Ventilatory Burden as a Measure of Obstructive Sleep Apnea Severity Is Predictive of Cardiovascular and All-Cause Mortality.

Rationale: The apnea-hypopnea index (AHI), used for the diagnosis of obstructive sleep apnea, captures only the frequency of respiratory events and has demonstrable limitations. Objectives: We propose a novel automated measure, termed "ventilatory burden" (VB), that represents the proportion of overnight breaths with less than 50% normalized amplitude, and we show its ability to overcome limitations of AHI. Methods: Data from two epidemiological cohorts (EPISONO [Sao Paolo Epidemiological Study] and SHHS [Sleep Heart Health Study]) and two retrospective clinical cohorts (DAYFUN; New York University Center for Brain Health) were used in this study to 1) derive the normative range of VB, 2) assess the relationship between degree of upper airway obstruction and VB, and 3) assess the relationship between VB and all-cause and cardiovascular disease (CVD) mortality with and without hypoxic burden that was derived using an in-house automated algorithm. Measurements and Main Results: The 95th percentiles of VB in asymptomatic healthy subjects across the EPISONO and the DAYFUN cohorts were 25.2% and 26.7%, respectively (median [interquartile range], VBEPISONO, 5.5 [3.5-9.7]%; VBDAYFUN, 9.8 [6.4-15.6]%). VB was associated with the degree of upper airway obstruction in a dose-response manner (VBuntreated, 31.6 [27.1]%; VBtreated, 7.2 [4.7]%; VBsuboptimally treated, 17.6 [18.7]%; VBoff-treatment, 41.6 [18.1]%) and exhibited low night-to-night variability (intraclass correlation coefficient [2,1], 0.89). VB was predictive of all-cause and CVD mortality in the SHHS cohort before and after adjusting for covariates including hypoxic burden. Although AHI was predictive of all-cause mortality, it was not associated with CVD mortality in the SHHS cohort. Conclusions: Automated VB can effectively assess obstructive sleep apnea severity, is predictive of all-cause and CVD mortality, and may be a viable alternative to the AHI.

Effect of Aging and a Dual Orexin Receptor Antagonist on Sleep Architecture and Non-REM Oscillations Including an REM Behavior Disorder Phenotype in the PS19 Mouse Model of Tauopathy.

The impact of tau pathology on sleep microarchitecture features, including slow oscillations, spindles, and their coupling, has been understudied, despite the proposed importance of these electrophysiological features toward learning and memory. Dual orexin receptor antagonists (DORAs) are known to promote sleep, but whether and how they affect sleep microarchitecture in the setting of tauopathy is unknown. In the PS19 mouse model of tauopathy MAPT (microtubule-associated protein tau) P301S (both male and female), young PS19 mice 2-3 months old show a sleep electrophysiology signature with markedly reduced spindle duration and power and elevated slow oscillation (SO) density compared with littermate controls, although there is no significant tau hyperphosphorylation, tangle formation, or neurodegeneration at this age. With aging, there is evidence for sleep disruption in PS19 mice, characterized by reduced REM duration, increased non-REM and REM fragmentation, and more frequent brief arousals at the macrolevel and reduced spindle density, SO density, and spindle-SO coupling at the microlevel. In ∼33% of aged PS19 mice, we unexpectedly observed abnormal goal-directed behaviors in REM, including mastication, paw grasp, and forelimb/hindlimb extension, seemingly consistent with REM behavior disorder (RBD). Oral administration of DORA-12 in aged PS19 mice increased non-REM and REM duration, albeit with shorter bout lengths, and increased spindle density, spindle duration, and SO density without change to spindle-SO coupling, power in either the SO or spindle bands, or the arousal index. We observed a significant effect of DORA-12 on objective measures of RBD, thereby encouraging future exploration of DORA effects on sleep-mediated cognition and RBD treatment.SIGNIFICANCE STATEMENT The specific effect of tauopathy on sleep macroarchitecture and microarchitecture throughout aging remains unknown. Our key findings include the following: (1) the identification of a sleep EEG signature constituting an early biomarker of impending tauopathy; (2) sleep physiology deteriorates with aging that are also markers of off-line cognitive processing; (3) the novel observation that dream enactment behaviors reminiscent of RBD occur, likely the first such observation in a tauopathy model; and (4) a dual orexin receptor antagonist is capable of restoring several of the sleep macroarchitecture and microarchitecture abnormalities.

