Sleep Inertia Research Articles

Medications for daytime sleepiness in individuals with idiopathic hypersomnia.

Idiopathic hypersomnia is a disorder of excessive daytime sleepiness, often accompanied by long sleep times or pronounced difficulty in awakening, in the absence of a known cause. The optimal treatment strategy for idiopathic hypersomnia is currently unknown. To assess the effects of medications for daytime sleepiness and related symptoms in individuals with idiopathic hypersomnia and, in particular, whether medications may: 1. reduce subjective measures of sleepiness; 2. reduce objective measures of sleepiness; 3. reduce symptoms of cognitive dysfunction; 4. improve quality of life; and 5. be associated with adverse events. We searched the following databases on 4 February 2021: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 1 February 2021), and reference lists of articles. CRS Web includes randomized or quasi-randomized controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialized registers of Cochrane Review Groups, including the Cochrane Epilepsy Group. We previously searched the WHO ICTRP separately when loading of ICTRP records into CRS Web was temporarily suspended. Randomized studies comparing any medication to placebo, another medication, or a behavioral intervention. Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional data. We collected data on adverse events from the included trials. We included three trials, with a total of 112 participants. Risk of bias was low for the included studies. Two pharmaceutical company-sponsored trials compared modafinil with placebo, involving 102 participants, nearly all of whom had idiopathic hypersomnia without long sleep time. Modafinil significantly improved self-reported sleepiness on the Epworth Sleepiness Scale by 5.08 points more than placebo (95% confidence interval (CI) 3.01 to 7.16; 2 studies, 101 participants; high-certainty evidence). Modafinil also significantly improved disease severity on the Clinical Global Impression of Severity scale by 1.02 points (95% CI 0.11 to 1.93; 1 study, 30 participants; moderate-certainty evidence) and resulted in a greater proportion of participants who were "much improved" or "very much improved" on the Clinical Global Impression of Change (odds ratio (OR) for improvement 5.14, 95% CI 1.76 to 15.00; 1 study, 70 participants; moderate-certainty evidence). Ability to remain awake on the Maintenance of Wakefulness Test was significantly improved with modafinil, by 4.74 minutes more than with placebo (95% CI 2.46 to 7.01; 2 studies, 99 participants; high-certainty evidence).Ratings of exhaustion and effectiveness/performance were improved with modafinil compared to placebo in one study.Number of naps per week was no different between modafinil and placebo across two studies. Participants receiving modafinilexperienced more side effects, although the difference did not reach statistical significance (OR 1.68, 95% CI 0.28 to 9.94; 2 studies, 102 participants; low-certainty evidence). One trial studying 20 participants with different disorders of sleepiness included 10 participants with idiopathic hypersomnia, with or without long sleep time, and compared clarithromycin to placebo. We only included the subset of trial data for those participants with idiopathic hypersomnia, per our protocol. There were no significant differences between clarithromycin and placebo for the Epworth Sleepiness Scale, psychomotor vigilance testing, sleep inertia, other subjective ratings, or side effects. Modafinil is effective for the treatment of several aspects of idiopathic hypersomnia symptomatology, based on studies predominantly including participants with idiopathic hypersomnia without long sleep times, with low risk of bias, and evidence certainty ranging from high to low.There is insufficient evidence to conclude whether clarithromycin is effective for the treatment of idiopathic hypersomnia. There is a clear need for additional studies testing interventions for the treatment of idiopathic hypersomnia.

487 Effect of Lower-Sodium Oxybate on Sleep Inertia in Idiopathic Hypersomnia in a Double-Blind, Randomized Withdrawal Study

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness. A common feature is sleep inertia, which is prolonged difficulty waking up accompanied by confusion, disorientation, poor motor coordination, and repeated returns to sleep. Sleep inertia is burdensome to patients, resulting in missed work or school, and patients may be dependent on others to wake them. No treatment is currently approved for IH. The efficacy and safety of lower-sodium oxybate (LXB; Xywav™), a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®), was evaluated in a phase 3 study (NCT03533114) in adults with IH. We focus here on the drug effect on sleep inertia. Methods Eligible participants aged 18–75 years with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP). Participants were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale score. The visual analog scale for sleep inertia (VAS-SI) was included as an exploratory endpoint. The VAS-SI, administered daily during the last 2 weeks of screening before baseline, SDP, and DBRWP, is a self-reported retrospective measure of difficulty awakening each morning using a 100-mm line with anchors 0 (very easy) and 100 (very difficult). Results The safety population included 154 participants (mean±SD age, 40±14 years; 68% female); modified intent-to-treat population, n=115. VAS-SI scores gradually decreased from week 2 of screening (mean±SD, 56.6±25.1) to week 2 of SDP (29.0±20.8). During week 2 of DBRWP, VAS-SI scores worsened in participants randomized to placebo (n=59) compared with maintenance of improvement in participants continuing LXB treatment (n=56); LS mean difference (95% CI) in change from SDP, −22.2 (−29.7, −14.8); P<0.0001 (nominal). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Conclusion Sleep inertia improved with LXB treatment and significant differences were seen between placebo and LXB after DBRWP. The overall safety profile in participants with IH is consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals, Inc

