中國醫(yī)師協(xié)會神經(jīng)調(diào)控專業(yè)委員會電休克與神經(jīng)刺激學(xué)組

經(jīng)顱磁刺激(transcranial magnetic stimulation,TMS)由Barker等[1]于1985年創(chuàng)立。基于電磁感應(yīng)與電磁轉(zhuǎn)換原理，用刺激線圈瞬變電流產(chǎn)生的磁場穿透顱骨，產(chǎn)生感應(yīng)電流刺激神經(jīng)元引發(fā)一系列生理、生化反應(yīng)。作為非侵入性刺激技術(shù)，TMS作用于人腦引起神經(jīng)活動的改變，可檢測到運動誘發(fā)電位、腦電活動變化、腦血流、代謝和大腦功能狀態(tài)改變。其微觀作用包括細(xì)胞膜電位、動作電位、神經(jīng)遞質(zhì)、受體、突觸、神經(jīng)可塑性發(fā)生變化。

醫(yī)生應(yīng)掌握TMS工作原理和作用機(jī)制，并依據(jù)臨床表現(xiàn)、實驗室和影像學(xué)檢查結(jié)果，設(shè)計個體化治療方案。先根據(jù)大腦皮質(zhì)功能解剖體表投影決定刺激部位，再決定刺激模式、強(qiáng)度、頻率、間歇、療程等。TMS適應(yīng)證已經(jīng)擴(kuò)大到抑郁癥、癲癇、神經(jīng)性頭痛等[2]。

1 TMS模式分類[2]

1.1 單脈沖刺激 刺激皮層拇指運動區(qū)，用于測定MEP，測定治療能量或運動皮層功能障礙定量評估。

1.2 成對脈沖刺激 同一個線圈在數(shù)十毫秒內(nèi)先后發(fā)放2個脈沖，刺激同一腦區(qū)或2個不同線圈刺激不同腦區(qū)。常用于皮層興奮性評估。

1.3 重復(fù)脈沖刺激 按照固定頻率連續(xù)發(fā)放多個脈沖的刺激模式。通常用于臨床治療和暫時性興奮或抑制特定皮層功能區(qū)域。具體頻率參數(shù)設(shè)置依治療或研究目的而定。

1.4 爆發(fā)模式脈沖刺激 將一種固定頻率脈沖嵌套在另一種固定頻率脈沖中的刺激模式。常用爆發(fā)模式有爆發(fā)模式脈沖刺激(theta burst stimulation，TBS)，是將3個連續(xù)50 Hz脈沖嵌入5 Hz脈沖中。TBS序列分為2種：連續(xù)爆發(fā)模式脈沖刺激(continuous theta burst stimulation，cTBS)抑制皮層功能，間斷爆發(fā)模式脈沖刺激(intermittent theta burst stimulation，iTBS)(刺激2 s，間隔8 s)興奮皮層功能。

2 TMS治療風(fēng)險及評估[2]

癲癇及驚厥;頭皮刺痛、灼熱感;頭顱或體腔內(nèi)存在金屬磁性物質(zhì)(電子耳蝸、部分心臟起搏器等植入性醫(yī)療產(chǎn)品);聽力損害;誘發(fā)癲癇或驚厥發(fā)作風(fēng)險的藥物。

說明：高頻刺激有誘發(fā)癲癇或抽搐發(fā)作風(fēng)險。但低頻刺激可以用于抗癲癇治療[3]。12歲以下患者佩戴耳塞可以最大程度上避免噪音對聽力的損害。

3 重復(fù)經(jīng)顱磁刺激安全操作及治療規(guī)范

(1)重復(fù)經(jīng)顱磁刺激(repetitive transcranial mag-netic stimulation，rTMS)治療儀器屬于大型用電設(shè)備，保證電壓穩(wěn)定、電流不會過載，避免安全隱患。

(2)簽署知情同意書并完成安全篩查評估。

(3)首次治療測定患者皮層靜息運動閾值(resting motor threshold，RMT)?；颊呷∽换蜓雠P位，使用單脈沖模式刺激利手側(cè)(中國人多為右利手)拇指運動區(qū)皮層(M1)，刺激10次，其中5次可以誘發(fā)拇指外展肌運動(誘發(fā)拇指外展肌誘發(fā)電位達(dá)到50微幅以上)，該刺激強(qiáng)度能量為RMT。RMT存在個體差異，且治療能量大小是根據(jù)RMT進(jìn)行制定，是開展rTMS治療的必要環(huán)節(jié)[4]。

(4)根據(jù)治療目的選定rTMS強(qiáng)度、頻率和數(shù)目。應(yīng)嚴(yán)格限制在安全序列范圍內(nèi)，避免誘發(fā)癲癇風(fēng)險的安全序列[4]。

