Semin Respir Crit Care Med 2023; 44(05): 627-649
DOI: 10.1055/s-0043-1770342
Review Article

Control of Breathing

Jerome A. Dempsey
1   John Rankin Laboratory of Pulmonary Medicine, Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin
,
Joseph F. Welch
2   School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
› Author Affiliations
Funding Grant support for this study was provided by NHLBI.

Abstract

Substantial advances have been made recently into the discovery of fundamental mechanisms underlying the neural control of breathing and even some inroads into translating these findings to treating breathing disorders. Here, we review several of these advances, starting with an appreciation of the importance of V̇A:V̇CO2:PaCO2 relationships, then summarizing our current understanding of the mechanisms and neural pathways for central rhythm generation, chemoreception, exercise hyperpnea, plasticity, and sleep-state effects on ventilatory control. We apply these fundamental principles to consider the pathophysiology of ventilatory control attending hypersensitized chemoreception in select cardiorespiratory diseases, the pathogenesis of sleep-disordered breathing, and the exertional hyperventilation and dyspnea associated with aging and chronic diseases. These examples underscore the critical importance that many ventilatory control issues play in disease pathogenesis, diagnosis, and treatment.



Publication History

Article published online:
11 July 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Skatrud JB, Dempsey JA, Bhansali P, Irvin C. Determinants of chronic carbon dioxide retention and its correction in humans. J Clin Invest 1980; 65 (04) 813-821
  • 2 Malhotra A, Schwartz DR, Ayas N, Stanchina M, White DP. Treatment of oxygen-induced hypercapnia. Lancet 2001; 357 (9259): 884-885
  • 3 Purro A, Appendini L, Polillo C. et al. Mechanical determinants of early acute ventilatory failure in COPD patients: a physiologic study. Intensive Care Med 2009; 35 (04) 639-647
  • 4 Del Negro CA, Funk GD, Feldman JL. Breathing matters. Nat Rev Neurosci 2018; 19 (06) 351-367
  • 5 Baertsch NA, Baertsch HC, Ramirez JM. The interdependence of excitation and inhibition for the control of dynamic breathing rhythms. Nat Commun 2018; 9 (01) 843
  • 6 Ainsworth DM, Smith CA, Johnson BD, Eicker SW, Henderson KS, Dempsey JA. Vagal modulation of respiratory muscle activity in awake dogs during exercise and hypercapnia. J Appl Physiol 1992; 72 (04) 1362-1367
  • 7 Phillipson EA, Hickey RF, Bainton CR, Nadel JA. Effect of vagal blockade on regulation of breathing in conscious dogs. J Appl Physiol 1970; 29 (04) 475-479
  • 8 Schwarzacher SW, Rüb U, Deller T. Neuroanatomical characteristics of the human pre-Bötzinger complex and its involvement in neurodegenerative brainstem diseases. Brain 2011; 134 (Pt 1): 24-35
  • 9 Alheid GF, Milsom WK, McCrimmon DR. Pontine influences on breathing: an overview. Respir Physiol Neurobiol 2004; 143 (2-3): 105-114
  • 10 Montandon G, Horner R. CrossTalk proposal: The preBotzinger complex is essential for the respiratory depression following systemic administration of opioid analgesics. J Physiol 2014; 592 (06) 1159-1162
  • 11 Daristotle L, Berssenbrugge AD, Bisgard GE. Hypoxic-hypercapnic ventilatory interaction at the carotid body of awake goats. Respir Physiol 1987; 70 (01) 63-72
  • 12 Kumar P, Bin-Jaliah I. Adequate stimuli of the carotid body: more than an oxygen sensor?. Respir Physiol Neurobiol 2007; 157 (01) 12-21
  • 13 Guyenet PG, Stornetta RL, Bayliss DA. Central respiratory chemoreception. J Comp Neurol 2010; 518 (19) 3883-3906
  • 14 Guyenet PG. Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol 2014; 4 (04) 1511-1562
  • 15 Zera T, Moraes DJA, da Silva MP, Fisher JP, Paton JFR. The logic of carotid body connectivity to the brain. Physiology (Bethesda) 2019; 34 (04) 264-282
  • 16 Keir DA, Duffin J, Millar PJ, Floras JS. Simultaneous assessment of central and peripheral chemoreflex regulation of muscle sympathetic nerve activity and ventilation in healthy young men. J Physiol 2019; 597 (13) 3281-3296
  • 17 Prasad B, Morgan BJ, Gupta A. et al. The need for specificity in quantifying neurocirculatory vs. respiratory effects of eucapnic hypoxia and transient hyperoxia. J Physiol 2020; 598 (21) 4803-4819
  • 18 Takakura AC, Moreira TS, Colombari E, West GH, Stornetta RL, Guyenet PG. Peripheral chemoreceptor inputs to retrotrapezoid nucleus (RTN) CO2-sensitive neurons in rats. J Physiol 2006; 572 (Pt 2): 503-523
  • 19 Blain GM, Smith CA, Henderson KS, Dempsey JA. Contribution of the carotid body chemoreceptors to eupneic ventilation in the intact, unanesthetized dog. J Appl Physiol 2009; 106 (05) 1564-1573
