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BackgroundWhile obstructive sleep apnea (OSA) and insomnia symptoms in neurotypical populations are associated with Alzheimer's disease (AD), their association with dementia in adults with Down syndrome (DS) remains less clear, even though these symptoms are prevalent and treatable in DS. Understanding their associations with AD-related dementia status, cognitive impairment, and functional deterioration may lead to interventions to slow decline or disease progression in adults with DS.ObjectiveTo characterize differences in OSA and insomnia symptom expression by dementia status, and to determine which sleep factors support dementia diagnosis.MethodsMultimodal consensus conference was used to determine dementia status in 52 adults with DS (52.2 ± 6.4 years, 21 women). Cognitive impairment, adaptive behavior skills, and symptoms of OSA and insomnia were quantified using validated assessments for adults with DS and their primary informants.ResultsA sex by dementia status interaction demonstrated that older women with DS and dementia had more severe terminal insomnia but not OSA symptoms relative to older women with DS who were cognitively stable (CS). Greater insomnia symptom severity was associated with greater functional impairments in social and self-care domains adjusting for age, sex, premorbid intellectual impairment, and dementia status.ConclusionsInsomnia symptoms are more severe in women with DS with dementia than in women with DS and no dementia, and regardless of dementia status or sex, more severe insomnia symptoms are associated with greater impairment in activities of daily living. These findings underscore the potential importance of early insomnia symptom evaluation and treatment in women with DS at risk of developing AD.

Determining the most effective insomnia medication for patients may require therapeutic trials of different medications. In addition, medication side effects, interactions with co-administered medications, and declining therapeutic efficacy can necessitate switching between different insomnia medications or deprescribing altogether. Currently, little guidance exists regarding the safest and most effective way to transition from one medication to another. Thus, we developed evidence-based guidelines to inform clinicians regarding best practices when deprescribing or transitioning between insomnia medications. Five U.S.-based sleep experts reviewed the literature involving insomnia medication deprescribing, tapering, and switching and rated the quality of evidence. They used this evidence to generate recommendations through discussion and consensus. When switching or discontinuing insomnia medications, we recommend benzodiazepine hypnotic drugs be tapered while additional CBT-I is provided. For Z-drugs zolpidem and eszopiclone (and not zaleplon), especially when prescribed at supratherapeutic doses, tapering is recommended with a 1-2-day delay in administration of the next insomnia therapy when applicable. There is no need to taper DORAs, doxepin, and ramelteon. Lastly, off-label antidepressants and antipsychotics used to treat insomnia should be gradually reduced when discontinuing. In general, offering individuals a rationale for deprescribing or switching and involving them in the decision-making process can facilitate the change and enhance treatment success.

While both patients and physicians consider sleep to be important, sleep health may not receive appropriate consideration during patient visits with health care professionals (HCPs). We completed the first large-scale survey of people with trouble sleeping (PWTS) and physicians who treat insomnia to understand their perspectives and potential discrepancies between them. The Harris Poll conducted online surveys of adult PWTS and HCPs (primary care physicians [PCPs] and psychiatrists) in the United States from September to October 2021. Respondents included 1001 PWTS, 300 PCPs, and 152 psychiatrists. Most HCPs agreed that sleep is critical to good health, yet very few reported routinely conducting full sleep histories on their patients. Approximately 30% of PWTS reported that their PCP never asks about sleep; zero HCPs in this survey reported "never" inquiring. Few HCPs reported being "very satisfied" with current treatment options; 50% of PCPs reported their patients being satisfied. Two-thirds of PWTS did not believe current treatment options adequately improved their sleep. This survey provides evidence that both PWTS and physicians agreed on the importance of sleep, but that treatment is often perceived as ineffective. This survey identifies a need for HCPs to address insomnia management and treatment gaps.

Given the high rate of depression associated with narcolepsy or obstructive sleep apnea (OSA), this analysis compared effects of solriamfetol treatment of excessive daytime sleepiness (EDS) in participants with/without a history of depression (DHx+/DHx-). This secondary analysis included data from two randomized, controlled trials in which participants were randomized to 12 weeks placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg/day. Efficacy/safety (combined solriamfetol doses) was summarized for DHx+/DHx-subgroups. 27.5% (65/236) with narcolepsy and 23.4% (111/474) with OSA were DHx+. In narcolepsy (DHx+ and DHx-), 40-min Maintenance of Wakefulness Test (MWT40) mean sleep latency increased (5.4 and 7.0 min), Epworth Sleepiness Scale (ESS) score decreased (3.8 and 3.5 points), and percentage of participants improved on Patient Global Impression of Change (PGI-C) was higher (31.7% and 39.4%) relative to placebo. In OSA (DHx+ and DHx-), MWT40 mean sleep latency increased (7.7 and 10.7 min), ESS decreased (3.5 and 3.7 points), and percentage of participants improved on PGI-C was higher (41.1% and 29.4%) relative to placebo. Common treatment-emergent adverse events (headache, decreased appetite, nausea, anxiety) were similar in DHx+/DHx-. This study suggests that safety and efficacy of solriamfetol for treating EDS in narcolepsy and OSA are not affected by depression history. Moreover, the findings emphasize the high prevalence of depression in people with sleep disorders and suggest that increased awareness of this association may have clinical significance.

Study objectivesFast frequency sleep spindles are reduced in aging and Alzheimer's disease (AD), but the mechanisms and functional relevance of these deficits remain unclear. The study objective was to identify AD biomarkers associated with fast sleep spindle deficits in cognitively unimpaired older adults at risk for AD.MethodsFifty-eight cognitively unimpaired, β-amyloid-negative, older adults (mean ± SD; 61.4 ± 6.3 years, 38 female) enriched with parental history of AD (77.6%) and apolipoprotein E (APOE) ε4 positivity (25.9%) completed the study. Cerebrospinal fluid (CSF) biomarkers of central nervous system inflammation, β-amyloid and tau proteins, and neurodegeneration were combined with polysomnography (PSG) using high-density electroencephalography and assessment of overnight memory retention. Parallelized serial mediation models were used to assess indirect effects of age on fast frequency (13 to

