導(dǎo)語(yǔ):隨著人口老齡化進(jìn)程加快及社會(huì)環(huán)境的不斷變化,神經(jīng)系統(tǒng)疾病及其相關(guān)功能障礙的發(fā)病率逐年上升,已成為威脅人類健康、影響患者生活質(zhì)量的重要公共衛(wèi)生問題。其中,吞咽障礙作為神經(jīng)系統(tǒng)疾病常見的并發(fā)癥,不僅顯著增加患者的病死率,還給患者及其家庭帶來沉重的身心負(fù)擔(dān)。在此背景下,加強(qiáng)相關(guān)領(lǐng)域的深入研究、提升疾病的診療水平顯得尤為重要。本期“吞咽障礙的評(píng)估與治療”專題精心遴選并匯編了該領(lǐng)域的優(yōu)秀學(xué)術(shù)論文,旨在與廣大醫(yī)學(xué)工作者共享前沿科研成果與實(shí)踐經(jīng)驗(yàn),激發(fā)創(chuàng)新思維,推動(dòng)精準(zhǔn)診療進(jìn)步,助力我國(guó)吞咽障礙康復(fù)醫(yī)學(xué)的高質(zhì)量發(fā)展。
——專刊召集人
通信作者簡(jiǎn)介:竇祖林,主任醫(yī)師,教授,博士生導(dǎo)師,中山大學(xué)附屬第三醫(yī)院康復(fù)醫(yī)學(xué)科學(xué)科帶頭人,腦病中心副主任。30余年來一直從事臨床醫(yī)療、教學(xué)與科研工作。在功能性吞咽障礙的評(píng)估與治療、肉毒毒素注射治療肌肉痙攣、腦損傷后的運(yùn)動(dòng)及認(rèn)知障礙康復(fù)等方面經(jīng)驗(yàn)豐富,在神經(jīng)性吞咽障礙領(lǐng)域的診治水平在國(guó)內(nèi)處于領(lǐng)導(dǎo)地位,作為中國(guó)吞咽障礙領(lǐng)域首席專家,在國(guó)際上享有盛譽(yù)。現(xiàn)任亞洲吞咽障礙協(xié)會(huì)副主席、中國(guó)康復(fù)醫(yī)學(xué)會(huì)副會(huì)長(zhǎng)、廣東省康復(fù)醫(yī)學(xué)會(huì)會(huì)長(zhǎng)、《中華物理醫(yī)學(xué)與康復(fù)雜志》副總編輯、中國(guó)康復(fù)醫(yī)學(xué)會(huì)吞咽障礙康復(fù)專業(yè)委員會(huì)名譽(yù)主任委員、中國(guó)康復(fù)醫(yī)學(xué)會(huì)科技管理與評(píng)審專業(yè)委員會(huì)副主任委員、第五屆廣東省保健會(huì)診專家、中國(guó)康復(fù)醫(yī)學(xué)會(huì)地方康復(fù)醫(yī)學(xué)會(huì)工作委員會(huì)第一屆委員會(huì)主任委員、《腦病通訊》第一屆編輯委員會(huì)顧問。主持國(guó)家自然科學(xué)基金面上項(xiàng)目5項(xiàng),包括國(guó)家重點(diǎn)研發(fā)項(xiàng)目在內(nèi)的各類各級(jí)科研項(xiàng)目60余項(xiàng);獲發(fā)明及實(shí)用新型專利15項(xiàng);獲廣東省政府科學(xué)技術(shù)獎(jiǎng)二、三等獎(jiǎng)各1項(xiàng);主持《中國(guó)吞咽障礙評(píng)估與治療康復(fù)專家共識(shí)(2013,2017版)》《吞咽障礙膳食營(yíng)養(yǎng)管理中國(guó)專家共識(shí)(2019版)》《中國(guó)吞咽障礙康復(fù)管理指南(2023版)》等的編寫。主編《實(shí)用癱瘓康復(fù)》《痙攣評(píng)估與治療》《吞咽障礙評(píng)估與治療》等專著、 本科生規(guī)劃教材《作業(yè)治療學(xué)》 與指南等13部;副主編參編專著、教材20余部。在國(guó)內(nèi)外專業(yè)雜志以第一作者或通信作者發(fā)表論文180余篇,其中SCI收錄全文70余篇。E-mail: douzulin@mail.sysu.edu.cn。
