穆思雨 許敏鵬 何 峰 張力新 明 東

(天津大學(xué)精密儀器與光電子工程學(xué)院，天津 300072)

引言

經(jīng)顱電刺激(transcranial electric stimulation, TES)是一種非侵入式大腦功能調(diào)控手段，通過微弱的電流作用于大腦皮層來調(diào)節(jié)突觸可塑性、神經(jīng)元興奮性以及個(gè)體行為表現(xiàn)，具有無痛、安全、操作便捷等優(yōu)點(diǎn)，近年來受到廣泛關(guān)注。目前已有較多研究證實(shí)，TES能夠提高大腦的工作記憶[1]、注意力[2]和學(xué)習(xí)能力[2]等認(rèn)知功能，改善癲癇[3-4]、抑郁[5-6]、失語[7-8]、纖維肌痛[9-10]、成癮[11-13]等臨床病癥，特別是對(duì)腦卒中后的運(yùn)動(dòng)功能康復(fù)具有積極的作用。

腦卒中(stroke)俗稱“中風(fēng)”，是導(dǎo)致成年人殘疾的首要病因[14]。30%～66%的患者在發(fā)病6個(gè)月之后仍會(huì)遺留不同程度的運(yùn)動(dòng)功能障礙，嚴(yán)重影響其生活自理能力和社會(huì)參與能力[15]，因此提出有效的治療方法十分必要。TES作為一種新興的治療方式已被用于卒中后的運(yùn)動(dòng)功能康復(fù)過程。相較于傳統(tǒng)卒中康復(fù)方式，TES能夠靶向性地調(diào)節(jié)皮層興奮性，提高突觸效率，從而更加有效地改善卒中患者的運(yùn)動(dòng)功能[16-19]。

本研究將先從TES的類型參數(shù)、安全性問題、神經(jīng)作用機(jī)制以及刺激后效應(yīng)等方面展開闡明TES的相關(guān)基本知識(shí)，重點(diǎn)介紹TES對(duì)卒中后運(yùn)動(dòng)功能康復(fù)的作用原理和目前已取得的成果，最后總結(jié)該領(lǐng)域亟待解決的重要問題。

1 經(jīng)顱電刺激的類型參數(shù)及安全性問題

1.1 經(jīng)顱電刺激的類型參數(shù)

TES主要包括經(jīng)顱直流電刺激(transcranial direct current stimulation，tDCS)和經(jīng)顱交流電刺激(transcranial alternating current stimulation,tACS)兩大類。刺激方式通常為雙電極刺激(陽極或稱刺激電極，陰極或稱參考電極)，其刺激電流大小一般為1～2 mA。當(dāng)刺激開始施加時(shí)，電流從0 mA緩慢上升到設(shè)定值，該過程通常持續(xù)15 s左右，稱為上升期(fall in)；當(dāng)刺激結(jié)束時(shí)，電流從設(shè)定值緩慢下降到0 mA，該過程通常也持續(xù)15 s左右，稱為下降期(fall out)。目前研究所采用的tDCS/tACS刺激時(shí)程通常為10～30 min[20-21]。電極的擺放位置是影響刺激電流空間分布及流向的重要因素，很大程度上決定了刺激的有效性[20,22]。例如，增大電極間的距離能夠提高刺激電流的作用強(qiáng)度和深度[23]。電極位置的選定可參考國際10～20系統(tǒng)的電極坐標(biāo)，也可借助基于經(jīng)顱磁刺激(transcranial magnetic stimulation，TMS)的神經(jīng)導(dǎo)航系統(tǒng)來完成[24-25]。TES所使用的電極片面積一般為15～35 cm2。減小刺激電極的面積可提高刺激電流的聚焦度，與此同時(shí)增大參考電極的面積則將進(jìn)一步改善其聚焦性[20]。但是由于TES的靶向精度低，刺激電極面積過小將會(huì)影響刺激電流對(duì)靶區(qū)的覆蓋程度。

tDCS有陽極刺激、陰極刺激和偽刺激等3種方式。陽極tDCS指將陽極放在靶區(qū)，如初級(jí)運(yùn)動(dòng)區(qū)、背外側(cè)前額葉等，陰極放在參考區(qū)域，一般選為對(duì)側(cè)的眶上區(qū)域、肩部或者頸部。陰極tDCS與之相反，即陰極放在靶區(qū)，陽極放在參考區(qū)域。偽刺激不會(huì)產(chǎn)生后效應(yīng)，一般作為對(duì)照實(shí)驗(yàn)來消除實(shí)驗(yàn)過程中的安慰劑效應(yīng)，除刺激時(shí)長(一般為30 s)外其他刺激參數(shù)與實(shí)驗(yàn)組相同。

卒中后的運(yùn)動(dòng)功能康復(fù)研究一般采用陽極刺激作用于患者的患側(cè)運(yùn)動(dòng)皮層，結(jié)合電極片面積的大小，選用1～2 mA電流，單次刺激15 min或連續(xù)重復(fù)刺激若干天[26]。

1.2 經(jīng)顱電刺激的安全性問題

目前研究認(rèn)為，合理使用經(jīng)顱電刺激不會(huì)對(duì)人體產(chǎn)生傷害。McCreery等證明電流密度小于25 mA/cm2的電刺激不會(huì)損壞大腦組織。以1 mA電流強(qiáng)度，35 cm2刺激面積的tDCS為例，測(cè)量得到的靶點(diǎn)(刺激電極中心位置下12 mm處)電流密度接近0.1 mA/cm2，因此，經(jīng)顱電刺激是相對(duì)安全的[27-28]。tDCS的副作用一般表現(xiàn)為刺激區(qū)域相應(yīng)頭皮的輕微不適感，該現(xiàn)象在刺激結(jié)束后消失。tACS的副作用一般表現(xiàn)為短暫的光幻視現(xiàn)象(Phosphene)。不同刺激區(qū)域、強(qiáng)度、頻率以及受試者基礎(chǔ)狀態(tài)都會(huì)導(dǎo)致不同程度的光幻視現(xiàn)象[29]。例如，在睜眼靜息狀態(tài)下，對(duì)受試者施加tACS(刺激電極置于枕區(qū)，參考電極置于對(duì)側(cè)眶上區(qū)域)，相同強(qiáng)度的20 Hz刺激比10 Hz刺激誘發(fā)的光幻視現(xiàn)象更明顯；而在閉眼靜息狀態(tài)下，10 Hz刺激比20 Hz刺激誘發(fā)的光幻視現(xiàn)象更明顯。Kanai等認(rèn)為光幻視現(xiàn)象的產(chǎn)生是由于交流電流通過頭皮的容積傳導(dǎo)效應(yīng)(volume conduction effects)刺激到了視網(wǎng)膜細(xì)胞[30]。

目前研究表明，TES作用于卒中患者的運(yùn)動(dòng)功能康復(fù)是相對(duì)安全的，只有在極少數(shù)情況下，患者會(huì)產(chǎn)生短暫的癢感、刺痛感或者頭痛等癥狀[26]。

2 經(jīng)顱電刺激的作用機(jī)制及后效應(yīng)

2.1 經(jīng)顱電刺激的作用機(jī)制

研究證實(shí)tDCS能夠改變神經(jīng)元的靜息電位，其刺激效果具有極性特點(diǎn)。當(dāng)施加陽極tDCS時(shí)，神經(jīng)元發(fā)生去極化效應(yīng)，即細(xì)胞膜電位差減小，激活神經(jīng)元活性；當(dāng)施加陰極tDCS時(shí)，神經(jīng)元發(fā)生超極化效應(yīng)，即細(xì)胞膜電位差增大，抑制神經(jīng)元的活性。

tDCS對(duì)于神經(jīng)元膜電位的影響主要通過改變局部離子濃度以及神經(jīng)元放電頻率來實(shí)現(xiàn)。藥理學(xué)研究證實(shí)，鈉離子和鈣離子通道阻斷劑可使tDCS的即時(shí)效應(yīng)消失[31]。Hiromu等利用鈣離子成像技術(shù)對(duì)活體小鼠觀察，發(fā)現(xiàn)tDCS作用期間的星形細(xì)胞鈣離子濃度大幅上升[32]。神經(jīng)生理學(xué)實(shí)驗(yàn)證明，神經(jīng)元處于靜態(tài)電場(chǎng)(直流電場(chǎng))時(shí)放電頻率將發(fā)生改變。當(dāng)陽極tDCS靠近神經(jīng)元胞體或樹突時(shí)，神經(jīng)元自發(fā)放電頻率增加；當(dāng)陰極靠近時(shí)，放電頻率減少[33]。

