- 2016 - Pilot Grant
The respiratory chemoreflex is central to the pathophysiology of obstructive sleep apnea, periodic breathing at high altitude, congestive heart failure, hypoventilation syndromes and chronic obstructive lung disease. Activation of the respiratory chemoreflex in these chronic conditions also causes sustained increases in sympathetic drive. Excessive sympathetic activation has a range of adverse consequences on health, including hypertension, anxiety, impaired glucose handling, cardiac arrhythmogenesis, endothelial dysfunction, and induction / progression of myocardial dysfunction.
We propose a novel central hypothesis – that a persistently hyper-responsive respiratory chemoreflex causes 1) a wide variety of sleep apnea syndromes, including syndromes currently termed ‘complex sleep apnea’, ‘idiopathic central sleep apnea’ (ICSA), heart failure related CSA, a subset of ‘obstructive sleep apnea’, and high-altitude sleep apnea (High Chemosensitivity Sleep Apnea, HCSA); 2) pervasive multi system effects of sustained day and night chemoreflex activation. HCSA, we propose, is the sleep state expression of a more generalized “chemoreflex syndrome”.
The core pathology in HCSA is an enhanced hypercapnic ventilatory response. During sleep, this high respiratory control system “gain” causes sleep apnea during non-rapid eye movement (NREM) sleep. Thus one biomarker of HCSA is the occurrence of non-REM dominant sleep apnea identified during conventional polysomnography.
Continuous positive airway pressure (CPAP) is not a fully effective therapy for HCSA – sleep fragmentation, periodic breathing or obstructive events persist in NREM but not REM sleep, while central apneas tend to decrease with time on treatment. We have developed an improved treatment for HSCA that minimizes CO2 fluctuations during CPAP. This treatment uses a non-vented mask and adjunctive dead space, and it can improve the clinical management of NREM-dominant sleep apnea. However, residual sleep fragmentation and sleep apnea (readily quantifiable on the high resolution flow data available in current generation CPAP devices) is common. This results in persistently unrefreshing sleep, fatigue, and we suspect, non-dipping of blood pressure.
Meditation and certain yogic breathing practices have profound effects on the autonomic nervous system, including sympathetic drive and vagal tone. The pervasive effects of these maneuvers is demonstrated by functional magnetic imaging studies, showing modulation of activity in the central autonomic network, including the insula, the anterior cingulate and the ventromedial prefrontal cortex. Meditation and slow breathing approaches also reduce the slope of the hypercapnic ventilatory response, of key importance in our thinking.
Several innovations enable our proposal. Frist, current CPAP technology allows easy tracking of actual breathing even on a nightly basis, transmitted wirelessly via Wi-Fi modems – the dynamics and time constants of the effects of therapy are readily quantified. Second, technology developed at the Beth Israel Deaconess Medical Center (BIDMC) by co-investigator Dr. Thomas used ECG-based analysis of cardiopulmonary coupling, providing unique measures of sleep quality and stability. The software is implemented in a FDA approved wearable device (M1, www.slepeimage.com) that we will use to track the efficacy of our integrated breathing modulation approach, which we term IYBAM (pronounced “e-bam”, Integrated Yogic Breathing and Meditation. Finally, we introduce smartphone-based cognitive tracking to sleep apnea medicine.
Hypothesis 1: IYBAM reduces the slope of the hypercapnic ventilatory response (HCVR) in complex apnea.
Aim 1: Assess HCVR pre and post a 60-day IYBAM vs. sham protocol, in compliant patients with residual apnea on therapy flow waveforms.
Hypothesis 2: IYBAM increases stable breathing and subjective/objective sleep quality in complex apnea.
Aim 2: Assess home therapy respiratory waveforms including quantifying stable breathing, and high frequency cardiopulmonary coupling, and subjective sleep quality, pre/post 60-days of IYBAM.
Hypothesis 3: IYBAM improve nocturnal blood pressure in complex apnea.
Aim 3: Measure ambulatory BP pre/post 60 days of IYBAM.
Hypothesis 4: IYBAM improves vigilance, attention, and information processing speed
Aim 4: Assess, using the Defense Automated Neurobehavioral Assessment (DANA) smartphone-based cognition App, the impact of IYBAM on cognitive function.
