OBSTRUCTIVE SLEEP APNEA: ELECTRICALSTIMULATION TREATMENT

MESUT SAHIN

JINGTAO HUANG

Louisiana Tech UniversityRuston, Louisiana

1. INTRODUCTION

Obstructive sleep apnea (OSA) is an intermittent occlu-sion of the upper airways (UAW) resulting in frequentarousals during sleep (Fig. 1) (1). OSA is a prevalent prob-lem among middle-aged overweight males. Surgicalapproaches offer only partial relief and the outcome ofthe surgery is not predictable preoperatively. No drugtherapy exists that is effective for the long-term (2). Thebest therapy currently available is a nasal mask thatapplies a continuous positive airway pressure (CPAP) tokeep the airways open. Most common complications ofOSA are restless sleep, excessive daytime sleepiness, job-related accidents, impaired short-term memory, hyper-tension, congestive heart failure, and decreased libido.Personality disorders and other psychological problemsmay further complicate the situation in the long run.

OSA is recognized at an increasing rate as more sleepcenters open around the world. In most epidemiology stud-ies, the severity of the OSA is rated by the number of ob-structive apnea and hypopnea (intermittent within abreath) episodes per hour of sleep (apnea-hypopnea index,AHI). In a recent review, it was estimated that roughly 1out of every 5 adults has at least mild OSA (defined byAHI � 5) and 1 out of 15 has at least moderate OSA (de-fined by AHI � 15) in predominantly white populations(3). Another report concluded that 1–4% of the male pop-ulation in Sweden suffers from OSA (4). In a small town inWestern Australia, at least 8.5% of the men and 4% of thewomen had evidence of sleep-disordered breathing for atleast one-third of the night (5). In another study conducted

in Australia, the prevalence of sleep-disordered breathing(AHI > 15) in a sample of 2,202 subjects between the agesof 35 and 69 was at least 3.6% (5.7% in men and 1.2% inwomen) (6). These statistics demonstrate that OSA is aprevalent sleep disorder in all parts of the world.

The pathogenesis of OSA has been extensively studiedand reviewed (1,7–11). The current research suggests thatalong the secondary variables like excessive weight,gender, age, and the use of drugs that depress the upperairway tone, mainly two factors render the upper airwaysvulnerable for obstructions: the anatomical and neuro-muscular factors. Some of the anatomical factors thatreduce the size of the air passage are extra adipose tissuein the pharynx and a small or recessed lower jaw.

The fall in the tonic and phasic activity of the UAWmuscles during sleep increases the UAW collapsibilityand results in the closure of the pharynx in the face ofunfavorable anatomical measures. Earlier, the phasicgenioglossal (GG) activity in OSA patients was shown tobe approximately three times that of normal patients dur-ing wakefulness to compensate for the anatomic restric-tion of the flow (12). In a more recent report, the OSApatients had higher tonic, phasic, and peak phasic GG ac-tivity than control subjects for a wide range of epiglotticpressure changes during wakefulness (13). As the slope ofthe GG activity versus the epiglottic pressure wasthe same for both groups, this report concluded that thehigh GG activity in patients was a product of increasedtonic activation of the muscles, combined with increasednegative-pressure generation during inspiration. On theother hand, it has been shown that GG and tensor palatinimuscle activities had significantly larger decrements thancontrols during alpha-theta transition at the sleep onset(12,14–17) [although the decrease in the GG activity wasnot always present (18)]. The large decrease in the UAWmuscle activity from its elevated level renders the UAWsmore collapsible compared with normal subjects. The GGactivity further decreases during a transition from nonrapid eye movement (NREM) to REM sleep (19). Finally,because the negative airway pressure created by the

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Figure 1. A typical pattern of upper-airwayocclusion (AO) in a patient. Although present,the genioglossal (GG) activity is low during theocclusions while the pressure swings in the air-ways are maximal. An arousal occurs just priorto the termination of the occlusive phase, as in-dicated by the EEG, and the inspiration re-sumes with a large peak in the GG activity. Thepatient relapses back into occlusions after a fewbreaths until the next arousal (1).