通信作者簡(jiǎn)介:溫紅梅,主任醫(yī)師,博士生導(dǎo)師,中山大學(xué)附屬第三醫(yī)院康復(fù)醫(yī)學(xué)科副主任兼專科主任、吞咽障礙醫(yī)學(xué)中心主任。長(zhǎng)期致力于神經(jīng)系統(tǒng)疾病所致吞咽、認(rèn)知和運(yùn)動(dòng)障礙康復(fù)的臨床和基礎(chǔ)研究。廣東省杰出青年醫(yī)學(xué)人才,美國(guó)哈佛醫(yī)學(xué)院Spaulding康復(fù)醫(yī)院訪問學(xué)者。現(xiàn)任中國(guó)康復(fù)醫(yī)學(xué)會(huì)吞咽障礙康復(fù)專委會(huì)副主任委員,中華醫(yī)學(xué)會(huì)物理醫(yī)學(xué)與康復(fù)分會(huì)言語(yǔ)治療學(xué)組副組長(zhǎng),廣東省康復(fù)醫(yī)學(xué)會(huì)吞咽障礙康復(fù)分會(huì)名譽(yù)主任委員。主持國(guó)家自然科學(xué)基金4項(xiàng),以第一、通信/共同通信作者在Brain Stimul、Neurology、Stroke、CNS Neurosci Ther等國(guó)際期刊發(fā)表相關(guān)論文80余篇。主編專著2部,副主編專著1部。獲發(fā)明/實(shí)用新型專利6項(xiàng),獲廣東省科技進(jìn)步獎(jiǎng)二等獎(jiǎng)1項(xiàng)、中國(guó)康復(fù)醫(yī)學(xué)會(huì)科學(xué)技術(shù)進(jìn)步獎(jiǎng)一等獎(jiǎng)4項(xiàng)、廣東省康復(fù)醫(yī)學(xué)會(huì)科學(xué)技術(shù)進(jìn)步獎(jiǎng)一等獎(jiǎng)1項(xiàng)。E-mail: wenhongm@mail.sysu.edu.cn。
【摘要】 吞咽障礙不僅嚴(yán)重影響患者的生活質(zhì)量,還顯著提高了并發(fā)癥發(fā)生率及死亡風(fēng)險(xiǎn)。近年來,神經(jīng)調(diào)控技術(shù)通過靶向干預(yù)外周及中樞神經(jīng)環(huán)路,為吞咽功能康復(fù)帶來了突破性的治療。文章系統(tǒng)介紹了該領(lǐng)域的關(guān)鍵技術(shù)及其最新進(jìn)展:在外周刺激方面,重點(diǎn)介紹了咽腔電刺激和迷走神經(jīng)刺激等技術(shù);在中樞調(diào)控方面,著重探討了重復(fù)經(jīng)顱磁刺激和經(jīng)顱直流電刺激的應(yīng)用。這些神經(jīng)調(diào)控技術(shù)通過調(diào)節(jié)神經(jīng)可塑性、改善神經(jīng)與肌肉的協(xié)調(diào)等多重機(jī)制發(fā)揮療效。未來發(fā)展應(yīng)聚焦于多模態(tài)技術(shù)整合及個(gè)體化治療方案優(yōu)化,從而推動(dòng)吞咽障礙的精準(zhǔn)康復(fù)發(fā)展。
【關(guān)鍵詞】 吞咽障礙;神經(jīng)調(diào)控;康復(fù)治療
Application and prospects of neuromodulation techniques in the treatment of dysphagia
LI Chao, WU Haiwan, QIAO Jia, YE Qiuping, XIE Chunqing, CHEN Jiemei, DAI Meng, DOU Zulin , WEN Hongmei
(Department of Rehabilitation Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China)
Corresponding authors: DOU Zulin, E-mail: douzulin@mail.sysu.edu.cn; WEN Hongmei, E-mail: wenhongm@mail.sysu.edu.cn