(5)rTMS治療靶點定位。

常用治療靶點腦區(qū)定位方法有3種：①先測定M1區(qū)，可以觀測到外顯運動反應(yīng)進(jìn)行確定，之后以M1區(qū)作為參照點，沿頭皮各個方向進(jìn)行定位;②參照國際標(biāo)準(zhǔn)腦電電極10～20導(dǎo)聯(lián)系統(tǒng)定位(圖1);③借助腦影像導(dǎo)航技術(shù)定位。腦影像包括：全腦T1、T2結(jié)構(gòu)像、各類功能像等(如腦血流、靜息態(tài)、功能區(qū)激活像等)。

(6)治療過程中不良反應(yīng)的評定。

圖1 國際標(biāo)準(zhǔn)腦電電極10～20導(dǎo)聯(lián)系統(tǒng)定位

4 rTMS臨床治療推薦

以下內(nèi)容為共識循證依據(jù)的參照標(biāo)準(zhǔn)：由歐洲神經(jīng)學(xué)會聯(lián)盟提出[5]。根據(jù)證據(jù)價值由高到低，分為Ⅰ～Ⅳ 4個級別。此外還參考了牛津大學(xué)循證醫(yī)學(xué)中心的循證依據(jù)標(biāo)準(zhǔn)，即優(yōu)先考慮系統(tǒng)綜述中獲得的證據(jù)，也列入級別Ⅰ中。文獻(xiàn)檢索截止到2017年11月PubMed數(shù)據(jù)庫。

4.1 抑郁癥(美國食品和藥品監(jiān)督管理局適應(yīng)證)加拿大、新西蘭、以色列、美國都已批準(zhǔn)rTMS可以用于治療抑郁癥。rTMS可以單獨或聯(lián)合藥物治療。但是對于病情嚴(yán)重，伴有自殺觀念的抑郁癥患者不建議單獨使用rTMS。

臨床推薦1：rTMS高頻刺激左背外側(cè)前額葉(left dorsolateral prefrontal cortex,l-DLPFC)或低頻刺激右背外側(cè)前額葉(right dorsolateral prefrontal cortex,r-DLPFC)，用于抑郁癥急性期療效肯定，連續(xù)4～6周，必要時可延長治療時間。Ⅰ級一致證據(jù)[6-8]。

臨床推薦2：先前急性期rTMS治療受益，目前復(fù)發(fā)的患者。Ⅰ級一致證據(jù)[6-8]。

臨床推薦3：rTMS可作為急性期治療獲益患者的后續(xù)或維持治療。Ⅰ級一致證據(jù)[9-10]。

臨床推薦4：rTMS可以單獨或聯(lián)合抗抑郁藥或其他精神類藥物。Ⅱ級一致證據(jù)[8]。

4.2 慢性神經(jīng)性或非神經(jīng)性疼痛

臨床推薦1：rTMS高頻刺激疼痛區(qū)域?qū)?cè)皮層運動區(qū)(M1)用于治療慢性神經(jīng)痛。Ⅰ級一致證據(jù)[11-17]。

臨床推薦2：rTMS低頻刺激枕葉用于治療偏頭痛(美國食品和藥品監(jiān)督管理局批準(zhǔn))。Ⅰ級一致證據(jù)。

臨床推薦3：rTMS高頻刺激l-DLPFC或運動皮層用于治療非神經(jīng)性疼痛，如纖維肌痛、復(fù)雜區(qū)域疼痛綜合征Ⅰ型。Ⅱ、Ⅲ、Ⅳ級證據(jù)[18-19]。

4.3 運動障礙

臨床推薦1：rTMS高頻或低頻刺激輔助運動皮層或運動皮層改善帕金森病運動癥狀。Ⅰ、Ⅱ、Ⅲ級證據(jù)[20-22]。

臨床推薦2：rTMS高頻刺激或低頻刺激運動區(qū)M1或輔助運動區(qū)，用于治療藥物誘發(fā)震顫。Ⅲ級一致證據(jù)[23-24]。

臨床推薦3：rTMS高頻刺激l-DLPFC治療帕金森病合并抑郁癥。Ⅱ、Ⅲ級證據(jù)[25-30]。

臨床推薦4：rTMS低頻刺激運動區(qū)治療肌張力障礙。Ⅲ級一致證據(jù)[20-21]。

4.4 中風(fēng)

臨床推薦1：rTMS高頻刺激受累側(cè)皮層運動區(qū)或低頻刺激健側(cè)皮層運動區(qū)，用于治療運動區(qū)中風(fēng)。Ⅱ、Ⅲ級證據(jù)[31-33]。

