The Clinical Efficacy And Mechanism Of RTMS Intervention In Parkinson’s Disease

BackgroundParkinson’s disease(PD)is a progressive neurodegenerative disease,which causes heavy economic burden to individuals,families,and society.However,at present,the effect of drug treatment and surgical treatment of PD is limited,and it is urgent to explore its neural mechanism and develop new safe and effective treatment methods with few side effects.The onset of PD is mostly unilateral and the left and right limbs are uncoordinated.It indicates that the lateralization and synergetic function of the brain may be abnormal.Exploring the brain regions with PD lateralization and abnormal synergetic function will help to understand its neural mechanism and explore more possible and effective targets for future treatment.Repetitive transcranial magnetic stimulation(rTMS)is a non-invasive and widely used neuromodulation technique.Previous studies have confirmed the clinical efficacy of rTMS on PD,but there is still a certain heterogeneity,which may be related to the different sensitivity of the symptoms of PD to rTMS or the differences in demographic,clinical characteristics,and brain function.Freezing of gait(FOG)is one of the most serious sports complications of PD patients,and it is the main risk factor for patients to fall,often leading to fractures,traffic accidents,scalds,and other accidents,which seriously affects the quality of life of patients.Although there have been some studies on the treatment of FOG with rTMS in the past,the clinical efficacy is poor,which may be related to the selection of target sites and stimulation dose.Many studies have shown that the lower leg primary motor cortex(M1-LL),the cortical center in cortico-basal ganglia-thalamo-cortical motor circuit,is a potential effective target for FOG treatment,and that high-dose stimulation is more likely to improve clinical symptoms than low-dose rTMS stimulation.Therefore,the paradigm of high-dose rTMS targeting on M1-LL may be effective in improving FOG symptoms.Studies have shown that executive control and attention function are impaired in patients with FOG.The Executive control network(ECN),which includes the prefrontal cortex,inferior parietal lobe and other regions,plays an important role in adaptive cognitive control.Therefore,exploring the changes in ECN before and after rTMS stimulation of FOG may help further elucidate the relevant neural mechanisms.ObjectiveThis study was based on rs-fMRI to explore the lateralization of PD and the cooperation function to explore potential targets,and then based on the existing targets to explore the efficacy and predictive factors of rTMS in the treatment of various symptoms of PD.Finally,based on the effective stimulation points reported in the past,high-dose of rTMS was used to intervene patients with FOG patients to explore its clinical efficacy and neural mechanism.(1)The onset of PD is mostly unilateral,and walking is accompanied by uncoordinated limb movements.Based on the new brain lateralization and cooperation indicators,this study aimed to explore the brain areas with PD lateralization and cooperation dysfunction.(2)In this study,we aimed to explore the efficacy of rTMS on different motor symptom clusters of PD patients,and then explore the demographic,clinical,and imaging predictors of symptom improvement respectively.(3)The main goal of this open-label trial was to investigate the clinical efficacy of the high-dose iTBS protocol in symptoms of FOG.At the same time,rs-fMRI was used to explore the changes of ECN before and after treatment to explore the neural mechanism of rTMS on the improvement of clinical symptoms of FOG patients.Methods(1)We recruited 70 patients with PD and 70 healthy controls matched with demographic data to complete rs-fMRI scanning.And then we calculated the autonomous index(AI)of the lateralization index of the voxel level,and the connectivity between functional homologous voxels(CFH)to determine the abnormal brain area,and then calculate the functional connectivity of the whole brain with the abnormal lateralization brain area as the seed.(2)We recruited 31 and 39 patients with PD in the two groups of experiments separately.Based on the targets calculated in the first study,these 70 PD patients received a course of rTMS treatment on the left supplementary motor area(SMA)and underwent rs-fMRI and clinical symptom evaluation before and after treatment.According to previous studies,the scores of the United Parkinson’s Disease Rating Scale Part Ⅲ(UPDRSⅢ)were divided into six symptom groups,axial dysfunction,resting tremor,rigidity,bradykinesia affecting right and left extremities,and postural tremor.In the first group,an open label rTMS intervention experiment was conducted to evaluate the improvement of rTMS on various motor symptom clusters of PD.The second experiment was a randomized controlled trial(RCT).In this experiment,the patients were divided into real and sham stimulation groups to further verify the improvement of rTMS on various motor symptom clusters.Then,we combine the real groups from the two experiments to further calculate the baseline demographic and clinical predictors of symptom improvement,and used the subthalamic nucleus(STN)seedmap as the area of interest to obtain dynamic functional connectivity map to calculate the imaging predictors of symptom improvement.