Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study.

BACKGROUND: Sleep-disordered breathing is associated with major morbidity and mortality. However, its prevalence has mainly been selectively studied in populations at risk for sleep-disordered breathing or cardiovascular diseases. Taking into account improvements in recording techniques and new criteria used to define respiratory events, we aimed to assess the prevalence of sleep-disordered breathing and associated clinical features in a large population-based sample. METHODS: Between Sept 1, 2009, and June 30, 2013, we did a population-based study (HypnoLaus) in Lausanne, Switzerland. We invited a cohort of 3043 consecutive participants of the CoLaus/PsyCoLaus study to take part. Polysomnography data from 2121 people were included in the final analysis. 1024 (48%) participants were men, with a median age of 57 years (IQR 49-68, range 40-85) and mean body-mass index (BMI) of 25·6 kg/m(2) (SD 4·1). Participants underwent complete polysomnographic recordings at home and had extensive phenotyping for diabetes, hypertension, metabolic syndrome, and depression. The primary outcome was prevalence of sleep-disordered breathing, assessed by the apnoea-hypopnoea index. FINDINGS: The median apnoea-hypopnoea index was 6·9 events per h (IQR 2·7-14·1) in women and 14·9 per h (7·2-27·1) in men. The prevalence of moderate-to-severe sleep-disordered breathing (≥15 events per h) was 23·4% (95% CI 20·9-26·0) in women and 49·7% (46·6-52·8) in men. After multivariable adjustment, the upper quartile for the apnoea-hypopnoea index (>20·6 events per h) was associated independently with the presence of hypertension (odds ratio 1·60, 95% CI 1·14-2·26; p=0·0292 for trend across severity quartiles), diabetes (2·00, 1·05-3·99; p=0·0467), metabolic syndrome (2·80, 1·86-4·29; p<0·0001), and depression (1·92, 1·01-3·64; p=0·0292). INTERPRETATION: The high prevalence of sleep-disordered breathing recorded in our population-based sample might be attributable to the increased sensitivity of current recording techniques and scoring criteria. These results suggest that sleep-disordered breathing is highly prevalent, with important public health outcomes, and that the definition of the disorder should be revised. FUNDING: Faculty of Biology and Medicine of Lausanne, Lausanne University Hospital, Swiss National Science Foundation, Leenaards Foundation, GlaxoSmithKline, Ligue Pulmonaire Vaudoise.

Genomic and proteomic approaches towards an understanding of sleep.

The basic functions of sleep are still unclear, however, recent advances in genomics and proteomics have begun to contribute to our understanding of both normal and pathological sleep. In this review, we focus primarily on normal sleep and wake that have been studied in model organisms such as mice. Mice have been especially valuable since many different inbred strains exist that differ in sleep-related traits, and genes can be altered by either mutagenesis or targeted approaches. Advances in QTL (Quantitative Trait Loci) analysis have also helped to identify important sleep related genes, and several other QTLs have been mapped as a first step toward finding the genes that underlie basic sleep traits. In addition to more traditional genetic approaches, the abundance of different mRNAs across sleep and wake can now be studied and compared in different brain regions much more thoroughly using microarray methods. Progress at the protein level has been more difficult, but a few studies have begun to investigate changes in proteins during sleep and wake, and we present some of our own preliminary data in this area. A knowledge of which genes and proteins control or respond to changes in sleep will not only help answer fundamental questions, but may also suggest novel drug targets for improving multiple aspects of sleep and wake.

Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis.

