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Hypoglossal nerve stimulation—Optimizing its therapeutic potential in obstructive sleep apnea

  • Alan R. Schwartz
    Correspondence
    5501 Hopkins Bayview Circle, Baltimore, MD 20124, USA. Tel.: +1 410-550-0572; fax: +1 410 550 2612.
    Affiliations
    Division of Pulmonary, Critical Care and Sleep Medicine, Johns Hopkins School of Medicine, USA
    Johns Hopkins Sleep Disorders Center (Bayview Campus), USA
    Center for Interdisciplinary Sleep Research and Education, USA
    Johns Hopkins Sleep Medicine Fellowship Training Program, USA
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Published:August 26, 2014DOI:https://doi.org/10.1016/j.jns.2014.08.022
      Obstructive sleep apnea is characterized by recurrent periods of upper airway obstruction (apneas and hypopneas) during sleep, leading to nocturnal hypercapnia, repeated oxyhemoglobin desaturations and arousals [
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      ]. Obstructive sleep apnea is a major cause of morbidity and mortality in Western society [
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      ,
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      • Olson E.J.
      • Somers V.K.
      Day–night pattern of sudden death in obstructive sleep apnea.
      ], and contributes significantly to the development and progression of neurocognitive, metabolic, cardiovascular, and oncologic diseases [
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      • Goldberg A.P.
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      Obstructive sleep apnea as a risk factor for stroke and death.
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      • Krieger E.M.
      • Lorenzi-Filho G.
      Early signs of atherosclerosis in obstructive sleep apnea.
      ,
      • Marin J.M.
      • Carrizo S.J.
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      Obstructive sleep apnea and acute myocardial infarction: clinical implications of the association.
      ,
      • Marin J.M.
      • Carrizo S.J.
      • Vicente E.
      • Agusti A.G.
      Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.
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      • Nieto F.J.
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      • Lind B.K.
      • Shahar E.
      • Samet J.M.
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      • et al.
      Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study.
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      • Young T.
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      Prospective study of the association between sleep-disordered breathing and hypertension.
      ,
      • Punjabi N.M.
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      • Beamer B.A.
      • O'Donnell C.P.
      Sleep-disordered breathing, glucose intolerance, and insulin resistance.
      ,
      • Punjabi N.M.
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      • Gottlieb D.J.
      • Givelber R.
      • Resnick H.E.
      Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study.
      ,
      • Yaffe K.
      • Laffan A.M.
      • Harrison S.L.
      • Redline S.
      • Spira A.P.
      • Ensrud K.E.
      • et al.
      Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women.
      ,
      • Nieto F.J.
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      • Finn L.
      • Hla K.M.
      • Farre R.
      Sleep disordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study.
      ,
      • Drager L.F.
      • Lopes H.F.
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      • Trombetta I.C.
      • Toschi-Dias E.
      • Alves M.J.
      • et al.
      The impact of obstructive sleep apnea on metabolic and inflammatory markers in consecutive patients with metabolic syndrome.
      ]. Sleep apnea treatment is plagued by poor adherence to nasal continuous positive airway pressure (CPAP) [
      • Kribbs N.B.
      • Pack A.I.
      • Kline L.R.
      • Smith P.L.
      • Schwartz A.R.
      • Schubert N.M.
      • et al.
      Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea.
      ] despite efficacy in the sleep laboratory. Alternatively, surgical or medical weight loss strategies can offer definitive treatment, although responses in sleep apnea to weight loss are variable, and significant sleep apnea remains in nearly 50% of patients even after massive weight loss [
      • Ashrafian H.
      • Le Roux C.W.
      • Rowland S.P.
      • Ali M.
      • Cummin A.R.
      • Darzi A.
      • et al.
      Metabolic surgery and obstructive sleep apnoea: the protective effects of bariatric procedures.
      ,
      • Dixon J.B.
      • Schachter L.M.
      • O'Brien P.E.
      • Jones K.
      • Grima M.
