Narcolepsy and the Dissociation of REM Sleep and Cataplexy through Ambient Temperature Manipulation

Narcolepsy is characterized by increased REM sleep propensity and cataplexy. Although narcolepsy is caused by the selective loss or dysfunction of hypocretin (Hcrt) neurons within the lateral hypothalamus (LH), mechanisms underlying REM sleep propensity and cataplexy remain to be elucidated. We have recently shown that wild type (WT) mice increase REM sleep expression when exposed to thermoneutral ambient temperature (Ta) warming during the light (inactive) phase. We hypothesized that the loss of Hcrt may lead to exaggerated responses with respect to increased REM sleep and cataplexy during Ta warming. To test this hypothesis, Hcrt-KO mice were implanted for chronic sleep recordings and housed in a temperature-controlled cabinet. Sleep-wake expression and both spontaneous cataplexy and food-elicited cataplexy were evaluated at constant Ta and during a Ta manipulation protocol. Here we show several unexpected findings. First, Hcrt-KO mice show opposite circadian patterns with respect to REM sleep responsiveness to thermoneutral Ta warming compared to WT mice. As previously demonstrated, WT mice increased REM sleep when Ta warming is presented during the inactive (light) phase, whereas Hcrt-KO showed a significant decrease in REM sleep expression. In contrast, Hcrt-KO mice increased REM sleep expression upon exposure to Ta warming when presented during the active (dark) phase, a circadian time when WT mice showed no significant changes in REM sleep as a function of Ta. Second, we found that REM sleep and cataplexy can be dissociated through Ta manipulation. Specifically, although Ta warming significantly increased REM sleep expression in Hcrt-KO mice during the active phase, cataplexy bout number and total cataplexy duration significantly decreased. In contrast, cataplexy expression was favoured during Ta cooling when REM sleep expression significantly decreased. Finally, video actigraphy and sleep-wake recordings in Hcrt-KO mice demonstrated that Ta manipulation did not significantly alter waking motor activity patterns or waking or NREM sleep durations. These data suggest that neural circuits gating REM sleep and cataplexy expression can be dissociated with Ta manipulation.

Characterizing psychiatric hypersomnia on campus: contributions of chronotype, insomnia, and tiredness

Study Objectives: The sleep of students contains several features rendering it worthy of independent investigation. Sleep duration is an important aspect of sleep health and wellbeing, however the assessment of psychiatric hypersomnia has been hampered by the absence of a single unitary scale of this construct. With the recent publication of the Hypersomnia Severity Index, research can now examine this condition in greater detail.Methods: Here we consider how the candidate variables of sleep propensity, fatigue, chronotype and insomnia may be associated with hypersomnia scores in a sample of 140 students. Results suggest that hypersomnia was significantly predicted by these measures, but not age or gender. We then model a pathway from chronotype to hypersomnia, including these factors as potential mediators.Results: Results suggest that hypersomnia was significantly predicted by these measures, but not age or gender. The proposed pathway from chronotype to hypersomnia warrants further study.Conclusions: Future studies should expand upon this preliminary report and consider longitudinally and prospectively how hypersomnia is linked to poor mental health in well-characterized samples of students and other young adults.

Assessment of morning sleep propensity with lemborexant in adults with insomnia disorder in a randomized, placebo-controlled crossover study

Objective To evaluate effects of lemborexant (LEM), a dual orexin receptor antagonist, on next-morning sleep propensity assessed by a modified Multiple Sleep Latency Test (M-MSLT) in adults with insomnia disorder. Methods Study 107 (E2006-A001-107) was a phase 1, randomized, double-blind, four-period crossover study. Subjects (n=69) received oral single-dose placebo, LEM 5 mg (LEM5), and LEM 10 mg (LEM10) at bedtime in periods 1–3 in a randomized crossover and open-label flurazepam 30 mg in period 4. After an 8-h overnight sleep opportunity, the M-MSLT measured average sleep onset latency (SOL). Mean change from baseline in average SOL vs. placebo of -6.0 min or more was considered clinically meaningful. Other sleep propensity assessments included the proportion of subjects with average SOL >6 min shorter than placebo. LEM plasma concentrations, safety, and tolerability were also assessed. Results M-MSLT assay sensitivity was confirmed by a clinically meaningful decrease in average SOL with flurazepam vs. placebo (least squares mean [LSM] difference –6.06 min; 1-sided p<0.0001). In contrast, decreases in average SOL with LEM5 (LSM difference vs. placebo –1.15 min; 1-sided p=0.0262) and LEM10 (–3.48 min; p<0.0001) did not meet the pre-defined threshold for a clinically meaningful effect (LEM5, –2.12; LEM10, –4.46). Some individuals did experience higher sleep propensity (average SOL >6.0 min shorter than placebo), particularly with LEM10 (LEM10, 29.4%; LEM5, 13.2%). Conclusions In contrast to flurazepam, LEM5 and LEM10 did not show clinically meaningful mean increases in next-morning sleep propensity vs. placebo. The possibility that some subjects may experience residual morning effects cannot be excluded.