Successful completion of the pilot project will provide key new information, understanding and delineate appropriate targets for further investigating the effect of Yoga and Meditation practices on sleep, sleep- respiration, and sleep/global autonomic regulation.
- Mokhlesi B. Obesity hypoventilation syndrome: a state-of-the-art review. Respiratory care 2010;55:1347-62; discussion 63-5.
- Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H. An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. American journal of respiratory and critical care medicine 2010;181:626-44.
- Iturriaga R, Moya EA, Del Rio R. Carotid body potentiation induced by intermittent hypoxia: implications for cardiorespiratory changes induced by sleep apnoea. Clinical and experimental pharmacology & physiology 2009;36:1197-204.
- Richalet JP, Larmignat P, Poitrine E, Letournel M, Canoui-Poitrine F. Physiological risk factors for severe high-altitude illness: a prospective cohort study. American journal of respiratory and critical care medicine 2012;185:192-8.
- Solin P, Roebuck T, Johns DP, Walters EH, Naughton Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure. American journal of respiratory and critical care medicine 2000;162:2194-200.
- Narkiewicz K, Pesek CA, van de Borne PJ, Kato M, Somers Enhanced sympathetic and ventilatory responses to central chemoreflex activation in heart failure. Circulation 1999;100:262-7.
- Andreas S, von zur Muhlen F, Stevens J, Kreuzer Nocturnal oxygen and hypercapnic ventilatory response in patients with congestive heart failure. Respiratory medicine 1998;92:426-31.
- Kobayashi S, Nishimura M, Yamomoto M, Akiyama Y, Miyamoto K, Kawamaki Relationship between breathlessness and hypoxic and hypercapnic ventilatory response in patients with COPD. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology 1996;9:2340-5.
- Beecroft JM, Duffin J, Pierratos A, Chan CT, McFarlane P, Hanly PJ. Decreased chemosensitivity and improvement of sleep apnea by nocturnal hemodialysis. Sleep medicine 2009;10:47-54.
- Beecroft J, Duffin J, Pierratos A, Chan CT, McFarlane P, Hanly PJ. Enhanced chemo-responsiveness in patients with sleep apnoea and end-stage renal disease. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology 2006;28:151-8.
- Giannoni A, Emdin M, Bramanti F, et al. Combined increased chemosensitivity to hypoxia and hypercapnia as a prognosticator in heart failure. Journal of the American College of Cardiology 2009;53:1975- 80.
- Giannoni A, Emdin M, Poletti R, et al. Clinical significance of chemosensitivity in chronic heart failure: influence on neurohormonal derangement, Cheyne-Stokes respiration and arrhythmias. Clin Sci (Lond) 2008;114:489-97.
- Gilmartin GS, Lynch M, Tamisier R, Weiss JW. Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity. American journal of physiology Heart and circulatory physiology 2010;299:H925-31.
- Gilmartin GS, Tamisier R, Curley M, Weiss JW. Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in American journal of physiology Heart and circulatory physiology 2008;295:H778-85.
- Tamisier R, Hunt BE, Gilmartin GS, Curley M, Anand A, Weiss JW. Hemodynamics and muscle sympathetic nerve activity after 8 h of sustained hypoxia in healthy American journal of physiology Heart and circulatory physiology 2007;293:H3027-35.
- Berssenbrugge A, Dempsey J, Iber C, Skatrud J, Wilson P. Mechanisms of hypoxia-induced periodic breathing during sleep in humans. The Journal of physiology 1983;343:507-26.
- Dempsey JA, Skatrud A sleep-induced apneic threshold and its consequences. Am Rev Respir Dis 1986;133:1163-70.
- Dempsey JA, Smith CA, Przybylowski T, et The ventilatory responsiveness to CO(2) below eupnoea as a determinant of ventilatory stability in sleep. The Journal of physiology 2004;560:1-11.
- Henke KG, Arias A, Skatrud JB, Dempsey Inhibition of inspiratory muscle activity during sleep. Chemical and nonchemical influences. Am Rev Respir Dis 1988;138:8-15.
- Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey Effect of ventilatory drive on carbon dioxide sensitivity below eupnea during sleep. American journal of respiratory and critical care medicine 2002;165:1251-60.
- Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey Carotid body denervation eliminates apnea in response to transient hypocapnia. J Appl Physiol 2003;94:155-64.
- Skatrud JB, Dempsey JA. Interaction of sleep state and chemical stimuli in sustaining rhythmic ventilation. J Appl Physiol 1983;55:813-22.
- Xie A, Skatrud JB, Puleo DS, Dempsey JA. Influence of arterial O2 on the susceptibility to posthyperventilation apnea during sleep. J Appl Physiol 2006;100:171-7.
- Xie A, Skatrud JB, Puleo DS, Rahko PS, Dempsey JA. Apnea-hypopnea threshold for CO2 in patients with congestive heart failure. American journal of respiratory and critical care medicine 2002;165:1245-50.
- Ainslie PN, Duffin Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement and interpretation. American journal of physiology Regulatory, integrative and comparative physiology 2009.
- Xie A, Skatrud JB, Khayat R, Dempsey JA, Morgan B, Russell D. Cerebrovascular response to carbon dioxide in patients with congestive heart failure. American journal of respiratory and critical care medicine 2005;172:371-8.
- Xie A, Skatrud JB, Barczi SR, et al. Influence of cerebral blood flow on breathing stability. J Appl Physiol
- White Pathogenesis of obstructive and central sleep apnea. American journal of respiratory and critical care medicine 2005;172:1363-70.
- Bradley Crossing the threshold: implications for central sleep apnea. American journal of respiratory and critical care medicine 2002;165:1203-4.
- Ponikowski P, Banasiak W. Chemosensitivity in chronic heart failure. Heart Fail Monit 2001;1:126-31.
- Smith CA, Rodman JR, Chenuel BJ, Henderson KS, Dempsey JA. Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: central vs. peripheral chemoreceptors. J Appl Physiol 2006;100:13-9.
- 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;103:578-86.
- Xie A, Rutherford R, Rankin F, Wong B, Bradley TD. Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. American journal of respiratory and critical care medicine 1995;152:1950-5.
- Xie A, Wong B, Phillipson EA, Slutsky AS, Bradley Interaction of hyperventilation and arousal in the pathogenesis of idiopathic central sleep apnea. American journal of respiratory and critical care medicine 1994;150:489-95.
- Xie A, Rankin F, Rutherford R, Bradley Effects of inhaled CO2 and added dead space on idiopathic central sleep apnea. J Appl Physiol 1997;82:918-26.
- Salloum A, Rowley JA, Mateika JH, Chowdhuri S, Omran Q, Badr MS. Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure. American journal of respiratory and critical care medicine 2010;181:189-93.
- Xie A, Bedekar A, Skatrud JB, Teodorescu M, Gong Y, Dempsey The heterogeneity of obstructive sleep apnea (predominant obstructive vs pure obstructive apnea). Sleep 2011;34:745-50.
- Loewen A, Ostrowski M, Laprairie J, et al. Determinants of ventilatory instability in obstructive sleep apnea: inherent or acquired? Sleep 2009;32:1355-65.
- Younes M. Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders. J Appl Physiol 2008;105:1389-405.
- Younes M, Ostrowski M, Atkar R, Laprairie J, Siemens A, Hanly Mechanisms of breathing instability in patients with obstructive sleep apnea. J Appl Physiol 2007;103:1929-41.
- Edwards BA, Sands SA, Eckert DJ, et al. Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep The Journal of physiology 2012;590:1199-211.
- Wellman A, Eckert DJ, Jordan AS, et A method for measuring and modeling the physiological traits causing obstructive sleep apnea. J Appl Physiol 2011;110:1627-37.
- Wellman A, Malhotra A, Jordan AS, Stevenson KE, Gautam S, White DP. Effect of oxygen in obstructive sleep apnea: role of loop Respiratory physiology & neurobiology 2008;162:144-51.
- Suzuki M, Ogawa H, Okabe S, et al. The effect of upper airway structural changes on central chemosensitivity in obstructive sleep apnea-hypopnea. Sleep & breathing = Schlaf & Atmung 2004;8:73-83.