  • 20 Blain GM, Smith CA, Henderson KS, Dempsey JA. Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO(2). J Physiol 2010; 588 (Pt 13): 2455-2471
  • 21 Smith CA, Blain GM, Henderson KS, Dempsey JA. Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2: role of carotid body CO2 . J Physiol 2015; 593 (18) 4225-4243
  • 22 Rodman JR, Curran AK, Henderson KS, Dempsey JA, Smith CA. Carotid body denervation in dogs: eupnea and the ventilatory response to hyperoxic hypercapnia. J Appl Physiol 2001; 91 (01) 328-335
  • 23 Dahan A, Nieuwenhuijs D, Teppema L. Plasticity of central chemoreceptors: effect of bilateral carotid body resection on central CO2 sensitivity. PLoS Med 2007; 4 (07) e239
  • 24 Curran AK, Rodman JR, Eastwood PR, Henderson KS, Dempsey JA, Smith CA. Ventilatory responses to specific CNS hypoxia in sleeping dogs. J Appl Physiol 2000; 88 (05) 1840-1852
  • 25 Smith CA, Engwall MJ, Dempsey JA, Bisgard GE. Effects of specific carotid body and brain hypoxia on respiratory muscle control in the awake goat. J Physiol 1993; 460: 623-640
  • 26 Daristotle L, Engwall MJ, Niu WZ, Bisgard GE. Ventilatory effects and interactions with change in PaO2 in awake goats. J Appl Physiol 1991; 71 (04) 1254-1260
  • 27 Gourine AV, Funk GD. On the existence of a central respiratory oxygen sensor. J Appl Physiol 2017; 123 (05) 1344-1349
  • 28 Olson Jr EB, Vidruk EH, Dempsey JA. Carotid body excision significantly changes ventilatory control in awake rats. J Appl Physiol 1988; 64 (02) 666-671
  • 29 Becker H, Polo O, McNamara SG, Berthon-Jones M, Sullivan CE. Ventilatory response to isocapnic hyperoxia. J Appl Physiol 1995; 78 (02) 696-701
  • 30 Becker HF, Polo O, McNamara SG, Berthon-Jones M, Sullivan CE. Effect of different levels of hyperoxia on breathing in healthy subjects. J Appl Physiol 1996; 81 (04) 1683-1690
  • 31 Patinha D, Pijacka W, Paton JFR, Koeners MP. Cooperative oxygen sensing by the kidney and carotid body in blood pressure control. Front Physiol 2017; 8: 752
  • 32 Soliz J, Joseph V, Soulage C. et al. Erythropoietin regulates hypoxic ventilation in mice by interacting with brainstem and carotid bodies. J Physiol 2005; 568 (Pt 2): 559-571
  • 33 Barioni NO, Derakhshan F, Tenorio Lopes L. et al. Novel oxygen sensing mechanism in the spinal cord involved in cardiorespiratory responses to hypoxia. Sci Adv 2022; 8 (12) eabm1444
  • 34 Dean JB, Mulkey DK, Henderson III RA, Potter SJ, Putnam RW. Hyperoxia, reactive oxygen species, and hyperventilation: oxygen sensitivity of brain stem neurons. J Appl Physiol 2004; 96 (02) 784-791
  • 35 Clanton TL. Hypoxia-induced reactive oxygen species formation in skeletal muscle. J Appl Physiol 2007; 102 (06) 2379-2388
  • 36 Whipp BJ. Control of the exercise hyperpnea: the unanswered question. Adv Exp Med Biol 2008; 605: 16-21
  • 37 Santin JM. How important is the CO2 chemoreflex for the control of breathing? Environmental and evolutionary considerations. Comp Biochem Physiol A Mol Integr Physiol 2018; 215: 6-19
  • 38 Mouradian GC, Forster HV, Hodges MR. Acute and chronic effects of carotid body denervation on ventilation and chemoreflexes in three rat strains. J Physiol 2012; 590 (14) 3335-3347
  • 39 Hodges MR, Forster HV, Papanek PE, Dwinell MR, Hogan GE. Ventilatory phenotypes among four strains of adult rats. J Appl Physiol 2002; 93 (03) 974-983
  • 40 Souza GMPR, Kanbar R, Stornetta DS, Abbott SBG, Stornetta RL, Guyenet PG. Breathing regulation and blood gas homeostasis after near complete lesions of the retrotrapezoid nucleus in adult rats. J Physiol 2018; 596 (13) 2521-2545
  • 41 Phillipson EA, Bowes G, Townsend ER, Duffin J, Cooper JD. Role of metabolic CO2 production in ventilatory response to steady-state exercise. J Clin Invest 1981; 68 (03) 768-774
  • 42 Yamamoto WS, Edwards Jr MW. Homeostasis of carbon dioxide during intravenous infusion of carbon dioxide. J Appl Physiol 1960; 15: 807-818
  • 43 Sheldon MI, Green JF. Evidence for pulmonary CO2 chemosensitivity: effects on ventilation. J Appl Physiol 1982; 52 (05) 1192-1197
  • 44 Ponikowski P, Banasiak W. Chemosensitivity in chronic heart failure. Heart Fail Monit 2001; 1 (04) 126-131
  • 45 Schultz HD, Sun SY. Chemoreflex function in heart failure. Heart Fail Rev 2000; 5 (01) 45-56
  • 46 Stickland MK, Miller JD, Smith CA, Dempsey JA. Carotid chemoreceptor modulation of regional blood flow distribution during exercise in health and chronic heart failure. Circ Res 2007; 100 (09) 1371-1378
  • 47 Schultz HD, Marcus NJ, Del Rio R. Role of the carotid body chemoreflex in the pathophysiology of heart failure: a perspective from animal studies. Adv Exp Med Biol 2015; 860: 167-185