【Abstract】 Dysphagia not only severely affects patients’ quality of life but also significantly increases the incidence of complications and mortality risk. In recent years, neuromodulation technologies have provided breakthrough therapeutic strategies for swallowing rehabilitation by targeting peripheral and central neural circuits. This article systematically reviews the key technologies and recent advances in this field: for peripheral stimulation, it highlights pharyngeal electrical stimulation and vagus nerve stimulation; for central modulation, it focuses on the applications of repetitive transcranial magnetic stimulation and transcranial direct current stimulation. These neuromodulation techniques exert their therapeutic effects through multiple mechanisms, including regulating neural plasticity and improving neuromuscular coordination. Future development should focus on the integration of multimodal technologies and optimization of personalized treatment strategies to promote the establishment of a precise rehabilitation system for dysphagia.
【Key words】 Dysphagia;Neuromodulation;Rehabilitation therapy
吞咽是一個(gè)高度復(fù)雜的生理過程,需要口腔、咽部及食管等多個(gè)結(jié)構(gòu)提供精確的感覺輸入,中樞神經(jīng)系統(tǒng)整合處理信息,并由頭頸部相關(guān)肌群實(shí)現(xiàn)有序協(xié)作輸出[1-2]。具體來說,感覺信息首先通過三叉神經(jīng)(Ⅴ)、面神經(jīng)(Ⅶ)、舌咽神經(jīng)(Ⅸ)及迷走神經(jīng)(Ⅹ)等顱神經(jīng)傳遞至大腦[3],隨后在延髓內(nèi)的感覺運(yùn)動(dòng)處理中心完成初步整合。延髓作為吞咽的中樞模式發(fā)生器,其活動(dòng)還受到大腦皮層、小腦等高級(jí)中樞神經(jīng)區(qū)域的調(diào)節(jié)[3-4]。最終,口輪匝肌、舌肌和咽縮肌等頭頸部肌肉在精確激活下,協(xié)同完成食物或液體從口腔安全轉(zhuǎn)運(yùn)至胃部的全過程。一旦這一復(fù)雜的感覺-運(yùn)動(dòng)通路因各種疾病被破壞,便可能導(dǎo)致吞咽障礙的發(fā)生。
近年來,隨著人口老齡化進(jìn)程加快及相關(guān)基礎(chǔ)疾病發(fā)病率的提升,吞咽障礙的發(fā)病率呈逐年上升趨勢(shì)。最新循證醫(yī)學(xué)證據(jù)表明,急性腦卒中患者中約有42%出現(xiàn)吞咽障礙[5],總體患病率高達(dá)38.57%[6]。在神經(jīng)退行性疾病領(lǐng)域,吞咽障礙同樣常見:多發(fā)性硬化和帕金森病患者的患病率分別為44.8%和60%以上[7-8]。與此同時(shí),頭頸部腫瘤等患者的吞咽障礙發(fā)生率也達(dá)41%~58%[9]。這些數(shù)據(jù)顯示,吞咽障礙在多種疾病背景下普遍存在,并對(duì)患者健康構(gòu)成嚴(yán)重威脅,因此,探索其有效的治療手段已成為當(dāng)前臨床和科研領(lǐng)域的關(guān)注重點(diǎn)。
