Curr Neurol Neurosci Rep (2015) 15:12 DOI 10.1007/s11910-015-0537-1
SLEEP (M THORPY, M BILLIARD, SECTION EDITORS)
Neurogenic Changes in the Upper Airway of Obstructive Sleep Apnoea Julian P. Saboisky & Jane E. Butler & Billy L. Luu & Simon C. Gandevia
# Springer Science+Business Media New York 2015
Abstract Obstructive sleep apnoea (OSA) is linked to local neural injury that evokes airway muscle remodelling. The upper airway muscles of patients with OSA are exposed to intermittent hypoxia as well as vibration induced by snoring. A range of electrophysiological and other studies have established altered motor and sensory function of the airway in OSA. The extent to which these changes impair upper airway muscle function and their relationship to the progression of OSA remains undefined. This review will collate the evidence for upper airway remodelling in OSA, particularly the electromyographic changes in upper airway muscles of patients with OSA. Keywords Remodelling . Reinnervation . Denervation . Genioglossus . Tongue . Respiratory . Fibre density . Motor unit potential . Electromyography . Quantitative EMG Introduction Obstructive sleep apnoea (OSA) is a common sleep disorder with serious consequences including fragmented sleep, recurrent hypoxemia, greater risk of cardiovascular mortality, excessive daytime sleepiness, depression, impaired learning and memory, as well as an increased risk of accidents [e.g. 1–4]. Factors that contribute to frequent collapse of the upper airway in sleep include constricted space due to poor upper airway anatomy, insufficient neuromuscular drive, high intraluminal negative pressure and external influences on the pharyngeal space such as increased fat [5, 6]. Continuous positive airway This article is a part of the Topical Collection on Sleep J. P. Saboisky (*) : J. E. Butler : B. L. Luu : S. C. Gandevia Neuroscience Research Australia, University of New South Wales, Barker Street, PO Box 1165, Randwick Sydney, NSW 2031, Australia e-mail: [email protected]
pressure (CPAP) is regarded as the best standard treatment for OSA. It reduces apnoeas and hypopnoeas and can decrease mean arterial blood pressure [7•]. CPAP has little risk for the patient, but it has relatively poor adherence (50 %) [e.g. 8, 9]. In preventing sleep apnoea, CPAP acts to splint the airway open such that less muscle activation is required to maintain airway patency [10, 11]. This review will focus on the evidence for remodelling of upper airway muscles in OSA due to neurogenic change. They are associated with denervation, collateral sprouting and reinnervation of upper airway dilator muscles. These changes alter the multiunit electromyographic (EMG) signal, and this needs to be considered when EMG signals are an outcome variable. Anatomy of Pharyngeal Airway The human pharyngeal airway is by any standard dynamically complex. Unique demands placed on this relatively small conduit have seen it evolve and adapt to swallowing, vocalisation and importantly breathing. To achieve this range of tasks, the conduit is not a simple stable rigid tube [12]. The human upper airway comprises more than 20 muscles and can be divided into three segments: the velopharynx, oropharynx and hypopharynx. Each segment is walled by muscles and is a potential site of airway obstruction. The velopharynx is the most collapsible segment of the upper airway and is usually the site of most constriction [13]. There are five pairs of muscles which control the velopharyngeal airway, and they interact dynamically with muscles in the oropharynx. In the oropharynx, eight intrinsic and eight extrinsic muscles collectively form a muscular hydrostat known as the tongue [14–16]. Some muscles contract rhythmically in stable quiet breathing [10, 17–19], but they can also be activated to generate other tongue movements [14, 20]. The hyoid arch forms the lower margin of the hypopharynx and is suspended by 12 muscles from the tongue and it links to the infrahyoid muscles. The floating hyoid in
12
Page 2 of 7
humans has likely contributed indirectly to the evolution of language but it also affects the patency of the airway particularly at the level of the hypopharynx [21]. The upper airway muscles in humans have a relatively high density of nerve fibres and terminals [22•]. The shape of the airway has been compared between patients with OSA and healthy control subjects, with dynamic imaging revealing that the upper airway size varies throughout the respiratory cycle [e.g. 13, 20, 23–25]. While the oropharyngeal and hypopharyngeal spaces of patients with OSA are similar in size to the those of the control subjects [13], the velopharynx is not. The velopharyngeal space (measured in expiration) has a ~40 % smaller cross-sectional area in patients with OSA compared to matched control subjects (30 vs 106 mm2, respectively) [13, 26, 27]. Therefore, it is possible that the mechanical coupling to the velopharyngeal space from the genioglossus via the palatopharyngeus muscles is important for control of the reduced cross-sectional area in patients with OSA. Some of the neurophysiological changes considered below may further impair this neuromechanical control of the upper airway.