Study objectivesTo determine whether subjective measures of exercise and sleep are associated with cognitive complaints and whether exercise effects are mediated by sleep.MethodsThis study analyzed questionnaire data from adults (18-89) enrolled in a recruitment registry. The Cognitive Function Instrument (CFI) assessed cognitive complaints. Medical Outcomes Study Sleep Scale (MOS-SS) subscales and factor scores assessed sleep quality, daytime sleepiness, nighttime disturbance, and insomnia and obstructive sleep apnea (OSA)-like symptoms. Exercise frequency was defined as the weekly number of exercise sessions. Exercise frequency, MOS-SS subscales, and factor scores were examined as predictors of CFI score, adjusting for age, body mass index, education, sex, cancer diagnosis, antidepressant usage, psychiatric conditions, and medical comorbidities. Analyses of covariance examined the relationship between sleep duration groups (short, mid-range, and long) and CFI score, adjusting for covariates. Mediation by sleep in the exercise-CFI score relationship was tested.ResultsData from 2106 adults were analyzed. Exercise and MOS-SS subscales and factor scores were associated with CFI score. Higher Sleep Adequacy scores were associated with fewer cognitive complaints, whereas higher Sleep Somnolence, Sleep Disturbance, Sleep Problems Index I, Sleep Problems Index II, and factor scores were associated with more cognitive complaints. MOS-SS subscales and factor scores, except Sleep Disturbance and the insomnia factor score, mediated the association between exercise and cognitive complaints.ConclusionsThe relationship between exercise frequency and subjective cognitive performance is mediated by sleep. In particular, the mediation effect appears to be driven by symptoms possibly suggestive of OSA which are negatively associated with exercise engagement, sleep quality, daytime sleepiness, and subjective cognitive performance.

Study objectivesAerobic fitness (AF) and sleep are major determinants of health in adolescents and impact neurocognitive and psychological development. However, little is known about the interactions between AF and sleep during the developmental transition experienced across adolescence. This study aimed to consider the relationships between AF and habitual sleep patterns and sleep neurophysiology in healthy adolescents.MethodsSubjects (mean age = 14.6 ± 2.3 years old, range 11-17, 11 females) were evaluated for AF (peak VO2 assessed by ramp-type progressive cycle ergometry in the laboratory), habitual sleep duration and efficiency (7-14 days actigraphy), and topographic patterns of spectral power in slow wave, theta, and sleep spindle frequencies in non-rapid eye movement (NREM) sleep using overnight polysomnography (PSG) with high-density electroencephalography (hdEEG, 128 channels).ResultsSignificant relationships were observed between peak VO2 and habitual bedtime (r = -0.650, p = .009) and wake-up time (r = -0.603, p = .017), with greater fitness associated with going to bed and waking up earlier. Peak VO2 significantly predicted slow oscillations (0.5-1 Hz, p = .018) and theta activity (4.5-7.5 Hz, p = .002) over anterior frontal and central derivations (p < .001 and p = .001, respectively) after adjusting for sex and pubertal development stage. Similar associations were detected for fast sleep spindle activity (13-16 Hz, p = .006), which was greater over temporo-parietal derivations.ConclusionsGreater AF was associated with a more mature pattern of topographically-specific features of sleep EEG known to support neuroplasticity and cognitive processes and which are dependent on prefrontal cortex and hippocampal function in adolescents and adults. AF was also correlated with a smaller behavioral sleep phase delay commonly seen during adolescence.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by disrupting motor enactments during REM sleep, but also cognitive impairments across several domains. In addition to REM sleep abnormalities, we hypothesized that RBD patients may also display EEG abnormalities during NREM sleep. We collected all-night recordings with 256-channel high-density EEG in nine RBD patients, predominantly early-onset medicated individuals, nine sex- and age- matched healthy controls, and nine additional controls with matched medications and comorbidities. Power spectra in delta to gamma frequency bands were compared during both REM and NREM sleep, between phasic and tonic REM sleep, and between the first versus last cycle of NREM sleep. Controls, but not RBD patients, displayed a decrease in beta power during phasic compared to tonic REM sleep. Compared to controls, RBD patients displayed a reduced decline in SWA from early to late NREM sleep. Overnight changes in the distribution of the amplitude of slow waves were also reduced in RBD patients. Without suppression of beta rhythms during phasic REM sleep, RBD patients might demonstrate heightened cortical arousal, favoring the emergence of behavioral episodes. A blunted difference between REM sleep sub-stages may constitute a sensitive biomarker for RBD. Moreover, reduced overnight decline in SWA suggests a reduced capacity for synaptic plasticity in RBD patients, which may favor progression towards neurodegenerative diseases.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by disrupting motor enactments during REM sleep, but also cognitive impairments across several domains. In addition to REM sleep abnormalities, we hypothesized that RBD patients may also display EEG abnormalities during NREM sleep. We collected all-night recordings with 256-channel high-density EEG in nine RBD patients, predominantly early-onset medicated individuals, nine sex- and age- matched healthy controls, and nine additional controls with matched medications and comorbidities. Power spectra in delta to gamma frequency bands were compared during both REM and NREM sleep, between phasic and tonic REM sleep, and between the first versus last cycle of NREM sleep. Controls, but not RBD patients, displayed a decrease in beta power during phasic compared to tonic REM sleep. Compared to controls, RBD patients displayed a reduced decline in SWA from early to late NREM sleep. Overnight changes in the distribution of the amplitude of slow waves were also reduced in RBD patients. Without suppression of beta rhythms during phasic REM sleep, RBD patients might demonstrate heightened cortical arousal, favoring the emergence of behavioral episodes. A blunted difference between REM sleep sub-stages may constitute a sensitive biomarker for RBD. Moreover, reduced overnight decline in SWA suggests a reduced capacity for synaptic plasticity in RBD patients, which may favor progression towards neurodegenerative diseases.

