347 Discussion objectively verify wakefulness and task adherence, something previous studies often lacked [76]. As sleep-wake misperception is frequent in central disorders of hypersomnolence [446], we advise future fMRI studies on central disorders of hypersomnolence to include objective wakefulness monitoring through eye tracking and/or concurrent EEG recordings. Combining EEG-fMRI poses technical challenges because the EEG signal is subject to ballistocardiogram (BCG), MR-induced gradient and helium pump artefacts [310]. Extensive data cleaning is necessary before reliable sleepwake scoring can be conducted. For our analyses shown in Chapter 8, we used carbon wire loops as additional sensors to accurately track unpredictable artefacts related to subtle movements in the scanner [311, 312]. In our multicentre collaboration with Concordia University we are working on methodological comparisons of different hardware and software cleaning tools to provide guidelines to optimally clean MRI-acquired EEG, EOG and EMG recordings for sleep-wake scoring and spectral analyses. Brain clearance in central disorders of hypersomnolence As we identified widespread DWI differences, the question arises whether other brain processes influencing water diffusion may be affected in narcolepsy type 1. Recent studies revealed that the brain undergoes clearance of waste metabolites through cerebrospinal fluid flow during sleep [447]. CSF flow in the perivascular spaces is modulated by vasomotion and cardiorespiratoryrelated pulsations [448, 449]. The effects of disturbed sleep on brain clearance (and possibly water diffusion) remain largely unknown and require further investigations. Especially in central disorders of hypersomnolence, where there are ample diurnal and nocturnal sleep–wake alterations, this requires detailed investigation [4]. Two studies have so far aimed to investigate brain clearance in the context of narcolepsy. A not significant tendency towards lower DTI-ALPS indices was seen in narcolepsy type 1 (suggesting altered CSF dynamics) and not in narcolepsy type 2 [450]. This frequently employed surrogate marker for perivascular fluid flow has recently been heavily criticised because of its oversimplification of CSF flow and seems insufficient as a brain-wide clearance marker [451]. Another study used ultrafast fMRI to investigate physiological brain pulsations (vasomotor, cardiac and respiratory) and identified altered brain fluid dynamics in narcolepsy type 1, particularly in regions involved in the reticular formation [448]. Individuals with narcolepsy type 1 however did not discontinue medication in this study and no objective verification of wakefulness was included. Despite first clues of altered brain clearance in narcolepsy type 11
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