Restoration of motor-evoked cortical activity is a distinguishing feature of the most effective rehabilitation therapy after stroke

Background An ischemic stroke is followed by the remapping of motor representation and extensive changes in cortical excitability involving both hemispheres. Although stimulation of the ipsilesional motor cortex, especially when paired with motor training, facilitates plasticity and functional restoration, the mechanisms underneath the reshaping of cortical functionality are widely unknown. Objective We investigated the spatio-temporal features of motor-evoked cortical activity associated with generalized recovery after stroke, and its dependence on the type of rehabilitative treatment. Methods We designed a novel rehabilitative treatment that combines neuro-plasticizing intervention with motor training. Specifically, optogenetic stimulation of peri-infarct excitatory neurons expressing Channelrhodopsin-2 was associated with daily motor training on a robotic device. The effectiveness of the combined therapy was compared with spontaneous recovery and with the single treatments (i.e. individually administered optogenetic stimulation or motor training). Results We found that only the combined therapy promotes generalized recovery of forelimb function and the rescue of spatio-temporal features of motor-evoked activity. Generalized recovery results from a new excitatory/inhibitory balance between hemispheres as revealed by the augmented motor response flanked by the increased expression of parvalbumin positive neurons in the peri-infarct area. Conclusions Our findings demonstrate that though behavioral recovery is not necessarily associated with the restoration of pre-stroke motor-evoked activity, the reestablishment of pre-stroke activation transients was a distinguishing feature of the most efficient therapeutic approach, the combined therapy. ### Competing Interest Statement The authors have declared no competing interest.