022 Cytokines as correlates of reported symptoms in disorders of hypersomnolence

Abstract Introduction Cytokines are known for their role in inflammation, and more recently in sleepiness and fatigue. There is a paucity of data regarding cytokines in Idiopathic Hypersomnia (IH) and Narcolepsy Type 2 (NT2) as defined by the International Classifications of Sleep Disorders-Third Edition. Additionally the heterogenous cohort of patients with excessive daytime sleepiness (EDS), but do not meet criteria for a sleep disorder, has not been studied separately from IH patients. Methods The study cohort was a convenience sample evaluated at a single tertiary-care sleep center between 2016 and 2019. Diagnoses were IH, NT2, EDS, and controls (based on sleep laboratory testing). The following cytokines were measured using the Mesoscale U-PLEX biomarker assay: G-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, MCP-1, and TNF-α. Demographic data and survey data pertaining to sleepiness, depression, and sleep inertia were available for all. Results The study cohort consisted of 22 controls, 26 patients with EDS, 51 patients with IH, and 12 patients with NT2. There were no significant differences between diagnosis and any cytokine. Pearson correlations showed significant negative correlations between G-CSF concentrations with depression (p=0.05) and sleep inertia (p<0.01) in patients but not controls. In controls, hours slept per week positively correlated with G-CSF (p=0.05), but this was not true in patients with EDS, IH, or NT2. IL-8 level was negatively correlated with reported sleep inertia in sleepy patients (p=0.05), but not controls. Conclusion Though differences in cytokines levels between diagnostic groups did not reach significance, several cytokines correlated with severity of reported symptoms in disorders of hypersomnolence. G-CSF and IL-8 may serve as a biomarker for symptoms of depression and sleep inertia in sleepiness disorders, and thus could be a targeted for therapies. Support (if any) Hypersomnia Foundation Grant

512 Confirmatory Factor Analysis of the Sleep Inertia Questionnaire in a Clinical Sample with Sleep Disorders

Abstract Introduction The Sleep Inertia Questionnaire (SIQ) was developed and validated in patients with mood disorders to evaluate difficulties with becoming fully awake after nighttime sleep or daytime naps in a multidimensional manner. However, few data are available regarding its psychometric properties in clinical samples with sleep disorders. Methods 211 patients (43.0±16.4 years old, 68% female, 17% minority) evaluated at the Behavioral Sleep Medicine (BSM) program of Penn State Health Sleep Research & Treatment Center completed the SIQ. All patients were diagnosed using ICSD-3 criteria, with 111 receiving a diagnosis of chronic insomnia disorder (CID), 48 of a central disorder of hypersomnolence (CDH), and 52 of other sleep disorders (OSD). Structural equation modelling was used to conduct confirmatory factor analysis (CFA) of the SIQ. Results CFA supported four SIQ dimensions of “physiological”, “cognitive”, “emotional” and “response to” (RSI) sleep inertia with adequate goodness-of-fit (TLI=0.90, CFI=0.91, GFI=0.85, RMSEA=0.08). Internal consistency was high (α=0.94), including that of its dimensions (physiological α=0.89, cognitive α=0.94, emotional α=0.67, RSI α=0.78). Dimension inter-correlations were moderate to high (r=0.42–0.93, p<0.01), indicating good construct validity. Convergent validity showed moderate correlations with Epworth sleepiness scale (ESS) scores (r=0.38) and large correlations with Flinders fatigue scale (FFS) scores (r=0.65). Criterion validity showed significantly (p<0.01) higher scores in subjects with CDH (69.0±16.6) as compared to those with CID (54.4±18.3) or OSD (58.5±20.0). A SIQ cut-off score ≥57.5 provided a sensitivity/specificity of 0.77/0.65, while a cut-off score ≥61.5 provided a sensitivity/specificity of 0.71/0.70 to identify CDH vs. ESS<10 (AUC=0.76). Conclusion The SIQ shows satisfactory indices of reliability and construct validity in a clinically-diverse sleep disorders sample. Its criterion validity is supported by its divergent association with hypersomnia vs. insomnia disorders, as well as its adequate sensitivity/specificity to identify patients with CDH. The SIQ can help clinicians easily assess the complex dimensionality of sleep inertia and target behavioral sleep treatments. Future studies should confirm the best SIQ cut-off score by including good sleeping controls, while clinical studies should determine its minimal clinically important difference after pharmacological or behavioral treatments. Support (if any):