Interactive Associations of Neuropsychiatry Inventory-Questionnaire Assessed Sleep Disturbance and Vascular Risk on Alzheimer's Disease Stage Progression in Clinically Normal Older Adults.

Background: To determine whether sleep disturbance (SD) and vascular-risk interact to promote Alzheimer's disease (AD) stage-progression in normal, community-dwelling older adults and evaluate their combined risk beyond that of established AD biomarkers. Methods: Longitudinal data from the National Alzheimer's Coordinating Center Uniform-Dataset. SD data (i.e., SD+ vs. SD-), as characterized by the Neuropsychiatric Inventory-Questionnaire, were derived from 10,600 participants at baseline, with at-least one follow-up visit. A subset (n = 361) had baseline cerebrospinal fluid (CSF) biomarkers and MRI data. The Framingham heart study general cardiovascular disease (FHS-CVD) risk-score was used to quantify vascular risk. Amnestic mild cognitive impairment (aMCI) diagnosis during follow-up characterized AD stage-progression. Logistic mixed-effects models with random intercept and slope examined the interaction of SD and vascular risk on prospective aMCI diagnosis. Results: Of the 10,600 participants, 1,017 (9.6%) reported SD and 6,572 (62%) were female. The overall mean (SD) age was 70.5 (6.5), and follow-up time was 5.1 (2.7) years. SD and the FHS-CVD risk-score were each associated with incident aMCI (aOR: 1.42 and aOR: 2.11, p < 0.01 for both). The interaction of SD and FHS-CVD risk-score with time was significant (aOR: 2.87, p < 0.01), suggesting a synergistic effect. SD and FHS-CVD risk-score estimates remained significantly associated with incident aMCI even after adjusting for CSF (Aß, T-tau, P-tau) and hippocampal volume (n = 361) (aOR: 2.55, p < 0.01), and approximated risk-estimates of each biomarker in the sample where data was available. Conclusions: Clinical measures of sleep and vascular risk may complement current AD biomarkers in assessing risk of cognitive decline in older adults.

Selective Continuous Positive Airway Pressure Withdrawal With Supplemental Oxygen During Slow-Wave Sleep as a Method of Dissociating Sleep Fragmentation and Intermittent Hypoxemia-Related Sleep Disruption in Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is considered to impair memory processing and increase the expression of amyloid-ß (Aß) and risk for Alzheimer's disease (AD). Given the evidence that slow-wave sleep (SWS) is important in both memory and Aß metabolism, a better understanding of the mechanisms by which OSA impacts memory and risk for AD can stem from evaluating the role of disruption of SWS specifically and, when such disruption occurs through OSA, from evaluating the individual contributions of sleep fragmentation (SF) and intermittent hypoxemia (IH). In this study, we used continuous positive airway pressure (CPAP) withdrawal to recapitulate SWS-specific OSA during polysomnography (PSG), creating conditions of both SF and IH in SWS only. During separate PSGs, we created the conditions of SWS fragmentation but used oxygen to attenuate IH. We studied 24 patients (average age of 55 years, 29% female) with moderate-to-severe OSA [Apnea-Hypopnea Index (AHI); AHI4% > 20/h], who were treated and adherent to CPAP. Participants spent three separate nights in the laboratory under three conditions as follows: (1) consolidated sleep with CPAP held at therapeutic pressure (CPAP); (2) CPAP withdrawn exclusively in SWS (OSA SWS ) breathing room air; and (3) CPAP withdrawn exclusively in SWS with the addition of oxygen during pressure withdrawal (OSA SWS + O 2). Multiple measures of SF (e.g., arousal index) and IH (e.g., hypoxic burden), during SWS, were compared according to condition. Arousal index in SWS during CPAP withdrawal was significantly greater compared to CPAP but not significantly different with and without oxygen (CPAP = 1.1/h, OSA SWS + O2 = 10.7/h, OSA SWS = 10.6/h). However, hypoxic burden during SWS was significantly reduced with oxygen compared to without oxygen [OSA SWS + O 2 = 23 (%min)/h, OSA SWS = 37 (%min)/h]. No significant OSA was observed in non-rapid eye movement (REM) stage 1 (NREM 1), non-REM stage 2 (NREM 2), or REM sleep (e.g., non-SWS) in any condition. The SWS-specific CPAP withdrawal induces OSA with SF and IH. The addition of oxygen during CPAP withdrawal results in SF with significantly less severe hypoxemia during the induced respiratory events in SWS. This model of SWS-specific CPAP withdrawal disrupts SWS with a physiologically relevant stimulus and facilitates the differentiation of SF and IH in OSA.

