Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study

Background

Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.

Methods and Findings

We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.

Conclusions

Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing. Please see later in the article for the Editors'' Summary     

Sleep-Dependent Reactivation of Ensembles in Motor Cortex Promotes Skill Consolidation

Despite many prior studies demonstrating offline behavioral gains in motor skills after sleep, the underlying neural mechanisms remain poorly understood. To investigate the neurophysiological basis for offline gains, we performed single-unit recordings in motor cortex as rats learned a skilled upper-limb task. We found that sleep improved movement speed with preservation of accuracy. These offline improvements were linked to both replay of task-related ensembles during non-rapid eye movement (NREM) sleep and temporal shifts that more tightly bound motor cortical ensembles to movements; such offline gains and temporal shifts were not evident with sleep restriction. Interestingly, replay was linked to the coincidence of slow-wave events and bursts of spindle activity. Neurons that experienced the most consistent replay also underwent the most significant temporal shift and binding to the motor task. Significantly, replay and the associated performance gains after sleep only occurred when animals first learned the skill; continued practice during later stages of learning (i.e., after motor kinematics had stabilized) did not show evidence of replay. Our results highlight how replay of synchronous neural activity during sleep mediates large-scale neural plasticity and stabilizes kinematics during early motor learning.     

Tonsillectomy versus Tonsillotomy for Sleep-Disordered Breathing in Children: A Meta Analysis

Objectives

Tonsillotomy has gained popular acceptance as an alternative to the traditional tonsillectomy in the management of sleep-disordered breathing in children. Many studies have evaluated the outcomes of the two techniques, but uncertainty remains with regard to the efficacy and complications of tonsillotomy versus a traditional tonsillectomy. This study was designed to investigate the efficacy and complications of tonsillotomy versus tonsillectomy, in terms of the short- and long-term results.

Methods

We collected data from electronic databases including MEDLINE, EMBASE, and the Cochrane Library. The following inclusion criteria were applied: English language, children, and prospective studies that directly compared tonsillotomy and tonsillectomy in the management of sleep disordered breathing. Subgroup analysis was then performed.

Results

In total, 10 eligible studies with 1029 participants were included. Tonsillotomy was shown to be advantageous over tonsillectomy in short-term measures, such as a lower hemorrhage rate, shorter operation time, and faster pain relief. In long-term follow-up, there was no significant difference in resolution of upper-airway obstructive symptoms, the quality of life, or postoperative immune function between the tonsillotomy and tonsillectomy groups. The risk ratio of SDB recurrence was 3.33 (95% confidence interval = 1.62 6.82, P = 0.001), favoring tonsillectomy at an average follow-up of 31 months.

Conclusions

Tonsillotomy may be advantageous over tonsillectomy in the short term measures and there are no significant difference of resolving obstructive symptoms, quality of life and postoperative immune function. For the long run, the dominance of tonsillotomy may be less than tonsillectomy with regard to the rate of sleep-disordered breathing recurrence.     

Memory Consolidation in the Cerebellar Cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA_A agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage.     

Learning to Attend to Threat Accelerates and Enhances Memory Consolidation

Practice on a procedural task involves within-session learning and between-session consolidation of learning, with the latter requiring a minimum of about four hours to evolve due to involvement of slower cellular processes. Learning to attend to threats is vital for survival and thus may involve faster memory consolidation than simple procedural learning. Here, we tested whether attention to threat modulates the time-course and magnitude of learning and memory consolidation effects associated with skill practice. All participants (N = 90) practiced in two sessions on a dot-probe task featuring pairs of neutral and angry faces followed by target probes which were to be discriminated as rapidly as possible. In the attend-threat training condition, targets always appeared at the angry face location, forming an association between threat and target location; target location was unrelated to valence in a control training condition. Within each attention training condition, duration of the between-session rest interval was varied to establish the time-course for emergence of consolidation effects. During the first practice session, we observed robust improvement in task performance (online, within-session gains), followed by saturation of learning. Both training conditions exhibited similar overall learning capacities, but performance in the attend-threat condition was characterized by a faster learning rate relative to control. Consistent with the memory consolidation hypothesis, between-session performance gains (delayed gains) were observed only following a rest interval. However, rest intervals of 1 and 24 hours yielded similar delayed gains, suggesting accelerated consolidation processes. Moreover, attend-threat training resulted in greater delayed gains compared to the control condition. Auxiliary analyses revealed that enhanced performance was retained over several months, and that training to attend to neutral faces resulted in effects similar to control. These results provide a novel demonstration of how attention to threat can accelerate and enhance memory consolidation effects associated with skill acquisition.     