      • Lambert G.
      • et al.
      Surgical vs conventional therapy for weight loss treatment of obstructive sleep apnea: a randomized controlled trial.
      ,
      • Fredheim J.M.
      • Rollheim J.
      • Sandbu R.
      • Hofso D.
      • Omland T.
      • Roislien J.
      • et al.
      Obstructive sleep apnea after weight loss: a clinical trial comparing gastric bypass and intensive lifestyle intervention.
      ,
      • Greenburg D.L.
      • Lettieri C.J.
      • Eliasson A.H.
      Effects of surgical weight loss on measures of obstructive sleep apnea: a meta-analysis.
      ,
      • Lettieri C.J.
      • Eliasson A.H.
      • Greenburg D.L.
      Persistence of obstructive sleep apnea after surgical weight loss.
      ]. Moreover, despite advances in understanding neurochemical control of ventilation and pharyngeal patency during sleep [
      • Dempsey J.A.
      • Veasey S.C.
      • Morgan B.J.
      • O'Donnell C.P.
      Pathophysiology of sleep apnea.
      ], effective pharmacologic treatments and alternatives to CPAP are still lacking.
      The development of pharyngeal obstruction during sleep has been widely attributed to a loss of pharyngeal neuromuscular activity. Initially, investigators focused on the role of dilator muscles, viz., the genioglossus, in maintaining pharyngeal patency by preventing the tongue from prolapsing into the pharynx [
      • Remmers J.E.
      • deGroot W.J.
      • Sauerland E.K.
      • Anch A.M.
      Pathogenesis of upper airway occlusion during sleep.
      ]. This concept gave rise to the development of electrical pacemakers for the hypoglossal nerve to treat sleep apnea by augmenting genioglossus activity during sleep [
      • Miki H.
      • Hida W.
      • Shindoh C.
      • Kikuchi Y.
      • Chonan T.
      • Taguchi O.
      • et al.
      Effects of electrical stimulation of the genioglossus on upper airway resistance in anesthetized dogs.
      ]. In early pre-clinical trials, investigators demonstrated that hypoglossus and direct genioglossus electrical stimulation led to marked decreases in pharyngeal collapsibility [
      • Schwartz A.R.
      • Thut D.C.
      • Russ B.
      • Seelagy M.
      • Yuan X.
      • Brower R.G.
      • et al.
      Effect of electrical stimulation of the hypoglossal nerve on airflow mechanics in the isolated upper airway.
      ] and relief of airflow obstruction during sleep [
      • Schwartz A.R.
      • Eisele D.W.
      • Hari A.
      • Testerman R.
      • Erickson D.
      • Smith P.L.
      Electrical stimulation of the lingual musculature in obstructive sleep apnea.
      ,
      • Eisele D.W.
      • Smith P.L.
      • Alam D.S.
      • Schwartz A.R.
      Direct hypoglossal nerve stimulation in obstructive sleep apnea.
      ]. These proof-of-concept studies in humans and animals spurred the development of fully implantable hypoglossal nerve stimulating systems for therapeutic purposes [
      • Schwartz A.R.
      • Bennett M.L.
      • Smith P.L.
      • De Backer W.
      • Hedner J.
      • Boudewyns A.
      • et al.
      Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea.
      ].
      To date, therapeutic efficacy of several implantable hypoglossal stimulating systems has been examined in several early stage “feasibility” trials [
      • Schwartz A.R.
      • Bennett M.L.
      • Smith P.L.
      • De Backer W.
      • Hedner J.
      • Boudewyns A.
      • et al.
      Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea.
      ,
      • Eastwood P.R.
      • Barnes M.
      • Walsh J.H.
      • Maddison K.J.
      • Hee G.
      • Schwartz A.R.
      • et al.
      Treating obstructive sleep apnea with hypoglossal nerve stimulation.
      ,
      • Mwenge G.B.
      • Rombaux P.
      • Dury M.
      • Lengele B.
