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Sleep and Breathing

, Volume 23, Issue 2, pp 413–423 | Cite as

REM obstructive sleep apnea: risk for adverse health outcomes and novel treatments

  • Andrew W. VargaEmail author
  • Babak Mokhlesi
Sleep Breathing Physiology and Disorders • Review

Abstract

Rapid eye movement (REM) sleep was discovered nearly 60 years ago. This stage of sleep accounts for approximately a quarter of total sleep time in healthy adults, and it is mostly concentrated in the second half of the sleep period. The majority of research on REM sleep has focused on neurocognition. More recently, however, there has been a growing interest in understanding whether obstructive sleep apnea (OSA) during the two main stages of sleep (REM and non-REM sleep) leads to different cardiometabolic and neurocognitive risk. In this review, we discuss the growing evidence indicating that OSA during REM sleep is a prevalent disorder that is independently associated with adverse cardiovascular, metabolic, and neurocognitive outcomes. From a therapeutic standpoint, we discuss limitations of continuous positive airway pressure (CPAP) therapy given that 3 or 4 h of CPAP use from the beginning of the sleep period would leave 75% or 60% of obstructive events during REM sleep untreated. We also review potential pharmacologic approaches to treating OSA during REM sleep. Undoubtedly, further research is needed to establish best treatment strategies in order to effectively treat REM OSA. Moreover, it is critical to understand whether treatment of REM OSA will translate into better patient outcomes.

Keywords

Rapid eye movement Sleep OSA Cardiovascular Neurocognitive Diabetes Memory Mood Treatment Pharmacologic 

Abbreviations

AHI

Apnea-hypopnea index

AHI4%

Apnea-hypopnea index using 4% oxygen desaturation criteria

AHI3%a

Apnea-hypopnea index using 3% oxygen desaturation criteria and/or arousal

BMI

Body mass index

CPAP

Continuous positive airway pressure

DREADD

Designer receptor exclusively activated by designer drugs

EDS

Excessive daytime sleepiness

EPAP

Expiratory positive airway pressure

GIRK

G protein coupled inward rectifying potassium channels

MSLT

Multiple sleep latency test

Non-REM

Non-rapid eye movement sleep

PSG

Polysomnography

REM

Rapid eye movement

Notes

Acknowledgements

We thank Ward D. Pettibone for assistance in creation of the figures.

Funding information

A.W.V is supported by the American Sleep Medicine Foundation Junior Faculty Award, an American Thoracic Society Foundation Unrestricted Grant, the Friedman Brain Institute Saint-Amand Award, and NIA awards R01AG056682 and R21AG059179. B.M. is supported by National Institutes of Health grant R01HL119161 and by the Merck Investigator Studies Program. These sponsors had no role in the design or conduct of this research.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

For this type of study, formal consent is not required.

