Altered functional connectivity between cortical motor areas and the spinal cord in chronic stroke

Systems neuroscience research has significantly contributed to our current understanding of alterations in brain structure and function after ischemic stroke and their importance for recovery processes. Technical limitations have excluded the spinal cord from imaging-based research. Available data are restricted to few microstructural analyses. Functional connectivity data are absent. The present study sought to address this gap of knowledge and assess alterations in cortical and spinal cord activation and changes in corticospinal coupling in chronic stroke. Thirteen well-recovered patients underwent combined cortical and spinal functional MRI while performing a simple visually guided force generation task. Task-related activation was localized in ipsilesional primary motor cortex (M1), premotor ventral cortex (PMV), and supplementary motor area (SMA), as well as in the cervical spinal cord. Psycho-physiological interactions and linear modelling were used to infer functional connectivity between cortical motor regions and the cervical spinal cord and their associations with motor deficits. The main finding was that PMV and SMA showed topographically distinct alterations in their connectivity with the spinal cord. Specifically, for SMA, we found a reduced coupling with voxels localised in the ipsilateral ventral spinal cord. For PMV, an enhanced coupling was detected with ventral, and intermediate central spinal zones. Lower SMA- and higher PMV-related spinal cord couplings located in similar areas were directly correlated with residual deficits. Collectively, this work provides first-in-human functional insights into stroke-related alterations in the functional connectivity between cortical motor areas and the spinal cord with patterns of directionality and topography suggesting that different premotor areas and spinal neuronal assemblies might be differentially prone to and involved in coupling changes. It adds a novel, promising approach to better understand stroke recovery in general, and to develop innovative models to comprehend groundbreaking treatment strategies with spinal cord stimulation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) SFB 936 - 178316478 - C1 (CG) & A6 (CB) and Exzellenzstipendium from the Else Kroener-Fresenius-Stiftung (2020_EKES.16) (RS). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the local ethics committee of the Medical Association of Hamburg (PV6026). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Processed brain and spinal cord activation data and demographic data to reproduce the findings are available from the corresponding author upon reasonable request.