Hyperarousal features in the sleep architecture of individuals with and without insomnia.

Sleep architecture encodes relevant information on the structure of sleep and has been used to assess hyperarousal in insomnia. This study investigated whether polysomnography-derived sleep architecture displays signs of hyperarousal in individuals with insomnia compared with individuals without insomnia. Data from Phase 3 clinical trials, private clinics and a cohort study were analysed. A comprehensive set of sleep architecture features previously associated with hyperarousal were retrospectively analysed focusing on sleep-wake transition probabilities, electroencephalographic spectra and sleep spindles, and enriched with a novel machine learning algorithm called the Wake Electroencephalographic Similarity Index. This analysis included 1710 individuals with insomnia and 1455 individuals without insomnia. Results indicate that individuals with insomnia had a higher likelihood of waking from all sleep stages, and showed increased relative alpha during Wake and N1 sleep and increased theta power during Wake when compared with individuals without insomnia. Relative delta power was decreased and Wake Electroencephalographic Similarity Index scores were elevated across all sleep stages except N3, suggesting more wake-like activity during these stages in individuals with insomnia. Additionally, sleep spindle density was decreased, and spindle dispersion was increased in individuals with insomnia. These findings suggest that insomnia is characterized by a dysfunction in sleep quality with a continuous hyperarousal, evidenced by changes in sleep-wake architecture.

Association of novel measures of sleep disturbances with blood pressure: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Mechanisms underlying blood pressure (BP) changes in obstructive sleep apnoea (OSA) are incompletely understood. We assessed the associations between BP and selected polysomnography (PSG) traits: sleep depth, airflow limitation measurements and OSA-specific hypoxic burden. METHODS: This cross-sectional analysis included 2055 participants from the Multi-Ethnic Study of Atherosclerosis who underwent PSG and BP measurements in 2010-2013. Sleep depth was assessed using the 'OR product', a continuous measure of arousability. Airflow limitation was assessed by duty cycle (Ti/Tt) and % of breaths with flow limitation, and hypoxia by 'hypoxic burden'. Primary outcomes were medication-adjusted systolic BP (SBP) and diastolic BP (DBP). We used generalised linear models adjusted for age, sex, race/ethnicity, smoking, education, body mass index, alcohol use, periodic limb movements and alternative physiological disturbances. RESULTS: The sample had a mean age of 68.4 years and apnoea-hypopnoea index of 14.8 events/hour. Sleep depth was not significantly associated with BP. Every 1 SD increment in log-transformed non-rapid eye movement duty cycle was associated with 0.9% decrease in SBP (95% CI: 0.1% to 1.6%), even after adjusting for sleep depth and hypoxic burden. Every 1 SD increment in log-transformed hypoxic burden was associated with a 1.1% increase in SBP (95% CI: 0.1% to 2.1%) and 1.9% increase in DBP (95% CI: 1.0% to 2.8%) among those not using hypertension medications. CONCLUSIONS: Higher duty cycle was associated with lower SBP overall and hypoxic burden with higher SBP and DBP among non-BP medication users. These findings suggest changes in both respiratory effort and oxygenation during sleep influence BP.

Associations between quantitative sleep EEG and subsequent cognitive decline in older women.

The pathophysiological processes of Alzheimer's dementia predate its clinical manifestation. Sleep disturbances can accelerate the aging process and are common features of dementia. This study examined whether quantitative sleep electroencephalogram changes predate the clinical development of mild cognitive impairment and/or incident dementia. We collected data from a nested case-control sample of women (mean age 83 years) from the Sleep and Cognition Study, an ancillary study to the longitudinal Study of Osteoporotic Fractures, who were characterized as cognitively normal at the time of a baseline polysomnography study (Study of Osteoporotic Fractures visit 8) based on a Mini-Mental Status Exam (MMSE) score >24. Cases (n = 85) were women who developed new mild cognitive impairment or dementia by objective cognitive testing 5 years after polysomnography. Controls were women with no mild cognitive impairment/dementia (n = 85) at baseline or at follow-up. Differences in electroencephalogram absolute and relative power density were observed between the two groups. Specifically, higher electroencephalogram power values were found in the dementia/mild cognitive impairment group, for the alpha (p = .01) and theta bands (p = .04) in non-rapid eye movement sleep, as well as alpha (p = .04) and sigma (p = .04) bands in rapid eye movement sleep. In contrast, there were no group differences in traditional polysomnography measures of sleep architecture and sleep stage distribution, as well as sleep apnea and periodic limb movement indices. Our results provide evidence for quantitative electroencephalogram changes, which precede the clinical onset of cognitive decline and the diagnosis of dementia in elderly women, and support the application of quantitative sleep electroencephalogram analysis as a promising biomarker for imminent cognitive decline.