References

  1. 1.
    Grace KP, Hughes SW, Horner RL (2013) Identification of the mechanism mediating genioglossus muscle suppression in REM sleep. Am J Respir Crit Care Med 187:311–319CrossRefGoogle Scholar
  2. 2.
    Douglas NJ, White DP, Weil JV, Pickett CK, Zwillich CW (1982) Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 126:758–762Google Scholar
  3. 3.
    Douglas NJ, White DP, Weil JV, Pickett CK, Martin RJ, Hudgel DW et al (1982) Hypoxic ventilatory response decreases during sleep in normal men. Am Rev Respir Dis 125:286–289Google Scholar
  4. 4.
    Findley LJ, Wilhoit SC, Suratt PM (1985) Apnea duration and hypoxemia during REM sleep in patients with obstructive sleep apnea. Chest 87:432–436CrossRefGoogle Scholar
  5. 5.
    Krieger J, Sforza E, Boudewijns A, Zamagni M, Petiau C (1997) Respiratory effort during obstructive sleep apnea: role of age and sleep state. Chest 112:875–884CrossRefGoogle Scholar
  6. 6.
    Peppard PE, Ward NR, Morrell MJ (2009) The impact of obesity on oxygen desaturation during sleep-disordered breathing. Am J Respir Crit Care Med 180:788–793CrossRefGoogle Scholar
  7. 7.
    Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA (1997) Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 99:106–109CrossRefGoogle Scholar
  8. 8.
    Duce B, Kulkas A, Langton C, Toyras J, Hukins C (2017) The prevalence of REM-related obstructive sleep apnoea is reduced by the AASM 2012 hypopnoea criteria. Sleep BreathGoogle Scholar
  9. 9.
    Mokhlesi B, Punjabi NM (2012) “REM-related” obstructive sleep apnea: an epiphenomenon or a clinically important entity? Sleep 35:5–7CrossRefGoogle Scholar
  10. 10.
    O'Connor C, Thornley KS, Hanly PJ (2000) Gender differences in the polysomnographic features of obstructive sleep apnea. Am J Respir Crit Care Med 161:1465–1472CrossRefGoogle Scholar
  11. 11.
    Koo BB, Patel SR, Strohl K, Hoffstein V (2008) Rapid eye movement-related sleep-disordered breathing: influence of age and gender. Chest 134:1156–1161CrossRefGoogle Scholar
  12. 12.
    Resta O, Carpanano GE, Lacedonia D, Di Gioia G, Giliberti T, Stefano A et al (2005) Gender difference in sleep profile of severely obese patients with obstructive sleep apnea (OSA). Respir Med 99:91–96CrossRefGoogle Scholar
  13. 13.
    Haba-Rubio J, Janssens JP, Rochat T, Sforza E (2005) Rapid eye movement-related disordered breathing: clinical and polysomnographic features. Chest 128:3350–3357CrossRefGoogle Scholar
  14. 14.
    Koo BB, Dostal J, Ioachimescu O, Budur K (2008) The effects of gender and age on REM-related sleep-disordered breathing. Sleep Breath 12:259–264CrossRefGoogle Scholar
  15. 15.
    Conwell W, Patel B, Doeing D, Pamidi S, Knutson KL, Ghods F, Mokhlesi B (2012) Prevalence, clinical features, and CPAP adherence in REM-related sleep-disordered breathing: a cross-sectional analysis of a large clinical population. Sleep Breath 16:519–526CrossRefGoogle Scholar
  16. 16.
    Mokhlesi B, Finn LA, Hagen EW, Young T, Hla KM, Van Cauter E et al (2014) Obstructive sleep apnea during REM sleep and hypertension. results of the Wisconsin Sleep Cohort. Am J Respir Crit Care Med 190:1158–1167CrossRefGoogle Scholar
  17. 17.
    Aurora RN, Crainiceanu C, Gottlieb DJ, Kim JS, Punjabi NM (2018) Obstructive sleep apnea during REM sleep and cardiovascular disease. Am J Respir Crit Care Med 197:653–660Google Scholar
  18. 18.
    Schütz SG, Jean-Louis G, Rapoport DM, Ayappa I, Varga AW (2016) REM-related sleep apnea and cardiovascular risk. SLEEP 39:A164–A165Google Scholar
  19. 19.
    Khan A, Harrison SL, Kezirian EJ, Ancoli-Israel S, O’Hearn D, Orwoll E et al (2013) Obstructive sleep apnea during rapid eye movement sleep, daytime sleepiness, and quality of life in older men in Osteoporotic Fractures in Men (MrOS) Sleep Study. J Clin Sleep Med 9:191–198Google Scholar