WaveSleepNet: An interpretable deep convolutional neural network for the continuous classification of mouse sleep and wake.

BACKGROUND: Recent advancement in deep learning provides a pivotal opportunity to potentially supplement or supplant the limiting step of manual sleep scoring. NEW METHOD: In this paper, we characterize the WaveSleepNet (WSN), a deep convolutional neural network (CNN) that uses wavelet transformed images of mouse EEG/EMG signals to autoscore sleep and wake. RESULTS: WSN achieves an epoch by epoch mean accuracy of 0.86 and mean F1 score of 0.82 compared to manual scoring by a human expert. In mice experiencing mechanically induced sleep fragmentation, an overall epoch by epoch mean accuracy of 0.80 is achieved by WSN and classification of non-REM (NREM) sleep is not compromised, but the high level of sleep fragmentation results in WSN having greater difficulty differentiating REM from NREM sleep. We also find that WSN achieves similar levels of accuracy on an independent dataset of externally acquired EEG/EMG recordings with an overall epoch by epoch accuracy of 0.91. We also compared conventional summary sleep metrics in mice sleeping ad libitum. WSN systematically biases sleep fragmentation metrics of bout number and bout length leading to an overestimated degree of sleep fragmentation. COMPARISON WITH EXISTING METHODS: In a cross-validation, WSN has a greater macro and stage-specific accuracy compared to a conventional random forest classifier. Examining the WSN, we find that it automatically learns spectral features consistent with manual scoring criteria that are used to define each class. CONCLUSION: These results suggest to us that WSN is capable of learning visually agreeable features and may be useful as a supplement to human manual scoring.

Post-error recruitment of frontal sensory cortical projections promotes attention in mice.

The frontal cortex, especially the anterior cingulate cortex area (ACA), is essential for exerting cognitive control after errors, but the mechanisms that enable modulation of attention to improve performance after errors are poorly understood. Here we demonstrate that during a mouse visual attention task, ACA neurons projecting to the visual cortex (VIS; ACAVIS neurons) are recruited selectively by recent errors. Optogenetic manipulations of this pathway collectively support the model that rhythmic modulation of ACAVIS neurons in anticipation of visual stimuli is crucial for adjusting performance following errors. 30-Hz optogenetic stimulation of ACAVIS neurons in anesthetized mice recapitulates the increased gamma and reduced theta VIS oscillatory changes that are associated with endogenous post-error performance during behavior and subsequently increased visually evoked spiking, a hallmark feature of visual attention. This frontal sensory neural circuit links error monitoring with implementing adjustments of attention to guide behavioral adaptation, pointing to a circuit-based mechanism for promoting cognitive control.

Altered K-complex morphology during sustained inspiratory airflow limitation is associated with next-day lapses in vigilance in obstructive sleep apnea.