500 Correlation of the Idiopathic Hypersomnia Severity Scale With Other Measures of Sleep Parameters in a Phase 3 Trial

Abstract Introduction The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses core Idiopathic Hypersomnia (IH) symptom severity. The relationship between IHSS scores and other IH symptom measures, such as the Epworth Sleepiness Scale (ESS; measures daytime sleepiness), sleep inertia visual analog scale (VAS-SI; measures sleep inertia), and Patient Global Impression of Change (PGIc; measures patients’ self-assessed change in symptoms), has not been established. This post hoc analysis analyzed correlations between the IHSS and ESS, VAS-SI, and PGIc using data from a clinical trial (NCT03533114) evaluating lower-sodium oxybate (LXB; Xywav™) for the treatment of IH. Methods During a clinical trial, the IHSS (0–50 score range) and ESS (0–24 score range) were completed at baseline; the IHSS, ESS, and PGIc (ordinal, 7 categories) were completed during an open-label treatment titration and optimization period (OLTTOP), after the OLTTOP, after a stable-dose period (SDP), and after a double-blind, randomized withdrawal period (DBRWP). The VAS-SI (0–100 score range) was completed during screening, SDP, and DBRWP. Correlation coefficients (rs) for IHSS vs ESS and VAS-SI were estimated from the within-subject variance matrix using a repeated-measures linear mixed model (LMM). The correlation between changes in IHSS score and PGIc was assessed using a Kruskal-Wallis test. Results IHSS scores correlated positively with ESS scores (rs [95% CI], 0.77 [0.73, 0.81]) and VAS-SI scores (0.69 [0.63, 0.75]). IHSS total score change was correlated with PGIc rank (chi-square with 6 degrees of freedom = 595.8, nominal P<0.001). The LMM showed that a 3-point change in ESS score corresponded to an average 3.99-point change in IHSS score; a 10-point change in VAS-SI score corresponded to an average 3-point change in IHSS score. Participants very much improved in the PGIc had a −12.13 (95% CI: −13.23, −11.04) expected change in IHSS score. Participants much improved in the PGIc had a −8.39 (95% CI: −9.30, −7.48) expected change in IHSS score. Conclusion IHSS scores or score changes strongly correlated with individual instruments assessing excessive daytime sleepiness, sleep inertia, and self-reported global symptoms, suggesting that the IHSS is a reliable, comprehensive measure of these symptoms of IH. Support (if any) Jazz Pharmaceuticals

495 Efficacy of Lower-Sodium Oxybate on Idiopathic Hypersomnia, Measured by the Idiopathic Hypersomnia Severity Scale

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder with no approved treatment, characterized by excessive daytime sleepiness, prolonged sleep time, and sleep inertia. The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses severity of IH symptoms, including symptoms related to night/inertia (component I) and day/performance (component II). Individual IHSS items measure symptom frequency, intensity, and consequences using 3- or 4-point Likert scales, yielding a total score (range, 0–50), comprising component I (range, 0–16) and component II (range, 0–34). Higher scores indicate worse symptoms. In a recent clinical trial of the efficacy and safety of lower-sodium oxybate (LXB; Xywav™) for the treatment of IH, the IHSS was a key efficacy measure. Methods Eligible participants 18–75 years of age with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week stable-dose period (SDP). Participants were randomized to placebo or continued LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The IHSS was completed at baseline, during OLTTOP (weeks 1, 4, and 8), and at the end of OLTTOP, SDP, and DBRWP. Change in IHSS total score from SDP to DBRWP was a key secondary endpoint. Results The efficacy population included 115 participants (mean±SD age, 41±14 years; 71% female). At baseline and the end of SDP, respectively, mean±SD IHSS scores were 31.6±8.3 and 15.3±8.5 for total score, 10.3±3.6 and 5.4±2.8 for component I (night/inertia), and 21.2±5.8 and 9.9±6.5 for component II (day/performance). Worsening from SDP to DBRWP was observed in patients randomized to placebo compared with LXB in IHSS total scores (estimated median difference [95% CI], −12.0 [−15.0, −8.0]; significant P<0.0001), component I scores (LS mean difference [95% CI], −3.9 [−4.9, −2.9]; nominal P<0.0001), and component II scores (LS mean difference [95% CI], −7.8 [−9.6, −5.9]; nominal P<0.0001). Results on all individual IHSS items reflected an improvement with LXB treatment over time during OLTTOP, which remained consistent during SDP. Conclusion These results support the efficacy of LXB for the treatment of IH symptoms, as assessed with the IHSS. Support (if any) Jazz Pharmaceuticals

302 Sleep, Sleepiness, and Performance Across Three In-Flight Bunk Rest Opportunities

Abstract Introduction Airline pilots are required to take a rest break in a bunk during long-haul flights in an effort to reduce sleepiness during critical phases of flight. It is unclear, however, whether each rest break affords equal opportunity for sleep. We aimed to characterize sleep, sleepiness, and performance outcomes across three in-flight rest breaks during long-haul flights. Methods Thirty-seven pilots wore actiwatches and completed sleep diaries for approximately two weeks while flying a variety of long-haul routes (n=126 flights). Self-reported in-flight bunk rest (BR) periods were used to set rest intervals and sleep was estimated within these intervals using actigraphy software (wake threshold set to medium). Pilots provided Karolinska Sleepiness Scale ratings (KSS) and performed a 5-minute psychomotor vigilance task (PVT) before landing. A linear mixed-effects model with participant included as a random effect and allowed to vary by intercept was used to assess differences between BR opportunities. Results The majority (97%, n=122) of BR periods contained sleep (as estimated by actigraphy). The mean (+/- standard deviation) sleep duration for the first, middle, and third BR opportunity was 152.8 (69.7), 149.2 (44.1), 125.2 (44.9) minutes, respectively. There was a significant effect of BR opportunity for sleep duration (F(2,54) = 3.747, p=.03) and KSS (F(2,44) = 7.869, p=.001). Bonferroni adjusted planned pairwise contrasts revealed that pilots using the third BR obtained significantly less sleep than in the first BR (p=.029). KSS ratings prior to landing were higher for the third BR compared to both the first (p=.001) and middle BR (p=.017). There were no significant differences for PVT speed or lapses (all p>05). Conclusion These results suggest that the last rest break is associated with shorter sleep, lower alertness, and no differences in performance relative to the other rest breaks. Further analysis is required to determine whether the higher KSS ratings following the third rest break are associated with sleep inertia, or whether other factors may be involved. Support (if any) NASA Airspace Operations and Safety Program, System-Wide Safety Project

841 PAP Therapy Data Provides Clues To Comorbid Sleep Disorders

Abstract Introduction Obstructive sleep apnea (OSA) is a common condition and positive airway pressure (PAP) therapy is the treatment of choice. Treatment guidelines recommend monitoring objective PAP usage data to track treatment efficacy. A typical report includes the percentage of days/month and cumulative hours/day a PAP device was used. In addition, PAP therapy timing can be graphically viewed with use plotted by time/day. This latter presentation reveals patterns of usage that can identify comorbid sleep disorders. Report of case(s) Case 1: A 65-year-old male with OSA presented with sleep inertia despite compliance with PAP therapy. Therapy timing data revealed a delayed circadian phase, with bedtime of 4 am and wake time of 1 pm. Circadian phase advancement therapy was added. Case 2: An 86-year-old male with OSA presented with daytime sleepiness after years of excellent PAP usage. Two years earlier, he was diagnosed with Parkinson’s disease and developed increasing afternoon sleepiness. Compliance data showed a mild reduction in PAP usage. However, therapy timing data revealed an irregular sleep-wake rhythm disorder with sleep scattered around the clock, consistent with neurodegenerative disease. Case 3: A 70 year-old-female with PTSD and OSA presented with persistent tiredness and difficulty initiating and maintaining sleep despite good compliance with PAP therapy. Her timing data showed irregular sleep times with long gaps in usage suggestive of sleep maintenance insomnia. After starting a behavioral treatment regimen her pattern regularized and awakenings reduced, seen by consistent PAP use. Case 4: An 80-year-old female with OSA complained of early morning awakenings despite PAP use with good compliance. Review of PAP therapy timing revealed a pattern suggestive of advanced sleep-wake phase disorder. Circadian phase delay therapy was started. Conclusion Patients with OSA on PAP therapy may have comorbid sleep disorders impacting sleep quality. PAP therapy data can provide information on sleep-wake behavior similar to actigraphy to help diagnose these conditions and track treatment response. Support (if any) None

