Abstract
There is much speculation that respiratory motor long-term facilitation may have a significant impact on apnea severity in individuals with sleep apnea because this disorder is characterized by exposure to intermittent hypoxia, one stimulus known to initiate long-term facilitation. It has been suggested that activation of long-term facilitation may serve to mitigate apnea by facilitating minute ventilation and, perhaps more importantly, upper airway muscle activity. The less discussed but equally plausible situation is that exposure to intermittent hypoxia might ultimately lead to the promotion of apnea. There are at least two scenarios in which apnea might be promoted following exposure to intermittent hypoxia. In both scenarios, long-term facilitation of upper airway muscle activity is initiated but ultimately rendered ineffective because of muscle fatigue or the initiation of other forms of respiratory plasticity, more specifically progressive augmentation of the hypoxic ventilatory response. The primary goal of this chapter is to discuss whether the complex interactions of various forms of respiratory motor neuronal plasticity have a beneficial or a detrimental impact on breathing stability in individuals with sleep apnea. The overall conclusion is that exposure to intermittent hypoxia should not be considered exclusively beneficial or detrimental to breathing stability in individuals with sleep apnea. Rather, the beneficial or detrimental outcomes of exposure to intermittent hypoxia are likely dependent on a variety of circumstances and the complex interactions between various forms of respiratory motor plasticity.
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Aboubakr SE, Taylor A, Ford R, et al. Long-term facilitation in obstructive sleep apnea patients during NREM sleep. J Appl Physiol. 2001;91:2751–7.
Ahuja D, Mateika JH, Diamond MP, et al. Ventilatory sensitivity to carbon dioxide before and after episodic hypoxia in women treated with testosterone. J Appl Physiol. 2007;102:1832–8.
Ancoli-Israel S, Kripke DF, Klauber MR, et al. Sleep-disordered breathing in community-dwelling elderly. Sleep. 1991;14:486–95.
Babcock MA, Badr MS. Long-term facilitation of ventilation in humans during NREM sleep. Sleep. 1998;21:709–16.
Bach KB, Mitchell GS. Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent. Respir Physiol. 1996;104:251–60.
Badr MS. Effect of ventilatory drive on upper airway patency in humans during NREM sleep. Respir Physiol. 1996;103:1–10.
Badr MS, Kawak A, Skatrud JB, et al. Effect of induced hypocapnic hypopnea on upper airway patency in humans during NREM sleep. Respir Physiol. 1997;110:33–45.
Badr MS, Toiber F, Skatrud JB, et al. Pharyngeal narrowing/occlusion during central sleep apnea. J Appl Physiol. 1995;78:1806–15.
Baker-Herman TL, Bavis RW, Dahlberg JM, et al. Differential expression of respiratory long-term facilitation among inbred rat strains. Respir Physiol Neurobiol. 2010;170:260–7.
Behan M, Zabka AG, Thomas CF, et al. Sex steroid hormones and the neural control of breathing. Respir Physiol Neurobiol. 2003;136:249–63.
Bradford A, McGuire M, O’Halloran KD. Does episodic hypoxia affect upper airway dilator muscle function? Implications for the pathophysiology of obstructive sleep apnoea. Respir Physiol Neurobiol. 2005;147:223–34.
Cala SJ, Sliwinski P, Cosio MG, et al. Effect of topical upper airway anesthesia on apnea duration through the night in obstructive sleep apnea. J Appl Physiol. 1996;81:2618–26.
Charbonneau M, Marin JM, Olha A, et al. Changes in obstructive sleep apnea characteristics through the night. Chest. 1994;106:1695–701.
Chowdhuri S, Pierchala L, Aboubakr SE, et al. Long-term facilitation of genioglossus activity is present in normal humans during NREM sleep. Respir Physiol Neurobiol. 2008;160:65–75.
Chowdhuri S, Shanidze I, Pierchala L, et al. Effect of episodic hypoxia on the susceptibility to hypocapnic central apnea during NREM sleep. J Appl Physiol. 2010;108:369–77.