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diaphragm muscle during inspiration is not sufficientlybalanced by the dilating forces of the UAW muscles, theairways collapse at the most vulnerable sites: the soft pal-ate (nasopharynx or velopharynx) or behind the tongue(i.e. oropharynx) (20). It is worth noting that central apneadiffers from obstructive apnea in its origin and form.As the respiratory drive ceases in the central apneas com-pletely, breathing does not occur even if the upper airwaysare open. This article deals only with OSA.

These reports cited above present a scenario that canpotentially be corrected by direct activation of the musclesinvolved using small electric currents. After all, the OSApatients are able to keep their airways open voluntarilyduring wakefulness or resume breathing upon arousalfrom sleep. The extra dilating forces needed to keep theairway patency during sleep can potentially be providedby electrical stimulation of the UAWmuscles or the nervesthat innervate them. The objective then becomes findingthe right set of muscles or nerves that can dilate the siteof obstruction maximally with minimum disturbance tothe subject. The sensation caused by the electrical stimu-lation, however, should not even cause micro-arousals.Otherwise, the main objective would be defeated byreducing the total amount of time that the patient spendsin deep stages of sleep.

The discussion above leads to the conclusion that thehypoglossal nerve (HG) and the tongue muscles thatare supplied by the HG nerve are potential targets forstimulation (Fig. 2) (21). The HG nerve innervates the ex-trinsic muscles of the tongue (i.e., the genioglossus (GG),styloglossus and the hyoglossus), the intrinsic musclesthat reshape the tongue, and the geniohyoid muscle. Thetongue is the structure with the largest displacementin the region and can potentially relieve the naso- andoropharynx with its forward movement. In addition to thedilation function, activation of the tongue muscles can

increase the stiffness of the airways and therefore reducethe collapsibility during the negative pressure swings ofinspiration. The GG, the fan-shaped muscle underneaththe tongue, is the tongue protrusor and its activity isresponsible for anterior positioning of the tongue, whereasthe styloglossus and hyoglossus are considered as retrac-tor muscles (Fig. 2). The genioglossus fibers normallycontract during inspiration as part of a reflex that is elic-ited by the negative pharyngeal pressure. Therefore, thestudies have concentrated around augmenting this phasiccontraction either by direct activation of the GG or selec-tive stimulation of the medial branch of the HG nerve thatresults in GG activation. Those efforts are summarized inthe next section below.

2. CURRENT APPROACHES TO ACTIVATE THE TONGUEMUSCLES

2.1. Genioglossal Stimulation

A study conducted in nine OSA patients demonstrated thatunilateral GG stimulation with acutely implanted wireelectrodes could increase the inspiratory airflow at moder-ate levels of nasal positive airway pressure (CPAP) withoutarousing the patients from sleep (22). The GG activationincreased the maximum inspiratory flow rates signifi-cantly (although the flow limitation was not completelyabolished) whereas the retractor muscle (hyoglossus andstyloglossus) stimulation decreased it. The repetitive GGstimulation in four of those patients decreased the AHIfrom 65.6711.5 to 9.075.8 episodes/h. In another study,electrical stimulation via percutaneously inserted bipolar-hooked wires successfully increased the diameter of thehypopharyngeal airway as much as 284% of the restingdiameter during wakefulness in nine of the 14 patientsstudied (23). In seven awake healthy subjects, the UAWs

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Figure 2. The hypoglossal nerve and the musclesthat it innervates: the intrinsic and extrinsic mus-cles of the tongue and the geniohyoid. Genioglossusis considered as the main tongue protrusor of theextrinsic muscles and the hyoglossus and sty-loglossus as the retractor muscles (21). (This figureis available in full color at http://www.mrw.interscience.wiley.com/ebe.)

2 OBSTRUCTIVE SLEEP APNEA: ELECTRICAL STIMULATION TREATMENT

were first partially occluded by applying an external pres-sure to the submental hyoid region. Then, the transmuco-sal stimulation of the tongue base, which presumablyactivated the GG, effectively reduced the pharyngeal re-sistance (about 42%), despite the fact that submental stim-ulation (see below) did not generate any statisticallysignificant changes in the same study (24). Another grouptested the effects of direct GG stimulation on UAW resis-tance in anesthetized dogs (25). Upper airway resistance(Rua) increased during both inspiration and expirationwhen the tracheal negative pressure was switched from 5to 20 cmH2O. Airway resistance was significantly reducedby stimulation of the GG. The effect of stimulation on air-way resistance varied remarkably with the stimulationfrequency and reached a plateau above 50Hz.

