The neuropharmacology of upper airway motor control in the awake and asleep states: implications for obstructive sleep apnoea

Obstructive sleep apnoea is a common and serious breathing problem that is caused by effects of sleep on pharyngeal muscle tone in individuals with narrow upper airways. There has been increasing focus on delineating the brain mechanisms that modulate pharyngeal muscle activity in the awake and asleep states in order to understand the pathogenesis of obstructive apnoeas and to develop novel neurochemical treatments. Although initial clinical studies have met with only limited success, it is proposed that more rational and realistic approaches may be devised for neurochemical modulation of pharyngeal muscle tone as the relevant neurotransmitters and receptors that are involved in sleep-dependent modulation are identified following basic experiments.     

Pathogenesis of obstructive sleep apnea.

The pathogenesis of obstructive sleep apnea (OSA) has been under investigation for over 25 years, during which a number of factors that contribute to upper airway (UA) collapse during sleep have been identified. Structural/anatomic factors that constrict space for the soft tissues surrounding the pharynx and its lumen are crucial to the development of OSA in many patients. Enlargement of soft tissues enveloping the pharynx, including hypertrophied tonsils, adenoids, and tongue, is also an important factor predisposing to UA collapse, inasmuch as this can impinge on the pharyngeal lumen and narrow it during sleep. Other factors, including impairment of UA mechanoreceptor sensitivity and reflexes that maintain pharyngeal patency and respiratory control system instability, have also been identified as possible mechanisms facilitating UA instability. This suggests that OSA may be a heterogeneous disorder, rather than a single disease entity. Therefore, the extent to which various pathogenic factors contribute to the phenomenon of repetitive collapse of the UA during sleep probably varies from patient to patient. Further elucidation of specific pathogenic mechanisms in individuals with OSA may facilitate the development of new therapies that can be tailored to individual patient needs according to the underlying mechanism(s) of their disease.     

Geniohyoid muscle activity in normal men during wakefulness and sleep

Reduction in the activity of upper airway "dilator" muscles during sleep may allow the pharyngeal airway to collapse in some individuals. However, quantitative studies concerning the effect of sleep on specific upper airway muscles that may influence pharyngeal patency are sparse and inconclusive. We studied seven normal men (mean age 27, range 22-37 yr) during a single nocturnal sleep study and recorded sleep staging parameters, ventilation, and geniohyoid muscle electromyogram (EMGgh) during nasal breathing throughout the night. Anatomic landmarks for placement of intramuscular geniohyoid recording electrodes were determined from a cadaver study. These landmarks were used in percutaneous placement of wire electrodes, and raw and moving-time-averaged EMGgh activities were recorded. Sleep stage was determined using standard criteria. Stable periods of wakefulness and non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep were selected for analysis. The EMGgh exhibited phasic inspiratory activity during wakefulness and sleep in all subjects. In six of seven subjects, mean and peak inspiratory EMGgh activities were significant (P less than 0.05) reduced during stages 2 and 3/4 NREM sleep and REM sleep compared with wakefulness. This reduction of EMGgh activity was shown to result from a sleep-related decline in the level of tonic muscle activity. Phasic inspiratory EMGgh activity during all stages of sleep was not significantly different from that during wakefulness. Of interest, tonic, phasic, and peak EMGgh activities were not significantly reduced during REM sleep compared with any other sleep stage in any subject. In addition, the slope of onset of phasic EMGgh activity was not different during stage 2 NREM and REM sleep compared with wakefulness in these subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recent advances in obstructive sleep apnea pathophysiology and treatment