511 Pathological sleep prolongation and sleep onset REM period

Introduction ICSD-3 employs two definitions of pathological sleepiness: sleep prolongation with 24-hour total sleep time (24hrPSG TST) ≥660 and high sleep propensity with mean sleep latency(mSL) ≤8 min on MSLT. Multiple SOREMPs on MSLT reflects the pathophysiology (sleep instability) of narcolepsy, but it is not clear whether the lack of SOREMPs is associated with the pathophysiology of idiopathic hypersomnia. We performed 24hr PSG and PSG-MSLT sequentially to understand the meaning of SOREMP in those with pathological sleep prolongation. Methods Fifty-six consecutive patients visiting Seiwa Hospital or Koishikawa Tokyo Hospital affiliated to Institute of Neuropsychiatry with suspected idiopathic hypersomnia with habitually long sleep time were evaluated by 3-day sleep studies: unattended 24hr PSG followed by PSG and MSLT from January 2017 to November 2020. After excluding inadequate recordings or other sleep pathologies, we analyzed 52 data and found that 39 patients (23 females, 21.8 ± 7.9 years old, BMI 20.4 ± 2.5 kg/m2) exhibited pathological sleep prolongation. Results We divided 39 patients with pathological sleep prolongation into those with at least one SOREMP(n=9) and those without SOREMP(n=30) and explored differences in clinical symptoms and PSG variables. There were no differences in conventional sleep variables except for PSG sleep latency, shorter in those with SOREMP (20.8min vs 43.8min, p=0.032). Also 24hr PSG sleep variables showed no differences except for the number of NREM-REM cycles, more in those with SOREMP (10.4 vs 8.1, p=0.037). Frequency of clinical symptoms such as REM related phenomena and various symptoms characteristic for idiopathic hypersomnia did not differ between groups except for less frequency of general malaise p=0.003 and orthostatic hypotension p=0.049 in those with SOREMP. We had similar results when we compared 5 patients with multiple SOREMPs and 30 patients without SOREMP. Conclusion Our results indicated that sleep variables and clinical characteristics of idiopathic hypersomnia in those with pathological sleep prolongation were mostly the same regardless of the status of SOREMP on MSLT, suggesting that the absence of SOREMPs on MSLT were not fundamentally related to the pathophysiology of those with pathological sleep prolongation (idiopathic hypersomnia with long sleep time). Support (if any):

Cerebrospinal fluid monoamine levels in central hypersomnolence disorders

Study objectives Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear. The neurobiology underlying sleepiness in other central hypersomnolence disorders, narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH), is currently unknown. Methods Eleven biogenic amines including the monoaminergic neurotransmitters and their metabolites and five trace amines were measured in the cerebrospinal fluid (CSF) of 94 drug-free subjects evaluated at the French National Reference Center for Narcolepsy: 39 NT1(orexin-deficient) patients, 31 patients with objective sleepiness non-orexin deficient (NT2 and IH), and 24 patients without objective sleepiness. Results Three trace amines were undetectable in the sample: Tryptamine, Octopamine, and 3-iodothyronamine. No significant differences were found among the three groups for quantified monoamines and their metabolites in crude and adjusted models; however, CSF 5-HIAA levels tended to increase in NT1 compared to other patients after adjustment. Most of biomarkers were not associated with ORX-A levels, clinical or neurophysiological parameters, but a few biomarkers (e.g., MHPG and norepinephrine) correlated with daytime sleepiness and high REM sleep propensity. Conclusion We found no striking differences among CSF monoamines, their metabolites and trace amine levels, and few associations between them and key clinical or neurophysiological parameters in NT1,NT2/IH and patients without objective sleepiness. Although mostly negative, these findings are a significant contribution to our understanding of the neurobiology of hypersomnolence in these disorders that remain mysterious and deserve further exploration.

Effect of Sudarshan Kriya Yoga (SKY) on daytime and situational sleep propensity in novice practitioners: a prospective cohort study

ObjectivesHectic, late-night lifestyle has reduced 90 min sleep in 20% adults resulting in insomnia and excessive daytime sleepiness (EDS). We assess the scope of Sudarshan Kriya Yoga (SKY), a 4-component, breathing process in reducing EDS, generally and situationally.MethodsThis is a prospective, controlled study involving randomized subjects without any sleep-wake cycle anomalies and prior experience in SKY. Subjects (n=52) performed 30 min of SKY for 6 days/week for 8 weeks, while controls (n=53) performed sitting activity and Suryanamaskar for 4-weeks each. Epworth Sleepiness Scale (ESS) was used to measure EDS at 0, 4, and 8 weeks.ResultsSKY group showed significant ESS score improvements between 0–4 weeks and 4–8 weeks of 1.22 (p=0.0001) and 1.66 (p=0.001) respectively. Controls however failed to improve with score differences of 0.02 (p=0.892) and 0.02 (p=0.8212) respectively. SKY group showed significant ESS score improvement over controls at 4-weeks (difference=1.74; p=0.013) and 8-weeks (difference eight; p=0.0001). Improvement was most for obese people and those sitting in a halted car.ConclusionsImprovement in subjects’ nighttime sleep and daytime wakefulness in SKY practitioners can be attributed to polyvagal theory. Increased heart rate variability (HRV) alterations and sympathetic hyperarousal in chronic insomnia; and cholinergic and GABAergic dysregulation in anxiety disorders are countered by regulated vagal nerve stimulation post SKY. Our study establishes effectivity of SKY in reducing EDS (total and situational), provides a clinical correlation for prior polysomnographic evidence and paves way for larger trials directed towards SKY prescriptions for insomnia.

My Husband Tells Me I’m Lazy

Idiopathic hypersomnia is a chronic disorder of excessive daytime sleepiness that is characterized by unrefreshing sleep despite normal or long sleep times and sleep inertia. Both symptoms can interfere with normal functioning. The diagnosis requires confirmation of sleepiness or increased sleep propensity via actigraphy, polysomnography, and/or multiple sleep latency test. Clinical evaluation, sleep diagnostics, and laboratory testing must exclude other disorders of excessive sleepiness. Treatment options are limited by the lack of approval by the U.S. Food and Drug Administration of any medications for this indication, as well as the relatively small number of clinical trials including patients with this disorder. Off-label treatments may be used and new treatments are being researched.