These reports suggest that the GG activation alone iscapable of improving the airway patency. Nevertheless,chronic implantation of wire electrodes in the tongue isnot feasible for this approach to become a clinical tool. Apossible alternative paradigm for direct GG stimulation isto use a floating type of microelectrode without intercon-nects to the outside world, such as the BIONs. The resultsof the BIONs implants in OSA patients have not beenreported yet [see (26) for a preliminary report] and noother floating stimulators are being tested for this pur-pose, to our knowledge.

2.2. Submental Stimulation

Similar to the direct GG stimulation, it is the GG muscleagain that is targeted with transcutaneous stimulationswith electrodes placed underneath the mandible, thelower jaw. Miki et al. (27) examined the effects of submen-tal electrical stimulation in six patients. The stimulationsdecreased the frequency of apneic episodes, apnea time/total sleep time, the longest apnea duration, and the num-ber of times that oxygen saturation dropped below 85%per hour significantly compared with those control nights.The stimulations neither caused arousals, nor affected theblood pressure or the heart rate significantly. Hida et al.reported in 13 patients that submental stimulation re-duced the frequency and duration of apneic episodes withan improvement in the sleep quality and daytime sleepi-ness (28). These effects remained for at least two nightsfollowing the five successive stimulation nights. None ofthe patients was awakened by the stimulation and nonecomplained of pain or any other discomfort caused bystimulations. Another report by this group demonstratedthat the effect of submental stimulation on upper airwaycollapsibility was similar to that of hypoglossal nervestimulation in anesthetized dogs (29), which was to de-crease the collapsibility and expand the UAW size.

A controversial study was reported by Edmonds et al.(30) in eight male patients with OSA that submental andsubhyoidal transcutaneous electrical stimulations failedto prevent sleep-disordered breathing or to improve sleeparchitecture. Transcutaneous stimulation did not enlargethe upper airways during wakefulness, nor did it preventthe upper airways from collapsing during sleep. Deckeret al. (31) reported that submental stimulation had incon-sistent effects in seven OSA patients, terminating only

22% of the apneas. The submental stimulation was dis-comforting during wakefulness. Nonetheless, the stimulusintensity producing arousal during sleep was significantlygreater than that producing barely tolerable discomfortduring wakefulness. Schnall et al. (24) tested the dilatoryeffects of upper airway muscle contractions induced bytranscutaneous electrical stimulation in awake subjects.Only sublingual stimulation produced measurable tongueprotrusion, which was believed to be the effect of GG ac-tivation, and helped preserve the upper airway patencywhile a pressure load was applied exogenously. Neithersubmental (geniohyoid) nor paralaryngeal (sternohyoidand sternothyroid) muscle stimulation, no matter aloneor combined, could cause any tongue protrusion.

In summary, the reports on submental stimulation arecontroversial, which can be explained by nonspecific acti-vation of the GG because of the tissue present between thestimulating electrodes and the target site. The electrodesize and the position can play a significant role on themuscle recruitment function with transcutaneous stimu-lation. The submental approach is attractive because of itsnon-invasiveness and ease of application. The success rateand the severity of the OSA cases that can benefit fromthis approach remains to be seen in a larger-scale study.

2.3. Hypoglossal Nerve Stimulation

Electrical nerve stimulation has a number of advantagesover muscle stimulation. The electrode interface is me-chanically more stable during activation and, therefore,the recruitment characteristics are better defined. Neuralstimulation requires much less energy than muscle stim-ulation. Thus, the HG nerve stimulation should be pre-ferred over GG activation if the same function can beachieved. Furthermore, HG is mainly a motor nerve. Al-though it is not known exactly how many afferent fibersare present in the human HG nerve, the experience inclinical trials suggests that HG nerve stimulation at mod-erate levels does not cause pain to the subject duringwakefulness and the threshold for arousal is even higherduring sleep (31).