Obstructive sleep apnea (OSA) is a sleep disorder characterized by recurring collapse of the pharyngeal airway leading to restricted airflow. OSA is becoming increasingly common with at least moderate disease now evident in 17% of middle aged men and 9% of women. The list of recognized adverse health consequences associated with OSA is growing and includes daytime symptoms of sleepiness, impaired cognition and risk of motor vehicle accidents as well as associations with hypertension, cardiovascular morbidity, malignancy and all-cause mortality. In this context adequate treatment of OSA is imperative; however, there are well-recognized pitfalls in the uptake and usage of the standard treatment modality, Continuous Positive Airway Pressure (CPAP). A broad range of pathophysiological mechanisms are now recognized beyond an anatomically smaller pharyngeal airway and impaired compensatory pharyngeal muscle responsiveness. Perturbations in ventilatory control stability, low arousal threshold, sleep-related decrease in lung volume and fluid redistribution as well as upper airway surface tension have all been shown to variously contribute to sleep-disordered breathing. Many new therapies are emerging from these advances in understanding of the mechanisms of OSA. Although many may not be universally effective, the promise of phenotyping patients according to their individual pathophysiology in order to target one or more therapies may prove highly effective and allow the treatment of OSA towards a personalized medicine approach.

     

Effects of nasal CPAP therapy on respiratory and spontaneous arousals in infants with OSA.

Obstructive sleep apnea (OSA) in infants has been shown to resolve frequently without a cortical arousal. It is unknown whether infants do not require arousal to terminate apneas or whether this is a consequence of the OSA. We studied the apnea and arousal patterns of eight infants with OSA before and after treatment with nasal continuous positive airway pressure (CPAP). These infants were age matched to eight untreated infants with OSA and eight normal infants. Polysomnographic studies were performed on each infant. We found that the majority of central and obstructive apneas were terminated without arousal in all OSA infants. After several weeks of nasal CPAP treatment, the proportion of apneas terminating with an arousal during rapid-eye-movement sleep increased in treated infants compared with untreated infants. Spontaneous arousals during rapid-eye-movement sleep were reduced in all OSA infants; however, during CPAP treatment, the spontaneous arousals increased to the normal control level. We conclude that OSA in infants possibly depresses the arousal response and treatment of these infants with nasal CPAP partially reverses this depression.     

Glucose-regulated protein Grp78 affects characteristics of sleep and thermoregulation in rats

It was shown previously that sleep deprivation in representatives of warm-blooded animals evokes an elevation of the glucose-regulated protein 78 (Grp78) gene expression in the brain structures involved in the control of sleep and thermoregulation. However it is currently unknown what role the increased Grp78 expression plays in the mechanisms that maintain homeostasis of sleep and thermoregulation. Using electrophysiological methods, it has been shown in this study that microinjections of Grp78 into the third brain ventricle of Wistar rats evokes an increase mostly in deep non-rapid-eye-movement (NREM) sleep (due to a lengthening of the NREM sleep episodes) and a decrease in the amount of rapid-eye-movement sleep. The period of deep NREM sleep was accompanied by a reduced muscle contractile activity. Our results provide evidence that Grp78 is implicated in the molecular mechanisms of maintenance of deep NREM sleep typically accompanied by a decrease in muscle contractile activity.     

Chronic recordings of hypoglossal nerve activity in a dog model of upper airway obstruction.

The activity of the hypoglossal nerve was recorded during pharyngeal loading in sleeping dogs with chronically implanted cuff electrodes. Three self-coiling spiral-cuff electrodes were implanted in two beagles for durations of 17, 7, and 6 mo. During quiet wakefulness and sleep, phasic hypoglossal activity was either very small or not observable above the baseline noise. Applying a perpendicular force on the submental region by using a mechanical device to narrow the pharyngeal airway passage increased the phasic hypoglossal activity, the phasic esophageal pressure, and the inspiratory time in the next breath during non-rapid-eye-movement sleep. The phasic hypoglossal activity sustained at the elevated level while the force was present and increased with increasing amounts of loading. The hypoglossal nerve was very active in rapid-eye-movement sleep, especially when the submental force was present. The data demonstrate the feasibility of chronic recordings of the hypoglossal nerve with cuff electrodes and show that hypoglossal activity has a fast and sustained response to the internal loading of the pharynx induced by applying a submental force during non-rapid-eye-movement sleep.     

Shared genetic risk factors for obstructive sleep apnea and obesity.

