Sleep, 19(10):827-853 © 1996 American Sleep Disorders Association and Sleep Research Society

State of the Art Review

Motor Control of the Pharyngeal Musculature and Implications for the Pathogenesis

of Obstructive Sleep Apnea

Richard L. Horner

Center for Sleep and Respiratory Neurobiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Summary: Obstructive sleep apnea is a common breathing problem that results in recurrent episodes of nighttime hypoxemia, hypercapnia, brady tachycardia, and hypertension, as well as sleep disturbance and daytime hypersom­nolence. The obstruction is located in the oropharynx and is caused by hypotonia of the pharyngeal dilator muscles. In this paper, the various mechanisms affecting motor output to the upper airway muscles are reviewed. In particular, the respiratory function of the pharyngeal dilator muscles, the various reflex mechanisms underlying their control, and the effects of sleep on these mechanisms are discussed. The literature relevant to the central neuronal circuits and neurotransmitters that may be involved in the state-dependent activity of the pharyngeal dilator muscles is also reviewed. In addition to an examination of these basic mechanisms, consideration is given throughout this review as to how these mechanisms may relate to the normal control of pharyngeal patency awake and asleep and how they may be involved in the pathogenesis of ohstructive sleep apnea. Key words: Respiration-Sleep-Pharynx­Upper airway-Obstructive sleep apnea.

Determining the factors affecting the maintenance of upper airway (VA) patency has gained major im­portance since the recognition of obstructive sleep ap­nea (OSA) (1,2). OSA affects 2-4% of the middle­aged population (3) and is a major public health prob­lem (4). Repetitive obstructive apneas result in recur­rent nighttime hypoxemia, hypercapnia, brady­tachycardia, and hypertension, as well as sleep distur­bance. OSA is associated with increased risk for the development of systemic hypertension, cardiac ar­rhythmias, myocardial infarction and stroke, and symptoms such as excessive daytime sleepiness and increased risk for vehicular accidents (5-10). Obstruc­tive apneas are characterized by cessation of oronasal airflow in the presence of attempted (but ineffective) respiratory efforts and are caused by VA occlusion; hypopneas are caused by partial VA obstruction. The resolution of OSA by tracheostomy (11) and nasopha­ryngeal intubation (12) indicates a pharyngeal location

Accepted for publication August 1996. Address correspondence and reprint requests to Richard L. Hor­

ner, Ph.D., Center for Sleep and Respiratory Neurobiology, Hospital of the University of Pennsylvania, 991 Maloney Bldg., 3600 Spruce St., Philadelphia, PA 19104-4283, U.S.A.

for the obstruction, an observation which has been confirmed by imaging studies (13-19) and pharyngeal pressure measurements (20-22). VA occlusion occurs almost always at the level of the soft palate, but in about one-half of the patients with OS A, the obstruc­tion also extends caudally to regions behind the tongue (13-16,18,20-22). In rapid eye movement (REM) sleep, the lower level of the obstruction may extend to even more caudal levels compared to non-REM (22).

Remmers et al. (12) have proposed that VA collapse occurs when the intraluminal negative (NEG) pres­sures generated by the respiratory pump muscles dur­ing inspiration are inadequately opposed by pharyn­geal dilator muscle activation. Given the importance of the soft palate and tongue in the pathogenesis of OSA, this review concentrates, predominantly, on the control of the VA muscles in this region of the phar­ynx. The central respiratory control of VA muscles and the mechanical consequences of their activation are discussed in section I, and the question of whether pharyngeal muscle activation affects VA size and/or compliance is addressed. Data on within-breath changes in VA size and muscle activity in normal sub­jects and patients with OSA are also examined, and

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828 R. L. HORNER

the implications for the pathogenesis of OSA are em­phasized. In section II, the reflex activation of UA muscles by NEG intraluminal pressure is reviewed with special emphasis on recent data obtained in hu­mans awake and asleep. In particular, the question of whether such reflexes have a role in the pathogenesis of OSA is discussed. Reflexes elicited by other stimuli relevant to OSA are reviewed in the next section. In section IV, the literature relevant to the central neural circuits and neurotransmitters that may be involved in the state-dependent modulation of UA motor output is reviewed, and the relevance of these data to the clin­ical arena is discussed. In the concluding section, se­lected issues relevant to the pathogenesis of OSA are discussed and some unanswered questions are identi­fied.

(I) UPPER AIRWAY MUSCLES

(i) Activation during respiration

The respiratory activity and putative respiratory ac­tions of some major UA muscles are summarized in Table 1. Inspiratory-related genioglossus (GG) activity is typically recorded with intramuscular electrodes in humans (e.g. 23-25), although such activity is record­ed less often with intraoral surface electrodes unless driven by chemostimulation (26) or loaded inspiration (27). In animals, the levator and tensor palatini (TP) muscles show phasic inspiratory and tonic expiratory activity (28,29). In humans, similar patterns of activity have been reported for the levator and palatoglossus muscles (30,31), but TP typically shows tonic activity throughout the respiratory cycle awake and asleep even in the presence of inspiratory loading (32,33). These recent studies showing inspiratory levator and tonic TP activity contrast with an earlier study show­ing the opposite patterns of respiratory activity (34). The potential relevance of GG activity to OSA is well documented (12). However, respiratory-related palatal muscle activity may be particularly relevant because UA occlusions occur almost always at the level of the soft palate in OSA (13-16,18,20-22), and decreases in palatal muscle activity are associated with increases in retropalatal airway resistance (32) and onset of OSA (35).

(ii) Mechanical consequences of UA muscle activation during respiration

Inspiratory-related decreases in pressure are record­ed in the isolated, sealed UA of animals (36-39) sug­gesting a net UA dilating force during inspiration. In­creased GG activity is often taken to indicate tongue protrusion and enlargement of the pharyngeal airspace

Sleep. Vol. 19. No. 10. 1996

because such an effect is produced in animals during electrical stimulation (40,41). However, unequivocal evidence for an airway dilating effect of respiratory­related GG activity has only recently been demonstrat­ed in humans. In laryngectomized subjects breathing via a tracheal stoma (i.e. avoiding pharyngeal pressure changes that can indirectly affect tongue position), GG activation is associated with anterior tongue movement and increased airway size (42). However, in goats breathing via the UA (i.e. experiencing inspiratory NEG pressures), measurements of GG muscle length with sonimicrometry have shown that passive GG lengthening and posterior tongue displacement can oc­cur in inspiration (43). For these breaths, passive GG lengthening occurred until the muscle generated suf­ficient active tension to elicit shortening. This obser­vation might explain why humans breathing through an intact UA do not show significant oropharyngeal dilatation in inspiration (44-46); the airway narrowing effects of NEG inspiratory pressure (47) may offset the airway dilating effects of UA dilator muscle acti­vation.

The increases in retropalatal airway resistance as­sociated with decreased TP activity (32) provides cor­relative evidence for a mechanical role of this muscle in affecting airway patency. However, the relatively low correlation coefficients between TP activity and retropalatal resistance across sleep-wake states (32) suggest that changes in the activity of other palatal muscles are also probably involved. Given the impor­tance of the palatal region in OSA (see above), the relative importance and mechanical contribution of the different palatal muscles to the maintenance of airway patency needs to be determined.

Changes in alae nasi activity in humans may not significantly affect nasal resistance (48). However, electrical stimulation and anterior movement of the hy­oid arch reduces UA resistance (49), suggesting a me­chanical contribution to pharyngeal patency from the hyoid muscles. Hyoid position may be relevant to OSA since mass loading of the UA results in posterior hyoid displacement, oropharyngeal narrowing, in­creased UA resistance, and makes the UA more col­lapsible (50). This effect of mass loading on the hyoid may simulate the effects of submental fat in OSA pa­tients (51).

Relevance to OSA. Understanding which UA mus­cles are most critical for the maintenance of UA pa­tency and preventing airway collapse has important implications for any strategy designed to increase UA dilator muscle tone and prevent OSA. However, from a mechanical standpoint it is still not well understood which UA dilator muscles are most critical for pre­venting OSA. This may be because the coordinated dilatation of the whole oropharyngeal musculature is

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UPPER AIRWAY MOTOR CONTROL 829

TABLE 1. Some upper airway muscles: anatomical location, putative respiratory action, nervous innervation, respiratory­related activity, effects of sleep, and responses to negative airway pressure

Muscle location and name Putative respiratory action Innervation RR activity Sleep -ve P

Nose and palate Alac nasi Dilatation of nares Facial (VII) ,j, i Tensor veli palatini Stiffens palate (7) Trigeminal (V) I or tonic ,j, i Levator veli palatini Raises palate Pharyngeal plexus (IX, X) I i Palatoglossus Opens retropalatal space (7) Pharyngeal plexus (IX, X) i Palatopharyngeus Closes pharynx Pharyngeal plexus (IX, X) 7

Oral pharynx Genioglossus Tongue protrusion Hypoglossal (XII) Hyoglossus Tongue retraction Hypoglossal (XII) 7 Styloglossus Tongue retraction Hypoglossal (XII) I? Stylopharyngeus Elevates pharynx Glossopharyngeal (IX) I? Constrictors Constricts pharynx Pharyngeal plexus (IX, X) E7 Digastric-anterior Dilates pharynx Trigeminal (V) 7 Digastric-posterior Dilates pharynx Facial (VII) ?

Hyoid

(i) Attached superiorly i Geniohyoid Dilates pharnyx? Hypoglossal (XII)

Mylohyoid 7 Trigeminal (V) 7 Stylohyoid 7 Facial (VII) ?

(ii) Attached inferiorly Thyrohyoid 7 Hypoglossal (XII)/Cl Sternohyoid Dilates pharnyx? Ansa Cervicalis (Cl-C,) I? or tonic i Sternothyroid Dilates pharynx? Ansa Cervical is (Cl-C,) 17 i

Larynx

Posterior cricoarytenoid Abducts vocal cords Recurrent laryngeal (X) I ,j, i Thyroarytenoid Adducts vocal cords Recurrent laryngeal (X) E ,j,

Lateral cricoarytenoid Adducts vocal cords Recurrent laryngeal (X) 7 Arytenoid Adducts vocal cords Recurrcnt laryngeal (X) ? Cricothyroid Tenses vocal cords External branch of lIE ,j, i

superior laryngeal (X)

Abbreviations: RR, respiratory related; I, inspiratory; E, expiratory; lIE, mixed activity; I? or E7, inspiratory or expiratory activity recorded under some circumstances; ?, some uncertainty or not documented; ,j" decrease in sleep compared to awake; -ve P, response to negative airway pressure.