  • 48 Ding Y, Li YL, Schultz HD. Role of blood flow in carotid body chemoreflex function in heart failure. J Physiol 2011; 589 (Pt 1): 245-258
  • 49 Marcus NJ, Del Rio R, Ding Y, Schultz HD. KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure. J Physiol 2018; 596 (15) 3171-3185
  • 50 Siński M, Lewandowski J, Przybylski J. et al. Tonic activity of carotid body chemoreceptors contributes to the increased sympathetic drive in essential hypertension. Hypertens Res 2012; 35 (05) 487-491
  • 51 Tafil-Klawe M, Trzebski A, Klawe J, Pałko T. Augmented chemoreceptor reflex tonic drive in early human hypertension and in normotensive subjects with family background of hypertension. Acta Physiol Pol 1985; 36 (01) 51-58
  • 52 Abdala AP, McBryde FD, Marina N. et al. Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat. J Physiol 2012; 590 (17) 4269-4277
  • 53 Pijacka W, Moraes DJ, Ratcliffe LE. et al. Purinergic receptors in the carotid body as a new drug target for controlling hypertension. Nat Med 2016; 22 (10) 1151-1159
  • 54 Brognara F, Felippe ISA, Salgado HC, Paton JFR. Autonomic innervation of the carotid body as a determinant of its sensitivity - implications for cardiovascular physiology and pathology. Cardiovasc Res 2021; 117 (04) 1015-1032
  • 55 Acker H, O'Regan RG. The effects of stimulation of autonomic nerves on carotid body blood flow in the cat. J Physiol 1981; 315: 99-110
  • 56 Andreas S, Haarmann H, Klarner S, Hasenfuss G, Raupach T. Increased sympathetic nerve activity in COPD is associated with morbidity and mortality. Lung 2014; 192 (02) 235-241
  • 57 Heindl S, Lehnert M, Criée CP, Hasenfuss G, Andreas S. Marked sympathetic activation in patients with chronic respiratory failure. Am J Respir Crit Care Med 2001; 164 (04) 597-601
  • 58 Stickland MK, Fuhr DP, Edgell H. et al. Chemosensitivity, cardiovascular risk, and the ventilatory response to exercise in COPD. PLoS One 2016; 11 (06) e0158341
  • 59 Phillips DB, Steinback CD, Collins SÉ. et al. The carotid chemoreceptor contributes to the elevated arterial stiffness and vasoconstrictor outflow in chronic obstructive pulmonary disease. J Physiol 2018; 596 (15) 3233-3244
  • 60 Hansen J, Sander M. Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia. J Physiol 2003; 546 (Pt 3): 921-929
  • 61 Berssenbrugge A, Dempsey J, Iber C, Skatrud J, Wilson P. Mechanisms of hypoxia-induced periodic breathing during sleep in humans. J Physiol 1983; 343: 507-524
  • 62 Robinson TD, Freiberg DB, Regnis JA, Young IH. The role of hypoventilation and ventilation-perfusion redistribution in oxygen-induced hypercapnia during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161 (05) 1524-1529
  • 63 Nakayama K. Surgical removal of the carotid body for bronchial asthma. Dis Chest 1961; 40: 595-604
  • 64 Abdo WF, Heunks LM. Oxygen-induced hypercapnia in COPD: myths and facts. Crit Care 2012; 16 (05) 323
  • 65 Chen TK, Knicely DH, Grams ME. Chronic kidney disease diagnosis and management: a review. JAMA 2019; 322 (13) 1294-1304
  • 66 Franchitto N, Despas F, Labrunee M. et al. Cardiorenal anemia syndrome in chronic heart failure contributes to increased sympathetic nerve activity. Int J Cardiol 2013; 168 (03) 2352-2357
  • 67 Converse Jr RL, Jacobsen TN, Toto RD. et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 1992; 327 (27) 1912-1918
  • 68 Masuo K, Mikami H, Ogihara T, Tuck M. Hormonal mechanisms in blood pressure reduction during hemodialysis in patients with chronic renal failure. Hypertens Res 1995; 18 (Suppl. 01) S201-S203
  • 69 Despas F, Detis N, Dumonteil N. et al. Excessive sympathetic activation in heart failure with chronic renal failure: role of chemoreflex activation. J Hypertens 2009; 27 (09) 1849-1854
  • 70 Hering D, Zdrojewski Z, Król E. et al. Tonic chemoreflex activation contributes to the elevated muscle sympathetic nerve activity in patients with chronic renal failure. J Hypertens 2007; 25 (01) 157-161
  • 71 Ye C, Qiu Y, Zhang F. et al. Chemical stimulation of renal tissue induces sympathetic activation and a pressor response via the paraventricular nucleus in rats. Neurosci Bull 2020; 36 (02) 143-152
  • 72 Semenza GL, Prabhakar NR. Neural regulation of hypoxia-inducible factors and redox state drives the pathogenesis of hypertension in a rodent model of sleep apnea. J Appl Physiol 2015; 119 (10) 1152-1156
  • 73 Prabhakar NR, Semenza GL. Oxygen sensing and homeostasis. Physiology (Bethesda) 2015; 30 (05) 340-348
  • 74 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 (Pt 2): 705-716