      • Rodenstein D.
      Targeted hypoglossal neurostimulation for obstructive sleep apnoea. A 1 year pilot Study.
      ,
      • de Heyning PH Van
      • Badr M.S.
      • Baskin J.Z.
      • Cramer Bornemann M.A.
      • De Backer W.A.
      • Dotan Y.
      • et al.
      Implanted upper airway stimulation device for obstructive sleep apnea.
      ,
      • Kezirian E.J.
      • Goding Jr., G.S.
      • Malhotra A.
      • O'Donoghue F.J.
      • Zammit G.
      • Wheatley J.R.
      • et al.
      Hypoglossal nerve stimulation improves obstructive sleep apnoea: 12-month outcomes.
      ] and one “pivotal” trial [
      • Strollo Jr., P.J.
      • Soose R.J.
      • Maurer J.T.
      • de VN Cornelius J.
      • Froymovich O.
      • Hanson R.D.
      • et al.
      Upper-airway stimulation for obstructive sleep apnea.
      ]. Despite differences in patient selection, implantation site and stimulating paradigms, these studies have demonstrated consistent improvements in sleep apnea, as reflected by decreases in the apnea–hypopnea index, a major metric of disease severity. Nevertheless, significant residual sleep apnea has been observed in these trials with approximately a third of patients failing to demonstrate adequate responses to hypoglossal nerve stimulation therapy [
      • Strollo Jr., P.J.
      • Soose R.J.
      • Maurer J.T.
      • de VN Cornelius J.
      • Froymovich O.
      • Hanson R.D.
      • et al.
      Upper-airway stimulation for obstructive sleep apnea.
      ]. The reasons for suboptimal responses to hypoglossal stimulation, however, remain unclear.
      In an effort to optimize responses to hypoglossal stimulation, investigators employed a variety of strategies to refine patient inclusion criteria. One approach has been to restrict enrollment in clinical trials to patients with only mild to moderate obesity, in whom elevations in pharyngeal collapsibility are less pronounced than those with severe obesity [
      • Kirkness J.P.
      • Schwartz A.R.
      • Schneider H.
      • Punjabi N.M.
      • Maly J.J.
      • Laffan A.M.
      • et al.
      Contribution of male sex, age, and obesity to mechanical instability of the upper airway during sleep.
      ,
      • Polotsky M.
      • Elsayed-Ahmed A.S.
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      • Smith P.L.
      • Schneider H.
      • et al.
      Effect of age and weight on upper airway function in a mouse model.
      ,
      • Schwartz A.R.
      • Gold A.R.
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      • Wise R.A.
      • Permutt S.
      • et al.
      Effect of weight loss on upper airway collapsibility in obstructive sleep apnea.
      ,
      • Brennick M.J.
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      • Pickup S.
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      • Zhu J.X.
      • et al.
      Tongue fat infiltration in obese versus lean zucker rats.
      ,
      • Schwab R.J.
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      • Pierson R.
      • Mackley A.
      • Hachadoorian R.
      • Arens R.
      • et al.
      Identification of upper airway anatomic risk factors for obstructive sleep apnea with volumetric magnetic resonance imaging.
      ]. Another approach has been to exclude patients with the most severe sleep apnea [
      • de Heyning PH Van
      • Badr M.S.
      • Baskin J.Z.
      • Cramer Bornemann M.A.
      • De Backer W.A.
      • Dotan Y.
      • et al.
      Implanted upper airway stimulation device for obstructive sleep apnea.
      ,
      • Strollo Jr., P.J.
      • Soose R.J.
      • Maurer J.T.
      • de VN Cornelius J.
      • Froymovich O.
      • Hanson R.D.
      • et al.
      Upper-airway stimulation for obstructive sleep apnea.
      ], who may require dramatic improvements to fully treat their disorder. In these patients, hypoglossal stimulation may not stiffen the airway sufficiently to overcome marked elevations in pharyngeal collapsibility, thereby limiting the improvement pharyngeal patency during sleep [
      • Schwartz A.R.
