Response of human tongue protrudor and retractors to hypoxia and hypercapnia

It is well established that the genioglossus muscle (tongue protrudor) has a role in protecting or enhancing upper airway patency in individuals with obstructive sleep apnea. However, no investigation completed to date has addressed the role of the styloglossus and hyoglossus muscles (tongue retractors) in maintaining upper airway patency in humans. As a first step toward this goal, the present investigation was designed to examine the response of human tongue protrudor and retractor muscles during a breathhold maneuver and in steady-state hypoxic hypercapnia. The results showed that the protrudor and retractor muscles were coactivated under both conditions. Measurements of onset time of electromyographic activity during steady-state hypoxic hypercapnia revealed that phasic protrudor and retractor activity was initiated immediately before or during the early part of inspiration. We conclude that the tongue protrudor and retractor muscles are coactivated in response to hypoxia and hypercapnia, and that the tongue retractors may have a significant role in protecting upper airway patency during both apnea and hyperpnea.     

PO2-dependent changes in intrinsic and extrinsic tongue muscle activities in the rat

RATIONALE: Historically, respiratory-related research in sleep apnea has focused exclusively on the extrinsic tongue muscles (i.e., genioglossus, hyoglossus, and styloglossus). Until recently, the respiratory control and function of intrinsic tongue muscles (i.e., inferior and superior longitudinalis, transverses, and verticalis), which comprise the bulk of the tongue, were unknown. OBJECTIVES: The current study sought to determine if extrinsic and intrinsic tongue muscles are coactivated in conditions of hypoxemia comparable to that experienced by adults with obstructive sleep apnea. MEASUREMENTS: Esophageal pressure and EMG activity of an extrinsic (hyoglossus) and an intrinsic (superior longitudinal) tongue muscle were studied in anesthetized, tracheotomized, spontaneously breathing rats. Average EMG activity was compared in a control gas condition (Pa(O2), 160 +/- 12 mm Hg) and in mild isocapnic hypoxia (Pa(O2), 69 +/- 7.2 mm Hg), with and without brief (3-breath) airway occlusions, pre- and postbilateral vagotomy. MAIN RESULTS: (1) intrinsic and extrinsic tongue muscles are coactivated in mild hypoxia, (2) airway occlusion increased the activities of intrinsic retractor muscles in mild hypoxia, and (3) extrinsic retractor muscles have a steeper rate of rise of activity and an earlier burst onset relative to intrinsic retractor activities in mild hypoxia. CONCLUSIONS: These findings support our working hypothesis that airway patency is maintained not simply by activation of extrinsic tongue muscles but by the coactivation of intrinsic and extrinsic protrudor and retractor muscles.     

Sublingual electrical stimulation of the tongue during wakefulness and sleep

Pharyngeal obstruction in patients with obstructive sleep apnea (OSA) is thought to result from decreased upper airway muscle tone during sleep. The goal of the present study was to estimate the role of the tongue muscles in maintaining pharyngeal patency during sleep. Using non-invasive, sub-lingual surface electrical stimulation (ES), we measured tongue protrusion force during wakefulness and upper airway resistance during sleep in seven healthy subjects and six patients with OSA. During wakefulness, ES produced similar protrusion forces in healthy subjects and patients with OSA. ES of the anterior sublingual surface, causing preferential contraction of the genioglossus, resulted in smaller effects than combined ES of the anterior and lateral surface, which also stimulated tongue retractors. During sleep, trans-pharyngeal resistance decreased and peak inspiratory flow rate increased from 319+/-24 to 459+/-27 and from 58+/-16 to 270+/-35 ml/sec for healthy subjects and OSA patients, respectively (P<0.001). However, ES was usually unsuccessful in reopening the upper airway in the presence of complete apneas. We conclude that non-invasive ES of the tongue improves flow dynamics during sleep. Combined activation of tongue protrusors and retractors may have a beneficial mechanical effect. The magnitude of responses observed suggests that in addition to the stimulated muscles, other muscles and/or forces have a substantial impact on pharyngeal patency.     