  • 75 Niewinski P, Ponikowski P. The story of carotid body resection for HF: how an intriguing pathophysiology concept became a valid target for intervention. Eur Heart J 2017; 38 (47) 3481-3482
  • 76 Narkiewicz K, Ratcliffe LE, Hart EC. et al. Unilateral carotid body resection in resistant hypertension: a safety and feasibility trial. JACC Basic Transl Sci 2016; 1 (05) 313-324
  • 77 Honda Y. Respiratory and circulatory activities in carotid body-resected humans. J Appl Physiol 1992; 73 (01) 1-8
  • 78 Banzett RB, Lansing RW, Binks AP. Air hunger: a primal sensation and a primary element of dyspnea. Compr Physiol 2021; 11 (02) 1449-1483
  • 79 Moosavi SH, Golestanian E, Binks AP, Lansing RW, Brown R, Banzett RB. Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans. J Appl Physiol 2003; 94 (01) 141-154
  • 80 Simonson TS, Baker TL, Banzett RB. et al. Silent hypoxaemia in COVID-19 patients. J Physiol 2021; 599 (04) 1057-1065
  • 81 Porzionato A, Emmi A, Stocco E. et al. The potential role of the carotid body in COVID-19. Am J Physiol Lung Cell Mol Physiol 2020; 319 (04) L620-L626
  • 82 Eckert DJ, Malhotra A. Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008; 5 (02) 144-153
  • 83 Dempsey JA, Xie A, Patz DS, Wang D. Physiology in medicine: obstructive sleep apnea pathogenesis and treatment–considerations beyond airway anatomy. J Appl Physiol 2014; 116 (01) 3-12
  • 84 Horner RL. Emerging principles and neural substrates underlying tonic sleep-state-dependent influences on respiratory motor activity. Philos Trans R Soc Lond B Biol Sci 2009; 364 (1529): 2553-2564
  • 85 Orem J, Lovering AT, Dunin-Barkowski W, Vidruk EH. Tonic activity in the respiratory system in wakefulness, NREM and REM sleep. Sleep 2002; 25 (05) 488-496
  • 86 Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T. Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice. J Appl Physiol 2007; 102 (01) 241-248
  • 87 Gestreau C, Bévengut M, Dutschmann M. The dual role of the orexin/hypocretin system in modulating wakefulness and respiratory drive. Curr Opin Pulm Med 2008; 14 (06) 512-518
  • 88 Laviolette L, Niérat MC, Hudson AL, Raux M, Allard E, Similowski T. The supplementary motor area exerts a tonic excitatory influence on corticospinal projections to phrenic motoneurons in awake humans. PLoS One 2013; 8 (04) e62258
  • 89 Williams RH, Jensen LT, Verkhratsky A, Fugger L, Burdakov D. Control of hypothalamic orexin neurons by acid and CO2 . Proc Natl Acad Sci U S A 2007; 104 (25) 10685-10690
  • 90 Benarroch EE. Control of the cardiovascular and respiratory systems during sleep. Auton Neurosci 2019; 218: 54-63
  • 91 Simon PM, Dempsey JA, Landry DM, Skatrud JB. Effect of sleep on respiratory muscle activity during mechanical ventilation. Am Rev Respir Dis 1993; 147 (01) 32-37
  • 92 Orem J, Montplaisir J, Dement WC. Changes in the activity of respiratory neurons during sleep. Brain Res 1974; 82 (02) 309-315
  • 93 Henke KG, Arias A, Skatrud JB, Dempsey JA. Inhibition of inspiratory muscle activity during sleep. Chemical and nonchemical influences. Am Rev Respir Dis 1988; 138 (01) 8-15
  • 94 Dubois M, Chenivesse C, Raux M. et al. Neurophysiological evidence for a cortical contribution to the wakefulness-related drive to breathe explaining hypocapnia-resistant ventilation in humans. J Neurosci 2016; 36 (41) 10673-10682
  • 95 Henke KG, Badr MS, Skatrud JB, Dempsey JA. Load compensation and respiratory muscle function during sleep. J Appl Physiol 1992; 72 (04) 1221-1234
  • 96 Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. Carotid body denervation eliminates apnea in response to transient hypocapnia. J Appl Physiol 2003; 94 (01) 155-164
  • 97 Chow CM, Xi L, Smith CA, Saupe KW, Dempsey JA. A volume-dependent apneic threshold during NREM sleep in the dog. J Appl Physiol 1994; 76 (06) 2315-2325
  • 98 Smith CA, Chenuel BJ, Henderson KS, Dempsey JA. The apneic threshold during non-REM sleep in dogs: sensitivity of carotid body vs. central chemoreceptors. J Appl Physiol 2007; 103 (02) 578-586
  • 99 Leevers AM, Simon PM, Xi L, Dempsey JA. Apnoea following normocapnic mechanical ventilation in awake mammals: a demonstration of control system inertia. J Physiol 1993; 472: 749-768
  • 100 Xi L, Smith CA, Saupe KW, Henderson KS, Dempsey JA. Effects of rapid-eye-movement sleep on the apneic threshold in dogs. J Appl Physiol 1993; 75 (03) 1129-1139
  • 101 Khoo MC. Determinants of ventilatory instability and variability. Respir Physiol 2000; 122 (2-3): 167-182
  • 102 Dempsey JA, Smith CA. Update on chemoreception: influence on cardiorespiratory regulation and pathophysiology. Clin Chest Med 2019; 40 (02) 269-283