Effect of daridorexant on sleep architecture in patients with chronic insomnia disorder - A pooled post hoc analysis of two randomized Phase 3 clinical studies.

STUDY OBJECTIVES: Post-hoc analysis to evaluate the effect of daridorexant on sleep architecture in people with insomnia, focusing on features associated with hyperarousal. METHODS: We studied sleep architecture in adults with chronic insomnia disorder from two randomized Phase 3 clinical studies (Clinicaltrials.gov: NCT03545191 and NCT03575104) investigating 3 months of daridorexant treatment (placebo, daridorexant 25 mg, daridorexant 50 mg). We analyzed sleep-wake transition probabilities, EEG spectra and sleep spindle properties including density, dispersion, and slow oscillation phase coupling. The Wake EEG Similarity Index (WESI) was determined using a machine learning algorithm analyzing the spectral profile of the EEG. RESULTS: At Month 3, daridorexant 50 mg decreased Wake-to-Wake transition probabilities (P<0.05) and increased the probability of transitions from Wake-to-N1 (P<0.05), N2 (P<0.05), and REM sleep (P<0.05), as well as from N1-to-N2 (P<0.05) compared to baseline and placebo. Daridorexant 50 mg decreased relative beta power during Wake (P=0.011) and N1 (P<0.001) compared to baseline and placebo. During Wake, relative alpha power decreased (P<0.001) and relative delta power increased (P<0.001) compared to placebo. Daridorexant did not alter EEG spectra bands in N2, N3, and REM stages or in sleep spindle activity. Daridorexant decreased the WESI score during Wake compared to baseline (P=0.004). Effects with 50 mg were consistent between Month 1 and Month 3 and less pronounced with 25 mg. CONCLUSION: Daridorexant reduced EEG features associated with hyperarousal as indicated by reduced Wake-to-Wake transition probabilities and enhanced spectral features associated with drowsiness and sleep during Wake and N1.

The Effect of Obstructive Sleep Apnea on Sleep-dependent Emotional Memory Consolidation.

Rationale: A growing body of evidence suggests that sleep is critical for the adaptive processing and consolidation of emotional information into long-term memory. Previous research has indicated that emotional components of scenes particularly benefit from sleep in healthy groups, yet sleep-dependent emotional memory processes remain unexplored in clinical cohorts, including those with obstructive sleep apnea (OSA). This line of research is important as it will add to the understanding of how disrupted sleep in OSA contributes to both impaired cognition and emotion dysregulation. Objectives: To test the hypothesis that individuals with OSA will have impaired sleep-dependent memory consolidation, with the greatest impact being on memory for emotional content. Methods: In this study, a group of newly diagnosed patients with OSA (n = 26; 10 female; average age, 42.5 years) and a matched group of healthy control subjects (n = 24; 13 female; average age, 37 years) were enrolled in the study at Beth Israel Deaconess Medical Center. Participants encoded scenes with negative or neutral foreground objects placed on neutral backgrounds before a night of polysomnographically recorded sleep. In the morning, they completed a recognition test in which old and new scene objects and backgrounds, presented separately and one at a time, were judged as old, new, or similar compared with what had been previously viewed. Results: Patients with OSA had a deficit in recognition memory for the scenes. Overall recognition (the ability to recognize old items as either old or similar) was impaired across all scene elements, both negative and neutral objects and backgrounds, whereas specific recognition (correctly identifying old items as old) was impaired only for negative objects. Across all participants, successful overall recognition correlated positively with sleep efficiency and rapid eye movement (REM) sleep, whereas successful specific memory recognition correlated only with REM sleep. Conclusions: Our findings indicate that fragmented sleep and reduced REM sleep, both hallmarks of OSA, are associated with disruptions in general memory impairment and veridical memory for emotional content, which could alter emotional regulation and contribute to comorbid emotional distress in OSA.