  20. 20.
    Acosta-Castro P, Hirotsu C, Marti-Soler H, Marques-Vidal P, Tobback N, Andries D, Waeber G, Preisig M, Vollenweider P, Haba-Rubio J, Heinzer R (2018) REM-associated sleep apnoea: prevalence and clinical significance in the HypnoLaus cohort. In: Eur Respir J, vol 52, p 1702484Google Scholar
  21. 21.
    Dean DA, Wang R, Jacobs DR, Duprez D, Punjabi NM, Zee PC et al (2015) A systematic assessment of the association of polysomnographic indices with blood pressure: the Multi-Ethnic Study of Atherosclerosis (MESA). Sleep 38:587–596CrossRefGoogle Scholar
  22. 22.
    Hung J, Whitford EG, Parsons RW, Hillman DR (1990) Association of sleep apnoea with myocardial infarction in men. Lancet 336:261–264CrossRefGoogle Scholar
  23. 23.
    Marin JM, Carrizo SJ, Vicente E, Agusti AG (2005) Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 365:1046–1053CrossRefGoogle Scholar
  24. 24.
    Arzt M, Young T, Finn L, Skatrud JB, Bradley TD (2005) Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med 172:1447–1451CrossRefGoogle Scholar
  25. 25.
    Redline S, Yenokyan G, Gottlieb DJ, Shahar E, O’Connor GT, Resnick HE, Diener-West M, Sanders MH, Wolf PA, Geraghty EM, Ali T, Lebowitz M, Punjabi NM (2010) Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 182:269–277CrossRefGoogle Scholar
  26. 26.
    Peppard PE, Young T, Palta M, Skatrud J (2000) Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342:1378–1384CrossRefGoogle Scholar
  27. 27.
    Cano-Pumarega I, Duran-Cantolla J, Aizpuru F, Miranda-Serrano E, Rubio R, Martinez-Null C et al (2011) Obstructive sleep apnea and systemic hypertension: longitudinal study in the general population: the Vitoria Sleep Cohort. Am J Respir Crit Care Med 184:1299–1304CrossRefGoogle Scholar
  28. 28.
    Cano-Pumarega I, Barbe F, Esteban A, Martinez-Alonso M, Egea C, Duran-Cantolla J et al (2017) Sleep apnea and hypertension: are there sex differences? The Vitoria Sleep Cohort. Chest 152:742–750CrossRefGoogle Scholar
  29. 29.
    O'Connor GT, Caffo B, Newman AB, Quan SF, Rapoport DM, Redline S, Resnick HE, Samet J, Shahar E (2009) Prospective study of sleep-disordered breathing and hypertension: the Sleep Heart Health Study. Am J Respir Crit Care Med 179:1159–1164CrossRefGoogle Scholar
  30. 30.
    Somers VK, Dyken ME, Clary MP, Abboud FM (1995) Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 96:1897–1904CrossRefGoogle Scholar
  31. 31.
    Somers VK, Dyken ME, Mark AL, Abboud FM (1993) Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 328:303–307CrossRefGoogle Scholar
  32. 32.
    Appleton SL, Vakulin A, Martin SA, Lang CJ, Wittert GA, Taylor AW, McEvoy RD, Antic NA, Catcheside PG, Adams RJ (2016) Hypertension is associated with undiagnosed OSA during rapid eye movement sleep. Chest 150:495–505CrossRefGoogle Scholar
  33. 33.
    Mokhlesi B, Hagen EW, Finn LA, Hla KM, Carter JR, Peppard PE (2015) Obstructive sleep apnoea during REM sleep and incident non-dipping of nocturnal blood pressure: a longitudinal analysis of the Wisconsin Sleep Cohort. Thorax 70:1062–1069CrossRefGoogle Scholar
  34. 34.
    Sarigianni M, Dimitrakopoulos K, Tsapas A (2014) Non-dipping status in arterial hypertension: an overview. Curr Vasc Pharmacol 12:527–536CrossRefGoogle Scholar
  35. 35.
    Cuspidi C, Sala C, Tadic M, Rescaldani M, Grassi G, Mancia G (2015) Untreated masked hypertension and subclinical cardiac damage: a systematic review and meta-analysis. Am J Hypertens 28:806–813CrossRefGoogle Scholar
  36. 36.
    Jouvet M, Michel F, Mounier D (1960) Comparative electroencephalographic analysis of physiological sleep in the cat and in man. Rev Neurol (Paris) 103:189–205Google Scholar
