-related OSA were more likely to be female (P = 0.042), and had lower prevalence of adenotonsillar hypertrophy (P = 0.043) compared with children with other OSA subtypes. Children with REM-related OSA slept longer in the supine position (P = 0.003), had shorter duration of NREM1 sleep (P = 0.018), lower nadir SpO2 (P = 0.005), and a higher oxygen desaturation index 3% (ODI3%) (P = 0.014), and lower arousal index (P = 0.034) compared with other OSA subtypes. Female gender and supine sleep was the independent risk factors for REM-related OSA.ConclusionThe prevalence of REM-related OSA was 50.3%. OAHIREM should be considered as an important parameter in future clinical research studies done in children with OSA.

Automatized online prediction of slow-wave peaks during non-rapid eye movement sleep in young and old individuals: Why we should not always rely on amplitude thresholds.

Brain-state-dependent stimulation during slow-wave sleep is a promising tool for the treatment of psychiatric and neurodegenerative diseases. A widely used slow-wave prediction algorithm required for brain-state-dependent stimulation is based on a specific amplitude threshold in the electroencephalogram. However, due to decreased slow-wave amplitudes in aging and psychiatric conditions, this approach might miss many slow-waves because they do not fulfill the amplitude criterion. Here, we compared slow-wave peaks predicted via an amplitude-based versus a multidimensional approach using a topographical template of slow-wave peaks in 21 young and 21 older healthy adults. We validate predictions against the gold-standard of offline detected peaks. Multidimensionally predicted peaks resemble the gold-standard regarding spatiotemporal dynamics but exhibit lower peak amplitudes. Amplitude-based prediction, by contrast, is less sensitive, less precise and - especially in the older group - predicts peaks that differ from the gold-standard regarding spatiotemporal dynamics. Our results suggest that amplitude-based slow-wave peak prediction might not always be the ideal choice. This is particularly the case in populations with reduced slow-wave amplitudes, like older adults or psychiatric patients. We recommend the use of multidimensional prediction, especially in studies targeted at populations other than young and healthy individuals.

Translational Pharmacology of PRAX-944, a Novel T-Type Calcium Channel Blocker in Development for the Treatment of Essential Tremor.

BackgroundEssential tremor is the most common movement disorder with clear unmet need. Mounting evidence indicates tremor is caused by increased neuronal burst firing and oscillations in cerebello‐thalamo‐cortical circuitry and may be dependent on T‐type calcium channel activity. T‐type calcium channels regulate sigma band electroencephalogram (EEG) power during non‐rapid eye movement sleep, representing a potential biomarker of channel activity. PRAX‐944 is a novel T‐type calcium channel blocker in development for essential tremor.ObjectivesUsing a rat tremor model and sigma‐band EEG power, we assessed pharmacodynamically‐active doses of PRAX‐944 and their translation into clinically tolerated doses in healthy participants, informing dose selection for future efficacy trials.MethodsHarmaline‐induced tremor and spontaneous locomotor activity were used to assess PRAX‐944 efficacy and tolerability, respectively, in rats. Sigma‐power was used as a translational biomarker of T‐type calcium channel blockade in rats and, subsequently, in a phase 1 trial assessing pharmacologic activity and tolerability in healthy participants.ResultsIn rats, PRAX‐944 dose‐dependently reduced tremor by 50% and 72% at 1 and 3 mg/kg doses, respectively, without locomotor side effects. These doses also reduced sigma‐power by ~30% to 50% in rats. In healthy participants, sigma‐power was similarly reduced by 34% to 50% at 10 to 100 mg, with no further reduction at 120 mg. All doses were well tolerated.ConclusionsIn rats, PRAX‐944 reduced sigma‐power at concentrations that reduced tremor without locomotor side effects. In healthy participants, comparable reductions in sigma‐power indicate that robust T‐type calcium channel blockade was achieved at well‐tolerated doses that may hold promise for reducing tremor in patients with essential tremor. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Preventing Dementia Using Saffron, The Kampo Medicine, Kamiuntanto, and Their Combination, Kamiuntantokabankoka.

The objective of this review is to evaluate the anti-dementia activities of saffron and its combination with Kampo medicine. The Kampo formula Kamiuntanto composed of 13 crude drugs is well known for its anti-dementia activity. A significant increase in choline acetyltransferase activity and mRNA levels were observed. Polygala radix was identified as the most essential component drug in Kamiuntanto, probably due to the saponins, tenuifolin, and sinapinic acid. Ginseng was also identified as an essential Kamiuntanto component in terms of its synergistic functions with Polygala radix. Saffron, which was recommended in the Bencao Gangmu for memory and dementia, and is used as an anti-spasmodic, anti-catarrhal, and sedative herbal drug. Saffron and its major constituent, crocin were shown to enhance learning-memory, non-rapid eye movement (rem) sleep, and inhibit depression and neuronal cell death due to strong anti-oxidant and anti-inflammation activities. In addition based on the epidemiological studies such as the treatment of sleeping disorders and the clinical trials of saffron for Alzheimer patients, we demonstrated the indirect and direct anti-dementia activities of crocin and saffron.

Sedative-Hypnotic Activity of the Water Extracts of Coptidis Rhizoma in Rodents.

