Clinical effectiveness of internet-based cognitive behavioral therapy for insomnia in routine secondary care: results of a randomized controlled trial.

Introduction: Delivering cognitive behavioral therapy for insomnia over the internet bears the advantage of accessibility and uptake to many patients suffering from chronic insomnia. In the current study, we aimed to investigate the effectiveness of internet-based cognitive behavioral therapy for insomnia (iCBT-I) in routine care. Materials and methods: We conducted a two-arm non-blinded randomized controlled trial with care as usual (CAU) as a control condition. Participants were recruited in a specialized outpatient sleep medicine department. Both arms had access to other healthcare resources, and the intervention group had access to the iCBT-I program for 2 months. The primary outcome was insomnia severity, measured by the Insomnia Severity Index (ISI). Secondary outcomes were fatigue severity, daytime sleepiness, affective symptoms, dysfunctional beliefs and attitudes about sleep, sleep locus of control, sleep hygiene, sleep efficiency (SE), sleep onset latency, wake time after sleep onset (WASO), and total sleep time (TST). Linear mixed models for repeated measures were used to analyze the longitudinal data at baseline, post-treatment, and after 3 months of follow-up. The trial was registered at www.clinicaltrials.gov (NCT04300218 21.04.2020). Results: The results showed a significant time*group interaction effect (p = 0.001) at post-treatment with between-group effect size (d = 0.51), indicating that the ISI decreased by a score of 3.8-fold in the iCBT-I group than in the CAU group. There was no significant difference in ISI between groups at follow-up. Regarding secondary outcomes, dysfunctional beliefs about sleep, SE, and WASO decreased significantly during treatment in the intervention group with between-group effect sizes d = 0.35, d = -0.51, and d = 0.47, respectively. At the follow-up, between-group effects on DBAS and SE remained significant: d = 0.36 and d = -0.63, respectively. For TST, we observed a significant time*group effect of d = -0.38 only after follow-up. Conclusion: Our findings suggest that iCBT-I has a significant effect on insomnia severity at post-treatment compared to CAU. iCBT-I further improved dysfunctional beliefs about sleep and improved subjective sleep characteristics, such as SE, WASO, and TST during 3 months after treatment. Clinical trial registration: www.clinicaltrials.gov, identifier (NCT04300218).

Phototherapy of Alzheimer's Disease: Photostimulation of Brain Lymphatics during Sleep: A Systematic Review.

The global number of people with Alzheimer's disease (AD) doubles every 5 years. It has been established that unless an effective treatment for AD is found, the incidence of AD will triple by 2060. However, pharmacological therapies for AD have failed to show effectiveness and safety. Therefore, the search for alternative methods for treating AD is an urgent problem in medicine. The lymphatic drainage and removal system of the brain (LDRSB) plays an important role in resistance to the progression of AD. The development of methods for augmentation of the LDRSB functions may contribute to progress in AD therapy. Photobiomodulation (PBM) is considered to be a non-pharmacological and safe approach for AD therapy. Here, we highlight the most recent and relevant studies of PBM for AD. We focus on emerging evidence that indicates the potential benefits of PBM during sleep for modulation of natural activation of the LDRSB at nighttime, providing effective removal of metabolites, including amyloid-ß, from the brain, leading to reduced progression of AD. Our review creates a new niche in the therapy of brain diseases during sleep and sheds light on the development of smart sleep technologies for neurodegenerative diseases.

Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Narcolepsy is a life-long disorder characterised by excessive daytime sleepiness and cataplexy, often arising in childhood or adolescence. Pitolisant, a selective histamine H3 receptor inverse agonist, has been approved in Europe and USA for adults with narcolepsy with or without cataplexy, with a favourable safety profile. This phase 3 study aimed to assess the safety and efficacy of pitolisant in children with narcolepsy with or without cataplexy. METHODS: For this double-blind, randomised, placebo-controlled, multisite study, we recruited patients aged 6-17 years with narcolepsy with or without cataplexy in 11 sleep centres in five countries (Italy, France, Netherlands, Russia, and Finland). Participants were required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and to have not received psychostimulants for at least 14 days before enrolment; participants who needed anticataplectics (including sodium oxybate) were required to have been on a stable dose for at least 1 month. Participants were randomly assigned to treatment with pitolisant or placebo in a 2:1 ratio at the end of screening. Randomisation was stratified by study centre and treatment was allocated using an interactive web response system. After a 4-week screening period including a 2-week baseline period, patients entered in a 4-week individual up-titration scheme from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo; treatment was administered at a stable dose for 4 weeks, followed by a 1-week placebo period. For the primary analysis, we assessed pitolisant versus placebo using change in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of double-blind period in the full analysis set, defined as all randomly allocated patients who received at least one dose of treatment and who had at least one baseline UNS value. A decrease in the UNS total score reflects a reduction in both excessive daytime sleepiness and cataplexy. All adverse events were assessed in the safety population, defined as all participants who took at least one dose of study medication. An open-label follow-up is ongoing. This study is registered at ClinicalTrials.gov, NCT02611687. FINDINGS: Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned (mean age 12·9 [SD 3·0] years, 61 [55%] male, and 90 [82%] with cataplexy; 72 assigned to pitolisant and 38 to placebo); 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. The mean adjusted difference in UNS total score from baseline to the end of the double-blind period was -6·3 (SE 1·1) in the pitolisant group and -2·6 (1·4) in the placebo group (least squares mean difference -3·7; 95% CI -6·4 to -1·0, p=0·007). Treatment-emergent adverse events were reported in 22 (31%) of 72 patients in the pitolisant group and 13 (34%) of 38 patients in the placebo group. The most frequently reported adverse events (affecting ≥5% of patients) in either group were headache (14 [19%] in the pitolisant group and three [8%] in the placebo group) and insomnia (five [7%] in the pitolisant group and one [3%] in the placebo group). INTERPRETATION: Pitolisant treatment resulted in an improvement in narcolepsy symptoms in children, although the UNS was not validated for use in children with narcolepsy when our study began. The safety profile was similar to that reported in adults but further studies are needed to confirm long-term safety. FUNDING: Bioprojet.

