Pharyngeal motor control and the pathogenesis of obstructive sleep apnea

doi:10.1016/j.resp.2007.07.009

Respiratory Physiology & Neurobiology

Volume 160, Issue 1, 1 January 2008, Pages 1-7

https://doi.org/10.1016/j.resp.2007.07.009 Get rights and content

Abstract

The upper airway in patients with obstructive sleep apnea (OSA) is thought to collapse during sleep at least in part, because of a sleep related reduction in upper airway dilator muscle activity. Therefore, a comprehensive understanding of the neural regulation of these muscles is warranted. The dilator muscles can be classified in two broad categories; those that have respiratory related activity and those that fire constantly throughout the respiratory cycle. The motor control of these two groups likely differs with the former receiving input from respiratory neurons and negative pressure reflex circuits. The activity of both muscle groups is reduced shortly after sleep onset, indicating that both receive input from brainstem neurons involved in sleep regulation. In the apnea patient, this may lead to pharyngeal airway collapse. This review briefly describes the currently proposed sleep and respiratory neural pathways and how these circuits interact with the upper airway dilator muscle motorneurones, including recent evidence from animal studies.

Section snippets

General introduction

Obstructive sleep apnea (OSA) is a disorder of repetitive upper airway collapse during sleep that affects at least 2–4% of the adult US population (Young et al., 1993). During airway collapse, ventilation is reduced (hypopnea) or absent (apnea) and hypoxia and hypercapnia develop. These blood gas changes increase respiratory drive until the upper airway re-opens (which is often associated with an arousal from sleep), at which time ventilation increases to reverse the blood gas abnormalities.

Overview of pharyngeal anatomy and musculature

The pharyngeal airway extends from the epiglottis to the nasal choanae (Fig. 1) and is, with the exception of the posterior pharyngeal wall, largely unsupported by bony structures making it susceptible to collapse with the negative pressures generated during inspiration. The airway has therefore often been considered a collapsible tube, which behaves like a Starling resistor. In this model, the airflow through the tube is determined by the collapsibility of the tube wall (pharyngeal airway wall

Pharyngeal muscle activity during wake/sleep

Much of the work investigating pharyngeal muscle control has focused on the genioglossus muscle. This is likely because of the difficulties in recording other airway dilator muscles and also because the genioglossus has been thought to be particularly important with regard to OSA pathogenesis. This is a result of its elevated activity in OSA, respiratory related activity and response to relevant respiratory stimuli such as CO₂ and negative airway pressure. We will review the research regarding

Neural regulation of sleep

The cortical activation that characterizes wakefulness is generated by a number of neurons including the cholinergic pedunculopontine (PPT) and laterodorsal tegmental (LDT) nuclei, the noradrenergic locus cereuleus (LC), the dopaminergic ventral periaqueductal gray (vPAG), the serotonergic raphe nuclei, and the histaminergic tuberomamillary nucleus (TMN) (Fuller et al., 2006). These neurons have a higher firing frequency during wakefulness than NREM sleep as do neurons in the lateral

Neural regulation of breathing

Current evidence suggests that there are two groups of respiratory rhythm generating neurons, the pre-Boetzinger complex (PBC) and retrotrapezoid nucleus (RTN) or parafacial respiratory group (pFRG), which are proposed to be synchronised under normal conditions to provide the respiratory rhythm (Fig. 2, pink box: neurons regulating breathing, reviewed in Feldman and Del Negro, 2006). In vitro slices show that PBC neurons have a respiratory related rhythm that persists when synaptic transmission

Summary

OSA is a disorder in which the afflicted individual is reliant on increased upper airway dilator muscle activity to maintain patency of an anatomically compromised upper airway. During sleep this mechanism fails, likely due to loss of the wakefulness drive and decrements in respiratory neural drive and negative pressure responsiveness. However, our understanding of these mechanisms is far from complete. Thus, considerable additional work addressing pharyngeal anatomy, physiology and neural

Acknowledgements

We would like to thank Nancy Chamberlin and Atul Malhotra for their helpful comments regarding this manuscript and acknowledge the support of the American Heart Association and National Institutes of Health.

