{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T22:36:33Z","timestamp":1767998193702,"version":"3.49.0"},"reference-count":36,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:00:00Z","timestamp":1764720000000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007744","name":"Association pour le D\u00e9veloppement et l'Organisation de la Recherche en Pneumologie et sur le Sommeil","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007744","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Comparative Neurology"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Breathing is inherently variable due to the nonlinear dynamics of its brainstem neural control. In amphibians, a gill and a lung oscillator interact to produce breathing but the lung oscillator is necessary and sufficient to produce a mathematically complex behavior. In mammals, where the preB\u00f6tzinger complex (preB\u00f6tC) is considered homologous to the amphibian lung oscillator and the retrotrapezoid nucleus\/parafacial respiratory group (RTN\/pFRG) homologous to the amphibian gill oscillator, the origin of ventilatory complexity is not known. We address this question by characterizing ventilation variability in\n                    <jats:italic>Phox2b<\/jats:italic>\n                    mutant mice lacking the RTN\/pFRG and human patients with\n                    <jats:italic>Phox2b<\/jats:italic>\n                    mutation\u2010confirmed congenital central hypoventilation syndrome (CCHS). Ventilatory recordings were obtained from\n                    <jats:italic>Phox2b<\/jats:italic>\n                    <jats:sup>27<\/jats:sup>\n                    <jats:italic>\n                      <jats:sup>ala\/+<\/jats:sup>\n                    <\/jats:italic>\n                    \u2014dying within hours after birth\u2014and\n                    <jats:italic>\n                      Egr2\n                      <jats:sup>cre\/+<\/jats:sup>\n                    <\/jats:italic>\n                    ;\n                    <jats:italic>\n                      Phox2b\n                      <jats:sup>27ala\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice\u2014generally surviving until adulthood\u2014and their wild\u2010type (WT) littermates, during behavioral quiescence at various developmental stages. Human data were collected from CCHS patients and healthy controls during quiet wakefulness. Variability was assessed using the coefficient of variation, complexity using noise titration (noise limit, NL), and sensitivity to initial conditions using the largest Lyapunov exponent (LLE). Mice from both mutant lineages exhibited greater variability at early developmental stages, which decreased with maturation in\n                    <jats:italic>\n                      Egr2\n                      <jats:sup>cre<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\/+<\/jats:sup>\n                    ;\n                    <jats:italic>\n                      Phox2b\n                      <jats:sup>27ala\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice. NL was consistently higher in mutant mice than in WT, indicating preserved or even enhanced ventilatory complexity despite RTN\/pFRG dysfunction. CO\n                    <jats:sub>2<\/jats:sub>\n                    reduced variability but did not affect complexity. In humans, no differences were observed between patients and controls for variability, NL, or LLE. Ventilatory complexity persists in mice lacking a functional RTN\/pFRG and despite\n                    <jats:italic>Phox2b<\/jats:italic>\n                    mutations in humans, suggesting that the pontomedullary rhythm and pattern generators that include the preB\u00f6tC may be its principal source. This supports the analogy between mammalian and amphibian rhythm generators.\n                  <\/jats:p>","DOI":"10.1002\/cne.70117","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T14:59:51Z","timestamp":1764773991000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ventilatory Complexity Persists in\n                    <i>Phox2b<\/i>\n                    Mutant Mice Lacking the Retrotrapezoid Nucleus\/Parafacial Respiratory Group (RTN\/pFRG) and in Humans With Congenital Central Hypoventilation Syndrome"],"prefix":"10.1002","volume":"533","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-0046","authenticated-orcid":false,"given":"Christian","family":"Straus","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMRS1158 Neurophysiologie Respiratoire Exp\u00e9rimentale et Clinique  Paris France"},{"name":"AP\u2010HP, Groupe Hospitalier Universitaire APHP\u2010Sorbonne Universit\u00e9, h\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re, Service des Explorations Fonctionnelles de la Respiration, de l'Exercice et de la Dyspn\u00e9e, D\u00e9partement R3S  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Ranohavimparany","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMRS1158 Neurophysiologie Respiratoire Exp\u00e9rimentale et Clinique  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nelina","family":"Ramanantsoa","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Inserm UMR 1141, NeuroDiderot  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lysandre","family":"Tremoureux","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMRS1158 Neurophysiologie Respiratoire Exp\u00e9rimentale et Clinique  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxime","family":"Patout","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMRS1158 Neurophysiologie Respiratoire Exp\u00e9rimentale et Clinique  Paris France"},{"name":"AP\u2010HP, Groupe Hospitalier Universitaire APHP\u2010Sorbonne Universit\u00e9, h\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re, Service des Pathologies du Sommeil &amp; Centre de R\u00e9f\u00e9rence Maladies Rares \u201cHypoventilation Centrales Cong\u00e9nitales\u201d, D\u00e9partement R3S  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie\u2010No\u00eblle","family":"Fiamma","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMRS1158 Neurophysiologie Respiratoire Exp\u00e9rimentale et Clinique  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florence","family":"Cayetanot","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMRS1158 Neurophysiologie Respiratoire Exp\u00e9rimentale et Clinique  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7845-9618","authenticated-orcid":false,"given":"Boris","family":"Matrot","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Inserm UMR 1141, NeuroDiderot  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Gallego","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Inserm UMR 1141, NeuroDiderot  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0085-9021","authenticated-orcid":false,"given":"Laurence","family":"Bodineau","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMRS1158 Neurophysiologie Respiratoire Exp\u00e9rimentale et Clinique  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2868-9279","authenticated-orcid":false,"given":"Thomas","family":"Similowski","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMRS1158 Neurophysiologie Respiratoire Exp\u00e9rimentale et Clinique  Paris France"},{"name":"AP\u2010HP, Groupe Hospitalier Universitaire APHP\u2010Sorbonne Universit\u00e9, h\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re, D\u00e9partement R3S  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1130"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.10193.1"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/381215a0"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0375-9601(90)90841-B"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709115105"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200411\u20101528OC"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2006.12.001"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00792.2006"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2019.09.002"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.91.5.1962"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-9863-7_1215"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201038583\u20106"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075740"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00517"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.2953\u201014.2015"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1113\/jp285158"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2011.00031"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature16964"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/75776"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apm.2018.10.031"},{"key":"e_1_2_13_22_1","doi-asserted-by":"crossref","unstructured":"Marchenko V. 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