Periodic Limb Movements Syndrome in Patients With Cerebral Small Vessel Disease: Protocol for a Prospective Observational Study.

Background: Cerebrovascular diseases are the leading cause of cognitive decline and dementia. Therefore, the investigation of the potential ways to slow down the disease progression is an important research field. Periodic limb movements in sleep (PLMS) are known to be associated with transient changes in heart rate and blood pressure. These changes might influence the course of cerebral small vessel disease (cSVD). Nevertheless, the clinical significance of PLMS, particularly its influence on cardiovascular diseases course, is still controversial and underinvestigated. Methods/design: Patients from 60 to 75 years old diagnosed with cSVD will undergo nocturnal polysomnography. Subjects with apnea/hypopnea index under 5 will be enrolled. Sleep quality and daytime functioning will be assessed at baseline with self-reported questionnaires. Brain MRI and cognitive assessment will be performed at baseline and in the 2-year follow-up. Progression of cSVD markers and cognitive dysfunction will be compared between patients with PLMS index (PLMI) equal to or more than 15 movements per hour of sleep and controls (PLMI <15/h). Discussion: The negative role of PLMS in cSVD progression and related cognitive decline is expected. We suppose that patients with PLMS tend to worsen in cognitive performance more rapidly than age-, gender-, and comorbidity-matched controls. We also expect them to have more rapid white matter hyperintensities and other cSVD marker progression. The limitations of the study protocol are the short follow-up period, the absence of a treatment group, and inability to make a conclusion about causality.

Xerostomia and hyposalivation in patients with obstructive sleep apnoea.

OBJECTIVE: (a) To report the xerostomia prevalence and severity in patients with obstructive sleep apnoea (OSA). (b) To assess the saliva pH in patients with OSA. DESIGN: Simultaneous cohort observational clinical study. SETTING: In Sleep Medicine Centre at Lomonosov Moscow State University from March to June 2019. PARTICIPANTS: The study was conducted on 30 patients with OSA aged from 35 to 65 years. MAIN OUTCOMES MEASURES: The diagnosis of sleep apnoea was made after standard polysomnography using the Domino programme. The severity of OSA was indicated using the Apnoea-Hypopnea Index. Xerostomia was evaluated using Fox's test. Hyposalivation was evaluated by measurement of salivary flow rate. Determination of the saliva pH was carried out with a pH metre. Statistical analysis was performed by one-way ANOVA and Tukey-Kramer multi-comparison test. RESULTS: Twenty-two out of 30 (73.3%) patients were diagnosed with "dry mouth". Hyposalivation was observed in 6 out of 30 (20%). Dry mouth on awakening was observed in 60.0%, 72.7% and 88.9% of patients with mild, moderate and severe OSA, respectively. The average salivary flow rate was 0.28 mL/min, 0.24 mL/min and 0.14 mL/min, respectively. The average pH value in patients with mild, moderate and severe apnoea was 6.40 ± 0.017, 6.15 ± 0.27 and 5.87 ± 0.24, respectively. CONCLUSIONS: In patient with mild and moderate OSA, the saliva amount and rate are similar (P > .05). With the increase of OSA severity, both these parameters change (P < .001). The acidity of the saliva was correlated with the level of OSA, and it statistically increased with the increment of the OSA severity (P < .05-P < .001).

Age- and gender-associated differences in the sleepy brain's electroencephalogram.

