Stroke recovery related changes in brain reactivity based on modulation of intracortical inhibition

The neuronal processes sustaining motor recovery after stroke are still largely unknown. Cortical excitation/inhibition dynamics have been suggested previously as a key mechanism occurring after a stroke. Their supportive or maladaptive role immediately after a stroke and during the process of recovery are still not completely understood; it is hypothesized that similar mechanisms (e.g., disinhibition) might yield differential functional roles depending on the stage after the stroke (e.g., acute vs. subacute vs. chronic) and the degree of deficit. Here, we used TMS-EEG to study brain reactivity, motor cortical excitability as well as intracortical inhibition and their impact on residual motor function and recovery longitudinally in a large cohort of stroke patients. EEG responses evoked by TMS applied to the ipsilesional motor cortex (iMC) were acquired in 66 stroke patients in the acute (1-week), sub-acute (3-weeks) and chronic stage (3-months). Readouts of ipsilesional cortical reactivity, excitability and intracortical inhibition were drawn from TMS-evoked potentials and derived metrics. Residual function of the upper limb was quantified through a detailed motor evaluation. A large proportion of patients, especially the most affected ones, exhibited large, simple TMS-evoked neuronal responses. Bayesian correlations revealed a link between higher excitability in iMC in the acute and stronger reduction of impairment determined by the upper extremity Fugl-Meyer (FM-UE) score in the early chronic stage. Furthermore, a decrease of this abnormally large response in the following months was related to better motor recovery. When investigating the underlying mechanisms with a focus on the intracortical GABAergic system, the present results revealed changes in intracortical inhibition in the first week after stroke that were associated with better recovery. Additionally, restoration of intracortical inhibition was present in patients, who recovered the most. Furthermore, the large component observed in a relevant part of the patients masks underlying mechanisms reflecting the importance of changes in intracortical inhibition for successful recovery. The present results strongly support the view of a beneficial role of cortical disinhibition in the first week after a stroke that promotes neuronal plasticity and recovery. However, to sustain long-term motor recovery, cortical disinhibition needs to be transient with crucial restoration of normal levels of intracortical inhibition. TMS-EEG has the exciting potential to provide proxies to better understand underlying mechanisms of stroke revovery, to determine outcome and to help to tailor interventional treatment strategies to each patient based on the brain reactivity status. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by 'Personalized Health and Related Technologies' of the ETH Domain, the Defitech Foundation and the Wyss Center for Bio and Neuroengineering ### 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 Cantonal Ethics Committee Vaud, Switzerland, gave ethical approval for this work 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data related to this article and all the custom scripts and JASP files are available upon reasonable request to the corresponding author.