Rapid functional remodeling of the targeted contralesional hemisphere induced by one week of noninvasive closed-loop neurofeedback guides motor recovery in post-stroke patients with chronic motor impairment: a phase I trial

Post-stroke hemiplegia of the upper extremities continues to pose a significant therapeutic hurdle. Contralesional uncrossed corticospinal pathways (CST) are involved in the recovery processes. Here, we test the feasibility, safety, and preliminary efficacy of targeted upregulation of uncrossed CST excitability using self-modulation training of cortical activities. In this phase I trial, eight individuals with persistent (1-8 years) severe post-stroke motor disability, who did not respond to conventional rehabilitation, voluntarily actuated their affected shoulder using a closed-loop, noninvasive digital connection, bridging the contralesional motor cortex (M1) and an exoskeleton robot. While patients attempted to elevate the affected arm, scalp electroencephalogram signals over the contralesional M1 were processed online to provide them with feedback on induced excitability change. Extensive neurophysiological examinations were conducted to evaluate the intervention effect using whole-head EEG and magnetic stimulations. The digital connection reconstructed neural pathways, allowing arm elevation contingent on voluntary upregulation of contralesional M1 excitability without any adverse effects. As evidenced by clinical score increases and neurophysiological examinations, seven days of consecutive system use resulted in rapid, sustained, and clinically significant improvement in motor function when removed from the system and promoted contralesional M1 functional remodeling. This closed-loop system is safe, feasible, and a promising intervention that recruits intact neural resources to allow patients to recover upper-extremity motor abilities. Larger clinical trials are needed to confirm these results. ### Competing Interest Statement J.U. is a founder and representative director of the university startup company, LIFESCAPES Inc., which is involved in the research, development, and sales of rehabilitation devices, including brain-machine interfaces. He receives a salary from LIFESCAPES Inc. and holds shares in LIFESCAPES Inc. S.I receives a salary from LIFESCAPES Inc. This company does not have any relationships with the device or setup used in the current study. The remaining authors declare no competing interests. ### Clinical Trial UMIN000017525 ### Funding Statement This study was funded by the Strategic Research Program for Brain Sciences from the Ministry of Education, Culture, Sports, Science, and Technology of Japan Grant Number 15H05880 and JSPS KAKENHI Grant Number 20H05923, Japan. ### 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 institutional ethics review board at Keio University School of Medicine approved the study (approval 20140442 and 20241023), registered with the University Hospital Medical Information Network (UMIN) (UMIN000017525). 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