494 Placebo-Controlled, Double-Blind, Randomized Withdrawal Study of Lower-Sodium Oxybate in Adults With Idiopathic Hypersomnia

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia. No US/EU medication is approved for treatment of IH. Lower-sodium oxybate (LXB; Xywav™; previously designated JZP-258) is a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®). The efficacy and safety of LXB was evaluated in adults with IH. Methods Eligible participants aged 18–75 years with IH began once- or twice-nightly LXB treatment entering an open-label titration and optimization period (10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP); they were then randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score; key secondary endpoints were proportion of participants who reported worsening (minimally/much/very much worse) on Patient Global Impression of Change (PGIc) and change in Idiopathic Hypersomnia Severity Scale (IHSS) score, all from end of SDP to end of DBRWP. Results The study enrolled 154 participants (mean±SD age, 40±14 years; 68% female; mean±SD ESS, 16±3.6); mean±SD dose was 6.0±1.6 g/night. Mean±SD ESS score (n=115) decreased over open-label titration/optimization (15.7±3.8 at baseline, 9.8±4.5 at week 4, and 6.1±4.0 at the end of the SDP). At the end of the DBRWP, significant worsening was observed in participants randomized to placebo, compared with maintenance of improvement in participants randomized to continue LXB, in ESS scores (n=115; LS mean difference [95% CI] in change from SDP, −6.51 [−7.99, −5.03]; P<0.0001), in the PGIc (88.1% for placebo vs 21.4% for LXB; P<0.0001), and in IHSS scores (estimated median difference [95% CI], −12.00 [−15.0, −8.0]; P<0.0001). Common adverse events (AEs) included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Serious AEs occurred in 4 participants (non-cardiac chest pain, rhabdomyolysis, syncope, and nephrolithiasis/pyelonephritis); none were reported related to study drug. Conclusion In participants with IH, LXB demonstrated a clinically meaningful effect on excessive daytime sleepiness, self-reported global change, and overall IH symptom severity. The overall safety profile was consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals

075 Systematic Individual Differences in Vulnerability to Sleep Inertia

Abstract Introduction Sleep inertia (SI), the transient grogginess and disorientation that occurs upon awakening, may be particularly problematic in on-call operations that require safety-sensitive and time-critical action, such as healthcare and emergency response. The magnitude of SI is determined by multiple factors, including sleep history, and anecdotal evidence suggests individuals may differ considerably in susceptibility to impairment from SI. Methods As part of a larger study investigating individual differences in neurobehavioral impairment, N=21 healthy adults (aged 21–38y; 9 females) completed three laboratory-based neurobehavioral testing sessions, each preceded by baseline sleep. Baseline sleep and nightly at-home sleep opportunities during the week prior were either 12h (extended) or 6h (restricted); two sessions involved extension and one involved restriction in randomized, counterbalanced order. Baseline sleep opportunities ended at 10:00, whereupon subjects completed a 60min neurobehavioral test battery, which began with the Karolinska Sleepiness Scale (KSS). The test battery was repeated every 2h throughout the testing sessions. Results A nonlinear mixed-effects regression, controlling for prior sleep restriction/extension and session number, was used to estimate the subjective magnitude of SI immediately upon awakening from baseline sleep, as measured by KSS scores, and the exponential dissipation rate of the effect relative to KSS scores later in the day (12:00-20:00). Following prior sleep extension, SI was associated with a 1.82±0.59 KSS score increase (p=0.006), which subsequently dissipated from a level of 4.80±0.65 to 2.98±0.29 (p=<0.001) later in the day. Following prior sleep restriction, SI was associated with a 1.58±0.58 KSS score increase (p=0.014), which subsequently dissipated from a level of 5.39±0.63 to 3.80±0.30 later in the day. SI took ~45min to dissipate to a negligible level based on a time constant estimate of 23.6±15.8min. Importantly, there were substantial, systematic individual differences in the magnitude of SI, with a between-subjects standard deviation of 1.15±0.42 points on the KSS (ICC=0.51, F=19.5, p<0.001). Conclusion We observed sizeable, systematic individual differences in subjective sleepiness due to sleep inertia. To what degree these individual differences predict objective performance deficits remains to be investigated. Support (if any) NASA grant NAG9-1161 and CDMRP grant W81XWH-20-1-0442

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.