Direct hypoglossal nerve stimulation in UAW isolateddogs caused a remarkable decrease of upper airway com-pliance (29), defined as the slope of the pressure-volume(P-V) curve. With chronic implants in dogs, it has beenshown that unilateral hypoglossal nerve stimulation canincrease the peak upper-airway flow from 0.1L/s to 1.6L/stested over a 3-month period (32). Histological examina-tion revealed no nerve damage resulting from chronicstimulation. In humans with intraoperative acute nerve-cuff implants on the HG nerve, the pharyngeal size at thelevel of the tongue base was increased to twice the sizeof the intubation tube in one study (33), and the flow ofinspired air was doubled in another (34). Stimulation ofthe medial branch was nearly as good and was superior tostimulation of other branches in the latter study (34). Hy-poglossal nerve stimulation at both loci during sleep con-sistently resulted in increased inspiratory airflow withoutarousals from sleep. Stimulation of the distal HG nerve tothe GG caused protrusion and contralateral deviation ofthe tongue in another study by the same group (35). The

OBSTRUCTIVE SLEEP APNEA: ELECTRICAL STIMULATION TREATMENT 3

former group noted that the current amplitude needed toopen the obstructed airways was below the level to causetongue protrusion (33).

Decker et al. (31) reported that the HG nerve stimula-tion with percutaneously inserted wire electrodes pro-vided tongue protrusion at minimal discomfort inhumans terminated only 23% of the apneic events. Stim-ulation with bipolar needle electrodes by another groupwas shown to interrupt obstructions in human subjectswithout arousals (36). As discussed by the former group,the inefficiency of the stimulations with wire electrodescould be because of misplacement of the wires around thenerve trunk resulting in the recruitment of retractorymuscles before the protruser muscles of the tongue.

The most advanced efforts on HG stimulation has beenlead by a group at Johns Hopkins University and theircollaborators from other research centers and MedtronicsInc., MN. In an international collaboration effort, thisgroup chronically implanted eight OSA patients with adevice that stimulated the hypoglossal nerve unilaterally(37). The device consisted of an implantable intrathoracicpressure sensor for synchronization with breathing, a pro-grammable pulse-generating device, and a stimulatinghalf-cuff nerve electrode (Fig. 3) placed around the medialbranch of the HG nerve. Electrical stimulation was deliv-ered for the entire night after the onset of sleep and sig-nificantly reduced the mean apnea-hypopnea index inNREM and REM sleep stages and reduced the severityof oxyhemoglobin desaturations. The long-term stimula-tion at night was tolerated by all the patients without anyadverse effects. Apnea was eliminated entirely in allpatients, but the intermittent inspiratory flow limitation(snoring) remained. The stimulation seemed to be most ef-fective for patients with retroglossal obstruction. Poor syn-chronization, electrode breakage, and sensor malfunctionprevented the continuation of the study in some patients.

In summary, HG nerve stimulation seems to be a prom-ising treatment method for OSA. Different levels of success

in the cited reports are most likely because of anatomicalvariations across the subjects, the site of obstruction, andthe site of electrode implantation. Room for improvementsexists before this approach can become a clinical tool. Oneof these techniques that offers a potential for improve-ment, selective nerve stimulation, is discussed below.

2.4. Selective Stimulation of the Hypoglossal Nerve

Selective nerve stimulation is a technique that has beendeveloped to improve the motor function obtained withelectrical stimulation of the peripheral nerves with cuffelectrodes. This technique was recently applied to the HGnerve for more effective removal of UAW obstructions(38,39). A flat-interface-nerve electrode (FINE) with mul-tiple contacts (40) was used for selectively activatingthe fascicles inside the HG nerve trunk. A FINE withnine contacts was implanted on the proximal hypoglossalnerve trunk in a dog (38). The data showed that ge-nioglossus or geniohyoid could selectively be activatedfrom the main HG trunk by delivering small currentsthrough selected contacts. A 17-contact FINE implantedimmediately proximal to the branching point (Fig. 4) gen-erated selective activation of the protrusor (genioglossus)or the retractor muscles (hyoglossus and styloglossus), al-though selective activation of the styloglossus or thehyoglossus muscle was not possible (39).