Study objectivesAerobic fitness (AF) and sleep are major determinants of health in adolescents and impact neurocognitive and psychological development. However, little is known about the interactions between AF and sleep during the developmental transition experienced across adolescence. This study aimed to consider the relationships between AF and habitual sleep patterns and sleep neurophysiology in healthy adolescents.MethodsSubjects (mean age = 14.6 ± 2.3 years old, range 11-17, 11 females) were evaluated for AF (peak VO2 assessed by ramp-type progressive cycle ergometry in the laboratory), habitual sleep duration and efficiency (7-14 days actigraphy), and topographic patterns of spectral power in slow wave, theta, and sleep spindle frequencies in non-rapid eye movement (NREM) sleep using overnight polysomnography (PSG) with high-density electroencephalography (hdEEG, 128 channels).ResultsSignificant relationships were observed between peak VO2 and habitual bedtime (r = -0.650, p = .009) and wake-up time (r = -0.603, p = .017), with greater fitness associated with going to bed and waking up earlier. Peak VO2 significantly predicted slow oscillations (0.5-1 Hz, p = .018) and theta activity (4.5-7.5 Hz, p = .002) over anterior frontal and central derivations (p < .001 and p = .001, respectively) after adjusting for sex and pubertal development stage. Similar associations were detected for fast sleep spindle activity (13-16 Hz, p = .006), which was greater over temporo-parietal derivations.ConclusionsGreater AF was associated with a more mature pattern of topographically-specific features of sleep EEG known to support neuroplasticity and cognitive processes and which are dependent on prefrontal cortex and hippocampal function in adolescents and adults. AF was also correlated with a smaller behavioral sleep phase delay commonly seen during adolescence.

Study objectivesSleep disturbance is significantly associated with suicidal ideation. However, the majority of past research has examined the relationship between insomnia and suicidality. The current exploratory study examined the relationship of circadian rhythm dysregulation (eveningness, seasonality, and rhythmicity) with suicidality.MethodsWe examined the association of insomnia, eveningness, seasonality, and rhythmicity with suicidal ideation in 103 participants with depression, insomnia, and suicidality within a larger 8-week double-blinded randomized control trial primarily examining whether cautious use of zolpidem extended-release or placebo reduced suicidal ideation. All participants additionally received an open-label selective serotonin reuptake inhibitor. Methodological strengths of the current analyses included consideration of multiple sleep-wake constructs, adjustment for relevant covariates, investigation of relationships over the course of treatment, and use of both self-report measures and objective measurement with actigraphy.ResultsOver the course of treatment, self-reported eveningness and greater insomnia severity were independently correlated with greater suicidal ideation, whereas actigraphic delayed sleep timing was related to suicidal ideation at a trend level. At the end of treatment, those with greater suicidal ideation demonstrated lower actigraphic activity levels. There were no significant relationships between self-reported seasonality and actigraphic measures of sleep disturbance and suicidality.ConclusionsSelf-reported delays in sleep timing, objectively lower activity levels, and self-reported insomnia severity correlated independently with greater suicidal ideation in those with depression, insomnia, and suicidality. These exploratory findings highlight the need to consider sleep-wake constructs more broadly in those with suicidality in future research studies in order to improve more definitively both assessment and intervention efforts.Clinical trial registrationRegistry: ClinicalTrials.gov; Name: Reducing Suicidal Ideation through Insomnia Treatment; URL: https://clinicaltrials.gov/ct2/show/NCT01689909; Identifier: NCT01689909 Rumble ME, McCall MV, Dickson DA, Krystal AD, Rosenquist PB, Benca RM. An exploratory analysis of the association of circadian rhythm dysregulation and insomnia with suicidal ideation over the course of treatment in individuals with depression, insomnia, and suicidal ideation. J Clin Sleep Med. 2020;16(8):XXX-XXX.

ObjectiveThe authors sought to determine whether targeted treatment of insomnia with controlled-release zolpidem (zolpidem-CR) in suicidal adults with insomnia would provide a reduction in suicidal ideation superior to placebo.MethodsReducing Suicidal Ideation Through Insomnia Treatment was an 8-week three-site double-blind placebo-controlled parallel-group randomized controlled trial of zolpidem-CR hypnotic therapy compared with placebo, in conjunction with an open-label selective serotonin reuptake inhibitor. Participants were medication-free 18- to 65-year-olds with major depressive disorder, insomnia, and suicidal ideation. Suicidal ideation was the main outcome, measured first by the Scale for Suicide Ideation and second by the Columbia-Suicide Severity Rating Scale (C-SSRS).ResultsA total of 103 participants were randomly assigned to receive zolpidem-CR (N=51) or placebo (N=52) (64 women and 39 men; mean age=40.5 years). Zolpidem-CR had a robust anti-insomnia effect, especially in patients with the most severe insomnia symptoms. No significant treatment effect was observed on the Scale for Suicide Ideation (least squares mean estimate=-0.56, SE=0.83, 95% CI=-2.19, 1.08), but the reduction in scores was significantly positively related to improvement in insomnia after accounting for the effect of other depression symptoms. The C-SSRS indicated that zolpidem-CR had a significant treatment effect (least squares mean estimate=-0.26, SE=0.12, 95% CI=-0.50, -0.02). The advantage for zolpidem-CR in reducing suicidal ideation on the C-SSRS was greater in patients with more severe insomnia. No deaths or suicide attempts occurred.ConclusionsAlthough the results do not support the routine prescription of hypnotic medication for mitigating suicidal ideation in all depressed outpatients with insomnia, they suggest that coprescription of a hypnotic during initiation of an antidepressant may be beneficial in suicidal outpatients, especially in patients with severe insomnia.

In this paper, we report the rate of previously undiagnosed obstructive sleep apnea (OSA) in a randomized clinical trial (RCT) of suicidal patients with major depressive disorder (MDD). One hundred and twenty-five suicidal adults with MDD were recruited into a RCT. None were suspected to have OSA. Fourteen percent met diagnostic criteria for OSA. The Apnea Hypopnea Index (AHI) was predicted by increasing age, male sex, and higher Body Mass Index. However, neither the degree of daytime sleepiness nor the degree of insomnia predicted AHI severity. A high degree of suspicion is warranted for OSA in suicidal patients with MDD, and for patients with treatment-resistant depression. ClinicalTrials.gov identifier: NCT01689909.