- Hudgel DW, Weil JV. Asthma associated with decreased hypoxic ventilatory drive. A family study. Ann Intern Med 1974;80:623-5.
- Kawakami Y, Yamamoto H, Yoshikawa T, Shida A. Chemical and behavioral control of breathing in adult twins. Am Rev Respir Dis 1984;129:703-7.
- Kawakami Y, Irie T, Kishi F, et al. Familial aggregation of abnormal ventilatory control and pulmonary function in chronic obstructive pulmonary disease. Eur J Respir Dis 1981;62:56-64.
- Fleetham JA, Arnup ME, Anthonisen Familial aspects of ventilatory control in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1984;129:3-7.
- Tankersley Genetic aspects of breathing: on interactions between hypercapnia and hypoxia. Respir Physiol Neurobiol 2003;135:167-78.
- Tankersley CG. A genomic model for differential hypoxic ventilatory responses. Adv Exp Med Biol 2000;475:75-85.
- Collins DD, Scoggin CH, Zwillich CW, Weil JV. Hereditary aspects of decreased hypoxic response. J Clin Invest 1978;62:105-10.
- Mountain R, Zwillich C, Weil J. Hypoventilation in obstructive lung disease. The role of familial factors. The New England journal of medicine 1978;298:521-5.
- Nishimura M, Yamamoto M, Yoshioka A, Akiyama Y, Kishi F, Kawakami Y. Longitudinal analyses of respiratory chemosensitivity in normal subjects. Am Rev Respir Dis 1991;143:1278-81.
- Strohl KP. Periodic breathing and genetics. Respir Physiol Neurobiol 2003;135:179-85.
- Kawakami Y, Yoshikawa T, Shida A, Asanuma Y. Relationship between hypoxic and hypercapnic ventilatory responses in man. Jpn J Physiol 1981;31:357-68.
- Zwillich C, McCullough R, Guilleminault C, Cummiskey J, Weil Respiratory control in the parents of sudden infant death syndrome victims. Ventilatory control in SIDS parents. Pediatr Res 1980;14:762-4.
- Weil JV. Variation in human ventilatory control-genetic influence on the hypoxic ventilatory response. Respir Physiol Neurobiol 2003;135:239-46.
- Schiffman PL, Remolina C, Westlake RE, Santiago TV, Edelman NH. Ventilatory response to isocapnic hypoxia in parents of victims of sudden infant death syndrome. Chest 1982;81:707-10.
- Huey KA, Low MJ, Kelly MA, Juarez R, Szewczak JM, Powell FL. Ventilatory responses to acute and chronic hypoxia in mice: effects of dopamine D(2) receptors. J Appl Physiol 2000;89:1142-50.
- Bonora M, Bernaudin JF, Guernier C, Brahimi-Horn Ventilatory responses to hypercapnia and hypoxia in conscious cystic fibrosis knockout mice Cftr. Pediatr Res 2004;55:738-46.
- Aizenfisz S, Dauger S, Durand E, et Ventilatory responses to hypercapnia and hypoxia in heterozygous c-ret newborn mice. Respir Physiol Neurobiol 2002;131:213-22.
- Jokic R, Zintel T, Sridhar G, Gallagher CG, Fitzpatrick MF. Ventilatory responses to hypercapnia and hypoxia in relatives of patients with the obesity hypoventilation syndrome. Thorax 2000;55:940-5.
- Redline S, Leitner J, Arnold J, Tishler PV, Altose MD. Ventilatory-control abnormalities in familial sleep apnea. American journal of respiratory and critical care medicine 1997;156:155-60.
- Tankersley CG, Fitzgerald RS, Kleeberger SR. Differential control of ventilation among inbred strains of mice. Am J Physiol 1994;267:R1371-7.
- Kuwaki T, Cao WH, Kurihara Y, et Impaired ventilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1. Am J Physiol 1996;270:R1279-86.
- Kline DD, Prabhakar Peripheral chemosensitivity in mutant mice deficient in nitric oxide synthase. Adv Exp Med Biol 2000;475:571-9.
- Renolleau S, Dauger S, Vardon G, et al. Impaired ventilatory responses to hypoxia in mice deficient in endothelin-converting-enzyme-1. Pediatr Res 2001;49:705-12.