Dale-Nagle EA, Hoffman MS, Macfarlane PM, et al. Spinal plasticity following intermittent hypoxia: implications for spinal injury. Ann N Y Acad Sci. 2010;1198:252–9.
Dempsey JA. Crossing the apnoeic threshold: causes and consequences. Exp Physiol. 2005;90:13–24.
Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory responsiveness to CO2 below eupnoea as a determinant of ventilatory stability in sleep. J Physiol. 2004;560:1–11.
Dempsey JA, Veasey SC, Morgan BJ, et al. Pathophysiology of sleep apnea. Physiol Rev. 2010;90:47–112.
Duffin J. The role of the central chemoreceptors: a modeling perspective. Respir Physiol Neurobiol. 2010;173:230–43.
Duffin J. Measuring the ventilatory response to hypoxia. J Physiol. 2007;584:285–93.
Duffin J, Mohan RM, Vasiliou P, et al. A model of the chemoreflex control of breathing in humans: model parameters measurement. Respir Physiol. 2000;120:13–26.
Fanfulla F, Patruno V, Bruschi C, et al. Obstructive sleep apnoea syndrome: is the “half-night polysomnography” an adequate method for evaluating sleep profile and respiratory events? Eur Respir J. 1997;10:1725–9.
Foster GE, McKenzie DC, Milsom WK, et al. Effects of two protocols of intermittent hypoxia on human ventilatory, cardiovascular and cerebral responses to hypoxia. J Physiol. 2005;567:689–99.
Fuller DD. Episodic hypoxia induces long-term facilitation of neural drive to tongue protrudor and retractor muscles. J Appl Physiol. 2005;98:1761–7.
Fuller DD, Baker TL, Behan M, et al. Expression of hypoglossal long-term facilitation differs between substrains of Sprague–Dawley rat. Physiol Genomics. 2001;4:175–81.
Gerst III DG, Yokhana SS, Carney LM, et al. The hypoxic ventilatory response and ventilatory long-term facilitation are altered by time of day and repeated daily exposure to intermittent hypoxia. J Appl Physiol. 2011;110:15–28.
Harris DP, Balasubramaniam A, Badr MS, et al. Long-term facilitation of ventilation and genioglossus muscle activity is evident in the presence of elevated levels of carbon dioxide in awake humans. Am J Physiol Regul Integr Comp Physiol. 2006;291:R1111–9.
Hudgel DW, Chapman KR, Faulks C, et al. Changes in inspiratory muscle electrical activity and upper airway resistance during periodic breathing induced by hypoxia during sleep. Am Rev Respir Dis. 1987;135:899–906.
Jordan AS, Catcheside PG, O’Donoghue FJ, et al. Long-term facilitation of ventilation is not present during wakefulness in healthy men or women. J Appl Physiol. 2002;93:2129–36.
Katayama K, Smith CA, Henderson KS, et al. Chronic intermittent hypoxia increases the CO2 reserve in sleeping dogs. J Appl Physiol. 2007;103:1942–9.
Khodadadeh B, Badr MS, Mateika JH. The ventilatory response to carbon dioxide and sustained hypoxia is enhanced after episodic hypoxia in OSA patients. Respir Physiol Neurobiol. 2006;150:122–34.
Koehle MS, Sheel AW, Milsom WK, et al. Two patterns of daily hypoxic exposure and their effects on measures of chemosensitivity in humans. J Appl Physiol. 2007;103:1973–8.
Lavie P. Incidence of sleep apnea in a presumably healthy working population: a significant relationship with excessive daytime sleepiness. Sleep. 1983;6:312–8.
Lee DS, Badr MS, Mateika JH. Progressive augmentation and ventilatory long-term facilitation are enhanced in sleep apnoea patients and are mitigated by antioxidant administration. J Physiol. 2009;587:5451–67.