Background. With the eyes closed, an increase in sleepiness is associated with a decrease of spectral electroencephalographic (EEG) power in the high-frequency rage (i.e. alpha activity) and an increase of the power in the low-frequency range (i.e. theta activity). It has been suggested that the changes in the high- and low-frequency ranges might determine the two (earlier and later) drowsiness stages that precede sleep onset, respectively.Objective. We tested whether such spectral EEG signatures of sleepiness vary with age or gender.Approach. The EEG signal was recorded at 2 h intervals in 48 volunteers (15-67 years, 27 females) deprived of sleep between Friday evening and Sunday evening. The EEG signatures of sleepiness were calculated by expressing each EEG spectrum as a deviation from the initial (Friday evening) EEG spectrum.Main results. An age- and gender-specific variation was found in the signatures. Only the pattern of age-associated variation changed with an increase in the sleepiness level. A two-stage response to the increase of sleepiness was confirmed, but only in younger study participants. Subjective sleepiness was associated with neither age nor gender.Significance. In sleep-deprivation research, accounting for age- and gender-specific variations in the spectral EEG measures of drowsiness might be recommended. The results did not reveal any disturbance of the motivational function of subjective sleepiness in older study participants.

Effectiveness and Cost-Effectiveness of Internet-Based Cognitive Behavioral Therapy for Insomnia in Clinical Settings.

BACKGROUND: Internet-delivered cognitive-behavior treatment for insomnia (iCBT-I) has the potential to fill the gap created by the discrepancy between insomnia cases and number of trained professionals. Although the effectiveness of this method was proven in multiple studies conducted in research settings, its feasibility in routine care is still unclear. Predictors, mediators, and moderators of treatment effect remain uncertain since previous studies often give contradictory results. The present study aims to investigate clinical effectiveness and cost-effectiveness of an internet-based CBT-I program Sleepsy in comparison with care as usual (CAU) among patients with CI recruited from clinical settings. Baseline data will be further analyzed to find predictors of treatment outcome. METHODS/DESIGN: The proposed study is a parallel-group randomized controlled trial comparing CAU plus iCBT-I with CAU in a clinical setting. One hundred ten participants will be referred from the medical doctors in Moscow. Both groups will have access to CAU, which corresponds to the treatment prescribed by the referring doctor. Patients of the first group will additionally get access to the iCBT-I program with the opportunity to contact a specialist (guidance on request) in a secured environment. The primary outcome is insomnia severity change from pre- to post-treatment. Secondary outcomes include change of subjective sleep characteristics, life quality, fatigue, daytime sleepiness, comorbid affective disorders, dysfunctional beliefs about sleep, sleep hygiene, healthcare consumption, productivity losses, and longer term outcomes at 3 months follow-up. Predictor analysis will include baseline scores of the aforementioned outcomes along with treatment expectancies and personality traits. DISCUSSION: The proposed study is one of the first studies evaluating whether iCBT-I also works in routine care. We expect that recruitment of the participants let us determine the target group more precisely and exclude health problems interfering with treatment. Using CAU as control condition may result in a loss of power to detect a meaningful difference. Nevertheless, this approach is reasonable since it reconstructs the clinical situation faced by practicing doctors.

Evening chronotype, late weekend sleep times and social jetlag as possible causes of sleep curtailment after maintaining perennial DST: ain't they as black as they are painted?

People sleep less in response to setting social clocks earlier relative to the sun clocks. We proposed here a model-based approach for estimating sleep loss as the difference between weekend and weekday risetimes divided on the difference between weekend risetime and weekday bedtime. We compared this approach with a traditional approach to estimating sleep curtailment as the difference in weekly average sleep duration in two conditions. Weekday and weekend sleep times reported for 320 samples provided possibility of testing whether evening types with later weekend sleep times and larger social jetlag differ from morning types with earlier weekend sleep times and smaller social jetlag on amount of sleep lost (1) throughout the week and (2) in response to an advance of weekday wakeups, for instance, after the expected installation of perennial Daylight Saving Time (DST). We found that (1) an amount of sleep lost due to advancing shift of weekday wakeups depends upon neither chronotype nor weekend sleep times nor social jetlag, (2) a very large amount of sleep is usually lost by evening types with later weekend sleep times and larger social jetlag and (3) an essential sleep loss is caused by our usual work/school schedules, even in morning types with early weekend sleep times and small social jetlag. As compared to such permanent sleep losses experienced by any types, an additional loss due to switching from Standard Time (ST) to perennial DST are expected to be relatively small. We also found that the traditional way of calculation of sleep curtailment leads to paradoxical conclusions, such as (1) sleep loss is larger when social jetlag is smaller, not larger, (2) sleep loss is larger when weekend sleep times are earlier, not later, (3) despite 1-h difference between two student samples in weekday wakeups, their sleep losses can be identical.