Biochemistry of Anterior,Medial, and Posterior Genioglossus Muscle in the Rat

The tongue plays a vital role in swallowing actions. However, tongue muscles have been understudied, and it is unclear if tongue muscles are homogeneous with respect to muscle fiber-type distribution. We examined myosin heavy chain (MHC) composition of anterior, medial, and posterior sections of the genioglossus muscle (GG) using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in ten adult (9 months old) male Fischer 344/Brown Norway hybrid rats. We found that Type IIx MHC predominated in the anterior, medial, and posterior regions of the GG muscle (p = 0.002), followed by IIa, then IIb. The anterior GG contained a significantly greater (p = 0.004) proportion of Type IIa than did the medial or posterior regions, while the posterior GG contained a significantly greater (p = 0.002) proportion of Type IIb MHC than did the medial or anterior GG. Accordingly, we found variable expression of MHC isoforms across anterior, medial, and posterior portions of the GG muscle, with more fast-contracting isoforms found posteriorly. Because motor control of the tongue requires precise and rapid movements for bolus manipulation and airway protection, variable expression of MHC isoforms along the anteroposterior axis of the GG muscle may be required to efficiently achieve deglutition and maintenance of airway patency. This work was funded by a grant from the National Institute of Deafness & Other Communication Disorders (R01 DC005935) and the University of Wisconsin School of Medicine and Public Health.     

Effect of nasal airway positive pressure on upper airway size and configuration

The effect of nasal airway positive pressure (NAPP) on upper airway size and configuration during wakefulness was studied by computerized tomography in 12 obese subjects with obstructive sleep apnea (OSA), seven weight- and age-matched subjects without OSA, and 12 normal subjects. NAPP of 10 to 12 cm H2O was associated with a significant increase in airway area throughout the upper airway in all three groups. The change in airway area per cm H2O NAPP increased from nasopharynx to hypopharynx. The change in airway area per cm H2O NAPP was significantly smaller in the OSA than in the normal subjects in the region of the soft palate. Electromyographic recordings of the genioglossus and alae nasi muscles with and without NAPP during wakefulness in five of the OSA and five of the normal subjects showed either a decrease or no change in phasic and tonic activity with NAPP. In a separate series of experiments in an additional five OSA and five normal subjects, NAPP of zero, 5, 10, and 15 cm H2O was associated with a linear increase in airway area at a given airway level. These results indicate that (1) the increase in pharyngeal cross-sectional area with application of NAPP during wakefulness is smaller in OSA than in normal subjects in the region of the soft palate and (2) changes in upper airway muscle activity may accompany changes in upper airway size and configuration.     

Tongue protrusion force and fatiguability in male and female subjects.

Limb and respiratory muscle (diaphragm) strength and fatiguability have been extensively studied in man and are known to vary with age and sex. However, in contrast to limb muscles and the diaphragm, force and fatiguability characteristics have not been studied in upper airway muscles. This study examines the hypotheses that tongue protrusion strength or fatiguability, determined by the properties of the intrinsic muscles and genioglossus, may change with age and may be reduced in males compared to females. A force transducer was used to compare maximal tongue protrusion force (Fmax) and fatiguability in 81 males and 86 females matched for age (mean+/-SD, 43+/-19 yrs, 42+/-19 yrs, respectively). Fatiguability indices were based on the time that subjects could maintain 50% of Fmax. Fmax declined with age in both males (r=-0.57, p<0.001) and females (r=-0.56, p<0.001). Fmax in males was greater than in females (males 26+/-8 N; females 20+/-7 N; p<0.001). However, after correction of Fmax for sex differences in total body muscle (fat-free mass) there was no significant difference between males and females (p=0.3). There was also no difference in fatiguability between males and females (p=0.5). In conclusion, tongue protrusion strength is greater in males compared to females, and decreases with age. If these differences also apply to patients with sleep apnoea, the reduction in maximal tongue protrusion force with age could be of relevance to the observed increase in prevalence and severity of sleep apnoea-hypopnoea syndrome in middle age, but would not explain the gender difference in prevalence.     

Injection of l-glutamate into the insular cortex produces sleep apnea and serotonin reduction in rats

Purpose

Obstructive sleep apnea (OSA) is primarily characterized by repetitive episodes of complete or partial obstruction of airflow during sleep. The neuronal and cellular mechanisms underlying this process are not fully understood, although the focus of some studies is on putative serotonin (5-HT) mechanisms, and serotonergic therapy may be beneficial to OSA patients. This study aimed to demonstrate possible changes in 5-HT associated with induction of OSA in a rat model.

Methods

Apnea was induced in rats by injection of l-glutamate (l-Glu) into the insular cortex. We examined changes in: (1) simultaneous genioglossus and diaphragm EMG activity; and (2) peripheral and cerebral levels of 5-HT, by histology.

Results

Injection of l-glutamate (l-Glu) into the insular cortex induced apnea in the rats. l-Glu stimulation of the insular cortex also produced significant reductions in plasma 5-HT levels and the expression of 5-HT in the brainstem. In addition, lower activity was observed in the GG and a higher activity was observed in the diaphragm, as compared to controls.

Conclusion

Data indicate that l-Glu stimulation of the insular cortex simulates the electrical activity of the genioglossus muscle and diaphragm in sleep apnea, and contributes to reduced peripheral and cerebral 5-HT levels in rats. The results of our study suggest that 5-HT may play a role in the pathogenesis of OSA.     

Upper airway collapsibility, dilator muscle activation and resistance in sleep apnoea.

The calibre of the upper airway is thought to be dependant upon its passive anatomy/collapsibility and the activation of pharyngeal dilator muscles. During awake periods, the more collapsible upper airway in obstructive sleep apnoea (OSA) increases the dilator muscle activity through a negative-pressure reflex. A direct correlation between the critical closing pressure (P(crit)), as a measure of anatomy/collapsability and electromyogram (EMG) activity of genioglossus EMG (GG-EMG) and tensor palatini EMG (TP-EMG), was hypothesised. The relationship between these indices and pharyngeal resistance (R(phar)) was also examined. The study involved eight males with a mean age of 48 (interquartile range 46-52) yrs with OSA, and an apnoea/hypopnoea index of 75 (65-101).hr(-1) on two nights breathing normally and on nasal continuous positive airway pressure (nCPAP). The P(crit )was measured during nonrapid eye movement sleep on nCPAP using brief, incremental reductions in mask pressure. GG-EMG and TP-EMG were measured breath-by-breath, awake, during sleep onset and on nCPAP. R(phar) was measured using airway pressures and flow. Wakeful GG-EMG, early sleep TP-EMG and the sleep decrement in TP-EMG were directly related to P(crit). Muscle activation was negatively correlated with R(phar) for TP-EMG awake and GG-EMG early in sleep. In conclusion these results confirm that dilator muscle activation is directly related to airway narrowing and reduces resistance across patients with obstructive sleep apnoea.     

Biochemistry of the Anterior, Medial, and Posterior Genioglossus in the Aged Rat

Age-related tongue weakness may contribute to swallowing deficits in the elderly. One contributing factor may be an alteration in muscle-fiber-type properties with aging. However, it is not clear how muscle fiber types within the aged tongue may vary from those found in young adults, or how fiber types may vary across the anteroposterior axis of the extrinsic tongue muscles. We examined the myosin heavy chain (MHC) composition of anterior, medial, and posterior sections of the genioglossus muscle (GG) in ten old male Fischer 344/Brown Norway rats and compared findings to previously reported data from young adult male rats. Significant differences (p < 0.01) between young adult and old rats were found in the distribution of MHC isoforms along the anteroposterior axis of the muscle. In the anterior, medial, and posterior regions, there was a significantly smaller proportion of type IIb MHC in the old rat GG muscles, while the proportion of type IIx MHC was significantly greater. In the medial region, the proportion of type I MHC was found to be significantly greater in the old rats. Thus, we found a shift to more slowly contracting muscle fibers in the aged rat tongue.     

