經(jīng)顱直流電刺激對健康人群反應(yīng)抑制的影響*

郭志華 盧宏亮 黃 鵬 朱 霞

經(jīng)顱直流電刺激對健康人群反應(yīng)抑制的影響*

郭志華 盧宏亮 黃 鵬 朱 霞

(空軍軍醫(yī)大學(xué)軍事醫(yī)學(xué)心理學(xué)系, 西安 710032)

反應(yīng)抑制是指抑制不恰當(dāng)?shù)幕虿环袭?dāng)前需要的行為的能力, 研究表明反應(yīng)抑制主要與額下回、背外側(cè)前額葉和前輔助運(yùn)動(dòng)區(qū)的功能有關(guān)。經(jīng)顱直流電刺激(tDCS)是一種非侵入式腦刺激技術(shù), 近年來對健康人群使用tDCS刺激相應(yīng)腦區(qū)從而影響反應(yīng)抑制功能的研究日益增多, 但主要研究結(jié)果不一致。闡明tDCS影響反應(yīng)抑制具體的神經(jīng)機(jī)制、減少tDCS研究的異質(zhì)性、探索更有效的tDCS刺激方式和確定tDCS效果的年齡依賴性差異已成為目前亟待解決的問題。

反應(yīng)抑制, 經(jīng)顱直流電刺激, 額下回, 背外側(cè)前額葉, 前輔助運(yùn)動(dòng)區(qū), 停止信號(hào)任務(wù), go/nogo任務(wù)

1 前言

當(dāng)需要做出反應(yīng)的時(shí)候我們會(huì)產(chǎn)生反應(yīng), 但是當(dāng)反應(yīng)不合時(shí)宜或者不再需要時(shí), 我們還要能夠抑制住這種反應(yīng)沖動(dòng)。比如, 當(dāng)走到路口, 綠燈突然變紅, 這時(shí)就不得不抑制住邁步向前的沖動(dòng); 當(dāng)看到一個(gè)魯莽的人闖紅燈時(shí), 司機(jī)抑制正在進(jìn)行的踩油門動(dòng)作; 當(dāng)點(diǎn)擊電子郵件上的發(fā)送按鈕時(shí), 突然意識(shí)到寄給了錯(cuò)誤的人, 會(huì)中止發(fā)送。這些情境中都涉及反應(yīng)抑制。反應(yīng)抑制(response inhibition)是指抑制不恰當(dāng)?shù)幕虿辉傩枰男袨榈哪芰? 以便人們基于環(huán)境變化做出靈活的和目標(biāo)指向的行為反應(yīng), 是執(zhí)行功能的重要組成部分(Diamond, 2013; Sandrini et al., 2020; Verbruggen & Logan, 2008, 2009)。反應(yīng)抑制是認(rèn)知能力中最為重要的部分之一, 對健康人群至關(guān)重要, 眾多研究表明, 反應(yīng)抑制與許多病理狀態(tài)密切相關(guān), 注意缺陷多動(dòng)障礙(attention deficit hyperactivity disorder, ADHD) (Clark et al., 2007; Oosterlaan et al., 1998; Schachar et al., 2005; van Rooij et al., 2015)、強(qiáng)迫癥(obsessive compulsive disorder, OCD) (Brunelin et al., 2018; Chamberlain et al., 2005; de Wit et al., 2012; Gowda et al., 2019)、精神分裂癥(schizophrenia) (Hughes et al., 2012; Thakkar et al., 2011; Zandbelt et al., 2011)、物質(zhì)成癮(substance addition) (Hardee et al., 2014; Mahmood et al., 2013; Steele et al., 2014)等精神障礙都存在反應(yīng)抑制能力的缺陷; 反應(yīng)抑制還與決策(decision making) (Xu et al., 2020)、工作記憶(working memory) (Alderson et al., 2017)等認(rèn)知能力相關(guān), 是人能夠正常生活所需的基本能力(Wu et al., 2021)。反應(yīng)抑制作為基本認(rèn)知能力, 可以表現(xiàn)為許多具體能力, 所以反應(yīng)抑制能力提升還使相關(guān)的具體能力改善, 比如軍人的反應(yīng)抑制能力與戰(zhàn)斗力生成有關(guān), 有研究表明反應(yīng)抑制能力與士兵們對武器的掌控力有關(guān), 反應(yīng)抑制提高可以減少由于反應(yīng)抑制失敗而導(dǎo)致的射擊錯(cuò)誤, 可以使模擬射擊情境中的平民傷亡顯著減少(Biggs et al., 2015; Davis & Smith, 2019)。近年來, 對反應(yīng)抑制神經(jīng)機(jī)制的探究引起了研究者們的廣泛興趣。Go/Nogo任務(wù)(Go/Nogo task, GNG)和停止信號(hào)任務(wù)(stop signal task, SST)是研究反應(yīng)抑制的常見范式(Cunillera et al., 2016), 結(jié)合神經(jīng)影像學(xué)、經(jīng)顱磁刺激(transcranial magnetic stimulation, TMS)和神經(jīng)電生理(electroencephalogram, EEG)等技術(shù), 大量研究表明反應(yīng)抑制功能與前額葉(prefrontal cortex, PFC)以及基底神經(jīng)節(jié)(basal ganglia)密切相關(guān), 其中前額葉主要涉及右側(cè)額下回(right inferior frontal gyrus, rIFG/right inferior frontal cortex, rIFC)、背外側(cè)前額葉皮層(dorsolateral prefrontal cortex, DLPFC)、前輔助運(yùn)動(dòng)區(qū)(pre-supplementary motor area, pre-SMA)。

右側(cè)額下回(rIFG/rIFC), 是影響反應(yīng)抑制功能的重要腦區(qū)(Aron et al., 2003; Aron & Poldrack, 2006; Aron, 2007; Erika-Florence et al., 2014; Juan & Muggleton, 2012; Rodrigo et al., 2014; Sandrini et al., 2020; Schroeder et al., 2020)。對腦損傷和功能損傷的研究充分支持rIFG對反應(yīng)抑制的作用, Aron等人(2003)發(fā)現(xiàn)rIFG損傷的病人反應(yīng)抑制任務(wù)的表現(xiàn)下降; Chambers等人(2006)通過經(jīng)顱磁刺激降低rIFG的興奮性以達(dá)到功能損傷的目的, 結(jié)果發(fā)現(xiàn)反應(yīng)抑制能力降低。背外側(cè)前額葉(DLPFC)也在反應(yīng)抑制中發(fā)揮作用(Chen et al., 2021; Dubreuil-Vall et al., 2019; Hwang et al., 2010; Sandrini et al., 2020), Hwang等人(2010)在被試左側(cè)DLPFC區(qū)域施加高頻重復(fù)經(jīng)顱磁刺激從而興奮該腦區(qū), 與假刺激組相比, 真刺激組在康納斯連續(xù)性能測試中表現(xiàn)更好, 表明反應(yīng)抑制能力提升。許多研究表明前輔助運(yùn)動(dòng)區(qū)(pre-SMA)也參與反應(yīng)抑制過程(Duann et al., 2009; Gowda et al., 2019; Kohl et al., 2019; Sandrini et al., 2020; Sharp et al., 2010; Tan et al., 2019), Dambacher等人(2014)通過完成GNG和SST時(shí)的功能磁共振成像(functional magnetic resonance imaging, fMRI)發(fā)現(xiàn)成功抑制時(shí)被試的pre-SMA的激活增加; 還有研究發(fā)現(xiàn)pre-SMA損傷的被試在SST中的成績顯著低于健康對照組, 表明反應(yīng)抑制能力下降(Floden & Stuss, 2006)?；咨窠?jīng)節(jié)(basal ganglia)是一組皮質(zhì)下神經(jīng)核團(tuán)的統(tǒng)稱, 是反應(yīng)抑制神經(jīng)通路的重要環(huán)節(jié)(Aron, Behrens, et al., 2007; Aron & Poldrack, 2006; Duann et al., 2009; Neubert et al., 2010; Zandbelt et al., 2013), 包括尾狀核、殼核、蒼白球和丘腦底核等, 其中尾狀核、殼核和蒼白球合稱紋狀體。Duann等人(2009)使用SST和fMRI揭示rIFC與pre-SMA之間存在功能性連接, 而pre-SMA通過尾狀核和丘腦底核與初級(jí)運(yùn)動(dòng)皮質(zhì)(primary motor cortex, M1)相連接, 從而抑制行為動(dòng)作; Aron, Behrens等人(2007)使用彌散加權(quán)成像(diffusion-weighted imaging, DWI)白質(zhì)束成像顯示IFC、丘腦底核和pre-SMA之間存在白質(zhì)束連接。有研究者提出額葉?基底神經(jīng)節(jié)模型解釋反應(yīng)抑制的可能的神經(jīng)機(jī)制(Aron & Poldrack, 2006; Aron et al., 2014; Hannah & Aron, 2021; Jahfari et al., 2011; Li et al., 2020; Wessel, 2018; Sandrini et al., 2020; Tan et al., 2019), 在此模型中, rIFG、pre-SMA產(chǎn)生停止命令并將其傳遞給基底節(jié), 該指令隨后通過基底神經(jīng)節(jié)輸出核發(fā)送到運(yùn)動(dòng)丘腦, 減少對運(yùn)動(dòng)皮層的驅(qū)動(dòng), 從而抑制運(yùn)動(dòng)沖動(dòng)。

