{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:03:10Z","timestamp":1791118990070,"version":"4.1.0"},"reference-count":67,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurophysiology"],"published-print":{"date-parts":[[2005,3]]},"abstract":"<jats:p>Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses and loss of breathlessness to hypercapnia, yet arouse from sleep to high CO<jats:sub>2<\/jats:sub>, suggesting intact chemoreceptor afferents. The syndrome provides a means to differentiate brain areas controlling aspects of breathing. We used functional magnetic resonance imaging to determine brain structures responding to inspired 5% CO<jats:sub>2<\/jats:sub>-95% O<jats:sub>2<\/jats:sub>in 14 CCHS patients and 14 controls. Global signal changes induced by the challenge were removed on a voxel-by-voxel basis. A priori-defined volume-of-interest time trends (assessed with repeated measures ANOVA) and cluster analysis based on modeling each subject to a step function (individual model parameter estimates evaluated with t-test, corrected for multiple comparisons) revealed three large response clusters to hypercapnia distinguishing the two groups, extending from the 1) posterior thalamus through the medial midbrain to the dorsolateral pons, 2) right caudate nucleus, ventrolaterally through the putamen and ventral insula to the mid-hippocampus, and 3) deep cerebellar nuclei to the dorsolateral cerebellar cortex bilaterally. Smaller clusters and defined areas of group signal differences in the midline dorsal medulla, amygdala bilaterally, right dorsal-posterior temporal cortex, and left anterior insula also emerged. In most sites, early transient or sustained responses developed in controls, with little, or inverse change in CCHS subjects. Limbic and medullary structures regulating responses to hypercapnia differed from those previously shown to mediate loaded breathing ventilatory response processing. The findings show the significant roles of cerebellar and basal ganglia sites in responding to hypercapnia and the thalamic and midbrain participation in breathing control.<\/jats:p>","DOI":"10.1152\/jn.00863.2004","type":"journal-article","created":{"date-parts":[[2004,11,4]],"date-time":"2004-11-04T01:24:47Z","timestamp":1099531487000},"page":"1647-1658","source":"Crossref","is-referenced-by-count":106,"title":["Hypercapnic Exposure in Congenital Central Hypoventilation Syndrome Reveals CNS Respiratory Control Mechanisms"],"prefix":"10.1152","volume":"93","author":[{"given":"R. M.","family":"Harper","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. M.","family":"Macey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. A.","family":"Woo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. E.","family":"Macey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. G.","family":"Keens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Gozal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. R.","family":"Alger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"crossref","unstructured":"Amaral DG.The amygdala, social behavior, and danger detection.Ann NY Acad Sci1000: 337\u2013347, 2003.","DOI":"10.1196\/annals.1280.015"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.160.1.16010"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1038\/ng1130"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5687(01)00300-0"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.1997.0290"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200007140-00012"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.4.2029"},{"key":"R8","unstructured":"Carpenter Mand Batton R.Connections of the fastigial nucleus in the cat and monkey. In:The Cerebellum\u2014New Vistas, edited by Palay S and Chan-Palay V. Berlin: Springer-Verlag, 1982, p. 250\u2013295."},{"key":"R9","doi-asserted-by":"crossref","unstructured":"Cechetto DFand Chen SJ.Subcortical sites mediating sympathetic responses from insular cortex in rats.Am J Physiol258: R245\u2013R255, 1990.","DOI":"10.1152\/ajpregu.1990.258.1.R245"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1016\/j.prrv.2004.04.009"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1071563"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1995.sp020947"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.2001.0760"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00866"},{"key":"R15","unstructured":"Dejours P.The regulation of ventilation during muscular exercise in man.J Physiol (Paris)51: 929\u2013935, 1959."