Sources: 28-34,40-42,48,49,59,75,79,81,84,95-98,100,101,107,125, 131 ,267-272.

most relevant for maintenance of UA patency (i.e. there is no critical muscle group) or that the mechanics of the most critical muscles are not as well understood as the less critical ones. Electrical activation of the GG and hyoid muscles makes the UA less vulnerable to suction collapse in animals (49,52-54). Given this re­sult, it is perplexing that, in humans, submental tran­scutaneous electrical stimulation is ineffective in in­creasing UA size, decreasing resistance, and relieving OSA in the absence of arousal (55-58). However, when pharyngeal resistance is increased by external pressure, sublingual electrical stimulation can signifi­cantly reduce pharyngeal resistance (58). The lack of efficacy of UA electrical stimulation could be due to (i) lack of specificity with transcutaneous stimulation (e.g. activating tongue protruders and retractors), (ii) stimuli not being optimally delivered in phase with inspiration, (iii) the level of tolerable stimulation being insufficient to significantly alter airway mechanics, an­d/or (iv) the muscles targeted not being critical to the maintenance of airway patency and OSA, e.g. sub-

mental stimulation does not target the palatal muscles that may be more relevant. Given that the retropalatal airspace is the site of minimal UA cross-sectional area when awake (particularly in OSA patients) and, unlike behind the tongue, UA collapse almost always occurs at the level of the palate during obstructive apneas (13-16,18,20-22), then this may be the primary site of UA collapse and most critical for obstructive ap­neas. Although the effects of sleep on palatal muscle activity were noted years ago (e.g. 34,35), it is only recently that there has been renewed interest in the respiratory function and reflex control of these muscles awake and asleep (see sections II, III). However, the relative importance of the individual palatal muscles to the maintenance of UA patency awake and asleep and the mechanical consequences of their activation are still not well understood (59,60). Given the poten­tial major importance of the retropalatal airspace in the pathogenesis of OSA, it is important to define even these basic aspects of palatal muscle function. Fur­thermore, although technically more difficult, electrical

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830 R. L. HORNER

activation of these muscles may be more effective in preventing UA collapse than submental stimulation.

(iii) Does VA muscle activation affect VA compliance?

Activation of UA muscles increases the ability of the airway to resist collapse by NEG pressure (52-54,61), and it has been suggested that increased wall stiffness is an important factor (52,61). However, with­out absolute or relative measurements of airway vol­ume, it is not possible to determine if UA muscle ac­tivation improves airway stability by a major effect on airway size, wall stiffness, or both (Fig. 1). It is im­portant to distinguish between these mechanisms be­cause the effects of UA muscle activation on pharyn­geal mechanics are fundamentally different in each case. In this respect, a confounding problem in the literature is that the terms "upper airway closing pres­sure" and "wall stiffness" are often used interchange­ably despite the fact that a change in closing pressure is not a measure of wall stiffness (62), e.g. in response to increased UA muscle activity, a more NEG closing pressure could result from an increase in airway size without a change in wall stiffness (Fig. 1B).

Indices of wall stiffness have been obtained from the slope of the UA pressure-volume relationship in animals (38,63,64) and humans (65). This relationship is repeatable within subjects and can be described by a straight line (64,65). However, in the region of the velopharynx in patients with OSA, the mechanics of the hypotonic airway are well described by an expo­nential pressure-area relationship with high compli­ance near closing pressure (66). In anesthetized ani­mals, abolition of UA muscle activity by paralysis makes UA closing pressures less NEG (i.e. decreases resistance to collapse) and decreases UA volume (as judged by the smaller volume changes required to pro­duce UA closure), but it does not change the slope of the UA pressure-volume relationship (63). In addition, the slope of the UA pressure-volume relationship is the same in the live and post-mortem animal (64) de­spite the absence of muscle activity after death and the much more positive closing pressures (52). UA closing pressures also correlate significantly with the volumes removed from the airway to produce closure but not with the slopes of the pressure-volume relationships (64). It has also been demonstrated that the slopes of the UA pressure-volume relationships in apneic dogs undergoing passive UA inflation are similar to the slopes during chemoreceptor-mediated active UA dil­atation (38). In humans, the slope of the UA pressure­volume relationship is unchanged by either hypoxia or hypercapnia (65). These data suggest that in response to an increase in UA muscle activity a more NEG clos-

Sleep, Vol. 19. No. 10, 1996

A Volume (ml) 30

20

UA clOSing pressure ~

10

-20 -10

o

-10

B Volume (ml) 30

B

'- /:: Increasing UA volume X

/ c / /

o

-10

c Volume (ml) 30

20 A

/J .<

.< / .< / .<

-20 D _10 A, E

o

-10

:d(V)

o 10 20

/ /

/

Pressure (em H20)

/ /

/ / ~ecreaSing UA volume

10 20 Pressure (em H20)

Increasing compliance <I I .<-:" 7 7"

I .< .< Decreasing compliance I .<

1;,.--'<

10 20 Pressure (emH2O)

FIG. 1. Schema to illustrate how upper airway (UA) closing pres­sure can be affected by changes in airway size and/or wall stiffness. Panel A shows that airway volume decreases in response to col­lapsing pressures, and that airway closure occurs at some value of negative (NEG) pressure (i.e. the closing pressure). At the closing pressure, a residual volume is present in the upper airway (i.e. above and below the collapsed segment). The slope of the pharyngeal pres­sure (P)-volume (V) relationship yields an index of wall stiffness (compliance). Panel B shows that in the absence of a change in compliance, an increase in airway size (A -) B) makes closing pres­sures more NEG (A, -) B,), whereas decreases in airway size (A -) C) make closing pressures more positive (A, -) C,). Panel C shows that in the absence of a change in airway size, a decrease in compliance makes closing pressures more NEG (A, -) D), whereas increases in compliance make closing pressures more positive (A, -) E).

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UPPER AIRWAY MOTOR CONTROL 831

N'-"

E ,S

m (II

260

220

180

~ 140 o ~ Q)

rr en 100

e ()

60

20

o

Retropalatal airspace

.-------------.~- --e. Normal

OSA

200 400 600 800

Tidal volume (ml)

260

220 ~ E §. (II 180 ~ (II

~ 140 .2 '0 Q)

rr 100 en en e () 60

20

o

Glossopharyngeal airspace

Normal

OSA

200 400 600 800

Tidal volume (ml)

FIG. 2. Upper airway cross-sectional area plotted as a function of tidal volume in a normal subject and a patient with obstructive sleep apnea (OSA). Data are shown for the retropalatal airspace (i.e. posterior to the soft palate) and glossopharyngeal airspace (i.e. posterior to the tongue). Note that compared to normal subjects. patients with OSA have (i) smaller airways, (ii) larger changes in airway size during the breathing cycle (apparent in expiration), and (iii) minimal airway size at end-expiration. Plotted from data in Ref. 45. Solid lines with open symbols = inspiration (I), dashed lines with closed symbols = expiration (E), dotted line = extrapolation between end-inspiration and the beginning of expiration and between end-expiration and the beginning of inspiration.

ing pressure results from a predominant effect on air­way size rather than wall stiffness (Fig. IB). However, a recent report has shown that electrical stimulation of GG during hyperventilation-induced apneas in anes­thetized OSA patients can change the slope of the UA pressure-area relationship, indicative of an increase in wall stiffness (67). This suggests that there is potential for increased GG activity to exert a measurable effect on wall stiffness if the activation is large enough.

Is the UA more compliant in patients with OSA? Although VA muscle activation may decrease the vul­nerability of the VA to suction collapse by a major effect on airway size, this still does not address the question of whether OSA patients have a more com­pliant airway than normals. During respiratory efforts against an occluded airway, changes in VA size are significantly greater in snoring subjects with OSA compared to weight matched snorers without OSA (68). This result has been taken to suggest that the OSA patients have a more compliant airway. The sig­nificantly larger percentage changes in oropharyngeal size in awake patients with OSA during tidal breath­ing, compared to weight matched controls, also sug­gest that a difference in airway distensibility may exist between these groups (69). This notion is supported by the observations of Schwab et al. (45) who have observed that awake patients with OSA not only have smaller oropharyngeal airways than normal subjects,

but they also have larger expansion of this airway, particularly in the retropalatal region (Fig. 2), i.e. the site that closes during OSA (13-16,18,20-22). How­ever, although these observations suggest that the crit­ical region of the UA may indeed be more distensible in patients with OSA, it should be noted that this effect is only apparent on expiration, i.e. at a time when the pharyngeal dilator muscles become less active. It re­mains to be determined whether the differences in UA size changes during breathing in awake subjects with and without OSA (Fig. 2) result from differences in UA dilator muscle activation during inspiration (which subsequently lead to different size changes in expira­tion) and/or result from actual differences in the com­pliance of the airway walls due to the positive pres­sures encountered in expiration. In support of the for­mer mechanism, increased waking GG activity is ob­served in OSA patients compared to subjects without OSA (70), and this may lead to larger volume changes in expiration when these muscles become less active. The observation that positive pressures between 0 and 15 cm H20 (which inhibit VA dilator muscle activity) cause similar changes in oropharyngeal size in obese­matched subjects with and without OSA suggests that there may be no difference in UA compliance between these groups (71). In summary, it is questionable if patients with OSA have more compliant pharyngeal airways than normal subjects, and some observations

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832 R. L. HORNER

suggest that there may not be a measurable difference when the confounding effects of muscle activity are taken into account. In this respect, many studies mea­suring UA "compliance" are limited by ongoing UA muscle activity that is, in itself, affected by the respi­ratory cycle and the NEG pressures used to measure the compliance (see section II).

Olson et al. (62) have emphasised the role of non­muscular structures contributing to UA collapsibility; structures associated with muscle (e.g. connective tis­sue and blood vessels) may contribute significantly to airway wall stiffness. The stiffness of heart muscle de­pends on the amount of connective tissue surrounding groups of myocytes (72) and the perfusion pressure in the vascular bed (73). The contribution of such factors to UA compliance has not yet been demonstrated but may be relevant. For example, hypercapnia makes the VA more resistant to suction collapse even in the pres­ence of muscular paralysis (63,74), suggesting that CO2 can improve UA stability by mechanisms other than the neurally mediated effect on pharyngeal dilator muscle activity.

(iv) Timing of UA muscle activation during inspiration and mechanical consequences

Inspiratory activation of the alae nasi, GG, posterior cricoarytenoid (PCA), and hyoid muscles precedes that of the diaphragm in the anesthetized dog (49,75) and cat (76). In humans, inspiratory activation of the alae nasi and PCA precedes the onset of airflow (77,78), and GG activity increases before and reaches peak ac­tivity earlier than the diaphragm (79,80). The interval between the onset and peak of force production during isometric supramaximal contraction has been used as an index of the relative speeds of contraction for dif­ferent muscles. Using this index, the alae nasi and in­trinsic muscles of the larynx have faster contraction times compared to the diaphragm (81). Furthermore, the geniohyoid and sternohyoid muscles have histo­chemical characteristics usually associated with fast contractile properties (82). The fast contractile prop­erties of VA dilator muscles coupled with their inspi­ratory pre-activation indicates an effective physiolog­ical role for these muscles in the maintenance of UA patency. In support of this inspiratory pre-activation having a mechanical effect, the onset and peak of in­spiratory-related decreases in pressure in the isolated UA of dogs precedes the onset and peak of inspiratory tidal volume by approximately 80 and 640 mseconds, respectively (37).