Many medicinal plants have been used in Asia for treating a variety of mental diseases, including insomnia and depression. However, their sedative–hypnotic effects and mechanisms have not been clarified yet. Accordingly, the objective of this study was to investigate the sedative–hypnotic effects of water extracts of five medicinal plants: Coptidis Rhizoma, Lycii Fructus, Angelicae sinensis Radix, Bupleuri Radix, and Polygonum multiflorum Thunberg. The binding abilities of five medicinal plant extracts to the GABAA–BZD and 5-HT2C receptors were compared. Their abilities to activate arylalkylamine N-acetyltransferase (AANAT), a melatonin synthesis enzyme, in pineal cells were also determined. Following in vitro tests, the sedative and hypnotic activities of extracts with the highest activities were determined in an animal sleep model. In the binding assay, the water extracts of Coptidis Rhizoma (WCR) showed high binding affinity to the GABAA–BZD and 5-HT2C receptors in a dose-dependent manner. Additionally, WCR increased the AANAT activity up to five times compared with the baseline level. Further animal sleep model experiments showed that WCR potentiated pentobarbital-induced sleep by prolonging the sleep time. It also decreased the sleep onset time in mice. In addition, WCR reduced wake time and increased non-rapid eye movement (NREM) sleep without EEG power density (percentages of δ, θ, and α waves) during NREM sleep in rats. WCR could effectively induce NREM sleep without altering the architectural physiologic profile of sleep. This is the first report of the sedative–hypnotic effect of Coptidis Rhizoma possibly by regulating GABAA and 5-HT2C receptors and by activating AANAT activity.

Rare cause of neonatal apnea from congenital central hypoventilation syndrome

BackgroundCongenital central hypoventilation syndrome (CCHS) is a rare condition caused by mutations in the Paired-Like Homeobox 2B (PHOX2B) gene. It causes alveolar hypoventilation and autonomic dysregulation. This report aimed to raise awareness of this rare cause of neonatal apnea and hypoventilation as well as described the diagnostic work up to confirm the diagnosis in resource-limited setting where polysomnography for neonate is unavailable.Case presentationA late preterm female newborn born from a non-consanguineous primigravida 31-year-old mother had desaturation soon after birth followed by apnea and bradycardia. After becoming clinically stable, she still had extubation failure from apnea without hypercapnic ventilatory response which worsened during non-rapid eye movement (NREM) sleep. After exclusion of other etiologies, we suspected congenital central hypoventilation syndrome and sent genetic testing. The result showed a PHOX2B gene mutation which confirmed the diagnosis of CCHS. We gave the patient’s caregivers multidisciplinary home respiratory care training including tracheostomy care, basic life support, and simulation training for respiratory problem solving. Then, the patient was discharged and scheduled for follow-up surveillance for associated conditions.ConclusionDiagnosis of CCHS in neonates includes the main clue of the absence ofhypercapnic ventilatory response which worsens during non-rapid eye movement(NREM) sleep after exclusion of other causes. Molecular testing for PHOX2Bgene mutation was used to confirm the diagnosis.

Late-Onset Focal Epilepsy: Electroclinical Features and Prognostic Role of Leukoaraiosis.

The aim of this study was to describe the electroclinical and prognostic characteristics, and to investigate the role of leukoaraiosis in outpatients with new-onset elderly focal epilepsy aged ≥60 years, referred to a tertiary epilepsy center between 2005 and December 31, 2020. Among the 720 patients who were referred to the center, we retrospectively selected 162 consecutive outpatients, with a first referral for recent-onset focal epilepsy of unknown cause (UC) or structural cause (SC), and collected a clinical and standard-Electroencephalogram (S-EEG), 24-h ambulatory EEG (A-EEG), and neuroimaging data. We also analyzed the seizure prognosis after titration of the first antiseizure medication (ASM). One hundred and four UC and 58 SC patients, followed up for 5.8 ± 5.3 years (mean ± SD), were included. Compared with the SC group, the patients with UC showed a predominance of focal seizures with impaired awareness (51.9% of cases) and focal to bilateral tonic-clonic seizures during sleep (25%); conversely, the SC group, more frequently, had focal to bilateral tonic-clonic seizures during wakefulness (39.6%) and focal aware seizures (25.8%) (p < 0.0001). Oral or gestural automatisms were prevalent in UC epilepsy (20.2 vs. 6.9% in the SC group, p = 0.04). In UC compared to patients with SC, interictal epileptiform discharges showed a preferential temporal lobe localization (p = 0.0007), low expression on S-EEG, and marked activation during deep Non-Rapid Eye Movement (NREM) sleep (p = 0.003). An overall good treatment response was found in the whole sample, with a probability of seizure freedom of 68.9% for 1 year. The cumulative probability of seizure freedom was significantly higher in the UC compared with the SC group (p < 0.0001). The prognosis was worsened by leukoaraiosis (p = 0.012). In the late-onset focal epilepsy of unknown cause, electroclinical findings suggest a temporal lobe origin of the seizures. This group showed a better prognosis compared with the patients with structural epilepsy. Leukoaraiosis, per se, negatively impacted on seizure prognosis.