Neuropathic Change in Upper Airway Muscles in OSA Electrophysiological evidence for a link between upper airway remodelling and OSA derives from several studies. Studies that relate to neurogenic changes in upper airway muscles are summarised in Table 1. It shows general hypotheses, the overall findings and possible underlying mechanisms. The studies have used intramuscular EMG techniques to determine whether there are changes in the upper airway musculature in humans with OSA. The first indication of a possible abnormality was provided by Mezzanotte and colleagues [28] and subsequently reinvestigated by Fogel and colleagues [29]. Both studies quantified intramuscular multiunit EMG in quiet breathing and expressed it as a percentage of a maximal value obtained in a voluntary contraction [28, 29]. Mezzanotte and colleagues reported a ~3-fold (40.6 % vs 12.7 % maximum, respectively) increase in genioglossus activation in patients with OSA compared to healthy subjects during quiet breathing (Table 1). Based on these data, they hypothesised that there was a ‘neuromuscular compensatory mechanism’ to maintain or improve airway patency during wakefulness [28, 29]. Fogel and colleagues [29] reported a ~2-fold increase in activity in patients with OSA compared to control subjects but with comparatively low levels of muscle activity (11.0 % vs 6.4 % maximum, respectively). Similarly, Katz and White [30] found a ~2-fold increase in genioglossus EMG in children with OSA compared to control subjects using surface intraoral electrodes (3.6 % vs 1.6 % maximum, respectively). Surface electromyography with submental electrodes, in adults, also revealed increased activity in patients with OSA [31]. Muscle
Curr Neurol Neurosci Rep (2015) 15:12
conduction velocity in genioglossus is higher in patients with OSA [32], a change which can occur in repeated exercise bouts [33], but the mechanism of this effect in OSA has not been studied in detail. Furthermore, studies using intramuscular EMG have revealed that inspiratory activation is maintained during stable NREM sleep [34–37] and that there is an impaired reflex response to induced airway obstruction during sleep in patients with OSA [38]. To examine the ‘compensatory’ drive hypothesis and to assess directly if there was an increase in hypoglossal motoneurone output, the behaviour of single motor units in quiet breathing has been examined. Initially, investigations sought to assess if there was increased neural drive in patients with OSA by comparing the discharge frequencies of populations of single motor units. There are six firing patterns of genioglossus motor units in quiet breathing [17], and they were similar in proportion in both normal and OSA groups [39]. Further, the discharge rates of these genioglossus units were not consistently higher in OSA patients than those in healthy control subjects [39]. The similarity in motor unit discharge rates argues against a compensatory increase in neural drive [10, 39], at least during wakefulness. In addition, the number of motor units recorded at each site in quiet breathing was not different, suggesting comparable levels of recruitment [39, 40•]. However, the genioglossus motor units in patients with OSA were recruited ~100 ms earlier (inspiratory phasic units 91 ms and inspiratory tonic units 106 ms earlier) than those in control subjects relative to inspiratory airflow, consistent with previous multiunit EMG recordings (see Table 1) [39]. The advanced activation of the genioglossus in patients with OSA may reflect advanced descending drive from the medulla. However, obese subjects have delayed onset of airflow compared to timing of diaphragm activation [41]. Therefore, a limitation of recording from a single upper airway (genioglossus) muscle is the uncertainty as to whether the early recruitment of its motor units reflects earlier central respiratory drive or if airflow was delayed due to the increased inertia of the airway and thoracoabdominal structures. In addition to the analysis of rate coding and recruitment of single genioglossus motor units, measurements of the morphology of motor unit potentials has been performed in two independent studies with intramuscular needle electrodes [39, 40•]. Needle EMG recordings were made at multiple sites in genioglossus when supine awake subjects were breathing quietly. Genioglossus motor unit potentials in patients with OSA had similar peak-to-peak amplitudes compared to control subjects (398 vs 383 μV, respectively). However, the motor unit potentials in the patients with OSA were ~23 % longer in duration, 14.6 % greater in area [39] and had a 33 % increase in complexity (reflecting the number of phase changes in the motor unit potential) compared to control subjects [40•]. Recently, Zhang and colleagues [42] extended these findings and reported that motor units in the posterior regions of the
Compensatory drive in OSA Compensatory drive in OSA
Neurogenic changes in palatopharyngeus
Katz & White 2003 [30] Saboisky et al. 2007 [39]
Hagander, 2006 [44]
Motor unit potential morphology Motor unit potential duration sub-analysis controls (older vs younger) 14.1±0.7 vs 10.5±0.3 ms
Age effects and neurogenic ↑ changes
Saboisky et al. 2014 [49]
• Denervation and collateral spouting
• Denervation and collateral spouting
Remodelled muscle fibres—decrease muscle fibre conduction velocity
• Denervation and collateral spouting
• Denervation and collateral spouting
• Denervation and collateral spouting
• Onset of airflow may be altered due to increased body weight
• ↑ rate coding and recruitment • Early motor unit recruitment • Motor units ‘saturated’ as already discharging quickly • Drive not increased
• Early motor unit recruitment
• ↑ rate coding and recruitment
Possible underlying mechanism
• Do hypoglossal motoneurons show alterations in rate coding or rate modulation in anterior versus posterior genioglossus? • Do discharge rates of hypoglossal motoneurons show alterations in rate coding or rate modulation with age?