Effects of chronic episodic hypoxia on rat upper airway muscle contractile properties and fiber-type distribution

OBJECTIVE: Contraction of upper airway (UA) muscles such as the geniohyoids and sternohyoids dilates and/or stabilizes the UA, thereby maintaining its patency. Obstructive sleep apnea (OSA) is caused by episodes of UA collapse, and this results in chronic episodic hypoxia. Chronic continuous hypoxia affects skeletal muscle structure and function, but the effects of chronic episodic hypoxia on UA muscle structure and function are unknown. DESIGN: Rats were exposed to alternating periods of hypoxia and normoxia twice per minute for 8 h/d for 5 weeks in order to mimic the intermittent hypoxia of OSA in humans. Isometric contractile properties were determined using strips of isolated geniohyoid and sternohyoid muscles in physiologic saline solution at 30 degrees C. Fiber-type distribution was determined using adenosine triphosphatase staining. RESULTS: Chronic episodic hypoxia had no significant effect on twitch or tetanic tension, twitch/tetanic tension ratio, contractile kinetics, tension-frequency relationship, or fiber-type distribution for either the sternohyoid or geniohyoid muscle. However, chronic episodic hypoxia did significantly increase sternohyoid and geniohyoid fatigue and reduced recovery from fatigue. CONCLUSIONS: Chronic episodic hypoxia increases UA muscle fatigue, an effect that may compromise the maintenance of UA patency.     

Local mechanisms drive genioglossus activation in obstructive sleep apnea

Individuals with obstructive sleep apnea (OSA) require increased pharyngeal muscle dilator activation during wakefulness to maintain upper airway patency. Negative pressure is one potential stimulus for this neuromuscular compensation. Individuals with OSA who have previously undergone tracheostomy provide an opportunity to study upper airway physiology in both the presence and absence of upper airway respiratory stimuli. If negative pressure (or another local airway stimulus) were important in driving pharyngeal dilator muscle activation, one would predict that during nasal breathing, the pharynx of a tracheostomized patient would be exposed to negative pressure, and that high levels of muscle activation would therefore be measured. Conversely, during breathing by the patient through the tracheal stoma, one would expect low levels of muscle activation in the absence of local stimuli. We measured a number of respiratory variables, including genioglossus activation under both nasal and tracheal stomal breathing conditions, in five patients. In all five patients there was a significant and substantial decrease in both peak phasic (100 +/- 0 to 53.4 +/- 9.2 arbitrary units [mean +/- SEM], p < 0.01) and tonic genioglossus activation (36.3 +/- 5.3 to 20.7 +/- 3.9 arbitrary units, p < 0.05) during stomal breathing as compared with nasal breathing. We conclude that local upper airway respiratory stimuli, possibly negative pressure, are important in mediating the increased pharyngeal dilator muscle activation seen in sleep apnea patients during wakefulness.     

Emerging Therapies for Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a prevalent disorder often associated with daytime sleepiness, cognitive dysfunction, and adverse cardiovascular consequences. Available therapies are limited by either lack of long-term adherence or low response rates. Two emerging therapies hold promise in providing alternatives to patients with OSA. The first stems from the importance of the upper-airway dilator muscles in maintaining pharyngeal stability. Electrical stimulation of the genioglossus muscle improves both upper-airway diameter and ameliorates pharyngeal obstruction. The results of phase I and II clinical trials hold promise, but the reported improvements in the apnea-hypopnea index vary between subjects and concerns about long-term safety await long-term studies. The second technology relies on creating an increased expiratory nasal resistance via a bidirectional valve designed to be worn just inside the nostrils. Initial findings of clinical trials suggest reduction in severity of sleep apnea and subjective daytime sleepiness. Considerable heterogeneity in response to the nasal device was noted despite the high adherence rates. It remains unclear which patients will likely benefit a priori from these devices.     