      • Gold A.R.
      • Schubert N.
      • Stryzak A.
      • Wise R.A.
      • Permutt S.
      • et al.
      Effect of weight loss on upper airway collapsibility in obstructive sleep apnea.
      ,
      • Gold A.R.
      • Schwartz A.R.
      The pharyngeal critical pressure. The whys and hows of using nasal continuous positive airway pressure diagnostically.
      ]. Investigators have suggested that such patients can be identified by the predominance of complete rather than partial airway obstruction (obstructive apneas vs. hypopneas) on routine sleep study [
      • Eastwood P.R.
      • Barnes M.
      • Walsh J.H.
      • Maddison K.J.
      • Hee G.
      • Schwartz A.R.
      • et al.
      Treating obstructive sleep apnea with hypoglossal nerve stimulation.
      ]. Alternatively, investigators have suggested that the site and pattern of pharyngeal collapse [
      • Schwartz A.R.
      • Bennett M.L.
      • Smith P.L.
      • De Backer W.
      • Hedner J.
      • Boudewyns A.
      • et al.
      Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea.
      ], as assessed during drug-induced sleep endoscopy, could predict responders to hypoglossal stimulation [
      • Strollo Jr., P.J.
      • Soose R.J.
      • Maurer J.T.
      • de VN Cornelius J.
      • Froymovich O.
      • Hanson R.D.
      • et al.
      Upper-airway stimulation for obstructive sleep apnea.
      ]. It is possible that anterior movement of lingual structures during hypoglossal stimulation produces greater responses in those with retroglossal rather than retropalatal obstruction [
      • Schwartz A.R.
      • Bennett M.L.
      • Smith P.L.
      • De Backer W.
      • Hedner J.
      • Boudewyns A.
      • et al.
      Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea.
      ]. The primary site of obstruction is usually located in the retropalatal airway [
      • Launois S.H.
      • Feroah T.R.
      • Campbell W.N.
      • Whitelaw W.A.
      • Remmers J.E.
      Site of obstruction in obstructive sleep apnea: influence on the outcome of uvulopalatopharyngoplasty.
      ,
      • Launois S.H.
      • Feroah T.R.
      • Campbell W.N.
      • Issa F.G.
      • Morrison D.
      • Whitelaw W.A.
      • et al.
      Site of pharyngeal narrowing predicts outcome of surgery for obstructive sleep apnea.
      ], which could account for residual sleep apnea during hypoglossal nerve stimulation in many patients. Nevertheless, some improvements in pharyngeal patency and sleep apnea can still be observed in patients with retropalatal obstruction, particularly in those demonstrating a high degree of mechanical linkage or “coupling” between tongue and palatal structures [
      • Isono S.
      • Tanaka A.
      • Nishino T.
      Dynamic interaction between the tongue and soft palate during obstructive apnea in anesthetized patients with sleep-disordered breathing.
      ,
      • Isono S.
      • Tanaka A.
      • Nishino T.
      Effects of tongue electrical stimulation on pharyngeal mechanics in anaesthetized patients with obstructive sleep apnoea.
      ,
      • Goding Jr., G.S.
      • Tesfayesus W.
      • Kezirian E.J.
      Hypoglossal nerve stimulation and airway changes under fluoroscopy.
      ]. Lingual–palatal coupling could also account for the development of pharyngeal collapse predominantly in the antero-posterior rather than lateral dimension during drug-induced sleep endoscopy [
      • de Heyning PH Van
      • Badr M.S.
      • Baskin J.Z.
      • Cramer Bornemann M.A.
      • De Backer W.A.
      • Dotan Y.
      • et al.
      Implanted upper airway stimulation device for obstructive sleep apnea.
      ,
      • Goding Jr., G.S.
      • Tesfayesus W.
      • Kezirian E.J.
      Hypoglossal nerve stimulation and airway changes under fluoroscopy.