Relevance for OSA. The small size of the orophar­yngeal airspace at end expiration, particularly in OSA patients (Fig. 2), makes this airway vulnerable to suc­tion collapse at the onset of inspiration and increases

Sleep, Vol. 19, No. 10, 1996

the demand on the UA dilator muscles to prevent col­lapse. Indeed, without inspiratory pre-activation and the fast contractile properties of these muscles, UA size in early inspiration in OSA patients may be too small for adequate airflow. Increased GG activity is observed in awake patients with OS A, which suggests a neuromuscular compensatory mechanism to prevent UA collapse (70). English bulldogs also experience OSA (83), and these dogs also exhibit increased wak­ing UA dilator muscle activity compared to dogs with­out OSA (84). Importantly, UA muscle biopsies in these dogs show an increased contribution of fast type muscle fibers and an increased number of morpholog­ically abnormal fibers (85). These effects are consis­tent with a UA dilator muscle compensatory response and altered pattern of usage in OSA, as well as the presence of muscle injury that may ultimately impair the ability of these muscles to maintain airway patency (85). The increased waking pharyngeal dilator muscle activity in patients with OSA has important implica­tions, although the mechanisms underlying this effect have yet to be determined (discussed further in section V).

(v) Effects of sleep on UA muscles

The change in activity from wake to sleep has not been reported for all the muscles in Table 1, but those that have been studied generally show decreased ac­tivity in non-REM sleep with further decreases in REM. The mechanical consequences of this decreased activity have been demonstrated by Goh et al. (39) who showed that the net dilating force acting on the UA during breathing (as measured by the amplitude of the pressure swings in the isolated UA) is decreased from wake to non-REM sleep and is frequently absent in REM. In addition to the decreases in phasic volume changes in sleep, it was also shown that baseline pres­sure in the isolated UA became more positive from wake to sleep, indicating a net decrease in volume (39) probably mediated by decreased tonic UA muscle ac­tivity. Similar conclusions have been derived from the sleeping cat (86). These tonic and phasic respiratory­related decreases in pharyngeal volume in sleep would make UA closing pressures more positive by moving the UA pressure-volume relationship downwards and to the right (Fig. IB) and would explain the increased pharyngeal resistance typically observed in sleep (87,88).

Relevance to OSA. Decreased UA dilator muscle ac­tivity in sleep (particularly REM) producing a decrease in pharyngeal volume would be expected to have a significant impact in individuals with an already small UA, such as patients with OSA. In these patients, a further shift of the UA pressure-volume relationship

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UPPER AIRWAY MOTOR CONTROL 833

Rectified and Integrated EMG (reset every 10 msec)

MWiN~M~ru'J·~ Raw GG EMG

Pressure

FIG. 3. Reflex activation of genioglossus muscle following a -15 cm H20 pressure change applied to the upper airway via a face mask in a normal subject. Note the short latency of genioglossus activation from the onset of the pressure change (=40 mseconds). Figure adapted from Ref. 266.

downwards and to the right would make the UA vul­nerable to suction collapse at minimal inspiratory pres­sures. The smaller UA in OSA patients, coupled with the sleep-related decrease in UA muscle activity, ex­plains the less NEG closing pressures in OSA patients compared to subjects without OSA (89,90) and the in­creased vulnerability for airway closure in REM (89,91,92).

(II) REFLEX PHARYNGEAL DILATOR MUSCLE ACTIVATION BY NEGATIVE

AIRWAY PRESSURE

In addition to central respiratory activation, UA di­lator muscles are also affected by a variety of afferent inputs. In this section, the physiological mechanisms underlying UA dilator muscle activation by NEG air­way pressure are reviewed. Particular attention is paid to this reflex because of its postulated role in defending the UA from suction collapse in the presence of in­spiratory NEG pressures (93,94).

(i) Pharyngeal dilator muscle responses to NEG airway pressure

Application of NEG pressure to the isolated UA of animals causes reflex activation in a variety of pha­ryngeal dilator muscles (49,75,95-97, see Table 1). Where NEG pressures have been sustained over sev­eral respiratory cycles, increases in pharyngeal dilator muscle activity during inspiration, as well as increases in tonic activity in expiration, are observed (49,75,95-97). The presence of reflex pharyngeal dilator muscle activation by NEG airway pressure has been recently demonstrated in humans (Fig. 3). Stimuli of NEG pres­sure cause short latency activation of the GG (98-

100), TP (101), levator palatini, and palatoglossus muscles (31). As in animals, sustained NEG pressure increases inspiratory-related GG activity as well as tonic expiratory activity (26,102). It is not known if the UA dilator muscles are selectively activated by NEG airway pressure. It remains to be determined if the tongue retractors are inhibited, unaffected, or even activated by NEG pressure.

Threshold of responses. Stimuli of at least -4 cm H20 cause detectable alae nasi, GG, and PCA re­sponses in conscious (97) and anesthetized dogs (75) and decerebrate cats (103). Stimuli between -3 and -6 cm H 20 cause detectable UA muscle responses in anesthetized rabbits (96). Where stimulus response curves have been performed in awake humans, stimuli between -4 and -15 cm H20 are required to cause significant GG responses (30,98). For the palatal mus­cles, stimuli as low as -2.5 cm H20 activate the le­vator palatini and palatoglossus (31). For the UA mus­cles mentioned, larger values of NEG pressure give larger responses (31,98). Innes et al. (27) observed no difference in the magnitude of GG activation if stimuli were applied at functional residual capacity or during inspiration.

Repeatability of responses. GG responses to NEG airway pressure show considerable variability between subjects, with some individuals showing characteris­tically large responses to a given stimulus (within and across days) and some showing characteristically small responses (98). Individuals with smaller responses may be less able to protect their airways from suction col­lapse. These differences may explain the variability between subjects in UA collapsibility in the presence of NEG airway pressure (25) and are discussed further in section V.

Latency of responses. The latencies of the pharyn­geal dilator muscle responses to NEG pressure are best judged in those studies that have used rapid onset (square-wave) pressure stimuli (31,98-101,104). In those studies, GG activation occurred 30-50 mseconds after the onset of the pressure change (98,100,104), and TP activation occurred after 50 mseconds (101). For GG, these latencies are much faster than the mean time for voluntary muscle activation (180 mseconds) suggesting a reflex response (98).

(ii) Effects of sleep on responses to NEG airway pressure

GG responses to NEG airway pressure in the dog are reduced in non-REM sleep compared to wake, with further reductions in REM (l05). In humans, GG (100,104) and TP (101) responses to NEG pressure are also reduced (but are still present) in non-REM sleep, with the reduced responses being associated with in-

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834 R. L. HORNER

creased UA collapsibility (101,104). The latencies of pharyngeal dilator muscle responses to NEG pressure are also affected by sleep-wake state. The latencies to step changes in pressure are increased from 30-50 mseconds in wakefulness to 80-130 mseconds in non­REM sleep for GG (98,100,104) and from 50 to 11 0 mseconds for TP (101). The reduced pharyngeal di­lator muscle responses to NEG pressure in sleep, and the increased latencies, may be a reflection of the extra synaptic input required to raise the membrane potential of UA motoneurons (MNs) from a relatively hyper­polarized level in sleep to a point when motor output is produced in response to the afferent input. However, such a mechanism would only apply to those UA MNs that were active awake and became silent asleep. In non-REM sleep, at least some MNs are still active as judged by generally persistent UA muscle activity (77,106,107). Therefore, the large increases in reflex latency asleep may suggest that (i) reflex responses are produced in a group of MN s that are silenced in sleep, (ii) the reflex pathways are different awake and asleep, and/or (iii) the receptors mediating the reflex responses are less readily stimulated in sleep due to some changes in airway configuration or deformability. These issues remain to be determined.

In studies using more physiological stimuli designed to mimic OSA (i.e. as opposed to square-wave stim­uli), NEG pressures generated by inspiratory resistive loading cause larger increases in V A resistance in non­REM sleep compared to wake, suggesting inadequate UA dilator muscle responses to loading (25,88). In the study by Weigand et al. (25), GG activation was not observed until 60-90 seconds after loading, suggesting that the activation may have been secondary to hy­poventilation and not mediated by UA mechanorecep­tors. Consistent with this, Kuna and Smickley (108) observed only small (5%) increases in GG activity on the first breath following nasal occlusion in non-REM sleep (and no responses in REM), but no activation was observed for the PCA (107). Continuous NEG airway pressure causes short latency increases in GG activity when awake, but no responses in non-REM or REM sleep unless accompanied by hypoxemia (in­duced by hypoventilation) or arousal (102). For palatal muscles, inspiratory loading when awake increases tonic TP activity, a response that occurs on the first breath and persists throughout loading (33). However, this response is absent in non-REM sleep (33). These observations support the concept that sleep reduces re­flex pharyngeal dilator muscle responses to NEG air­way pressure and reduces the ability of the UA to de­fend itself from suction collapse. One of the chief rea­sons for this effect of sleep is probably a major de­crease in the excitability of VA MNs that may effectively disable the reflex responses (see section

Sleep. Vol. 19, No. 10, 1996

Ant. Ethmoidal VI

Pterygo-Palatine v2

(Grt. & Lessor Palatine Brs)

~~ilIA~~'(Pha Brs)

~\-;--GIc)ssc)ph!lryngeal iX

Int. Laryngeal Ext. Laryngeal

(Br of Sup Laryngeal) X

Recurrent Laryngeal (Br of Vagus) X

FIG. 4. Schematic representation of the afferent innervation of the upper airway. Cranial nerves Y, IX, X, and XI are shown. Note that the innervation of the supraglottic larynx is via the internal branch of the superior laryngeal nerve, whereas the subglottic larynx is via the recurrent laryngeal nerve. The glossopharyngeal nerve inner­vates the tonsillar fossa (not shown), the posterior aspect of the tongue, and the posterior pharyngeal wall. Figure adapted from Ref. 266.

IV). However, in the context of the present discussion it should be mentioned that animals appear to have an immediate UA dilator muscle response both awake and asleep (105) whereas humans have an immediate response awake but only a slowly developing response asleep (25,33,88,102,107,108). Although differences between animals and humans in either the sensitivity of reflex VA muscle responses to NEG pressure or the magnitude of the sleep-related influences may account for this effect, it is also possible that animals have larger VA motor responses to the removal of vagal inputs during airway occlusion. The role of the Her­ing-Breuer reflex in affecting UA dilator muscle activ­ity is discussed in section III.

