Combination of Neurotechnologies Towards Personalized Neurorehabilitation for Stroke Patients

"Ensure healthy lives and promote well-being for all at all ages" is the third sustainable development goal for the United Nations Agenda of 2030. This doctoral thesis fully embodied this objective by targeting stroke, a leading cause of death and disability worldwide. Indeed, around 80% of stroke survivors experience motor deficits and around 20% of them remain severely impaired, preventing them to perform activities of daily living and reintegrate in society. Finding an effective rehabilitation strategy for this specific group of patients is critically needed and was the focus of this work.Within the AVANCER proof-of-concept clinical trial (clinicaltrials.gov NCT04448483), we have designed and developed an interventional protocol to enhance upper-limb functions in severely impaired chronic stroke patients. Our goal was to use a combination of synergistic neurotechnologies applied in a hierarchically organized and personalized fashion. All recruited patients underwent a cumulative personalized intervention consisting of two phases: the first used a brain-computer interface (BCI) to trigger a variety of patient- tailored movements supported by multi-channel functional electrical stimulation in combination with a hand exoskeleton. The second interventional phase added non- invasive brain stimulation by means of anodal transcranial direct current stimulation to the motor cortex to the initial approach. Each phase lasted a minimum of 11 daily sessions and was continued as long as there was an improvement. Clinical-behavioural and multimodal systems neuroscience assessments were acquired, before the first, at the switch to the second and at the end of the second interventional phase.Results from the first eleven patients were promising showing safety, feasibility, and potential efficacy of this novel personalized approach acting synergistically on the nervous and musculoskeletal system. The primary outcome of the study (i.e., 4-point improvement in the Fugl-Meyer assessment of the upper extremity) was met with an average increase of 6 points. Clinical motor improvements were paralleled by changes in motor-network function and structure. Functional changes were observed both in resting-state and during motor tasks. Structural changes were seen in the re-appearance of motor-evoked potentials.In AVANCER, the dosage of the therapy and the functionalities of the BCI set-up were tailored to each patient, while neuromodulation was applied in a non-personalized manner in terms of brain-state dependence. In the second part of this work, we have set the fundamentals for a personalized brain-state-dependent stimulation. Specifically, we made the first steps in view of a brain-to-brain computer interface (BBCI) where specific brain signals are corresponded by the response of both peripheral machines and neuromodulation. We have thoroughly analysed and compared the brain state estimation methods to find the most accurate one and understand the implications of different signal processing parameters and steps. We have also looked at the applicability of such stimulation on stroke patients and finally discussed the importance of personalizing such stimulation in terms of temporal and spatial targets in relation to the stroke-recovery stage.We hope that future interventions for motor rehabilitation after stroke will employ a BBCI and that a great numbers of patients will improve their well-being.