Explore The After-Effects Of Repeated Theta Burst Stimulation On Cortical Excitability

Background:Stroke has a high mortality rate and disability rate.In China,about 80%of stroke patients have residual dysfunction.There is a correlation between cortical excitability and brain injury,and promoting cortical functional reorganization is an important way to promote the recovery of residual dysfunction.Transcranial magnetic stimulation（TMS）is a noninvasive neuromodulation technique that is often used to regulate cortical excitability to balance hemispheric excitability and promote functional recovery.Theta burst stimulation（TBS）is a highly effective paradigm of TMS that can produce greater excitatory regulation in a shorter period time,and is widely used in clinical and scientific research.The therapeutic effect of TMS is affected by many factors,such as frequency,intensity,stimulus dose,time,coil type and so on.The formulation and application of clinical protocols for TMS has not been unified and there is a lack of standardized operating procedures.So far,the optimal therapeutic effect has not been explored.The purpose of this study is to explore a new application protocol of TMS,determine the optimal treatment paradigm,improve the application efficiency of TMS in the field of rehabilitation,and provide a reference for the setting of clinical program.Study 1 The after-effect of repeated intermittent theta burst stimulation at different session intervalObjective:The study aims to investigate the after-effect of repeated 3 blocks of intermittent theta burst stimulation（iTBS）over primary motor cortex（M1）with different stimulation time intervals on motor cortex excitability.Methods:The study has a cross-over design.Sixteen participants were assigned to 3 groups and received different repeated iTBS protocols during each session,Each intervention protocol consisted of 3 blocks of iTBS with 600 pulses（total 1800 pulses）.The three intervention schemes only applied different stimulus intervals of 0,10 and 30min,respectively:（A）3 blocks of iTBS with no interval（iTBS1800）;（B）3 sessions iTBS with 10min intervals（iTBS600×3*10）;（C）3 sessions iTBS with 30min intervals（iTBS600×3*30）.As washout period,each visit is separated by at least 7 days.We measured the motor cortical excitability changes and intracortical inhibition.Results:A dose of 1800 pulses iTBS per day is tolerable without any adverse reactions.There were significant differences between three groups in the variation of MEPs amplitude between the PROTOCOLS and the TIME effect within 60min after intervention(F_2,30=3.734,p=0.036;F_6,90=2.886,p=0.013).Compared with the baseline,the MEPs amplitude in iTBS1800 group decreased within 60min after intervention,and was significantly inhibited at 5min（p=0.049）.After that,the MEP amplitude gradually returned to the baseline level,which was similar to the baseline level at 45min and larger than the baseline MEPs amplitude at50min.iTBS600×3*10 group MEPs amplitude increased.The MEPs amplitude of the first two blocks was similar at 5min after iTBS intervention;the MEPs amplitude at5min after 3 blocks of iTBS stimulation was greater than that of the first two blocks,but there was no difference;at 10min,it was significantly higher than baseline（p=0.015）.The MEPs amplitude of iTBS600×3*30 group was facilitation.In addition,MEP amplitude increased gradually with the intervention dose and the facilitation effect lasted for 120min.Compared with baseline,MEPs amplitude increased significantly at 10min after first blocks of iTBS intervention（p=0.016）,10min（p=0.012）and 15min（p=0.019）after secondly blocks of iTBS intervention,and 5min,10min and 60min after intervention of third blocks iTBS（p=0.013,p=0.018,p=0.030）.No significant difference was found in intracortical inhibition among each group（p>0.05）.The subjects responded differently to different iTBS protocols.After the classic iTBS600,50%of the subjects showed facilitation response.In iTBS1800,25%of subjects showed a facilitation.In iTBS600×3*10 group,56.25%of the experimental subjects showed a facilitation.The facilitation of iTBS600×3*30 was more obvious than the other two iTBS protocols,75%of the subjects showed the facilitation.Conclusions:Repeated application of 3 blocks of iTBS could produce cumulative effect and lead to larger MEP amplitude,increase the response rate.Repeated iTBS with different time intervals had different after-effects on motor cortical excitability.Study 2 The effect of repeated iTBS on patients with severe upper limb dysfunction after strokeObjective:TBS can overregulate the cortical excitability of patients with brain injury,so as to promote the recovery of patients’motor function.In study 1,we found that repeated 3blocks of iTBS with 30min stimulation intervals had the best effect of regulating cortical excitability.We aimed to explore the effect of repeated 3 blocks of iTBS applied to the ipsilateral primary motor cortex of patients with severe upper extremity motor dysfunction after stroke on motor function recover and cortical excitability.Methods:Fifteen patients with subacute stroke and severe upper-limb impairment were recruited to this single-blind,sham-controlled study.Patients were divided into three groups:sham stimulation group（SG）,classic iTBS group（CG）and iTBS600×3*30min group（RG）.CG received a single session iTBS every day,followed by 60min of occupational therapy（OT）.Compared with the CG,SG used false coil（no magnetic effect was produced）.RG received 3 blcoks of iTBS intervention every day,with an interval of 30min for each block,and received OT training at the interval,total 60min.each patient received 10 sessions ipsilateral M1iTBS.The Upper limb Fugl-Meyer Assessment（UL-FMA）,Action Research Arm Test（ARAT）,Mini-Mental State Examination（MMSE）,Barthel Index（BI）and TMS measurement index were evaluated before and after the intervention,respectively.Results:All 15 subjects completed the intervention for 10 consecutive days without any adverse reactions.Both iTBS and sham stimulation applied to the affected motor cortex hand area enhanced motor recovery（p=0.004,p=0.001,p=0.002）.BI scores were significantly improved only in the CG and RG（p=0.040,p=0.010）,and there was no difference in other scores.The inter-group comparison showed that the improvement degree of UL-FMA of CG and RG was better than that of the SG（p=0.029,p=0.003）,while there was no inter-group difference between CG and RG（p>0.05）.Baseline TMS evaluation,one of RG’s MEP could not be induced on both hemispheres,while MEP could be induced in the unaffected hemisphere in other patients,and ipsilateral MEP could not be induced in most patients.There was no difference in MEP amplitude before and after intervention,and no significant change was found between groups（p>0.05）.Conclusion:Ipsilateral iTBS can improve the motor function of the upper extremity in stroke patients.Increasing the stimulating dose of iTBS has no significant effect on the improvement of motor function and the regulation of cortical excitability.