(iii) Afferent mechanisms mediating responses to NEG airway pressure

Problems of interpretation. The complexity of the VA afferent innervation is highlighted in Fig. 4. This complexity highlights the difficulty in assigning the reflex activation of pharyngeal dilator muscles to spe­cific receptors located at specific anatomical sites. It is also unlikely that the stimuli of NEG pressure used in most studies would modulate the activity of a single

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UPPER AIRWAY MOTOR CONTROL 835

receptor type, and some of the receptors involved may also be of mixed modality. With these caveats in mind, it is thought that the reflex responses to UA NEG pres­sure in animals are most likely mediated by mechan­osensitive receptors (93). The receptors and afferent nerves that may be most relevant to reflex pharyngeal dilator muscle responses to NEG airway pressure are discussed below.

Responses from the nasal airway. Trigeminal affer­ents mediate a component of the GG responses to NEG pressure in animals (103,109). The large reduc­tions in GG responses after selective nasopharyngeal anesthesia in humans also suggest a significant role for these afferents (99). Although the anatomical location and morphology of nasal "pressure" receptors are not well identified (110), Tsubone (11l) has shown in­creased discharge in single fibers of the anterior eth­moidal nerve in response to NEG pressure (threshold of -6 cm H20) in rats. Basner et al. (112) have ob­served decreased phasic inspiratory GG and alae nasi activity after selective anesthesia of the nasal mucosa and following diversion of the breathing route from the nasal to the oral cavity. These results are compat­ible with the concept that receptors in the nasal mucosa may mediate UA dilator muscle activation in the pres­ence of nasal inspiratory NEG pressure and/or flow. Such receptors are ideally placed to detect nasal NEG pressures (e.g. caused by increased nasal resistance) and produce compensatory reflex U A dilator muscle activation to prevent airway narrowing in more com­pliant downstream segments.

Responses from the laryngopharynx. In animals (75,109) and humans (99), the internal branches of the superior laryngeal nerve (SLN) mediate an important component of the reflex pharyngeal dilator muscle re­sponses to NEG airway pressure. Respiratory-related afferent activity has been identified in the internal branches of the SLN in the dog with marked increases in activity accompanying changes in transmural pres­sure (113-115). Three types of mechanosensitive end­ings have been identified using single fiber recordings (113); these have been classified as receptors respond­ing to changes in transmural pressure (pressure recep­tors), decreases in temperature (flOW/cold receptors), and the degree of local muscle contraction (drive re­ceptors). The pattern of activity of the pressure recep­tors appears to be most suitable to produce the reflex pharyngeal dilator muscle activation in response to NEG pressure (93,114). Pressure receptors constitute the largest proportion of the laryngeal mechanosensi­tive endings identified in the dog (64%), with most being activated during spontaneous inspiration (65%) and during inspiration against an occluded UA (84%). In cats, laryngeal NEG pressure and the integrity of the SLN are necessary for phasic inspiratory GG ac-

tivation (116). In rabbits, the excitatory effects of pos­itive pressure and the inhibitory effects of NEG pres­sure on the responses of laryngeal pressure receptors (117,118) does not fit well with the observed UA di­lator muscle responses to NEG airway pressure (95). However, the SLN mediate an important component of the reflex GG activation in response to NEG pressure in rabbits (109,119). Therefore, in rabbits, different re­ceptors from those studied above may mediate the GG responses to NEG airway pressure, or the central path­ways may be different from those in cats.

Since the reflex UA dilator muscle responses to NEG pressure are reduced/abolished by topical anes­thesia of the laryngeal mucosa in animals (75,109), the laryngeal pressure receptors mediating these responses are probably located superficially rather than in the intrinsic musculature, ligaments, and joints (110). In­deed, receptors responding to gentle mechanical stim­ulation of the laryngeal epithelium (therefore pre­sumed to be located in the mucosa and submucosa) are promptly affected by topically applied lidocaine (120), whereas the activity of joint receptors is unaf­fected by topical anesthesia (121). In humans, anes­thesia of the internal branches of the SLN renders the laryngeal mucosa insensitive to mechanical stimula­tion and significantly decreases GG responses to NEG airway pressure (99). Laryngeal receptors sensitive to NEG pressure are ideally placed to mediate reflex pha­ryngeal dilator muscle activation in the presence of partial or complete oropharyngeal occlusion and, therefore, may have a potential role in preventing (or terminating) episodes of obstructive apnea.

Responses from the oropharynx. In animals (75,103,109) and humans (99), there is little evidence for glossopharyngeal nerve afferents being of much importance in mediating UA dilator muscle responses to NEG airway pressure. Receptors with afferent fibers in the pharyngeal branches of the glossopharyngeal nerves of the cat have been shown to be activated by NEG and positive pressures (122). However, sections of these nerves augmented, rather than decreased, hy­poglossal motor nerve activity in response to NEG pressure (103), suggesting an inhibitory effect.

There is evidence for the presence of muscle spin­dles in the tongue musculature of primates (123,124). Increased afferent hypoglossal nerve activity has been recorded in response to tongue stretch in the anterior­posterior direction (123,124), suggesting that the GG muscle stretching effects of NEG airway pressure (43) may mediate a component of the reflex responses. The potential role of tongue stretch in mediating GG re­sponses to NEG airway pressure is controversial and needs to be systematically examined. However, indi­rect evidence suggests that the contribution of this mechanism may be minimal. GG responses to NEG

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836 R. L. HORNER

airway pressure are reduced to control levels after complete UA anesthesia, suggesting no residual con­tribution by a stretch reflex (99). Moreover, with sur­face anesthesia, the hypoglossal nerve would not be expected to be anesthetized due to its deep location (125), and tests of motor function suggest that this is the case (99).

Responses from lower larynx. There is evidence in humans that subglottal receptors may mediate a com­ponent of the reflex GG responses to NEG pressure (98,99). However, doubt for this mechanism arises be­cause, in contrast to UA stimuli, NEG pressure applied to the isolated lower airway of subjects with laryn­gectomy does not cause significant GG activation (27). It remains to be determined whether or not extrathor­acic sub-laryngeal receptors can contribute to reflex UA muscle activation to NEG pressure and if these putative subglottal responses are missing in these sub­jects with laryngectomy.

The VA considered as compartments and implica­tions for data interpretation. The receptors and affer­ent nerves mediating reflex UA dilator muscle re­sponses to NEG airway pressure have been discussed from the perspective of separate UA compartments. However, reflexes elicited from different UA com­partments are capable of affecting the entire UA as well as providing local control within a compartment. For instance, van Lunteren et al. (75) have shown that application of NEG pressure to the isolated nasal air­space caused more activation of the alae nasi com­pared to the peA, whereas the opposite pattern of ac­tivation was observed with pressure applied to the iso­lated laryngopharynx. This compartmental property of the UA also has important implications for the inter­pretation of studies designed to interfere with this re­flex using local anesthetics. Interpretation should take into account that anesthesia of one or more UA com­partments will only affect the reflex responses depend­ing on the contribution of that compartment to the total response and the threshold pressures required to elicit a response from the remaining compartments. It should not even be expected that total UA anesthesia will completely abolish the reflex UA muscle responses to NEG pressure because stimuli applied to the outside of the face (e.g. if delivered via a face mask) can itself cause significant responses (98,99). Therefore, ade­quate controls need to be performed to account for this effect (99). With local anesthetics, it is also essential to test for the efficacy of surface anesthesia (99). Fur­thermore, since behavioral responses may interfere with the reflex responses to the pressure stimuli, those components of the reflex that occur with delays com­patible with behavioral responses require additional controls, such as analyzing data before the reaction time for voluntary muscle activation (27,30,31,98,99).

Sleep, Vol. 19, No. 10, 1996

(iv) Is pharyngeal diJator muscle activation by NEG airway pressure relevant to OSA?

In awake humans, the normal UA NEG pressures encountered during resting breathing (typically <2 cm H20; Ref. 126) are smaller than the threshold pressures required to cause significant UA dilator muscle acti­vation. However, DeWeese and Sullivan (127) have shown that topical oropharyngeal and laryngophar­yngeal anesthesia can increase pharyngeal resistance in normal supine subjects, although this did not com­promise breathing during sleep. In contrast, UA an­esthesia increased the frequency of obstructive apneas and hypopneas' in normal sleeping subjects in a study by McNicholas et al. (128), although no subject de­veloped clinically significant OSA or oxygen desatur­ation. Overall, these results suggest that sensation of UA pressure may not be overly critical to preventing OSA in normal subjects.

In contrast to normals, snorers and OSA patients commonly experience large swings in airway pressure when asleep; inspiratory pressures of at least -10 to -40 cm HP are reported (12,129). Such NEG pres­sures are sufficient to produce significant pharyngeal dilator muscle activation (31,98) even during sleep (104). A working hypothesis might be that in addition to increases in central respiratory drive, reflex pharyn­geal dilator muscle responses to such large NEG pres­sures are responsible for keeping the airway open in chronic snorers and limiting the number of obstructive apneas. The increase in apnea index following UA an­esthesia in snorers (130) supports this hypothesis. In this context, the vibration associated with snoring itself may reflexly improve UA stability; small magnitude high frequency oscillations in airway pressure (30 Hz, <1 cm HP) can activate GG (131).

The pressures required to cause UA collapse are less NEG in OSA patients compared to normals and snor­ers without OSA (89-91,132,133). Although this in­creased UA collapsibility may result from the smaller airway of OSA patients (Figs. 1, 2), it may also result from abnormal reflex pharyngeal dilator muscle re­sponses to NEG pressure. At present, the important question of whether patients with OSA have impaired reflex responses to NEG airway pressure has not been directly addressed. However, in contrast to snorers and normal subjects, patients with OSA do not show an increase in apnea index following UA anesthesia (134,135) suggesting that these patients may already have an impaired ability to defend their UA from suc­tion collapse. Patients with OSA show evidence of UA tissue damage (136), edema (137), and reduced UA mucosal sensation (138). These changes may be brought on by the mechanical events associated with nights/years of snoring and repetitive nighttime ob-

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UPPER AIRWAY MOTOR CONTROL 837

structions. These mechanical events may cause periph­eral nerve (139-141) or muscle damage (85) and ul­timately impair the ability of the UA to defend itself from suction collapse. Cala et al. (142) have shown that UA sensory receptors playa role in mediating apnea termination at the beginning of the night in OSA patients, but that their contribution diminishes over­night as the number of apneas progresses. This result suggests that impairment of UA sensation may occur even over the course of a single night in OSA.