Study Objectives: The sleep-deprivation-induced changes in delta power, an electroencephalographical correlate of sleep need, and brain transcriptome profiles have importantly contributed to current hypotheses on sleep function. Because sleep deprivation also induces stress, we here determined the contribution of the corticosterone component of the stress response to the electrophysiological and molecular markers of sleep need in mice. Design: N/A Settings: Mouse sleep facility. Participants: C57BL/6J, AKR/J, DBA/2J mice. Interventions: Sleep deprivation, adrenalectomy (ADX). Measurements and Results: Sleep deprivation elevated corticosterone levels in 3 inbred strains, but this increase was larger in DBA/2J mice; i.e., the strain for which the rebound in delta power after sleep deprivation failed to reach significance. Elimination of the sleep-deprivation-associated corticosterone surge through ADX in DBA/2J mice did not, however, rescue the delta power rebound but did greatly reduce the number of transcripts affected by sleep deprivation. Genes no longer affected by sleep deprivation cover pathways previously implicated in sleep homeostasis, such as lipid, cholesterol (e.g., Ldlr, Hmgcs1, Dhcr7, -24, Fkbp5), energy and carbohydrate metabolism (e.g., Eno3, G6pc3, Mpdu1, Ugdh, Man1b1), protein biosynthesis (e.g., Sgk1, Alad, Fads3, Eif2c2, -3, Mat2a), and some circadian genes (Per1, -3), whereas others, such as Homer1a, remained unchanged. Moreover, several microRNAs were affected both by sleep deprivation and ADX. Conclusions: Our findings indicate that corticosterone contributes to the sleep-deprivation-induced changes in brain transcriptome that have been attributed to wakefulness per se. The study identified 78 transcripts that respond to sleep loss independent of corticosterone and time of day, among which genes involved in neuroprotection prominently feature, pointing to a molecular pathway directly relevant for sleep function.

Pattern recognition of sleep in rodents using piezoelectric signals generated by gross body movements.

Current research on sleep using experimental animals is limited by the expense and time-consuming nature of traditional EEG/EMG recordings. We present here an alternative, noninvasive approach utilizing piezoelectric films configured as highly sensitive motion detectors. These film strips attached to the floor of the rodent cage produce an electrical output in direct proportion to the distortion of the material. During sleep, movement associated with breathing is the predominant gross body movement and, thus, output from the piezoelectric transducer provided an accurate respiratory trace during sleep. During wake, respiratory movements are masked by other motor activities. An automatic pattern recognition system was developed to identify periods of sleep and wake using the piezoelectric generated signal. Due to the complex and highly variable waveforms that result from subtle postural adjustments in the animals, traditional signal analysis techniques were not sufficient for accurate classification of sleep versus wake. Therefore, a novel pattern recognition algorithm was developed that successfully distinguished sleep from wake in approximately 95% of all epochs. This algorithm may have general utility for a variety of signals in biomedical and engineering applications. This automated system for monitoring sleep is noninvasive, inexpensive, and may be useful for large-scale sleep studies including genetic approaches towards understanding sleep and sleep disorders, and the rapid screening of the efficacy of sleep or wake promoting drugs.

Age-related changes in sleep in inbred mice are genotype dependent.

Aging produces major changes in sleep structure and intensity which might be linked to cognitive impairment in the elderly. In this study, the genetic contribution to age-related changes in sleep was assessed in three inbred mouse strains of various ages. Baseline sleep and the response to 6 hours sleep deprivation (SD) achieved by gentle handling were quantified in young, middle-aged, and older male mice using electroencephalography. Total sleep time initially increased with age but then decreased in the oldest group mainly due to changes in sleep duration during the active phase. The effect of age on electroencephalographic (EEG) delta power depends on genotype and sleep pressure level with SD increasing the age-related differences. The strong effect of age upon the spectral profile of the different behavioral states was modulated by genetic background. Overall, our results suggest that sleep pressure can modulate the effect of age, that most sleep variables do not monotonically change with age in contrast to previous reports in humans and other species, and that genetic factors have a major impact on the aging processes affecting sleep.

Effect of expiratory positive airway pressure on sleep disordered breathing.

STUDY OBJECTIVES: We sought to determine the effect of expiratory positive airway pressure on end expiratory lung volume (EELV) and sleep disordered breathing in obstructive sleep apnea patients. DESIGN: Observational physiology study PARTICIPANTS: We studied 10 OSA patients during sleep wearing a facial mask. We recorded 1 hour of NREM sleep without treatment (baseline) and 1 hour with 10 cm H2O EPAP in random order, while measuring EELV and breathing pattern. RESULTS: The mean EELV change between baseline and EPAP was only 13.3 mL (range 2-25 mL). Expiratory time was significantly increased with EPAP compared to baseline 2.64 +/- 0.54 vs 2.16 +/- 0.64 sec (P = 0.002). Total respiratory time was longer with EPAP than at baseline 4.44 +/- 1.47 sec vs 3.73 +/- 0.88 sec (P = 0.3), and minute ventilation was lower with EPAP vs baseline 7.9 +/- 4.17 L/min vs 9.05 +/- 2.85 L/min (P = 0.3). For baseline (no treatment) and EPAP respectively, the mean apnea+hypopnea index (AHI) was 62.6 +/- 28.7 and 56.8 +/- 30.3 events per hour (P = 0.4). CONCLUSION: In OSA patients during sleep, the application of 10 cm H2O EPAP led to prolongation of expiratory time with only marginal increases in FRC. These findings suggest important mechanisms exist to avoid hyperinflation during sleep.