The objective of the study was to determine if sleep disorder, depression or anxiety screening status was associated with safety outcomes in a diverse population of hospital workers. A sample of shift workers at four hospitals participated in a prospective cohort study. Participants were screened for five sleep disorders, depression and anxiety at baseline, then completed prospective monthly surveys for the next 6 months to capture motor vehicle crashes, near-miss crashes, occupational exposures and medical errors. We tested the associations between sleep disorders, depression and anxiety and adverse safety outcomes using incidence rate ratios adjusted for potentially confounding factors in a multivariable negative binomial regression model. Of the 416 hospital workers who participated, two in five (40.9%) screened positive for a sleep disorder and 21.6% screened positive for depression or anxiety. After multivariable adjustment, screening positive for a sleep disorder was associated with 83% increased incidence of adverse safety outcomes. Screening positive for depression or anxiety increased the risk by 63%. Sleep disorders and mood disorders were independently associated with adverse outcomes and contributed additively to risk. Our findings suggest that screening for sleep disorders and mental health screening can help identify individuals who are vulnerable to adverse safety outcomes. Future research should evaluate sleep and mental health screening, evaluation and treatment programmes that may improve safety.

BackgroundEpidemiological data have demonstrated seasonal and circadian patterns of suicidal deaths. Several reviews and meta-analyses have confirmed the relationship between sleep disturbance and suicidality. However, these reviews/meta-analyses have not focused on seasonal and circadian dysfunction in relation to suicidality, despite the common presence of this dysfunction in patients with mood disorders. Thus, the current literature review analyzed studies investigating person-specific chronotype, seasonality, and rhythmicity in relation to suicidal thoughts and behaviors.MethodsStudy authors reviewed articles related to individual-level chronotype, seasonality, and rhythmicity and suicidality that were written in English and not case reports or reviews.ResultsThis review supports a relationship between an eveningness chronotype, greater seasonality, and decreased rhythmicity with suicidal thoughts and behaviors in those with unipolar depression, as well as in other psychiatric disorders and in children/adolescents.LimitationsThese findings need to be explored more fully in mood disordered populations and other psychiatric populations, in both adults and children, with objective measurement such as actigraphy, and with chronotype, seasonality, and rhythmicity as well as broader sleep disturbance measurement all included so the construct(s) most strongly linked to suicidality can be best identified.ConclusionsEveningness, greater seasonality, and less rhythmicity should be considered in individuals who may be at risk for suicidal thoughts and behaviors and may be helpful in further tailoring assessment and treatment to improve patient outcome.

ObjectiveTo determine the relationship between sleep quality and CSF markers of Alzheimer disease (AD) pathology in late midlife.MethodsWe investigated the relationship between sleep quality and CSF AD biomarkers in a cohort enriched for parental history of sporadic AD, the Wisconsin Registry for Alzheimer's Prevention. A total of 101 participants (mean age 62.9 ± 6.2 years, 65.3% female) completed sleep assessments and CSF collection and were cognitively normal. Sleep quality was measured with the Medical Outcomes Study Sleep Scale. CSF was assayed for biomarkers of amyloid metabolism and plaques (β-amyloid 42 [Aβ42]), tau pathology (phosphorylated tau [p-tau] 181), neuronal/axonal degeneration (total tau [t-tau], neurofilament light [NFL]), neuroinflammation/astroglial activation (monocyte chemoattractant protein-1 [MCP-1], chitinase-3-like protein 1 [YKL-40]), and synaptic dysfunction/degeneration (neurogranin). To adjust for individual differences in total amyloid production, Aβ42 was expressed relative to Aβ40. To assess cumulative pathology, CSF biomarkers were expressed in ratio to Aβ42. Relationships among sleep scores and CSF biomarkers were assessed with multiple regression, controlling for age, sex, time between sleep and CSF measurements, and CSF assay batch.ResultsWorse subjective sleep quality, more sleep problems, and daytime somnolence were associated with greater AD pathology, indicated by lower CSF Aβ42/Aβ40 and higher t-tau/Aβ42, p-tau/Aβ42, MCP-1/Aβ42, and YKL-40/Aβ42. There were no significant associations between sleep and NFL or neurogranin.ConclusionsSelf-report of poor sleep was associated with greater AD-related pathology in cognitively healthy adults at risk for AD. Effective strategies exist for improving sleep; therefore sleep health may be a tractable target for early intervention to attenuate AD pathogenesis.

ObjectiveDepression is often associated with disruptions in sleep and circadian rhythms. We aimed to confirm these relationships via actigraphic assessment in a large, population-based sample and test whether sex moderates these relationships.MethodsA total of 418 participants (age = 35-85 years, mean [standard deviation] = 57.04 [11.47]) completed questionnaires and 1 week of actigraphy, used to calculate sleep and rest-activity statistics including mesor (mean activity level), amplitude (height of rhythm), and acrophase (time of day that rhythm peaks).ResultsDepressive symptoms, assessed via Center for Epidemiologic Studies Depression Scale, were associated with disrupted sleep and rest-activity rhythms. Furthermore, men demonstrated longer sleep onset latency (SOL, B = -13.28, p < .001), longer wake time after sleep onset (B = -6.26, p < .01), lower sleep efficiency (B = 5.91, p < .001), and lower total sleep time (TST, B = 33.16, p < .001) than women. Sex moderated the relationship between depression and SOL, TST, mesor, and amplitude; sex-stratified models revealed that higher depression scores were associated with greater SOL (B = 1.05, p < .001) and less TST (B = -0.87, p < .10) for women with higher depressive symptoms, but lower mesor (B = -1.75, p < .01) and amplitude (B = -1.94, p < .01) for men with higher depressive symptoms.ConclusionsDepressive symptoms were related to disrupted sleep continuity and rest-activity rhythms in this population-based sample; however, these relationships differed by sex. Women with greater depressive symptoms exhibited difficulty with sleep continuity, whereas men with greater depressive symptoms demonstrated disruption throughout the 24-hour rhythm.

ObjectiveMenopause is widely believed to be an established cause of sleep disorders, but evidence for this theory is inconclusive. Attributing any sleep problem to normal processes of menopause may lead to underdiagnosis of treatable sleep disorders in midlife women. This study uses detailed longitudinal data on sleep and menopausal health from participants in the Sleep in Midlife Women Study to investigate whether risk and severity of sleep-disordered breathing increase with progression through menopause, accounting for changes in age and body habitus.MethodsA total of 219 women aged 38 to 62 years were recruited from participants in the Wisconsin Sleep Cohort Study. Menopause status was determined from daily diaries in which participants reported menstrual flow, hot flashes, and use of hormonal medications. Each participant underwent in-home polysomnography studies every 6 months, to measure the apnea-hypopnea index (AHI) (N = 1,667 studies). Linear models with empirical standard errors were fit for logarithm of AHI on menopause status and years in menopause, adjusting for age, body mass index, waist girth, and neck girth.ResultsCompared with women in premenopause, AHI was 21% higher among participants in perimenopause (95% CI, -4 to 54), 31% higher among participants in postmenopause (95% CI, 2-68), and 41% higher among participants whose menopausal stage could not be distinguished between peri- and postmenopause (95% CI, 8-82). Among women who had begun perimenopause, each additional year in menopause was associated with 4% greater AHI (95% CI, 2-6).ConclusionsProgression through menopause is associated with greater sleep-disordered breathing severity. This association is independent of aging and changes in body habitus.

