Diffusion tensor imaging demonstrates brainstem and cerebellar abnormalities in congenital central hypoventilation syndrome

Abstract

Congenital central hypoventilation syndrome (CCHS) patients show reduced breathing drive during sleep, decreased hypoxic and hypercapnic ventilatory responses, and autonomic and affective deficits, suggesting both brainstem and forebrain injuries. Forebrain damage was previously described in CCHS, but methodological limitations precluded detection of brainstem injury, a concern because genetic mutations in CCHS target brainstem autonomic nuclei. To assess brainstem and cerebellar areas, we used diffusion tensor imaging-based measures, namely axial diffusivity, reflecting water diffusion parallel to fibers, and sensitive to axonal injury, and radial diffusivity, measuring diffusion perpendicular to fibers, and indicative of myelin injury. Diffusion tensor imaging was performed in 12 CCHS and 26 controls, and axial and radial diffusivity maps were compared between groups using analysis of covariance (covariates; age and gender). Increased axial diffusivity in CCHS appeared within the lateral medulla and clusters with injury extended from the dorsal midbrain through the periaqueductal gray, raphé, and superior cerebellar decussation, ventrally to the basal-pons. Cerebellar cortex and deep nuclei, and the superior and inferior cerebellar peduncles showed increased radial diffusivity. Midbrain, pontine, and lateral medullary structures, and the cerebellum and its fiber systems are injured in CCHS, likely contributing to the characteristics found in the syndrome.

Figure 1

Brainstem areas with significantly increased axial diffusivity only. Abnormal clusters appeared in the dorsal midbrain on the midline, caudally through the periaqueductal gray, oculomotor nuclei and dorsal and central raphé and the decussation of the superior cerebellar peduncle (a, d, j), ventrally to the mid-pons toward the basalpons (b, g, k), ending in the midline of the caudal basal pons (c, l). Other abnormal brain areas emerged in bilateral crus cerebri, extending to the hippocampus and amygdala (e, f, h, i), and right lateral medulla (m, n, o). All images are in neurological convention (L = Left, R = Right), and color scale represents t-statistic values (p < 0.05, false discovery rate correction for multiple comparisons).

Figure 2

Cerebellar sites with significantly increased radial diffusivity only. Regions with significant deficits emerged in the bilateral superior (a, b, d, e, g, i) and inferior cerebellar peduncles (f, k, l), bilateral cerebellar cortices (c, h, n, o) and deep nuclei (j, m). Figure conventions are the same as in Figure 1.

Figure 3

Structural injury overlapped some of the previously reported functional deficits in another group of CCHS subjects. The upper panels show selected regions of structural injury (yellow) based on axial and radial diffusivity measures, and the lower panels show sites of functional deficits (blue) to hypercapnic (adapted from, Harper RM et al., J Neurophysiol. 93:1647-58, Copyright © 2005 The American Physiological Society, with permission), hypoxic, and cold pressor (adapted from, Macey PM et al., Pediatr Res 57:500-509, Copyright © 2005 International Pediatric Research Foundation) challenges. Comparable areas are indicated by circles, and numbers indicate overlapping structural and functional deficits.