Age, fatigue, and excitation-contraction coupling in masseter muscles of rats

The purpose of this study was to determine if masseter muscle endurance changes with increasing age and, if so, to examine mechanisms of fatigue. Characteristics of fatigue were measured under isometric conditions using high-frequency stimulation of anterior deep masseter (ADM) muscles of male Fischer 344 rats, 5 to 24 months old, and fed a hard (HD) or a soft (SD) diet. Potentiating effects of caffeine on ADM muscle performance in vitro were also examined. Fatigability increased by 48% with age in muscles of HD rats. Muscles of SD rats were highly fatigable at all ages. Increased HD fatigability was associated with significantly decreased concentrations of Na+/K+-adenosine triphosphatase (22%) and decreased responsiveness to caffeine postfatigue (29%). The pH levels decreased similarly in fatigued muscles of all groups. We conclude that the age-related increase in fatigability is associated with alterations in excitation-contraction coupling mechanisms. However, differences between SD and HD on ADM muscles represent possible fiber-type transitions.     

Relationship between upper airway and inspiratory pump muscle force in obstructive sleep apnea

BACKGROUND: Upper airway (UA) patency during inspiration is determined by the balance between dilating forces generated by UA dilator muscle activity and collapsing forces related to the decreased intraluminal pressure that accompanies flow generated by inspiratory muscle activity. It is possible that the relative strengths of UA dilator and inspiratory pump muscles could be an important determinant of the susceptibility to UA collapse during sleep (ie, obstructive sleep apnea [OSA]). METHODS: Measurements of tongue protrusion (TP) force and maximum inspiratory pressure (Pimax) were obtained in 94 patients admitted for overnight polysomnography for suspected OSA, quantified by apnea-hypopnea index (AHI). RESULTS: There was a direct linear relationship between TP force and Pimax (r(2) = 0.37, p < 0.001). A high ratio of TP force to Pimax (greater than group 90th percentile, 0.027 kg/cm H(2)O) appeared to protect against OSA, as moderate-to-severe OSA (AHI > 20/h) was not observed in any individual with a ratio above this threshold. AHI was not linearly related to TP force, Pimax, or the ratio of TP force to Pimax. CONCLUSIONS: UA muscle strength is linearly related to inspiratory pump muscle strength. The ratio of UA muscle strength (TP force) and inspiratory pump muscle strength (Pimax) was not different between individuals with and without OSA; however, a high wakeful ratio of TP force to Pimax appears to be associated with a reduced propensity to moderate-to-severe OSA.     

Obstructive sleep apnea following bilateral carotid body resection

A patient who had undergone bilateral carotid body resection five years earlier for palliation of chronic airflow obstruction was found to have severe obstructive sleep apnea. He presented with hypercapnic respiratory failure, which improved after tracheostomy. A physiologic mechanism is proposed to explain this association. Previously reported studies of anesthetized animals suggest that loss of peripheral chemoreceptor activity could selectively decrease neural output to the genioglossus, the main protrusor muscle of the tongue, predisposing the upper airway to inspiratory occlusion.     

Recent advances in understanding the pathogenesis of obstructive sleep apnea

PURPOSE OF REVIEW: The pathogenesis of obstructive sleep apnea (OSA) is incompletely understood. Historically it was believed that patients with OSA have a small upper airway (often due to obesity) that is kept patent during wakefulness by the activity of upper airway dilating muscles. With the reduction in muscle tone at sleep onset, the airway collapses and causes apnea. While this appears to be the case for many patients with OSA, other patients show no major airway anatomic defects or minimal obesity. RECENT FINDINGS: This has led to the concept that other factors such as unstable ventilatory control and changes in lung volume during sleep may be involved in the pathogenesis of OSA. Recently there have been several advances in our understanding of how these mechanisms are involved in OSA pathogenesis. SUMMARY: A more complete understanding of apnea pathogenesis may improve therapeutic techniques and reduce the consequences of OSA.     