Causal Contribution of Awake Post-encoding Processes to Episodic Memory Consolidation

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Chronic Intermittent Hypoxia Is Independently Associated with Reduced Postoperative Opioid Consumption in Bariatric Patients Suffering from Sleep-Disordered Breathing

BackgroundEvidence suggests that recurrent nocturnal hypoxemia may affect pain response and/or the sensitivity to opioid analgesia. We tested the hypothesis that nocturnal hypoxemia, quantified by sleep time spent at an arterial saturation (SaO₂) < 90% and minimum nocturnal SaO₂ on polysomnography, are associated with decreased pain and reduced opioid consumption during the initial 72 postoperative hours in patients having laparoscopic bariatric surgery.MethodsWith Institutional Review Board approval, we examined the records of all patients who underwent laparoscopic bariatric surgery between 2004 and 2010 and had an available nocturnal polysomnography study. We assessed the relationships between the time-weighted average of pain score and total opioid consumption during the initial 72 postoperative hours, and: (a) the percentage of total sleep time spent at SaO₂ < 90%, (b) the minimum nocturnal SaO₂, and (c) the number of apnea/hypopnea episodes per hour of sleep. We used multivariable regression models to adjust for both clinical and sleep-related confounders.ResultsTwo hundred eighteen patients were included in the analysis. Percentage of total sleep time spent at SaO₂ < 90% was inversely associated with total postoperative opioid consumption; a 5-%- absolute increase in the former would relatively decrease median opioid consumption by 16% (98.75% CI: 2% to 28%, P = 0.006). However, the percentage of total sleep time spent at SaO₂ < 90% was not associated with pain. The minimum nocturnal SaO₂ was associated neither with total postoperative opioid consumption nor with pain. In addition, neither pain nor total opioid consumption was significantly associated with the number of apnea/hypopnea episodes per hour of sleep.ConclusionsPreoperative nocturnal intermittent hypoxia may enhance sensitivity to opioids.     

The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline

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Sleep Deprivation Impairs Consolidation of Cued Fear Memory in Rats

Post-learning sleep facilitates negative memory consolidation and also helps preserve it over several years. It is believed, therefore, that sleep deprivation may help prevent consolidation of fearful memory. Its effect, however, on consolidation of negative/frightening memories is not known. Cued fear-conditioning (CuFC) is a widely used model to understand the neural basis of negative memory associated with anxiety disorders. In this study, we first determined the suitable circadian timing for consolidation of CuFC memory and changes in sleep architecture after CuFC. Thereafter, we studied the effect of sleep deprivation on CuFC memory consolidation. Three sets of experiments were performed in male Wistar rat (n = 51). In experiment-I, animals were conditioned to cued-fear by presenting ten tone-shock paired stimuli during lights-on (7 AM) (n = 9) and lights-off (7 PM) (n = 9) periods. In experiment-II, animals were prepared for polysomnographic recording (n = 8) and changes in sleep architecture after CuFC was determined. Further in experiment-III, animals were cued fear-conditioned during the lights-off period and were randomly divided into four groups: Sleep-Deprived (SD) (n = 9), Non-Sleep Deprived (NSD) (n = 9), Stress Control (SC) (n = 9) and Tone Control (n = 7). Percent freezing amount, a hallmark of fear, was compared statistically in these groups. Rats trained during the lights-off period exhibited significantly more freezing compared to lights-on period. In CuFC trained animals, total sleep amount did not change, however, REM sleep decreased significantly. Further, out of total sleep time, animals spent proportionately more time in NREM sleep. Nevertheless, SD animals exhibited significantly less freezing compared to NSD and SC groups. These data suggest that sleep plays an important role in the consolidation of cued fear-conditioned memory.     