Huang et al. imaged the upper airways in anesthetizedbeagles to assess the effects of selective stimulation of themain HG nerve trunk (41). A fiberoscopy lead (diam.5mm) was inserted through the cut end of the tracheacephalad and positioned immediately past the proximalrim of the trachea while the head was fixed at either 301 or601 from the horizontal. Transoral images showed thatstimulations delivered through various electrode contactscould generate different activation patterns of the tonguemuscles (Fig. 5) (41), including medial or lateral dilationor constriction of the oropharynx at the root of the tongue.Some of these tongue-activation patterns translated into asubstantial increase in the oropharyngeal size whereasothers did not have any effect (41), which suggests thatmultiple muscle-activation patterns can be generated withselective HG stimulation, and some of these patterns maybe more effective than others for removing the UAW ob-structions. This result may, in turn, increase the size ofthe patient population that can benefit from the HG nervestimulation as a treatment method for OSA.

3. CONTINUOUS VERSUS CLOSED-LOOP STIMULATION

An important question, still unanswered, is if a feedbacksignal to synchronize the stimulations with breathingis necessary. Can the stimulations be applied continuouslywithout causing muscle fatigue overnight? The currentliterature shows that the stimulation level needed forfunctional results is much lower than the maximumrecruitment level of the muscles, and this level is notdiscomforting to the patients during wakefulness. Anopen-loop, continuous stimulation paradigm may reducethe number of apnea/hypopnea episodes in a mild OSApatient by merely decreasing the UAW compliance, which

5 mm

Figure 3. The half-cuff neural electrode with tripolar contacts(Model 3990) developed by Medtronic, Inc. for stimulation of theHG nerve in patients.

4 OBSTRUCTIVE SLEEP APNEA: ELECTRICAL STIMULATION TREATMENT

suggests that continuous stimulation may be an accept-able paradigm, eliminating the need for a feedback signal.However, reducing the total time of muscle stimulationmay still be of interest because intensive activation mayresult in conversion of the fatigueable fibers to fatigue re-sistant ones in the long term. The contribution of thischange to the upper airway patency remains to be seen.Thus, the use of a feedback signal has the potential toimprove the overall success of the device.

In addition, the starting point of the pulse train withineach breath may be a critical parameter for the bestresults. It may be much easier to keep the airways openthrough the inspiratory cycle by turning the stimulustrain on prior to the onset of the inspiratory phaserather than trying to dilate the airways against the sur-face tension of the lining liquid after they collapse (42),which is particularly true if the ‘‘delayed activation of theupper airway inspiratory muscles’’ plays a role in the

Figure 4. Placement of the flat-interface-nerve elec-trode on the hypoglossal nerve for selective stimula-tion (39).

Medial Lateral At Rest

Figure 5. Tongue (top row) and pharyngeal images (bottom row) captured simultaneously to compare the effects of medial and lateralcontact stimulation with the flat-interface-nerve electrode in an anesthetized beagle. The head was 301 from the horizontal with the mouthopen to image the tongue. Top row, left to right: the control image at rest, stimulation through the lateral, and medial contacts of the FINE.The tongue area that is activated by the stimulation is marked with a circle in each image. The bottom row shows the correspondingpharyngeal images taken with a 5mm fiberoscopy lead inserted through the cut end of the trachea cephalad and placed immediately pastthe rim of the trachea. The septum in the middle is the caudal end of the soft palate (the arrow in the bottom-left image). The nasopharynxis the opening below the soft palate and the oropharynx is the one above (dog is in supine position). The lateral contact stimulation dilatesthe oropharynx toward the ipsilateral side and the medial contact stimulation dilates the oropharynx bilaterally (41). (This figure isavailable in full color at http://www.mrw.interscience.wiley.com/ebe.)

OBSTRUCTIVE SLEEP APNEA: ELECTRICAL STIMULATION TREATMENT 5

pathogenesis of the obstructions, as suggested by Hudgeland Harasick (43).

