【作者】 刘曼华；

【导师】 毛成洁；

【作者基本信息】 苏州大学 ， 神经病学（专业学位）， 2023， 硕士

【摘要】 目的疼痛是帕金森病(Parkinson’s disease,PD)常见的非运动症状之一,给患者带来严重负担。目前PD相关疼痛的评估不足,治疗手段更加有限。本研究拟通过随机对照研究,评估初级运动皮层(Primary Motor Cortex,M1)的20Hz重复经颅磁刺激(repetitive Transcranial Magnetic Stimulation,rTMS)治疗对 PD 伴慢性骨骼肌痛患者的疗效和安全性,并结合静息态脑电图(Electroencephalography,EEG),探索M1-rTMS治疗对大脑神经电活动及脑网络的影响,为理解rTMS镇痛效果潜在的神经电生理机制提供依据。方法本研究最终纳入39例伴慢性骨骼肌痛的PD患者,将其以2:1的比例随机分配至M1-rTMS组(26例)或sham-rTMS组(13例)。两组受试者均接受7天的神经导航个体化精准M1区高频磁刺激治疗,并分别在治疗前、治疗后、1月后、2月后的“开期”完善量表的评估。疼痛相关量表包括11点数字评分法(0-10Numeric Rating Scale,NRS),中文版 King 帕金森病疼痛量表(The Chinese version of the King’s PD Pain Scale,KPPS-CV),中文改良版 KPPS(The modified Chinese version of the KPPS,MKPPS-CV)。其他临床症状的评估包括运动症状及抑郁、焦虑、自主神经症状、睡眠、生活质量等。采用线性混合效应模型进行重复测量分析,结果表示为相应量表得分在随访2月内的平均变化。除临床症状外,同时采集患者治疗前后的静息态EEG数据。根据疼痛改善率将M1-rTMS组患者分为有反应组、无反应组。对各组患者EEG数据的各频段进行频谱分析和功能连接分析,探索rTMS治疗对皮层神经活动的影响及其镇痛效果的潜在电生理机制。结果7天rTMS治疗后,与sham-rTMS组相比,M1-rTMS组的MKPPS-CV维度一得分(P=0.003)、KPPS-CV 维度一得分(P=0.035)、NRS 得分(P=0.013)、汉密尔顿抑郁量表(Hamilton Depression Scale,HAMD)得分(P=0.016)、帕金森病睡眠量表(PD Sleep Scale-2,PDSS-2)得分(P=0.025)、PD 患者生活质量问卷39项(PD Quality of Life Questionnaire,PDQ-39)得分(P=0.008)明显下降。随访分析表明,M1-rTMS组对抑郁的改善持续至治疗后1月,对疼痛、睡眠及生活质量的改善持续至治疗后2个月。EEG频谱分析发现,M1-rTMS组治疗后,左侧顶枕叶低gamma频段(30-50Hz)的功率谱密度(Power Spectral Density,PSD)较治疗前下降(P=0.015);左侧顶枕叶(P=0.008)及右侧顶枕叶(P=0.041)高gamma频段(50-80Hz)的PSD较治疗前下降;sham-rTMS组均无类似变化。M1-rTMS组治疗后高gamma频段PSD下降程度显著高于sham-rTMS组,尤其是左侧顶枕叶的通道PO3(P=0.0464)。进一步将M1-rTMS组治疗后疼痛明显改善的患者和无明显改善的患者归为有反应组和无反应组,结果表明,有反应组的左侧顶枕叶高gamma频段的PSD较治疗前明显下降(P=0.037),无反应组无类似变化。且有反应组治疗后PSD下降程度明显高于sham-rTMS 组,尤其是左侧顶枕叶的通道 PO3(P=0.0432)、PO7(P=0.0359)、PO5(P=0.0219)。EEG功能连接分析发现,治疗后,M1-rTMS组theta频段额-颞区即FC1-T8电极对的相位延迟指数(Phase Lag Index,PLI)增加,有反应组具有同样结果。结论PD伴慢性骨骼肌痛患者在接受为期7天的M1区20Hz rTMS精准干预治疗后,疼痛的频率和强度、抑郁症状、睡眠质量、生活质量均得到改善,疗效至少维持2个月。M1区高频rTMS治疗通过降低患者顶枕叶gamma频段的功率谱密度,增强额-颞区theta频段的功能连接,发挥其缓解PD慢性骨骼肌痛的神经调控作用。更多还原

