Mapping the network underpinnings of central post-stroke pain and analgesic neuromodulation

Central post-stroke pain (CPSP) is a debilitating and often treatment-refractory condition that affects numerous stroke patients. The location of lesions most likely to cause pain and the identity of the functional brain networks that they impinge upon remains incompletely understood. We aimed to (1) elucidate which lesion locations are most frequently accompanied by pain; (2) explore CPSP-associated functional networks; and (3) examine how neuromodulation interacts with these networks. This multi-site study investigated 17 CPSP patients who received deep brain stimulation (DBS; n=12) or motor cortex stimulation (MCS; n=5). Pain-causing lesions were manually segmented and normalized to standard space. To identify areas linked to high risk of pain, the locations of CPSP lesions and 220 control lesions were compared using voxelwise odds-ratio mapping. The functional connectivity of pain-causing lesions was obtained using a large (n=1000) normative resting state functional MRI connectome and compared to that of control lesions and therapeutic DBS activation volumes. Brain regions most associated with CPSP risk (highest value=63 times) were located along the ascending somatosensory pathways. These areas and the majority of individual CPSP lesions were functionally connected to anterior/middle cingulate cortex, insula, thalamus, and inferior parietal lobule (PBonferroni<0.05). Extent of connectivity to thalamus, inferior parietal lobule, and precuneus also differed between CPSP and control lesions (PBonferroni<0.05). Posterior insula and thalamus shared connectivity with both CPSP lesions and pain-alleviating DBS activation volumes (PBonferroni<0.05). These findings further clarify the topography and functional connectivity of pain-causing brain lesions, and provide new insights into the network-level mechanism of CPSP neuromodulation.