343 Discussion narcolepsy type 1 experience. We therefore advise future studies to similarly implement the higher difficulty level but with longer task durations. Individuals with narcolepsy type 1 also showed longer SART reaction times compared to controls during moderate task difficulty and seemed to sacrifice speed to improve accuracy. When task difficulty increased, they were unable to maintain stable task performance and made significantly more mistakes (while maintaining similar slow reaction times), especially when the task blocks progressed. In the active sleep resistance paradigm described in Chapter 8 we observed similar delayed eye-closure in individuals with narcolepsy type 1 when switching between active sleep resistance and waking rest conditions. It remains unknown whether the longer reaction times and higher error rates are non-specific results of chronic excessive daytime sleepiness or represent distinct cognitive features of narcolepsy type 1. Upcoming studies should therefore aim to include healthy control groups after sleep deprivation. Multiple resting state and other task-based fMRI studies have identified extensive functional connectivity differences in narcolepsy type 1 [76], and most consistent findings include the compromised capacity of the default mode network (DMN), the primary resting network, to disengage from active networks when cognitively challenged [114, 115, 266, 442]. This inability of the DMN to uncouple from other networks suggests a dysregulation in narcolepsy type 1 in favour of staying awake over actual cognitive performance [116]. Despite the different task-specific activation patterns shown in Chapters 7 and 8, our between-group differences may represent similar underlying disease mechanisms. Individuals with narcolepsy type 1 constantly fight not falling asleep, and it seems plausible that cognitive reserves and sensory input are utilized to maintain wakefulness. This is possibly also displayed by the inability of individuals with narcolepsy type 1 to upregulate their attention networks to sustain performance in the higher difficulty level (Chapter 7), and the increased visual activation when actively resisting sleep (Chapter 8). Inclusion of sleepdeprived healthy individuals and/or individuals with narcolepsy type 1 treated with stimulants, could aid testing this hypothesis in future studies. Methodological considerations Multiple methodological limitations should be considered when interpreting our brain imaging and microscopy results. Most importantly, the presented studies included relatively small samples and require replication in larger populations. We aimed to optimize our study designs to allow for reliable statistical comparisons despite these small samples by including clinically welldefined groups of narcolepsy type 1 with matched control samples across 11
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