ObjectiveInsomnia is associated with increased risk for suicide. The Food and Drug Administration (FDA) has mandated that warnings regarding suicide be included in the prescribing information for hypnotic medications. The authors conducted a review of the evidence for and against the claim that hypnotics increase the risk of suicide.MethodThis review focused on modern, FDA-approved hypnotics, beginning with the introduction of benzodiazepines, limiting its findings to adults. PubMed and Web of Science were searched, crossing the terms "suicide" and "suicidal" with each of the modern FDA-approved hypnotics. The FDA web site was searched for postmarketing safety reviews, and the FDA was contacted with requests to provide detailed case reports for hypnotic-related suicide deaths reported through its Adverse Event Reporting System.ResultsEpidemiological studies show that hypnotics are associated with an increased risk for suicide. However, none of these studies adequately controlled for depression or other psychiatric disorders that may be linked with insomnia. Suicide deaths have been reported from single-agent hypnotic overdoses. A separate concern is that benzodiazepine receptor agonist hypnotics can cause parasomnias, which in rare cases may lead to suicidal ideation or suicidal behavior in persons who were not known to be suicidal. On the other hand, ongoing research is testing whether treatment of insomnia may reduce suicidality in adults with depression.ConclusionsThe review findings indicate that hypnotic medications are associated with suicidal ideation. Future studies should be designed to assess whether increases in suicidality result from CNS impairments from a given hypnotic medication or whether such medication decreases suicidality because of improvements in insomnia.

Study objectivesTo examine scalp and source power topography in sleep arousals disorders (SADs) using high-density EEG (hdEEG).MethodsFifteen adult subjects with sleep arousal disorders (SADs) and 15 age- and gender-matched good sleeping healthy controls were recorded in a sleep laboratory setting using a 256 channel EEG system.ResultsScalp EEG analysis of all night NREM sleep revealed a localized decrease in slow wave activity (SWA) power (1-4 Hz) over centro-parietal regions relative to the rest of the brain in SADs compared to good sleeping healthy controls. Source modelling analysis of 5-minute segments taken from N3 during the first half of the night revealed that the local decrease in SWA power was prominent at the level of the cingulate, motor, and sensori-motor associative cortices. Similar patterns were also evident during REM sleep and wake. These differences in local sleep were present in the absence of any detectable clinical or electrophysiological sign of arousal.ConclusionsOverall, results suggest the presence of local sleep differences in the brain of SADs patients during nights without clinical episodes. The persistence of similar topographical changes in local EEG power during REM sleep and wakefulness points to trait-like functional changes that cross the boundaries of NREM sleep. The regions identified by source imaging are consistent with the current neurophysiological understanding of SADs as a disorder caused by local arousals in motor and cingulate cortices. Persistent localized changes in neuronal excitability may predispose affected subjects to clinical episodes.

Study objectivesSuvorexant is an orexin receptor antagonist approved for treating insomnia at a maximum dose of 20 mg. Phase-3 trials evaluated two age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg with the primary focus on 40/30 mg. We report here results from pooled analyses of the 20/15 mg dose-regime, which was evaluated as a secondary objective in the trials.MethodsPrespecified analysis of pooled data from two identical randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥ 65 years) patients with insomnia. Patients were randomized to suvorexant 20/15 mg (non-elderly/elderly), suvorexant 40/30 mg (non-elderly/elderly), or placebo; by design, fewer patients were randomized to 20/15 mg. Efficacy was assessed by self-reported and polysomnography (PSG; subset of patients) sleep maintenance and onset endpoints.ResultsSuvorexant 20/15 mg (N = 493 treated) was effective compared to placebo (N = 767 treated) on patient-reported and PSG sleep maintenance and onset endpoints at Night-1 (PSG endpoints) / Week-1 (subjective endpoints), Month-1 and Month-3, except for effects on PSG sleep onset at Month-3. Suvorexant 20/15 mg was generally well tolerated, with 3% of patients discontinuing due to adverse events over 3 months vs. 5.2% on placebo. Somnolence was the most common adverse event (6.7% vs. 3.3% for placebo). There was no systematic evidence of rebound or withdrawal signs or symptoms when suvorexant was discontinued after 3 months of nightly use.ConclusionsSuvorexant 20/15 mg improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.Clinical trial registrationClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629.

Study objectivesTo examine nonrapid eye movement (NREM) sleep in insomnia using high-density electroencephalography (EEG).MethodsAll-night sleep recordings with 256 channel high-density EEG were analyzed for 8 insomnia subjects (5 females) and 8 sex and age-matched controls without sleep complaints. Spectral analyses were conducted using unpaired t-tests and topographical differences between groups were assessed using statistical non-parametric mapping. Five minute segments of deep NREM sleep were further analyzed using sLORETA cortical source imaging.ResultsThe initial topographic analysis of all-night NREM sleep EEG revealed that insomnia subjects had more high-frequency EEG activity (> 16 Hz) compared to good sleeping controls and that the difference between groups was widespread across the scalp. In addition, the analysis also showed that there was a more circumscribed difference in theta (4-8 Hz) and alpha (8-12 Hz) power bands between groups. When deep NREM sleep (N3) was examined separately, the high-frequency difference between groups diminished, whereas the higher regional alpha activity in insomnia subjects persisted. Source imaging analysis demonstrated that sensory and sensorimotor cortical areas consistently exhibited elevated levels of alpha activity during deep NREM sleep in insomnia subjects relative to good sleeping controls.ConclusionsThese results suggest that even during the deepest stage of sleep, sensory and sensorimotor areas in insomnia subjects may still be relatively active compared to control subjects and to the rest of the sleeping brain.