- Chen J, He L, Dinger B, Stensaas L, Fidone S. Role of endothelin and endothelin A-type receptor in adaptation of the carotid body to chronic Am J Physiol Lung Cell Mol Physiol 2002;282:L1314-23.
- Gosselin LE, Barkley JE, Spencer MJ, McCormick KM, Farkas Ventilatory dysfunction in mdx mice: impact of tumor necrosis factor-alpha deletion. Muscle Nerve 2003;28:336-43.
- Rong W, Gourine AV, Cockayne DA, et Pivotal role of nucleotide P2X2 receptor subunit of the ATP- gated ion channel mediating ventilatory responses to hypoxia. J Neurosci 2003;23:11315-21.
- Adachi T, Ishikawa K, Hida W, et al. Hypoxemia and blunted hypoxic ventilatory responses in mice lacking heme oxygenase-2. Biochem Biophys Res Commun 2004;320:514-22.
- Boudinot E, Yamada M, Wess J, Champagnat J, Foutz Ventilatory pattern and chemosensitivity in M1 and M3 muscarinic receptor knockout mice. Respir Physiol Neurobiol 2004;139:237-45.
- Malik MT, Peng YJ, Kline DD, Adhikary G, Prabhakar Impaired ventilatory acclimatization to hypoxia in mice lacking the immediate early gene fos B. Respir Physiol Neurobiol 2005;145:23-31.
- Zhang Y, Furuyama K, Adachi T, et al. Hypoxemia and attenuated hypoxic ventilatory responses in mice lacking heme oxygenase-2: evidence for a novel role of heme oxygenase-2 as an oxygen sensor. Adv Exp Med Biol 2006;580:161-6; discussion 351-9.
- Oyamada Y, Yamaguchi K, Murai M, Hakuno H, Ishizaka A. Role of Kir2.2 in hypercapnic ventilatory response during postnatal development of mouse. Respir Physiol Neurobiol 2005;145:143-51.
- Lahiri S, Maret K, Sherpa Dependence of high altitude sleep apnea on ventilatory sensitivity to hypoxia. Respiration physiology 1983;52:281-301.
- Kobayashi S, Nishimura M, Yamamoto M, Akiyama Y, Kishi F, Kawakami Y. Dyspnea sensation and chemical control of breathing in adult twins. Am Rev Respir Dis 1993;147:1192-8.
- Moore GC, Zwillich CW, Battaglia JD, Cotton EK, Weil Respiratory failure associated with familial depression of ventilatory response to hypoxia and hypercapnia. The New England journal of medicine 1976;295:861-5.
- Funada Y, Nishimura Y, Kamemura K, et Familial adult onset primary alveolar hypoventilation syndrome. Intern Med 2001;40:526-31.
- Scoggin CH, Doekel RD, Kryger MH, Zwillich CW, Weil JV. Familial aspects of decreased hypoxic drive in endurance athletes. J Appl Physiol 1978;44:464-8.
- Dunai J, Kleiman J, Trinder J. Ventilatory instability during sleep onset in individuals with high peripheral chemosensitivity. J Appl Physiol 1999;87:661-72.
- Bhaumik G, Sharma RP, Dass D, et al. Hypoxic ventilatory response changes of men and women 6 to 7 days after climbing from 2100 m to 4350 m altitude and after descent. High altitude medicine & biology 2003;4:341-8.
- Garcia N, Hopkins SR, Powell Effects of intermittent hypoxia on the isocapnic hypoxic ventilatory response and erythropoiesis in humans. Respiration physiology 2000;123:39-49.
- Hupperets MD, Hopkins SR, Pronk MG, et al. Increased hypoxic ventilatory response during 8 weeks at 3800 m altitude. Respiratory physiology & neurobiology 2004;142:145-52.
- Katayama K, Sato Y, Morotome Y, et al. Intermittent hypoxia increases ventilation and Sa(O2) during hypoxic exercise and hypoxic chemosensitivity. J Appl Physiol 2001;90:1431-40.
- Powell FL, Milsom WK, Mitchell Time domains of the hypoxic ventilatory response. Respiration physiology 1998;112:123-34.