Ling L, Fuller DD, Bach KB, et al. Chronic intermittent hypoxia elicits serotonin-dependent plasticity in the central neural control of breathing. J Neurosci. 2001;21:5381–8.
Lusina SJ, Kennedy PM, Inglis JT, et al. Long-term intermittent hypoxia increases sympathetic activity and chemosensitivity during acute hypoxia in humans. J Physiol. 2006;575:961–70.
Mahamed S, Mitchell GS. Respiratory long-term facilitation: too much or too little of a good thing? Adv Exp Med Biol. 2008;605:224–7.
Mahamed S, Mitchell GS. Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp Physiol. 2007;92:27–37.
Mateika JH, Fregosi RF. Long-term facilitation of upper airway muscle activities in vagotomized and vagally intact cats. J Appl Physiol. 1997;82:419–25.
Mateika JH, Mendello C, Obeid D, et al. Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans. J Appl Physiol. 2004;96:1197–205.
Mateika JH, Millrood DL, Kim J, et al. Response of human tongue protrudor and retractors to hypoxia and hypercapnia. Am J Respir Crit Care Med. 1999;160:1976–82.
Mateika JH, Narwani G. Intermittent hypoxia and respiratory plasticity in humans and other animals: does exposure to intermittent hypoxia promote or mitigate sleep apnoea? Exp Physiol. 2009;94:279–96.
McEvoy RD, Popovic RM, Saunders NA, et al. Effects of sustained and repetitive isocapnic hypoxia on ventilation and genioglossal and diaphragmatic EMGs. J Appl Physiol. 1996;81:866–75.
McGuire M, Ling L. Ventilatory long-term facilitation is greater in 1- vs. 2-mo-old awake rats. J Appl Physiol. 2005;98:1195–201.
McGuire M, MacDermott M, Bradford A. The effects of chronic episodic hypercapnic hypoxia on rat upper airway muscle contractile properties and fiber-type distribution. Chest. 2002;122:1400–6.
McGuire M, Zhang Y, White DP, et al. Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats. J Appl Physiol. 2003;95:1499–508.
McKay LC, Janczewski WA, Feldman JL. Episodic hypoxia evokes long-term facilitation of genioglossus muscle activity in neonatal rats. J Physiol. 2004;557:13–8.
Millhorn DE, Eldridge FL, Waldrop TG. Prolonged stimulation of respiration by a new central neural mechanism. Respir Physiol. 1980;41:87–103.
Mitchell GS, Baker TL, Nanda SA, et al. Invited review: intermittent hypoxia and respiratory plasticity. J Appl Physiol. 2001;90:2466–75.
Mitchell GS, Johnson SM. Neuroplasticity in respiratory motor control. J Appl Physiol. 2003;94:358–74.
Morelli C, Badr MS, Mateika JH. Ventilatory responses to carbon dioxide at low and high levels of oxygen are elevated after episodic hypoxia in men compared with women. J Appl Physiol. 2004;97:1673–80.
Morris KF, Baekey DM, Shannon R, et al. Respiratory neural activity during long-term facilitation. Respir Physiol. 2000;121:119–33.
Morris KF, Gozal D. Persistent respiratory changes following intermittent hypoxic stimulation in cats and human beings. Respir Physiol Neurobiol. 2004;140:1–8.
Nakamura A, Olson Jr EB, Terada J, et al. Sleep state dependence of ventilatory long-term facilitation following acute intermittent hypoxia in Lewis rats. J Appl Physiol. 2010;109:323–31.
Olson Jr EB, Bohne CJ, Dwinell MR, et al. Ventilatory long-term facilitation in unanesthetized rats. J Appl Physiol. 2001;91:709–16.
Onal E, Burrows DL, Hart RH, et al. Induction of periodic breathing during sleep causes upper airway obstruction in humans. J Appl Physiol. 1986;61:1438–43.
Pavlova MK, Duffy JF, Shea SA. Polysomnographic respiratory abnormalities in asymptomatic individuals. Sleep. 2008;31:241–8.