This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of central disorders of hypersomnolence in adults and children. The review focuses on prescription medications with U.S. Food & Drug Administration approval and nonpharmacologic interventions studied for the treatment of symptoms caused by central disorders of hypersomnolence. The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to perform a systematic review. Randomized controlled trials and observational studies addressing pharmacological and nonpharmacological interventions for central disorders of hypersomnolence were identified. Statistical analyses were performed to determine the clinical significance of all outcomes. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process was used to assess the evidence for the purpose of making specific treatment recommendations. The literature search identified 678 studies; 144 met the inclusion criteria and 108 provided data suitable for statistical analyses. Evidence for the following interventions is presented: armodafinil, clarithromycin, clomipramine, dextroamphetamine, flumazenil, intravenous immune globulin (IVIG), light therapy, lithium, l-carnitine, liraglutide, methylphenidate, methylprednisolone, modafinil, naps, pitolisant, selegiline, sodium oxybate, solriamfetol, and triazolam. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. Maski K, Trotti LM, Kotagal S, etal. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(9):1895-1945.

Time Course of Sleep Inertia Dissipation in Memory Tasks

Sleep inertia (SI) refers to a complex psychophysiological phenomenon, observed after awakening, that can be described as the gradual recovery of waking-like status. The time course of cognitive performance dissipation in an everyday life condition is still unclear, especially in terms of the sleep stage at awakening (REM or NREM-stage 2) and the relative effects on performance. The present study aimed to investigate the SI dissipation in different memory performances upon spontaneous morning awakening after uninterrupted nighttime sleep. Eighteen young adults (7 females; mean age 24.9 ± 3.14 years) spent seven non-consecutive nights (one baseline, three REM awakenings and three St2 awakenings) in the laboratory under standard polysomnographic (PSG) control. Participants were tested after three REM awakenings and three St2 awakenings, and three times at 11:00 a.m. as a control condition. In each testing session, participants filled in the Global Vigor and Affect Scale and carried out one memory task (episodic, semantic, or procedural task). For each condition, participants were tested every 10 min within a time window of 80 min. In accordance with previous studies, SI affected subjective alertness throughout the entire time window assessed. Moreover, SI significantly affected performance speed but not accuracy in the semantic task. With reference to this task, the SI effect dissipated within 30 min of awakening from REM, and within 20 min of awakening from St2. No significant SI effect was observed on episodic or procedural memory tasks.

The Awakening Futures Sound Positive! Commentary On The Efficacy For Audio To Counteract Sleep Inertia

The Awakening Futures Sound Positive! Commentary On The Efficacy For Audio To Counteract Sleep Inertia

The Inert Brain: Explaining Neural Inertia as Post-anaesthetic Sleep Inertia.

“Neural inertia” is the brain’s tendency to resist changes in its arousal state: it is manifested as emergence from anaesthesia occurring at lower drug doses than those required for anaesthetic induction, a phenomenon observed across very different species, from invertebrates to mammals. However, the brain is also subject to another form of inertia, familiar to most people: sleep inertia, the feeling of grogginess, confusion and impaired performance that typically follows awakening. Here, we propose a novel account of neural inertia, as the result of sleep inertia taking place after the artificial sleep induced by anaesthetics. We argue that the orexinergic and noradrenergic systems may be key mechanisms for the control of these transition states, with the orexinergic system exerting a stabilising effect through the noradrenergic system. This effect may be reflected at the macroscale in terms of altered functional anticorrelations between default mode and executive control networks of the human brain. The hypothesised link between neural inertia and sleep inertia could explain why different anaesthetic drugs induce different levels of neural inertia, and why elderly individuals and narcoleptic patients are more susceptible to neural inertia. This novel hypothesis also enables us to generate several empirically testable predictions at both the behavioural and neural levels, with potential implications for clinical practice.

Idiopathic hypersomnia: a homogeneous or heterogeneous disease?

