341 Discussion during active sleep resistance. This might be attributable to an enhanced need of visual focus to resist sleep, or may reflect a more rapid decline in alertness levels when resting. These studies have offered key insights into brain structure and functional activation patterns linked to common symptoms in individuals with narcolepsy type 1, such as vigilance complaints and difficulties maintaining wakefulness. Interpretation of these findings, methodological considerations and important future perspectives will hereafter be discussed. Brain structure in narcolepsy type 1 The widespread DWI differences described in Chapter 5 have been replicated by other researchers [105-110]. The most pronounced differences were found in the ventral diencephalon, comprising the hypothalamus, and hypothalamusseeded tractography to the midbrain. The extent of the other observed abnormalities implies that narcolepsy type 1 is an almost brain-wide disorder not just limited to the hypothalamus. Based on the findings shown in Chapter 5, we could not definitively assert that individuals with narcolepsy type 1 exhibit less efficient brain wiring. This uncertainty arises because DWI relies on indirect measures of water diffusion to estimate white matter integrity, with the assumption that diffusion is relatively unrestricted along axon bundles compared to directions perpendicular to the axonal bundles [210]. From conventional DWI findings, it therefore remains unclear whether myelin and/or axonal integrity are affected [210, 211], or whether other processes involving water diffusion such as sleep-related CSF flow play an important mediating role. The microscopic white matter assessment presented in Chapter 6 provided the necessary confirmation of white matter integrity disruptions in narcolepsy type 1. Through the Netherlands Brain Bank of the Netherlands Institute of Neuroscience we analysed white matter integrity using a globally unique dataset of donors with narcolepsy type 1 and carefully matched controls. The specificity of the significant microscopy findings enabled us to identify lower axonal density as the primary substrate underlying the DWI findings, while dismissing abnormalities in myelin integrity as the main contributing factor. Most pronounced differences were seen in the brainstem, and the mesencephalic reticular formation in particular. Nuclei within this region are normally crucial for promoting wakefulness and suppress muscle atonia and REM sleep [254], and loss of hypothalamic innervation could possibly explain typical narcolepsy type 1 symptomatology [255-257]. It could possibly also explain the relatively frequent symptoms of REM sleep behaviour disorder (RBD) in narcolepsy type 1 [440, 441]. Compared to 11
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