The importance of reflex pharyngeal dilator muscle activation by NEG pressure in the pathogenesis of OSA has yet to be determined. As well as possible differences in reflex responses between subjects (e.g. between normals, snorers, and OSA patients) and within subjects (e.g. overnight, across years, and with and without alcohol), the effects of age-related changes in reflex pathways (143) may also be impor­tant for the natural history of OSA. In conclusion, re­flex UA muscle activation by NEG pressure may be of little relevance to the normal maintenance of airway patency due to the relatively small NEG pressures en­countered in normal breathing. However, it is reason­able to postulate that this reflex may prevent airway closure in snorers during sleep who experience larger swings in airway pressure. As such, any impairment of this reflex in snorers, e.g. via any of the mechanisms described above, may result in OSA. The implications of this notion are discussed further in section V.

(III) OTHER PHARYNGEAL REFLEXES RELEVANT TO OSA

(i) Coordinated respiratory responses to NEG airway pressure

NEG airway pressure alters the pattern of breathing in addition to causing UA dilator muscle activation. Pharyngeal NEG pressure in dogs increases inspira­tory time and decreases the rate of rise of diaphragm activity while peak diaphragm activity is unchanged (75). In rabbits, NEG airway pressure increases inspi­ratory and expiratory times (144,145), a response me­diated primarily by the SLN (145). The responses to NEG pressure stimuli in the rabbit depend upon the time of application; stimuli applied in early inspiration transiently inhibit the diaphragm, increase total inspi­ratory time (146) and cause greater UA dilator muscle activation compared to stimuli applied in late inspira­tion (147). In cats, Hwang et al. (103) showed that NEG airway pressure caused no consistent change in respiratory timing. However, increased laryngeal air­way CO2 reflexly augments the GG responses to NEG pressure in this species (116) and slows respiratory frequency (116,148). This effect of CO2 may be rele-

vant to promoting pharyngeal patency as airway CO2

increases during hypopneas and obstructive apneas. In humans, oropharyngeal NEG pressure causes negligi­ble increases in inspiratory time (with no change in other ventilatory variables), suggesting that the oro­pharynx does not makc an important contribution to the response of the respiratory pump muscles to me­chanical loading (149).

Integrated reflex responses to NEG pressure and relevance to pharyngeal patency. The reflex responses to UA NEG pressure in animals (i.e. pharyngeal di­lator muscle activation, increased inspiratory time, and the absence of diaphragm activation) indicates the presence of an integrated feedback mechanism acting to reduce peak inspiratory flow and the pressure de­crease in the pharyngeal compartment and, therefore, to maintain pharyngeal patency. Such integrated re­sponses may also exist in humans. Inspiratory UA NEG pressure applied to tracheostomized sleeping in­fants reduces mean and peak inspiratory airflow (150). In awake adults, continuous NEG airway pressure in­creases inspiratory time and GG activity (102). In an­other study in awake adults, UA NEG pressure also activated GG but not the diaphragm, and no changes in the magnitude or pattern of ventilation were ob­served (26).

(ii) VA muscle responses to the absence of lung inflation during inspiration

The absence of lung inflation during inspiration leads to increased peak phrenic nerve activity (due to increased inspiratory time) but no increase in the rate of rise of phrenic activity (76,151,152). This response is attributed to the removal of inhibitory inputs related to lung stretch (i.e. the Hering-Breuer reflex) since in­creased pulmonary afferent stretch receptor discharge accompanies inspiration with lung inflation, whereas only minor changes in discharge accompanies inspi­ratory efforts against a closed airway (153). Increased peak UA motor nerve activity is also observed during inspiration without lung inflation, a response that has been attributed to the removal of vagally mediated in­hibition of UA MNs (76,151,152). Inspiration with lung inflation reduces the inspiratory activity in a va­riety of UA nerves and muscles (79,154). Some UA muscles (e.g. the sternohyoid in the dog, Ref. 49) may not even exhibit any inspiratory-related activity before vagotomy due to strong vagal inhibition. As such, this effect needs to be taken into account in describing any respiratory-related modulation of UA muscles. In anesthetized cats, vagal activity exerts an inhibitory effect on the GG responses to NEG pressure although this can be over-ridden by increased chemoreceptor drive (155).

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838 R. L. HORNER

Relevance to OSA. A vag ally-mediated inhibition of UA dilator muscle activity during lung inflation (or rather a dis-inhibition of this activity in the absence of lung inflation) has potential relevance to OSA. During OSA, the obstructed UA prevents chest wall expansion during inspiration, and such a mechanism may activate pharyngeal dilator muscles and promote UA patency. However, in humans, there is little evidence in support of an important role of the vagus nerves in modulating respiratory timing either during resting breathing (156) or during lung inflation in the tidal volume range (157,158). For UA dilator muscles, the responses to airway occlusion in sleep are minimal in the absence of significant pressure changes and chemoreceptor stimulation (107,108). However, although this may be taken to suggest that a reduction in vagally mediated inhibition of UA dilator muscles plays a minimal role in their activation during airway occlusion when asleep, the potential role of vagal inputs in controlling UA dilator muscle activity awake and asleep has not been well characterized in humans.

(iii) VA muscle responses to increased chemoreceptor drive

Chemoreceptor stimulation activates the muscles of the respiratory pump awake and asleep causing in­creased ventilation. Chemoreceptor stimulation also activates a variety of UA dilator muscles (79,159). Chemoreceptor-mediated UA dilator muscle activation is relevant to OSA because hypercapnia and hypoxia develop during apneas, and UA dilator muscle acti­vation by changes in blood gases may potentially con­tribute to the relief of the obstruction. In animals, pref­erential activation of UA dilator muscles (with respect to the diaphragm) often accompanies chemostimula­tion (79). However, much of the evidence relating to the preferential activation of UA muscles is based upon experiments performed in reduced preparations, and there is debate as to whether these responses are due to the peculiarities associated with anesthesia, de­cerebration, or species differences (see Ref. 79 for re­view). With this caveat in mind, increased chemore­ceptor drive increases hypoglossal activity more than phrenic in the chloralose anesthetized (160), awake (161), and sleeping (162) cat but increases hypoglossal activity in proportion to the phrenic in decerebrate cats (163). In awake humans, alae nasi, GG, and PCA ac­tivities all increase with chemoreceptor activation. However, these changes occur "in proportion" to in­creases in ventilation and diaphragm activity, suggest­ing that UA muscles are not preferentially activated with respect to those of the respiratory pump (77,79,164). Similar responses have also been ob­served in sleeping infants (165). However, in infants,

Sleep, Vol. 19, No. 10, 1996

the CO2 threshold for UA dilator muscle activation is higher than that for the diaphragm (165). Oral diaze­pam decreases GG activity during CO2 re-breathing "out of proportion" to the decreased tidal volume (166), and alcohol has similar effects (167).

Overall implications for OSA. An effect of sleep on the setpoint and/or slope of the UA dilator muscle re­sponses to CO2 may be an important factor contrib­uting to the maintenance of airway patency. For ex­ample, the CO2 at sleep onset may initially be too low for UA dilator muscle activation if (as in infants) these muscles have a higher setpoint for activation than does the diaphragm. This difference in setpoint and initial mismatch in CO2 driven muscle activation may lead to UA instability predisposing to OSA. Such a mech­anism may explain why obstructive apneas are more frequent in light compared to deep non-REM sleep (168,169) when the CO2 at sleep onset is transiently lower compared to established sleep (170) and less UA dilator muscle activation may occur (171). A prefer­ential decrease in the excitability of UA MNs at sleep onset (169,172-174) may explain such a change in set point; the central neural mechanisms that may mediate such an effect of sleep are discussed in section IV.

In contrast to the importance of a potential change in setpoint at sleep onset favoring UA obstruction, if similar degrees of UA and diaphragm activation occur with chemostimulation throughout an obstructive ap­nea (i.e. the slope of the responses are the same), then this would appear not to be an important mechanism favoring termination of a UA obstruction. However, during OSA, the additional excitatory inputs to UA MNs (e.g. resulting from NEG airway pressure and reduced vagal inhibition) may be expected to cause additional pharyngeal dilator muscle activation (155,175). However, it appears that the potential for preferential UA dilator muscle activation by the phys­iological stimuli normally present during OSA may not be realized. In sleeping humans, GG activity in­creases in proportion with diaphragm activity during airway occlusions (108,164), and only at arousal are large increases in GG activity observed (102,108). In addition, UA closing pressures do not change over successive breaths of an obstructive apnea (89,91), in­dicating no preferential UA dilator muscle activation. These data suggest that although the physiological stimuli that develop during obstructive apneas can all reflexly activate UA dilator muscles, this activation is not enough to preferentially stimulate these muscles and re-establish airway patency before arousal. Since physiological monitoring of OSA patients almost in­variably shows an association between apnea termi­nation and arousal (12,168) then arousal per se may be necessary for relief of obstruction since the other protective mechanisms are insufficient.

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UPPER AIRWAY MOTOR CONTROL 839

(iv) Other inputs

Baroreceptor reflexes. Obstructive apneas are asso­ciated with increases in blood pressure during airway occlusion, with further increases accompanying arous­al from sleep and relief of obstruction (10). Increases in blood pressure are associated with a baroreceptor­mediated inhibition of respiratory-related hypoglossal nerve activity in anesthetized and decerebrate animals (176,177) and reductions in GG activity in awake hu­mans (178). This reflex may be relevant to OSA since the blood pressure increases caused by obstructive ap­neas may inhibit VA dilator muscle activity and pre­dispose to subsequent apneas. The significance of this inhibitory mechanism remains to be determined. How­ever, an important role for this reflex in affecting UA mechanics has been questioned because increases in carotid sinus pressure cause minimal changes in UA resistance in awake and sleeping dogs (179).

Jaw opening. Animal and human studies (see Ref. 180 for review) have shown that passive alterations in mandibular position cause changes in GG activity, with increases in GG activity accompanying jaw open­ing. A significant part of this reflex appears to be me­diated by receptors in the temporomandibular joint (180), with temporomandibular joint nerve stimulation leading to activation of hypoglossal MNs (124,181). This reflex may be involved in increasing UA size to compensate for the airway narrowing effect of jaw opening (180).

(IV) CENTRAL NEURAL MECHANISMS AFFECTING UPPER AIRWAY MOTOR

OUTPUT

It has been emphasized throughout this review that sleep has major effects on UA motor activity and re­flex mechanisms, and, in certain individuals, these ef­fects of sleep can predispose one to OSA. In this sec­tion, some of the central neural circuits and neurotrans­mitters involved in modulating motor output to the or­opharyngeal muscles, and the state-dependency of these circuits, are discussed. This section is not meant to provide a comprehensive review of the central ef­fects of sleep on respiratory motor activity; for in­-depth reviews of the effects of sleep on the control of breathing, the reader is referred to some excellent articles (169,170,172-174,182).