  37. 37.
    Cajochen C, Pischke J, Aeschbach D, Borbely AA (1994) Heart rate dynamics during human sleep. Physiol Behav 55:769–774CrossRefGoogle Scholar
  38. 38.
    Zinchuk AV, Jeon S, Koo BB, Yan X, Bravata DM, Qin L, Selim BJ, Strohl KP, Redeker NS, Concato J, Yaggi HK (2018) Polysomnographic phenotypes and their cardiovascular implications in obstructive sleep apnoea. Thorax 73:472–480Google Scholar
  39. 39.
    Barbe F, Duran-Cantolla J, Sanchez-de-la-Torre M, Martinez-Alonso M, Carmona C, Barcelo A et al (2012) Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 307:2161–2168CrossRefGoogle Scholar
  40. 40.
    McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano O, Chen R, Drager LF, Liu Z, Chen G, du B, McArdle N, Mukherjee S, Tripathi M, Billot L, Li Q, Lorenzi-Filho G, Barbe F, Redline S, Wang J, Arima H, Neal B, White DP, Grunstein RR, Zhong N, Anderson CS (2016) CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med 375:919–931CrossRefGoogle Scholar
  41. 41.
    Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek J, Kanarek R, Maratos-Flier E (1996) A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380:243–247CrossRefGoogle Scholar
  42. 42.
    Guan JL, Uehara K, Lu S, Wang QP, Funahashi H, Sakurai T, Yanagizawa M, Shioda S (2002) Reciprocal synaptic relationships between orexin- and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus: a novel circuit implicated in feeding regulation. Int J Obes Relat Metab Disord 26:1523–1532CrossRefGoogle Scholar
  43. 43.
    Tsuneki H, Wada T, Sasaoka T (2010) Role of orexin in the regulation of glucose homeostasis. Acta Physiol (Oxford) 198:335–348CrossRefGoogle Scholar
  44. 44.
    Vetrivelan R, Kong D, Ferrari LL, Arrigoni E, Madara JC, Bandaru SS, Lowell BB, Lu J, Saper CB (2016) Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice. Neuroscience 336:102–113CrossRefGoogle Scholar
  45. 45.
    Alnaji A, Law GR, Scott EM (2016) The role of sleep duration in diabetes and glucose control. Proc Nutr Soc 75:512–520CrossRefGoogle Scholar
  46. 46.
    Briancon-Marjollet A, Weiszenstein M, Henri M, Thomas A, Godin-Ribuot D, Polak J (2015) The impact of sleep disorders on glucose metabolism: endocrine and molecular mechanisms. Diabetol Metab Syndr 7:25CrossRefGoogle Scholar
  47. 47.
    Stoohs RA, Facchini F, Guilleminault C (1996) Insulin resistance and sleep-disordered breathing in healthy humans. Am J Respir Crit Care Med 154:170–174CrossRefGoogle Scholar
  48. 48.
    Lindberg E, Theorell-Haglow J, Svensson M, Gislason T, Berne C, Janson C (2012) Sleep apnea and glucose metabolism: a long-term follow-up in a community-based sample. Chest 142:935–942CrossRefGoogle Scholar
  49. 49.
    Reutrakul S, Mokhlesi B (2017) Obstructive sleep apnea and diabetes: a state of the art review. Chest 152:1070–1086CrossRefGoogle Scholar
  50. 50.
    Pamidi S, Wroblewski K, Broussard J, Day A, Hanlon EC, Abraham V, Tasali E (2012) Obstructive sleep apnea in young lean men: impact on insulin sensitivity and secretion. Diabetes Care 35:2384–2389CrossRefGoogle Scholar
  51. 51.
    Lin QC, Zhang XB, Chen GP, Huang DY, Din HB, Tang AZ (2012) Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome in nonobese adults. Sleep Breath 16:571–578CrossRefGoogle Scholar
  52. 52.
    Bialasiewicz P, Pawlowski M, Nowak D, Loba J, Czupryniak L (2009) Decreasing concentration of interstitial glucose in REM sleep in subjects with normal glucose tolerance. Diabet Med 26:339–344CrossRefGoogle Scholar
  53. 53.
    Thakkar M, Mallick BN (1993) Rapid eye movement sleep-deprivation-induced changes in glucose metabolic enzymes in rat brain. Sleep 16:691–694Google Scholar
  54. 54.