【Abstract】 Object:Pain is an increasingly recognized non-motor symptom of Parkinson’s disease(PD),with significant prevalence and negative impact on the quality of life of patients.In this randomised,placebo-controlled study,we will assess the efficacy and safety of 20 Hzrepetitive transcranial magnetic stimulation(rTMS)delivered to primary motor cortex(M1)in PD patients with chronic musculoskeletal pain.What’s more,we adopted the resting-state Electroencephalography(EEG)directly provide information on the cortical mechanisms before and after rTMS of M1,and explored their relationship with the improvement of symptoms.Methods:39 PD patients with musculoskeletal pain were randomly assigned in a 2:1 ratio to receive 7 sessions of either 20-Hz rTMS(n=26)or sham stimulation(n=13)over the primary motor cortex based on individual neuronavigation.All the participants were evaluated before,after,one month,and two months after treatment in the "ON" medication state.pain scores were assessed on a numeric rating scale(NRS),The Chinese version of the King’s PD Pain Scale(KPPS-CV),The modified Chinese version of the KPPS(MKPPS-CV).other clinical scales included motor and non-motor symptoms,depression,anxiety,autonomic symptoms,sleep quality,and the overall severity of PD.We used a mixed model repeated measures analysis to compare between active M1-rTMS,and sham-rTMS for the change over the course of two months.In addition to evaluating pain and other clinical symptoms,we collected the resting-state EEG data of PD patients in Study 1 before and after treatment at the same time.According to pain reduction,M1-rTMS group were divided into responders and non-responders.We explored EEG measures that are most strongly associated with pain reductions under rTMS intervention.These included the power of neuronal oscillations and functional connectivity.Results:After 7 sessions of rTMS treatment,analyses revealed significant group × time interactions for the Domain 1 of MKKPS-CV(P=0.003),the Domain 1 of KPPS-CV(P=0.035),NRS(P=0.013);Hamilton Depression Scale(P=0.016),PD Sleep Scale-2(P=0.025),PD Quality of Life Questionnaire(P=0.008).Further analysis showed that the repetitive transcranial magnetic stimulation group,but not the sham stimulation group,could effectively improve the pain and clinical symptoms of PD patients.This improvement in depression lasted until 1 month after treatment,and improvement in pain,sleep and quality of life could last up to 2 months after treatment.Power spectrum analysis revealed that the Power Spectral Density(PSD)at low gamma frequency band(from 30 to 50 Hz)of M1-rTMS group was significantly lower after treatment,especially in left posterior electrodes(P=0.015).PSD at high gamma frequency band(from 50 to 70 Hz)of M1-rTMS group was significantly lower after treatment in left posterior electrodes(P=0.008)and right posterior electrodes(P=0.041).similar change was not observed in sham-rTMS group.The PSD difference at gamma band of the M1-rTMS group was higher than that of the sham group in left posterior electrodes,especially in channel PO3(P=0.0464).Further,M1-rTMS group were divided into responders and non-responders.The PSD at high gamma band of Responders was significantly lower after treatment in left posterior electrodes(P=0.037).similar change was not observed in non-Responders.The PSD difference at high gamma band of Responders group was higher than that of the sham group in left posterior electrodes,especially in channel PO3(P=0.0432),PO7(P=0.0359),PO5(P=0.0219).Functional connectivity analysis revealed that the Phase Lag Index(PLI)value at theta band(4-8Hz)of M1-rTMS group was significantly higher after treatment in FC1-T8 electrode pair,the same change was observed in Responders.Conclusion:In this sham-controlled trial,the protocol of 7 sessions of 20Hz-rTMS to the motor cortex could alleviate the severity and frequency of musculoskeletal pain in patients with Parkinson’s disease,and improve other clinical symptoms,such as depression,sleep and quality of life,lasting up to 2 months after treatment.The PSD of M1-rTMS group was evidently lower at gamma frequency,and a clear difference in EEG energy distribution was mainly observed in posterior electrodes.Functional connectivity for the M1-rTMS group exhibited higher connectivity at theta band in frontal-temporal electrodes.This may indicate that perhaps these measures reflect functional changes associated with the therapeutic process or improvement in pain.更多还原