tDCS對(duì)于神經(jīng)元活動(dòng)的激活與抑制可以通過經(jīng)顱磁刺激誘導(dǎo)相應(yīng)軀體產(chǎn)生的運(yùn)動(dòng)誘發(fā)電位(motor evoked potential，MEP)來評(píng)估。MEP的潛伏期、波幅等能夠?qū)崟r(shí)反映快傳播性皮質(zhì)脊髓束的激活性、皮質(zhì)興奮性神經(jīng)傳導(dǎo)通路的完整性以及上運(yùn)動(dòng)神經(jīng)元細(xì)胞膜的興奮性[34]。當(dāng)逐漸增大刺激強(qiáng)度時(shí)，MEP波幅與其所對(duì)應(yīng)的經(jīng)顱磁刺激強(qiáng)度所組成的曲線稱為募集曲線(recruitment curve，RC)，其斜率與被激活的皮質(zhì)脊髓神經(jīng)元數(shù)量相關(guān)[34]，反映了皮質(zhì)內(nèi)以及皮質(zhì)運(yùn)動(dòng)傳導(dǎo)通路中神經(jīng)突觸連接的效能和強(qiáng)度[35]。對(duì)受試者的初級(jí)運(yùn)動(dòng)皮層施加陽極tDCS，同時(shí)結(jié)合經(jīng)顱磁刺激測(cè)量對(duì)側(cè)第一背側(cè)骨間肌(first dorsal interosseous，F(xiàn)DI)的MEP，發(fā)現(xiàn)陽極tDCS使其MEP幅值升高[16]，RC曲線的斜率增大，而陰極tDCS使得MEP幅值降低[36]，證明陽極tDCS能夠增強(qiáng)初級(jí)運(yùn)動(dòng)皮層的興奮性，陰極tDCS能夠抑制其興奮性。

此外，也有研究發(fā)現(xiàn)tDCS會(huì)引起局部腦血流量(regional cerebral blood flow，rCBF)[37]、突觸效率[38]以及神經(jīng)營養(yǎng)因子表達(dá)的變化[39]。結(jié)合MRI成像的tDCS研究證實(shí)，在刺激結(jié)束后陽極tDCS能顯著增加局部腦血流量，陰極tDCS則顯著減少局部腦血流量[40]。Fritsch等證實(shí)陽極tDCS能夠增強(qiáng)突觸可塑性，改善運(yùn)動(dòng)技能學(xué)習(xí)[39]，同時(shí)促進(jìn)腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor，BDNF)的表達(dá)，抑制GABA(γ-氨基丁酸，是一種中樞神經(jīng)系統(tǒng)的抑制性傳遞物質(zhì)，能夠降低神經(jīng)元活性)的分泌[41-42]。

目前tACS的作用原理尚不明確，現(xiàn)有觀點(diǎn)認(rèn)為tACS以頻率特異的方式，通過對(duì)神經(jīng)元網(wǎng)絡(luò)的同步/去同步來改變大腦振蕩節(jié)律。一定頻率的tACS能夠調(diào)制神經(jīng)元的放電頻率，與之發(fā)生諧振效應(yīng)。對(duì)受試者枕區(qū)施加alpha頻段(8～13 Hz)的tACS后，發(fā)現(xiàn)其alpha頻段的能量增加，且這種作用持續(xù)了至少30 min[43]。類似地，當(dāng)對(duì)受試者施加10 Hz的tACS后，受試者的alpha頻段能量峰值頻率更接近10 Hz[44]。

2.2 刺激后效應(yīng)

經(jīng)顱電刺激結(jié)束之后，其對(duì)大腦皮層的效應(yīng)不會(huì)立刻消失，而將保持一段時(shí)間，這種現(xiàn)象稱為后效應(yīng)(aftereffects)。后效應(yīng)的持續(xù)時(shí)間受刺激類型、強(qiáng)度以及時(shí)程等因素的影響[17,45-47]。經(jīng)過15～20 mintDCS作用后產(chǎn)生的后效應(yīng)時(shí)間通常不少于30 min。重復(fù)性tDCS相對(duì)于單次tDCS的后效應(yīng)持續(xù)時(shí)間更長。后效應(yīng)的產(chǎn)生是因?yàn)閠DCS促進(jìn)了N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid，NMDA)受體激活以及BDNF的表達(dá)，從而增強(qiáng)了長時(shí)程增強(qiáng)效應(yīng)(long-time potentiation，LTP)[39]。實(shí)驗(yàn)證明，對(duì)小鼠進(jìn)行美沙芬(一種NMDA受體對(duì)抗藥)處理后再施加經(jīng)顱電刺激，刺激結(jié)束后不產(chǎn)生后效應(yīng)[17,48-49]。對(duì)攜帶Val66Met基因的小鼠(BDNF分泌水平低于正常小鼠)施加tDCS，其后效應(yīng)持續(xù)時(shí)間相對(duì)于正常小鼠縮短[50]。