- Townsend NE, Gore CJ, Hahn AG, et al. Hypoxic ventilatory response is correlated with increased submaximal exercise ventilation after live high, train low. European journal of applied physiology 2005;94:207- 15.
- Townsend NE, Gore CJ, Hahn AG, et al. Living high-training low increases hypoxic ventilatory response of well-trained endurance athletes. J Appl Physiol 2002;93:1498-505.
- Nopmaneejumruslers C, Kaneko Y, Hajek V, Zivanovic V, Bradley TD. Cheyne-Stokes respiration in stroke: relationship to hypocapnia and occult cardiac dysfunction. American journal of respiratory and critical care medicine 2005;171:1048-52.
- Mansfield DR, Solin P, Roebuck T, Bergin P, Kaye DM, Naughton The effect of successful heart transplant treatment of heart failure on central sleep apnea. Chest 2003;124:1675-81.
- McGinty D, Littner M, Beahm E, Ruiz-Primo E, Young E, Sowers Sleep related breathing disorders in older men: a search for underlying mechanisms. Neurobiol Aging 1982;3:337-50.
- Guilleminault C, Cummiskey J. Progressive improvement of apnea index and ventilatory response to CO2 after tracheostomy in obstructive sleep apnea syndrome. Am Rev Respir Dis 1982;126:14-20.
- Fletcher Recurrence of sleep apnea syndrome following tracheostomy. A shift from obstructive to central apnea. Chest 1989;96:205-9.
- Chenuel BJ, Smith CA, Skatrud JB, Henderson KS, Dempsey Increased propensity for apnea in response to acute elevations in left atrial pressure during sleep in the dog. J Appl Physiol 2006;101:76-83.
- Verbraecken J, De Backer W, Willemen M, De Cock W, Wittesaele W, Van de Chronic CO2 drive in patients with obstructive sleep apnea and effect of CPAP. Respiration physiology 1995;101:279-87.
- Verbraecken J, Willemen M, De Cock W, et Influence of longterm CPAP therapy on CO(2) drive in patients with obstructive sleep apnea. Respiration physiology 2000;123:121-30.
- Verbraecken J, Willemen M, Wittesaele W, Van de Heyning P, De Backer W. Short-term CPAP does not influence the increased CO2 drive in idiopathic central sleep Monaldi Arch Chest Dis 2002;57:10-8.
- Spicuzza L, Bernardi L, Balsamo R, Ciancio N, Polosa R, Di Maria G. Effect of treatment with nasal continuous positive airway pressure on ventilatory response to hypoxia and hypercapnia in patients with sleep apnea syndrome. Chest 2006;130:774-9.
- Thomas RJ, Terzano MG, Parrino L, Weiss JW. Obstructive sleep-disordered breathing with a dominant cyclic alternating pattern–a recognizable polysomnographic variant with practical clinical implications. Sleep 2004;27:229-34.
- Thomas RJ, Mietus JE, Peng CK, et al. Differentiating obstructive from central and complex sleep apnea using an automated electrocardiogram-based method. Sleep 2007;30:1756-69.
- Thomas RJ. Alternative approaches to treatment of Central Sleep Apnea. Sleep medicine clinics 2014;9:87-104.
- Gilmartin GS, Daly RW, Thomas RJ. Recognition and management of complex sleep-disordered breathing. Curr Opin Pulm Med 2005;11:485-93.
- Stanchina M, Robinson K, Corrao W, Donat W, Sands S, Malhotra A. Clinical Use of Loop Gain Measures to Determine Continuous Positive Airway Pressure Efficacy in Patients with Complex Sleep A Pilot Study. Ann Am Thorac Soc 2015;12:1351-7.
- Weil JV. Sleep at high altitude. High altitude medicine & biology 2004;5:180-9.
- Badr Central sleep apnea in patients with congestive heart failure. Heart failure reviews 2009;14:135-41.
- Gilmartin G, McGeehan B, Vigneault K, et al. Treatment of positive airway pressure treatment- associated respiratory instability with enhanced expiratory rebreathing space (EERS). Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 2010;6:529-38.
