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Aims  To quantify the arousal burden (AB) across large cohort studies and determine its association with long-term cardiovascular (CV) and overall mortality in men and women. Methods and results  We measured the AB on overnight polysomnograms of 2782 men in the Osteoporotic Fractures in Men Study (MrOS) Sleep study, 424 women in the Study of Osteoporotic Fractures (SOF) and 2221 men and 2574 women in the Sleep Heart Health Study (SHHS). During 11.2 ± 2.1 years of follow-up in MrOS, 665 men died, including 236 CV deaths. During 6.4 ± 1.6 years of follow-up in SOF, 105 women died, including 47 CV deaths. During 10.7 ± 3.1 years of follow-up in SHHS, 987 participants died, including 344 CV deaths. In women, multivariable Cox proportional hazard analysis adjusted for common confounders demonstrated that AB is associated with all-cause mortality [SOF: hazard ratio (HR) 1.58 (1.01–2.42), P = 0.038; SHHS-women: HR 1.21 (1.06–1.42), P = 0.012] and CV mortality [SOF: HR 2.17 (1.04–4.50), P = 0.037; SHHS-women: HR 1.60 (1.12–2.28), P = 0.009]. In men, the association between AB and all-cause mortality [MrOS: HR 1.11 (0.94–1.32), P = 0.261; SHHS-men: HR 1.31 (1.06–1.62), P = 0.011] and CV mortality [MrOS: HR 1.35 (1.02–1.79), P = 0.034; SHHS-men: HR 1.24 (0.86–1.79), P = 0.271] was less clear. Conclusions Nocturnal AB is associated with long-term CV and all-cause mortality in women and to a lesser extent in men.

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The dynamic interplay between central and autonomic nervous system activities plays a pivotal role in orchestrating sleep. Macrostructural changes such as sleep-stage transitions or phasic, brief cortical events elicit fluctuations in neural outflow to the cardiovascular system, but the causal relationships between cortical and cardiovascular activities underpinning the microstructure of sleep are largely unknown. Here, we investigate cortical–cardiovascular interactions during the cyclic alternating pattern (CAP) of non-rapid eye movement sleep in a diverse set of overnight polysomnograms. We determine the Granger causality in both 507 CAP and 507 matched non-CAP sequences to assess the causal relationships between electroencephalography (EEG) frequency bands and respiratory and cardiovascular variables (heart period, respiratory period, pulse arrival time and pulse wave amplitude) during CAP. We observe a significantly stronger influence of delta activity on vascular variables during CAP sequences where slow, low-amplitude EEG activation phases (A1) dominate than during non-CAP sequences. We also show that rapid, high-amplitude EEG activation phases (A3) provoke a more pronounced change in autonomic activity than A1 and A2 phases. Our analysis provides the first evidence on the causal interplay between cortical and cardiovascular activities during CAP. Granger causality analysis may also be useful for probing the level of decoupling in sleep disorders. This article is part of the theme issue ‘Advanced computation in cardiovascular physiology: new challenges and opportunities’.

Study Objectives To determine in children with obstructive sleep apnea (OSA) the effect of adenotonsillectomy on the cyclic alternating pattern (CAP) and the relationship between CAP and behavioral, cognitive, and quality-of-life measures. Methods CAP parameters were analyzed in 365 overnight polysomnographic recordings of children with mild-to-moderate OSA enrolled in the Childhood Adenotonsillectomy Trial (CHAT), randomized to either early adenotonsillectomy (eAT) or watchful waiting with supportive care (WWSC). We also analyzed CAP in a subgroup of 72 children with moderate OSA (apnea-hypopnea index>10) that were part of the CHAT sample. Causal mediation analysis was performed to determine the independent effect of changes in CAP on selected outcome measures. Results At baseline, a higher number of A1-phases per hour of sleep was significantly associated with worse behavioral functioning (caregiver BRIEF GCE: ρ=0.24, P=0.042; caregiver Conners’ Rating Scale Global Index: ρ=0.25, P=0.036) and lower quality of life (OSA-18: ρ=0.27, P=0.022; PedsQL: ρ=-0.29, P=0.015) in the subgroup of children with moderate OSA, but not across the entire sample. At 7-months follow-up, changes in CAP parameters were comparable between the eAT and WWSC arms. CAP changes did not account for significant proportions of variations in behavioral, cognitive and quality-of-life performance measures at follow-up. Conclusions We show a significant association between the frequency of slow, high-amplitude waves with behavioral functioning as well as the quality-of-life in children with moderate OSA. Early adenotonsillectomy in children with mild-to-moderate OSA does not alter the microstructure of NREM sleep compared to watchful waiting after an approximately 7 month period of follow-up. Clinical Trial The study “A Randomized Controlled Study of Adenotonsillectomy for Children With Obstructive Sleep Apnea Syndrome” was registered at Clinicaltrials.gov (#NCT00560859).

Study Objectives To assess the microstructural architecture of non-rapid eye movement (NREM) sleep known as cyclic alternating pattern (CAP) in relation to the age, gender, self-reported sleep quality, and the degree of sleep disruption in large community-based cohort studies of older people. Methods We applied a high-performance automated CAP detection system to characterize CAP in 2,811 men from the Osteoporotic Fractures in Men Sleep Study (MrOS) and 426 women from the Study of Osteoporotic Fractures (SOF). CAP was assessed with respect to age and gender and correlated to obstructive apnea–hypopnea index, arousal index (AI-NREM), and periodic limb movements in sleep index. Further, we evaluated CAP across levels of self-reported sleep quality measures using analysis of covariance. Results Age was significantly associated with the number of CAP sequences during NREM sleep (MrOS: p = 0.013, SOF = 0.051). CAP correlated significantly with AI-NREM (MrOS: ρ = 0.30, SOF: ρ = 0.29). CAP rate, especially the A2+A3 index, was inversely related to self-reported quality of sleep, independent of age and sleep disturbance measures. Women experienced significantly fewer A1-phases compared to men, in particular, in slow-wave sleep (N3). Conclusions We demonstrate that automated CAP analysis of large-scale databases can lead to new findings on CAP and its subcomponents. We show that sleep disturbance indices are associated with the CAP rate. Further, the CAP rate is significantly linked to subjectively reported sleep quality, independent from traditionally scored markers of sleep fragmentation. Finally, men and women show differences in the microarchitecture of sleep as identified by CAP, despite similar macro-architecture.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

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