    Xu J, Long YS, Gozal D, Epstein PN (2009) Beta-cell death and proliferation after intermittent hypoxia: role of oxidative stress. Free Radic Biol Med 46:783–790CrossRefGoogle Scholar
  55. 55.
    Wang N, Khan SA, Prabhakar NR, Nanduri J (2013) Impairment of pancreatic beta-cell function by chronic intermittent hypoxia. Exp Physiol 98:1376–1385CrossRefGoogle Scholar
  56. 56.
    Shpirer I, Rapoport MJ, Stav D, Elizur A (2012) Normal and elevated HbA1C levels correlate with severity of hypoxemia in patients with obstructive sleep apnea and decrease following CPAP treatment. Sleep Breath 16:461–466CrossRefGoogle Scholar
  57. 57.
    Bialasiewicz P, Czupryniak L, Pawlowski M, Nowak D (2011) Sleep disordered breathing in REM sleep reverses the downward trend in glucose concentration. Sleep Med 12:76–82CrossRefGoogle Scholar
  58. 58.
    Chami HA, Gottlieb DJ, Redline S, Punjabi NM (2015) Association between glucose metabolism and sleep-disordered breathing during REM sleep. Am J Respir Crit Care Med 192:1118–1126CrossRefGoogle Scholar
  59. 59.
    Grimaldi D, Beccuti G, Touma C, Van Cauter E, Mokhlesi B (2014) Association of obstructive sleep apnea in rapid eye movement sleep with reduced glycemic control in type 2 diabetes: therapeutic implications. Diabetes Care 37:355–363CrossRefGoogle Scholar
  60. 60.
    Young LR, Taxin ZH, Norman RG, Walsleben JA, Rapoport DM, Ayappa I (2013) Response to CPAP withdrawal in patients with mild versus severe obstructive sleep apnea/hypopnea syndrome. Sleep 36:405–412CrossRefGoogle Scholar
  61. 61.
    Chervin RD, Aldrich MS (1998) The relation between multiple sleep latency test findings and the frequency of apneic events in REM and non-REM sleep. Chest 113:980–984CrossRefGoogle Scholar
  62. 62.
    Punjabi NM, Bandeen-Roche K, Marx JJ, Neubauer DN, Smith PL, Schwartz AR (2002) The association between daytime sleepiness and sleep-disordered breathing in NREM and REM sleep. Sleep 25:307–314Google Scholar
  63. 63.
    Chami HA, Baldwin CM, Silverman A, Zhang Y, Rapoport D, Punjabi NM, Gottlieb DJ (2010) Sleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing. Am J Respir Crit Care Med 181:997–1002CrossRefGoogle Scholar
  64. 64.
    Varga AW, Kishi A, Mantua J, Lim J, Koushyk V, Leibert DP, Osorio RS, Rapoport DM, Ayappa I (2014) Apnea-induced rapid eye movement sleep disruption impairs human spatial navigational memory. J Neurosci 34:14571–14577CrossRefGoogle Scholar
  65. 65.
    Lee SA, Paek JH, Han SH (2016) REM-related sleep-disordered breathing is associated with depressive symptoms in men but not in women. Sleep Breath 20:995–1002CrossRefGoogle Scholar
  66. 66.
    Liu Y, Su C, Liu R, Lei G, Zhang W, Yang T, Miao J, Li Z (2011) NREM-AHI greater than REM-AHI versus REM-AHI greater than NREM-AHI in patients with obstructive sleep apnea: clinical and polysomnographic features. Sleep Breath 15:463–470CrossRefGoogle Scholar
  67. 67.
    Pamidi S, Knutson KL, Ghods F, Mokhlesi B (2011) Depressive symptoms and obesity as predictors of sleepiness and quality of life in patients with REM-related obstructive sleep apnea: cross-sectional analysis of a large clinical population. Sleep Med 12:827–831CrossRefGoogle Scholar
  68. 68.
    Stickgold R, Walker MP (2013) Sleep-dependent memory triage: evolving generalization through selective processing. Nat Neurosci 16:139–145CrossRefGoogle Scholar
  69. 69.
    Cai DJ, Mednick SA, Harrison EM, Kanady JC, Mednick SC (2009) REM, not incubation, improves creativity by priming associative networks. Proc Natl Acad Sci U S A 106:10130–10134CrossRefGoogle Scholar
  70. 70.
    Karni A, Tanne D, Rubenstein BS, Askenasy JJ, Sagi D (1994) Dependence on REM sleep of overnight improvement of a perceptual skill. Science 265:679–682CrossRefGoogle Scholar
  71. 71.