      ]. In contrast, concentric collapse of the pharyngeal lumen in both the antero-posterior and lateral dimensions has been identified as a potentially important negative predictor of responses to hypoglossal stimulation [
      • de Heyning PH Van
      • Badr M.S.
      • Baskin J.Z.
      • Cramer Bornemann M.A.
      • De Backer W.A.
      • Dotan Y.
      • et al.
      Implanted upper airway stimulation device for obstructive sleep apnea.
      ]. Nonetheless, considerable work is still required in large numbers of implanted patients to optimize selection criteria and predict responses to hypoglossal stimulation.
      Therapeutic responses to hypoglossal stimulation may depend on which lingual muscles are recruited by stimulating the hypoglossal nerve. These muscles are recruited dynamically along with other pharyngeal, cervical and respiratory pump muscles to integrate aero-digestive functions of the upper airway. Reductions in neuromuscular tone can increase airway collapsibility by decreasing caudal traction on pharyngeal structures [
      • Thut D.C.
      • Schwartz A.R.
      • Roach D.
      • Wise R.A.
      • Permutt S.
      • Smith P.L.
      Tracheal and neck position influence upper airway airflow dynamics by altering airway length.
      ] and/or by decompressing tissues around the pharynx [
      • Kairaitis K.
      • Parikh R.
      • Stavrinou R.
      • Garlick S.
      • Kirkness J.P.
      • Wheatley J.R.
      • et al.
      Upper airway extraluminal tissue pressure fluctuations during breathing in rabbits.
      ]. Effects of lingual muscles on pharyngeal patency [
      • Oliven A.
      • Odeh M.
      • Allan J.J.
      • Smith P.L.
      • Schwartz A.R.
      Electrical co-activation of tongue protrusors and retractors in patients with obstructive sleep apnea.
      ,
      • Oliven A.
      • O'hearn D.J.
      • Boudewyns A.
      • Odeh M.
      • De B.W.
      • de HP Van
      • et al.
      Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea.
      ,
      • Oliven A.
      • Odeh M.
      • Geitini L.
      • Oliven R.
      • Steinfeld U.
      • Schwartz A.R.
      • et al.
      Effect of co-activation of tongue protrusor and retractor muscles on pharyngeal lumen and airflow in sleep apnea patients.
      ] have traditionally been largely attributed to the protrusor action of the genioglossus. This muscle can prevent the tongue from prolapsing into the pharynx, while unopposed action of the styloglossus and hyoglossus muscles retracts the tongue and occludes the pharynx [
      • Schwartz A.R.
      • Eisele D.W.
      • Hari A.
      • Testerman R.
      • Erickson D.
      • Smith P.L.
      Electrical stimulation of the lingual musculature in obstructive sleep apnea.
      ]. When these muscles were activated physiologically or stimulated electrically, however, they acted in concert to stabilize tongue position and maintain retrolingual airway patency [
      • Fuller D.
      • Mateika J.H.
      • Fregosi R.F.
      Co-activation of tongue protrudor and retractor muscles during chemoreceptor stimulation in the rat.
      ,
      • Fuller D.
      • Williams J.S.
      • Janssen P.L.
      • Fregosi R.F.
      Effect of co-activation of tongue protrudor and retractor muscles on tongue movements and pharyngeal airflow mechanics in the rat.
      ]. They also modulated retropalatal patency through the zone of apposition between the dorsum of the tongue and anterior surface of the soft palate, particularly in lean compared to obese individuals [
      • Isono S.
      • Tanaka A.
      • Nishino T.
      Effects of tongue electrical stimulation on pharyngeal mechanics in anaesthetized patients with obstructive sleep apnoea.
      ,
      • Isono S.
      • Tanaka A.
      • Sho Y.
      • Konno A.
      • Nishino T.
      Advancement of the mandible improves velopharyngeal airway patency.
      ,
      • Isono S.
      • Tanaka A.
      • Tagaito Y.
      • Sho Y.
