Hypercapnic exposure in congenital central hypoventilation syndrome reveals CNS respiratory control mechanisms.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses and loss of breathlessness to hypercapnia, yet arouse from sleep to high CO2, 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% CO2-95% O2 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.

Hypoxia reveals posterior thalamic, cerebellar, midbrain, and limbic deficits in congenital central hypoventilation syndrome.

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, thus 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 them with cluster and volume-of-interest procedures, during a baseline and 2-min hypoxic (15% O(2), 85% N(2)) 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 being 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.

fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses to CO2 and hypoxia and reduced drive to breathe during sleep but retain appropriate breathing patterns in response to volition or increased exercise. Breath-by-breath influences on heart rate are also deficient. Using functional magnetic resonance imaging techniques, we examined responses over the brain to voluntary forced expiratory loading, a task that CCHS patients can perform but that results in impaired rapid heart rate variation patterns normally associated with the loading challenge. Increased signals emerged in control (n = 14) over CCHS (n = 13; ventilator dependent during sleep but not waking) subjects in the cingulate and right parietal cortex, cerebellar cortex and fastigial nucleus, and basal ganglia, whereas anterior cerebellar cortical sites and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in CCHS patients. Primary motor and sensory areas bordering the central sulcus showed comparable responses in both groups. The delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas suggest that rapid cardiorespiratory integration deficits in CCHS may stem from defects in these sites. Additional autonomic and perceptual motor deficits may derive from cingulate and parietal cortex aberrations.

Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by diminished upper airway muscle phasic and tonic activation during sleep, but enhanced activity during waking. We evaluated neural mechanisms underlying these patterns with functional magnetic resonance imaging procedures during baseline and expiratory loading conditions in nine medication-free OSA and 16 control subjects. Both groups developed similar expiratory loading pressures, but appropriate autonomic responses did not emerge in OSA cases. Reduced neural signals emerged in OSA cases within the frontal cortex, anterior cingulate, cerebellar dentate nucleus, dorsal pons, anterior insula and lentiform nuclei. Signal increases in OSA over control subjects developed in the dorsal midbrain, hippocampus, quadrangular cerebellar lobule, ventral midbrain and ventral pons. Fastigial nuclei and the amygdala showed substantially increased variability in OSA subjects. No group differences were found in the thalamus. OSA patients show aberrant responses in multiple brain areas and inappropriate cardiovascular responses to expiratory loading, perhaps as a consequence of previously-demonstrated limbic, cerebellar and motor area gray matter loss.