Both obesity and obstructive sleep apnea (OSA) are complex disorders with multiple risk factors, which interact in a complicated fashion to determine the overall phenotype. In addition to environmental risk factors, each disorder has a strong genetic basis that is likely due to the summation of small to moderate effects from a large number of genetic loci. Obesity is a strong risk factor for sleep apnea, and there are some data to suggest sleep apnea may influence obesity. It is therefore not surprising that many susceptibility genes for obesity and OSA should be shared. Current research suggests that approximately half of the genetic variance in the apnea hypopnea index is shared with obesity phenotypes. Genetic polymorphisms that increase weight will also be risk factors for apnea. In addition, given the interrelated pathways regulating both weight and other intermediate phenotypes for sleep apnea such as ventilatory control, upper airway muscle function, and sleep characteristics, it is likely that there are genes with pleiotropic effects independently impacting obesity and OSA traits. Other genetic loci likely interact with obesity to influence development of OSA in a gene-by-environment type of effect. Conversely, environmental stressors such as intermittent hypoxia and sleep fragmentation produced by OSA may interact with obesity susceptibility genes to modulate the importance that these loci have on defining obesity-related traits.     

The CC Genotype of the Delta-Sarcoglycan Gene Polymorphism rs13170573 Is Associated with Obstructive Sleep Apnea in the Chinese Population

Obstructive sleep apnea (OSA) is a highly heterogeneous sleep disorder, and increasing evidence suggests that genetic factors play a role in the etiology of OSA. Airway muscle dysfunction might promote pharyngeal collapsibility, mutations or single nucleotide polymorphisms (SNPs) in the delta-sarcoglycan (SCGD) gene associated with muscle dysfunction. To evaluate if SCGD gene SNPs are associated with OSA, 101 individuals without OSA and 97 OSA patients were recruited randomly. The genotype distributions of SNPs (rs157350, rs7715464, rs32076, rs13170573 and rs1835919) in case and control populations were evaluated. The GG, GC and CC genotypes of rs13170573 in control and OSA groups were 51.5% and 37.1%, 36.6% and 35.1%, and 11.9% and 27.8%, respectively. Significantly fewer OSA patients possessed the GG genotype and significantly more possessed the CC genotype compared with controls. Further multivariate logistic regression analysis showed that the CC genotype was an independent risk factor for OSA, with an odds ratio (OR) of 2.17 (95% confidence interval [CI]: 1.19–6.01). Other factors, such as age ≥50 years, male gender, body mass index (BMI) ≥25 kg/m², low-density lipoprotein cholesterol (LDL-C) level ≥3.33 mg/dL, smoking and hypertension, were also independent risk factors for OSA in our multivariate logistic regression model.     

Reduced genioglossal activity with upper airway anesthesia in awake patients with OSA.

We examined whether topical upper airway anesthesia leads to a reduction in genioglossal (GG) electromyogram (EMG) in patients with obstructive sleep apnea (OSA). Airway mechanics were also evaluated. In 13 patients with OSA, we monitored GG EMG during tidal breathing and during the application of pulses of negative airway pressure (-10 to -12 cmH(2)O). Airflow resistance and airway collapsibility were determined. All measurements were performed with and without topical anesthesia (lidocaine). Anesthesia led to a significant fall in the peak GG EMG response to negative pressure from 36.1 +/- 4.7 to 24.8 +/- 5.3% (SE) of maximum (P < 0.01). This was associated with a fall in phasic and tonic EMG during tidal breathing (phasic from 24.4 +/- 4.1 to 16.4 +/- 3.4% of maximum and tonic from 10.9 +/- 1.6 to 8.0 +/- 1.3% of maximum, P < 0.01). A significant rise in pharyngeal airflow resistance was also observed. Our results demonstrate that topical receptor mechanisms in the nasopharynx importantly influence dilator muscle activity and are likely important in driving the augmented dilator muscle activity seen in the apnea patient.     

Load compensation and respiratory muscle function during sleep.

