151 White Matter Connectivity in Narcolepsy Type 1 sex-matched and a standardized data acquisition and a three-way analysis strategy were used. By also adding RD and AD to the outcome measures, this study fills an important gap in the current literature as a more in-depth interpretation of the origin of the differences is included. The relatively sporadic significance in the ROI-based (II) and tractography analyses (III) – compared to the widely present TBSS abnormalities – could mainly be attributed to intrinsic methodological differences, as averaging outcome measures within and between ROIs omits significant subregions, while TBSS (I) identifies subtler per-voxel differences [234]. The effect of crossing fibres and the relatively low proportion of hypocretin-producing neurons within the fibre bundles they follow, could further explain this. However, TBSS (I) is incapable of providing information on interregional connectivity and regions subject to anatomical variability as only regions containing dense white matter bundles are included [235]. This could also explain the combination of significantly lower AD in patients in the midbrain in the ROI-based analyses (II) and the absence of significant AD differences in the TBSS results (I). Given the distinct strengths and limitations of the individual methods and as previously suggested by Wakana et al. (2007) [236], we would recommend standard implementation of combined analysis techniques for future research. Although findings are robust, some limitations of our study also need to be addressed. An important limitation to the presented study is the limited sample size that was included. Future research should include larger samples to enable reliable subgroup analyses investigating the relationship between the presence of narcolepsy-related symptoms, neuropsychological measures, and the observed microstructural white matter abnormalities of patients with narcolepsy. Additionally, five patients had used psychotropic medication before inclusion. Even though medication was discontinued, this could have influenced results. It should also be noted that the ventral diencephalon is a more reliable ROI than the hypothalamus for the ROI analyses, as this last region is particularly susceptible to CSF contamination and hence to partial volume artefacts. This is less relevant for tractography analyses, as a result of the used FA threshold. Conclusion The reported whole-brain (I), localized ROI (II) and connectivity (III) differences clearly show lower FA in patients with narcolepsy compared to controls. In combination with the TBSS results showing brain-wide higher RD, this would indicate that narcolepsy type 1 patients suffer from a combination of lower 5
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