      • Nishino T.
      Pharyngeal patency in response to advancement of the mandible in obese anesthetized persons.
      ,
      • Isono S.
      Contribution of obesity and craniofacial abnormalities to pharyngeal collapsibility in patients with obstructive sleep apnea.
      ]. In further studies, investigators demonstrated heterogeneous responses to stimulating horizontally- and vertically-oriented genioglossus fibers. They found that horizontal fibers, which move the base of the tongue anteriorly, were more effective in restoring airway patency [
      • Dotan Y.
      • Golibroda T.
      • Oliven R.
      • Netzer A.
      • Gaitini L.
      • Toubi A.
      • et al.
      Parameters affecting pharyngeal response to genioglossus stimulation in sleep apnoea.
      ]. In fact, anterior tongue movement produced the greatest improvements in airway patency in subjects whose tongue and soft palate encroached more markedly on the pharyngeal lumen than did lateral pharyngeal wall tissues [
      • Dotan Y.
      • Golibroda T.
      • Oliven R.
      • Netzer A.
      • Gaitini L.
      • Toubi A.
      • et al.
      Parameters affecting pharyngeal response to genioglossus stimulation in sleep apnoea.
      ,
      • Leiter J.C.
      Upper airway shape: is it important in the pathogenesis of obstructive sleep apnea?.
      ]. Actions of these extrinsic lingual muscles can be further modulated by intrinsic tongue muscles that markedly alter the conformation of the tongue. Thus, complex interactions of lingual and other muscles can modulate pharyngeal patency by controlling the shape, stiffness and position of the tongue [
      • Zaidi F.N.
      • Meadows P.
      • Jacobowitz O.
      • Davidson T.M.
      Tongue anatomy and physiology, the scientific basis for a novel targeted neurostimulation system designed for the treatment of obstructive sleep apnea.
      ].
      Various combinations of lingual muscles can be recruited by stimulating specific segments of the hypoglossal nerve at different intensities. In general, proximal nerve stimulation recruits tongue protrusor and retractor muscles, whereas distal stimulation isolates the action of protrusor muscles [
      • Schwartz A.R.
      • Eisele D.W.
      • Hari A.
      • Testerman R.
      • Erickson D.
      • Smith P.L.
      Electrical stimulation of the lingual musculature in obstructive sleep apnea.
      ,
      • Eisele D.W.
      • Smith P.L.
      • Alam D.S.
      • Schwartz A.R.
      Direct hypoglossal nerve stimulation in obstructive sleep apnea.
      ]. These observations led investigators to suggest that stimulating the entire hypoglossal nerve distally instead of proximally conferred a therapeutic advantage [
      • Schwartz A.R.
      • Bennett M.L.
      • Smith P.L.
      • De Backer W.
      • Hedner J.
      • Boudewyns A.
      • et al.
      Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea.
      ], which was later confirmed in a follow-up study [
      • de Heyning PH Van
      • Badr M.S.
      • Baskin J.Z.
      • Cramer Bornemann M.A.
      • De Backer W.A.
      • Dotan Y.
      • et al.
      Implanted upper airway stimulation device for obstructive sleep apnea.
      ]. Distal stimulation, however, is also likely to recruit genioglossus fibers that depress the tongue, which counteract beneficial effects of muscle fibers that dilate the pharynx [
      • Oliven A.
      • Odeh M.
      • Geitini L.
      • Oliven R.
      • Steinfeld U.
      • Schwartz A.R.
      • et al.
      Effect of co-activation of tongue protrusor and retractor muscles on pharyngeal lumen and airflow in sleep apnea patients.
      ]. Stimulating the proximal nerve, on the other hand, likely activates muscles that both retract and protrude the tongue to variable degrees [
      • Eisele D.W.
      • Smith P.L.
      • Alam D.S.
      • Schwartz A.R.
      Direct hypoglossal nerve stimulation in obstructive sleep apnea.
      ,
      • Oliven A.