The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus.

Low-threshold (T-type) Ca(2+) channels encoded by the Ca(V)3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Ca(V)3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. Ca(V)3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Ca(V)3.3(-/-) mouse line and demonstrate that Ca(V)3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Ca(V)3.3 channels prevented oscillatory bursting in the low-frequency (4-10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Ca(V)3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. T currents in Ca(V)3.3(-/-) mice were <30% compared with those in WT mice, and the remaining current, carried by Ca(V)3.2 channels, generated dendritic [Ca(2+)](i) signals insufficient to provoke oscillatory bursting that arises from interplay with Ca(2+)-dependent small conductance-type 2 K(+) channels. Finally, naturally sleeping Ca(V)3.3(-/-) mice showed a selective reduction in the power density of the σ frequency band (10-12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for Ca(V)3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development.

Retinoic acid signaling affects cortical synchrony during sleep.

Delta oscillations, characteristic of the electroencephalogram (EEG) of slow wave sleep, estimate sleep depth and need and are thought to be closely linked to the recovery function of sleep. The cellular mechanisms underlying the generation of delta waves at the cortical and thalamic levels are well documented, but the molecular regulatory mechanisms remain elusive. Here we demonstrate in the mouse that the gene encoding the retinoic acid receptor beta determines the contribution of delta oscillations to the sleep EEG. Thus, retinoic acid signaling, which is involved in the patterning of the brain and dopaminergic pathways, regulates cortical synchrony in the adult.

Endothelial dependant coronary vasoreactivity measured by 82Rb cardiac PET in obstructive sleep apnea patients before and after CPAP treatment

Introduction: Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular diseases. Endothelial dysfunction is believed to be one of the pathophysiological mechanism underlying this association. Our aim was to compare endothelial dependent coronary vasoreactivity in obstructive sleep apnea (OSA) patients and controls by quantifying myocardial blood flow (MBF) response to cold pressure testing (CPT) with 82Rb cardiac PET/CT. Methods: Twenty-four OSA patients (2W/22M, mean age 58 yo, mean BMI 28.6 kg/m2) with an apnea-hypopnea index (AHI) >30/h and 9 healthy volunteers (AHI <10/h) underwent a full night sleep recording (PSG) and a dynamic 82 Rb cardiac PET/CT scan at rest, during CPT and adenosine stress. In OSA patients the same measurements (PSG and PET/CT) were respeated 6 weeks after initiating continuous positive airway pressure (autoCPAP) treatment. To reflect differences in baseline cardiac work, values were normalized according to ratepressure product (RPP). Results: At baseline, untreated OSA patients had a mean AHI of 48.8/h and showed a lower MBF response to CPT than controls (1.1 ± 0.2 mL/min/g vs. 1.3 ± 0.4 mL/min/g, P = 0.048). When treated with CPAP, CPT-MBF was not different between controls and well-treated OSA patients (1.2 ± 0.3 mL/min/g vs 1.3 ± 0.4 mL/min/g, P = 0.68), but it was significantly lower for insufficiently treated patients (n = 10) with a residual AHI >10/h (0.9 ± 0.2 mL/min/g vs 1.3 ± 0.4 mL/min/g, P = 0.03). There was also a trend toward a difference in CPT-MBF between insufficiently and well-treated OSA patients (1.2 ± 0.3 mL/min/g vs 0.9 ± 0.2 mL/min/g, P = 0.15). Conclusion: Untreated OSA patients have an impaired coronary endothelial function as measured by MBF response to CPT compared to control subjects. This difference disappears after 6 weeks of autoCPAP therapy but only in OSA patients showing a good response to CPAP (AHI <10/h). Further studies are needed to determine by which mechanism OSA and CPAP treatment influence coronary vasoreactivity.

Genetics of narcolepsy and other major sleep disorders.