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Obstructive sleep apnea (OSA) is a sleep disordered breathing condition characterized by recurrent upper airway collapse. The resultant repetitive hypoxemia, arousals from sleep, and other effects are associated with several adverse health effects including systemic hypertension, cardiac arrhythmias, heart failure, pulmonary hypertension, stroke, and diabetes. Daytime sleepiness and neuropsychiatric effects of OSA are also a considerable burden to patients. Prevalence of OSA is high with an estimated global case load nearing 1 billion. Lab based polysomnography is still considered the gold standard for the diagnosis of OSA. In recent years, the use of home-based sleep apnea testing has increased and has been incorporated in to the American Academy of Sleep Medicine's recommended clinical algorithm for testing and treatment of OSA. The cornerstone of treatment remains positive airway pressure devices along with weight loss and risk factor modifications. Continuous positive airway pressure (CPAP) treatment has been consistently shown to lower blood pressure, reduce sleepiness, and is associated with improvements in heart failure metrics and readmission rates. OSA refractory to CPAP treatment may need bilevel positive airway pressure devices. Additionally, a variety of surgical interventions targeting the oropharynx and surrounding structures are available and can be considered in selected patients. Most surgeries still result in a degree of residual OSA for most patients. A recent innovation in the surgical realm is the ability to implant a hypoglossal nerve stimulator, which stimulates the genioglossus muscle to modulate airway collapsibility. Many advances have been made in our understanding of OSA with concomitant technological advances leading to several treatment options; nevertheless, research opportunities abound in understanding the pathogenesis and consequences of OSA as well the effects on these consequences with therapy.
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Currently, no pharmacotherapy is routinely used for obstructive sleep apnea (OSA). Recently, combined noradrenergic plus antimuscarinic agents have been evaluated for the treatment of OSA in several trials. This systematic review and meta-analysis following PRISMA guidelines investigated the efficacy and safety of this combination drug regimen for the treatment of OSA. Seven databases were systematically screened for randomized controlled trials (RCTs) studying combined noradrenergic plus antimuscarinic agents for OSA to April 2022. Nine RCTs were identified for systematic review and five for meta-analysis. There were significant differences between OSA patients taking noradrenergic plus antimuscarinic agents and placebo with respect to sleep apnea-hypopnea index [mean difference (MD) −11.27 events/h, 95%CI (−21.69, −0.84) events/h; P = 0.03]; nadir oxygen saturation [MD 5.06%, 95% CI (2.57, 7.55)%; P < 0.0001], and arousal index [MD -8.17 events/h, 95% CI (−15.01, −1.33) events/h; P = 0.02] but not sleep efficiency. Our systematic review revealed that drug therapy modestly improved loop gain and upper airway collapsibility but decreased arousal threshold. A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on one night significantly reduced OSA severity and improved OSA upper airway function. The long-term efficacy and safety of drug combinations in OSA patients now require further study.
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Citation Excerpt :
Remmers et al. suggested that the dilator muscles fail to counteract the large negative intraluminal pressures that develop at and downstream to the obstruction (Remmers et al., 1978). It was also suggested that the GG was unable to maintain pharyngeal patency due to a decrease in activity of other upper airway muscles that do not exhibit phasic activity (“tonic muscles”) (Tangel et al., 1992; Fogel et al., 2004; Jordan and White, 2008). More recently, Younes et al. suggested that GG activation during apneas and hypopneas fails to reach a threshold required to prevent collapse (Younes et al., 2012).
In patients with OSA, substantial increases in genioglossus (GG) activity during hypopneas/apneas usually fail to restore normal airflow. The present study was undertaken to evaluate if this phenomenon can be explained by reduced activation of other peri-pharyngeal muscles.
We recorded EMGs of the GG and four other peri-pharyngeal muscles (accessory dilators, AD), in 8 patients with OSA and 12 healthy subjects, during wakefulness and sleep. Repetitive events of flow limitation were induced during sleep. The events with the highest increases in AD activity were evaluated, to assess if combined activation of both the GG and AD to levels higher than while awake ameliorate airflow reduction during sleep.
Flow limitation triggered large increases in GG-EMG, but only modest augmentation in AD activity. Nevertheless, phasic EMG activity was present in 40 % of the ADs during sleep. In multiple events, increases of both GG and AD activity to levels substantially higher than while awake were not associated with improvement in airflow.
We conclude that sleep-induced reduction in AD response to airway obstruction cannot completely explain the failure of upper airway dilators to maintain pharyngeal patency. We speculate that reduction in dilator muscle efficacy may be due to the alterations in motor units recruitment patterns during sleep.
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Published by Elsevier B.V.

Frontiers reviewPharyngeal motor control and the pathogenesis of obstructive sleep apnea

Abstract

Section snippets

General introduction

Overview of pharyngeal anatomy and musculature

Pharyngeal muscle activity during wake/sleep

Neural regulation of sleep

Neural regulation of breathing

Summary

Acknowledgements

Chest

Brain Res.

Brain Res. Brain Res. Rev.

Respir. Physiol.

Lancet

Lancet

Respir. Physiol.

Sleep Med. Rev.

Association of sleep-disordered breathing and the occurrence of stroke

Am. J. Respir. Crit. Care Med.

Breathing route influences upper airway muscle activity in awake normal adults

J. Appl. Physiol.

Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model

J. Clin. Invest.

Genioglossus premotoneurons and the negative pressure reflex in rats

J. Physiol.

Endogenous excitatory drive modulating respiratory muscle activity across sleep–wake states

Am. J. Respir. Crit. Care Med.

Effect of posture and breathing route on genioglossal electromyogram activity in normal subjects and in patients with the sleep apnea/hypopnea syndrome

Am. Rev. Resp. Dis.

Looking for inspiration: new perspectives on respiratory rhythm

Nat. Rev. Neurosci.

The effect of sleep onset on upper airway muscle activity in patients with sleep apnoea versus controls

J. Physiol.

Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback

J. Biol. Rhythms

Motor control of the pharyngeal musculature and implications for the pathogenesis of obstructive sleep apnea

Sleep

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

Respir. Res.

Genioglossus muscle activity during stable sleep in patients with obstructive sleep apnea

Am. J. Resp. Crit. Care Med.

Recent advances in understanding the pathogenesis of obstructive sleep apnea

Curr. Opin. Pulm. Med.

Central nervous system distribution of the transcription factor Phox2b in the adult rat

J. Comp. Neurol.

Changes in airway resistance during sleep onset

J. Appl. Physiol.

Sleep-disordered breathing and neuropsychological deficits. A population-based study

Am. J. Respir. Crit. Care Med.

Inspiratory coactivation of the genioglossus enlarges retroglossal space in laryngectomized humans

J. Appl. Physiol.

Principles and Practice of Sleep Medicine

Frontiers review
Pharyngeal motor control and the pathogenesis of obstructive sleep apnea