149 White Matter Connectivity in Narcolepsy Type 1 patterns, as they describe whole-brain axonal branching of hypocretinexpressing neurons from the hypothalamus, except for the cerebellum [208]. We take the absence of WM differences in the cerebellum, the absence of significant differences after the control TBSS analysis with randomized groups, and the specific significance in only the lower FA and higher RD contrasts as a sign of the robustness of our results. Region-of-interest analyses (II) In the ROI analyses, lower FA was found in patients, especially in the highly significant left ventral diencephalon. In the post-hoc analyses, significantly higher RD was also found in this region in addition to significantly lower AD in the midbrain. (II). The ventral diencephalon is filled with a variety of sleepwake regulation areas, including those in the hypothalamus and superior midbrain. Other included regions are related to motor functioning and the reward system, such as the subthalamic nucleus, substantia nigra and red nucleus and connecting fibres of the crus cerebri, lenticular fasciculus and medial lemniscus. The lower AD in the midbrain indicates axonal loss in patients [231] and could be explained by the loss of hypothalamic projections running through the midbrain towards sleep-wake-, motor- and reward-regulating nuclei in the brainstem, including the ventral tegmental area, locus coeruleus and laterodorsal tegmental, raphe and pedunculopontine tegmental nuclei [208]. The ROI findings further validate the correspondence between WM integrity disruptions in patients with narcolepsy and sleep-wake, reward system and motor complaints. Tractography analyses (III) Although not always significant, the overall lower FA and generally lower volume of patients’ tracts indicate a correlation between hypocretin deficiency and WM integrity disruptions in fibre bundles connecting with the hypothalamus, especially passing through the midbrain (III). No direct comparison of these results could be made as this is the first tractography study in people with narcolepsy. Our reported overall projection pattern is in line with previous hypothalamic tractography results [232], where dense projections were found in healthy subjects to the thalamus, amygdala, parahippocampus and brainstem and cortically widespread bundles mainly to the central gyri, frontal and occipital lobe. Our study found dense tracts connecting the hypothalamus with the thalamus, amygdala and midbrain in all subjects, whereas more diffuse connections were often seen to the orbitofrontal and parahippocampal WM. Tracts towards the anterior cingulate WM were less prevalent. Connections to 5
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