Increased very low frequency pulsations and decreased cardiorespiratory pulsations suggest altered brain clearance in narcolepsy

Abstract

Abstract Background Narcolepsy is a chronic neurological disease characterized by daytime sleep attacks, cataplexy, and fragmented sleep. The disease is hypothesized to arise from destruction or dysfunction of hypothalamic hypocretin-producing cells that innervate wake-promoting systems including the ascending arousal network (AAN), which regulates arousal via release of neurotransmitters like noradrenalin. Brain pulsations are thought to drive intracranial cerebrospinal fluid flow linked to brain metabolite transfer that sustains homeostasis. This flow increases in sleep and is suppressed by noradrenalin in the awake state. Here we tested the hypothesis that narcolepsy is associated with altered brain pulsations, and if these pulsations can differentiate narcolepsy type 1 from healthy controls. Methods In this case-control study, 23 patients with narcolepsy type 1 (NT1) were imaged with ultrafast fMRI (MREG) along with 23 age- and sex-matched healthy controls (HC). The physiological brain pulsations were quantified as the frequency-wise signal variance. Clinical relevance of the pulsations was investigated with correlation and receiving operating characteristic analysis. Results We find that variance and fractional variance in the very low frequency (MREGvlf) band are greater in NT1 compared to HC, while cardiac (MREGcard) and respiratory band variances are lower. Interestingly, these pulsations differences are prominent in the AAN region. We further find that fractional variance in MREGvlf shows promise as an effective bi-classification metric (AUC = 81.4%/78.5%), and that disease severity measured with narcolepsy severity score correlates with MREGcard variance (R = −0.48, p = 0.0249). Conclusions We suggest that our novel results reflect impaired CSF dynamics that may be linked to altered glymphatic circulation in narcolepsy type 1.