STUDY OBJECTIVES: Determine if changes in K-complexes associated with sustained inspiratory airflow limitation (SIFL) during N2 sleep are associated with next-day vigilance and objective sleepiness. METHODS: Data from thirty subjects with moderate-to-severe obstructive sleep apnea who completed three in-lab polysomnograms: diagnostic, on therapeutic continuous positive airway pressure (CPAP), and on suboptimal CPAP (4 cmH2O below optimal titrated CPAP level) were analyzed. Four 20-min psychomotor vigilance tests (PVT) were performed after each PSG, every 2 h. Changes in the proportion of spontaneous K-complexes and spectral characteristics surrounding K-complexes were evaluated for K-complexes associated with both delta (∆SWAK), alpha (∆αK) frequencies. RESULTS: Suboptimal CPAP induced SIFL (14.7 (20.9) vs 2.9 (9.2); %total sleep time, p < 0.001) with a small increase in apnea-hypopnea index (AHI3A: 6.5 (7.7) vs 1.9 (2.3); p < 0.01) versus optimal CPAP. K-complex density (num./min of stage N2) was higher on suboptimal CPAP (0.97 ± 0.7 vs 0.65±0.5, #/min, mean ± SD, p < 0.01) above and beyond the effect of age, sex, AHI3A, and duration of SIFL. A decrease in ∆SWAK with suboptimal CPAP was associated with increased PVT lapses and explained 17% of additional variance in PVT lapses. Within-night during suboptimal CPAP K-complexes appeared to alternate between promoting sleep and as arousal surrogates. Electroencephalographic changes were not associated with objective sleepiness. CONCLUSIONS: Sustained inspiratory airflow limitation is associated with altered K-complex morphology including the increased occurrence of K-complexes with bursts of alpha as arousal surrogates. These findings suggest that sustained inspiratory flow limitation may be associated with nonvisible sleep fragmentation and contribute to increased lapses in vigilance.

Effects of obstructive sleep apnea on human spatial navigational memory processing in cognitively normal older individuals.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) prevalence increases with age, but whether OSA-related sleep disruption could interrupt the processing of previously encoded wake information thought to normally occur during sleep in cognitively normal older adults remains unknown. METHODS: Fifty-two older (age = 66.9 ± 7.7 years, 56% female), community-dwelling, cognitively normal adults explored a 3-D maze environment and then performed 3 timed trials before (evening) and after (morning) sleep recorded with polysomnography with a 20-minute morning psychomotor vigilance test. RESULTS: Twenty-two (22) participants had untreated OSA [apnea-hypopnea index (AHI4%) ≥ 5 events/h] where severity was mild on average [median (interquartile range); AHI4% = 11.0 (20.7) events/h] and 30 participants had an AHI4% < 5 events/h. No significant differences were observed in overnight percent change in completion time or in the pattern of evening presleep maze performance. However, during the morning postsleep trials, there was a significant interaction between OSA group and morning trial number such that participants with OSA performed worse on average with each subsequent morning trial, whereas those without OSA showed improvements. There were no significant differences in morning psychomotor vigilance test performance, suggesting that vigilance is unlikely to account for this difference in morning maze performance. Increasing relative frontal slow wave activity was associated with better overnight maze performance improvement in participants with OSA (r = .51, P = .02) but not in those without OSA, and no differences in slow wave activity were observed between groups. CONCLUSIONS: OSA alters morning performance in spatial navigation independent of a deleterious effect on morning vigilance or evening navigation performance. Relative frontal slow wave activity is associated with overnight performance change in older participants with OSA, but not those without.

Self-reported obstructive sleep apnea, amyloid and tau burden, and Alzheimer's disease time-dependent progression.