  • 103 Dempsey JA. Central sleep apnea: misunderstood and mistreated! F1000Res. 2019 ;8. DOI: 10.12688/f1000research.18358.1
  • 104 Bordier P, Lataste A, Hofmann P, Robert F, Bourenane G. Nocturnal oxygen therapy in patients with chronic heart failure and sleep apnea: a systematic review. Sleep Med 2016; 17: 149-157
  • 105 Marcus NJ, Del Rio R, Schultz EP, Xia XH, Schultz HD. Carotid body denervation improves autonomic and cardiac function and attenuates disordered breathing in congestive heart failure. J Physiol 2014; 592 (02) 391-408
  • 106 Del Rio R, Marcus NJ, Schultz HD. Inhibition of hydrogen sulfide restores normal breathing stability and improves autonomic control during experimental heart failure. J Appl Physiol 2013; 114 (09) 1141-1150
  • 107 Javaheri S. Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. Am J Respir Crit Care Med 2006; 173 (02) 234-237
  • 108 Khayat RN, Xie A, Patel AK, Kaminski A, Skatrud JB. Cardiorespiratory effects of added dead space in patients with heart failure and central sleep apnea. Chest 2003; 123 (05) 1551-1560
  • 109 Xie A, Teodorescu M, Pegelow DF. et al. Effects of stabilizing or increasing respiratory motor outputs on obstructive sleep apnea. J Appl Physiol 2013; 115 (01) 22-33
  • 110 Remmers JE, deGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978; 44 (06) 931-938
  • 111 Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev 2010; 90 (01) 47-112
  • 112 Onal E, Leech JA, Lopata M. Dynamics of respiratory drive and pressure during NREM sleep in patients with occlusive apneas. J Appl Physiol 1985; 58 (06) 1971-1974
  • 113 Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/occlusion during central sleep apnea. J Appl Physiol 1995; 78 (05) 1806-1815
  • 114 Warner G, Skatrud JB, Dempsey JA. Effect of hypoxia-induced periodic breathing on upper airway obstruction during sleep. J Appl Physiol 1987; 62 (06) 2201-2211
  • 115 Wellman A, Malhotra A, Jordan AS, Stevenson KE, Gautam S, White DP. Effect of oxygen in obstructive sleep apnea: role of loop gain. Respir Physiol Neurobiol 2008; 162 (02) 144-151
  • 116 Edwards BA, Sands SA, Eckert DJ. et al. Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea. J Physiol 2012; 590 (05) 1199-1211
  • 117 Gell LK, Vena D, Alex RM. et al. Neural ventilatory drive decline as a predominant mechanism of obstructive sleep apnoea events. Thorax 2022; 77 (07) 707-716
  • 118 Dempsey JA, La Gerche A, Hull JH. Is the healthy respiratory system built just right, overbuilt, or underbuilt to meet the demands imposed by exercise?. J Appl Physiol 2020; 129 (06) 1235-1256
  • 119 Forster HV, Haouzi P, Dempsey JA. Control of breathing during exercise. Compr Physiol 2012; 2 (01) 743-777
  • 120 Haldane JS, Priestley JG. The regulation of the lung-ventilation. J Physiol 1905; 32 (3-4): 225-266
  • 121 Aliverti A, Cala SJ, Duranti R. et al. Human respiratory muscle actions and control during exercise. J Appl Physiol 1997; 83 (04) 1256-1269
  • 122 Grimby G, Goldman M, Mead J. Respiratory muscle action inferred from rib cage and abdominal V-P partitioning. J Appl Physiol 1976; 41 (5, Pt. 1): 739-751
  • 123 Kaufman MP, Forster HV. Reflexes controlling circulatory, ventilatory and airway responses to exercise. In: Rowell LB, Shepherd JT. eds. Handbook of Physiology. New York: Oxford University Press; 381-447
  • 124 Oren A, Wasserman K, Davis JA, Whipp BJ. Effect of CO2 set point on ventilatory response to exercise. J Appl Physiol 1981; 51 (01) 185-189
  • 125 Dempsey JA, Vidruk EH, Mitchell GS. Pulmonary control systems in exercise: update. Fed Proc 1985; 44 (07) 2260-2270
  • 126 Shea SA, Andres LP, Shannon DC, Banzett RB. Ventilatory responses to exercise in humans lacking ventilatory chemosensitivity. J Physiol 1993; 468: 623-640
  • 127 Wasserman K, Whipp BJ, Koyal SN, Cleary MG. Effect of carotid body resection on ventilatory and acid-base control during exercise. J Appl Physiol 1975; 39 (03) 354-358
  • 128 Forster HV, Pan LG, Bisgard GE, Kaminski RP, Dorsey SM, Busch MA. Hyperpnea of exercise at various PIO2 in normal and carotid body-denervated ponies. J Appl Physiol 1983; 54 (05) 1387-1393
  • 129 Goodwin GM, McCloskey DI, Mitchell JH. Cardiovascular and respiratory responses to changes in central command during isometric exercise at constant muscle tension. J Physiol 1972; 226 (01) 173-190
  • 130 Krogh A, Lindhard J. The regulation of respiration and circulation during the initial stages of muscular work. J Physiol 1913; 47 (1-2): 112-136
  • 131 Eldridge FL, Millhorn DE, Waldrop TG. Exercise hyperpnea and locomotion: parallel activation from the hypothalamus. Science 1981; 211 (4484): 844-846