Effects of chronic intermittent asphyxia on rat diaphragm and limb muscle contractility

OBJECTIVE: In obstructive sleep apnea (OSA), there is intermittent upper airway (UA) collapse due to an imbalance between the collapsing force generated by the diaphragm and the stabilizing force of the UA muscles. This results in chronic intermittent asphyxia (CIA). We have previously shown that CIA affects UA muscle fatigue, but little is known about the effects of chronic hypoxia on diaphragm or on limb muscle contractile properties and structure. DESIGN: Rats were exposed to asphyxia and normoxia twice per minute for 8 h/d for 5 weeks to simulate the intermittent asphyxia of OSA in humans. Isometric contractile properties were determined from strips of isolated diaphragm, extensor digitorum longus (EDL), and soleus muscles in Krebs solution at 30 degrees C. EDL and soleus type 1 (slow, fatigue resistant), type 2A (fast, fatigue resistant), and type 2B (fast, fatigable) fiber distribution was determined using adenosine triphosphatase staining. RESULTS: CIA caused a significant increase in diaphragm, EDL, and soleus fatigue, and reduced recovery from fatigue. Most of the other contractile properties were unaffected aside from a small reduction in diaphragm half-relaxation time and EDL twitch tension and a small shift to the left in the EDL force-frequency curve. There was no change in soleus fiber-type distribution and a small increase in EDL type 2A fibers (46.1 +/- 1.2% vs 49.9 +/- 1.4%, control vs CIA [mean +/- SD]). CONCLUSIONS: CIA increases diaphragm, EDL, and soleus muscle fatigue. We speculate that if this also occurs in OSA, it would contribute to the pathophysiology of the condition.     

Analysis of the myoelectric characteristics of genioglossus in REM sleep and its improvement by CPAP treatment in OSA patients

Sleep and Breathing - To reveal the characteristics of genioglossus (GG) activation in moderate and severe obstructive sleep apnea (OSA) patients during rapid eye movement (REM) sleep compared with...     

Effect of nasal obstruction on upper airway muscle activation in normal subjects

It is not known whether nasal occlusion produces obstructive sleep apnea (OSA) by decreasing upper airway muscle activation via nasal reflexes or by increasing upper airway resistance and hence lowering the pressure in the pharnyx. The purpose of this study was to determine the effect of nasal occlusion on upper airway muscle activation. We studied seven men and measured alae nasi (AN) and genioglossal (GG) electromyograms (EMGs) during two nights of sleep, one with their nose open and the other with their nose occluded. Nasal occlusion produced OSA in all subjects and also increased the percentage of time during sleep in which phasic AN and GG EMG activity was present. Apneas tended to occur at the nadirs of EMG activity. This suggests that nasal occlusion generally increases respiratory drive to upper airway muscles during sleep and that it does not cause OSA by merely decreasing respiratory drive to these muscles.     

Respiratory-related discharge of genioglossus muscle motor units

RATIONALE: Little is known about the respiratory-related discharge properties of motor units driving any of the eight muscles that control the movement, shape, and stiffness of the mammalian tongue. OBJECTIVES: To characterize the respiratory-related discharge of genioglossus motor units as synaptic drive to the hypoglossal motoneuron pool is increased with hypercapnia. MEASUREMENTS: We recorded airflow, genioglossus muscle EMG activity, and the respiratory-related discharge of 30 genioglossus muscle motor units in spontaneously breathing, urethane-anesthetized rats under control conditions and in hypercapnia (inspired CO2: 3, 6, 9, and 12%, 3-5 min at each level). MAIN RESULTS: All motor units were active throughout all or most of inspiration. Nine of 30 units showed "preinspiratory" activity (discharge onset within the last 20% of expiration), with continued discharge into inspiration. Six inspiratory units transitioned to a preinspiratory pattern when inspired CO2 exceeded 6%. For the majority of units (23/30), discharge rate increased with hypercapnia, with the maximum increase averaging about 50%. The average variability of interspike intervals within a spike train increased from 33% under baseline conditions to 50% with maximal hypercapnia. CONCLUSIONS: (1) The discharge pattern of genioglossus muscle motor units can be altered by hypercapnia; (2) most, but not all, genioglossus motor units receive synaptic input from CO2-sensitive chemoreceptors; (3) individual motor units have a wide range of CO2 sensitivities; and (4) hypercapnia significantly increases the variability of motor unit discharge, which may enhance muscle force output.