Individualized closed-loop TMS synchronized with exoskeleton for modulation of cortical-excitability in patients with stroke: a proof-of-concept study

Background: Repetitive TMS is used in stroke rehabilitation with predefined passive low and high-frequency stimulation. Brain State-Dependent Stimulation (BSDS)/Activity-Dependent Stimulation (ADS) using bio-signal has been observed to strengthen synaptic connections. Without the personalization of brain-stimulation protocols, we risk a one-size-fits-all approach. Methods: We attempted to close the ADS loop via intrinsic-proprioceptive (via exoskeleton-movement) and extrinsic-visual-feedback to the brain. We developed a patient-specific brain stimulation platform with a two-way feedback system, to synchronize single-pulse TMS with exoskeleton along with adaptive performance visual feedback, in real-time, for a focused neurorehabilitation strategy to voluntarily engage the patient in the brain stimulation process. Results: The novel TMS Synchronized Exoskeleton Feedback (TSEF) platform, controlled by the patient's residual Electromyogram, simultaneously triggered exoskeleton movement and single-pulse TMS, once in 10 s, implying 0.Hz frequency. The TSEF platform was tested for a demonstration on three patients (n=3) with different spasticity on the Modified Ashworth Scale (MAS=1, 1+, 2) for one session each. Three patients completed their session in their own timing; patients with (more) spasticity tend to take (more) inter-trial intervals. A proof-of-concept study on two groups-TSEF-group and a physiotherapy control-group was performed for 45min/day for 20-sessions. Dose-matched Physiotherapy was given to control-group. Post 20 sessions, an increase in ipsilesional cortical-excitability was observed; Motor Evoked Potential increased by similar to 48.5 mu V at a decreased Resting Motor Threshold by similar to 15.6%, with improvement in clinical scales relevant to the Fugl-Mayer Wrist/Hand joint (involved in training) by 2.6 units, an effect not found in control-group. This strategy could voluntarily engage the patient. Conclusion: A brain stimulation platform with a real-time two-way feedback system was developed to voluntarily engage the patients during the brain stimulation process and a proof-of-concept study on three patients indicates clinical gains with increased cortical excitability, an effect not observed in the control-group; and the encouraging results nudge for further investigations on a larger cohort.