133 White Matter Connectivity in Narcolepsy Type 1 Introduction Narcolepsy type 1 is a severely disabling neurological condition, characterised by excessive daytime sleepiness (EDS), attention deficits, cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. It has been suggested that it is an autoimmune-mediated disorder but the exact pathophysiology remains to be discovered [206]. Patients with narcolepsy type 1 show a selective loss of hypothalamic neurons producing hypocretin (or orexin) [44, 45]. In an average healthy brain, each hemisphere comprises roughly 50,000–80,000 hypocretin-producing neurons, localized exclusively within the lateral and posterior hypothalamus [207]. Their axonal projections diffusely disperse over the brain excluding the cerebellum with particularly dense projections to the locus coeruleus, ventral tegmental area and the tuberomammillary, raphe, laterodorsal tegmental and pedunclopontine tegmental nuclei [208]. Hypocretin affects various neural networks; it maintains sleep-wake state stability, energy homeostasis, reward system regulation and cognitive and mood control [209]. Given the variety of complains in narcolepsy, a pertinent question is to what extent local and global white brain matter integrity and connectivity are affected. DTI is an MRI technique enabling in-vivo modelling of microstructural white matter (WM) morphology by means of water diffusivity variations in different tissue types [210]. Scalar variables of fractional anisotropy (FA) and mean, axial and radial diffusivity (MD, AD, RD) are normally used as outcome measures. Fractional anisotropy (FA), reflects how directionally constrained the diffusion of water is along axons. While higher FA values might indicate more coherent, intact axons and/or higher myelination, lower FA may imply loss of WM integrity and/or injury. MD is composed of the mean diffusion in all three diffusion directions as a quantitative measure of alterations in the extracellular volume. AD captures the most prominent direction, parallel to axon orientation and RD the mean of the remaining perpendicular two directions. Lower AD reflects axonal damage, whereas higher RD is related to lower axonal density, lower myelination and/or greater axon diameter [211-213]. The outcome measures reflect the sum of different underlying tissue characteristics within one voxel. Possible differences are often explained by a combination of aforementioned morphological features. Six diffusion tensor imaging (DTI) studies investigating structural WM morphology in people with narcolepsy compared to controls have previously been reported [84, 105-107, 109, 110]. Findings are inconsistent, but disruptions were found in the hypothalamus–thalamus–orbitofrontal pathway and the 5
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