IntroductionIdiopathic hypersomnia (IH) is a rare orphan disease characterized by excessive daytime sleepiness, frequently accompanied by prolonged nocturnal sleep and difficulties awakening, termed sleep inertia or sleep drunkenness. Severe sleepiness usually causes a greater handicap than manifestations of narcolepsy. MethodsForty-three IH patients (17 male, mean age 42.8 ± SD 12.2 years, range 20–67), diagnosed in the past 20 years according to ICSD-2 or ICSD-3 criteria were invited for clinical examination to evaluate the course, manifestations and severity of the disease, as well as clinical comorbidities. The patients completed a set of questionnaires scoring sleepiness, sleep inertia, fatigue, depression, anxiety, circadian preference, and quality of life. ResultsIH patients were divided according to the duration of nocturnal sleep at the time of their diagnosis into two cohorts: (1) with normal sleep duration (n = 25, 58.1%) and (2) with long sleep duration (n = 18, 41.9%). The mean duration of ad libitum sleep per 22 h in the second cohort was 732.0 ± 115.4 min (range 603–1100), and women markedly prevailed (n = 14, 77.8%). Age at disease onset was younger in the group with long sleep duration (21.2 ± 11.4 years versus 28.1 ± 13.6 years, p = 0.028), their MSLT latency was longer (7.2 ± 3.7 min versus 5.1 ± 1.7 min, p = 0.005), a history of sleep inertia prevailed (p = 0.005), and daily naps were mostly non-refreshing (p = 0.014). Additionally, questionnaires in the group with long sleep duration showed more severe sleep inertia (p = 0.007), fatigue (p = 0.004), and a tendency towards evening chronotype (p = 0.001). ConclusionsIH patients with long sleep duration differ clinically as well as by objective measures at the time of diagnosis and in long-term follow up from IH patients without long 24-h sleep time. In our opinion they represent an independent clinical entity to be considered in the revised ICSD-3 criteria.

Identifying Diurnal Variability of Brain Connectivity Patterns Using Graph Theory.

Significant differences exist in human brain functions affected by time of day and by people’s diurnal preferences (chronotypes) that are rarely considered in brain studies. In the current study, using network neuroscience and resting-state functional MRI (rs-fMRI) data, we examined the effect of both time of day and the individual’s chronotype on whole-brain network organization. In this regard, 62 participants (39 women; mean age: 23.97 ± 3.26 years; half morning- versus half evening-type) were scanned about 1 and 10 h after wake-up time for morning and evening sessions, respectively. We found evidence for a time-of-day effect on connectivity profiles but not for the effect of chronotype. Compared with the morning session, we found relatively higher small-worldness (an index that represents more efficient network organization) in the evening session, which suggests the dominance of sleep inertia over the circadian and homeostatic processes in the first hours after waking. Furthermore, local graph measures were changed, predominantly across the left hemisphere, in areas such as the precentral gyrus, putamen, inferior frontal gyrus (orbital part), inferior temporal gyrus, as well as the bilateral cerebellum. These findings show the variability of the functional neural network architecture during the day and improve our understanding of the role of time of day in resting-state functional networks.

NonREM Disorders of Arousal and Related Parasomnias: an Updated Review.

Parasomnias are abnormal behaviors and/or experiences emanating from or associated with sleep typically manifesting as motor movements of varying semiology. We discuss mainly nonrapid eye movement sleep and related parasomnias in this article. Sleepwalking (SW), sleep terrors (ST), confusional arousals, and related disorders result from an incomplete dissociation of wakefulness from nonrapid eye movement (NREM) sleep. Conditions that provoke repeated cortical arousals, and/or promote sleep inertia, lead to NREM parasomnias by impairing normal arousal mechanisms. Changes in the cyclic alternating pattern, a biomarker of arousal instability in NREM sleep, are noted in sleepwalking disorders. Sleep-related eating disorder (SRED) is characterized by a disruption of the nocturnal fast with episodes of feeding after arousal from sleep. SRED is often associated with the use of sedative-hypnotic medications, in particular the widely prescribed benzodiazepine receptor agonists. Compelling evidence suggests that nocturnal eating may in some cases be another nonmotor manifestation of Restless Legs Syndrome (RLS). Initial management should focus upon decreasing the potential for sleep-related injury followed by treating comorbid sleep disorders and eliminating incriminating drugs. Sexsomnia is a subtype of disorders of arousal, where sexual behavior emerges from partial arousal from nonREM sleep. Overlap parasomnia disorders consist of abnormal sleep-related behavior both in nonREM and REM sleep. Status dissociatus is referred to as a breakdown of the sleep architecture where an admixture of various sleep state markers is seen without any specific demarcation. Benzodiazepine therapy can be effective in controlling SW, ST, and sexsomnia, but not SRED. Paroxetine has been reported to provide benefit in some cases of ST. Topiramate, pramipexole, and sertraline can be effective in SRED. Pharmacotherapy for other parasomnias continues to be less certain, necessitating further investigation. NREM parasomnias may resolve spontaneously but require a review of priming and predisposing factors.