(i) UA motor nuclei and their pre-motor inputs

Orofacial motor nuclei share many common pre­motor inputs (183,184). Some of these inputs may be involved in synchronizing activation or inactivation in groups of orofacial MNs in a variety of behaviors. In

particular, a selection of these common pre-motor in­puts may be relevant to state-dependent control of the excitability of orofacial MNs. One major requirement for pre-motor systems relevant to the state-dependent control of MNs is that the pre-motor system itself must show state-dependence. Application of this criterion suggests that state-dependent control of UA MNs may originate from (i) neurons of the locus coeruleus (LC) complex, (ii) caudal raphe neurons (nuclei raphe ob­scurus, pallidus, and magnus), (iii) cholinergic neurons of the mesopontine tegmentum (pedunculopontine and laterodorsal tegmental nuclei), and/or (iv) the medul­lary reticular formation (see Refs. 173, 174, 182, 185-191 for reviews and discussion on the state-dependen­cy of these neuronal groups).

Both inhibitory and disfacilitatory (i.e. reduced ex­citation) state-dependent effects could account for de­creased UA MN activity in sleep. However, with re­spect to motor activity in REM sleep, it has been sug­gested that the mechanisms mediating hypotonia may be different for oropharyngeal MN s compared to pos­tural lumbar MNs. In carbachol-induced REM sleep­like atonia (see below for description of this model), the hypotonia of lumbar postural MNs appears to be mediated primarily by post-synaptic inhibition (involv­ing the inhibitory amino acid glycine) that has the same characteristics as the inhibition observed in nat­ural REM sleep (192). Neurons in the medullary re­ticular formation are thought to drive this inhibition, themselves being driven by neurons in the medial pon­tine reticular formation and the mesopontine tegmen­tum (see Refs. 188-191 for reviews). However, unlike lumbar MNs, there is little evidence for post-synaptic inhibition mediated by inhibitory amino acids (glycine or GABA) in the depression of hypoglossal activity in carbachol induced REM sleep-like atonia (193). Post­synaptic inhibitory mechanisms may playa role in the REM-related suppression of trigeminal MNs (194,195). For hypoglossal MNs, emphasis has re­cently been placed on the potential role of disfacilita­tion mediated through the caudal raphe and LC neu­rons. These nuclei provide an important source of the serotonin (5HT), thyrotropin-releasing hormone (TRH), substance P, and noradrenergic inputs to the hypoglossal and motor trigeminal nuclei that contain receptors for these neurotransmitters (196-203). The potential roles of state-dependent disfacilitatory and/or inhibitory processes in the sleep-related hypotonia of UA dilator muscles are discussed below.

(ii) Caudal raphe and LC inputs to oropharyngeal MNs

Serotonergic caudal raphe neurons show state-de­pendent activity with discharge declining from wake

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840 R. L. HORNER

to non-REM sleep, with minimal firing in REM (185,204-207). Caudal raphe neurons project densely to brain-stem and spinal MN pools and are thought to modulate motor output at their target sites (185). These raphe neurons also project to the hypoglossal (196,208) and motor trigeminal nuclei (197) and pro­vide a major source of the 5HT inputs to these sites (197,209,210). The caudal raphe nuclei exclusively provide the 5HT inputs to the hypoglossal nucleus (209,210). Serotonin exerts a tonic facilitatory effect on hypoglossal MNs, with 5HT1C/2-like receptors me­diating the responses (211); similar receptors have been implicated in the excitation of facial MNs by 5HT (212-214). In vitro studies using neonatal tissue slices have shown that 5HT depolarizes hypoglossal MNs and increases the slope of the relationship be­tween firing frequency and injected current (215). 5HT also exerts a facilitatory effect on trigeminal (216,217) and laryngeal MNs (218). In many caudal raphe neu­rons both- TRH and substance P are co-localized with 5HT (219,220), and these neurotransmitters are also excitatory to hypoglossal and spinal MNs (221-223). Taken together, these observations provide a mecha­nism by which sleep-related decreases in the activity of caudal raphe serotonergic neurons may lead to sleep-related decreases in the excitation (and a relative hyperpolarization) of UA dilator MNs. Fibers origi­nating from the ventromedial and ventrolateral por­tions of the hypoglossal nucleus innervate the GG and geniohyoid muscles, respectively (224-227). The rel­atively high concentration of receptors for 5HT, TRH, and substance P in the ventromedial subnuclei of the hypoglossus, compared to the ventrolateral subnuclei, also suggests that GG MNs may receive more caudal raphe terminals and/or may be more responsive to a withdrawal of these excitatory neurotransmitters in sleep (203).

Noradrenergic neurons of the LC and the dorsolat­eral pons also show state-dependent activity with dis­charge declining from wake to non-REM sleep with minimal firing in REM and large transient increases in activity occurring with alerting stimuli (187,228). LC noradrenergic neurons project widely throughout the central nervous system and are thought to enhance synaptic transmission at their target sites (229). LC neurons project to the hypoglossal and motor trigem­inal nuclei (183,198,199), and noradrenaline increases the excitability of hypoglossal (230) and trigeminal MNs (231). The depolarizing effect of noradrenaline on neonatal hypoglossal MNs in vitro is mediated by (Xl-adrenoreceptors (230) and, as with 5HT (215), nor­adrenaline increases the slope of the relationship be­tween firing frequency and injected current (230).

Implications for the effects of sleep on VA MNs. The decrements in caudal raphe and LC neuronal discharge

Sleep. Vol. 19, No. 10, 1996

in sleep (particularly REM sleep) and the consequent withdrawal of the excitatory effects of 5HT, as well as TRH, substance P, and noradrenaline on UA dilator MNs, is an attractive hypothesis to explain (at least in part) the relative hypotonia of pharyngeal dilator mus­cles in sleep, especially REM (197,211). That 5HT and noradrenaline both facilitate MN excitability (see Refs. 185,229 for reviews), in part by increasing membrane resistance, and, therefore, the slope of the relationship between firing frequency and injected current (215,230) also implies that withdrawal of these neu­rotransmitters would lead to decreased UA MN firing in response to excitatory inputs. Such an effect may be involved in the sleep-related reductions in UA di­lator muscle tone and reflex responses.

The discussion above highlights that there is appro­priate circuitry for state-dependent discharge of caudal raphe and LC neurons to affect UA motor activity. However, much of the validation of the hypothesis re­garding the state-dependence of hypoglossal output and the role of 5HT from the caudal raphe has come from work using reduced animal preparations. In de­cerebrate animals, microinjection of a cholinergic ag­onist (e.g. carbachol) into the pons evokes a state hav­ing most of the cardinal signs of REM sleep (for re­views see Refs. 182, 186). In particular, postural aton­ia, eye movements, ponto-geniculo-occipital waves, and a differential suppression of motor output to re­spiratory pump and UA muscles is produced, i.e. the U A muscles are more affected than those of the re­spiratory pump (182,186,232-234). Some of these changes indicative of REM sleep also occur in chron­ically instrumented (i.e. nondecerebrate) animals after carbachol (182). The carbachol induced REM sleep­like state is associated with decreased discharge of pu­tative serotonergic caudal raphe neurons having iden­tified axonal projections to the hypoglossal nucleus (Fig,S). This is similar to the behavior of caudal raphe cells in natural REM sleep (185,204-206). The car­bachol-induced REM sleep-like atonia also decreases 5HT in the hypoglossal nucleus as measured by mi­crodialysis (235). Application of exogenous 5HT to the hypoglossal nucleus can significantly reduce the suppression of hypoglossal activity in the carbachol­induced REM-like state (236). This, together with the demonstration that hypoglossal MNs are normally the subject of an endogenous serotonergic excitatory drive (211), has been taken to suggest that a withdrawal of 5HT has an important role in contributing to REM­related GG hypotonia.

The advantages of the carbachol model for the study of the state-dependence of UA motor output are that it allows for easier and better controlled use of neuro­physiological techniques than that possible in intact chronic animals and the application of neurochemicals

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UPPER AIRWAY MOTOR CONTROL 841

RAPHE CELL

FIRING RATE

XII

C4

,......, N :J: ~

w I-~ Ck:

C) Z Ck:

i: z ~ w ~

12.5

Hz ~ __ n-__ ~ ______ __

CARB. 0.46 1-'9

3

2

0

CONTROL CARB. RECOVERY 8-0H-DPAT

FIG. 5. The top panel shows that carbachol induced REM sleep-like atonia is associated with decreased discharge of caudal raphe neurons having identified axonal projections to the hypoglossal nucleus. Note that the change in caudal raphe firing rate parallels the suppression of motor activities. Signals from the top are: extracellularly recorded action potentials from the raphe cell, cell firing rate in successive 10 second bins, moving average of hypoglossal (XII) nerve activity (recorded from genioglossal branch), and moving average of the postural activity in a branch of the fourth cervical nerve (C4). The bottom panel shows the mean firing rates of 13 caudal raphe neurons projecting to the hypoglossal nucleus. All these cells show decreased discharge in the presence of carbachol induced REM sleep-like atonia. A return of activity following recovery from the atonia was observed in seven of seven cells. The serotonergic nature of these caudal raphe neurons is indicated by their inhibition following systemic administration of the serotonergic lA receptor agonist (::+:)8-hydroxy-2-(di-N-propylam­ino)tetrealin hydrobromide (8-0H-DPAT). Figure adapted, with permission, from Ref. 208.

to specific brain nuclei under controlled conditions. An­other advantage is that central state effects can be dis­sociated from compensatory reflex mechanisms because experiments are performed in artificially ventilated an­imals (see Refs. 186, 237, 238 for discussion). How­ever, the clear disadvantage of the carbachol preparation is that normal sleep is not present. Moreover, carbachol injected cats lack the characteristic large variability in respiration, acceleration of respiratory rate, and in­creased medullary respiratory neuronal activity (233,237) observed in normal cats in natural REM (174,239). Therefore, certain important components of respiratory changes in REM are missing in the car­bachol model that may have important implications (see

Refs. 173, 174, 186 and next section for further dis­cussion). Nevertheless, studies utilizing this model have provided some important insights into the brain-stem circuits and the neurotransmitters that may be 'involved in the state-dependence of VA motor output.

(iii) Natural sleep and medullary respiratory neuronal activity

State-dependent discharge of neurons compnsmg the brain-stem reticular formation are thought to be involved in the state-related modulation of medullary respiratory neuronal activity and respiratory output (see Refs. 172-174 for reviews). Neurons of the brain-

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842 R. L. HORNER

stem reticular formation system generally show de­creased activity in non-REM sleep compared to wake, with increased activity in REM (172-174,188,189). In anesthetized or decerebrate animals, electrical stimu­lation of the midbrain reticular formation can convert the activity of several respiratory muscles or motor nerves from a sleep-like pattern to one more like wake (173,174,240,241). Moreover, midbrain reticular stim­ulation preferentially activates the peA (174,240) and causes greater activation of hypoglossal and trigeminal motor nerves compared to the phrenic (241). These data suggest that UA MNs may be more dependant upon, or responsive to, reticular mechanisms for their activation than are diaphragmatic MNs. This might ex­plain the susceptibility of UA muscles to the effects of non-REM sleep (172-174,242) and anesthetics (243).