目前對(duì)于tACS后效應(yīng)的研究較少，其產(chǎn)生原因尚未得出明確結(jié)論。Neuling等證明，作用于頂葉皮層的1.5 mA、alpha頻段tACS能夠使得睜眼靜息狀態(tài)受試者的alpha波能量增強(qiáng)并至少持續(xù)30 min，同樣的實(shí)驗(yàn)條件下，處于閉眼狀態(tài)的受試者持續(xù)時(shí)間則少于30 min。該作者認(rèn)為tACS的后效應(yīng)持續(xù)時(shí)間與背景腦電的能量有關(guān)，睜眼狀態(tài)的背景alpha頻段腦電能量相較于閉眼狀態(tài)更低，較低的背景alpha頻段腦電能量狀態(tài)下能夠獲得更長的后效應(yīng)時(shí)間[51]。

3 經(jīng)顱電刺激對(duì)卒中后運(yùn)動(dòng)功能康復(fù)的作用

突觸可塑性與神經(jīng)系統(tǒng)的發(fā)育、損傷后修復(fù)以及學(xué)習(xí)記憶等功能有著密切的聯(lián)系。卒中后突觸功能發(fā)生消極變化，如興奮性降低、連接失控等，阻礙了患者運(yùn)動(dòng)功能的康復(fù)。因此，通過TES改善突觸可塑性將有助于其運(yùn)動(dòng)功能的康復(fù)。陽極tDCS能夠使神經(jīng)元發(fā)生去極化，解除鎂離子對(duì)NMDA受體通道的阻滯作用，從而使得鈣離子進(jìn)入突觸后膜。鈣離子是誘發(fā)LTP的初始信號(hào)，可促進(jìn)神經(jīng)遞質(zhì)的釋放，調(diào)節(jié)突觸可塑性。此外，陽極tDCS還能夠促進(jìn)BDNF的表達(dá)和分泌。卒中后BDNF的生成和釋放能夠?yàn)椴≡钪車钠べ|(zhì)神經(jīng)提供再生環(huán)境，改善神經(jīng)元的病理狀態(tài)，調(diào)節(jié)突觸傳遞效率和突觸可塑性，從而促進(jìn)卒中后的運(yùn)動(dòng)功能康復(fù)[52]。

在腦卒中慢性期，患者左右半球間經(jīng)胼胝體的失衡狀態(tài)是阻礙患側(cè)半球皮層運(yùn)動(dòng)區(qū)功能重組的另一個(gè)原因[53]。健康人左右半球運(yùn)動(dòng)皮層神經(jīng)元的興奮性是平衡的，即處于激活狀態(tài)的初級(jí)運(yùn)動(dòng)皮層通過胼胝體通路抑制對(duì)側(cè)半球初級(jí)運(yùn)動(dòng)皮層的活性。腦卒中發(fā)生之后，患側(cè)大腦半球的運(yùn)動(dòng)皮層對(duì)健側(cè)大腦半球的半球間抑制作用減弱，導(dǎo)致腦卒中發(fā)病后健側(cè)半球皮層活動(dòng)過于活躍，而患側(cè)半球皮層興奮性減弱。調(diào)節(jié)卒中患者的大腦皮層興奮性能夠改善其運(yùn)動(dòng)訓(xùn)練表現(xiàn)[54]。

針對(duì)腦卒中患者運(yùn)動(dòng)障礙的成因及其恢復(fù)機(jī)制，目前主要有3種經(jīng)顱電刺激模式。第一種是陽極tDCS刺激患側(cè)半球，以提高其興奮性。對(duì)健康被試進(jìn)行陽極tDCS研究，其易化作用主要表現(xiàn)為運(yùn)動(dòng)速度(或反應(yīng)時(shí)間)的改善或執(zhí)行任務(wù)正確率的提高[55-56]。同樣地，陽極tDCS作用于患側(cè)半球的初級(jí)運(yùn)動(dòng)皮層能夠改善輕微偏癱腦卒中患者的手部運(yùn)動(dòng)功能，使其執(zhí)行任務(wù)時(shí)間縮短，同時(shí)檢測(cè)到的MEP幅值也有所升高[49]；作用于下肢運(yùn)動(dòng)皮層，可以使皮層興奮性提高，MEP幅值升高，下肢的夾緊力增大[57-58]，最大伸膝長度短暫增加，證明陽極tDCS對(duì)中風(fēng)偏癱病人運(yùn)動(dòng)功能康復(fù)有潛在應(yīng)用[59]。第二種是陰極tDCS刺激健側(cè)半球，以抑制其興奮性。陰極tDCS作用于腦卒中患者健側(cè)半球的初級(jí)運(yùn)動(dòng)皮層能夠顯著減少患者完成JTT任務(wù)的時(shí)間，顯著改善患者的上肢運(yùn)動(dòng)功能評(píng)分(upper extremity fugl-meyer，UEFM)和運(yùn)動(dòng)范圍，同時(shí)健側(cè)半球皮層興奮性降低[60]。第三種是雙極tDCS，即陽極刺激患側(cè)半球，同時(shí)陰極刺激刺激健側(cè)半球，以此來達(dá)到均衡左右半球皮層興奮性的目的[18]。Fregni等發(fā)現(xiàn)對(duì)患者的初級(jí)運(yùn)動(dòng)皮層施加雙極tDCS，JTT測(cè)試結(jié)果有了顯著的改善[19]。

