{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T07:41:18Z","timestamp":1770277278775,"version":"3.49.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Neonatal survival requires precise control of breathing and cardiovascular action, with fatal consequences or severe injury without support. Prematurity presents multiple opportunities to disrupt cardiorespiratory regulation, leading to expressions of apnea of prematurity, periodic breathing, and inappropriate cardiovascular responses to apnea. Failed breathing control can result from altered breathing drives, typically arising from untimely development of sensory or motor coordination processes. Some drives, such as temperature, are a special concern in neonates with low body mass, enhancing susceptibility to rapid body cooling. Chemical drives, such as pH or CO<jats:sub>2<\/jats:sub> or O<jats:sub>2<\/jats:sub>, may be inadequately developed; in some conditions, such as congenital central hypoventilation syndrome (CCHS), breathing responses to CO<jats:sub>2<\/jats:sub> or low O<jats:sub>2<\/jats:sub> may be reduced or absent, and coupling of cardiovascular responses to breathing changes are abolished. Sleep states exert profound influences on both chemical and temperature drives, with rapid eye movement (REM) sleep potentially modifying descending temperature influences, and state transitions significantly altering respiratory responses to chemical stimuli. In addition, neonates spend the majority of time in REM sleep, a state which induces a generalized inhibition of skeletal muscle activity that abolishes muscle tone to upper airway and thoracic wall muscles, enhancing the likelihood for obstructive sleep apnea. Although disrupted regulatory drives can often be replaced by positive (or negative) pressure ventilation, such as continuous positive airway pressure or enhanced by manipulating neurotransmitter action <jats:italic>via<\/jats:italic> caffeine, those approaches may exert negative consequences in the long term; the lungs of neonates, especially premature infants, are fragile, and easily injured by positive pressure. The consequences of caffeine use, acting directly on neural receptors, although seemingly innocuous in the near-term, may have long-term concerns and disrupts the integrity of sleep. The developmental breathing field needs improved means to support ventilation when one or more drives to respiration fail, and when the cardiovascular system, depending heavily on interactions with breathing, is compromised. Neuromodulatory procedures which manipulate the vestibular system to stabilize breathing or use tactile or proprioceptive stimuli to activate long-established reflexive mechanisms coupling limb movement with respiratory efforts can provide support for central and obstructive apnea, as well as for periodic breathing and cardiovascular action, particularly during sleep.<\/jats:p>","DOI":"10.3389\/fped.2021.753215","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T17:58:57Z","timestamp":1633024737000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Neuromodulatory Support for Breathing and Cardiovascular Action During Development"],"prefix":"10.3389","volume":"9","author":[{"given":"Ronald M.","family":"Harper","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalpashri","family":"Kesavan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1164\/rccm.200807-1069ST","article-title":"An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management","volume":"181","author":"Weese-Mayer","year":"2010","journal-title":"Am J Respir Crit Care Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/ppul.20225","article-title":"Disordered respiratory control in children with partial cerebellar resections","volume":"40","author":"Chen","year":"2005","journal-title":"Pediatr Pulmonol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1164\/ajrccm\/140.2.368","article-title":"Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome","volume":"140","author":"Paton","year":"1989","journal-title":"Am Rev Resp Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1126\/science.368.6490.455","article-title":"The mystery of the pandemic's \u2018happy hypoxia\u2019","volume":"368","author":"Couzin-Frankel","year":"2020","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1164\/rccm.202006-2157CP","article-title":"Why COVID-19 silent hypoxemia is baffling to physicians","volume":"202","author":"Tobin","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1001\/archneur.1984.04050200032014","article-title":"Autonomic dysfunction and sleep apnea in olivopontocerebellar degeneration","volume":"41","author":"Chokroverty","year":"1984","journal-title":"Arch Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.resp.2013.06.019","article-title":"The emerging role of the parabrachial complex in the generation of wakefulness drive and its implication for respiratory control","volume":"188","author":"Martelli","year":"2013","journal-title":"Respir Physiol Neurobiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2119","DOI":"10.1152\/japplphysiol.01128.2001","article-title":"CO2 dialysis in nucleus tractus solitarius region of rat increases ventilation in sleep and wakefulness","volume":"92","author":"Nattie","year":"2002","journal-title":"J Appl Physiol (1985)"},{"key":"B9","first-page":"23","article-title":"The nature of the wakefulness stimulus for breathing","volume":"345","author":"Orem","year":"1990","journal-title":"Prog Clin Biol Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1071\/rd9960079","article-title":"Respiratory responses to preoptic\/anterior hypothalamic warming during sleep in kittens","volume":"8","author":"Ni","year":"1996","journal-title":"Reprod Fertil Dev."},{"key":"B11","first-page":"123","article-title":"Interaction between sleep and thermoregulation","volume":"1","author":"Parmeggiani","year":"1977","journal-title":"Waking Sleep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1203\/00006450-198207000-00002","article-title":"The effect of sleep state on active thermoreulation in the premature infant","volume":"16","author":"Darnall","year":"1982","journal-title":"Pediatric Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.siny.2016.04.006","article-title":"Preterm birth and cerebellar neuropathology","volume":"21","author":"Pierson","year":"2016","journal-title":"Semin Fetal Neonatal Med."},{"key":"B14","first-page":"331","article-title":"Why do Purkinje cells die so easily after global brain ischemia? 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