4. DETECTION OF OBSTRUCTIONS TO SYNCHRONIZESTIMULATIONS

If it is determined that the closed-loop approach is advan-tageous, a reliable method for detection of obstructivebreaths will have to be developed to apply the stimuluspulses only when needed. A few detection methods havebeen proposed to synchronize the electrical stimulationwith breathing while some others have been described as apart of an experimental procedure without evaluatingits contribution to the overall success of the stimulationparadigm. Among those physiological variables are thehypopharyngeal (22), esophageal (35), and intrathoracic(37) pressure; airflow detected with a thermistor near thenose or mouth (28); tracheal breath sounds (44); trachealinterring distance measured with a strain gauge (36); andthe HG nerve’s own activity as the feedback signal (45,46).Only the intrathoracic pressure method (37) has beentested in OSA patients to date with a chronically im-planted stimulator device. An algorithm was developed topredict the onset of the next inspiration to turn the stim-ulator on in advance before a negative intratrachealnegative pressure was developed by the respiratory drive.This group reports that synchronization was poor in twopatients, and electrode breakage and sensor malfunctionoccurred in five of the eight patients total. Although prom-ising, some practical problems still await solutions.

It was proposed that the coupling between the UAWmechanics and the HG nerve activity should be strongerthan any other secondary variable to be used for detectionof obstructions (45). This technique eliminates the needfor implantation of a separate sensor if the HG nerve isimplanted with a cuff electrode for stimulation. Two bea-gles with cylindrical cuff electrodes were implanted to re-cord the HG activity as a response to loading of the UAWsduring sleep. The loading paradigm was a remotely con-trolled force applied to the submental region externally.The phasic HG activity increased immediately in the fol-lowing breath as a response to the submental force andstayed at an elevated level as long as the force was applied(Fig. 6a) (45). The baseline signal increased slightly withthe submental force in one of the animals, but the increasein the baseline did not interfere with detection of the pha-sic component. The phasic HG signal began to increasebefore the esophageal pressure with an average time dif-ference of 177196 ms (mean7SD, 220 breaths). The HGactivity was detectable even at very low levels of UAWloading in this dog model (47). It remains to be seen if theobstructive breaths are detectable in OSA patients usingthe cuff electrode recordings of the HG nerve’s activity.

5. EVALUATION OF CURRENT APPROACHES

5.1. Stimulation Paradigms

In general, reports cited above are aimed at activating theGG directly or via stimulation of the medial branch of theHG nerve. Activation of the medial branch alone seems to

be as efficient as the main trunk of the HG nerve in agroup of patients (35). Can this be generalized to the restof the population with the given variations in the UAWanatomy and the degree of OSA severity? The tonguemovements have a large degree of freedom as manifestedduring mastication and swallowing. It is also a uniqueorgan that is capable of changing its shape voluntarilywith the recruitment of vertically and transversely locatedintrinsic muscles (48). Can a stimulation paradigm befound that uses these capabilities of the tongue forremoval of obstructions in a more effective way thansingle-branch stimulation can provide? Can such an ad-vanced stimulation paradigm also provide multiple modesof muscle activation so that a control algorithm can bedesigned to switch between these modes when the patientchanges his/her position in the bed?

To speculate on some of these questions, a paradigmaiming to recruit only the GG muscle and the whole

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Figure 6. Hypoglossal nerve activity as a response to externalloading in a dog model of upper airway obstruction. (A) A forcetransition maneuver in NREM sleep. The traces from top to bot-tom are the submental force, esophageal pressure, rectified-aver-aged HG activity, abdominal movements, and EEG signal. (B) Theaverage of 23 trials showing the rate of increase in the HG re-sponse. The rectified-integrated phasic HG activity (normalized)is plotted against the breath number. The force transition ma-neuvers take place within the sixth and seventh breaths (45).(This figure is available in full color at http://www.mrw.interscience.wiley.com/ebe.)

6 OBSTRUCTIVE SLEEP APNEA: ELECTRICAL STIMULATION TREATMENT

muscle at once is not likely to be the optimum solution forthe following reasons: (1) Genioglossus is a fan-shapedmuscle attaching to the ventral side of the tongue along itslongitudinal axis, the hyoid bone on one end and the man-dible on the other end (Fig. 2). Activation of the wholemuscle at once, rather than some selected portions ofit, can produce agonist forces and not a net force in theforward direction to pull the tongue out of the pharyngealcavity. (2) The forces generated by the tongue muscles arecontext-dependent (i.e., neck position). For certain posi-tions of the neck, the retractor muscles and the geniohyoidcan also be recruited to augment the pharyngeal dilationobtained with the GG alone. (3) Coordinated activationof the GG, the retractor, and the intrinsic muscles cangenerate forces not only to pull the tongue forward butalso push it downward to relieve the nasopharynx. (4)Coactivation of the antagonistic muscles can reduce thecollapsibility of the UAWs by stiffening the whole struc-ture. In animal and human experiments, the net result ofprotrusor (genioglossus) and retractor (styloglossus andhyoglossus) muscle coactivation is a rectraction of thetongue (35,48–50). Nevertheless, experiments in patientsdemonstrated that coactivation of these muscles causesincreased inspiratory flow rates (35). The question thenbecomes what is the stimulation paradigm or the right setof muscles to be activated that will maximize the func-tional outcome and thereby the patient population whocan benefit from this treatment method?

