Lesion network mapping of REM Sleep Behaviour Disorder

REM Sleep Behaviour Disorder (RBD) is a parasomnia characterised by dream enactment behaviour due to loss of sleep atonia during REM sleep. It is of considerable interest as idiopathic RBD is strongly associated with a high risk of future α-synuclein disorders. Whilst candidate brainstem structures for sleep atonia have been identified in animal studies, the precise mechanisms underpinning RBD in humans remain unclear. Here, we set out to empirically define a candidate anatomical RBD network using lesion network mapping. Our objective was to test the hypothesis that RBD is either due to damage to canonical RBD nodes previously identified in the animal literature, or disruption to the white matter connections between these nodes, or as a consequence of damage to some other brains regions. All published cases of secondary RBD arising due to discrete brain lesions were reviewed and those providing sufficient detail to estimate the original lesion selected. This resulted in lesion masks for 25 unique RBD cases. These were combined to create a lesion probability map, demonstrating the area of maximal overlap. We also obtained MRI lesion masks for 15 pontine strokes that had undergone sleep polysomnography investigations confirming the absence of RBD. We subsequently used these as an exclusion mask and removed any intersecting voxels from the aforementioned region of maximal overlap, creating a single candidate region-of-interest (ROIs) within the pons. This remaining region overlapped directly with the locus coeruleus. As sleep atonia is unlikely to be lateralized, a contralateral ROI was created via a left-right flip, and both were warped to the 100 healthy adult Human Connectome dataset. Probabilistic tractography was run from each ROI to map and characterize the white-matter tracts and connectivity properties. All reported lesions were within the brainstem but there was significant variability in location. Only half of these intersected with at least one of the six a priori RBD anatomical nodes assessed, however 72 % directly intersected with the white matter tracts created from the region of maximum overlap pontine ROIs, and the remainder were within 3.05 mm (±1.51 mm) of these tracts. 92 % of lesions were either at the level of region of maximum overlap or caudal to it. These results suggest that RBD is a brainstem disconnection syndrome, where damage anywhere along the tract connecting the rostral locus coeruleus and medulla may result in failure of sleep atonia, in line with the animal literature. This implies idiopathic disease may emerge through different patterns of damage across this brainstem circuit. This observation may account for the both the paucity of brainstem neuroimaging results reported to date and the observed phenotypic variability seen in idiopathic RBD.