• Studies conducted during quiet breathing. Is recruitment similar in voluntary breathing? • Estimation of remaining motor unit numbers • External stimulation of hypoglossal nerve?
• Studies conducted during voluntary contractions • Which other muscles are affected • Studies conducted during voluntary contractions
• Did not compare timing of diaphragm activation with genioglossus
Can units respond with increased discharge rates?
• Do children have neurogenic changes?
• Adequacy of multiunit EMG to reveal changes in drive • Is the neural drive intact during sleep in OSA
Limitations and questions
↑ = increase, ↔ = no change
Reference Podnar & Dolenc Groselj, 2010 [81] only appears in abstract form; it shows isolated neurogenic changes in the upper airway which has not been published
↑
Regional neurogenic changes
11.5±0.1 vs 10.3±0.1 ms
Zhang et al. 2014 [42]
↑
EMG median frequency no difference OSA vs. control (144 vs. 155 Hz) Muscle fibre conduction velocity in OSA vs control subjects (4.1 vs 1.9 m/s, P
SLEEP (M THORPY, M BILLIARD, SECTION EDITORS)
Neurogenic Changes in the Upper Airway of Obstructive Sleep Apnoea Julian P. Saboisky & Jane E. Butler & Billy L. Luu & Simon C. Gandevia
# Springer Science+Business Media New York 2015
Abstract Obstructive sleep apnoea (OSA) is linked to local neural injury that evokes airway muscle remodelling. The upper airway muscles of patients with OSA are exposed to intermittent hypoxia as well as vibration induced by snoring. A range of electrophysiological and other studies have established altered motor and sensory function of the airway in OSA. The extent to which these changes impair upper airway muscle function and their relationship to the progression of OSA remains undefined. This review will collate the evidence for upper airway remodelling in OSA, particularly the electromyographic changes in upper airway muscles of patients with OSA. Keywords Remodelling . Reinnervation . Denervation . Genioglossus . Tongue . Respiratory . Fibre density . Motor unit potential . Electromyography . Quantitative EMG Introduction Obstructive sleep apnoea (OSA) is a common sleep disorder with serious consequences including fragmented sleep, recurrent hypoxemia, greater risk of cardiovascular mortality, excessive daytime sleepiness, depression, impaired learning and memory, as well as an increased risk of accidents [e.g. 1–4]. Factors that contribute to frequent collapse of the upper airway in sleep include constricted space due to poor upper airway anatomy, insufficient neuromuscular drive, high intraluminal negative pressure and external influences on the pharyngeal space such as increased fat [5, 6]. Continuous positive airway This article is a part of the Topical Collection on Sleep J. P. Saboisky (*) : J. E. Butler : B. L. Luu : S. C. Gandevia Neuroscience Research Australia, University of New South Wales, Barker Street, PO Box 1165, Randwick Sydney, NSW 2031, Australia e-mail: [email protected]
pressure (CPAP) is regarded as the best standard treatment for OSA. It reduces apnoeas and hypopnoeas and can decrease mean arterial blood pressure [7•]. CPAP has little risk for the patient, but it has relatively poor adherence (50 %) [e.g. 8, 9]. In preventing sleep apnoea, CPAP acts to splint the airway open such that less muscle activation is required to maintain airway patency [10, 11]. This review will focus on the evidence for remodelling of upper airway muscles in OSA due to neurogenic change. They are associated with denervation, collateral sprouting and reinnervation of upper airway dilator muscles. These changes alter the multiunit electromyographic (EMG) signal, and this needs to be considered when EMG signals are an outcome variable. Anatomy of Pharyngeal Airway The human pharyngeal airway is by any standard dynamically complex. Unique demands placed on this relatively small conduit have seen it evolve and adapt to swallowing, vocalisation and importantly breathing. To achieve this range of tasks, the conduit is not a simple stable rigid tube [12]. The human upper airway comprises more than 20 muscles and can be divided into three segments: the velopharynx, oropharynx and hypopharynx. Each segment is walled by muscles and is a potential site of airway obstruction. The velopharynx is the most collapsible segment of the upper airway and is usually the site of most constriction [13]. There are five pairs of muscles which control the velopharyngeal airway, and they interact dynamically with muscles in the oropharynx. In the oropharynx, eight intrinsic and eight extrinsic muscles collectively form a muscular hydrostat known as the tongue [14–16]. Some muscles contract rhythmically in stable quiet breathing [10, 17–19], but they can also be activated to generate other tongue movements [14, 20]. The hyoid arch forms the lower margin of the hypopharynx and is suspended by 12 muscles from the tongue and it links to the infrahyoid muscles. The floating hyoid in