非侵入性腦刺激技術(shù)被廣泛用于反應(yīng)抑制的研究中, 如TMS (Chambers et al., 2006; Hwang et al., 2010; Obeso et al., 2013; Zandbelt et al., 2013), 然而近年來, 一種新興的非侵入性腦刺激技術(shù)——經(jīng)顱直流電刺激(transcranial direct current stimulation, tDCS)受到越來越多的關(guān)注。和神經(jīng)電生理、神經(jīng)影像學(xué)等闡明相關(guān)關(guān)系的技術(shù)相比, tDCS為研究腦功能與行為的因果關(guān)系提供了可能(Filmer et al., 2014; Martin et al., 2020; Yavari et al., 2018)。tDCS與TMS存在不同之處, 首先原理上, TMS通過放置在頭皮上的通電線圈引發(fā)磁場穿過顱骨, 使線圈下方垂直的腦區(qū)產(chǎn)生感應(yīng)電流, 從而調(diào)節(jié)大腦活動(dòng)與功能(de Boer et al., 2021); tDCS則通過放置在頭皮上的電極, 直接傳導(dǎo)微弱的直流電(一般0.5～2 mA), 部分電流穿過顱骨作用于大腦皮質(zhì), 影響大腦皮層活動(dòng)(Coffman et al., 2014)。tDCS有兩個(gè)極性, 一般陽極刺激會(huì)引起皮層興奮性增加, 陰極刺激導(dǎo)致興奮性降低(Nitsche & Paulus, 2000, 2001; Pisoni et al., 2018)。其次, 從安全性來說, TMS和tDCS在滿足納入標(biāo)準(zhǔn)后一般情況下使用都是比較安全的(Krishnan et al., 2015; O'Connell et al., 2014), 但即使是在遵循指南推薦的安全參數(shù)的情況下應(yīng)用, TMS特別是重復(fù)TMS (repetitive TMS, rTMS)也有可能導(dǎo)致嚴(yán)重不良反應(yīng), 比如有個(gè)案報(bào)道使用安全參數(shù)下的rTMS治療耳鳴被試(無可識(shí)別的導(dǎo)致癲癇的危險(xiǎn)因素)時(shí)誘發(fā)了癲癇(Nowak et al., 2006), 但這類不良反應(yīng)的發(fā)生率極低(Rossi et al., 2021); 在滿足tDCS排除標(biāo)準(zhǔn)后通常使用的tDCS方案(有合適的電極皮膚接觸面積和明確的電極位置、合適的刺激強(qiáng)度和持續(xù)時(shí)間)則是安全的(Bikson et al., 2016; Woods et al., 2016), 雖然可能引起刺痛、發(fā)癢、灼熱等感覺(Kessler et al., 2012; Zewdie et al., 2020), 但目前沒有嚴(yán)重不良反應(yīng)(如急性精神病)的報(bào)道(Valiengo et al., 2020)。一些研究者提出tDCS產(chǎn)生效果的神經(jīng)機(jī)制有兩種, 一種是非突觸機(jī)制, 即tDCS導(dǎo)致神經(jīng)元膜電位靜息電位發(fā)生變化, 使易于去極化或者超極化, 從而形成興奮或者抑制效應(yīng)(Nitsche & Paulus, 2001; Stagg & Nitsche, 2011), 這種機(jī)制通常產(chǎn)生短期效應(yīng); 第二種機(jī)制是基于突觸水平的長時(shí)程增強(qiáng)和長時(shí)程抑制的機(jī)制, 較長時(shí)間和重復(fù)的tDCS可以產(chǎn)生長時(shí)程后效應(yīng)(Di Rosa et al., 2019), 從而可以使受刺激的神經(jīng)元產(chǎn)生可塑性變化(Fritsch et al., 2010; Stagg & Nitsche, 2011)。總之, tDCS是一種安全可耐受、非侵入式、易于攜帶、操作方便的能夠調(diào)節(jié)大腦皮質(zhì)功能與認(rèn)知能力的技術(shù)(Bikson et al., 2016; Lu, Gong, et al., 2020; Sampaio-Junior et al., 2018; Valiengo et al., 2020; Weidler et al., 2020)。

反應(yīng)抑制作為健康人群認(rèn)知能力中最為重要的部分之一, 幸運(yùn)的是, 其具有可塑性, 研究表明通過認(rèn)知增強(qiáng)技術(shù)可以提升反應(yīng)抑制, 對健康人群提升方法主要有兩種, 一是反應(yīng)抑制認(rèn)知訓(xùn)練(Benikos et al., 2013; Manuel et al., 2010), 但是這種方法比較耗時(shí), 相對來說效率不高(Wu et al., 2021), 二是非侵入性腦刺激技術(shù), 尤其tDCS因?yàn)槠浼夹g(shù)優(yōu)勢被廣泛應(yīng)用。目前越來越多的研究者探索tDCS靶向刺激特定的解剖皮層區(qū)域?qū)Ψ磻?yīng)抑制的調(diào)節(jié)作用, 尤其聚焦于tDCS是否可以增強(qiáng)健康人群的反應(yīng)抑制, 這具有十分重要的意義, 比如可以提高健康人群對各種精神疾病的抵抗力, 也可以提高健康群體與反應(yīng)抑制相關(guān)的能力。因此本綜述對tDCS刺激特定腦區(qū)影響健康被試反應(yīng)抑制功能的研究進(jìn)行回顧, 這些研究靶向的腦區(qū)主要有rIFG、DLPFC和pre-SMA, 以行為學(xué)任務(wù)GNG和SST的表現(xiàn)為主要結(jié)果, 其中Nogo錯(cuò)誤率(或正確率)是GNG的主要指標(biāo), 停止信號(hào)反應(yīng)時(shí)(stop signal reaction time, SSRT)是SST的主要指標(biāo), 本文首先從三個(gè)主要的刺激腦區(qū)分別進(jìn)行論述, 歸納目前各個(gè)研究的參數(shù)及陽性或者陰性結(jié)果, 進(jìn)一步促進(jìn)對以往研究的理解, 然后討論總結(jié)以往研究存在的不足, 最后重點(diǎn)在于探討更科學(xué)高效、更有針對性、更標(biāo)準(zhǔn)化可重復(fù)地使用tDCS提升反應(yīng)抑制的未來研究方向, 為進(jìn)一步優(yōu)化tDCS提升健康人群反應(yīng)抑制的研究提供實(shí)證支持和理論依據(jù)。

2 tDCS刺激右側(cè)額下回對反應(yīng)抑制功能的影響

右側(cè)額下回是反應(yīng)抑制的高級(jí)腦區(qū), Aron等人(2014)把rIFC以及相關(guān)神經(jīng)網(wǎng)絡(luò)(額葉?基底神經(jīng)節(jié)網(wǎng)絡(luò))稱為“剎車”, 認(rèn)為反應(yīng)抑制依賴于rIFC的功能。目前大量tDCS研究選擇刺激右側(cè)額下回, 從而探究對反應(yīng)抑制功能的影響(表1)。

