FMRI Responses to Hyperoxia in Congenital Central Hypoventilation Syndrome

Abstract

Congenital Central Hypoventilation Syndrome (CCHS) patients show partial retention of peripheral chemoreception despite impaired ventilatory responses to CO 2 and hypoxia. The condition allows examination of central responses to hyperoxia, which minimizes afferent traffic from peripheral chemoreceptors. We used functional magnetic resonance imaging to assess blood oxygen level-dependent signals over the brain during a baseline and subsequent 2-min hyperoxia (100% O 2 ) period in 14 CCHS and 15 control subjects. After partitioning gray matter and correcting for global effects, the images were analyzed using volume-of-interest time trends followed by repeated-measures ANOVA and conventional cluster analyses. Respiratory rates initially (first 20 s) fell in CCHS, but rose in control subjects; CCHS heart rate increased in the first minute, and then decreased in the second minute, as in controls, but with muted rise and extent of decline. Multiple sites within the cerebellum, midbrain, and pons responded similarly to the challenge in both groups. Response patterns differed early in the right amygdala, paralleling initial respiratory pattern deficits, and late in the right insula, concomitant with cardiac rate differences. Signals also differed between groups in the medial and anterior cingulate, hippocampus, head of caudate, and lentiform nuclei, as well as pontine and midbrain structures and regions within the superior temporal and inferior frontal cortical gyri. The findings emphasize that structures that can alter respiratory timing, such as the amygdala, and modulate sympathetic outflow, such as the right insula, are deficient in CCHS. Medullary and pontine areas targeted by PHOX2B expression are also affected. In addition to impaired ventilatory responses to CO 2 and deficient breathing drive during sleep (1), patients with CCHS show inadequate breathing and cardiovascular responses to elevated or lowered levels of O 2 (2-5). The mechanisms involved in altered sensitivity to O 2 in CCHS remain unclear, because some degree of both central and peripheral chemoreception apparently is retained in the syndrome. Respiratory rates increase to hypoxia and decrease to hyperoxia (3,5,6), although both the respiratory and cardiovascular response patterns to challenges are distorted from the normal condition.Determining the neural mechanisms underlying response deficits to differing O 2 levels in CCHS is a significant issue for reasons other than the obvious respiratory implications: CNS responses to hypoxia or hyperoxia recruit the sympathetic nervous system to, among other cardiovascular actions, preferentially alter perfusion of the periphery. CCHS patients show substantial deficits in both sympathetic and parasympathetic components of autonomic nervous system control, which are manifested by such signs as extreme reduction in respiratoryrelated heart rate variability during sleep (7), diminished blood pressure "dipping" during the night (8), syncope to relatively mild provocation (9), a high incidence of cardiac arrhyth...

Functional Brain Deficits in Congenital Central Hypoventilation Syndrome: Commentary on the articles by Woo et al. on page 510 and Macey et al. on page 500.

“…Deficiencies also include loss of dyspnea (13) and reduced anxiety (14). This complex phenotype of CCHS suggests widespread functional brain deficits, although these had not been investigated until the present studies by Woo et al (1) and Macey et al (2).…”

“…During the hyperoxic challenge, the CCHS patients had alterations in early-onset and later respiratory patterns, as well as in respiratory-related heart rate variability, as previously described (10). Using fMRI to assess blood oxygen leveldependent signals in the brain, Woo et al (1) obtained the following results in CCHS patients exposed to hyperoxia: (i) comparable cerebellar and dorsal medial thalamic responses to those in controls; (ii) abnormal medullary and pontine responses in areas targeted by Phox2b expression; (iii) an early increase in activity in the right amygdala in response to hyperoxia, contrasting with the normal transient decline in the controls; (iv) absence of the late right insular response noted in the controls.…”

“…Woo et al (1) used cold pressure challenge and Macey et al (2) hyperoxia to induce these deficits. The results constitute the first evidence of functional brain abnormalities in specific locations, thereby providing information on the brain sites that generate some of the clinical characteristics of CCHS (3,4).…”

Congenital Central Hypoventilation Syndrome: A Comprehensive Review and Future Challenges

“…Regardless of the etiology of patients with CCHS, have clinically apparent abnormalities in the autonomic regulation of blood pressure, cardiac rhythm, pain and anxiety perception, papillary reactivity, temperature regulation, gut motility, urinary retention, and more [46][47][48][49][50][51], many of these functions are regulated within the rostral brain areas, especially within limbic structures. Fluid regulation and thermoregulation are controlled in anterior hypothalamus.…”

“…Patients with CCHS do not feel drives of inspiration at low O 2 and high CO 2 . The perception of dyspnea is regulated by the limbic areas including the amygdale, insular, and cingulate cortexes [54][55][56].…”