Aberrant neural responses to cold pressor challenges in congenital central hypoventilation syndrome

Patients with congenital central hypoventilation syndrome (CCHS), a condition characterized by impaired ventilatory responses to chemoreceptor stimulation, do not show the normal increase in respiratory rate and respiratory-related heart rate variation to cold forehead stimulation, a challenge that bypasses central chemoreceptors. We hypothesized that a forehead cold pressor challenge would reveal abnormal neural response patterns, as assessed by functional magnetic resonance imaging, in brain regions that are responsible for the integration of cold afferent stimulation with respiratory and cardiovascular output in patients with CCHS. Primary sensory thalamic and cortical areas for the forehead showed diminished responses in 13 patients with CCHS (ventilator dependent during sleep but not waking, no Hirschsprung's disease) compared with 14 control subjects, despite initial signal changes in the cortex being similar in both groups. Cerebellar cortex and deep nuclei; basal ganglia; and middle to posterior cingulate, insular, frontal, and temporal cortices showed reduced signal rises in patients with CCHS. Areas within the frontal and anterior cingulate cortices exhibited marked signal declines in control subjects but little change in patients with CCHS. No response occurred in either group in the dorsal medulla, but medial and ventral medullary areas showed enhanced signals in patients with CCHS. The cold pressor stimulation did not recruit dorsal medullary sites that would be affected by PHOX2B (a mutation of which is associated with the syndrome) expression in either group but demonstrated deficient cerebellar and medial medullary influences that, by action on rostral sites, may underlie the loss of respiratory responses.