      • Odeh M.
      • Geitini L.
      • Oliven R.
      • Steinfeld U.
      • Schwartz A.R.
      • et al.
      Effect of co-activation of tongue protrusor and retractor muscles on pharyngeal lumen and airflow in sleep apnea patients.
      ,
      • Kezirian E.J.
      • Boudewyns A.
      • Eisele D.W.
      • Schwartz A.R.
      • Smith P.L.
      • Van de Heyning P.H.
      • et al.
      Electrical stimulation of the hypoglossal nerve in the treatment of obstructive sleep apnea.
      ], making it difficult to predict its overall effect on pharyngeal patency. Thus, stimulating the distal and proximal hypoglossal nerve can activate combinations of lingual protrusor, retractor and depressor muscles that can attenuate responses in pharyngeal patency and sleep apnea severity.
      In the current issue of the Journal of Neurological Sciences, Zaidi et al. describe methods for activating specific lingual muscles alone and in combination. Using an elegant multi-contact lead to stimulate specific sectors of the rat hypoglossal nerve, these investigators examined differential effects of targeted stimulation on tongue position, shape and airway size. Their approach was motivated by prior work suggesting topographic organization of nerve fibers within the hypoglossal nerve [
      • Aldes L.D.
      Subcompartmental organization of the ventral (protrusor) compartment in the hypoglossal nucleus of the rat.
      ,
      • Chibuzo G.A.
      • Cummings J.F.
      An enzyme tracer study of the organization of the somatic motor center for the innervation of different muscles of the tongue: evidence for two sources.
      ,
      • Krammer E.B.
      • Rath T.
      • Lischka M.F.
      Somatotopic organization of the hypoglossal nucleus: a HRP study in the rat.
      ,
      • Lee S.
      • Eisele D.W.
      • Schwartz A.R.
      • Ryugo D.K.
      Peripheral course of genioglossal motor axons within the hypoglossal nerve of the rat.
      ,
      • McClung J.R.
      • Goldberg S.J.
      Organization of motoneurons in the dorsal hypoglossal nucleus that innervate the retrusor muscles of the tongue in the rat.
      ], despite the absence of well-defined histological fascicles [
      • Lee S.
      • Eisele D.W.
      • Schwartz A.R.
      • Ryugo D.K.
      Peripheral course of genioglossal motor axons within the hypoglossal nerve of the rat.
      ]. A recent clinical report also demonstrated improvements in sleep apnea with multi-channel hypoglossal stimulation [
      • Mwenge G.B.
      Targeted hypoglossal neurostimulation for obstructive sleep apnoea: a 1-year pilot study.
      ] that were comparable to those obtained with whole nerve stimulation [
      • Schwartz A.R.
      • Bennett M.L.
      • Smith P.L.
      • De Backer W.
      • Hedner J.
      • Boudewyns A.
      • et al.
      Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea.
      ,
      • Eastwood P.R.
      • Barnes M.
      • Walsh J.H.
      • Maddison K.J.
      • Hee G.
      • Schwartz A.R.
      • et al.
      Treating obstructive sleep apnea with hypoglossal nerve stimulation.
      ,
      • de Heyning PH Van
      • Badr M.S.
      • Baskin J.Z.
      • Cramer Bornemann M.A.
      • De Backer W.A.
      • Dotan Y.
      • et al.
      Implanted upper airway stimulation device for obstructive sleep apnea.
      ,
      • Kezirian E.J.
      • Goding Jr., G.S.
      • Malhotra A.
      • O'Donoghue F.J.
      • Zammit G.
      • Wheatley J.R.
      • et al.
      Hypoglossal nerve stimulation improves obstructive sleep apnoea: 12-month outcomes.
