342 Chapter 11 idiopathic RBD, different underlying pathophysiologies could account for the nuanced distinctions in phenotypes, such as the typically younger onset of RBD in narcolepsy compared to idiopathic RBD [441]. This could also clarify why, until now, narcolepsy has not shown an association with elevated incidence rates of alpha-synucleinopathies. The extensive almost brain-wide differences between people with narcolepsy type 1 and healthy individuals described in Chapters 5 and 6 are surprising. Are the extensive variations specific to hypocretin deficiency, or do these findings result from chronic exposure to excessive daytime sleepiness? Given the presence of just 100,000-160,000 hypocretin neurons in healthy individuals [44, 264], these results suggest a more complex pathway causing the lower axonal density in narcolepsy type 1, presumably not directly caused by hypocretin deficiency. Involvement of a secondary mechanism or the presence of a cascade of alterations related to hypocretin deficiency seems likely. A plausible perspective is that the observed structural effects are possibly secondary to the chronic symptoms associated with hypocretin deficiency. This is emphasized by the faster cortical thinning that has been reported in narcolepsy type 1 compared to controls after five years follow-up [265]. We believe that future research should focus on this possible cascade of indirect effects as this could give insight in the pathophysiology and differences in phenotypes of people with narcolepsy type 1. Brain functioning in narcolepsy type 1 In Chapters 7 and 8 we provide the functional neural correlates of vigilance and active sleep resistance in narcolepsy type 1 compared to healthy controls, respectively. Besides displaying the complexity of brain functioning in narcolepsy type 1, these results improve our pathophysiological understanding of key narcolepsy type 1 complaints. It seems contradictory that, despite the clear vigilance complaints in narcolepsy type 1, the overall SART between-group brain activation comparison presented in Chapter 7 did not reach significance. The neural differences with healthy controls were more subtle than we hypothesized. Despite having relatively short task blocks, group differences became apparent when reviewing time-on-task effects. Individuals with narcolepsy type 1 (in contrast to controls) were unable to increase activation of their attention networks when transitioning from attention initiation to sustained attention during the higher difficulty level. This contrast of sustained attention possibly approximates the everyday work or studying challenges individuals with
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