陽極tDCS刺激rIFG能夠提升反應(yīng)抑制能力。Jacobson等人(2011)對被試的rIFG 施加tDCS并要求被試在刺激后完成 SST, 實(shí)驗(yàn)結(jié)果顯示, 相比于假刺激, 陽極刺激會(huì)顯著降低SSRT, 但對對照任務(wù)(和SST唯一不同的是沒有停止信號(hào))沒有作用, 說明刺激rIFG特異性地改變反應(yīng)抑制能力, 而不是一般能力; 對照試驗(yàn)刺激位置為右側(cè)角回(right angular gyrus, rAG), 結(jié)果對反應(yīng)抑制沒有作用, 說明tDCS調(diào)節(jié)反應(yīng)抑制具有區(qū)域選擇性(regional selectivity), 因?yàn)閾?jù)報(bào)道rAG不參與反應(yīng)抑制(Chambers et al., 2006)。Campanella等人(2018)使用條件正確率函數(shù)(Conditional accuracy function, CAF)來衡量GNG任務(wù)表現(xiàn), 即快速反應(yīng)情況下反應(yīng)正確率會(huì)下降, 這可能比使用整體正確率更敏感, 結(jié)果發(fā)現(xiàn)陽極刺激rIFG后快速反應(yīng)的反應(yīng)正確率下降幅度減小, 表明反應(yīng)抑制效率提高。還有一些研究結(jié)果也表明陽極tDCS刺激rIFG可以提升被試的反應(yīng)抑制能力(Chen et al., 2019; Stramaccia et al., 2015)。有研究者結(jié)合神經(jīng)影像學(xué), 指出tDCS不僅在行為學(xué)水平, 還在神經(jīng)生理水平上影響反應(yīng)抑制能力。Sandrini等人(2020)進(jìn)行兩次實(shí)驗(yàn), 第一次獲取SST的行為學(xué)基線值, 第二次實(shí)驗(yàn)被試先進(jìn)行5 min的靜息態(tài)fMRI, 然后對rIFC進(jìn)行陽極tDCS或者假刺激, 電刺激結(jié)束后再次測量5 min靜息態(tài)fMRI, 隨后立即測量SST (與第一次實(shí)驗(yàn)相同), 同時(shí)收集事件相關(guān)fMRI。結(jié)果用𝞓SSRT (𝞓SSRT = SSRT(session 2)– SSRT(session 1))來反映tDCS對反應(yīng)抑制的影響, 與假刺激比較, 陽極tDCS顯著縮短𝞓SSRT, 事件相關(guān)fMRI顯示陽極刺激增強(qiáng)了stop試次時(shí)pre-SMA和丘腦底核的連接, 靜息態(tài)fMRI發(fā)現(xiàn)陽極刺激后在rIFC、尾狀核、pre-SMA和右側(cè)DLPFC間存在內(nèi)在連接的改變。

有研究發(fā)現(xiàn)陽極tDCS結(jié)合相應(yīng)反應(yīng)抑制任務(wù)訓(xùn)練能產(chǎn)生更好的提升效果。Ditye等人(2012) 研究了SST訓(xùn)練結(jié)合陽極tDCS刺激rIFG對反應(yīng)抑制的影響, 被試每天進(jìn)行8 min的SST訓(xùn)練和15 min的tDCS (1.5 mA), 重復(fù)4 d, 結(jié)果表明, 訓(xùn)練提高了反應(yīng)抑制能力, 而訓(xùn)練與tDCS結(jié)合產(chǎn)生的提升效果比只進(jìn)行訓(xùn)練更好, 這項(xiàng)研究為提升反應(yīng)抑制能力提供了一種新思路, 即將tDCS與訓(xùn)練相結(jié)合。Hogeveen等人(2016)將被試分成3組：傳統(tǒng)tDCS刺激rIFC (pad-IFC組)、高精度tDCS (HD-tDCS)刺激rIFC (HD-IFC組)、傳統(tǒng)tDCS刺激枕骨中部(pad-Oz組), 都為陽極刺激, 每組完成隨機(jī)平衡的2輪實(shí)驗(yàn)：在刺激時(shí)進(jìn)行SST訓(xùn)練和在刺激時(shí)進(jìn)行CRT (對照任務(wù))訓(xùn)練, 每輪實(shí)驗(yàn)前后使用SST進(jìn)行行為學(xué)測量, 結(jié)果顯示相比于pad-Oz組, pad-IFC組和HD-IFC組結(jié)合SST訓(xùn)練時(shí)提高了反應(yīng)抑制表現(xiàn), 再次證明了反應(yīng)抑制的腦區(qū)有選擇性, 而結(jié)合CRT訓(xùn)練時(shí), 3組都沒有顯著的提升效果, 表明訓(xùn)練的內(nèi)容也影響刺激效果, 可能是因?yàn)榕c反應(yīng)抑制相關(guān)更高的任務(wù)更能使相應(yīng)腦區(qū)的神經(jīng)元預(yù)激活, 因此也更容易被外部施加的電流激活。

表1 tDCS對右側(cè)額下回區(qū)域反應(yīng)抑制功能的影響

注：A: 陽極刺激; C: 陰極刺激; S: 假刺激; GNG: go/nogo任務(wù); GoRT: go試次反應(yīng)時(shí); SST: 停止信號(hào)任務(wù); modified SST: SST變式; SSRT: 停止信號(hào)反應(yīng)時(shí); GNG-SST: GNG和SST結(jié)合的任務(wù)。

有趣的是, 有研究者認(rèn)為反應(yīng)抑制分為反應(yīng)性抑制和主動(dòng)性抑制兩種類型, 右側(cè)額下回不僅與反應(yīng)性抑制有關(guān), 還參與主動(dòng)性抑制, 認(rèn)為主動(dòng)性抑制以go試次反應(yīng)時(shí)間增加為指標(biāo), 反應(yīng)性抑制以SSRT降低為指標(biāo)(Cai et al., 2016; Castro-Meneses et al., 2016; Cunillera et al., 2014, 2016)。Cunillera等人(2014)使用tDCS對被試的rIFC進(jìn)行刺激, 并使用GNG和SST結(jié)合的任務(wù)GNG-SST測量行為學(xué)表現(xiàn), 結(jié)果陽極tDCS使go試次反應(yīng)時(shí)增加, SSRT降低, 分別體現(xiàn)了對主動(dòng)性抑制與反應(yīng)性抑制的雙重影響。但在Cunillera等人(2016)的另一項(xiàng)研究中卻沒有得到一致的結(jié)論, 實(shí)驗(yàn)采用了和之前同樣的設(shè)計(jì), 結(jié)果顯示陽極tDCS使GoRT增加, 但對SSRT影響不顯著, 與之前的研究結(jié)果不一致(Cai et al., 2016; Cunillera et al., 2014), 未能證實(shí)右側(cè)額下回的雙重抑制功能, 另一項(xiàng)研究對rIFG施加刺激并使用SST衡量行為學(xué)表現(xiàn), 與假刺激相比, 陽極刺激時(shí)和刺激后SSRT都顯著降低, 但go試次反應(yīng)時(shí)沒有顯著差異(Castro-Meneses et al., 2016)。鑒于目前研究較少且得到的結(jié)果也不一致, 所以右側(cè)額下回是否具有雙重抑制功能還需進(jìn)一步研究。

雖然大多數(shù)研究表明陽極刺激右側(cè)額下回會(huì)改善反應(yīng)抑制功能, 但也有研究表明陽極tDCS沒有效果(Campanella et al., 2017; Dambacher et al., 2015; Friehs, Brauner, et al., 2021; Leite et al., 2018; Thunberg et al., 2020), 這可能是由于刺激設(shè)置不同(電流強(qiáng)度、刺激位置、參考電極位置、電極極性、持續(xù)時(shí)間等)、衡量反應(yīng)抑制的方法不同、人群特征等導(dǎo)致結(jié)果異質(zhì)性(Filmer et al., 2014; Mayer et al., 2020)。比如最近的一項(xiàng)研究將被試分為陽極刺激rIFG組(陰極位于右側(cè)DLPFC)、陰極刺激rIFG組(陽極位于右側(cè)DLPFC)和假刺激組, 在刺激前后完成SST, 結(jié)果顯示陽極刺激組SST行為表現(xiàn)沒有顯著改變, 可能是由于兩個(gè)刺激位點(diǎn)位置較近, 加上使用的是9 cm2的電極片, 電流易分散傳導(dǎo), 實(shí)際上電流沒有產(chǎn)生應(yīng)有的效果(Friehs, Brauner, et al., 2021)。有研究也得出tDCS對行為學(xué)任務(wù)無效的結(jié)論, 這可能是不同研究采用的方法學(xué)不同, 即采用GNG任務(wù)可能過于簡單, 相比SST可以通過調(diào)整停止信號(hào)延遲時(shí)間適應(yīng)性調(diào)節(jié)難度, GNG更容易產(chǎn)生天花板效應(yīng)(Campanella et al., 2017), 此外Campanella等人(2018)認(rèn)為使用整體錯(cuò)誤率檢測GNG表現(xiàn)的細(xì)微變化不夠敏感, 這可能也是Campanella等人(2017)沒有得到陽性結(jié)果的原因。Fujiyama等人(2021)分別對老年人(69 ± 5.8歲)和年輕人(24 ± 4.9歲)的rIFG施加陽極刺激和假刺激, 與假刺激相比, 陽極刺激使年輕人的SSRT顯著降低, 但對老年人作用不顯著, 表現(xiàn)出tDCS效應(yīng)的年齡依賴性。以上研究提示研究者們要充分考慮各種因素的影響, 以降低實(shí)驗(yàn)結(jié)果的異質(zhì)性。