吞咽障礙傳統(tǒng)治療方法主要包括3類:首先是代償性策略,如調(diào)整食物質(zhì)地(增稠液體或制成泥狀等),便于更安全地吞咽,盡管應(yīng)用普遍但相關(guān)循證證據(jù)有限[10]。其次為行為干預(yù)措施,在臨床醫(yī)師指導(dǎo)下完成特定行為訓(xùn)練,雖已被證實(shí)有效[11-12],但操作復(fù)雜、耗時(shí)不同且疾病類型需求各異。第3種則依賴不同類型的喂養(yǎng)管道[13],如鼻胃管、經(jīng)皮胃造口管等。鑒于傳統(tǒng)治療手段存在一定局限,近年來多種神經(jīng)調(diào)控技術(shù)逐步興起,通過對(duì)外周神經(jīng)或中樞神經(jīng)系統(tǒng)進(jìn)行特定刺激,可誘發(fā)神經(jīng)可塑性,以重建吞咽的生物力學(xué)功能。本文將對(duì)該領(lǐng)域的神經(jīng)調(diào)控技術(shù)進(jìn)行介紹。
1 外周神經(jīng)調(diào)控的相關(guān)技術(shù)
1.1 咽腔電刺激
咽腔電刺激(pharyngeal electrical stimulation,PES)通過導(dǎo)管電極將特定頻率和強(qiáng)度的電流傳遞至咽部黏膜,激活感覺傳入神經(jīng),調(diào)節(jié)中樞吞咽網(wǎng)絡(luò)的可塑性,從而改善吞咽障礙[14-15]。Hamdy等[16]發(fā)現(xiàn),PES可在健康人群中誘導(dǎo)吞咽運(yùn)動(dòng)皮層可塑性,表現(xiàn)為咽部運(yùn)動(dòng)代表區(qū)擴(kuò)大、皮層興奮性增強(qiáng)。Fraser等[17]進(jìn)一步證實(shí),PES可促進(jìn)急性腦卒中患者吞咽運(yùn)動(dòng)皮層可塑性恢復(fù),表現(xiàn)為未受損半球皮質(zhì)延髓束興奮性增強(qiáng),且與吞咽功能的即時(shí)改善呈正相關(guān)。多項(xiàng)隨機(jī)對(duì)照研究表明,PES具有降低吞咽障礙患者誤吸發(fā)生率、改善進(jìn)食狀態(tài)和縮短住院時(shí)間的作用[18-20];此外,PES能夠促進(jìn)腦卒中合并嚴(yán)重吞咽障礙患者的外周感覺恢復(fù),改善氣道保護(hù)功能并有利于氣管切開患者拔管[21-22]。一項(xiàng)病例報(bào)告顯示,PES可安全、有效地逆轉(zhuǎn)新型冠狀病毒感染患者拔除氣管插管后出現(xiàn)的嚴(yán)重神經(jīng)源性吞咽障礙[23]。鑒于上述,PES已被英國(guó)國(guó)家衛(wèi)生與保健優(yōu)化研究所(National Institute for Health and Clinical Excellence,NICE)推薦用于神經(jīng)源性氣管切開患者的吞咽障礙治療,顯示出其在臨床應(yīng)用中的潛力[24]。然而,亦有隨機(jī)對(duì)照研究結(jié)果顯示,PES治療亞急性腦卒中吞咽障礙患者的療效與假刺激組并無顯著差異,這可能與刺激強(qiáng)度設(shè)置不足等因素有關(guān),此外輕度吞咽障礙患者的自然恢復(fù),以及治療手段的差異也可能影響治療效果[25]。
