## 4 Discussion
### Neural Basis for the Benefits from Neuromodulators  
There is increasing evidence that motor recovery after stroke is associated with reorganization of the damaged brain [52; 53]. Specifically, [PERSON] et al. demonstrated that, during intensive rehabilitative training, monkeys recovered from UE paresis after infarction in association with enlargement of the motor map representing the disabled forearm [52].  
How do neuromodulators at the periphery regain motor recovery? It is speculated that the administration of NMES or rPMS to affected UE muscles could induce cortical reorganization of the affected hemisphere [23; 45; 54; 55]. Some studies have proposed the possible neural mechanism underlying UE function recovery mediated by NMES. A near-infrared spectroscopy study suggested the association of the ipsilateral sensorimotor cortex with the improvement in UE function by EMG-triggered NMES in chronic-phase stroke patients [23]. Seventeen patients in the chronic phase of stroke underwent NMES applied to affected UE once or twice a week for 5 months. After this period, UE function improved and hemodynamic responses in the sensory-motor cortex (SMC), measured by NIRS, were altered to be bilaterally activated in a hemisphere-dominant way during affected wrist/finger extension with EMG-triggered NMES relative to voluntary of wrist/finger extension. This activation shift to the affected SMC may be related to cortical plasticity induced by NMES, in conjunction with motor recovery. This view is supported by a previous study [53] (Figure 7). Another neuroimaging study demonstrated that the contralateral SMC was activated when administering NMES to the wrist extensor and flexor muscles [54]. In addition, a previous animal study addressed the effect of forepaw electrical stimulation during a 90 min period of right middle cerebral artery (MCA) occlusion on neurological and tissue outcomes in a rat model of reversible focal forebrain ischemia [56]. The cortical and striatal infarct volume were both significantly reduced in the group with stimulated forepaw contralateral to the occlusion relative to the ipsilateral stimulated group (48% total reduction). This suggested the neuroprotective effect of peripheral electrical stimulation contralateral to the ischemic hemisphere in the rat ischemic model. It remains unknown how this protection takes place, but it is most likely related to the contribution of NMES to neuronal reorganization. Altogether, NMES could produce cortical reorganization associated with motor recovery.  
A previous PET activation study [45] delineated the reorganization of the motor map induced by rPMS. The authors demonstrated that regional cerebral blood flow (rCBF) increases in the superior posterior parietal cortex and that the premotor cortex is associated with an improvement in spasticity in the paretic arm following rPMS treatment. The use of rPMS might produce cortical neuroplastic changes in conjunction with motor recovery.  
Another study of corticospinal excitability tested by means of transcranial magnetic stimulation demonstrated that rPMS generated an increase in motor-evoked potential (MEP) amplitude and a decrease in MEP latency [55]. In other words, higher MEP amplitudes represent the recruitment of a larger volume of residual pyramidal neurons in the M1 area after stroke [57]. Shorter MEP latencies can be interpreted as two potential changes: (1) better synchronicity of multiple descending volleys (I-wave) arising from rPMS, thus leading to a more efficient depolarization of spinal motor neurons [58] and (2) better recruitment of short-latency corticocortical projections from premotor areas to primary motor cortices (area 4) [59]. In other words, rPMS-induced proprioceptive inflows can be conveyed to the affected hemisphere mediated by thalamocortical and corticocortical fibers, resulting in the potentially enhanced synaptic connectivity of premotor and residual M1 cells [44].