3 tDCS刺激背外側(cè)前額葉對反應(yīng)抑制功能的影響

背外側(cè)前額葉與許多認(rèn)知功能有關(guān), 如工作記憶(Alizadehgoradel et al., 2020; Kumar et al., 2017)、注意(Boroda et al., 2020)、決策(Guo et al., 2018; He et al., 2016; Shen et al., 2016)、認(rèn)知控制(Gbadeyan, McMahon, et al., 2016), 但DLPFC也是反應(yīng)抑制的重要腦區(qū), 近年來該腦區(qū)也成為了tDCS研究反應(yīng)抑制功能的重要位點(diǎn), 相關(guān)研究見表2。

研究表明tDCS刺激DLPFC可以影響反應(yīng)抑制功能, 且左側(cè)和右側(cè)都有相關(guān)研究。Friehs和Frings (2018)選擇右側(cè)DLPFC為刺激位點(diǎn), 在刺激前后, 被試完成相同的SST, 結(jié)果陽極刺激使SSRT降低, 假刺激對SSRT沒有影響。最近Friehs, Dechant等人(2021)采用SST變式的研究也得到了一致的結(jié)果。Friehs和Frings (2019)另一項(xiàng)研究將被試分成陰極刺激組和假刺激組, 其他實(shí)驗(yàn)設(shè)計(jì)和之前的研究類似(Friehs & Frings, 2018), 結(jié)果陰極刺激使SSRT增加, 假刺激對SSRT沒有影響, 表明反應(yīng)抑制功能在陰極刺激右側(cè)DLPFC時(shí)受損, 結(jié)合之前的研究結(jié)論(Friehs & Frings, 2018), tDCS對反應(yīng)抑制的調(diào)節(jié)作用依賴于刺激極性特異性, 即陽極刺激右側(cè)DLPFC提高反應(yīng)抑制能力, 而陰極刺激右側(cè)DLPFC降低反應(yīng)抑制能力。Nejati等人(2018)使用陽極刺激左側(cè)DLPFC, 并在刺激后完成GNG, 相比于假刺激, 陽極刺激顯著增加了nogo試次的正確率, 表明反應(yīng)抑制能力提升。還有一些選擇左側(cè)DLPFC作為刺激位點(diǎn)的研究發(fā)現(xiàn)陽極tDCS可以降低SSRT和提高反應(yīng)抑制功能(Fehring et al., 2019; Mansouri et al., 2017)。以上研究結(jié)果表明tDCS刺激DLPFC可以影響反應(yīng)抑制功能, 并且右側(cè)DLPFC和左側(cè)DLPFC都與反應(yīng)抑制有關(guān), 說明DLPFC對反應(yīng)抑制的功能側(cè)化仍需繼續(xù)探究。

表2 tDCS對背外側(cè)前額葉反應(yīng)抑制功能的影響

注：A: 陽極刺激; C: 陰極刺激; S: 假刺激; DLPFC: 背外側(cè)前額葉; GNG: go/nogo任務(wù); PGNG: parametric Go/Nogo task, 參數(shù)go/nogo任務(wù); modified GNG: GNG變式; SST: 停止信號(hào)任務(wù); modified SST: SST變式; GoRT: go試次反應(yīng)時(shí); SSRT: 停止信號(hào)反應(yīng)時(shí)。

有研究者結(jié)合tDCS與反應(yīng)抑制訓(xùn)練探索對反應(yīng)抑制功能的影響。Dousset等人(2021)采用連續(xù)4天的tDCS結(jié)合GNG變式訓(xùn)練, 將被試分為單訓(xùn)練組、陽極刺激rIFG結(jié)合訓(xùn)練組、陽極刺激右側(cè)DLPFC結(jié)合訓(xùn)練組、假刺激結(jié)合訓(xùn)練組和空白對照組, 并在實(shí)驗(yàn)開始前(T0)、4天干預(yù)后(T1)以及T1一周后(T2)完成GNG測試, 結(jié)果顯示所有組go試次的反應(yīng)時(shí)都顯著降低(T0 > T1 = T2), 結(jié)合考慮go試次反應(yīng)時(shí)降低和nogo試次錯(cuò)誤率下降, 發(fā)現(xiàn)陽極刺激右側(cè)DLPFC結(jié)合訓(xùn)練的效果最好, 因?yàn)樵摻MT2的nogo試次錯(cuò)誤率比T0和T1都顯著下降。提示研究者利用tDCS結(jié)合合適的訓(xùn)練任務(wù)增強(qiáng)反應(yīng)抑制功能可能是更加有效的方法。但也有研究表明tDCS結(jié)合訓(xùn)練并沒有產(chǎn)生顯著效應(yīng), Sedgmond等人(2019)使用單次tDCS結(jié)合GNG變式訓(xùn)練, 發(fā)現(xiàn)與假刺激相比, 陽極刺激對反應(yīng)抑制沒有顯著影響, 這可能是個(gè)體差異和單次刺激效果不穩(wěn)定導(dǎo)致的, 表明tDCS刺激DLPFC結(jié)合反應(yīng)抑制訓(xùn)練需要更多深入的研究。

tDCS研究結(jié)果的異質(zhì)性是一個(gè)常見問題, 雖然研究表明tDCS能夠影響反應(yīng)抑制能力, 但也有一部分研究發(fā)現(xiàn)tDCS刺激DLPFC對反應(yīng)抑制的行為表現(xiàn)沒有影響。Lapenta等人(2014)使用陽極刺激右側(cè)DLPFC, 陰極放置在左側(cè)DLPFC, 結(jié)果發(fā)現(xiàn)陽極刺激的GNG變式任務(wù)表現(xiàn)與假刺激沒有區(qū)別, 但是EEG結(jié)果顯示相比于假刺激, 陽極刺激使N2平均負(fù)振幅減少以及P3a平均正振幅增加, 分別表示被試抑制nogo試次時(shí)的沖突減少和動(dòng)作抑制增強(qiáng), 為tDCS增強(qiáng)反應(yīng)抑制提供了神經(jīng)生理的證據(jù), 而行為學(xué)結(jié)果不顯著可能是由于出現(xiàn)了天花板效應(yīng)。Stramaccia等人(2015)應(yīng)用tDCS刺激右側(cè)DLPFC和rIFG, 在刺激結(jié)束15 min后完成SST, 結(jié)果陽極和陰極刺激右側(cè)DLPFC后測得的SSRT與假刺激后測得的SSRT沒有顯著區(qū)別, 但陽極刺激rIFG卻使SSRT比假刺激顯著降低, 這可能是因?yàn)橛覀?cè)DLPFC的刺激效果持續(xù)時(shí)間較短, 因此在15 min后的SST作用已不明顯, 也可能是不同的腦區(qū)對反應(yīng)抑制進(jìn)程的貢獻(xiàn)確實(shí)存在差別。Chen等人(2021)將被試分成陽極刺激右側(cè)DLPFC (同時(shí)陰極位于左側(cè)眶上區(qū))、陰極刺激右側(cè)DLPFC (同時(shí)陽極位于左側(cè)眶上區(qū))和假刺激組, 在刺激前后完成SST, 結(jié)果發(fā)現(xiàn)陽極和陰極刺激都能使SSRT顯著降低, 而假刺激則沒有差異, 與之前的研究發(fā)現(xiàn)陰極刺激使SSRT增加不一致(Friehs & Frings, 2019), 這可能是由于電極放置位置不一致導(dǎo)致的, Friehs和Frings (2019)把陰極置于右側(cè)DLPFC, 將陽極放置在左側(cè)三角肌, Chen等人(2021)在陰極刺激右側(cè)DLPFC時(shí), 陽極位于左側(cè)眶上區(qū), 這可能促進(jìn)了眶上區(qū)活動(dòng), 間接影響了與反應(yīng)抑制相關(guān)的額葉區(qū)域, 如DLPFC (Kringelbach & Rolls, 2004)?？偨Y(jié)以上研究, 可見行為學(xué)任務(wù)難度、刺激腦區(qū)、電極位置都會(huì)影響tDCS研究的結(jié)果; 結(jié)合以往文獻(xiàn), 其他刺激參數(shù)設(shè)置, 比如電極極性、電流大小、刺激持續(xù)時(shí)間也會(huì)影響tDCS的效果(Chan et al., 2021; Filmer et al., 2014)。

