150 Chapter 5 other, not mentioned regions were out of this study’s scope. The reason why more diffuse tracts are sometimes not detected when using tractography, is related to the partial volume effect. The contribution of diffuse tracts to the overall diffusion measures of a voxel is only marginal when the voxel also contains more dense tracts, resulting in loss of information [233]. Future research with increased spatial resolution and higher b-values could resolve this. Interpretation The exact origin of the WM differences remains unexplained, but previous research [213, 231] has suggested that lower FA and higher RD results from a combination of lower axonal density, lower myelination and/or greater axon diameter within affected areas. The extent of the observed abnormalities implies that narcolepsy type 1 is a brain-wide disorder not just limited to the hypothalamus. Considering the relatively limited 50,000–80,000 hypocretinproducing neurons normally present [207], these results suggest a more complex pathway causing the WM abnormalities in patients, presumably not directly caused by hypocretin deficiency. Involvement of a secondary mechanism or the presence of a cascade of alterations related to hypocretin deficiency seems likely. A similar pathophysiology has been suggested by Juvodden et al. (2018) [105]. The limited significant differences in the studied connections passing through the hypothalamus further contradicts that the observed differences are solely of hypothalamic origin. In fact, it implies that narcolepsy type 1 is a brain-wide disorder, not just limited to the hypothalamus. We believe that future research should focus on this possible cascade of indirect effects, or parallel to, related to hypocretin deficiency as this could also give insight in the pathophysiology of different symptoms experienced by patients. It could also explain the susceptibility of patients to develop certain symptoms. The absence a significant correlation between time since symptom onset and FA was unexpected. Similar results were previously seen [105, 106] and might be due to the relative end-stage narcolepsy in all studies. This indicated that when the chronic narcolepsy state has been reached, the brain reaches structural end-stage white matter composition. A comparison between patients in different disease stages, implementing a multimodal analysis strategy, should be the target of future research. Methodological strengths and limitations We assessed a homogeneous group of patients using a multimodal analysis strategy, to improve data quality and interpretability. All controls were age- and
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