臨床推薦2：rTMS高頻或低頻刺激布洛卡區(qū)，治療運動性失語癥。Ⅲ、Ⅳ級證據(jù)[34-35]。

臨床推薦3：爆發(fā)模式cTBS 序列刺激左側(cè)后頂葉皮層治療偏側(cè)忽略。Ⅲ級一致證據(jù)[36-37]。

4.5 癲癇

臨床推薦1：rTMS低頻刺激皮層癲癇灶治療癲癇發(fā)作。Ⅱ、Ⅲ級證據(jù)[38-40]。

4.6 耳鳴

臨床推薦1：rTMS低頻刺激顳葉或顳頂葉皮層，高頻刺激r-DLPFC治療耳鳴。Ⅱ、Ⅲ級證據(jù)[41]。

4.7 焦慮障礙

臨床推薦1：rTMS高頻刺激r-DLPFC或低頻刺激l-DLPFC治療創(chuàng)傷后應(yīng)激障礙。Ⅲ級一致證據(jù)[42-44]。

臨床推薦2：rTMS低頻刺激r-DLPFC和顳頂區(qū)治療驚恐發(fā)作和廣泛性焦慮。Ⅲ級一致證據(jù)[45-46]。

4.8 強(qiáng)迫癥

臨床推薦1：rTMS高頻或低頻刺激雙側(cè)DLPFC治療強(qiáng)迫癥。Ⅱ、Ⅲ級證據(jù)[47-50]。

4.9 精神分裂癥

臨床推薦1：rTMS低頻刺激顳頂葉皮層治療幻聽。Ⅱ、Ⅲ級證據(jù)[51-57]。

臨床推薦2：rTMS高頻刺激l-DLPFC或雙側(cè)DLPFC改善精神分裂癥陰性癥狀。Ⅱ、Ⅲ級證據(jù)[58-61]。

4.10 物質(zhì)成癮

臨床推薦1：rTMS高頻刺激l-DLPFC降低毒品渴求(心癮)，目前證據(jù)提示沒有長期效果。Ⅱ、Ⅲ級證據(jù)[62-66]。

4.11 睡眠障礙

臨床推薦1：rTMS低頻1Hz刺激雙側(cè)DLPFC和頂枕區(qū)域治療睡眠障礙。Ⅱ、Ⅲ級證據(jù)[67-68]。

5 關(guān)于臨床治療特殊群體的幾點說明

5.1 孕婦 磁場強(qiáng)度隨距離迅速衰減，所以胎兒不太可能受到TMS影響。抑郁孕婦成功接受TMS治療而胎兒未出現(xiàn)副作用[69-71]。臨床上孕婦接受TMS治療應(yīng)避免直接刺激腰椎。作為TMS操作者的孕婦應(yīng)至少遠(yuǎn)離線圈0.7 m[72]。

5.2 兒童 研究證實單脈沖和成對脈沖TMS用于兒童安全[73]。發(fā)育過程中的因素確實影響兒童接受TMS安全性：①皮質(zhì)興奮性水平(新生兒皮質(zhì)興奮性高，刺激能量過高需要注意TMS誘發(fā)癲癇可能);②囟門關(guān)閉與否(未閉要特別注意避免機(jī)械損傷)；③外耳道生長(年齡小于2歲兒童需要特別注意保護(hù)聽力)。兒童年齡小于2歲慎用[2]。

6 問題與展望

以往應(yīng)用TMS的最大難題是如何精準(zhǔn)刺激靶點。Karlstr?m等[72]和Bohning等[74]于1998年將神經(jīng)導(dǎo)航定位系統(tǒng)應(yīng)用于TMS，通過與fMRI/CT等影像技術(shù)結(jié)合實現(xiàn)了可視化TMS，結(jié)合PET、SPECT、DTI、fMRI、磁共振波譜等技術(shù)可以更好地探討TMS的治療機(jī)制。目前存在主要問題包括：①治療效果的影響因素；②各類疾病作用機(jī)制；③rTMS與藥物治療的結(jié)合。

寫作組長：許 毅(浙江大學(xué)醫(yī)學(xué)院附屬第一醫(yī)院)

寫作組成員

李 達(dá)(浙江大學(xué)醫(yī)學(xué)院附屬第一醫(yī)院，執(zhí)筆人)

譚立文(中南大學(xué)湘雅二醫(yī)院)

劉衛(wèi)青(昆明醫(yī)科大學(xué)第一附屬醫(yī)院)

石 川(北京大學(xué)第六醫(yī)院)

傅建明(嘉興市第二人民醫(yī)院)

許 毅(浙江大學(xué)醫(yī)學(xué)院附屬第一醫(yī)院)

安建雄(中國醫(yī)科大學(xué)航空總醫(yī)院)

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