12
Page 2 of 7
humans has likely contributed indirectly to the evolution of language but it also affects the patency of the airway particularly at the level of the hypopharynx [21]. The upper airway muscles in humans have a relatively high density of nerve fibres and terminals [22•]. The shape of the airway has been compared between patients with OSA and healthy control subjects, with dynamic imaging revealing that the upper airway size varies throughout the respiratory cycle [e.g. 13, 20, 23–25]. While the oropharyngeal and hypopharyngeal spaces of patients with OSA are similar in size to the those of the control subjects [13], the velopharynx is not. The velopharyngeal space (measured in expiration) has a ~40 % smaller cross-sectional area in patients with OSA compared to matched control subjects (30 vs 106 mm2, respectively) [13, 26, 27]. Therefore, it is possible that the mechanical coupling to the velopharyngeal space from the genioglossus via the palatopharyngeus muscles is important for control of the reduced cross-sectional area in patients with OSA. Some of the neurophysiological changes considered below may further impair this neuromechanical control of the upper airway.
Neuropathic Change in Upper Airway Muscles in OSA Electrophysiological evidence for a link between upper airway remodelling and OSA derives from several studies. Studies that relate to neurogenic changes in upper airway muscles are summarised in Table 1. It shows general hypotheses, the overall findings and possible underlying mechanisms. The studies have used intramuscular EMG techniques to determine whether there are changes in the upper airway musculature in humans with OSA. The first indication of a possible abnormality was provided by Mezzanotte and colleagues [28] and subsequently reinvestigated by Fogel and colleagues [29]. Both studies quantified intramuscular multiunit EMG in quiet breathing and expressed it as a percentage of a maximal value obtained in a voluntary contraction [28, 29]. Mezzanotte and colleagues reported a ~3-fold (40.6 % vs 12.7 % maximum, respectively) increase in genioglossus activation in patients with OSA compared to healthy subjects during quiet breathing (Table 1). Based on these data, they hypothesised that there was a ‘neuromuscular compensatory mechanism’ to maintain or improve airway patency during wakefulness [28, 29]. Fogel and colleagues [29] reported a ~2-fold increase in activity in patients with OSA compared to control subjects but with comparatively low levels of muscle activity (11.0 % vs 6.4 % maximum, respectively). Similarly, Katz and White [30] found a ~2-fold increase in genioglossus EMG in children with OSA compared to control subjects using surface intraoral electrodes (3.6 % vs 1.6 % maximum, respectively). Surface electromyography with submental electrodes, in adults, also revealed increased activity in patients with OSA [31]. Muscle
Curr Neurol Neurosci Rep (2015) 15:12
conduction velocity in genioglossus is higher in patients with OSA [32], a change which can occur in repeated exercise bouts [33], but the mechanism of this effect in OSA has not been studied in detail. Furthermore, studies using intramuscular EMG have revealed that inspiratory activation is maintained during stable NREM sleep [34–37] and that there is an impaired reflex response to induced airway obstruction during sleep in patients with OSA [38]. To examine the ‘compensatory’ drive hypothesis and to assess directly if there was an increase in hypoglossal motoneurone output, the behaviour of single motor units in quiet breathing has been examined. Initially, investigations sought to assess if there was increased neural drive in patients with OSA by comparing the discharge frequencies of populations of single motor units. There are six firing patterns of genioglossus motor units in