  • 132 Eldridge FL, Millhorn DE, Kiley JP, Waldrop TG. Stimulation by central command of locomotion, respiration and circulation during exercise. Respir Physiol 1985; 59 (03) 313-337
  • 133 Thornton JM, Guz A, Murphy K. et al. Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans. J Physiol 2001; 533 (Pt 3): 823-836
  • 134 Williamson JW, McColl R, Mathews D, Mitchell JH, Raven PB, Morgan WP. Brain activation by central command during actual and imagined handgrip under hypnosis. J Appl Physiol 2002; 92 (03) 1317-1324
  • 135 Morgan W, Raven P, Drinkwater B, Horvath S. Perceptual and metabolic responsivity to standard bicycle ergometry following various hypnotic suggestions. Clin Exp Hypn 1973; 21: 86-101
  • 136 An X, Bandler R, Ongür D, Price JL. Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys. J Comp Neurol 1998; 401 (04) 455-479
  • 137 Paterson DJ. Defining the neurocircuitry of exercise hyperpnoea. J Physiol 2014; 592 (03) 433-444
  • 138 Bandler R, Carrive P. Integrated defence reaction elicited by excitatory amino acid microinjection in the midbrain periaqueductal grey region of the unrestrained cat. Brain Res 1988; 439 (1-2): 95-106
  • 139 Basnayake SD, Hyam JA, Pereira EA. et al. Identifying cardiovascular neurocircuitry involved in the exercise pressor reflex in humans using functional neurosurgery. J Appl Physiol 2011; 110 (04) 881-891
  • 140 Casaburi R, Whipp BJ, Wasserman K, Beaver WL, Koyal SN. Ventilatory and gas exchange dynamics in response to sinusoidal work. J Appl Physiol 1977; 42 (02) 300-301
  • 141 Tibes U. Reflex inputs to the cardiovascular and respiratory centers from dynamically working canine muscles. Some evidence for involvement of group III or IV nerve fibers. Circ Res 1977; 41 (03) 332-341
  • 142 Kao F. An experimental study of the pathway involved in exercise hyperpnea employing cross-circulation techniques. In: Cunningham DJC, Lloyd BB. eds. Regulation of Human Respiration. Oxford: Blackwell; 1963
  • 143 Coote JH, Hilton SM, Perez-Gonzalez JF. The reflex nature of the pressor response to muscular exercise. J Physiol 1971; 215 (03) 789-804
  • 144 McCloskey DI, Mitchell JH. Reflex cardiovascular and respiratory responses originating in exercising muscle. J Physiol 1972; 224 (01) 173-186
  • 145 Amann M, Blain GM, Proctor LT, Sebranek JJ, Pegelow DF, Dempsey JA. Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans. J Appl Physiol 2010; 109 (04) 966-976
  • 146 Haouzi P. Tracking pulmonary gas exchange by breathing control during exercise: role of muscle blood flow. J Physiol 2014; 592 (03) 453-461
  • 147 Haouzi P, Hill JM, Lewis BK, Kaufman MP. Responses of group III and IV muscle afferents to distension of the peripheral vascular bed. J Appl Physiol 1999; 87 (02) 545-553
  • 148 Band DM, Wolff CB, Ward J, Cochrane GM, Prior J. Respiratory oscillations in arterial carbon dioxide tension as a control signal in exercise. Nature 1980; 283 (5742): 84-85
  • 149 Murphy K, Stidwill RP, Cross BA. et al. Is hypercapnia necessary for the ventilatory response to exercise in man?. Clin Sci (Lond) 1987; 73 (06) 617-625
  • 150 Dempsey J, Neder A, Phillips D, O'Donnell D. The physiology and pathophysiology of exercise hyperpnea. In: Chen R, Guyenet P. eds. Respiratory Neurology: Physiology and Clinical Disorders, Part I. Amsterdam: Elsevier; 2022
  • 151 Asmussen E, Johansen SH, Jorgensen M, Nielsen M. On the nervous factors controlling respiration and circulation during exercise. Experiments with curarization. Acta Physiol Scand 1965; 63: 343-350
  • 152 Amann M, Proctor LT, Sebranek JJ, Eldridge MW, Pegelow DF, Dempsey JA. Somatosensory feedback from the limbs exerts inhibitory influences on central neural drive during whole body endurance exercise. J Appl Physiol 2008; 105 (06) 1714-1724
  • 153 Vogiatzis I, Aliverti A, Golemati S. et al. Respiratory kinematics by optoelectronic plethysmography during exercise in men and women. Eur J Appl Physiol 2005; 93 (5-6): 581-587
  • 154 Aaron EA, Seow KC, Johnson BD, Dempsey JA. Oxygen cost of exercise hyperpnea: implications for performance. J Appl Physiol 1992; 72 (05) 1818-1825
  • 155 Johnson BD, Babcock MA, Suman OE, Dempsey JA. Exercise-induced diaphragmatic fatigue in healthy humans. J Physiol 1993; 460: 385-405
  • 156 Mador MJ, Magalang UJ, Rodis A, Kufel TJ. Diaphragmatic fatigue after exercise in healthy human subjects. Am Rev Respir Dis 1993; 148 (6, Pt 1): 1571-1575
  • 157 Sheel AW, Boushel R, Dempsey JA. Competition for blood flow distribution between respiratory and locomotor muscles: implications for muscle fatigue. J Appl Physiol 2018; 125 (03) 820-831