- Huang Y, Mai W, Hu Y, et Poor sleep quality, stress status, and sympathetic nervous system activation in nondipping hypertension. Blood pressure monitoring 2011;16:117-23.
- Esler M, Kaye Sympathetic nervous system activation in essential hypertension, cardiac failure and psychosomatic heart disease. Journal of cardiovascular pharmacology 2000;35:S1-7.
- Lambert E, Dawood T, Straznicky N, et al. Association between the sympathetic firing pattern and anxiety level in patients with the metabolic syndrome and elevated blood Journal of hypertension 2010;28:543-50.
- Kuklinska AM, Mroczko B, Musial WJ, et al. Endothelial dysfunction and sympathetic nervous system activation in young patients with essential arterial hypertension and without hypercholesterolaemia. Acta cardiologica 2010;65:535-40.
- Tsioufis C, Kordalis A, Flessas D, et al. Pathophysiology of resistant hypertension: the role of sympathetic nervous system. International journal of hypertension 2011;2011:642416.
- Huggett RJ, Burns J, Mackintosh AF, Mary DA. Sympathetic neural activation in nondiabetic metabolic syndrome and its further augmentation by hypertension. Hypertension 2004;44:847-52.
- Grassi G, Arenare F, Quarti-Trevano F, Seravalle G, Mancia G. Heart rate, sympathetic cardiovascular influences, and the metabolic syndrome. Progress in cardiovascular diseases 2009;52:31-7.
- Kishi T, Hirooka Y, Konno S, Sunagawa Angiotensin II receptor blockers improve endothelial dysfunction associated with sympathetic hyperactivity in metabolic syndrome. Journal of hypertension 2012;30:1646-55.
- Sverrisdottir YB, Jansson LM, Hagg U, Gan Muscle sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy individuals. PloS one 2010;5:e9257.
- Lichtor T, Davis HR, Johns L, Vesselinovitch D, Wissler RW, Mullan S. The sympathetic nervous system and atherosclerosis. Journal of neurosurgery 1987;67:906-14.
- Pauletto P, Scannapieco G, Pessina Sympathetic drive and vascular damage in hypertension and atherosclerosis. Hypertension 1991;17:III75-81.
- Brandt MC, Mahfoud F, Reda S, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant Journal of the American College of Cardiology 2012;59:901-9.
- Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation 2003;108:560-5.
- Trombetta IC, Maki-Nunes C, Toschi-Dias E, et al. Obstructive sleep apnea is associated with increased chemoreflex sensitivity in patients with metabolic syndrome. Sleep 2012;35:(In Press).
- Leung RS, Huber MA, Rogge T, Maimon N, Chiu KL, Bradley Association between atrial fibrillation and central sleep apnea. Sleep 2005;28:1543-6.
- Mehra R, Stone KL, Varosy PD, et al. Nocturnal Arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) Archives of internal medicine 2009;169:1147-55.
- May AM, Blackwell T, Stone PH, et al. Central Sleep-disordered Breathing Predicts Incident Atrial Fibrillation in Older Men. American journal of respiratory and critical care medicine 2016;193:783-91.
- Craigmyle NA. The beneficial effects of meditation: contribution of the anterior cingulate and locus coeruleus. Front Psychol 2013;4:731.
- Lazar SW, Bush G, Gollub RL, Fricchione GL, Khalsa G, Benson H. Functional brain mapping of the relaxation response and meditation. Neuroreport 2000;11:1581-5.
- Lundblad LC, Fatouleh RH, McKenzie DK, Macefield VG, Henderson LA. Brain stem activity changes associated with restored sympathetic drive following CPAP treatment in OSA subjects: a longitudinal investigation. Journal of neurophysiology 2015;114:893-901.
- Lundblad LC, Fatouleh RH, Hammam E, McKenzie DK, Macefield VG, Henderson LA. Brainstem changes associated with increased muscle sympathetic drive in obstructive sleep apnoea. Neuroimage 2014;103:258-66.
- Fatouleh RH, Lundblad LC, Macey PM, McKenzie DK, Henderson LA, Macefield VG. Reversal of functional changes in the brain associated with obstructive sleep apnoea following 6 months of CPAP. Neuroimage Clin 2015;7:799-806.