The sleeping state places unique demands on the ventilatory control system. The sleep-induced increase in airway resistance, the loss of consciousness, and the need to maintain the sleeping state without frequent arousals require the presence of complex compensatory mechanisms. The increase in upper airway resistance during sleep represents the major effect of sleep on ventilatory control. This occurs because of a loss of muscle activity, which narrows the airway and also makes it more susceptible to collapse in response to the intraluminal pressure generated by other inspiratory muscles. The magnitude and timing of the drive to upper airway vs. other inspiratory pump muscles determine the level of resistance and can lead to inspiratory flow limitation and complete upper airway occlusion. The fall in ventilation with this mechanical load is not prevented, as it is in the awake state, because of the absence of immediate compensatory responses during sleep. However, during sleep, compensatory mechanisms are activated that tend to return ventilation toward control levels if the load is maintained. Upper airway protective reflexes, intrinsic properties of the chest wall, muscle length-compensating reflexes, and most importantly chemoresponsiveness of both upper airway and inspiratory pump muscles are all present during sleep to minimize the adverse effect of loading on ventilation. In non-rapid-eye-movement sleep, the high mechanical impedance combined with incomplete load compensation causes an increase in arterial PCO2 and augmented respiratory muscle activity. Phasic rapid-eye-movement sleep, however, interferes further with effective load compensation, primarily by its selective inhibitory effects on the phasic activation of postural muscles of the chest wall. The level and pattern of ventilation during sleep in health and disease states represent a compromise toward the ideal goal, which is to achieve maximum load compensation and meet the demand for chemical homeostasis while maintaining sleep state.     

Mandible position and activation of submental and masseter muscles during sleep.

Movement of the mandible could influence pharyngeal airway caliber because the mandible is attached to the tongue and to muscles that insert on the hyoid bone. In normal subjects and patients with obstructive sleep apnea (OSA) we measured jaw position during sleep with strain gauges, as well as masseter and submental electromyograms, airflow, esophageal pressure, oximetry, electroencephalograms, and electrooculograms. Jaws of patients with OSA were open more than those of normal subjects at end expiration and opened further at end inspiration, particularly at the termination of apneas when the masseter and submental muscles contracted. Masseter activation occurred only in patients with OSA and in a pattern similar to that of submental muscles. Jaw opening at end expiration could narrow the upper airway, whereas opening at end inspiration could reflect efforts to expand the airway with tracheal tug and with submental muscle activation and efforts to open the mouth to allow mouth breathing. Masseter contraction does not close the jaw but may serve to stabilize it.     

Effect of the velopharynx on intraluminal pressures in reconstructed pharynges derived from individuals with and without sleep apnea

The most collapsible part of the upper airway in the majority of individuals is the velopharynx which is the segment positioned behind the soft palate. As such it is an important morphological region for consideration in elucidating the pathogenesis of obstructive sleep apnea (OSA). This study compared steady flow properties during inspiration in the pharynges of nine male subjects with OSA and nine body-mass index (BMI)- and age-matched control male subjects without OSA. The k  –ω$\omega$SST turbulence model was used to simulate the flow field in subject-specific pharyngeal geometric models reconstructed from anatomical optical coherence tomography (aOCT) data. While analysis of the geometry of reconstructed pharynges revealed narrowing at velopharyngeal level in subjects with OSA, it was not possible to clearly distinguish them from subjects without OSA on the basis of pharyngeal size and shape alone. By contrast, flow simulations demonstrated that pressure fields within the narrowed airway segments were sensitive to small differences in geometry and could lead to significantly different intraluminal pressure characteristics between subjects. The ratio between velopharyngeal and total pharyngeal pressure drops emerged as a relevant flow-based criterion by which subjects with OSA could be differentiated from those without.     