Cognitive profile and brain morphological changes in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is accompanied by neurocognitive impairment, likely mediated by injury to various brain regions. We evaluated brain morphological changes in patients with OSA and their relationship to neuropsychological and oximetric data. Sixteen patients affected by moderate-severe OSA (age: 55.8±6.7 years, 13 males) and fourteen control subjects (age: 57.6±5.1 years, 9 males) underwent 3.0 Tesla brain magnetic resonance imaging (MRI) and neuropsychological testing evaluating short- and long-term memory, executive functions, language, attention, praxia and non-verbal learning. Volumetric segmentation of cortical and subcortical structures and voxel-based morphometry (VBM) were performed. Patients and controls differed significantly in Rey Auditory-Verbal Learning test (immediate and delayed recall), Stroop test and Digit span backward scores. Volumes of cortical gray matter (GM), right hippocampus, right and left caudate were smaller in patients compared to controls, with also brain parenchymal fraction (a normalized measure of cerebral atrophy) approaching statistical significance. Differences remained significant after controlling for comorbidities (hypertension, diabetes, smoking, hypercholesterolemia). VBM analysis showed regions of decreased GM volume in right and left hippocampus and within more lateral temporal areas in patients with OSA. Our findings indicate that the significant cognitive impairment seen in patients with moderate-severe OSA is associated with brain tissue damage in regions involved in several cognitive tasks. We conclude that OSA can increase brain susceptibility to the effects of aging and other clinical and pathological occurrences.

Macro and micro sleep architecture and cognitive performance in older adults.

We sought to determine which facets of sleep neurophysiology were most strongly linked to cognitive performance in 3,819 older adults from two independent cohorts, using whole-night electroencephalography. From over 150 objective sleep metrics, we identified 23 that predicted cognitive performance, and processing speed in particular, with effects that were broadly independent of gross changes in sleep quality and quantity. These metrics included rapid eye movement duration, features of the electroencephalography power spectra derived from multivariate analysis, and spindle and slow oscillation morphology and coupling. These metrics were further embedded within broader associative networks linking sleep with aging and cardiometabolic disease: individuals who, compared with similarly aged peers, had better cognitive performance tended to have profiles of sleep metrics more often seen in younger, healthier individuals. Taken together, our results point to multiple facets of sleep neurophysiology that track coherently with underlying, age-dependent determinants of cognitive and physical health trajectories in older adults.

Cognitive replay of visuomotor learning at sleep onset: temporal dynamics and relationship to task performance.

STUDY OBJECTIVES: Studies of neural activity in animals and humans suggest that experiences are "replayed" in cortical and hippocampal networks during NREM sleep. Here, we examine whether memory reactivation in sleeping humans might also be evident within reports of concomitant subjective experience (i.e., dreaming). DESIGN: Participants were trained on an engaging visuomotor learning task across a period of one or more days, and sleep onset mentation was collected at variable intervals using the "Nightcap" home-monitoring device. Verbal reports of sleep onset mentation were obtained either at the beginning of the night, or following 2 h of initial sleep. SETTING: Data were collected in participants' home environments, via the Nightcap monitoring system, and at The Center for Sleep and Cognition, Beth Israel Deaconess Medical Center, Boston MA. PARTICIPANTS: 43 healthy, medication-free college students (16 males, age 18-25 years). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The learning task exerted a powerful, direct effect on verbal reports of mentation during light NREM sleep (stages 1 and 2). On post-training nights, a full 30% of all verbal reports were related to the task. The nature of this cognitive "replay" effect was altered with increasing durations of sleep, becoming more abstracted from the original experience as time into sleep increased. CONCLUSIONS: These observations are interpreted in light of memory consolidation theory, and demonstrate that introspective reports can provide a valuable window on cognitive processing in the sleeping brain.

