339 Discussion respectively been reported in narcolepsy type 2 and idiopathic hypersomnia [439]. Hypocretinergic involvement in narcolepsy type 2 has not been carefully ruled out yet. Given the frequent diagnostic cross-over between central disorders of hypersomnolence in absence of cataplexy, this theory could be similarly applied to idiopathic hypersomnia without long sleep time. The frequent self-reported triggers and association with preceding type A H1N1 influenza season severity comparable to narcolepsy type 1 provides first clues for possible immunological pathophysiologies and justifies further exploration of hypocretinergic involvement in narcolepsy type 2 and idiopathic hypersomnia without long sleep time. If true, this would also imply that opioids could potentially provide symptom relief in narcolepsy type 2 and idiopathic hypersomnia without long sleep time. Effects of differences in HLA genotypes between central disorders of hypersomnolence should be taken into account in these studies as it could explain differences in reported triggers and possible partial hypocretin deficiency. Section B – The Present: Brain Structure and Functioning in Narcolepsy Type 1 Narcolepsy type 1 is characterized by hypocretin deficiency, which is known to normally have a widespread neural projection pattern [208]. This could explain the diversity in symptoms individuals with narcolepsy type 1 experience. Despite the clear link with hypocretin deficiency, the neural correlates of narcolepsy type 1 remain only partially understood. Within this section we implemented a combination of MRI, concurrent EEG-fMRI measurements and microscopic immunohistochemical white matter assessment. Analyses presented in Chapters 5, 7 and 8 have been performed using the same well-defined sample of drug-free individuals with narcolepsy type 1 and age- and sex-matched healthy controls. Chapter 5 describes multimodal assessment of white matter morphology using DWI-based TBSS, quantitative ROI analyses and hypothalamus seededtractography. Where TBSS resulted in widespread significantly lower white matter integrity excluding the cerebellum in narcolepsy type 1, the ROIbased analyses found localized lower white matter integrity in the ventral diencephalon, thalamus and midbrain. Hypothalamus-seeded tractography additionally showed lower connectivity with the midbrain. No significant correlations with disease duration or Epworth Sleepiness Scale (ESS) scores were present. The combination of significant DWI outcome measures (fractional 11
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