  • 158 Johnson BD, Badr MS, Dempsey JA. Impact of the aging pulmonary system on the response to exercise. Clin Chest Med 1994; 15 (02) 229-246
  • 159 Reeves J, Dempsey J, Grover R. Pulmonary circulation during exercise. In: Weir E, Reeves J. eds. Pulmonary Vascular Physiology and Pathophysiology. New York: Marcel Dekker; 1989: 107-133
  • 160 Pelkonen M, Notkola IL, Lakka T, Tukiainen HO, Kivinen P, Nissinen A. Delaying decline in pulmonary function with physical activity: a 25-year follow-up. Am J Respir Crit Care Med 2003; 168 (04) 494-499
  • 161 McClaran SR, Babcock MA, Pegelow DF, Reddan WG, Dempsey JA. Longitudinal effects of aging on lung function at rest and exercise in healthy active fit elderly adults. J Appl Physiol 1995; 78 (05) 1957-1968
  • 162 Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Antó JM. Regular physical activity modifies smoking-related lung function decline and reduces risk of chronic obstructive pulmonary disease: a population-based cohort study. Am J Respir Crit Care Med 2007; 175 (05) 458-463
  • 163 O'Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164 (05) 770-777
  • 164 Neder JA, Phillips DB, O'Donnell DE, Dempsey JA. Excess ventilation and exertional dyspnoea in heart failure and pulmonary hypertension. Eur Respir J 2022; 60 (05) x
  • 165 Gagnon P, Bussières JS, Ribeiro F. et al. Influences of spinal anesthesia on exercise tolerance in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186 (07) 606-615
  • 166 Amann M, Regan MS, Kobitary M. et al. Impact of pulmonary system limitations on locomotor muscle fatigue in patients with COPD. Am J Physiol Regul Integr Comp Physiol 2010; 299 (01) R314-R324
  • 167 Dominelli PB, Archiza B, Ramsook AH. et al. Effects of respiratory muscle work on respiratory and locomotor blood flow during exercise. Exp Physiol 2017; 102 (11) 1535-1547
  • 168 Harms CA, Babcock MA, McClaran SR. et al. Respiratory muscle work compromises leg blood flow during maximal exercise. J Appl Physiol 1997; 82 (05) 1573-1583
  • 169 Langer D, Ciavaglia C, Faisal A. et al. Inspiratory muscle training reduces diaphragm activation and dyspnea during exercise in COPD. J Appl Physiol 2018; 125 (02) 381-392
  • 170 Dempsey JA, Blain GM, Amann M. Are type III-IV muscle afferents required for a normal steady-state exercise hyperpnoea in humans?. J Physiol 2014; 592 (03) 463-474
  • 171 Maltais F, Simard AA, Simard C, Jobin J, Desgagnés P, LeBlanc P. Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. Am J Respir Crit Care Med 1996; 153 (01) 288-293
  • 172 Ribeiro F, Thériault ME, Debigaré R, Maltais F. Should all patients with COPD be exercise trained?. J Appl Physiol 2013; 114 (09) 1300-1308
  • 173 Johnson Jr RL. Gas exchange efficiency in congestive heart failure. Circulation 2000; 101 (24) 2774-2776
  • 174 Woods PR, Olson TP, Frantz RP, Johnson BD. Causes of breathing inefficiency during exercise in heart failure. J Card Fail 2010; 16 (10) 835-842
  • 175 Olson TP, Joyner MJ, Eisenach JH, Curry TB, Johnson BD. Influence of locomotor muscle afferent inhibition on the ventilatory response to exercise in heart failure. Exp Physiol 2014; 99 (02) 414-426
  • 176 Mitchell GS, Johnson SM. Neuroplasticity in respiratory motor control. J Appl Physiol 2003; 94 (01) 358-374
  • 177 Feldman JL, Mitchell GS, Nattie EE. Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 2003; 26: 239-266
  • 178 Martin PA, Mitchell GS. Long-term modulation of the exercise ventilatory response in goats. J Physiol 1993; 470: 601-617
  • 179 Wood HE, Fatemian M, Robbins PA. A learned component of the ventilatory response to exercise in man. J Physiol 2003; 553 (Pt 3): 967-974
  • 180 Somjen G. The missing error signal-regulation beyond negative chemofeedback. News Physiol Sci 1992; 7: 184-185
  • 181 Poon CS, Tin C, Yu Y. Homeostasis of exercise hyperpnea and optimal sensorimotor integration: the internal model paradigm. Respir Physiol Neurobiol 2007; 159 (01) 1-13 , discussion 14–20
  • 182 Mitchell GS, Babb TG. Layers of exercise hyperpnea: modulation and plasticity. Respir Physiol Neurobiol 2006; 151 (2-3): 251-266
  • 183 Cathcart AJ, Herrold N, Turner AP, Wilson J, Ward SA. Absence of long-term modulation of ventilation by dead-space loading during moderate exercise in humans. Eur J Appl Physiol 2005; 93 (04) 411-420
  • 184 Moosavi SH, Guz A, Adams L. Repeated exercise paired with “imperceptible” dead space loading does not alter VE of subsequent exercise in humans. J Appl Physiol 2002; 92 (03) 1159-1168
  • 185 Basting TM, Abe C, Viar KE, Stornetta RL, Guyenet PG. Is plasticity within the retrotrapezoid nucleus responsible for the recovery of the PCO2 set-point after carotid body denervation in rats?. J Physiol 2016; 594 (12) 3371-3390