},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2002.88.3.1500"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.1995.1007"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1016\/S0361-9230(98)00125-7"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1994.76.5.2076"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1993.74.1.379"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.153.2.8564130"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.162.5.2005012"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-197811000-00003"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.1998.tb02240.x"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00702.2002"},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.1999.0505"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1172\/JCI101995"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1046\/j.1439-054X.2002.02187.x"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1998.79.5.2383"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1002\/1522-2586(200011)12:5<757::AID-JMRI14>3.0.CO;2-4"},{"key":"R31","unstructured":"Littell RC, Milliken GA, Stroup WW, and Wolfinger RD.SAS System for Mixed Models.Cary, NC: SAS Institute, 1996."},{"key":"R32","doi-asserted-by":"publisher","DOI":"10.1038\/35084005"},{"key":"R33","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1986.250.3.C418"},{"key":"R34","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1838(89)90092-1"},{"key":"R35","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00359.2004"},{"key":"R36","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2003.09.006"},{"key":"R37","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2003.12.042"},{"key":"R38","unstructured":"Macey PM, Macey KE, Woo MA, Keens TG, and Harper RM.Aberrant neural responses to cold pressor challenges in congenital central hypoventilation syndrome.Pediatr ResIn press (a)."},{"key":"R39","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000125262.82405.3C"},{"key":"R40","unstructured":"Macey PM, Woo MA, Macey KE, Keen TG, Saeed MM, Alger J, and Harper RM.Hypoxia reveals posterior thalamic, cerebellar, midbrain and limbic deficits in congenital central hypoventilation syndrome.J Appl PhysiolIn press (b)."},{"key":"R41","unstructured":"Marcus CL, Bautista DB, Amihyia A, Ward SL, and Keens TG.Hypercapneic arousal responses in children with congenital central hypoventilation syndrome.Pediatrics88: 993\u2013998, 1991."},{"key":"R42","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00594.2002"},{"key":"R43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.24.9868"},{"key":"R44","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-22-08828.1997"},{"key":"R45","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(88)90125-4"},{"key":"R46","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.42.9.1727"},{"key":"R47","doi-asserted-by":"crossref","unstructured":"Oren J, Kelly DH, and Shannon DC.Long-term follow-up of children with congenital central hypoventilation syndrome.Pediatrics80: 375\u2013380, 1987.","DOI":"10.1542\/peds.80.3.375"},{"key":"R48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.381bb.x"},{"key":"R49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.4.2041"},{"key":"R50","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/140.2.368"},{"key":"R51","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.163.4.2005057"},{"key":"R52","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(86)90182-X"},{"key":"R53","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(95)00525-0"},{"key":"R54","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63392-5"},{"key":"R55","unstructured":"Schad\u00e9 Jand McMenemey W.Selective Vulnerability of the Brain in Hypoxaemia.Philadelphia, PA: A. A. Davis Co. 1963."},{"key":"R56","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(93)90006-V"},{"key":"R57","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02800-6"},{"key":"R58","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/140.4.1021"},{"key":"R59","unstructured":"Teppema LJand Dahan A.Central chemoreceptors. In:Pharmacology and Pathophysiology of the Control of Breathing, edited by Ward DS, Dahan A, and Teppema LJ. New York: Marcel Dekker, 2005."},{"key":"R60","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.10438"},{"key":"R61","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20527"},{"key":"R62","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(05)80901-1"},{"key":"R63","unstructured":"Welsh JP, Yuen G, Placantonakis DG, Vu TQ, Haiss F, O'Hearn E, Molliver ME, and Aicher SA.Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus.Adv Neurol89: 331\u2013359, 2002."},{"key":"R64","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199203000-00020"},{"key":"R65","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1994.77.3.1232"},{"key":"R66","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1997.82.4.1177"},{"key":"R67","doi-asserted-by":"publisher","DOI":"10.1080\/147342202753203078"}],"container-title":["Journal of Neurophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/jn.00863.2004","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T22:38:03Z","timestamp":1682807883000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/jn.00863.2004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,3]]},"references-count":67,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2005,3]]}},"alternative-id":["10.1152\/jn.00863.2004"],"URL":"https:\/\/doi.org\/10.1152\/jn.00863.2004","relation":{},"ISSN":["0022-3077","1522-1598"],"issn-type":[{"value":"0022-3077","type":"print"},{"value":"1522-1598","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,3]]}}}