Learning leads to rapid microstructural changes in gray (GM) and white (WM) matter. Do these changes continue to accumulate if task training continues, and can they be reverted by sleep? We addressed these questions by combining structural and diffusion weighted MRI and high-density EEG in 16 subjects studied during the physiological sleep/wake cycle, after 12 h and 24 h of intense practice in two different tasks, and after post-training sleep. Compared to baseline wake, 12 h of training led to a decline in cortical mean diffusivity. The decrease became even more significant after 24 h of task practice combined with sleep deprivation. Prolonged practice also resulted in decreased ventricular volume and increased GM and WM subcortical volumes. All changes reverted after recovery sleep. Moreover, these structural alterations predicted cognitive performance at the individual level, suggesting that sleep's ability to counteract performance deficits is linked to its effects on the brain microstructure. The cellular mechanisms that account for the structural effects of sleep are unknown, but they may be linked to its role in promoting the production of cerebrospinal fluid and the decrease in synapse size and strength, as well as to its recently discovered ability to enhance the extracellular space and the clearance of brain metabolites.

ObjectiveChanges in slow waves during non-rapid eye movement (NREM) sleep in response to acute total sleep deprivation are well-established measures of sleep homeostasis. This investigation utilized high-density electroencephalography (hdEEG) to examine topographic changes in slow waves during repeated partial sleep deprivation.MethodsTwenty-four participants underwent a 6-day sleep restriction protocol. Spectral and period-amplitude analyses of sleep hdEEG data were used to examine changes in slow wave energy, count, amplitude, and slope relative to baseline.ResultsChanges in slow wave energy were dependent on the quantity of NREM sleep utilized for analysis, with widespread increases during sleep restriction and recovery when comparing data from the first portion of the sleep period, but restricted to recovery sleep if the entire sleep episode was considered. Period-amplitude analysis was less dependent on the quantity of NREM sleep utilized, and demonstrated topographic changes in the count, amplitude, and distribution of slow waves, with frontal increases in slow wave amplitude, numbers of high-amplitude waves, and amplitude/slopes of low amplitude waves resulting from partial sleep deprivation.ConclusionsTopographic changes in slow waves occur across the course of partial sleep restriction and recovery.SignificanceThese results demonstrate a homeostatic response to partial sleep loss in humans.

Sleeping brain activity reflects brain anatomy and physiology. The aim of this study was to use high density (256 channel) electroencephalography (EEG) during sleep to characterize topographic changes in sleep EEG power across normal aging, with high spatial resolution. Sleep was evaluated in 92 healthy adults aged 18-65 years old using full polysomnography and high density EEG. After artifact removal, spectral power density was calculated for standard frequency bands for all channels, averaged across the NREM periods of the first 3 sleep cycles. To quantify topographic changes with age, maps were generated of the Pearson's coefficient of the correlation between power and age at each electrode. Significant correlations were determined by statistical non-parametric mapping. Absolute slow wave power declined significantly with increasing age across the entire scalp, whereas declines in theta and sigma power were significant only in frontal regions. Power in fast spindle frequencies declined significantly with increasing age frontally, whereas absolute power of slow spindle frequencies showed no significant change with age. When EEG power was normalized across the scalp, a left centro-parietal region showed significantly less age-related decline in power than the rest of the scalp. This partial preservation was particularly significant in the slow wave and sigma bands. The effect of age on sleep EEG varies substantially by region and frequency band. This non-uniformity should inform the design of future investigations of aging and sleep. This study provides normative data on the effect of age on sleep EEG topography, and provides a basis from which to explore the mechanisms of normal aging as well as neurodegenerative disorders for which age is a risk factor.

Sleeping brain activity reflects brain anatomy and physiology. The aim of this study was to use high density (256 channel) electroencephalography (EEG) during sleep to characterize topographic changes in sleep EEG power across normal aging, with high spatial resolution. Sleep was evaluated in 92 healthy adults aged 18-65 years old using full polysomnography and high density EEG. After artifact removal, spectral power density was calculated for standard frequency bands for all channels, averaged across the NREM periods of the first 3 sleep cycles. To quantify topographic changes with age, maps were generated of the Pearson's coefficient of the correlation between power and age at each electrode. Significant correlations were determined by statistical non-parametric mapping. Absolute slow wave power declined significantly with increasing age across the entire scalp, whereas declines in theta and sigma power were significant only in frontal regions. Power in fast spindle frequencies declined significantly with increasing age frontally, whereas absolute power of slow spindle frequencies showed no significant change with age. When EEG power was normalized across the scalp, a left centro-parietal region showed significantly less age-related decline in power than the rest of the scalp. This partial preservation was particularly significant in the slow wave and sigma bands. The effect of age on sleep EEG varies substantially by region and frequency band. This non-uniformity should inform the design of future investigations of aging and sleep. This study provides normative data on the effect of age on sleep EEG topography, and provides a basis from which to explore the mechanisms of normal aging as well as neurodegenerative disorders for which age is a risk factor.

PurposeObservational studies suggest that menopausal hormone therapy protects against sleep-disordered breathing, but such findings may be biased by a "healthy user effect." When the Women's Health Initiative Study reported in 2002 that estrogen-progestin therapy increases heart disease risk, many women discontinued hormone therapy. We investigate healthy user bias in the association of hormone therapy with sleep-disordered breathing in the Sleep in Midlife Women Study.MethodsA total of 228 women aged 38 to 62 years were recruited from the Wisconsin Sleep Cohort Study. They underwent polysomnography to measure apnea-hypopnea index, at home semiannually from 1997 to 2006, and in the sleep laboratory every four years (n = 1828 studies). Hormone therapy was recorded monthly. Linear models with empirical standard errors regressed logarithm of apnea-hypopnea index on hormone use with a pre- or post-July 2002 interaction, adjusting for menopause and age.ResultsThe association of hormone therapy and sleep-disordered breathing was heterogeneous (P < .01); apnea-hypopnea index among users was 15% lower in the early period (95% confidence interval, -27% to -1%), but similar to nonusers in the late.ConclusionsHormone therapy was negatively associated with sleep-disordered breathing only until the Women's Health Initiative results were publicized. Hormone therapy may have been a marker for healthfulness in the early period, creating a spurious association with sleep-disordered breathing.