研究表明tDCS刺激DLPFC的效果不僅與刺激參數(shù)設(shè)置有關(guān), 還與個(gè)體差異有較大關(guān)系。Nieratschker等人(2015)發(fā)現(xiàn)COMT基因型不同, tDCS產(chǎn)生的效果也不同, 他們使用陰極tDCS刺激左側(cè)DLPFC, 并完成參數(shù)GNG任務(wù)(parametric Go/Nogo task, PGNG), 結(jié)果與假刺激相比, 反應(yīng)抑制能力受損只在COMT基因Val純合子個(gè)體上觀察到, 對Met等位基因攜帶者沒有影響, 這可能與COMT基因Val158Met多態(tài)性影響前額葉多巴胺能活性有關(guān), 而tDCS調(diào)節(jié)執(zhí)行功能時(shí)也受到前額葉多巴胺濃度的影響, 表明遺傳因素會(huì)影響tDCS對反應(yīng)抑制功能的作用, 但Plewnia等人(2013)研究發(fā)現(xiàn)COMT基因型與tDCS對反應(yīng)抑制沒有交互作用, 這說明COMT基因型是否影響tDCS作用需要進(jìn)一步探索。還有研究關(guān)注人格特質(zhì)對tDCS調(diào)節(jié)反應(yīng)抑制的影響, Weidacker等人(2016)讓健康被試完成病態(tài)人格量表修正問卷(Psychopathic Personality Inventory-Revised, PPI-R), 然后對右側(cè)DLPFC實(shí)施陽極刺激、陰極刺激和假刺激三種條件, 隨后完成PGNG, 結(jié)果發(fā)現(xiàn)冷酷分量表得分越高, 陰極刺激下高任務(wù)難度的PGNG表現(xiàn)更好, 這與一般情況下陰極刺激使PGNG表現(xiàn)更差相違背, 這可能是由于冷酷特質(zhì)者皮質(zhì)興奮性遞質(zhì)和抑制性遞質(zhì)失衡, 即谷氨酸和GABA比例失調(diào), 而陰極刺激可以減少興奮性谷氨酸水平, 恢復(fù)谷氨酸和GABA的比例, 這可能使反應(yīng)抑制功能更好(Stagg et al., 2009)。Wu等人(2021)進(jìn)行組水平分析時(shí)發(fā)現(xiàn)陽極和陰極刺激右側(cè)DLPFC對反應(yīng)抑制沒有影響, 進(jìn)行個(gè)體水平分析后, 發(fā)現(xiàn)陰極刺激后基線水平越差的被試nogo正確率提升越高, 而基線水平越好的則表現(xiàn)越差, 互相抵消導(dǎo)致組水平?jīng)]有差異, 說明被試基線水平也是重要的個(gè)體差異因素。因此, 這些研究表明在tDCS研究中需要考慮被試的個(gè)體差異對tDCS作用的影響, 啟示未來的tDCS研究應(yīng)在實(shí)驗(yàn)設(shè)計(jì)、分析以及治療應(yīng)用中考慮個(gè)體的變異性, 以減少結(jié)果的異質(zhì)性并促進(jìn)個(gè)性化的神經(jīng)刺激方法的發(fā)展。

4 tDCS刺激前輔助運(yùn)動(dòng)區(qū)對反應(yīng)抑制功能的影響

前輔助運(yùn)動(dòng)區(qū)是反應(yīng)抑制的重要神經(jīng)基礎(chǔ), 是額葉?基底神經(jīng)節(jié)模型中的重要節(jié)點(diǎn), 同樣也成為了tDCS研究反應(yīng)抑制的熱門腦區(qū)(Aron, Durston, et al., 2007; Borgomaneri et al., 2020; Hsu et al., 2011; Liang et al., 2014; Sandrini et al., 2020; Verbruggen & Logan, 2008)。有關(guān)研究見表3。

大量行為學(xué)證據(jù)表明陽極tDCS刺激pre-SMA能夠提升反應(yīng)抑制能力。Hsu等人(2011)對pre-SMA實(shí)施陽極刺激、陰極刺激和無刺激, 刺激后完成SST, 結(jié)果發(fā)現(xiàn)與陰極刺激和無刺激條件相比, 陽極刺激stop試次錯(cuò)誤率顯著下降, 但SSRT沒有差異, SSRT是通過SSD間接計(jì)算得到的(Verbruggen & Logan, 2008, 2009), 本研究通過前測確定的關(guān)鍵SSD (stop試次錯(cuò)誤率保持在50%左右時(shí)的SSD)仍然應(yīng)用到了后測中, 沒有考慮tDCS對SSD的影響, 所以SSRT沒有得到顯著結(jié)果, 但陽極刺激使stop試次錯(cuò)誤率顯著降低也表明tDCS刺激pre-SMA提升了反應(yīng)抑制功能。Kwon和Kwon (2013a)通過陽極刺激pre-SMA、陽極刺激M1還有假刺激共三輪實(shí)驗(yàn), 發(fā)現(xiàn)陽極刺激pre-SMA的SSRT顯著降低。同年Kwon和Kwon (2013b)的研究重復(fù)了該結(jié)果, 實(shí)驗(yàn)對pre-SMA進(jìn)行陽極tDCS, 并在刺激前、刺激時(shí)、刺激后完成SST, 與假刺激相比, 陽極刺激時(shí)和刺激后的SSRT顯著降低。Fujiyama等人(2021)對一組老年人(68.5 ± 5.3歲)的pre-SMA應(yīng)用陽極刺激和假刺激后, 發(fā)現(xiàn)與假刺激相比, 陽極刺激使SSRT顯著降低。這些研究說明陽極tDCS刺激pre-SMA可以提升反應(yīng)抑制能力, pre-SMA是tDCS影響反應(yīng)抑制的重要靶點(diǎn)。

表3 tDCS對前輔助運(yùn)動(dòng)區(qū)反應(yīng)抑制功能的影響

注：A: 陽極刺激; C: 陰極刺激; S: 假刺激; SST: 停止信號(hào)任務(wù); modified SST: SST變式; SSRT: 停止信號(hào)反應(yīng)時(shí)。

陽極tDCS刺激pre-SMA提升反應(yīng)抑制不僅有行為學(xué)證據(jù), 還有神經(jīng)生理水平的證據(jù)支持。Liang等人(2014)的研究重復(fù)了Hsu等人(2011)的發(fā)現(xiàn), 與無tDCS的對照相比, 陽極刺激使stop試次錯(cuò)誤率降低, 同時(shí)他們還發(fā)現(xiàn)了SSRT的降低, 表明反應(yīng)抑制能力提升, 并通過EEG信號(hào)的多尺度熵(multiscale entropy, MSE)分析從神經(jīng)生理水平證明tDCS提升效果的有效性, 發(fā)現(xiàn)更高的MSE和更好的反應(yīng)抑制表現(xiàn)有關(guān), 并且陽極tDSC可以進(jìn)一步提高M(jìn)SE。Yu等人(2015)同樣發(fā)現(xiàn)陽極刺激pre-SMA提升反應(yīng)抑制能力, 不論是陽極刺激前后測比較還是和假刺激比較, SSRT都顯著降低, 并且tDCS使pre-SMA和腹內(nèi)側(cè)前額葉皮質(zhì)(ventromedial prefrontal cortex, vmPFC)的血氧水平依賴(blood oxygen level dependent, BOLD)反應(yīng)增加, tDCS誘發(fā)的BOLD信號(hào)增加與被試反應(yīng)抑制效率提升以及pre-SMA與vmPFC間功能連接增強(qiáng)成正相關(guān)。這些研究進(jìn)一步說明了pre-SMA是反應(yīng)抑制功能的重要腦區(qū), 同時(shí)表明使用tDCS可以提升反應(yīng)抑制。

雖然大多數(shù)研究都說明了陽極刺激pre-SMA可以提升反應(yīng)抑制能力, 但也有研究表明tDCS對行為學(xué)表現(xiàn)沒有改善效果。Bender等人(2017)使用陽極刺激、陰極刺激和假刺激3種條件作用于pre-SMA, 并在刺激開始前、刺激結(jié)束立即和刺激結(jié)束20 min后這3個(gè)時(shí)間點(diǎn)測試變式SST, 發(fā)現(xiàn)和陰極刺激與假刺激相比, 陽極刺激的SSRT和抑制成功率都沒有差異, 與之前Liang等人(2014)和Yu等人(2015)的研究發(fā)現(xiàn)不一致, 可能是使用的電流強(qiáng)度與之前的研究相比較小, 持續(xù)時(shí)間也較短(見表2), 也可能是參考電極放置位置不同導(dǎo)致的, Bender等人(2017)將參考電極放置在右側(cè)乳突位置, 而Liang等人(2014)和Yu等人(2015)的研究中參考電極都放置在左臉頰。Fujiyama等人(2021)發(fā)現(xiàn)陽極刺激使老年人(68.5 ± 5.3歲)SSRT顯著降低, 但對年輕人(22.4 ± 4.2歲)作用不顯著, 這可能是由于某些被試pre- SMA區(qū)域的解剖特征(比如顱骨厚度)使刺激強(qiáng)度不足, 也可能是刺激效應(yīng)的年齡依賴性導(dǎo)致的。根據(jù)文獻(xiàn)報(bào)道, tDCS電流強(qiáng)度、持續(xù)時(shí)間、參考電極位置和人群特征等不同, 會(huì)產(chǎn)生不同的實(shí)驗(yàn)結(jié)果(Filmer et al., 2014; Mayer et al., 2020)。