    Plihal W, Born J (1997) Effects of early and late nocturnal sleep on declarative and procedural memory. J Cogn Neurosci 9:534–547CrossRefGoogle Scholar
  72. 72.
    Rasch B, Gais S, Born J (2009) Impaired off-line consolidation of motor memories after combined blockade of cholinergic receptors during REM sleep-rich sleep. Neuropsychopharmacology 34:1843–1853CrossRefGoogle Scholar
  73. 73.
    Barsky MM, Tucker MA, Stickgold R (2015) REM sleep enhancement of probabilistic classification learning is sensitive to subsequent interference. Neurobiol Learn Mem 122:63–68CrossRefGoogle Scholar
  74. 74.
    Nishida M, Pearsall J, Buckner RL, Walker MP (2009) REM sleep, prefrontal theta, and the consolidation of human emotional memory. Cereb Cortex 19:1158–1166CrossRefGoogle Scholar
  75. 75.
    van der Helm E, Yao J, Dutt S, Rao V, Saletin JM, Walker MP (2011) REM sleep depotentiates amygdala activity to previous emotional experiences. Curr Biol 21:2029–2032CrossRefGoogle Scholar
  76. 76.
    van der Helm E, Walker MP (2011) Sleep and emotional memory processing. Sleep Med Clin 6:31–43CrossRefGoogle Scholar
  77. 77.
    Sloan MA (1972) The effects of deprivation of rapid eye movement (REM) sleep on maze learning and aggression in the albino rat. J Psychiatr Res 9:101–111CrossRefGoogle Scholar
  78. 78.
    Boyce R, Glasgow SD, Williams S, Adamantidis A (2016) Causal evidence for the role of REM sleep theta rhythm in contextual memory consolidation. Science 352:812–816CrossRefGoogle Scholar
  79. 79.
    Cedernaes J, Osorio RS, Varga AW, Kam K, Schioth HB, Benedict C (2017) Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer’s disease. Sleep Med Rev 31:102–111CrossRefGoogle Scholar
  80. 80.
    Sharma, R.A., A.W. Varga, O.M. Bubu et al. (2017) Obstructive sleep apnea severity affects amyloid burden in cognitively normal elderly: a longitudinal study. Am J Respir Crit Care Med,Google Scholar
  81. 81.
    Pase MP, Himali JJ, Grima NA, Beiser AS, Satizabal CL, Aparicio HJ, Thomas RJ, Gottlieb DJ, Auerbach SH, Seshadri S (2017) Sleep architecture and the risk of incident dementia in the community. Neurology 89:1244–1250CrossRefGoogle Scholar
  82. 82.
    Lettieri CJ, Williams SG, Collen JF, Wickwire EM (2017) Treatment of obstructive sleep apnea: achieving adherence to positive airway pressure treatment and dealing with complications. Sleep Med Clin 12:551–564CrossRefGoogle Scholar
  83. 83.
    Berry RB, Kryger MH, Massie CA (2011) A novel nasal expiratory positive airway pressure (EPAP) device for the treatment of obstructive sleep apnea: a randomized controlled trial. Sleep 34:479–485CrossRefGoogle Scholar
  84. 84.
    Kryger MH, Berry RB, Massie CA (2011) Long-term use of a nasal expiratory positive airway pressure (EPAP) device as a treatment for obstructive sleep apnea (OSA). J Clin Sleep Med 7:449–53BGoogle Scholar
  85. 85.
    Naismith SL, Winter VR, Hickie IB, Cistulli PA (2005) Effect of oral appliance therapy on neurobehavioral functioning in obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med 1:374–380Google Scholar
  86. 86.
    Aarab G, Lobbezoo F, Hamburger HL, Naeije M (2011) Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnea: a randomized, placebo-controlled trial. Respiration 81:411–419CrossRefGoogle Scholar
  87. 87.
    Strollo PJ Jr, Soose RJ, Maurer JT, de Vries N, Cornelius J, Froymovich O et al (2014) Upper-airway stimulation for obstructive sleep apnea. N Engl J Med 370:139–149CrossRefGoogle Scholar
  88. 88.
    Mason M, Welsh EJ, Smith I (2013) Drug therapy for obstructive sleep apnoea in adults. Cochrane Database Syst Rev: CD003002Google Scholar
  89. 89.
    Horner RL, Grace KP, Wellman A (2017) A resource of potential drug targets and strategic decision-making for obstructive sleep apnoea pharmacotherapy. Respirology 22:861–873CrossRefGoogle Scholar
