Rewiring the disordered connectome with circuit-based paired stimulation after stroke-a randomized, double-blind and controlled Phase II trial

The cortico-cortical paired associative stimulation, a combined stimulation based on two brain regions, may be an effective strategy for stroke rehabilitation. Our aim was to confirm that the cortico-cortical paired associative stimulation strengthens the connection between brain regions in the motor circuit and promotes improvements in motor function. This was a randomized double-blind, controlled Phase II trial. 44 Stroke patients were treated in a rehabilitation hospital from October 2020 to January 2021 and were randomly assigned to the sham stimulation group and the cortico-cortical paired associative stimulation group. Patients in both groups received 12 days of rehabilitation therapy. Cortico-cortical paired associative stimulation group received one treatment of cortico-cortical paired associative stimulation invention. Both groups received behavioural assessments such as the Fugl-Meyer upper-extremity scale and resting-state functional MRI scans prior to the intervention and on Day 14. 40 patients completed the intervention session. The results of Fugl-Meyer upper-extremity scale showed a more significant improvement in motor function in the cortico-cortical paired associative stimulation group (6.33 ± 1.29) than in the sham stimulation group (3.16 ± 1.38) (P < 0.001). The functional connectivity showed that cortico-cortical paired associative stimulation strengthens connections between brain regions. Correlation analysis confirmed that the enhancement of functional connectivity was positively correlated with the recovery of Fugl-Meyer upper-extremity scale (r² = 0.146, P = 0.034; r² = 0.211, P = 0.0093). The results of functional connectivity suggest that cortico-cortical paired associative stimulation strengthens connections between brain regions. It is expected that this study will provide a positive viewpoint for the neurorehabilitation of stroke patients based on the circuit-level plasticity. (Chinese Clinical Trial Registry: ChiCTR2000036685).