Sleep enhances category learning.

The ability to categorize objects and events in the world around us is a fundamental and critical aspect of human learning. We trained healthy adults on a probabilistic category-learning task in two different training modes. The aim of this study was to see whether either form of probabilistic category learning (feedback or observational) undergoes subsequent enhancement during sleep. Our results suggest that after training, a good night of sleep can lead to improved performance the following day on such tasks.

REM-related obstructive sleep apnea: when does it matter? Effect on motor memory consolidation versus emotional health.

STUDY OBJECTIVES: The clinical importance of obstructive sleep apnea, which can be prevalent during rapid eye movement (REM) sleep, is unclear. The current study examines the effect of REM-related obstructive sleep apnea on motor memory consolidation as well as on mood states. METHODS: We compared performance on the motor sequence task (MST), psychomotor vigilance test (PVT), Functional Outcomes of Sleep Questionnaire, and the Profile of Mood State (POMS) survey between 3 groups: healthy controls (n = 18), REM-exclusive OSA (n = 17), and patients with OSA with respiratory events throughout REM and non-rapid eye movement (NREM) sleep (n = 18). RESULTS: As expected, performance on the MST improved overnight in the healthy control group. An improvement which was similar in magnitude was also observed in the REM-exclusive OSA group whereas patients with similar OSA during REM and NREM sleep showed reduced overnight memory consolidation. Consistent with these results, we found a correlation between overnight MST improvement and the apnea hypopnea index during NREM sleep (P = .041), but not during REM sleep (P = .424). However, patients with REM-exclusive apnea demonstrated the most negative emotions based on scoring highest on the POMS survey (P = .019). CONCLUSIONS: Our results provide evidence that although apneas occurring only during REM sleep do not have an effect on the encoding and stabilization of motor sequence memories, they are deleterious for emotional health.

Brainstem lesions are associated with sleep apnea in multiple sclerosis.

BACKGROUND: Studies linking MRI findings in MS patients with obstructive sleep apnea severity are limited. OBJECTIVE: We conducted a retrospective study to assess MRI abnormalities associated with obstructive sleep apnea (OSA) in patients with multiple sclerosis (MS). METHODS: We performed retrospective chart review of 65 patients with multiple sclerosis who had undergone polysomnography (PSG) for fatigue as well as brain MRI. We measured the number of lesions in the brainstem and calculated the standardized third ventricular width (sTVW) as a measure of brain atrophy, and subsequently performed correlation analyses of the apnea-hypopnea index (AHI) with brainstem lesion location, sTVW, and Expanded Disability Status Scale (EDSS). RESULTS: MS Patients with OSA were significantly older and had a higher body mass index (BMI) and higher AHI measures than patients without OSA. After adjustment for covariates, significant associations were found between AHI and lesion burden in the midbrain (p < 0.01) and pons (p = 0.05), but not medulla. CONCLUSIONS: Midbrain and pontine lesions burden correlated with AHI, suggesting MS lesion location could contribute to development of OSA.

Evaluation of an automated pipeline for large-scale EEG spectral analysis: the National Sleep Research Resource.

STUDY OBJECTIVES: We present an automated sleep electroencephalogram (EEG) spectral analysis pipeline that includes an automated artifact detection step, and we test the hypothesis that spectral power density estimates computed with this pipeline are comparable to those computed with a commercial method preceded by visual artifact detection by a sleep expert (standard approach). METHODS: EEG data were analyzed from the C3-A2 lead in a sample of polysomnograms from 161 older women participants in a community-based cohort study. We calculated the sensitivity, specificity, accuracy, and Cohen's kappa measures from epoch-by-epoch comparisons of automated to visual-based artifact detection results; then we computed the average EEG spectral power densities in six commonly used EEG frequency bands and compared results from the two methods using correlation analysis and Bland-Altman plots. RESULTS: Assessment of automated artifact detection showed high specificity [96.8%-99.4% in non-rapid eye movement (NREM), 96.9%-99.1% in rapid eye movement (REM) sleep] but low sensitivity (26.7%-38.1% in NREM, 9.1-27.4% in REM sleep). However, large artifacts (total power > 99th percentile) were removed with sensitivity up to 87.7% in NREM and 90.9% in REM, with specificities of 96.9% and 96.6%, respectively. Mean power densities computed with the two approaches for all EEG frequency bands showed very high correlation (≥0.99). The automated pipeline allowed for a 100-fold reduction in analysis time with regard to the standard approach. CONCLUSION: Despite low sensitivity for artifact rejection, the automated pipeline generated results comparable to those obtained with a standard method that included manual artifact detection. Automated pipelines can enable practical analyses of recordings from thousands of individuals, allowing for use in genetics and epidemiological research requiring large samples.

