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1 Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
2 School of Nursing, UCLA, Los Angeles, CA, USA
3 Pediatric Pulmonology, Childrens Hospital Los Angeles, Los Angeles, CA, USA
4 Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
5 Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: rharper{at}ucla.edu.
Congenital Central Hypoventilation Syndrome (CCHS) patients show deficient respiratory and cardiac responses to hypoxia and hypercapnia, despite apparently intact arousal responses to hypercapnia and adequate respiratory motor mechanisms, providing a model to evaluate functioning of particular brain mechanisms underlying breathing. We used functional magnetic resonance imaging to assess blood oxygen level dependent signals, corrected for global signal changes, and evaluated with cluster and volume-of-interest procedures, during a baseline and two-minute hypoxic (15% O2, 85% N2) challenge in 14 CCHS and 14 age- and gender-matched control subjects. Hypoxia elicited significant (p<0.05) differences in magnitude and timing of responses between groups in cerebellar cortex and deep nuclei, posterior thalamic structures, limbic areas (including the insula, amygdala, ventral anterior thalamus, and right hippocampus), dorsal and ventral midbrain, caudate, claustrum, and putamen. Deficient responses to hypoxia included no, or late changes in CCHS patients with declining signals in control subjects, a falling signal in CCHS patients with no change in controls, or absent early transient responses in CCHS. Hypoxia resulted in signal declines but no group differences in hypothalamic and dorsal medullary areas, the latter a target for PHOX2B, mutations of which occur in the syndrome. The findings extend previously-identified posterior thalamic, midbrain and cerebellar roles for normal mediation of hypoxia found in animal fetal and adult preparations, and suggest significant participation of limbic structures in responding to hypoxic challenges, which likely include cardiovascular and air hunger components. Failing structures in CCHS include areas additional to those associated with PHOX2B expression and chemoreceptor sites.
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