148 Chapter 5 disease duration (5.7 years) and the almost exclusive inclusion of patients that developed narcolepsy type 1 after H1N1-vaccination. Similar results were also seen in two other TBSS studies [106, 107] which reported selective extensively lower FA in patients with narcolepsy. Significant areas included the corpus callosum (the genu for Park et al., 2016 and body for Tezer et al., 2018), anterior internal capsule and thalamus. Tezer et al. (2018) additionally found lower FA in the midbrain, temporal lobe and cerebellum [107], whereas Park et al. (2016) also reported differences in the bilateral anterior cingulate, frontal lobe and left posterior internal capsule and thalamus [106]. These regions were also found to be abnormal in our study, except for the cerebellum. This slight difference could be related to the absence of hypocretin measurements in these two studies and the lower b-values that were used for DTI acquisition, which are known to influence the diffusion metrics. A fourth TBSS study [109] reported both lower and higher FA in the right hypothalamus, brainstem, corticospinal tract and temporal, frontal and parietal WM. Inconsistencies with this latter study in FA disruption directions are possibly related to the use of psychotropic drugs (mostly central nervous system stimulants) in these patients compared to our drug-free population, as medication is known to influence WM morphology [214]. Our results are in partial agreement with the whole-brain VBM-style study by Scherfler et al. (2012) that reported significantly lower FA and higher MD in the orbitofrontal cortex, anterior cingulate, singular lower MD in the ventral tegmental area, dorsal raphe nuclei and hypothalamus and lower FA measurements in the inferior frontal and inferior temporal cortices [84]. Comparability with this study is difficult though, as included subjects on average were over 55 years of age and generally still used psychotropic medication. A second VBM study (Nakamura et al., 2013) has described increased MD in the left inferior frontal gyrus and left parahippocampal gyrus/amygdala and lower MD in the postcentral gyrus in narcolepsy with cataplexy patients compared to controls [110]. Interestingly, the left laterisation of amygdala differences that was reported by Nakamura et al. (2013) could not be replicated in this study as we found no significant differences in FA and MD in the left amygdala in the ROI analyses [110]. The reliability of these VBM-style approaches remains problematic given its susceptibility to bias from incorrect subject alignment and the inconsistent use of smoothing, making interpretability complex [228-230]. This could have especially affected the latter study due to its limited spatial resolution (3.5 mm voxel thickness) and the 12 mm smoothing that was used. The brain-wide TBSS abnormalities excluding the cerebellum, are in concordance with previous histological findings on normal hypocretin projection
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