Peng YJ, Overholt JL, Kline D, et al. Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci USA. 2003;100:10073–8.
Peng YJ, Prabhakar NR. Reactive oxygen species in the plasticity of respiratory behavior elicited by chronic intermittent hypoxia. J Appl Physiol. 2003;94:2342–9.
Peng YJ, Yuan G, Ramakrishnan D, et al. Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol. 2006;577:705–16.
Pialoux V, Hanly PJ, Foster GE, et al. Effects of exposure to intermittent hypoxia on oxidative stress and acute hypoxic ventilatory response in humans. Am J Respir Crit Care Med. 2009;180:1002–9.
Pierchala LA, Mohammed AS, Grullon K, et al. Ventilatory long-term facilitation in non-snoring subjects during NREM sleep. Respir Physiol Neurobiol. 2008;160:259–66.
Powell FL, Milsom WK, Mitchell GS. Time domains of the hypoxic ventilatory response. Respir Physiol. 1998;112:123–34.
Ray AD, Magalang UJ, Michlin CP, et al. Intermittent hypoxia reduces upper airway stability in lean but not obese Zucker rats. Am J Physiol Regul Integr Comp Physiol. 2007;293:R372–8.
Reite M, Jackson D, Cahoon RL, et al. Sleep physiology at high altitude. Electroencephalogr Clin Neurophysiol. 1975;38:463–71.
Salloum A, Rowley JA, Mateika JH, et al. Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure. Am J Respir Crit Care Med. 2010;181:189–93.
Serebrovskaya TV, Swanson RJ, Karaban IN, et al. Intermittent hypoxia alters hypoxic ventilatory responses. Fiziol Zh. 1999;45:9–18.
Sforza E, Krieger J, Petiau C. Nocturnal evolution of respiratory effort in obstructive sleep apnoea syndrome: influence on arousal threshold. Eur Respir J. 1998;12:1257–63.
Shkoukani M, Babcock MA, Badr MS. Effect of episodic hypoxia on upper airway mechanics in humans during NREM sleep. J Appl Physiol. 2002;92:2565–70.
Tamisier R, Gilmartin GS, Launois SH, et al. A new model of chronic intermittent hypoxia in humans: effect on ventilation, sleep, and blood pressure. J Appl Physiol. 2009;107:17–24.
Teppema LJ, Dahan A. The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis. Physiol Rev. 2010;90:675–754.
Terada J, Nakamura A, Zhang W, et al. Ventilatory long-term facilitation in mice can be observed during both sleep and wake periods and depends on orexin. J Appl Physiol. 2008;104:499–507.
Veasey SC, Zhan G, Fenik P, et al. Long-term intermittent hypoxia: reduced excitatory hypoglossal nerve output. Am J Respir Crit Care Med. 2004;170:665–72.
White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med. 2005;172:1363–70.
Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328:1230–5.
Zabka AG, Behan M, Mitchell GS. Long term facilitation of respiratory motor output decreases with age in male rats. J Physiol. 2001;531:509–14.
Zabka AG, Mitchell GS, Behan M. Ageing and gonadectomy have similar effects on hypoglossal long-term facilitation in male Fischer rats. J Physiol. 2005;563:557–68.
Zabka AG, Mitchell GS, Olson Jr EB, et al. Selected contribution: chronic intermittent hypoxia enhances respiratory long-term facilitation in geriatric female rats. J Appl Physiol. 2003;95:2614–23.
Acknowledgments
This work was supported by a grant from the National Heart, Lung, and Blood Institute and a VA Merit Award.
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Mateika, J.H. (2012). Effect of Intermittent Hypoxia on Breathing Stability in Individuals with Sleep Apnea. In: Xi, L., Serebrovskaya, T. (eds) Intermittent Hypoxia and Human Diseases. Springer, London. https://doi.org/10.1007/978-1-4471-2906-6_7
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