340 Chapter 11 anisotropy and radial diffusivity) suggested a combination of lower axonal density, lower myelination and/or greater axon diameter within affected areas of individuals with narcolepsy type 1. DWI did not allow for identification of the exact neurobiological substrates underlying these abnormalities. Chapter 6 covers extension of our work with human postmortem immunohistochemical analyses of microscopic white matter integrity in narcolepsy type 1 compared to matched control donors in cortical and brainstem regions. Axonal density was significantly lower in narcolepsy type 1 compared to controls in white matter of the reticular formation, pyramidal tract, corpus callosum and anterior cingulate gyrus. No significantly different axonal density was seen in the cerebellum nor in the axonal injury and myelin integrity measures in any of the regions, except for lower myelin density in narcolepsy type 1 in the secondary visual cortex. These findings align with prior in-vivo DWI reports and provide novel perspectives into the potential pathophysiological mechanisms underlying narcolepsy type 1, which may arise from hypocretin deficiency and/or chronic sleep-wake disruptions. Chapter 7 presents the adaptation of the sustained attention to response task (SART) with three difficulty levels to assess the fMRI brain activation patterns underlying the vigilance complaints in narcolepsy type 1. Individuals with narcolepsy type 1 – but not healthy controls – made significantly more mistakes with increasing difficulty and also had a tendency of longer reaction times across difficulty levels. The modified SART is a feasible fMRI vigilance task with similar task-positive brain activity in both groups within the cinguloopercular, frontoparietal, arousal, motor, and visual networks. Lower activity was observed in these attention- and arousal-related regions in narcolepsy type 1 compared to controls when transitioning from attention initiation to stable attention, specifically when vigilance demand was high. Significantly lower inhibitory motor activity was also found in relation to errors in the left pre- and postcentral gyri, suggesting impaired executive functioning in narcolepsy type 1. Chapter 8 shows us the neural correlates of active sleep resistance using a newly developed active sleep resistance paradigm. Concurrent EEG-fMRI was employed to objectively confirm wakefulness and task adherence. The active sleep resistance paradigm is a viable fMRI task, eliciting significant arousal- and visual-related activity during active sleep resistance. In control subjects, activation clusters were generally smaller compared to individuals with narcolepsy type 1, and no significant activation was observed in the brainstem. Formal comparison between groups revealed significantly higher activation in the left primary visual cortex among those with narcolepsy type 1
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