  90. 90.
    Sands SA, Edwards BA, Terrill PI, Taranto-Montemurro L, Azarbarzin A, Marques M, Hess LB, White DP, Wellman A (2018) Phenotyping pharyngeal pathophysiology using polysomnography in patients with obstructive sleep apnea. In: Am J Respir Crit care med, vol 197, pp 1187–1197Google Scholar
  91. 91.
    Bastedo T, Chan E, Park E, Liu H, Horner RL (2009) Modulation of genioglossus muscle activity across sleep-wake states by histamine at the hypoglossal motor pool. Sleep 32:1313–1324CrossRefGoogle Scholar
  92. 92.
    Trimmer JS (2015) Subcellular localization of K+ channels in mammalian brain neurons: remarkable precision in the midst of extraordinary complexity. Neuron 85:238–256CrossRefGoogle Scholar
  93. 93.
    Grace KP, Hughes SW, Shahabi S, Horner RL (2013) K+ channel modulation causes genioglossus inhibition in REM sleep and is a strategy for reactivation. Respir Physiol Neurobiol 188:277–288CrossRefGoogle Scholar
  94. 94.
    Topert C, Doring F, Wischmeyer E, Karschin C, Brockhaus J, Ballanyi K et al (1998) Kir2.4: a novel K+ inward rectifier channel associated with motoneurons of cranial nerve nuclei. J Neurosci 18:4096–4105CrossRefGoogle Scholar
  95. 95.
    Fleury Curado T, Fishbein K, Pho H, Brennick M, Dergacheva O, Sennes LU, Pham LV, Ladenheim EE, Spencer R, Mendelowitz D, Schwartz AR, Polotsky VY (2017) Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency. Sci Rep 7:44392CrossRefGoogle Scholar
  96. 96.
    Horton GA, Fraigne JJ, Torontali ZA, Snow MB, Lapierre JL, Liu H, Montandon G, Peever JH, Horner RL (2017) Activation of the hypoglossal to tongue musculature motor pathway by remote control. Sci Rep 7:45860CrossRefGoogle Scholar
  97. 97.
    Burdyga G, Lal S, Varro A, Dimaline R, Thompson DG, Dockray GJ (2004) Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin. J Neurosci 24:2708–2715CrossRefGoogle Scholar
  98. 98.
    Carley DW, Radulovacki M (2008) Pharmacology of vagal afferent influences on disordered breathing during sleep. Respir Physiol Neurobiol 164:197–203CrossRefGoogle Scholar
  99. 99.
    Carley DW, Paviovic S, Janelidze M, Radulovacki M (2002) Functional role for cannabinoids in respiratory stability during sleep. Sleep 25:391–398CrossRefGoogle Scholar
  100. 100.
    Calik MW, Radulovacki M, Carley DW (2014) Intranodose ganglion injections of dronabinol attenuate serotonin-induced apnea in Sprague-Dawley rat. Respir Physiol Neurobiol 190:20–24CrossRefGoogle Scholar
  101. 101.
    Prasad B, Radulovacki MG, Carley DW (2013) Proof of concept trial of dronabinol in obstructive sleep apnea. Front Psychiatry 4:1Google Scholar
  102. 102.
    Carley DW, Prasad B, Reid KJ, Malkani R, Attarian H, Abbott SM, Vern B, Xie H, Yuan C, Zee PC (2018) Pharmacotherapy of apnea by cannabimimetic enhancement, the PACE clinical trial: effects of dronabinol in obstructive sleep apnea. Sleep 41Google Scholar
  103. 103.
    Veasey SC, Fenik P, Panckeri K, Pack AI, Hendricks JC (1999) The effects of trazodone with L-tryptophan on sleep-disordered breathing in the English bulldog. Am J Respir Crit Care Med 160:1659–1667CrossRefGoogle Scholar
  104. 104.
    Boyd SB, Upender R, Walters AS, Goodpaster RL, Stanley JJ, Wang L, Chandrasekhar R (2016) Effective apnea-hypopnea index (“effective AHI”): a new measure of effectiveness for positive airway pressure therapy. Sleep 39:1961–1972CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Mount Sinai Integrative Sleep CenterIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Section of Pulmonary and Critical Care Medicine, Sleep Disorders CenterUniversity of ChicagoChicagoUSA

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