INTRODUCTION: Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) biomarkers in cognitively normal (CN) and mild cognitive impaired (MCI) participants. However, independent and combined effects of OSA, amyloid beta (Aß) and tau-accumulation on AD time-dependent progression risk is unclear. METHODS: Study participants grouped by biomarker profile, as described by the A/T/N scheme, where "A" refers to aggregated Aß, "T" aggregated tau, and "N" to neurodegeneration, included 258 CN (OSA-positive [OSA+] [A+TN+ n = 10, A+/TN- n = 6, A-/TN+ n = 10, A-/TN- n = 6 and OSA-negative [OSA-] [A+TN+ n = 84, A+/TN- n = 11, A-/TN+ n = 96, A-/TN- n = 36]) and 785 MCI (OSA+ [A+TN+ n = 35, A+/TN- n = 15, A-/TN+ n = 25, A-/TN- n = 16] and OSA- [A+TN+ n = 388, A+/TN- n = 28, A-/TN+ n = 164, A-/TN- n = 114]) older-adults from the Alzheimer's Disease Neuroimaging Initiative cohort. Cox proportional hazards regression models estimated the relative hazard of progression from CN-to-MCI and MCI-to-AD, among baseline OSA CN and MCI patients, respectively. Multi-level logistic mixed-effects models with random intercept and slope investigated the synergistic associations of self-reported OSA, Aß, and tau burden with prospective cognitive decline. RESULTS: Independent of TN-status (CN and MCI), OSA+/Aß+ participants were approximately two to four times more likely to progress to MCI/AD (P < .001) and progressed 6 to 18 months earlier (P < .001), compared to other participants combined (ie, OSA+/Aß-, OSA-/Aß+, and OSA-/Aß-). Notably, OSA+/Aß- versus OSA-/Aß- (CN and MCI) and OSA+/TN- versus OSA-/TN- (CN) participants showed no difference in the risk and time-to-MCI/AD progression. Mixed effects models demonstrated OSA synergism with Aß (CN and MCI [ß = 1.13, 95% confidence interval (CI), 0.74 to 1.52, and ß = 1.18, 95%CI, 0.82 to 1.54]) respectively, and with tau (MCI [ß = 1.31, 95% CI, 0.87 to 1.47]), P < .001 for all. DISCUSSION: OSA acts in synergism with Aß and with tau, and all three acting together result in synergistic neurodegenerative mechanisms especially as Aß and tau accumulation becomes increasingly abnormal, thus leading to shorter progression time to MCI/AD in CN and MCI-OSA patients, respectively.

Obstructive Sleep Apnea and Its Treatment in Aging: Effects on Alzheimer's disease Biomarkers, Cognition, Brain Structure and Neurophysiology.

Here we review the impact of obstructive sleep apnea (OSA) on biomarkers of Alzheimer's disease (AD) pathogenesis, neuroanatomy, cognition and neurophysiology, and present the research investigating the effects of continuous positive airway pressure (CPAP) therapy. OSA is associated with an increase in AD markers amyloid-ß and tau measured in cerebrospinal fluid (CSF), by Positron Emission Tomography (PET) and in blood serum. There is some evidence suggesting CPAP therapy normalizes AD biomarkers in CSF but since mechanisms for amyloid-ß and tau production/clearance in humans are not completely understood, these findings remain preliminary. Deficits in the cognitive domains of attention, vigilance, memory and executive functioning are observed in OSA patients with the magnitude of impairment appearing stronger in younger people from clinical settings than in older community samples. Cognition improves with varying degrees after CPAP use, with the greatest effect seen for attention in middle age adults with more severe OSA and sleepiness. Paradigms in which encoding and retrieval of information are separated by periods of sleep with or without OSA have been done only rarely, but perhaps offer a better chance to understand cognitive effects of OSA than isolated daytime testing. In cognitively normal individuals, changes in EEG microstructure during sleep, particularly slow oscillations and spindles, are associated with biomarkers of AD, and measures of cognition and memory. Similar changes in EEG activity are reported in AD and OSA, such as "EEG slowing" during wake and REM sleep, and a degradation of NREM EEG microstructure. There is evidence that CPAP therapy partially reverses these changes but large longitudinal studies demonstrating this are lacking. A diagnostic definition of OSA relying solely on the Apnea Hypopnea Index (AHI) does not assist in understanding the high degree of inter-individual variation in daytime impairments related to OSA or response to CPAP therapy. We conclude by discussing conceptual challenges to a clinical trial of OSA treatment for AD prevention, including inclusion criteria for age, OSA severity, and associated symptoms, the need for a potentially long trial, defining relevant primary outcomes, and which treatments to target to optimize treatment adherence.

