Widespread white matter connectivity abnormalities in narcolepsy type 1: A diffusion tensor imaging study

Abstract

Narcolepsy type 1 is caused by a selective loss of hypothalamic hypocretin-producing neurons, resulting in severely disturbed sleep-wake control and cataplexy. Hypocretin-producing neurons project widely throughout the brain, influencing different neural networks. We assessed the extent of microstructural white matter organization and brain-wide structural connectivity abnormalities in a homogeneous group of twelve drug-free patients with narcolepsy type 1 and eleven matched healthy controls using diffusion tensor imaging with multimodal analysis techniques. First, tract-based spatial statistics (TBSS) was carried out using fractional anisotropy (FA) and mean, axial and radial diffusivity (MD, AD, RD). Second, quantitative analyses of mean FA, MD, AD and RD were conducted in predefined regions-of-interest, including sleep-wake regulation-related, limbic and reward system areas. Third, we performed hypothalamus-seeded tractography towards the thalamus, amygdala and midbrain. TBSS analyses yielded brain-wide significantly lower FA and higher RD in patients. Localized significantly lower FA and higher RD in the left ventral diencephalon and lower AD in the midbrain, were seen in patients. Lower FA was also found in patients in left hypothalamic fibers connecting with the midbrain. No significant MD and AD differences nor a correlation with disease duration were found. The brain-wide, localized ventral diencephalon (comprising the hypothalamus and different sleep- and motor-related nuclei) and hypothalamic connectivity differences clearly show a heretofore underestimated direct and/or indirect effect of hypocretin deficiency on microstructural white matter composition, presumably resulting from a combination of lower axonal density, lower myelination and/or greater axon diameter.

Keywords: Diffusion tensor imaging; Disorders of excessive somnolence; Hypocretin; Magnetic resonance imaging; Narcolepsy; White matter.

Fig. 1

Axial slices displaying significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) in patients with narcolepsy type 1 compared to controls. The average FA map of all subjects forms the background with the skeleton image of the included voxels (green) and the significantly different voxels (red-yellow) on top. Significant results are 1 mm inflated for visualization purposes. The numbers represent the corresponding axial slice in MNI152 space.

Fig. 2

The averaged FA map masked with the JHU tractography atlas labels (red-yellow). Reported as absolute significantly different voxel count within the label/total voxels within the label, corresponding percentage of significant voxels, minimum p-value found within the label.

Fig. 3

The significant ROIs displayed in native space of one subject, for visualization purposes. The mean (and 95% confidence interval) FA and MD values are plotted for patients (P) and controls (C) separately with the corresponding p-value on top. The unrounded p-value for the midbrain was p = .049693 (**). After Bonferroni correction for multiple comparisons only the left ventral diencephalon (*) maintained significant.

Fig. 4

Connectivity of the hypothalamus of one subject. In A the overall connectivity of the hypothalamus by itself is shown. B-D represent components of A, connecting the hypothalamus with the ROIs. Significantly different FA values were plotted as mean with the corresponding 95% confidence interval for both patients (P) and controls (C).