(3)We recruited 32 patients and FOG and treated with a course of high-dose Intermittent Theta-Burst Stimulation(iTBS)on the left M1-LL(5 days,18000 pulses per day).The rs-fMRI scanning and clinical symptom evaluation were performed before and after treatment to explore the effect of hign-dose iTBS on gait,overall motor,and non-motor symptoms.At the same time,the imaging mechanism of rTMS improving FOG symptoms was explored by using the method of brain network analysis.Results(1)The AI of PD patients in the left angular gyrus was significantly higher than that of HCs(peak point t=5.48,MNI coordinates=[-51,-63,18],and cluster size=91 voxel).Further functional connectivity analysis showed that in PD patients,the connectivity values of left middle orbitofrontal gyrus,left middle frontal gyrus(MFG),left SMA were higher than those of HCs,and in right superior marginal gyrus,left anterior central gyrus and left posterior central gyrus were lower than those of HCs.The CFH of PD patients was significantly lower than that of HCs in the right sensorimotor cortex(peak point t=4.98,MNI coordinates=[42,-21,51],cluster size=21 voxel).(2)The score of rigidity was significantly improved after the treatment of real stimulation in the open-label experiment(Z=-3.8,P=0.0001),and there was also an interaction between the improvement in the RCT between the real and sham group(F=4.54,P=0.04).Post hoc analyses showed significant difference in the real group(P=0.005),while no significant difference in the sham group(P>0.99).The results of correlation analysis showed that the baseline UPDRSIII score(r=0.51,P=0.0001),axial dysfunction(r=0.34,P=0.01),rigidity(r=0.49,P=0.0002),bradykinesia affecting left extremities,(r=0.43,P=0.001)were significantly related to the improvement of UPDRSIII score.The improvement of rigidity in patients was only significantly correlated with the baseline rigidity score(r=0.55,P<0.0001).The results of multiple linear regression analysis showed the baseline rigidity score(β=0.38,p=0.02)and threshold(β=0.31,p=0.02)positively predicted the improvement of UPDRSⅢ.Baseline rigidity score(β=0.546,p<0.0001)positively predicted the improvement of rigidity.The results of imaging correlation analysis showed that there was a significant positive correlation between the seedmap of left STN and the dynamic functional connection of right MFG in PD patients and the improvement of rigidity(peak point r=0.58,MNI coordinates=[42,42,27],cluster size=11 voxels).(3)After the high-dose iTBS treatment,the Freezing of Gait Questionnaire,the time,and steps of the Timed Up-and-Go(TUG)test,the time,and steps of the 180°Standing Start 180° Turn Test(SS-180)test,UPDRSIII,mood,sleep and other non-motor symptom scores were significantly improved.At the follow-up of one month,most of the symptoms were still significantly improved compared with those in the baseline.After rTMS intervention,the functional connectivity between the left dorsolateral prefrontal lobe and the right inferior parietal lobule in the executive control network of FOG patients was significantly increased,and the increased functional connectivity values were significantly correlated with the improvement of steps of 5mTUG and SS180.Conclusion(1)This study demonstrated alterations of cerebral specialization and inter-hemispheric cooperation in PD patients using rs-fMRI.We found increased specialization in the left AG and decreased cooperation between bilateral sensorimotor regions in PD patients.And the increased lateralization of the left angular gyrus in PD patients is related to the increased connectivity with left SMA.(2)The cTBS on left SMA can steadily improve the overall motor symptoms and rigidity symptoms of PD.Baseline threshold and rigidity score are positive predictors of UPDRSIII improvement,and baseline rigidity score is positive predictors of rigidity improvement.The e left STNseedmap and the dynamic functional connectivity of the right MFG was the image predictor of rigidity improvement.(3)The high-dose iTBS targeting M1-LL can significantly improve the gait,motor,and non-motor symptoms of FOG patients,and was related to the increased functional connectivity within ECN.