也有研究將tDCS和運(yùn)動(dòng)康復(fù)療法相結(jié)合，治療后患者的運(yùn)動(dòng)功能得到明顯改善。陽極tDCS結(jié)合運(yùn)動(dòng)康復(fù)療法與僅進(jìn)行陽極tDCS相比，受試者的運(yùn)動(dòng)功能顯著提高，由此證明運(yùn)動(dòng)康復(fù)療法和tDCS結(jié)合能夠更大程度上易化運(yùn)動(dòng)表現(xiàn)[61-62]。此外接受雙極tDCS和運(yùn)動(dòng)康復(fù)療法的患者相較于只進(jìn)行運(yùn)動(dòng)康復(fù)療法的患者，有更顯著的運(yùn)動(dòng)功能改善，且后效應(yīng)至少持續(xù)1周[63]。

腦卒中的康復(fù)效果受許多因素的影響，如患者的年齡、性別、利手情況，以及腦卒中的類型、病灶位置、病灶大小、卒中程度、缺血受損害的嚴(yán)重性等[63]。例如，患側(cè)半球錐體束是否完整是影響tDCS作用效果的一個(gè)重要因素。將陰極tDCS作用于健側(cè)半球之后，患側(cè)半球錐體束完整的受試者的運(yùn)動(dòng)功能得到了顯著改善，而錐體束受損不完整的受試者的運(yùn)動(dòng)功能并沒有得到明顯改善[64]。

由于腦卒中病灶的大小、位置等的不確定以及評(píng)判標(biāo)準(zhǔn)的不一致，經(jīng)顱電刺激對(duì)于腦卒中患者的運(yùn)動(dòng)功能康復(fù)結(jié)果不盡相同，但是大部分研究都表明，經(jīng)顱電刺激對(duì)于腦卒中患者的運(yùn)動(dòng)功能障礙具有一定的改善作用，且相對(duì)安全。

4 總結(jié)與展望

總之，TES是一種無創(chuàng)、安全的大腦活動(dòng)調(diào)控手段，能夠調(diào)節(jié)皮層興奮性、突觸可塑性以及個(gè)體行為學(xué)表現(xiàn)，對(duì)于亞急性以及慢性腦卒中患者的運(yùn)動(dòng)功能康復(fù)具有積極的作用，在科學(xué)研究以及臨床治療方面得到了廣泛的應(yīng)用，但是目前仍存在一些亟待解決的問題。首先，TES的神經(jīng)機(jī)制尚不明確，大多研究成果來自于動(dòng)物實(shí)驗(yàn)，是否適用人腦有待取證。其次，由于現(xiàn)有技術(shù)設(shè)備的限制，較難開展TES下的腦電信號(hào)分析，從而無法實(shí)時(shí)觀察TES作用下大腦活動(dòng)的變化。再次，目前大多數(shù)TES研究只針對(duì)大腦局部區(qū)域，而較少開展多個(gè)腦網(wǎng)絡(luò)節(jié)點(diǎn)的聯(lián)合刺激，導(dǎo)致TES調(diào)節(jié)全腦網(wǎng)絡(luò)的理論基礎(chǔ)與實(shí)驗(yàn)方法的欠缺。最后，由于無法計(jì)算出TES作用于靶區(qū)的精確計(jì)量，導(dǎo)致刺激效果因時(shí)因人而異，穩(wěn)定性差。因此，解決以上問題將會(huì)更加有效地指導(dǎo)TES開展運(yùn)動(dòng)功能康復(fù)治療。

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