  • 186 Millhorn DE, Eldridge FL, Waldrop TG. Prolonged stimulation of respiration by a new central neural mechanism. Respir Physiol 1980; 41 (01) 87-103
  • 187 Smith CA, Bisgard GE, Nielsen AM. et al. Carotid bodies are required for ventilatory acclimatization to chronic hypoxia. J Appl Physiol 1986; 60 (03) 1003-1010
  • 188 Busch MA, Bisgard GE, Forster HV. Ventilatory acclimatization to hypoxia is not dependent on arterial hypoxemia. J Appl Physiol 1985; 58 (06) 1874-1880
  • 189 Nielsen AM, Bisgard GE, Vidruk EH. Carotid chemoreceptor activity during acute and sustained hypoxia in goats. J Appl Physiol 1988; 65 (04) 1796-1802
  • 190 Wang ZY, Olson Jr EB, Bjorling DE, Mitchell GS, Bisgard GE. Sustained hypoxia-induced proliferation of carotid body type I cells in rats. J Appl Physiol 2008; 104 (03) 803-808
  • 191 Powell FL. The influence of chronic hypoxia upon chemoreception. Respir Physiol Neurobiol 2007; 157 (01) 154-161
  • 192 Moya EA, Go A, Kim CB, Fu Z, Simonson TS, Powell FL. Neuronal HIF-1α in the nucleus tractus solitarius contributes to ventilatory acclimatization to hypoxia. J Physiol 2020; 598 (10) 2021-2034
  • 193 Dwinell MR, Powell FL. Chronic hypoxia enhances the phrenic nerve response to arterial chemoreceptor stimulation in anesthetized rats. J Appl Physiol 1999; 87 (02) 817-823
  • 194 Mulkey DK, Stornetta RL, Weston MC. et al. Respiratory control by ventral surface chemoreceptor neurons in rats. Nat Neurosci 2004; 7 (12) 1360-1369
  • 195 Hayashi F, Coles SK, Bach KB, Mitchell GS, McCrimmon DR. Time-dependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats. Am J Physiol 1993; 265 (4, Pt 2): R811-R819
  • 196 Fuller DD, Zabka AG, Baker TL, Mitchell GS. Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia. J Appl Physiol 2001; 90 (05) 2001-2006 , discussion 2000
  • 197 Baker-Herman TL, Fuller DD, Bavis RW. et al. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 2004; 7 (01) 48-55
  • 198 Baker-Herman TL, Mitchell GS. Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis. J Neurosci 2002; 22 (14) 6239-6246
  • 199 Devinney MJ, Fields DP, Huxtable AG, Peterson TJ, Dale EA, Mitchell GS. Phrenic long-term facilitation requires PKCθ activity within phrenic motor neurons. J Neurosci 2015; 35 (21) 8107-8117
  • 200 Ling L. Serotonin and NMDA receptors in respiratory long-term facilitation. Respir Physiol Neurobiol 2008; 164 (1-2): 233-241
  • 201 Vose AK, Welch JF, Nair J. et al. Therapeutic acute intermittent hypoxia: a translational roadmap for spinal cord injury and neuromuscular disease. Exp Neurol 2022; 347: 113891
  • 202 Navarrete-Opazo A, Mitchell GS. Therapeutic potential of intermittent hypoxia: a matter of dose. Am J Physiol Regul Integr Comp Physiol 2014; 307 (10) R1181-R1197
  • 203 Sutor T, Cavka K, Vose AK. et al. Single-session effects of acute intermittent hypoxia on breathing function after human spinal cord injury. Exp Neurol 2021; 342: 113735
  • 204 Trumbower RD, Jayaraman A, Mitchell GS, Rymer WZ. Exposure to acute intermittent hypoxia augments somatic motor function in humans with incomplete spinal cord injury. Neurorehabil Neural Repair 2012; 26 (02) 163-172
  • 205 Welch JF, Perim RR, Argento PJ. et al. Effect of acute intermittent hypoxia on cortico-diaphragmatic conduction in healthy humans. Exp Neurol 2021; 339: 113651
  • 206 Finn HT, Bogdanovski O, Hudson AL. et al. The effect of acute intermittent hypoxia on human limb motoneurone output. Exp Physiol 2022; 107 (06) 615-630
  • 207 Radia S, Vallence AM, Fujiyama H. et al. Effects of acute intermittent hypoxia on corticospinal excitability within the primary motor cortex. Eur J Appl Physiol 2022; 122 (09) 2111-2123
  • 208 Christiansen L, Urbin MA, Mitchell GS, Perez MA. Acute intermittent hypoxia enhances corticospinal synaptic plasticity in humans. eLife 2018; 7: 7
  • 209 Welch JF, Nair J, Argento PJ, Mitchell GS, Fox EJ. Acute intermittent hypercapnic-hypoxia elicits central neural respiratory motor plasticity in humans. J Physiol 2022; 600 (10) 2515-2533
  • 210 Xie A, Skatrud JB, Barczi SR. et al. Influence of cerebral blood flow on breathing stability. J Appl Physiol 2009; 106 (03) 850-856
  • 211 Deacon-Diaz NL, Sands SA, McEvoy RD, Catcheside PG. Daytime loop gain is elevated in obstructive sleep apnea but not reduced by CPAP treatment. J Appl Physiol 2018; 125 (05) 1490-1497
  • 212 Devinney MJ, Huxtable AG, Nichols NL, Mitchell GS. Hypoxia-induced phrenic long-term facilitation: emergent properties. Ann N Y Acad Sci 2013; 1279: 143-153