Interactions between sleep disruption, motor learning, and p70 S6 kinase 1 signaling.

Offline gains in motor performance after initial motor learning likely depend on sleep, but the molecular mechanisms by which this occurs are understudied. Regulation of mRNA translation via p70 S6 kinase 1 (S6K1) signaling represents one potential mechanism, as protein synthesis is thought to be increased during sleep compared to wake and is necessary for several forms of long-term memory. Using phosphorylation of ribosomal protein S6 (RpS6) as a readout of S6K1 activity, we demonstrate that a period of 10 h of acute sleep disruption impairs both S6K1 signaling and offline gains in motor performance on the rotarod in adult wild type C57/Bl6 mice. Rotarod motor learning results in increased abundance of RpS6 in the striatum, and inhibition of S6K1 either indirectly with rapamycin or directly with PF-4708671 diminished the offline improvement in motor performance without affecting the initial acquisition of rotarod motor learning when sleep is normal. In sum, S6K1 activity is required for sleep-dependent offline gains in motor performance and is inhibited following acute sleep disruption, while motor learning increases the abundance of striatal RpS6. Thus, S6K1 signaling represents a plausible mechanism mediating the beneficial effects of sleep on motor performance.

Dynamics of sleep spindles and coupling to slow oscillations following motor learning in adult mice.

Sleep spindles have been implicated in motor learning in human subjects, but their occurrence, timing in relation to cortical slow oscillations, and relationship to offline gains in motor learning have not been examined in animal models. In this study, we recorded EEG over bilateral primary motor cortex in conjunction with EMG for 24 h following a period of either baseline handling or following rotarod motor learning to monitor sleep. We measured several biophysical properties of sleep spindles and their temporal coupling with cortical slow oscillations (SO, <1 Hz) and cortical delta waves (1-4 Hz). Following motor learning, we found an increase in spindles during an early period of NREM sleep (1-4 h) without changes to biophysical properties such as spindle power, peak frequency and coherence. In this same period of early NREM sleep, both SO and delta power increased after motor learning. Notably, a vast majority of spindles were associated with minimal SO power, but in the subset that were associated with significant SO power (>1 z-score above the population mean), spindle-associated SO power was greater in spindles following motor learning compared to baseline sleep. Also, we did not observe a group-level preferred phase in spindle-SO or spindle-delta coupling. While SO power alone was not predictive of motor performance in early NREM sleep, both spindle density and the difference in the magnitude of the mean resultant vector length of the phase angle for SO-associated spindles, a measure of its coupling precision, were positively correlated with offline change in motor performance. These findings support a role for sleep spindles and their coupling to slow oscillations in motor learning and establish a model in which spindle timing and the brain circuits that support offline plasticity can be mechanistically explored.

Necessity of Sleep for Motor Gist Learning in Mice.

With respect to behavior, the term memory "consolidation" has canonically been used to describe increased fidelity during testing to a learned behavior shaped during training. While the sleeping brain appears to certainly aid in consolidation by this definition for a variety of memories, including motor memories, growing evidence suggests that sleep allows for much more flexible use of the information encountered during prior wakefulness. Sleep has been shown to augment the extraction of gist or patterns from wake experience in human subjects, but this has been difficult to recapitulate in animal models owing to the semantic requirements in many such tasks. Here we establish a model of motor gist learning in mice in which two bouts of exclusive forward running on the rotarod significantly augments the first experience of exclusive backward running. This augmentation does not occur if sleep is disrupted following the forward running template behavior or if a period of natural wakefulness follows one of the two bouts of exclusive forward running. This suggests that sleep is required for the extraction of the motor gist of forward running to apply to backward running.