Midlife may be an ideal window for intervention in Alzheimer's disease (AD). To determine whether sleep is associated with early signs of AD neuropathology (amyloid deposition) in late midlife, we imaged brain amyloid deposits using positron emission tomography with [C-11]Pittsburgh Compound B (PiB), and assessed sleep with the Epworth Sleepiness Scale and the Medical Outcomes Study Sleep Scale in 98 cognitively healthy adults (aged 62.4 ± 5.7 years) from the Wisconsin Registry for Alzheimer's Prevention. We used multiple regressions to test the extent to which sleep scores predicted regional amyloid burden. Participants reporting less adequate sleep, more sleep problems, and greater somnolence on the Medical Outcomes Study had greater amyloid burden in AD-sensitive brain regions (angular gyrus, frontal medial orbital cortex, cingulate gyrus, and precuneus). Amyloid was not associated with reported sleep amount, symptoms of sleep-disordered breathing, trouble falling asleep, or Epworth Sleepiness Scale. Poor sleep may be a risk factor for AD and a potential early marker of AD or target for preventative interventions in midlife.

Study objectivesDepression has been identified as the most common condition comorbid to insomnia, with findings pointing to the possibility that these disorders may be causally related to each other or may share common mechanisms. Some have suggested that comorbid insomnia and depression may have a different clinical course than either condition alone, and may thus require specific treatment procedures. In this report we examined the clinical characteristics of individuals referred to an academic sleep center who report comorbid symptoms of insomnia and depression and those with symptoms of insomnia outside the context of meaningful depression, and we identified differences between these groups with regard to several cognitive-related variables.MethodsLogistic regression analyses examined whether past week worry, dysfunctional beliefs about sleep, and insomnia symptom-focused rumination predicted group membership.ResultsIndividuals with comorbid symptoms of insomnia and depression reported more past-week worry, dysfunctional beliefs about sleep, and insomnia symptom-focused rumination, than those with symptoms of insomnia without significant depression symptoms. When including all three cognitive-related variables in our model, those with comorbid symptoms reported more severe insomnia symptom-focused rumination, even when controlling for insomnia and mental health severity, among other relevant covariates.ConclusionThe findings contribute to our understanding of the complex nature of comorbid symptoms of insomnia and depression and the specific symptom burden experienced by those with significant depression symptoms in the presence of insomnia. The findings also highlight the need for increased clinical attention to the sleep-focused rumination reported by these patients.

Study objectivesWe conducted an economic analysis of the HomePAP study, a multicenter randomized clinical trial that compared home-based versus laboratory-based testing for the diagnosis and management of obstructive sleep apnea (OSA).DesignA cost-minimization analysis from the payer and provider perspectives was performed, given that 3-mo clinical outcomes were equivalent.SettingSeven academic sleep centers.ParticipantsThere were 373 subjects at high risk for moderate to severe OSA.InterventionsSubjects were randomized to either home-based limited channel portable monitoring followed by unattended autotitration with continuous positive airway pressure (CPAP), versus a traditional pathway of in-laboratory sleep study and CPAP titration.Measurements and resultsFrom the payer perspective, per subject costs for the laboratory-based pathway were $1,840 (95% confidence interval [CI] $1,660, $2,015) compared to $1,575 (95% CI $1,439, $1,716) for the home-based pathway under the base case. Costs were $264 (95% CI $39, $496, P = 0.02) in favor of the home arm. From the provider perspective, per subject costs for the laboratory arm were $1,697 (95% CI $1,566, $1,826) compared to $1,736 (95% CI $1,621, $1,857) in the home arm, for a difference of $40 (95% CI -$213, $142, P = 0.66) in favor of the laboratory arm under the base case. The provider operating margin was $142 (95% CI $85, $202,P < 0.01) in the laboratory arm, compared to a loss of -$161 (95% CI -$202, -$120, P < 0.01) in the home arm.ConclusionsFor payers, a home-based diagnostic pathway for obstructive sleep apnea with robust patient support incurs fewer costs than a laboratory-based pathway. For providers, costs are comparable if not higher, resulting in a negative operating margin.Clinicaltrialsgov identifierNCT00642486.

ObjectiveTo investigate (1) circadian rest-activity rhythm disturbances among endometrial cancer patients as they recover from surgery in comparison to a historical reference group of women with no cancer history and (2) health- and treatment-related predictors of dysregulated rest-activity rhythms in endometrial cancer patients.Methods60 endometrial cancer patients participated in a prospective, longitudinal study with actigraphic assessment at 1week, 1month, and 4months post-surgery. 60 women without cancer from an epidemiological sample completed one actigraphic assessment, acting as a reference group.ResultsOn average, results revealed initial significant rest-activity dysregulation at 1week and 1month post-surgery for the endometrial cancer group and then significant recovery in rest-activity patterns at 4months post-surgery. Similarly, the cancer group had significantly more impaired rhythms than the reference group at 1week post-surgery, but demonstrated comparable rhythms by 4months post-surgery. Among the health- and treatment-related variables examined, obesity and receipt of more invasive surgery were found to predict more impaired rhythms at all time points.Conclusion(s)The current study highlights significant disturbances in rest-activity patterns for endometrial cancer patients initially during surgical recovery followed by improvement in these patterns by 4months post-surgery; however, obese patients and those having more invasive surgery demonstrated more impaired rest-activity patterns throughout the 4-month recovery period. Further research is warranted to understand how more impaired rest-activity patterns relate to health and quality of life outcomes.

