Objective: To investigate brainstem structural connectivity changes in REM sleep behavior disorder (RBD) patients using an in-vivo probabilistic brainstem nuclei atlas and 7 Tesla high angular resolution diffusion MR imaging.

Background: RBD is characterized by the absence of REM-sleep muscle atonia. RBD patients have up to 73.5% risk of developing a neurodegenerative synucleinopathy after 12 years from the RBD-diagnosis[1]. Brainstem pathophysiology underlying RBD has been described in animal models, yet it is understudied in living humans due to the lack of an in-vivo brainstem nuclei atlas and to the limited sensitivity of conventional MRI.

Method: Data acquisition: We performed 7 Tesla MRI [table1] in 12 RBD patients (age: 67.9±1.7 yrs) and 12 controls (age: 66.3±1.6 yrs), under IRB-approval.
Analysis: a) Preprocessing: see Table 1. b) Definition of seed and target regions for DTI-based connectivity analysis: see Table 2 and Figure 1[table2][figure1]. c) Single-subject and group DTI-based connectivity analysis: We run probabilistic tractography[2]and computed a “structural-connectivity-index” for each pair of seed-target masks (= fraction of streamlines propagated from seed reaching target). d) Statistical analysis: Wilcoxon test was used to compare the differences between groups.

Results: The structural connectome of brainstem nuclei relevant for RBD/premanifest-synucleinopathy showed connectivity changes (specifically in 14 out of 32 brainstem seeds) across groups (Z = 2.6, p < 0.01) mainly within brainstem nuclei[figure2]. Specifically, we found impaired connectivity in RBD between REM-on and REM-sleep muscle-atonia medullary areas. This is in agreement with animal studies showing decreased excitatory connectivity influences between REM-on regions and ventro-medullary nuclei, the latter projecting to spinal motoneurons critical for generating muscle atonia during REM-sleep[3,4]. Most of REM-off areas did not show differences in connectivity between groups. Interestingly, ponto-medullary brainstem nuclei, known to be involved in REM atonia, showed decreased structural inter-connectivity, possibly related to an underlying neurodegeneration process[3]. In contrast, meso-pontine regions showed overall increased inter-connectivity[figure3].

Conclusion: Decreased structural connectivity between REM-on and medullary brainstem nuclei underlies REM-sleep muscle atonia in RBD patients.

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