Central autonomic regulation in congenital central hypoventilation syndrome

Abstract

Congenital central hypoventilation syndrome (CCHS) patients show significant autonomic dysfunction in addition to the well-described loss of breathing drive during sleep. Some characteristics, for example, syncope, may stem from delayed sympathetic outflow to the vasculature; other symptoms, including profuse sweating, may derive from overall enhanced sympathetic output. The dysregulation suggests significant alterations to autonomic regulatory brain areas. Murine models of the genetic mutations present in the human CCHS condition indicate brainstem autonomic nuclei are targeted; however, the broad range of symptoms suggests more widespread alterations. We used functional magnetic resonance imaging (fMRI) to assess neural response patterns to the Valsalva maneuver, an autonomic challenge eliciting a sequence of sympathetic and parasympathetic actions, in nine CCHS and 25 control subjects. CCHS patients showed diminished and time-lagged heart rate responses to the Valsalva maneuver, and muted fMRI signal responses across multiple brain areas. During the positive pressure phase of the Valsalva maneuver, CCHS responses were muted, but were less so in recovery phases. In rostral structures, including the amygdala and hippocampus, the normal declining patterns were replaced by increasing trends or more modest declines. Earlier onset responses appeared in the hypothalamus, midbrain, raphé pallidus, and left rostral ventrolateral medulla. Phase-lagged responses appeared in cerebellar pyramis and anterior cingulate cortex. The time-distorted and muted central responses to autonomic challenges likely underlie the exaggerated sympathetic action and autonomic dyscontrol in CCHS, impairing cerebral autoregulation, possibly exacerbating neural injury, and enhancing the potential for cardiac arrhythmia.

Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Figures

Figure 1

A: Heart rate during four consecutive Valsalva challenge periods (gray vertical bars, 17.5 s each) in 9 CCHS and 25 control subjects. Shading of traces indicates standard deviation. B-C: Mean signal time trends in percent change relative to baseline period (time < 0 s) for CCHS and control subjects during four Valsalva challenge periods in B, ventral cerebellum and C, insular cortex. Averaged trends of D: mean heart rate, and E: mean load pressure over all four trials in CCHS and control subjects, with error bars indicating standard error of mean (based on RMANOVA). Gray dotted line represents minimum acceptable load pressure for the challenge.

Figure 2

Cluster analysis: regions of increased (warm colors) or decreased (cool colors) fMRI signal changes during the Valsalva maneuver in CCHS relative to controls (boxcar model). A: 1 medulla, including ventrolateral medulla (VLM) and raphé nuclei (magnus, obscurus, pallidus), 2 dorsal midbrain, 3 mid-cingulate, 4 hypothalamus, extending to midbrain, including ventral tegmental area (VTA), 5 mid-pons, B: 1 pons, C: 1 hippocampus, extending medially to septum, 2 thalamus, extending laterally to basal ganglia, D: 1 amygdala, 2 head of caudate, extending to cingulate, 3 internal capsule, extending laterally to putamen and right insular cortex, 4 globus pallidus, E: 1 left insula, 2 claustrum, 3 right putamen, extending laterally to cortex, F: 1&3 left and right ventral cerebellum, and 2 midline cerebellar cortex. Color scales indicate statistical significance (t statistic) of increasing (inc, warm colors) or decreasing (dec, cool colors) signal differences in CCHS relative to controls. Slice locations (right inset) are in MNI space. A: x = +4 mm, B: y = −40 mm, C: y = −14 mm, D: y = −2 mm, E: y = +14 mm, F: y = −78 mm.

Figure 3

Rostral/limbic brain areas. Mean signal time trends for 9 CCHS subjects and 25 controls averaged over four Valsalva challenge periods, 17.5 s each. Signals are in percent change relative to baseline. Inset panels show the VOI corresponding to each mean signal time trend.

Figure 4

Caudal brain areas. Mean signal time trends for 9 CCHS subjects and 25 controls averaged over four Valsalva challenge periods, 17.5 s each. Panel characteristics are as in Figure 3.

Figure 5

Timing differences. Mean signal time trends for areas with especially marked phase-lags (ACC, pyramis) and phase-leads (hypothalamus, raphé pallidus, midbrain, VTA); 9 CCHS subjects and 25 controls averaged over four Valsalva challenge periods, 17.5 s each; ACC = anterior cingulate cortex; VTA = ventral tegmental area. Panel characteristics are as in Figure 3.