In unanesthetized intact animals, medullary respi­ratory neurons show characteristic changes in activity with changes in sleep-wake state. In particular, the studies conducted by Orem and colleagues have shown that respiratory-related neurons that are more tonically active during wakefulness show decreased discharge in non-REM sleep, whereas cells with a strong respi­ratory-related phasic discharge, that is presumably tightly coupled to the respiratory rhythm generator, re­main active (173,174,244). It has been postulated that the tonic (nonrespiratory) input to medullary respira­tory neurons when awake (the "wakefulness stimu­lus") arises from the reticular formation (see Refs. 173, 174 for reviews). That stimulation of this region facilitates respiratory output and UA motor activity (see discussion above and review in Refs. 173, 174) supports this concept.

In natural REM sleep in cats, the level of medullary respiratory neuronal activity is greater than in non­REM (174,239,245) although there is considerable variation around the mean level of discharge in REM associated with tonic and phasic events (239). How­ever, this overall increased medullary respiratory neu­ronal discharge in natural REM sleep conflicts with the observations in the carbachol induced REM-like state in the decerebrate cat where such activity is de­creased after carbachol (233). It has been argued that the REM-like state produced by pontine carbachol likely produces a simultaneous, powerful, and long­lasting activation of the majority of cholinoceptive neurons (186,237). Since the reductions in respiratory rate that follow pontine carbachol are positively cor­related with the amount of acetylcholine released into the pontine tegmentum contralateral to carbachol in­jection (182,246), then any such intense activation of cholinoceptive neurons in the REM-like state after car­bachol may produce a shift toward lower activity in the spectrum of medullary respiratory neuronal dis-

Sleep. Vol. 19, No. 10, 1996

charge. This mechanism, coupled with the arguments that it is unlikely that all such cholinoceptive neurons are simultaneously active in natural REM sleep and that compensatory changes in respiratory neuronal ac­tivity in response to changes in blood gases and re­spiratory volume do not occur in the decerebrate mod­el, have been used to account for discrepancies in re­spiratory activity between natural REM and the car­bachol induced REM-like state (186,237). However, it has been stressed that one of the most important im­plications of the observation that medullary respiratory neuronal activity is increased in natural REM sleep is that the cause of the respiratory muscle depression in REM (e.g. UA and intercostal muscle hypotonia) can­not be a respiratory MN disfacilitation as a result of inactivation of medullary respiratory neurons (174). In contrast, it has been proposed that to explain the hy­potonia it is necessary to invoke a scheme in which the excitatory drive to medullary respiratory neurons by REM sleep is cancelled out by opposing inhibitory influences acting at the level of the MN (174,247). Such a scheme has been used to account for the effects of REM sleep on phrenic MN s (247, and Fig. 13-13 of Ref. 174). As mentioned previously, the hypotonia of postural lumbar MNs is thought to be mediated pri­marily by postsynaptic glycinergic inhibition (192). For UA MNs, postsynaptic inhibitory mechanisms are thought to playa part in the REM-related suppression of trigeminal MN activity (194,195), but for hypo­glossal MNs more emphasis has recently been placed on disfacilitation (as discussed above) because of the minimal role of postsynaptic inhibitory mechanisms in the carbachol induced REM-like state (193). However, glycine immunoreactive fibers have been identified around hypoglossal MNs as well as trigeminal MNs (248,249) and short-lasting inhibitory postsynaptic po­tentials that are sensitive to applied strychnine have been recorded in hypoglossal MNs (250). These data suggest that, as with other MNs, there is the potential for hypoglossal MNs to be affected by postsynaptic inhibitory mechanisms in natural REM sleep resulting in hypotonia (172,174,248). However, the relative im­portance of disfacilitation versus postsynaptic inhibi­tion of UA MNs in natural REM sleep and whether the relative importance of these mechanisms differs between groups of MNs (e.g. between hypoglossal, tri­geminal, laryngeal, intercostal, and phrenic) has yet to be determined.

(iv) State-dependent transmission of sensory inputs to UA MNs

The central projections and connections of the UA afferent nerves responsible for the reflex activation of hypoglossal MNs has been reviewed by Lowe

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UPPER AIRWAY MOTOR CONTROL 843

(124,180). SLN and glossopharyngeal inputs are thought to reach the hypoglossal nucleus via the nu­cleus of the solitary tract, whereas trigeminal inputs reach the hypoglossal nucleus via the sensory trigem­inal nucleus (124,180). The SLN carry a significant component of the afferent input mediating UA dilator muscle responses to NEG pressure (99,109, see sec­tion II). Serotonergic caudal raphe neurons project to the viscerosensory nucleus of the solitary tract (251), including those that are suppressed during the car­bachol-induced atonia (208). Thus, they have the po­tential to modulate synaptic transmission through the sensory relays (252) in a state-dependent manner (208). However, the specific sites, receptors, and neu­rons for such a potential state-related modulation of UA sensory inputs have yet to be determined. Syn­aptic transmission through the trigeminal sensory nu­cleus is reduced in REM sleep and postsynaptic in­hibition may playa role in this effect (253). In sum­mary, these observations suggest that, in addition to state-dependent mechanisms postsynaptically affect­ing the excitability of (and the output from) UA MNs, state-dependent mechanisms acting at different pre­motor levels may also affect the input to these MN s and influence UA dilator muscle tone and reflex re­sponses. However, the pathways by which sleep can affect reflexes relevant to UA patency have yet to be determined.

(v) Central mechanisms and implications for OSA

Understanding the brain-stem mechanisms and neurotransmitters involved in the control of UA di­lator muscle activity and reflex responses awake and asleep has important clinical implications. Determi­nation of these basic mechanisms may ultimately guide pharmacological approaches to improve UA stability, minimize sleep-related hypotonia, and pre­vent OSA. In this respect, it has recently been dem­onstrated that a systemic administration of 5HT an­tagonist in an animal model of OSA significantly re­duces VA dilator muscle activity and pharyngeal cross-sectional areas (254). This result supports the concept that serotonergic mechanisms may be in­volved, at least in part, in the maintenance of UA patency and may have a role in OSA. However, al­though it has been demonstrated that administration of fluoxetine (a 5HT re-uptake blocker) and L-tryp­tophan (a metabolic precursor of 5HT) reduces the apnea/hypopnea index in patients with OSA, the mag­nitude of the observed effects was only modest (255,256). This result highlights the need to deter­mine if the serotonergic mechanisms observed in the reduced preparation are operative and relevant in nor-

mally sleeping animals and humans and if these mechanisms have relevance to OSA. An attempt to increase oropharyngeal muscle tone with strychnine in a patient with OSA, to counteract putative glyci­nergic inhibition of oropharyngeal MNs in sleep, has also met with only limited success, but increases in TP and GG muscle activity were observed after strychnine (257). These results highlight that further work is needed to determine the potential roles, and synergistic effects, of the neurotransmitters that have been shown to affect UA .MN activity in vivo and in vitro and to determine their relevance in improving oropharyngeal muscle tone and UA stability in nat­ural sleep. Furthermore, since some of the neurotrans­mitters described above can also affect the output to respiratory pump as well as UA muscles, then sys­temic administration of these agents may increase pump muscle activity thereby negating some of the beneficial effects of increased UA dilator muscle tone. Therefore, further therapeutic potential may be gained by specifically targeting receptors located on UA MNs by using agents that are specific to partic­ular receptor subtypes and/or by targeting the MNs of the pharyngeal muscles most relevant to the main­tenance of airway patency and most susceptible to the effects of sleep.

(V) SUMMARY AND OVERALL IMPLICA TIONS FOR OSA

In previous sections, the respiratory function and reflex control of the pharyngeal dilator muscles awake and asleep were reviewed, and the central neu­ral circuits and neurotransmitters that may be in­volved in affecting motor output to the VA in a state­dependent fashion were examined. In each section, the immediate relevance of those basic mechanisms to the maintenance of UA patency and OSA were discussed. In this final section, selected issues rele­vant to the pathogenesis of OSA are discussed and unresolved issues are highlighted.

(i) General scheme for the effects of UA muscle activity on pharyngeal mechanics and the implications for OSA

UA narrowing, sleep-related pharyngeal muscle hypotonia, and the inspiratory pressures generated by respiratory pump muscles have been identified for many years by many authors (e.g. 12,92,169) as im­portant factors in the pathogenesis of OSA. However, recent data (discussed in section I) which suggest that there are profound within-breath changes in airway size, particularly in OSA patients, and that orophar-

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844 R. L. HORNER

yngeal muscle activation increases VA stability by a major effect on airway size rather than wall stiffness, allow for a more generalized model to illustrate the importance of VA muscle activity on the mechanics of the VA and the implications for OSA. As discussed in section I, OSA patients generally have a smaller VA than subjects without OSA, particularly in the region posterior to the soft palate. On the VA pres­sure-volume relationship, this anatomical situation immediately places OSA patients downwards and to the right of the curve for normal subjects and predis­poses them to VA collapse by smaller NEG pressures (Fig. 6A). However, there are large within-breath changes in VA size; the VA is of minimal size at end­expiration in OSA patients and this is particularly ap­parent in the critical region posterior to the soft palate (Fig. 2, Refs. 44, 45). This result is important because this small airway size at end-expiration in OSA pa­tients positions the VA pressure-volume curve even closer to a region where airway collapse can occur with minimal NEG inspiratory pressures generated by the respiratory pump muscles. It is established that inspiratory activation of the pharyngeal muscles counteracts the potential for VA collapse in a nar­rowed airway (e.g. 12,92,169). However, as dis­cussed, most evidence so far suggests that this oro­pharyngeal muscle activation increases VA stability by a major effect on airway size rather than wall stiff­ness (see section I). This effect implies that within an individual, pharyngeal muscle activation (e.g. due to wakefulness, inspiration, or reflex responses) can be viewed as improving VA stability by shifting the po­sition of the VA pressure-volume relationship up­wards and to the left, whereas decreases in pharyn­geal muscle activity (e.g. due to sleep, especially REM, anesthesia, alcohol, or benzodiazepines) can be viewed as having the opposite effect leading to de­creased VA stability (Fig. 6B). In individuals with already small VAs (particularly at end-expiration), any such decreases in VA dilator muscle activity would move the VA pressure-volume relationship into the critical region where the airway can close at minimal inspiratory NEG pressures or even at pres­sures above atmospheric (Fig. 6B). The reduction of VA muscle activity with benzodiazepines (166,258) and the less NEG closing pressures after alcohol (89) are consistent with the increased tendency to develop OSA with these substances (259-261). By consider­ing the effects of changes in VA muscle activity in this general scheme of VA pressure-volume relation­ships, the important interaction between airway size and pharyngeal muscle activity, and the implications for the maintenance of airway patency and the patho­genesis of OSA, are readily apparent. Some important issues relevant to this notion are discussed below.