Greater Cognitive Deficits with Sleep-disordered Breathing among Individuals with Genetic Susceptibility to Alzheimer Disease. The Multi-Ethnic Study of Atherosclerosis.

RATIONALE: There are conflicting findings regarding the link between sleep apnea and cognitive dysfunction. OBJECTIVES: Investigate associations between indicators of sleep-disordered breathing (SDB) and cognitive function in the Multi-Ethnic Study of Atherosclerosis and assess effect modification by the apolipoprotein ε-4 (APOE-ε4) allele. METHODS: A diverse population (N = 1,752) underwent type 2 in-home polysomnography, which included measurement of percentage sleep time less than 90% oxyhemoglobin saturation (%Sat < 90%) and apnea-hypopnea index (AHI). Epworth Sleepiness Scale score (ESS) and sleep apnea syndrome (SAS; AHI ≥ 5 and ESS > 10) were also analyzed. Cognitive outcomes included the Cognitive Abilities Screening Instrument; Digit Symbol Coding (DSC) test; and Digit Span Tests (DST) Forward and Backward. RESULTS: Participants were 45.4% men, aged 68.1 years (SD, 9.1 yr) with a median AHI of 9.0 and mean ESS of 6.0. Approximately 9.7% had SAS, and 26.8% had at least one copy of the APOE-ε4 allele. In adjusted analyses, a 1-SD increase in %Sat < 90% and ESS score were associated with a poorer attention and memory assessed by the DST Forward score (ß = -0.12 [SE, 0.06] and ß = -0.13 [SE, 0.06], respectively; P ≤ 0.05). SAS and higher ESS scores were also associated with poorer attention and processing speed as measured by the DSC (ß = -0.69 [SE, 0.35] and ß = -1.42 [SE, 0.35], respectively; P < 0.05). The presence of APOE-ε4 allele modified the associations of %Sat < 90% with DST forward and of ESS with DSC (Pinteraction ≤ 0.05). CONCLUSIONS: Overnight hypoxemia and sleepiness were associated with cognition. The average effect estimates were small, similar to effect estimates for several other individual dementia risk factors. Associations were strongest in APOE-ε4 risk allele carriers. Our results (1) suggest that SDB be considered among a group of modifiable dementia risk factors, and (2) highlight the potential vulnerability of APOE-ε4 risk allele carriers with SDB.

First night of CPAP: impact on memory consolidation attention and subjective experience.

OBJECTIVE: Neurocognitive deficits are common and serious consequences of obstructive sleep apnea (OSA). Currently, the gold standard treatment is continuous positive air pressure (CPAP) therapy, although the clinical responses to this intervention can be variable. This study examined the effect of one night of CPAP therapy on sleep-dependent memory consolidation, attention, and vigilance as well as subjective experience. METHODS: Fifteen healthy controls and 29 patients with obstructive sleep apnea of whom 14 underwent a full-night CPAP titration completed the psychomotor vigilance test (PVT) and motor sequence learning task (MST) in the evening and the morning after undergoing overnight polysomnography. All participants also completed subjective evaluations of sleep quality. RESULTS: Participants with OSA showed significantly less overnight improvement on the MST compared to controls without OSA, independent of whether or not they had received CPAP treatment, while there was no significant difference between the untreated OSA and CPAP-treated patients. Within the OSA group, only those receiving CPAP exhibited faster reaction times on the PVT in the morning. Compared to untreated OSA patients, they also felt subjectively more rested and reported that they slept better. CONCLUSION: Our results demonstrate an instant augmentation of subjective experience and, based on PVT results, attention and vigilance after one night of CPAP, but a lack of an effect on offline sleep-dependent motor memory consolidation. This dissociation may be explained by different brain structures underlying these processes, some of which might require longer continued adherence to CPAP to generate an effect.