The effect of post-lunch napping on mood, reaction time, and antioxidant defense during repeated sprint exercice.

To compare the effects of two nap opportunities (20 and 90 min) to countermeasure the transient naturally occurring increased sleepiness and decreased performances during the post-lunch dip (PLD). Fourteen highly trained judokas completed in a counterbalanced and randomized order three test sessions (control (No-nap), 20- (N20) and 90-min (N90) nap opportunities). Test sessions consisted of the running-based anaerobic sprint test (RAST), simple and multiple-choice reaction times (MCRT) and the Epworth sleepiness scale (ESS). From the RAST, the maximum (Pmax), mean (Pmean) and minimum (Pmin) powers were calculated. Blood samples were taken before and after the RAST to measure the effect of pre-exercise napping on energetic and muscle damage biomarkers and antioxidant defense. N20 increased Pmax and Pmean compared to No-nap (p < 0.001, d = 0.59; d = 0.66) and N90 (p < 0.001, d = 0.98; d = 0.72), respectively. Besides, plasma lactate and creatinine increased only when the exercise was performed after N20. Both N20 (p < 0.001, d = 1.18) and N90 (p < 0.01, d = 0.78) enhanced post-exercise superoxide dismutase activity compared to No-nap. However, only N20 enhanced post-exercise glutathione peroxidase activity (p < 0.001, d = 1.01) compared to pre-nap. Further, MCRT performance was higher after N20 compared to No-nap and N90 (p < 0.001, d = 1.15; d = 0.81, respectively). Subjective sleepiness was lower after N20 compared to No-nap (p < 0.05, d = 0.92) and N90 (p < 0.01, d = 0.89). The opportunity to nap for 20 min in the PLD enhanced RAST, MCRT performances, and antioxidant defense, and decreased sleepiness. However, the opportunity of 90 min nap was associated with decreased repeated sprint performances and increased sleepiness, probably because of the sleep inertia.

Sleep inertia in automated driving: Post-sleep take-over and driving performance

Sleep is emerging as a new driver state in automated driving. Post-sleep performance impairments due to sleep inertia, the transitional phase from sleep to wakefulness that can take up to 30 min, are a potential safety issue. Take-over performance immediately after sleep is impaired and drivers perceive the take-over as critical. The aim of the presented study was to assess take-over behavior immediately after sleep and driving behavior during the 10 min after sleep. A study with N = 31 drivers was conducted in a high-fidelity driving simulator. Take-over performance and driving performance were assessed a) under alert baseline conditions and b) after awakening from electroencephalography-confirmed stable sleep. Take-over performance 15 s after awakening was impaired resulting in more driving errors compared to the alert baseline. Lane keeping was dramatically impaired in the first 3 min after sleep and recovered rapidly. Drivers drove slower after sleep and speed keeping was less stable for at least 10 min. The results suggest that human-machine interaction design should account for the drivers’ impaired post-sleep driving performance.

Alarm Tones, Voice Warnings, and Musical Treatments: A Systematic Review of Auditory Countermeasures for Sleep Inertia in Abrupt and Casual Awakenings

Sleep inertia is a measurable decline in cognition some people experience upon and following awakening. However, a systematic review of the current up to date evidence of audio as a countermeasure has yet to be reported. Thus, to amend this gap in knowledge, the authors conducted this systematic review beginning with searches in three primary databases for studies published between the inception date of each journal and the year 2020. Search terms contained “Sleep Inertia” paired with: “Sound”; “Noise”; “Music”; “Alarm”; “Alarm Tone”; “Alarm Sound”; “Alarm Noise”; “Alarm Music”; “Alarm Clock”; “Fire Alarm”, and “Smoke Alarm”. From 341 study results, twelve were identified for inclusion against a priori conditions. A structured narrative synthesis approach generated three key auditory stimulus themes-(i) Noise, (ii) Emergency tone sequences; Voice Alarms and Hybrids, and (iii) Music. Across themes, participants have been assessed in two situational categories: emergency, and non-emergency awakenings. The results indicate that for children awakening in emergency conditions, a low pitch alarm or voice warnings appear to be more effective in counteracting the effects of sleep inertia than alarms with higher frequencies. For adults abruptly awakened, there is insufficient evidence to support firm conclusions regarding alarm types and voice signals. Positive results have been found in non-emergency awakenings for musical treatments in adults who preferred popular music, and alarms with melodic qualities. The results observed reflect the potential for sound, voice, and musical treatments to counteract sleep inertia post-awakening, and emphasize the requirements for further research in this domain.