The reduction of sleep-like perilesional cortical dynamics underlies clinical recovery in stroke

Introduction. Recent studies have shown that, following brain injury, sleep-like cortical dynamics intrude into wakefulness, potentially contributing to brain network disruption and behavioral deficits. Aim. We employ TMS in combination with EEG to detect these dynamics and assess their impact on brain networks and clinical evolution in awake stroke patients. Methods. Twelve patients with subacute unilateral ischemic cortical stroke underwent a longitudinal study with two assessments (t0 and t1), including clinical evaluation using the National Institutes of Health Stroke Scale (NIHSS) and TMS-EEG recordings targeting perilesional and contralesional cortical sites. Parameters such as slow wave amplitude (SWa), high-frequency power (HFp) suppression, and the Perturbational Complexity Index-state transition (PCIst) were analyzed to quantify sleep-like cortical dynamics and their network-level consequences. Results. Results demonstrated a significant clinical improvement (NIHSS score: 7.16 +/- 0.73 at t0, 4.33 +/- 0.74 at t1; W=78, P<0.001). Perilesional SWa and HFp suppression decreased significantly at t1 compared to t0 (T(11)=3.05, P=0.01 and T(11)=-3.39, P<0.01, respectively), along with recovery of PCIst values (T(11)=-2.35, P=0.04). Importantly, both the dissipation of sleep-like perilesional cortical dynamics and the recovery of network-level interactions correlated with patients' clinical improvement (Spearman rho=0.62, P=0.03; rho=-0.68, P=0.01, respectively). Conclusion. These findings underscore the potential of TMS-EEG as an objective measure of neurological evolution and suggest targeting sleep-like cortical dynamics as a viable strategy for post-stroke neuromodulation and rehabilitation. ### Competing Interest Statement MM is co-founder of Intrinsic Powers, Inc., a spin-off of the University of Milan; SS is advisor of Intrinsic Powers. The other authors report no competing interests or personal relationships that could have appeared to influence the work reported in this paper. ### Funding Statement This work was supported by the European Union's Horizon 2020 Framework Program for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3), by the Fondazione Regionale per la Ricerca Biomedica, Project ERAPERMED2019 101, GA 779282, by the Tiny Blue Dot Foundation, by the European Research Council (ERC 2022 SYG 101071900 NEMESIS), by the Ministero dell'Università e della Ricerca (PRIN 2022), by the "Ricerca Corrente" funding scheme of the Italian Ministry of Health, and by the Fondazione Fratelli Tullio e Vitaliano Confalonieri. ### 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: Ethics committee of Istituto di Ricerca a Carattere Scientifico - Istituti Clinici Scientifici Maugeri, Pavia, Italy 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors