18 Chapter 1 imaging (DWI) analyses to investigate white matter morphology through water diffusivity (Figure 2) [104]. Tract-based spatial statistics studies have reported consistent brain-wide differences irrespective of disease duration, mainly in the hypothalamus-thalamus-orbitofrontal pathway and brainstem as parts of the sleep-wake regulation system, the reward and limbic system, and the corticospinal tract [84, 105-107]. The fronto-occipital differences were negatively correlated with subjective sleepiness scores and positively correlated with REM sleep latency [108]. Two studies that used voxel-based statistics showed inconsistent DWI differences in hypothalamic, brainstem, and cortical regions [109, 110]. In Chapter 5 we present multimodal investigation of white matter morphology in narcolepsy type 1 using DWI-based tract-based spatial statistics (TBSS), quantitative regions-of-interest (ROI) analyses and hypothalamus seeded-tractography. In analyses described in Chapter 6 we perform postmortem human histopathological analyses in narcolepsy type 1 to further assess axonal density and injury, and myelin integrity. Figure 2. Diffusion-weighted imaging (DWI) studies investigating structural connectivity in central disorders of hypersomnolence. Regions were generally included in case there were at least three independent studies indicating white matter changes within this region in people with narcolepsy compared to controls. Reported differences could reflect any DWI outcome measure that represents white matter integrity, such as fractional anisotropy (FA) or mean diffusivity/apparent diffusion coefficient (MD/ADC). The numbers between brackets correspond to the reference numbers of the studies. The study by Chen et al. [212] did not divide narcolepsy into type 1 and type 2 when comparing structural connectivity to controls. Post hoc comparisons between narcolepsy type 1 and type 2 did not reveal differences between narcolepsy subtypes, and the study by Chen et al. [212] was thus reported for both the “NT1 < HC” and the “NT2 < HC” contrasts. HC = Healthy controls; NT1 = Narcolepsy type 1; NT2 = Narcolepsy type 2; WM = White matter. Figure was created with Biorender and adapted from Gool et al. [104].
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