Background/aimsSuicide is a major public health concern, yet there are very few randomized clinical trials that have been conducted to reduce suicidal ideation in patients at risk of suicide. We describe the rationale and refinements of such a trial that is designed to assess the effect of a hypnotic medication on suicidal ideation in adult outpatients currently experiencing suicidal ideation.Methods"Reducing Suicidal Ideation Through Insomnia Treatment" is a multi-site randomized clinical trial that includes three recruiting sites and one data management site. This 4-year study is in its second year of recruitment. The purpose of the study is to compare hypnotic medication versus placebo as an add-on treatment to a selective serotonin reuptake inhibitor as a means of reducing suicidal ideation in depressed adult outpatients with insomnia and suicidal ideation. The safety features of the study follow the 2001 National Institutes of Health guidelines for studies that include patients at risk of suicide.ResultsIn total, 584 potential participants have undergone telephone screening; 67% of these failed the phone screen, most often due to an absence of expressed suicidal ideation (26% of the telephone screen fails). A total of 115 people appeared for a face-to-face baseline assessment, and 40 of these had completed a taper off of their ineffective psychotropic medications before the baseline assessments. In all, 64% of those who completed baseline assessments failed to proceed to randomization, most commonly because of no clinically significant suicidal ideation (51% of those excluded at baseline). One participant was offered and accepted voluntary psychiatric hospitalization in lieu of study participation. Thus far, 40 participants have been randomized into the study and 88.7% of scheduled visits have been attended, with 93.8% adherence to the selective serotonin reuptake inhibitor and 91.6% adherence to the randomized hypnotic versus placebo. None of the randomized participants have required hospitalization or had a suicide attempt.ConclusionBy carefully considering the inclusion and exclusion criteria and other safety features, the safe conduct of randomized clinical trials in suicidal adult patients is possible, including the inclusion of participants who have undergone a prescribed tapering off of psychotropic medications prior to baseline assessment.

Schizophrenia is a devastating mental illness with a worldwide prevalence of approximately 1%. Although the clinical features of the disorder were described over one hundred years ago, its neurobiology is still largely elusive despite several decades of research. Schizophrenia is associated with marked sleep disturbances and memory impairment. Above and beyond altered sleep architecture, sleep rhythms including slow waves and spindles are disrupted in schizophrenia. In the healthy brain, these rhythms reflect and participate in plastic processes during sleep. This chapter discusses evidence that schizophrenia patients exhibit dysfunction of sleep-mediated plasticity on a behavioral, cellular, and molecular level and offers suggestions on how the study of sleeping brain activity can shed light on the pathophysiological mechanisms of the disorder.

ObjectivesTo assess how the characteristics of slow waves and spindles change in the falling-asleep process.DesignParticipants undergoing overnight high-density electroencephalographic recordings were awakened at 15- to 30-min intervals. One hundred forty-one falling-asleep periods were analyzed at the scalp and source level.SettingSleep laboratory.ParticipantsSix healthy participants.InterventionsSerial awakenings.ResultsThe number and amplitude of slow waves followed two dissociated, intersecting courses during the transition to sleep: slow wave number increased slowly at the beginning and rapidly at the end of the falling-asleep period, whereas amplitude at first increased rapidly and then decreased linearly. Most slow waves occurring early in the transition to sleep had a large amplitude, a steep slope, involved broad regions of the cortex, predominated over frontomedial regions, and preferentially originated from the sensorimotor and the posteromedial parietal cortex. Most slow waves occurring later had a smaller amplitude and slope, involved more circumscribed parts of the cortex, and had more evenly distributed origins. Spindles were initially sparse, fast, and involved few cortical regions, then became more numerous and slower, and involved more areas.ConclusionsOur results provide evidence for two types of slow waves, which follow dissociated temporal courses in the transition to sleep and have distinct cortical origins and distributions. We hypothesize that these two types of slow waves result from two distinct synchronization processes: (1) a "bottom-up," subcorticocortical, arousal system-dependent process that predominates in the early phase and leads to type I slow waves, and (2) a "horizontal," corticocortical synchronization process that predominates in the late phase and leads to type II slow waves. The dissociation between these two synchronization processes in time and space suggests that they may be differentially affected by experimental manipulations and sleep disorders.

Study objectivesTo examine the patterns of insomnia and sleep-related movement from ages 4.5 to 9 years, their concurrent associations with mental health symptoms in childhood, and the longitudinal associations of sleep-problem persistence with mental health symptoms at ages 9 and 18 years.DesignA 14-year prospective follow-up study. Assessments included maternal report on the Children's Sleep Habits Questionnaire at ages 4.5 and 9, and child mental health symptoms via maternal report at age 4.5, multi-informant (child, teacher, mother) report at age 9, and adolescent report at age 18.SettingCommunity.ParticipantsA total of 396 children (51% female).InterventionsN/A.Measurements and resultsSleep problems were more common at age 4.5 than 9; symptoms of insomnia and abnormal sleep movement both had persistence rates of 9-10%. At age 4.5, insomnia was associated with hostile-aggressive and hyperactive-distractible behavior, but there were no significant associations for sleep movement. At age 9, both insomnia and sleep movement were associated with symptoms of depression, externalizing, and attention deficit hyperactivity disorder (ADHD). Insomnia persistence was associated with symptoms of depression, externalizing, and ADHD at age 9 and anxiety and externalizing at age 18; sleep- movement persistence was associated with externalizing and ADHD at age 9, and ADHD at age 18. The age 18 persistence effects for insomnia and anxiety and for sleep movement and ADHD were significant when controlling for earlier mental health.ConclusionsChildhood insomnia and sleep movement are common and associated with mental health symptoms. Their persistence from middle to late childhood predicts associations with specific types of mental health symptoms at age 18.

Study objectivesObstructive sleep apnea (OSA) is associated with significant alterations in neuronal integrity resulting from either hypoxemia and/or sleep loss. A large body of imaging research supports reductions in gray matter volume, alterations in white matter integrity and resting state activity, and functional abnormalities in response to cognitive challenge in various brain regions in patients with OSA. In this study, we used high-density electroencephalography (hdEEG), a functional imaging tool that could potentially be used during routine clinical care, to examine the regional distribution of neural activity in a non-clinical sample of untreated men and women with moderate/severe OSA.DesignSleep was recorded with 256-channel EEG in relatively healthy subjects with apnea-hypopnea index (AHI) > 10, as well as age-, sex-, and body mass index-matched controls selected from a research population initially recruited for a study on sleep and meditation.SettingSleep laboratory.Patients or participantsNine subjects with AHI > 10 and nine matched controls.InterventionsN/A.Measurements and resultsTopographic analysis of hdEEG data revealed a broadband reduction in EEG power in a circumscribed region overlying the parietal cortex in OSA subjects. This parietal reduction in neural activity was present, to some extent, across all frequency bands in all stages and episodes of nonrapid eye movement sleep.ConclusionThis investigation suggests that regional deficits in electroencephalography (EEG) power generation may be a useful clinical marker for neural disruption in obstructive sleep apnea, and that high-density EEG may have the sensitivity to detect pathological cortical changes early in the disease process.