5 總結(jié)與展望

目前已經(jīng)有不少研究通過tDCS刺激不同腦區(qū)影響反應(yīng)抑制功能, 也產(chǎn)生了一些非常有意義的成果, 使得tDCS有極大潛力成為提升健康人群反應(yīng)抑制能力的工具, 但目前的研究還存在一些不足和亟待解決的問題：

(1) tDCS調(diào)節(jié)反應(yīng)抑制的神經(jīng)機(jī)制尚不明確, 主要包括兩方面的問題：一是反應(yīng)抑制的生理神經(jīng)環(huán)路還沒有闡釋清楚, 尤其是環(huán)路中皮層腦區(qū)作用的時(shí)間進(jìn)程; 二是使用tDCS調(diào)節(jié)反應(yīng)抑制的關(guān)鍵腦區(qū)(即經(jīng)刺激后對反應(yīng)抑制影響最大的腦區(qū))還不確定。隨著認(rèn)知神經(jīng)科學(xué)的發(fā)展, 研究者們認(rèn)識(shí)到反應(yīng)抑制的神經(jīng)基礎(chǔ)主要包括基底神經(jīng)節(jié)(basal ganglia)以及前額葉皮層的右側(cè)額下回(rIFG/rIFC)、背外側(cè)前額葉(DLPFC)和前輔助運(yùn)動(dòng)區(qū)(pre-SMA), 并且依據(jù)已有的研究發(fā)現(xiàn)這些腦區(qū)結(jié)構(gòu)互相連接功能互相影響, 所以研究者們提出額葉?基底神經(jīng)節(jié)模型, 為反應(yīng)抑制神經(jīng)機(jī)制的解釋提供了一條可能的路徑, 但該模型還存在一些不足：

首先皮層各腦區(qū)作用時(shí)間進(jìn)程不明確, 模型認(rèn)為rIFG、pre-SMA產(chǎn)生停止命令并將其傳遞給皮層下結(jié)構(gòu)(如丘腦底核), 但這兩個(gè)皮層腦區(qū)之間發(fā)揮功能的時(shí)間進(jìn)程仍不清楚, 現(xiàn)有一些研究的結(jié)論并不一致, 有研究認(rèn)為反應(yīng)抑制環(huán)路中rIFG可能在pre-SMA的功能上游(Osada et al., 2021; Zandbelt et al., 2013), 但Swann等人(2012)的研究表明反應(yīng)抑制過程中pre-SMA的活動(dòng)先于rIFG的活動(dòng), 也有研究者提出IFG與pre-SMA有著雙向連接(Rae et al., 2015), 但更多的研究并沒有明確報(bào)道兩者在反應(yīng)抑制環(huán)路上的功能位置(Aron et al., 2016; Hannah & Aron, 2021; Lofredi et al., 2021), 這提示確定rIFG和pre-SMA發(fā)揮功能的時(shí)間進(jìn)程還需要進(jìn)一步研究, 其中可能涉及的方法有侵入性電生理記錄如腦皮層電圖(electrocorticography, ECoG)。

其次, 目前的模型不包括DLPFC, 但是根據(jù)現(xiàn)有研究顯示DLPFC深入?yún)⑴c反應(yīng)抑制, 這說明該模型不夠全面, 是否還有更復(fù)雜的神經(jīng)環(huán)路仍不清楚, 反應(yīng)抑制的神經(jīng)機(jī)制還需進(jìn)一步的探究。此外, 目前tDCS調(diào)節(jié)反應(yīng)抑制的關(guān)鍵腦區(qū)(整個(gè)刺激中改善最明顯的腦區(qū))還不確定, tDCS刺激rIFG、DLPFC和pre-SMA都可以影響反應(yīng)抑制功能, 但這些結(jié)論一般是基于不同實(shí)驗(yàn)設(shè)計(jì)和實(shí)驗(yàn)參數(shù)設(shè)置得到的, 彼此不能直接比較, 就不能確定刺激后對反應(yīng)抑制影響最大的腦區(qū), 如果能夠通過更精密的驗(yàn)證方法使結(jié)果可以進(jìn)行比較, 或者在同一個(gè)實(shí)驗(yàn)中進(jìn)行嚴(yán)格控制, 使用tDCS對被試的不同腦區(qū)進(jìn)行分離刺激, 結(jié)合行為學(xué)、神經(jīng)電生理和神經(jīng)成像等技術(shù), 在控制其他條件的情況下, 僅有tDCS刺激腦區(qū)不同, 從而比較不同腦區(qū)對反應(yīng)抑制功能的確切作用, 將會(huì)進(jìn)一步明確tDCS影響反應(yīng)抑制功能的關(guān)鍵腦區(qū)。

(2)研究結(jié)果存在異質(zhì)性。反應(yīng)抑制是執(zhí)行功能的重要組成部分, 基于對反應(yīng)抑制神經(jīng)機(jī)制的認(rèn)識(shí)和經(jīng)顱直流電刺激技術(shù)的發(fā)展, 研究者們希望通過tDCS提升健康被試反應(yīng)抑制能力, 本文從刺激的不同腦區(qū)總結(jié)和分析了tDCS影響反應(yīng)抑制功能的研究, 由于基底神經(jīng)節(jié)是皮質(zhì)下結(jié)構(gòu), 解剖位置較深, 微電流不易達(dá)到, 相關(guān)研究極少, 所以絕大多數(shù)研究都選擇rIFG、DLPFC和pre-SMA作為刺激位點(diǎn)?？偟膩碚ftDCS是一種有效的調(diào)節(jié)反應(yīng)抑制能力的方法(de Boer et al., 2021; Schroeder et al., 2020), 但各個(gè)研究結(jié)果之間存在異質(zhì)性, 大多數(shù)結(jié)果表明tDCS能夠影響反應(yīng)抑制能力, 但因?yàn)閭€(gè)體差異性(Sedgmond et al., 2019; Weidacker et al., 2016)、刺激參數(shù)(電流大小、持續(xù)時(shí)間、電極尺寸、電極位置) (Chan et al., 2021; Chen et al., 2021; Friehs & Frings, 2019; Mayer et al., 2020)、行為學(xué)任務(wù)(分析方法、任務(wù)難度) (Campanella et al., 2017; Campanella et al., 2018; Lapenta et al., 2014)等因素, 也有研究得出無效的結(jié)論, 其中比較特別的因素是對行為學(xué)結(jié)果的分析方法不同也會(huì)產(chǎn)生不一致的結(jié)果, Campanella等人(2017)采用傳統(tǒng)錯(cuò)誤率分析方法時(shí), 結(jié)果表明GNG任務(wù)表現(xiàn)在組間沒有差別, 但對同一數(shù)據(jù)使用條件正確率函數(shù)衡量GNG表現(xiàn)時(shí), 結(jié)果表明陽極刺激rIFG后任務(wù)表現(xiàn)更好(Campanella et al., 2018), 也有研究者使用漂移擴(kuò)散模型(drift diffusion model, DDM)對已發(fā)表的一篇使用使用陽極tDCS刺激右側(cè)DLPFC和GNG任務(wù)的研究進(jìn)行重新分析, 但因?yàn)楸辉囀茿DHD患者, 該研究并沒有在前文提及, 結(jié)果發(fā)現(xiàn)使用傳統(tǒng)分析方法nogo正確率在陽極刺激組和假刺激組沒有差異, 但DDM分析結(jié)果表明陽極刺激提高了抑制的傾向降低了沖動(dòng)(Nejati et al., 2021)。