One third of the population is affected by a sleep disorder with a major social, medical, and economic impact. Although very little is known about the genetics of normal sleep, familial and twin studies indicate an important influence of genetic factors. Most sleep disorders run in families and in several of them the contribution of genetic factors is increasingly recognised. With recent advances in the genetics of narcolepsy and the role of the hypocretin/orexin system, the possibility that other gene defects may contribute to the pathophysiology of major sleep disorders is worth indepth investigation.

Trazodone increases arousal threshold in obstructive sleep apnoea.

A low arousal threshold is believed to predispose to breathing instability during sleep. The present authors hypothesised that trazodone, a nonmyorelaxant sleep-promoting agent, would increase the effort-related arousal threshold in obstructive sleep apnoea (OSA) patients. In total, nine OSA patients, mean+/-sd age 49+/-9 yrs, apnoea/hypopnoea index 52+/-32 events.h(-1), were studied on 2 nights, one with trazodone at 100 mg and one with a placebo, in a double blind randomised fashion. While receiving continuous positive airway pressure (CPAP), repeated arousals were induced: 1) by increasing inspired CO(2) and 2) by stepwise decreases in CPAP level. Respiratory effort was measured with an oesophageal balloon. End-tidal CO(2 )tension (P(ET,CO(2))) was monitored with a nasal catheter. During trazodone nights, compared with placebo nights, the arousals occurred at a higher P(ET,CO(2)) level (mean+/-sd 7.30+/-0.57 versus 6.62+/-0.64 kPa (54.9+/-4.3 versus 49.8+/-4.8 mmHg), respectively). When arousals were triggered by increasing inspired CO(2) level, the maximal oesophageal pressure swing was greater (19.4+/-4.0 versus 13.1+/-4.9 cm H(2)O) and the oesophageal pressure nadir before the arousals was lower (-5.1+/-4.7 versus -0.38+/-4.2 cm H(2)O) with trazodone. When arousals were induced by stepwise CPAP drops, the maximal oesophageal pressure swings before the arousals did not differ. Trazodone at 100 mg increased the effort-related arousal threshold in response to hypercapnia in obstructive sleep apnoea patients and allowed them to tolerate higher CO(2) levels.

Genes for normal sleep and sleep disorders.

Sleep and wakefulness are complex behaviors that are influenced by many genetic and environmental factors, which are beginning to be discovered. The contribution of genetic components to sleep disorders is also increasingly recognized as important. Point mutations in the prion protein, period 2, and the prepro-hypocretin/orexin gene have been found as the cause of a few sleep disorders but the possibility that other gene defects may contribute to the pathophysiology of major sleep disorders is worth in-depth investigations. However, single gene disorders are rare and most common disorders are complex in terms of their genetic susceptibility, environmental effects, gene-gene, and gene-environment interactions. We review here the current progress in the genetics of normal and pathological sleep.

Circadian clock genes and sleep homeostasis.

Circadian and sleep-homeostatic processes both contribute to sleep timing and sleep structure. Elimination of circadian rhythms through lesions of the suprachiasmatic nuclei (SCN), the master circadian pacemaker, leads to fragmentation of wakefulness and sleep but does not eliminate the homeostatic response to sleep loss as indexed by the increase in EEG delta power. In humans, EEG delta power declines during sleep episodes nearly independently of circadian phase. Such observations have contributed to the prevailing notion that circadian and homeostatic processes are separate but recent data imply that this segregation may not extend to the molecular level. Here we summarize the criteria and evidence for a role for clock genes in sleep homeostasis. Studies in mice with targeted disruption for core circadian clock genes have revealed alterations in circadian rhythmicity as well as changes in sleep duration, sleep structure and EEG delta power. Clock-gene expression in brain areas outside the SCN, in particular the cerebral cortex, depends to a large extent on prior sleep-wake history. Evidence for effects of clock genes on sleep homeostasis has also been obtained in Drosophila and humans, pointing to a phylogenetically preserved pathway. These findings suggest that, while within the SCN clock genes are utilized to set internal time-of-day, in the forebrain the same feedback circuitry may be utilized to track time spent awake and asleep. The mechanisms by which clock-gene expression is coupled to the sleep-wake distribution could be through cellular energy charge whereby clock genes act as energy sensors. The data underscore the interrelationships between energy metabolism, circadian rhythmicity, and sleep regulation.