Sleep. Vol. 19, No. 10, 1996

(ii) Wakefulness-dependent compensatory VA muscle activation in OSA patients

The discussion above highlights that VA size at end­expiration is critical in determining the position of in­dividuals on the VA pressure-volume relationship and their vulnerability to airway collapse by NEG pressure on the next inspiration (Fig. 6A). It is also clear that respiratory activation of VA dilator muscles is impor­tant in OSA patients because this keeps them away from the critical region on the VA pressure-volume relationship where airway collapse can easily occur (Fig. 6B). It appears that OSA patients have responded to this increased dependency on VA dilator muscle activity by increasing the respiratory activation of these muscles when awake (70). Awake animals with OSA show the same response (84). However, this compensatory VA response in OSA patients is clearly state-dependent because it is lost at sleep onset, and VA closure occurs (Fig. 6C). With respect to under­standing the pathogenesis of OSA, it is important to determine the mechanism(s) underlying the increased drive to the VA dilator muscles in awake patients and the neurochemical basis of the state dependence. How­ever, at present, these mechanisms are unknown. It is possible that the increased drive to the VA dilator mus­cles in awake OSA patients results from larger NEG pressures encountered in their narrower airways during inspiration. This hypothesis is initially attractive be­cause it is known that the NEG pressure-VA dilator muscle reflex is state dependent (100,10 1,104,105). However, as discussed in section II, the NEG pressures encountered during awake inspiration appear insuffi­cient to cause significant VA dilator muscle activation, and, therefore, this mechanism is unlikely to be re­sponsible for the large amount of VA muscle activity in awake OSA patients. This mechanism becomes more unlikely when one considers that this reflex may even be impaired in OSA patients because of the ap­parently adverse effects of obstructive apneas on the VA mucosa (see section II). It remains to be deter­mined whether the increased drive to the VA dilator muscles in awake OSA patients is the result of a learned (behavioral) response when awake or whether it is an adaption resulting from the abnormal pattern of VA muscle activation experienced when asleep (i.e. progressive recruitment during apneas and excessive activation at arousal). A recent study has shown that repetitive carotid sinus nerve stimulation in anesthe­tized cats can cause long-term facilitation of alae nasi and GG activities (262) in addition to the well-docu­mented facilitation of diaphragm output (263). Of ma­jor relevance, this long-term facilitation of VA mus­cles was greater than for the diaphragm, and persisted for at least 90 minutes poststimulation (262). It is in-

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UPPER AIRWAY MOTOR CONTROL

A Volume (ml) 30

B

-20 A,

o

-10

B Volume (ml) 30

t UA muscle activity: e.g. wake, inspiration, " 20 NEG pressure reflex, hypoxia, hypercapnia.

-20 -10

o

-10

c Volume (ml) 30

20

-20 -10

o

-10

Wake - Normal

Wake - OSA

Critical region for UA collapse ~ with minimal NEG pressure

10

10

20

Pressure (cmH20)

t UA muscle activity: e.g. sleep (particularly REM), expiration, anesthesia, alcohol, benzodiazepines.

20 Pressure (cmH20)

Wake - OSA

Sleep - OSA

Loss of wakefulness-dependent compensatory UA muscle activity

10 20 Pressure (cmH20)

845

FIG. 6. Schema to illustrate the general interactions between VA size and pharyngeal dilator muscle activity and the implications for the maintenance of airway patency and the pathogenesis of OSA. Panel A shows that the smaller resting VA size in OSA patients (A) compared to normals (B) predisposes the pharynx of OSA patients to collapse by smaller NEG pressures (AI versus Bl)' Panel B shows that because changes in VA muscle activity have a major effect on airway size rather than wall stiffness, then any increases in VA muscle activity will shift the pharyngeal pressure-volume relationship upwards and to the left and make VA closing pressures more NEG for a given level of muscle activation. Any decreases in VA muscle activity will have the opposite effect. Panel C shows that in awake OSA patients, oropharyngeal muscle activation maintains a level of airway volume that is sufficient to maintain airway patency at typical inspiratory pressures. However, loss of this wakefulness-dependent mechanism at sleep onset allows VA closure at minimal inspiratory pressures or even at pressures above atmospheric (the critical region for VA collapse with minimal inspiratory pressures is represented by the shaded region). See text for further details and Fig. 1 for additional explanation of the UA pressure-volume relationship and abbreviations.

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846 R. L. HORNER

teresting to speculate if this type of response is also relevant to the increased UA muscle activation ob­served in OSA patients. Ultimately, understanding the mechanism(s) underlying the increased drive to the UA dilator muscles in awake OSA patients and deter­mining the neurochemical basis of the state depen­dence has important implications for understanding the neural substrate of the "wakefulness stimulus" to the UA dilator muscles (which is critical in OSA patients, Fig. 6C) and for guiding possible pharmacological strategies to prevent the loss of this compensatory mechanism at sleep onset. As such, determining the neurochemical substrate for the sleep-related hypoton­ia of the UA muscles most critical to airway collapse becomes important (see section IV), as is determining whether there is a predominant effect of disfacilitation or postsynaptic inhibition of UA dilator MNs in REM sleep and whether these effects differ between differ­ent groups of MNs (e.g. between hypoglossal, trigem­inal, and respiratory pump MNs).

(iii) What role may VA reflexes to NEG airway pressure play in the pathogenesis and natural history of OSA?

The reflex activation of UA dilator muscles by NEG airway pressure has received much attention in recent years. The presence of this reflex response has given rise to the concepts that sensory feedback from the UA acts in concert with central respiratory drive to activate UA dilator muscles, and that this reflex plays an im­portant role in maintaining, or re-establishing, pharyn­geal patency in the presence of airway collapsing forc­es (93,94). The literature relevant to this reflex in hu­mans was reviewed in section II. However, based on these data, it was concluded that this reflex may not be overly important in the normal maintenance of air­way patency because of the relatively small NEG pres­sures encountered during inspiration. At the end of section III it was also concluded that in OSA, UA reflexes generally cause insufficient pharyngeal dilator muscle activation to re-establish airway patency, and that arousal from sleep is more critical to terminate obstructive apneas. Given these considerations, what role (if any) may UA reflexes to NEG airway pressure play in the pathogenesis and natural history of OSA?

Unlike normal subjects, the large NEG pressures en­countered during inspiration in snorers are sufficient to cause significant UA dilator muscle activation even during sleep. In snorers, this reflex response, in addi­tion to central respiratory activation, may be enough to maintain airway patency and prevent OSA (dis­cussed in section II). However, the magnitude of reflex pharyngeal dilator muscle activation to NEG airway pressure shows inherent differences between subjects

Sleep. Vol. 19. No. 10. 1996

that are consistent within and across days (98). In ad­dition to inherent differences in airway size, this may help explain the variability between subjects in UA collapsibility in the presence of NEG airway pressure (25). However, in the context of the present discussion, this observation also suggests that in the presence of NEG airway pressure those individuals with small UA reflex responses may be more prone to develop an ob­structive apnea or hypopnea, while those inafviduals with larger UA reflex responses may be better able to keep a more patent airway.

Several models and flow diagrams have been put forward to illustrate the various factors which can af­fect the UA and create a bias toward airway collapse in OSA patients (e.g. 12,92,169). For the generation of an obstructive apnea, such models have stressed the major importance of anatomical factors in producing airway narrowing and the effects of sleep on U A mo­tor activity compared to respiratory pump activity. Al­though the mechanisms underlying these issues have been better defined over the years, the major relevance of these concepts in the development of obstructive apneas have stood the test of time. However, a ques­tion of major importance relating to the pathogenesis of OSA is the natural history of this disorder and whether or not occasional snorers become chronic snorers who then develop worsening hypopneas and OSA over time (264). Previous models do not ade­quately address this issue because they generally con­sider the factors affecting UA collapse in patients with existing OSA. Given the paucity of longitudinal studies in sleep and breathing, the natural history of OSA is elusive and is a topic of debate. One testable hypothesis that follows from the previous discussions is that in the presence of a significant UA NEG airway pressure for any reason (e.g. because of a high-nasal resistance), any decrement in reflex pharyngeal dilator muscle activa­tion would lead to an increased tendency to develop hypopneas and OSA, and that individuals with already small UA reflex responses would be most susceptible (Fig. 7). A decrement in UA reflex responses to NEG airway pressure may result from alcohol or benzodi­azepine ingestion, age (143), or may even develop over time as a consequence of the likely detrimental effects of snoring and occasional obstructive apneas on the UA mucosa (see section II). In this scheme, snoring itself could lead to a worsening of the protective UA reflex thereby increasing the tendency for more apneas, with more apneas then leading to a worsening of the situa­tion. Evidence to support the contention that OSA pa­tients have impaired protective UA mucosal reflexes compared to snorers, who in tum are more reliant on these reflexes to maintain airway patency compared to non-snorers, was discussed in section II. In such a scheme for the pathogenesis of OSA, patients with ex-

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UPPER AIRWAY MOTOR CONTROL

Sleeping normal subject

! Narrower than normal airway

for this individual

Exaggerated UA NEG pressure

!

Structural:

/

e.g. t nasal resistance weight gain sleeping position "H UA muscle activity:

e.g. alcohol benzodiazepines

Reflex pharyngeal dilator muscle activation

/ '" Small responder Big responder

! /'" Snoring, hypopneas and....- Any decrement in reflex No change in reflex occasional apneas e.g. age

alcohol ! benzad;,zep;ne,

Decrement in UA mucosal sensation

/'" Decrement in UA reflex

___ ... ~ Worsening snoring, hypopneas and OSA

! Remain normal

847

FIG. 7. Schema to illustrate how changes in VA mucosal sensation and reflex pharyngeal dilator muscle responses to NEG airway pressure may be involved in the pathogenesis and natural history of obstructive sleep apnea. Abbreviations as for Fig. I.

lstmg OSA would be expected to have impaired VA sensation to mechanosensitive stimuli, as well as im­paired reflex pharyngeal dilator muscle responses to NEG pressure compared to snoring and non-snoring subjects without OSA. There is some evidence to sup­port the first hypothesis (138,265), but the latter hy­pothesis has not yet been formerly tested.

Acknowledgements: Dr. Leszek Kubin is thanked for supplying Fig. 5, for critical reading of this manuscript, and

for providing valuable suggestions throughout. Dr. Paul Or­sini is thanked for reviewing Table 1, and Professor Adrian Morrison is thanked for helpful discussion. Professor Abe Guz and Dr. J. Alastair Innes are thanked for previous dis­cussions. Mr. Harry Holden is thanked for anatomical advice and help in preparing Fig. 4.

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