所以在未來研究中, 要注意個(gè)體差異、刺激參數(shù)和行為學(xué)任務(wù)對tDCS效應(yīng)的影響, 這有助于tDCS研究方案的發(fā)展, 也有助于促進(jìn)研究的可重復(fù)性和減少結(jié)果的異質(zhì)性。本文對控制這三方面的影響因素提出一些建議, 第一, 控制研究對象的個(gè)體差異對實(shí)驗(yàn)的影響, 如年齡(Fujiyama et al., 2021)、基因型(Nieratschker et al., 2015; Plewnia et al., 2013)、人格特質(zhì)(Weidacker et al., 2016)、認(rèn)知基線水平(Wu et al., 2021)等, 建議在選擇研究對象時(shí)要明確相應(yīng)的特征, 在容易控制的因素中使被試同質(zhì)化, 并且使用被試內(nèi)設(shè)計(jì)更有利于減少個(gè)體間差異的影響, 但對于tDCS研究來說, 被試內(nèi)設(shè)計(jì)可能會(huì)導(dǎo)致盲法無效, 因?yàn)閠DCS會(huì)引起軀體感覺, 有研究表明被試對自己接受的刺激條件的信念會(huì)影響結(jié)果, 一個(gè)解決方法是使假刺激盡可能逼真, 并在每次刺激后用標(biāo)準(zhǔn)問卷評(píng)估被試對特定刺激條件的信念和軀體的感受(Braga et al., 2021; Friehs, Frings, & Hartwigsen, 2021), 此外被試內(nèi)設(shè)計(jì)還需注意控制學(xué)習(xí)和順序效應(yīng)。第二, 使用規(guī)范且明確的tDCS參數(shù), 如電極尺寸、電極位置、電流強(qiáng)度和持續(xù)時(shí)間, 在幾個(gè)主要參數(shù)確定后, 其他參數(shù)都可以由此派生, 因?yàn)樗鼈兘^大多數(shù)情況下由主要參數(shù)決定, 在某些情況下由主要參數(shù)和組織特性決定(Bikson et al., 2016)。以往研究使用的電極尺寸從約0.79 cm2的高精度tDCS使用的環(huán)形電極到35 cm2的矩形電極片, 在后續(xù)研究中出于刺激位置的精確性考慮, 電極與皮膚接觸面積不宜太大, 建議使用環(huán)形電極(高精度tDCS)。電極放置位置應(yīng)使用腦電10-20系統(tǒng)或者fMRI引導(dǎo)方法進(jìn)行定位, 前者操作簡單方便也是目前較多使用的, 后者則是更精確更理想的方法。如前文所述, 以往研究使用的電流強(qiáng)度范圍絕大多數(shù)為0.5～2 mA, 由電流強(qiáng)度和電極皮膚接觸面積可以算得平均電流密度(Bikson et al., 2016), 研究表明電流密度不是越大越好, 因?yàn)橐环矫鏁?huì)增加軀體疼痛感, 另一方面電流密度并不總是與效應(yīng)強(qiáng)度呈線性關(guān)系; 此外電流密度增大會(huì)增加有效電場穿透深度, 不同程度地激活大腦表層和皮層下組織(Nitsche et al., 2008), 改變研究的目標(biāo)腦區(qū), 產(chǎn)生額外影響, 所以目前并不能斷定應(yīng)該使用的電流強(qiáng)度大小, 建議實(shí)驗(yàn)前在確定電極位置、電極面積和電流強(qiáng)度后, 進(jìn)行模擬(如有限元分析腦模)以確定電場、電流和靶向腦區(qū)是否符合實(shí)驗(yàn)需要。電刺激持續(xù)時(shí)間從4 min 12 sec到25 min不等, Nitsche等人(2008)提出大于10 min的刺激通?？梢砸鸷笮?yīng), 但具體維持時(shí)間還與刺激的腦區(qū)有關(guān), 有研究報(bào)道13～20 min的tDCS刺激 DLPFC后神經(jīng)元靜息膜電位變化可持續(xù)90 min以上(Khaleghi et al., 2020), 且目前采用高精度tDCS的研究多使用20 min/次, 建議除特別的實(shí)驗(yàn)需要外可以采用20 min/次的刺激持續(xù)時(shí)間。第三, 減少行為學(xué)任務(wù)造成的異質(zhì)性, 如設(shè)置合適的行為學(xué)任務(wù)難度, 防止出現(xiàn)天花板效應(yīng)或者地板效應(yīng), 這可能需要提前進(jìn)行預(yù)實(shí)驗(yàn)來確定, 或者如停止信號(hào)任務(wù)采用自適應(yīng)方法調(diào)整難度; 采用廣泛使用的行為學(xué)任務(wù), 如停止信號(hào)任務(wù)和Go/Nogo任務(wù), 控制指導(dǎo)語、試次數(shù)、結(jié)果記錄方法、分析方法和結(jié)果報(bào)告等行為學(xué)任務(wù)特征, 比如Verbruggen等人(2019)提出了實(shí)施停止信號(hào)任務(wù)以及分析結(jié)果的共識(shí)指南, 促進(jìn)了SST的正確使用, 也減少了由于行為學(xué)任務(wù)導(dǎo)致的研究的異質(zhì)性。

(3) tDCS研究需要提升空間分辨率?，F(xiàn)有的tDCS研究多使用傳統(tǒng)tDCS (conventional tDCS), 傳統(tǒng)tDCS大多使用陽極和陰極2個(gè)矩形電極片, 面積大(約25～35 cm2) (Stagg & Nitsche, 2011), 空間分辨率低, 電流傳導(dǎo)分散, 不能精確刺激特定腦區(qū), 不僅對大腦皮質(zhì)作用效能下降, 而且使得研究者對行為結(jié)果的神經(jīng)機(jī)制的解釋變得復(fù)雜, 但是高精度tDCS (HD-tDCS)使這些問題得到改善, 常見HD-tDCS使用小直徑圓形電極(比如直徑1 cm), 一般是1個(gè)中心電極放置在目標(biāo)腦區(qū), 周圍呈圓形環(huán)繞的4個(gè)返回電極, 形成4 × 1陣列, 可以通過傳導(dǎo)更高空間分辨率的電流調(diào)節(jié)皮質(zhì)興奮性和行為表現(xiàn)(Bortoletto et al., 2016; Datta et al., 2009; Kuo et al., 2013; Martin et al., 2020; Villamar et al., 2013), 同時(shí)比傳統(tǒng)的tDCS產(chǎn)生更顯著的行為或神經(jīng)生理效應(yīng)(Gbadeyan, Steinhauser, et al., 2016; Kuo et al., 2013; Nikolin et al., 2015)。但目前針對健康人群反應(yīng)抑制的tDCS研究中使用HD-tDCS的較少, 相比于傳統(tǒng)tDCS, 考慮到HD-tDCS空間分辨率更高, 刺激腦區(qū)更精確, 相關(guān)神經(jīng)機(jī)制的解釋也可以更簡單, 有利于得到更高信效度的研究結(jié)果, 所以未來反應(yīng)抑制的tDCS研究應(yīng)該更多地使用HD-tDCS。

(4) tDCS結(jié)合反應(yīng)抑制訓(xùn)練的方法亟待研究。以往研究已知反應(yīng)抑制訓(xùn)練可以提升反應(yīng)抑制能力(Benikos et al., 2013; Manuel et al., 2010), 根據(jù)以上的一些研究, tDCS刺激相應(yīng)腦區(qū)也可以提升反應(yīng)抑制功能, 所以一些研究將訓(xùn)練與tDCS結(jié)合起來, 探索這種結(jié)合是否是一種更有效的方法。訓(xùn)練和電刺激結(jié)合分為在線(online)和離線(offline), 在線指訓(xùn)練和刺激同時(shí)進(jìn)行, 離線則是訓(xùn)練和刺激異步進(jìn)行。Diyte等人(2012)研究了4次SST訓(xùn)練結(jié)合離線陽極刺激 rIFG 對反應(yīng)抑制的影響, 發(fā)現(xiàn)訓(xùn)練提高了反應(yīng)抑制能力, 而結(jié)合陽極tDCS 產(chǎn)生的提升效果比只進(jìn)行訓(xùn)練更好; Hogeveen等人(2016)采用1次SST訓(xùn)練結(jié)合在線陽極tDCS刺激rIFC, 結(jié)果提高了反應(yīng)抑制能力, 但是CRT訓(xùn)練結(jié)合在線tDCS對反應(yīng)抑制沒有影響, 說明訓(xùn)練內(nèi)容也影響這種方法的效果; Dousset等人(2021)采用4次在線陽極tDCS刺激右側(cè)DLPFC結(jié)合GNG變式訓(xùn)練發(fā)現(xiàn)提高了反應(yīng)抑制能力; Sedgmond等人(2019)使用1次在線tDCS刺激右側(cè)DLPFC結(jié)合GNG變式訓(xùn)練發(fā)現(xiàn)對反應(yīng)抑制沒有影響。可以發(fā)現(xiàn)目前反應(yīng)抑制訓(xùn)練結(jié)合tDCS的研究存在幾個(gè)問題：(1)研究較少且結(jié)果不一致; (2)研究使用的在線/離線的結(jié)合方式也不一致; (3)刺激參數(shù)對結(jié)果有影響, 如刺激次數(shù)。所以tDCS結(jié)合反應(yīng)抑制訓(xùn)練需要進(jìn)一步研究, 以明確更有效的結(jié)合方式。