A method for measuring and modeling the physiological traits causing obstructive sleep apnea

There is not a clinically available technique for measuring the physiological traits causing obstructive sleep apnea (OSA). Therefore, it is often difficult to determine why an individual has OSA or to what extent the various traits contribute to the development of OSA. In this study, we present a noninvasive method for measuring four important physiological traits causing OSA: 1) pharyngeal anatomy/collapsibility, 2) ventilatory control system gain (loop gain), 3) the ability of the upper airway to dilate/stiffen in response to an increase in ventilatory drive, and 4) arousal threshold. These variables are measured using a single maneuver in which continuous positive airway pressure (CPAP) is dropped from an optimum to various suboptimum pressures for 3- to 5-min intervals during sleep. Each individual's set of traits is entered into a physiological model of OSA that graphically illustrates the relative importance of each trait in that individual. Results from 14 subjects (10 with OSA) are described. Repeatability measurements from separate nights are also presented for four subjects. The measurements and model illustrate the multifactorial nature of OSA pathogenesis and how, in some individuals, small adjustments of one or another trait (which might be achievable with non-CPAP agents) could potentially treat OSA. This technique could conceivably be used clinically to define a patient's physiology and guide therapy based on the traits.     

Induction of airway collapse with subatmospheric pressure in awake patients with sleep apnea

To determine whether the pharyngeal airway is abnormal in awake patients with obstructive sleep apnea (OSA), we measured the ability of the pharyngeal airway to resist collapse from subatmospheric pressure applied to the nose in awake subjects, 12 with OSA and 12 controls. Subatmospheric pressure was applied to subjects placed in the supine position through a tightly fitting face mask. We measured airflow at the mask as well as mask, pharyngeal, and esophageal pressures. Ten patients developed airway obstruction when subatmospheric pressures between 17 and 40 cmH2O were applied. Obstruction did not occur in two patients with the least OSA. Obstruction did not occur in 10 controls; one obese control subject developed partial airway obstruction when -52 cmH2O was applied as did another with -41 cmH2O. We conclude that patients with significant OSA have an abnormal airway while they are awake and that application of subatmospheric pressure may be a useful screening test to detect OSA.     

Auditory event-related potentials in obstructive sleep apnea: effects of treatment with nasal continuous positive airway pressure

Event-related potentials (ERPs) were recorded in 47 patients with obstructive sleep apnea (OSA) syndrome prior to and after 6 weeks of treatment with continuous positive airway pressure (CPAP). Compared with a control group, the OSA patients showed ERP abnormalities: lengthened P3 latencies and decreased N2-P3 amplitudes. After 6 weeks of CPAP treatment, there was a highly significant improvement in the abnormal ERPs: the P3 and N2 latencies were shortened, but remained longer than in controls, and the N2-P3 and N1-P2 amplitudes were increased. No correlations could be established with various sleep variables. ERPs may be used as an electrophysiological marker of brain dysfunction; treatment of OSA with CPAP is probably responsible for functional brain modifications. On the other hand, possible relationships between the ERP abnormalities and the neuropsychological disorders observed in OSA remain to be established.     

Genioglossus muscle activity and serotonergic modulation of hypoglossal motor output in obese Zucker rats.

Obese Zucker rats have a narrower and more collapsible upper airway compared with lean controls, similar to obstructive sleep apnea (OSA) patients. Genioglossus (GG) muscle activity is augmented in awake OSA patients to compensate for airway narrowing, but the neural control of GG activity in obese Zucker rats has not been investigated to determine whether such neuromuscular compensation also occurs. This study tests the hypotheses that GG activity is augmented in obese Zucker rats compared with lean controls and that endogenous 5-hydroxytryptamine (5-HT) contributes to GG activation. Seven obese and seven lean Zucker rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and they were implanted with GG and diaphragm wires for respiratory muscle recordings. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid and the 5-HT receptor antagonist mianserin (100 microM). Compared with lean controls, respiratory rates were increased in obese rats across sleep-wake states (P=0.048) because of reduced expiratory durations (P=0.007); diaphragm activation was similar between lean and obese animals (P=0.632). Respiratory-related, tonic, and peak GG activities were also similar between obese and lean rats (P>0.139). There was no reduction in GG activity with mianserin at the hypoglossal motor nucleus, consistent with recent observations of a minimal contribution of endogenous 5-HT to GG activity. These results suggest that despite the upper airway narrowing in obese Zucker rats, these animals have a sufficiently stable airway such that pharyngeal muscle activity is normal across sleep-wake states.     