- Fatouleh RH, Hammam E, Lundblad LC, et al. Functional and structural changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea. Neuroimage Clin 2014;6:275-83.
- Critchley HD, Nicotra A, Chiesa PA, et al. Slow breathing and hypoxic challenge: cardiorespiratory consequences and their central neural substrates. PloS one 2015;10:e0127082.
- Hernandez SE, Suero J, Barros A, Gonzalez-Mora JL, Rubia K. Increased Grey Matter Associated with Long-Term Sahaja Yoga Meditation: A Voxel-Based Morphometry Study. PloS one 2016;11:e0150757.
- Villemure C, Ceko M, Cotton VA, Bushnell Insular cortex mediates increased pain tolerance in yoga practitioners. Cereb Cortex 2014;24:2732-40.
- Engstrom M, Pihlsgard J, Lundberg P, Soderfeldt B. Functional magnetic resonance imaging of hippocampal activation during silent mantra meditation. J Altern Complement Med 2010;16:1253-8.
- Nakata H, Sakamoto K, Kakigi R. Meditation reduces pain-related neural activity in the anterior cingulate cortex, insula, secondary somatosensory cortex, and thalamus. Front Psychol 2014;5:1489.
- Tang YY, Lu Q, Geng X, Stein EA, Yang Y, Posner MI. Short-term meditation induces white matter changes in the anterior cingulate. Proceedings of the National Academy of Sciences of the United States of America 2010;107:15649-52.
- Tang YY, Lu Q, Feng H, Tang R, Posner MI. Short-term meditation increases blood flow in anterior cingulate cortex and insula. Front Psychol 2015;6:212.
- Kalyani BG, Venkatasubramanian G, Arasappa R, et al. Neurohemodynamic correlates of ‘OM’ chanting: A pilot functional magnetic resonance imaging study. Int J Yoga 2011;4:3-6.
- Doll A, Holzel BK, Bratec SM, et al. Mindful attention to breath regulates emotions via increased amygdala-prefrontal cortex connectivity. Neuroimage
- Holzel BK, Lazar SW, Gard T, Schuman-Olivier Z, Vago DR, Ott U. How Does Mindfulness Meditation Work? Proposing Mechanisms of Action From a Conceptual and Neural Perspective. Perspect Psychol Sci 2011;6:537-59.
- Beutler E, Beltrami FG, Boutellier U, Spengler Effect of Regular Yoga Practice on Respiratory Regulation and Exercise Performance. PloS one 2016;11:e0153159.
- Stanescu DC, Nemery B, Veriter C, Marechal C. Pattern of breathing and ventilatory response to CO2 in subjects practicing hatha-yoga. J Appl Physiol Respir Environ Exerc Physiol 1981;51:1625-9.
- Spicuzza L, Gabutti A, Porta C, Montano N, Bernardi L. Yoga and chemoreflex response to hypoxia and hypercapnia. Lancet 2000;356:1495-6.
- Bernardi L, Passino C, Spadacini G, et Reduced hypoxic ventilatory response with preserved blood oxygenation in yoga trainees and Himalayan Buddhist monks at altitude: evidence of a different adaptive strategy? European journal of applied physiology 2007;99:511-8.
- Bernardi L, Passino C, Wilmerding V, et al. Breathing patterns and cardiovascular autonomic modulation during hypoxia induced by simulated altitude. Journal of hypertension 2001;19:947-58.
- Thomas RJ, Mietus JE. Mapping sleep using coupled biological oscillations. Conference proceedings : Annual International Conference of the IEEE Engineering in Medicine and Biology Society IEEE Engineering in Medicine and Biology Society Conference 2011;2011:1479-82.
- Thomas RJ, Mietus JE, Peng CK, Goldberger AL. An electrocardiogram-based technique to assess cardiopulmonary coupling during sleep. Sleep 2005;28:1151-61.
- Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for Scoring Respiratory Events in Sleep: Update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. . Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 2012;8.
- Banzett RB, Adams L, O’Donnell CR, Gilman SA, Lansing RW, Schwartzstein RM. Using laboratory models to test treatment: morphine reduces dyspnea and hypercapnic ventilatory American journal of respiratory and critical care medicine 2011;184:920-7.