(5)不同刺激模式的效果有待探索。目前對健康人群反應(yīng)抑制功能的tDCS研究大多數(shù)是單次(single-session)刺激, 研究表明, 單次刺激有效時(shí)間持續(xù)較短, 20 min左右tDCS的效果持續(xù)時(shí)間約90 min (Khaleghi et al., 2020; Nitsche & Paulus, 2001), 也有研究報(bào)道單次HD-tDCS (2 mA, 10 min)的神經(jīng)變化可以持續(xù)2 h (Kuo et al., 2013), 但多次(multisession)刺激可以獲得長時(shí)程后效應(yīng)或者持久的大腦興奮性的變化(Meinzer et al., 2014; Turski et al., 2017), 并且研究表明多次刺激對健康人具有安全性、可行性、可耐受性(Paneri et al., 2016; Turski et al., 2017), 比如Paneri等人(2016)發(fā)現(xiàn)每周共5次(2 mA, 20 min/次), 連續(xù)6周的tDCS是安全可行的。目前多次重復(fù)刺激已經(jīng)較多應(yīng)用于其他領(lǐng)域的研究中, 比如運(yùn)動(dòng)功能(Dumel et al., 2016; Wessel et al., 2021)、注意力(Lu, Liu, et al., 2020)、工作記憶(Ke et al., 2019)等, 但針對健康人群反應(yīng)抑制功能的多次重復(fù)刺激研究較少, 未來需要更多相關(guān)研究來確定其有效性, 并且其長時(shí)程效應(yīng)尚未清楚, 重復(fù)刺激同一腦區(qū)是否會(huì)延長tDCS效果的持續(xù)時(shí)間, 也需要未來更多的持續(xù)追蹤研究。有研究表明tDCS與經(jīng)皮耳迷走神經(jīng)刺激(transcutaneous auricular vagus nerve stimulation, taVNS)同時(shí)應(yīng)用可以產(chǎn)生顯著協(xié)同效應(yīng), 具有以更有效的方式調(diào)節(jié)多個(gè)腦網(wǎng)絡(luò)的潛力(Sun et al., 2021)。目前使用tDCS調(diào)節(jié)反應(yīng)抑制功能沒有聯(lián)合其他刺激方法的研究報(bào)道, 所以可以進(jìn)一步研究tDCS與其他刺激方法(如taVNS)結(jié)合使用對反應(yīng)抑制的影響。此外, tDCS多腦區(qū)聯(lián)合刺激是一種新的刺激模式, 已初步應(yīng)用在運(yùn)動(dòng)功能和認(rèn)知功能如工作記憶等研究中(Dagan et al., 2018; Hill et al., 2018), Dagan等人(2018)報(bào)道tDCS同時(shí)刺激初級(jí)運(yùn)動(dòng)皮質(zhì)和左側(cè)背外側(cè)前額葉比只刺激初級(jí)運(yùn)動(dòng)皮質(zhì)或假刺激更能提升運(yùn)動(dòng)能力, 但目前tDCS影響健康人群反應(yīng)抑制功能的研究, 都是對單個(gè)腦區(qū)的刺激, 而依據(jù)已有的研究顯示有多個(gè)腦區(qū)參與反應(yīng)抑制, 所以將來的研究可以嘗試多個(gè)腦區(qū)聯(lián)合刺激, 探索這種方式是否比單腦區(qū)刺激對反應(yīng)抑制的影響更大。

(6)不同年齡段健康人群的研究較少。以往研究選擇的被試多是20～30歲左右的青年, 對不同年齡段的人群如兒童和老年人研究不多, 目前沒有相關(guān)研究選擇健康兒童作為被試, 選擇老年被試的也僅Fujiyama等人(2021)的一項(xiàng)研究, 該研究中對rIFG和pre-SMA都進(jìn)行了陽極刺激和假刺激, 結(jié)果發(fā)現(xiàn)相比于假刺激, 老年人群陽極刺激pre-SMA可以提升反應(yīng)抑制, 刺激rIFG則沒有效果, 該研究表明通過tDCS可塑性改變反應(yīng)抑制的能力在健康的老年人中是得到保持的, 但是陽極tDCS對反應(yīng)抑制的影響僅在刺激pre-SMA時(shí)是明顯的, 這表明在老化的大腦中, tDCS可能只調(diào)節(jié)了preSMA而不能調(diào)節(jié)rIFG, 從以往研究看, 青年群體中刺激rIFG和pre-SMA都可以調(diào)節(jié)反應(yīng)抑制, 這表明不同年齡群體tDCS刺激存在差異, 不能簡單將青年人群的研究結(jié)果推廣到其他年齡群體中。研究表明反應(yīng)抑制能力隨著年老而逐漸下降, 這與包括pre-SMA和rIFG在內(nèi)的特定抑制神經(jīng)網(wǎng)絡(luò)的功能連接和結(jié)構(gòu)弱化有關(guān)(Coxon et al., 2016; Hsieh & Lin 2017; Tan et al., 2019), 此外, 反應(yīng)抑制能力的下降會(huì)影響老年人的功能獨(dú)立性, 大大增加與人口老齡化有關(guān)的社會(huì)醫(yī)療保健和經(jīng)濟(jì)成本(Fujiyama et al., 2021; Tan et al., 2019); 對兒童來說, 抑制功能遵循一定的發(fā)展軌跡, 從嬰兒期開始出現(xiàn), 在幼兒期和學(xué)齡前期經(jīng)歷快速成熟, 并持續(xù)發(fā)展至青春期和成年早期, 良好的抑制功能對生活和長遠(yuǎn)的發(fā)展至關(guān)重要, 如學(xué)業(yè)成績、親社會(huì)行為和整體的身心健康等(Kerr-German et al., 2022; Zhou et al., 2021), 這種發(fā)展依賴于潛在大腦結(jié)構(gòu)和神經(jīng)網(wǎng)絡(luò), 尤其是前額葉皮質(zhì)的發(fā)育(Ordaz et al., 2013; Zhou et al., 2021), 這表明老年人和兒童都有反應(yīng)抑制增強(qiáng)的需求并且有相應(yīng)的神經(jīng)基礎(chǔ), 使得通過tDCS刺激特定腦區(qū)改善不同年齡群體反應(yīng)抑制的方法具有光明的應(yīng)用前景和必要的現(xiàn)實(shí)意義, 但tDCS調(diào)節(jié)健康人群反應(yīng)抑制的研究中選擇不同年齡段被試的很少, 考慮到老年、青年和兒童群體在各種生理特點(diǎn), 尤其是大腦解剖特點(diǎn)存在諸多差異, 未來應(yīng)增加對不同年齡段健康群體的相關(guān)研究, 這有助于了解不同年齡群體間tDCS應(yīng)用的差異和更有針對性和特異性應(yīng)用tDCS來提升反應(yīng)抑制。

綜上所述, tDCS是一種安全有效的非侵入式的腦刺激技術(shù), 使用tDCS刺激參與反應(yīng)抑制的腦區(qū), 可以調(diào)節(jié)相關(guān)皮質(zhì)的神經(jīng)活動(dòng), 達(dá)到影響反應(yīng)抑制功能的目的, 但是現(xiàn)在有關(guān)研究還存在一些不足和有待進(jìn)一步解決的問題, 未來的研究應(yīng)著力解決這些問題, 以明確tDCS影響反應(yīng)抑制功能的神經(jīng)機(jī)制, 減少tDCS研究的異質(zhì)性, 增加對不同年齡群體的研究, 并探索更有效的刺激方式：比如使用HD-tDCS提高空間分辨率、將tDCS與訓(xùn)練結(jié)合、多次重復(fù)刺激、tDCS與其他刺激方法結(jié)合等, 可以為tDSC更好更高效地用于健康人群反應(yīng)抑制功能提升提供更充足的證據(jù)。

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Effects of transcranial direct current stimulation on response inhibition in healthy people

GUO Zhi-Hua, LU Hong-Liang, HUANG Peng, ZHU Xia

(Department of Military Medical Psychology, Air Force Medical University, Xi’an 710032, China)

Response inhibition refers to the ability to inhibit actions that are inappropriate or incapable of meeting current demands. Studies have shown that response inhibition is mainly related to the functions of the inferior frontal gyrus, the dorsolateral prefrontal cortex, and the pre-supplementary motor area. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique. In recent years, an increasing number of studies have explored the effects of tDCS on response inhibition by stimulating corresponding brain regions in healthy people, but they have not arrived at consistent conclusions. In this context, it has become increasingly urgent to elucidate the specific neural mechanism underlying the effect of tDCS on response inhibition, reduce the heterogeneity of tDCS studies, explore more effective ways of tDCS stimulation, and determine the age-dependent differences in tDCS effect.

response inhibition, tDCS, IFG, DLPFC, pre-SMA, stop signal task, go/nogo task

B842

2021-12-01

*軍隊(duì)“十三五”重大項(xiàng)目(AWS17J012)資助。

朱霞, E-mail: zhuxia@fmmu.edu.cn