5.2. Functional Assessment Tools

It is evident that a single-dimensional measure like upperairway resistance or airflow is not sufficient as a functionalassessment tool for the HG or GG stimulation. The eval-uation methods for the electrical stimulation should reflectthe details of what happens to the UAW size and shape inits various compartments in addition to the measurementsof collapsibility. Recent reports on HG/GG stimulationhave used UAW imaging as an assessment tool. In somestudies, techniques that allow imaging of the pharyngeallumen directly with insertion of an endoscopic camerawere used (41,51–54). Imaging techniques that can takea transverse section and make cross-sectional and volu-metric measurements, such as magnetic resonance imag-ing (55–58), computer tomography (59), and fluoroscopy(59), were also used. The endoscopic methods have the dis-advantage of having a lead (rigid or flexible) inside theUAWs that may disturb the muscle function. On the otherhand, they are easy to use and do not require an expensiveimaging facility. The noninvasive techniques, however,provide more precise area and volume measurements atuser-selected depths of the airways without disturbing thestructures being imaged. In general, these recent reportsreflect the attempts for acquiring more functional infor-mation about exactly what the stimulations do in variouscompartments of the pharynx. Upper-airway mechanicalresistance, compliance of the pharyngeal passage, or thecritical pressure at which the airways collapse should stillbe measured independently. Despite the fact that these aresingle-dimensional variables and provide information onlyon the overall structure, it is still necessary to use these

measures along with the imaging tools for an accurate as-sessment of the function.

5.3. Animal Models

Appropriateness of the animal models and extrapolatingdata from these models to answer questions regarding aneural prosthesis for humans should be evaluatedcarefully. Major anatomical differences exist between thehuman and the common animal models used in thesestudies; primarily the cat and the dog. Across the species,variance in the shape of the hyoid bone and its attach-ments is one example. The relative size and the scaleof the structures may also introduce a difference in thepassive mechanical properties of the muscles. For in-stance, the critical pressure at which the airways collapsein an animal model may be significantly different thanthat of a human in an otherwise comparable study. Anes-thesia (e.g., chloralose, halothane, ketamine, and pento-barbital) suppresses the HG activity drastically (60).Decerebration is often used to eliminate the effects of an-esthesia. It is still questionable, however, how appropriateit is to extrapolate the data from a decerebrate model tomake conclusions about the condition of the UAWs duringsleep. These deviations from the human case limit the useof animal models for studying the consequences of theelectrical stimulation of the UAWmuscles or at least makeit difficult to translate the results to the humans.

5.4. What More y

Before electrical stimulation of the tongue muscles can be-come a clinically available neuroprosthetic device, the lon-gevity of the implanted electrodes at the site of the HGnerve, which experiences significant rotations and trans-lations, should be tested with chronic implants. With therecent advances in electrode technology, we anticipate thatthis testing will not be a major challenge in the near fu-ture. The set of tongue muscles to be activated and thepatterns of activation need to be studied carefully in hu-man patients to maximize the functional benefit. Selectivestimulation of the HG nerve may be the tool to use forgeneration of these patterns. A method of detection for theobstructive breaths and a closed-loop control algorithmthat is robust enough to work in all sleep stages and re-spiratory patterns should be developed. A unique approachis needed for the REM sleep because of its chaotic nature.A diagnostic measure is needed to predict the outcome ofthe HG nerve implants preoperatively. Sublingually in-serted wire electrodes that can activate the GGmay have autility as a diagnostic tool in this regard (61). Finally, oneshould not expect that every OSA patient will benefit fromsuch a neuroprosthetic device even after all the problemsare resolved. In most severe cases, it may not be possible togenerate the combination of forces necessary to keep theUAW patency before arousing the patient from sleep.

