134 Chapter 5 brainstem as parts of the sleep-wake regulation system, as well as in the reward and limbic system and the corticospinal tract. The findings of previous DTI studies including patients with narcolepsy type 1 or narcolepsy with cataplexy are summarized in Appendix A, Supplementary Table 1. Inconsistencies likely result from methodological differences between studies, including the use of central nervous system stimulants [214], small groups, age variability [33], differences in patient characteristics (narcolepsy related to H1N1-vaccination, disease duration and severity) and restricted outcome measures (only FA and MD), making the interpretation complex. Previous studies solely used whole-brain tract-based spatial statistics (TBSS) or whole-brain voxel-based morphometry (VBM) with diffusion metrics, which both are unable to assess interregional connectivity and compare regions subject to anatomical variation. Our aim was to identify the extent and nature of microstructural WM integrity disruptions in people with narcolepsy type 1 using a three-way analysis strategy, combining whole-brain TBSS (I), region-of-interest (ROI) analyses (II) and tractography (III). Where TBSS identifies whole-brain microstructural WM differences within regions of considerable proportion, the ROI-based analyses also assess average microstructural WM integrity in regions with anatomical variability, while hypothalamus-seeded tractography specifically assesses the hypothalamic connectivity throughout the brain. Given the diversity in symptoms experienced by patients, we hypothesized that patients in comparison to controls in general show brain-wide lower FA, higher RD and unaffected MD (I), localized lower FA in symptom-related regions (e.g. ventral diencephalon, midbrain, thalamus) (II) and in hypothalamus-seeded tracts to the thalamus, amygdala and midbrain. (III). In the TBSS analyses (I) we also expected significant relationships between longer disease durations, higher sleepiness scores and lower FA in regions related to the arousal system, including the pons, midbrain, thalamus and prefrontal cortex. Materials and methods Participants Twelve adults with narcolepsy type 1 were recruited at our outpatient narcolepsy clinic (Sleep-Wake Centre SEIN) and eleven age and sex groupmatched healthy controls were recruited through adverts in local newspapers. To be included, all subjects had to be 18–65 years old; right-handed according to the Edinburgh Handedness Scale [215] and have normal or corrected-tonormal vision. People with narcolepsy type 1 were diagnosed according to the
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