Control of motoneuron function and muscle tone during REM sleep, REM sleep behavior disorder and cataplexy/narcolepsy

REM sleep triggers a potent suppression of postural muscle tone - i.e., REM atonia. However, motor control during REM sleep is paradoxical because overall brain activity is maximal, but motor output is minimal. The skeletal motor system remains quiescent during REM sleep because somatic motoneurons are powerfully inactivated. Determining the mechanisms triggering loss of motoneuron function during REM sleep is important because breakdown in REM sleep motor control underlies sleep disorders such as REM sleep behavior disorder (RBD) and cataplexy/narcolepsy. For example, RBD is characterized by dramatic REM motor activation resulting in dream enactment and subsequent patient injury. In contrast, cataplexy a pathognomonic symptom of narcolepsy - is caused by the involuntary onset of REM-like atonia during wakefulness. This review highlights recent work from my laboratory that examines how motoneuron function is lost during normal REM sleep and it also identifies potential biochemical mechanisms underlying abnormal motor control in both RBD and cataplexy. First, I show that both GABAB and GABAA/glycine mediated inhibition of motoneurons is required for generating REM atonia. Next, I show that impaired GABA and glycine neurotransmission triggers the cardinal features of RBD in a transgenic mouse model. Last, I show that loss of an excitatory noradrenergic drive onto motoneurons is, at least in part, responsible for the loss of postural muscle tone during cataplexy in narcoleptic mice. Together, this research indicates that multiple transmitters systems are responsible for regulating postural muscle tone during REM sleep, RBD and cataplexy.     

Noradrenergic modulation of hypoglossal motoneuron excitability: developmental and putative state-dependent mechanisms

Hypoglossal (XII) motoneurons (MNs) contribute to diverse behaviors. Their innervation of the genioglossus muscle, a tongue protruder, plays a critical role in maintaining upper airway patency during breathing. Indeed, reduced activity in these motoneurons is implicated in sleep related disorders of breathing such as obstructive sleep apnea (OSA). The excitability of these MNs is modulated by multiple neurotransmitter systems. The focus of this review is on the modulation of XII MN excitability by norepinephrine (NE), which increases MN excitability through a variety of mechanisms. The level of noradrenergic drive, however, is very dynamic, varying on developmental, sleep-wake and even millisecond timescales relevant to transitions between behaviours. Here we review and provide new data on the maturation of the noradrenergic modulatory system, focusing on those elements specifically relevant to XII MN excitability including the: i) ontogeny of the noradrenergic cell group that provides the majority of the noradrenergic innervation to the XII nucleus, the Locus subcoeruleus (LsC); ii) time course over which the XII nucleus is innervated by noradrenergic nerve fibres, and; iii) ontogeny of XII MN sensitivity to NE. In the context of state-dependent changes in noradrenergic cell activity, we review mechanisms of NE action most relevant to its role in the muscle atonia of REM sleep. We conclude with a discussion of the hypothesis that the dynamics of MN modulation by NE extend to the spatial domain and recent data suggesting that noradrenergic modulation of the dendritic tree is not uniform but compartmentalized. Implications for information processing are discussed.     

Effects of upper airway anesthesia on pharyngeal patency during sleep

Pharyngeal patency depends, in part, on the tone and inspiratory activation of pharyngeal dilator muscles. To evaluate the influence of upper airway sensory feedback on pharyngeal muscle tone and thus pharyngeal patency, we measured pharyngeal airflow resistance and breathing pattern in 15 normal, supine subjects before and after topical lidocaine anesthesia of the pharynx and glottis. Studies were conducted during sleep and during quiet, relaxed wakefulness before sleep onset. Maximal flow-volume loops were also measured before and after anesthesia. During sleep, pharyngeal resistance at peak inspiratory flow increased by 63% after topical anesthesia (P less than 0.01). Resistance during expiration increased by 40% (P less than 0.01). Similar changes were observed during quiet wakefulness. However, upper airway anesthesia did not affect breathing pattern during sleep and did not alter awake flow-volume loops. These results indicate that pharyngeal patency during sleep is compromised when the upper airway is anesthetized and suggest that upper airway reflexes, which promote pharyngeal patency, exist in humans.