Structural anomaly in the reticular formation in narcolepsy type 1, suggesting lower levels of neuromelanin

Abstract

The aim of this study was to investigate structural changes in the brain stem of adolescents with narcolepsy, a disorder characterized by excessive daytime sleepiness, fragmented night-time sleep, and cataplexy. For this purpose, we used quantitative magnetic resonance imaging to obtain R1 and R2 relaxation rates, proton density, and myelin maps in adolescents with narcolepsy ( n = 14) and healthy controls ( n = 14). We also acquired resting state functional magnetic resonance imaging (fMRI) for brainstem connectivity analysis. We found a significantly lower R2 in the rostral reticular formation near the superior cerebellar peduncle in narcolepsy patients, family wise error corrected p = .010. Narcolepsy patients had a mean R2 value of 1.17 s −1 whereas healthy controls had a mean R2 of 1.31 s −1 , which was a large effect size with Cohen d = 4.14. We did not observe any significant differences in R1 relaxation, proton density, or myelin content. The sensitivity of R2 to metal ions in tissue and the transition metal ion chelating property of neuromelanin indicate that the R2 deviant area is one of the neuromelanin containing nuclei of the brain stem. The close proximity and its demonstrated involvement in sleep-maintenance, specifically through orexin projections from the hypothalamus regulating sleep stability, as well as the results from the connectivity analysis, suggest that the observed deviant area could be the locus coeruleus or other neuromelanin containing nuclei in the proximity of the superior cerebellar peduncle. Hypothetically, the R2 differences described in this paper could be due to lower levels of neuromelanin in this area of narcolepsy patients.

Neuroimaging of Narcolepsy and Primary Hypersomnias

“…Additionally, others have reported alterations of several DWI parameters (e.g., increased mean diffusivity values without fractional anisotropy changes) in the ventral tegmental area and the dorsal raphe nuclei of patients with narcolepsy-cataplexy (Scherfler and others 2012). A recent study by Drissi and others (2019) found signs of lower levels of neuromelanin in the rostral reticular formation of the brainstem. Altogether, wide ranging functional and structural neuroimaging techniques have provided complimentary data to suggest functional and anatomical changes of the brainstem may underlie the symptoms of narcolepsy.…”

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

“…Our present cardiac- and very low frequency -related results partly overlap with an earlier task- and resting-state imaging findings in patients with narcolepsy. In two studies, Drissi et al found that in patients with narcolepsy the dynamic resting activity of the DMN is unstable and that a lower R2 relaxation rate in the brainstem’s rostral reticular formation may indicate lower neuromelanin levels in the LC in narcolepsy when compared to the healthy population 11 , 15 . Moreover, in narcolepsy increased deactivation of the DMN has been observed under cognitive burden induced by a working memory test suggesting dysregulation of sustained attention by an imbalance in the utilization of cognitive resources 14 .…”

“…These AAN innervations participate in the control of autonomic functions and arousal/sleep via their respective neurotransmitters in dense innervations to the hypothalamus, thalamus, basal ganglia, and neocortex 9 . Earlier imaging studies in narcolepsy have shown structural alterations in cortical and subcortical brain regions including the limbic system and brainstem along its nuclei e.g., LC and neocortex 10 , 11 . Research conducted with task-fMRI have found altered activation of the amygdala, a part of the limbic system, in tasks with humor/reward paradigms along with increased deactivation of the default mode network (DMN) under cognitive burden in narcolepsy 12 – 14 .…”

Synthetic MRI: Technologies and Applications in Neuroradiology

“…59 Blystad et al 63 investigated the use of T 1 , T 2 , and PD obtained by the MDME method to identify active MS plaques without GBCA administration. Beyond MS, quantitative values from the MDME were used to show R2 differences associated with low concentrations of neuromelanin in the rostral reticular formation near the superior cerebellar peduncle in narcolepsy 64 ; to assess the degree of myelination in preterm neonates 65 and SWS 66 ; and to measure T 1 shortening in the globus pallidus related to multiple exposures to macrocyclic GBCA, specifically gadobutrol. 67 Quantitative maps obtained from MRF were used to diagnose hippocampal sclerosis (HS) in patients with mesial temporal lobe epilepsy (MTLE).…”