Untreated sleep-disordered breathing: links to aging-related decline in sleep-dependent memory consolidation.

BACKGROUND: Increasing age is associated with a decline in cognition and motor skills, while at the same time exacerbating one's risk of developing obstructive sleep apnea (OSA). OSA-related cognitive deficits are highly prevalent and can affect various memory systems including overnight memory consolidation on a motor sequence task. Thus, the aim of our study was to examine the effect of aging on sleep-dependent motor memory consolidation in patients with and without OSA. METHODS: We studied 44 patients (19-68 years) who had been referred by a physician for a baseline polysomnography (PSG) evaluation. Based on their PSG, patients were assigned either to the OSA group (AHI>5/h), or control (Non-OSA) group (AHI<5/h). All subjects performed the Psychomotor Vigilance Task (PVT) and the Motor Sequence Learning Task (MST) in the evening and again in the morning after their PSG. RESULTS: Despite similar learning in the evening, OSA subjects showed significantly less overnight improvement on the MST, both for immediate (OSA -2.7% ± 2.8% vs. controls 12.2% ± 3.5%; p = 0.002) and plateau improvement (OSA 4.9% ± 2.3% vs. controls 21.1%± 4.0%; p = 0.001). Within the OSA group, there was a significant negative correlation between overnight MST improvement and age (r(2) = 0.3; p = 0.01), an effect that was not observed in the Non-OSA group (r(2) = 0.08; p = 0.23). CONCLUSIONS: Consistent with previous research, healthy sleepers demonstrated a higher degree of sleep-dependent overnight improvement on the MST, an effect not mitigated by increasing age. However, the presence of untreated obstructive sleep apnea is associated with an aging-related cognitive deficit, otherwise not present in individuals without OSA. As other research has linked the presence of OSA to a higher likelihood of developing dementia, future studies are necessary to examine if the inhibition of memory consolidation is tied to the onset of neurodegenerative disease.

Obstructive sleep apnea is associated with impaired exercise capacity: a cross-sectional study.

OBJECTIVE: Obstructive sleep apnea (OSA) is associated with increased risk of adverse cardiovascular events. Because cardiopulmonary exercise testing (CPET) aids in prognostic assessment of heart disease, there is rising interest in its utility for cardiovascular risk stratification of patients with OSA. However, the relationship between OSA and exercise capacity is unclear. This study was conducted to test the hypothesis that OSA is associated with impaired exercise capacity. METHODS: Fifteen subjects with moderate-to-severe OSA (apnea-hypopnea index [AHI] ≥15 events/h) and 19 controls with mild or no OSA (AHI <15 events/h) were enrolled. Subjects underwent standard polysomnography to determine AHI and exclude other sleep disorders. Resting metabolic rate was measured via indirect calorimetry, followed by maximum, symptom-limited CPET. Subjects completed a sleep diary and physical activity questionnaire characterizing behaviors in the week prior to testing. RESULTS: Percent predicted peak oxygen uptake (V˙O2) was significantly lower in OSA subjects than controls (70.1%±17.5% vs 83.8%±13.9%; p = 0.02). Each 1-unit increase in log-transformed AHI was associated with a decrease in percent predicted peak V˙O2 of 3.20 (95% CI 0.53-5.88; p = 0.02). After adjusting for baseline differences, this association remained significant (p < 0.01). AHI alone explained 16.1% of the variability observed in percent predicted peak V˙O2 (p = 0.02). CONCLUSIONS: OSA is associated with impaired exercise capacity. Further study is needed to evaluate the utility of CPET for prognostic assessment of patients with OSA.