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Our team has demonstrated that functional electrical stimulation(FES)as beneficial effects on the cognition of vascular dementia through strengthening the suppression of LTP after stroke.However,the effectiveness of FES is limited and slow with long treatment period.One of the reasons is viable neurons become dormant(down-regulated),It has been shown that the known depressant effects of low-frequency rTMS can be increased and prolonged by preceding it with 6-Hz priming stimulation.Also,rTMS combined with motor learning training could promote hand recovery in stroke.That is because of Metaplasticity,the plasticity of synaptic plasticity,is thought to have a pivotal role in activity-dependent modulation of synaptic connectivity,which underlies learning and memory.If primly week and tetanic stimulation can increase the induction of LTP.LTP is one form of synaptic plasticity,whose expression requires repeated intense synaptic stimulation that engages 2-amino-3-hydroxy-5-methylisoxazole-4-propionic acid(AMPA)receptors(GluR)and N-methyl D-aspartate(NMDA)receptors and Mice overexpressing the NMDA receptor exhibited superior learning and memory.This study investigated whether priming 25Hz repetitive transcranial magnetic stimulation could enhance the facility effect of electrical stimulation on vascular dementia and study its molecular mechanism.We hypothesized that rTMS might increase the sensitivity of FES and further shorten the treatment period of FES to improve the functional recovery of rats with vascular dementia via the pathway of cAMP/PKA-MAPK-BDNF-CREB pathway which maintains phase of LTP.In this study,Wistar rats were randomly assigned into the sham,VaD,FES,rTMS,FES+rTMS groups.2VO surgery(with the bilateral common carotid arteries occluded)was performed.The sham group rats received the same experimental procedure with no artery occlusion.Electrode-implantation was executed in the I-Ex group.Briefly,one end of the wire was implanted with the insulation stripped off and looped them around the bellies and tendons of extensor digitorum communis muscle(EDC)and extensor carpi radialis muscle(ECR),and the other end was pierced through the skin of dorsal neck and connected to a stimulator(S8800 Stimulator,Astro-Med,USA).1 week after 2VO surgery,rats in FES group were stimulated by FES for 2 weeks.Then in the FES+rTMS group,rTMS(conductive shielding plate to improve accuracy of rTMS position)will be used prior to FES.After the intervention,the rats will be assessed in aspects of NOR test.The changes of protein expression associated cAMP/PKA-MAPK-BDNF-CREB signaling pathways in the maintain phase of LTP was measured.We found both FES and FES+rTMS groups showed recovery of cognitive performances,however no significant differences were found between FES and FES+rTMS groups.Interestingly,FES+rTMS group significantly increased levels of BDNF,pautophosphorylated CaMKII,ERK1/2 and CREB compared with FES group.The results of this study identified rTMS preceding FES on the both upper limbs of rats with ischemic stroke may improve the efficacy of FES,shorten treatment duration and enhance neurorehabilitation.