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FURTHER READING

ON PATHOGENESIS OF OSA

S. T. Kuna and J. E. Remmers, Neural and anatomic factors re-lated to upper airway occlusion during sleep. Med. Clin. North

Am. 1985; 69(6):1221–1243.

K. P. Strohl, N. S. Cherniack, and B. Gothe, Physiologic basis fortherapy for sleep apnea. Am. Rev. Respir. Dis. 1986; 134:791–802.

D. W. Hudgel, Mechanisms of obstructive sleep apnea. Chest

1992; 101:541–549.

K. G. Henke, M. S. Badr, J. B. Skatrud, and J. A. Dempsey, Loadcompensation and respiratory muscle function during sleep.J. Appl. Physiol. 1992; 72(4):1221–1234.

S. G. McNamara, R. R. Grunstein, and C. E. Sullivan, Obstructivesleep apnea. Thorax 1993; 48:754–764.

F. Kapsimalis and M. H. Kryger, Gender and obstructive sleepapnea syndrome, Part 1: Clinical features. Sleep 2002;25(4):412–419.

A. S. Jordan, D. P. White, and R. B. Fogel. Recent advances inunderstanding the pathogenesis of obstructive sleep apnea.Curr. Opin. Pulm. Med. 2003; 9:459–464.

R. Arens and C. L. Marcus, Pathophysiology of upper airway ob-struction: a developmental perspective. Sleep 2004; 27:997–1019.

R. B. Fogel, A. Malhotra, and D. P. White, Sleep 2: Pathophysi-ology of obstructive sleep apnoea/hypopnoea syndrome. Thorax2004; 59:159–163.

ON EPIDEMIOLOGY OF OSA

T. Gislason, M. Alquist, G. Erikson, A. Taube, and G. Bomem,Prevalence of sleep apnea syndrome among Swedish men: anepidemiological study. J. Clin. Epidemiol. 1988; 61:571–576.

OBSTRUCTIVE SLEEP APNEA: ELECTRICAL STIMULATION TREATMENT 9

H. Bearpark, L. Elliot, R. Grunstein, J. Hedner, S. Cullen,H. Schneider, W. Althaus, and C. Sullivan, Occurrence andcorrelates of sleep disordered breathing in the Australian townof Busselton: a preliminary analysis. Sleep 1993; 16:S3–S5.

L. G. Olsen, M. T. King, M. J. Hensley, and N. A. Saunders,A community study of snoring and sleep–disordered breathingprevalence. Am. J. Respir. Crit. Care Med. 1995; 152:711–716.

T. B. Young, P. Peppard, and D. J. Cottlieb, Epidemiology of ob-structive sleep apnea. Am. J. Respir. Crit. Care Med. 2002;165:1217–1239.

ON ELECTRICAL STIMULATION IN OSA

W. Hida, S. Okabe, H. Miki, Y. Kikuchi, O. Taguchi, T. Takishima,and K. Shirato, Effects of submental stimulation for severalconsecutive nights in patients with obstructive sleep apnoea.Thorax 1994; 49:446–452.

E. A. Mann, T. Burnett, S. Cornell, and C. L. Ludlow, The effectof neuromuscular stimulation of the genioglossus on thehypopharyngeal airway. The Laryngoscope 2002; 112:351–356.

A. Oliven, D. J. O’hearn, A. Boudewyns, M. Odeh, W. D. Backer,P. V. D. Heyning, P. L. Smith, D. W. Eisele, L. Allan, H. Schn-eider, R. Testerman, and A. R. Schwartz, Upper airway re-sponse to electrical stimulation of the genioglossus inobstructive sleep apnea. J. Appl. Physiol. 2003; 95:2023–2029.

D. W. Eisele, A. R. Schwartz, and P. L. Smith, Tongue neuromus-cular and direct hypoglossal nerve stimulation for obstructivesleep apnea. Otolaryngol. Clin. N. Am. 2003; 36:501–510.

ON UAW IMAGING IN OSA

R. J. Schwab, Upper airway imaging. Clin. Chest Med. 1998;19(1):33–54.

10 OBSTRUCTIVE SLEEP APNEA: ELECTRICAL STIMULATION TREATMENT