      ]. In the present study, the investigators demonstrated unique recruitment patterns with differential activation of specific lingual muscles when specific nerve sectors were stimulated with a circumferential electrode array. They also achieved greater degrees of airway opening with selective stimulation of a relatively discrete group of proximal hypoglossal nerve fibers compared to stimulating the distal medial branch en masse, which innervates both lingual protrusor and depressor muscles. Moreover, these investigators demonstrated that responses could be independently titrated by steering current between two contacts, thereby recruiting combinations of tongue muscles innervated by specific nerve fibers in a graded fashion. Of note, unilateral stimulation also produced some degree of airway opening on the contralateral side. Finally, stimulation could be applied to specific electrodes in alternating cyclical fashion to minimize the risk of neuromuscular fatigue. Taken together, the investigators' findings suggest that selective stimulation of specific lingual muscles (or groups of muscles) both in isolation and in combination can achieve greater degrees of airway opening than stimulating the whole proximal or distal hypoglossal nerve.
      The authors' findings in rats highlight the potential that selective stimulation of the hypoglossal nerve can optimally treat obstructive sleep apnea. The advantages of this approach could be further quantified if investigators also demonstrate improvements in upper airway function. Concomitant reductions in pharyngeal collapsibility [
      • Oliven A.
      • O'hearn D.J.
      • Boudewyns A.
      • Odeh M.
      • De B.W.
      • de HP Van
      • et al.
      Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea.
      ,
      • Oliven A.
      • Odeh M.
      • Geitini L.
      • Oliven R.
      • Steinfeld U.
      • Schwartz A.R.
      • et al.
      Effect of co-activation of tongue protrusor and retractor muscles on pharyngeal lumen and airflow in sleep apnea patients.
      ,
      • Oliven A.
      • Tov N.
      • Geitini L.
      • Steinfeld U.
      • Oliven R.
      • Schwartz A.R.
      • et al.
      Effect of genioglossus contraction on pharyngeal lumen and airflow in sleep apnoea patients.
      ,
      • Oliven A.
      • Kaufman E.
      • Kaynan R.
      • Oliven R.
      • Steinfeld U.
      • Tov N.
      • et al.
      Mechanical parameters determining pharyngeal collapsibility in patients with sleep apnea.
      ,
      • Oliven R.
      • Tov N.
      • Odeh M.
      • Gaitini L.
      • Steinfeld U.
      • Schwartz A.R.
      • et al.
      Interacting effects of genioglossus stimulation and mandibular advancement in sleep apnea.
      ,
      • Yoo P.B.
      • Durand D.M.
      Effects of selective hypoglossal nerve stimulation on canine upper airway mechanics.
      ] and/or increases in airflow [
      • Eisele D.W.
      • Smith P.L.
      • Alam D.S.
      • Schwartz A.R.
      Direct hypoglossal nerve stimulation in obstructive sleep apnea.
      ,
      • Schwartz A.R.
      • Thut D.C.
      • Brower R.G.
      • Gauda E.B.
      • Roach D.
      • Permutt S.
      • et al.
      Modulation of maximal inspiratory airflow by neuromuscular activity: effect of CO2.
      ,
      • Schwartz A.R.
      • Barnes M.
      • Hillman D.
      • Malhotra A.
      • Kezirian E.
      • Smith P.L.
      • et al.
      Acute upper airway responses to hypoglossal nerve stimulation during sleep in obstructive sleep apnea.
      ] with stimulation would serve to stabilize ventilation and abolish obstructive apneas and hypopneas. Additional work is still required to develop methods for identifying combinations of lingual muscles that act synergistically to maintain airway patency during sleep. These methods may necessitate steering current between specific electrodes as well as novel approaches for visualizing effects of stimulation on tongue shape, position, and stiffness. Some 25 years of work on hypoglossal stimulation have clearly demonstrated its therapeutic potential, and have ushered in a new frontier designed to optimize effects on pharyngeal patency and obstructive sleep apnea.

      Conflict of interest

      Dr. Schwartz' laboratory currently receives research support from ImThera. Dr. Schwartz previously served as a scientific advisor to Medtronics and Apnex Medical on hypoglossal stimulation therapy.

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