quiet breathing [17], and they were similar in proportion in both normal and OSA groups [39]. Further, the discharge rates of these genioglossus units were not consistently higher in OSA patients than those in healthy control subjects [39]. The similarity in motor unit discharge rates argues against a compensatory increase in neural drive [10, 39], at least during wakefulness. In addition, the number of motor units recorded at each site in quiet breathing was not different, suggesting comparable levels of recruitment [39, 40•]. However, the genioglossus motor units in patients with OSA were recruited ~100 ms earlier (inspiratory phasic units 91 ms and inspiratory tonic units 106 ms earlier) than those in control subjects relative to inspiratory airflow, consistent with previous multiunit EMG recordings (see Table 1) [39]. The advanced activation of the genioglossus in patients with OSA may reflect advanced descending drive from the medulla. However, obese subjects have delayed onset of airflow compared to timing of diaphragm activation [41]. Therefore, a limitation of recording from a single upper airway (genioglossus) muscle is the uncertainty as to whether the early recruitment of its motor units reflects earlier central respiratory drive or if airflow was delayed due to the increased inertia of the airway and thoracoabdominal structures. In addition to the analysis of rate coding and recruitment of single genioglossus motor units, measurements of the morphology of motor unit potentials has been performed in two independent studies with intramuscular needle electrodes [39, 40•]. Needle EMG recordings were made at multiple sites in genioglossus when supine awake subjects were breathing quietly. Genioglossus motor unit potentials in patients with OSA had similar peak-to-peak amplitudes compared to control subjects (398 vs 383 μV, respectively). However, the motor unit potentials in the patients with OSA were ~23 % longer in duration, 14.6 % greater in area [39] and had a 33 % increase in complexity (reflecting the number of phase changes in the motor unit potential) compared to control subjects [40•]. Recently, Zhang and colleagues [42] extended these findings and reported that motor units in the posterior regions of the
Compensatory drive in OSA Compensatory drive in OSA
Neurogenic changes in palatopharyngeus
Katz & White 2003 [30] Saboisky et al. 2007 [39]
Hagander, 2006 [44]
Motor unit potential morphology Motor unit potential duration sub-analysis controls (older vs younger) 14.1±0.7 vs 10.5±0.3 ms
Age effects and neurogenic ↑ changes
Saboisky et al. 2014 [49]
• Denervation and collateral spouting
• Denervation and collateral spouting
Remodelled muscle fibres—decrease muscle fibre conduction velocity
• Denervation and collateral spouting
• Denervation and collateral spouting
• Denervation and collateral spouting
• Onset of airflow may be altered due to increased body weight
• ↑ rate coding and recruitment • Early motor unit recruitment • Motor units ‘saturated’ as already discharging quickly • Drive not increased
• Early motor unit recruitment
• ↑ rate coding and recruitment
Possible underlying mechanism
• Do hypoglossal motoneurons show alterations in rate coding or rate modulation in anterior versus posterior genioglossus? • Do discharge rates of hypoglossal motoneurons show alterations in rate coding or rate modulation with age?
• Studies conducted during quiet breathing. Is recruitment similar in voluntary breathing? • Estimation of remaining motor unit numbers • External stimulation of hypoglossal nerve?
• Studies conducted during voluntary contractions • Which other muscles are affected • Studies conducted during voluntary contractions
• Did not compare timing of diaphragm activation with genioglossus
Can units respond with increased discharge rates?
• Do children have neurogenic changes?
• Adequacy of multiunit EMG to reveal changes in drive • Is the neural drive intact during sleep in OSA
Limitations and questions
↑ = increase, ↔ = no change
Reference Podnar & Dolenc Groselj, 2010 [81] only appears in abstract form; it shows isolated neurogenic changes in the upper airway which has not been published
↑
Regional neurogenic changes
11.5±0.1 vs 10.3±0.1 ms
Zhang et al. 2014 [42]
↑
EMG median frequency no difference OSA vs. control (144 vs. 155 Hz) Muscle fibre conduction velocity in OSA vs control subjects (4.1 vs 1.9 m/s, P
