Sensorimotor white matter projections and disease severity in primary Restless Legs Syndrome/ Willis-Ekbom Disease: a multimodal DTI analysis

Abstract Background Restless Legs Syndrome, a potentially disabling sleep disorder, also known as Willis-Ekbom disease (RLS/WED), may be caused by loss of inhibitory modulation of descending central motor pathways, structural changes in the somatosensory cortex, abnormal connectivity between motor and sensory areas, as well as by subtle abnormalities in white matter micro-organization. Objective To compare diffusion-tensor imaging (DTI) metrics in areas associated with sensory or motor function, as well as sensorimotor integration, between subjects with primary mild-to-severe RLS/WED and controls. Methods DTI metrics were assessed in 38 subjects with RLS/WED (14 mild to moderate, 24 severe to very severe) and 24 healthy age-matched controls with whole-brain Tract Based Spatial Statistics (TBSS), Region-of-interest (ROI) and probabilistic tractography based analyses. The ROIs corresponded to the corticospinal tract (CST) at the level of the cerebral peduncle; the superior, middle and inferior cerebellar peduncles. Subgroup analyses were made according to the severity of RLS/WED symptoms. The corticospinal tract was evaluated with probabilistic tractography. We also explored associations between significant findings and severity of symptoms with the Spearman’s correlation coefficient. Results TBSS analysis revealed decreased axial diffusivity (AD) in the left posterior thalamic radiation in RLS/WED. In subjects with severe RLS/WED, AD was reduced in the left posterior corona radiata and this reduction was negatively correlated with severity of symptoms. ROI-based analysis showed that radial diffusivity (RD) was increased in the superior cerebellar peduncles of individuals with severe RLS/WED. Tractography did not show between-group or subgroup differences. Conclusions Our results are consistent with subtle white matter changes, prominently in RLS/WED subjects with more severe symptoms, in areas related to sensory or motor function, as well as to sensorimotor integration, compared to controls. These findings support the hypothesis, raised by prior pathophysiological studies, of defective integration within these networks.