The Consolidation of Implicit Sequence Memory in Obstructive Sleep Apnea

Obstructive Sleep Apnea (OSA) Syndrome is a relatively frequent sleep disorder characterized by disrupted sleep patterns. It is a well-established fact that sleep has beneficial effect on memory consolidation by enhancing neural plasticity. Implicit sequence learning is a prominent component of skill learning. However, the formation and consolidation of this fundamental learning mechanism remains poorly understood in OSA. In the present study we examined the consolidation of different aspects of implicit sequence learning in patients with OSA. We used the Alternating Serial Reaction Time task to measure general skill learning and sequence-specific learning. There were two sessions: a learning phase and a testing phase, separated by a 10-hour offline period with sleep. Our data showed differences in offline changes of general skill learning between the OSA and control group. The control group demonstrated offline improvement from evening to morning, while the OSA group did not. In contrast, we did not observe differences between the groups in offline changes in sequence-specific learning. Our findings suggest that disrupted sleep in OSA differently affects neural circuits involved in the consolidation of sequence learning.     

Dual Role of an mps-2/KCNE-Dependent Pathway in Long-Term Memory and Age-Dependent Memory Decline

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Effects of Acute Methamphetamine on Emotional Memory Formation in Humans: Encoding vs Consolidation

Understanding how stimulant drugs affect memory is important for understanding their addictive potential. Here we examined the effects of acute d-methamphetamine (METH), administered either before (encoding phase) or immediately after (consolidation phase) study on memory for emotional and neutral images in healthy humans. Young adult volunteers (N = 60) were randomly assigned to either an encoding group (N = 29) or a consolidation group (N = 31). Across three experimental sessions, they received placebo and two doses of METH (10, 20 mg) either 45 min before (encoding) or immediately after (consolidation) viewing pictures of emotionally positive, neutral, and negative scenes. Memory for the pictures was tested two days later, under drug-free conditions. Half of the sample reported sleep disturbances following the high dose of METH, which affected their memory performance. Therefore, participants were classified as poor sleepers (less than 6 hours; n = 29) or adequate sleepers (6 or more hours; n = 31) prior to analyses. For adequate sleepers, METH (20 mg) administered before encoding significantly improved memory accuracy relative to placebo, especially for emotional (positive and negative), compared to neutral, stimuli. For poor sleepers in the encoding group, METH impaired memory. METH did not affect memory in the consolidation group regardless of sleep quality. These results extend previous findings showing that METH can enhance memory for salient emotional stimuli but only if it is present at the time of study, where it can affect both encoding and consolidation. METH does not appear to facilitate consolidation if administered after encoding. The study also demonstrates the important role of sleep in memory studies.     

Sex Differences in Long-Term Potentiation at Temporoammonic-CA1 Synapses: Potential Implications for Memory Consolidation

Sex differences in spatial memory have long been observed in humans, non-human primates and rodents, but the underlying cellular and molecular mechanisms responsible for these differences remain obscure. In the present study we found that adolescent male rats outperformed female rats in 7 d and 28 d retention probes, but not in learning trials and immediate probes, in the Morris water maze task. Male rats also had larger long-term potentiation (LTP) at hippocampal temproammonic-CA1 (TA-CA1) synapses, which have been implicated to play a key role in place field and memory consolidation, when protocols designed to elicit late-stage LTP (LLTP) were used. Interestingly, the ratio of evoked AMPA/NMDA currents was found to be smaller at TA-CA1 synapses in male rats compared to female rats. Protein biotinylation experiments showed that male rats expressed more surface GluN1 receptors in hippocampal CA1 stratum lacunosum-moleculare (SLM) than female rats, although GluA1 expression was also slightly higher in male rats. Taken together, our results suggest that differences in the expression of AMPA and NMDA receptors may affect LTP expression at TA-CA1 synapses in adolescent male and female rats, and thus possibly contribute to the observed sex difference in spatial memory.     

Coupling of Thalamocortical Sleep Oscillations Are Important for Memory Consolidation in Humans

Sleep, specifically non-rapid eye movement (NREM) sleep, is thought to play a critical role in the consolidation of recent memories. Two main oscillatory activities observed during NREM, cortical slow oscillations (SO, 0.5–1.0Hz) and thalamic spindles (12–15Hz), have been shown to independently correlate with memory improvement. Yet, it is not known how these thalamocortical events interact, or the significance of this interaction, during the consolidation process. Here, we found that systemic administration of the GABAergic drug (zolpidem) increased both the phase-amplitude coupling between SO and spindles, and verbal memory improvement in humans. These results suggest that thalamic spindles that occur during transitions to the cortical SO Up state are optimal for memory consolidation. Our study predicts that the timely interactions between cortical and thalamic events during consolidation, contribute to memory improvement and is mediated by the level of inhibitory neurotransmission.