為進(jìn)一步提升PES的治療效果,筆者團(tuán)隊(duì)對(duì)其參數(shù)進(jìn)行了優(yōu)化,通過調(diào)整波形(三角波與方波結(jié)合)及延長(zhǎng)脈沖寬度(10 ms),改良了刺激模式,旨在增強(qiáng)感覺傳入、減少肌肉疲勞,并將其命名為改良咽腔電刺激(modified pharyngeal electrical stimulation,mPES),而且以個(gè)案形式報(bào)道了mPES應(yīng)用于慢性重度神經(jīng)源性吞咽障礙患者的治療,結(jié)果顯示mPES可顯著促進(jìn)吞咽功能的改善,且療效可持續(xù)數(shù)周[26]。隨后開展的單臂前瞻性研究證實(shí)經(jīng)過連續(xù)2周的mPES干預(yù)后,患者的功能性經(jīng)口攝食量表(Functional Oral Intake Scale,F(xiàn)OIS)和喉鏡吞咽評(píng)估(Flexible Endoscopic Evaluation of Swallowing,F(xiàn)EES)的滲漏-誤吸評(píng)分均顯著改善,且未發(fā)現(xiàn)嚴(yán)重不良反應(yīng)[27]。通過功能近紅外光譜(functional near-infrared spectroscopy,fNIRS)對(duì)腦皮層的神經(jīng)活動(dòng)進(jìn)行觀察,發(fā)現(xiàn)mPES可激活與吞咽相關(guān)的多個(gè)腦區(qū),包括初級(jí)感覺皮層、初級(jí)運(yùn)動(dòng)皮層和感覺聯(lián)合皮層等,提示mPES可通過誘導(dǎo)神經(jīng)網(wǎng)絡(luò)的可塑性變化,優(yōu)化腦功能連接,改善吞咽功能[28]。
在實(shí)驗(yàn)研究方面,建立大鼠缺血性腦卒中后吞咽障礙模型,優(yōu)化mPES刺激參數(shù)的研究發(fā)現(xiàn),
1 mA強(qiáng)度、5 Hz頻率(每次10 min,連續(xù)3 d)為最佳刺激方案,缺血后72 h開始干預(yù)療效最佳,可改善大鼠吞咽功能,包括縮短咽部通過時(shí)間、減少吞咽間隔和增加吞咽食團(tuán)面積。此參數(shù)下,感覺運(yùn)動(dòng)皮層中N-甲基-D-天冬氨酸受體1(N-methyl-D-aspartate receptor 1,NMDAR1)和鈣調(diào)素依賴性蛋白激酶Ⅱα亞型(Ca2+/calmodulin-dependent protein
kinase Ⅱα,CaMKⅡα)表達(dá)顯著上調(diào),提示該刺激模式最有利于增強(qiáng)皮層興奮性和功能恢復(fù)[29-30],為mPES臨床干預(yù)提供了實(shí)驗(yàn)依據(jù)。
1.2 迷走神經(jīng)刺激
迷走神經(jīng)刺激(vagus nerve stimulation,VNS)是一種通過電刺激調(diào)節(jié)迷走神經(jīng)活動(dòng)的治療方法。該技術(shù)最初應(yīng)用于抑郁癥和癲癇等神經(jīng)系統(tǒng)疾病,近年研究者發(fā)現(xiàn)其對(duì)腦卒中后功能障礙具有顯著治療潛力。根據(jù)刺激方式的不同,VNS主要分為植入性迷走神經(jīng)刺激(implant vagus nerve stimulation,iVNS)和經(jīng)皮迷走神經(jīng)刺激(transcutaneous vagus nerve stimulation,tVNS),其中tVNS因無創(chuàng)性更受臨床青睞,在規(guī)范操作下具有較高的安全性,其非侵入性特點(diǎn)降低了傳統(tǒng)VNS的并發(fā)癥風(fēng)險(xiǎn)。tVNS包括經(jīng)耳迷走神經(jīng)刺激(transcutaneous auricular vagal nerve stimulation,taVNS)和經(jīng)頸迷走神經(jīng)刺激(transcutaneous cervical vagal nerve stimulation,tcVNS),taVNS電極置于耳甲腔,刺激迷走神經(jīng)纖維耳支,tcVNS則通過經(jīng)皮電極直接刺激頸部迷走神經(jīng)干[31]。
在臨床研究中,Wang等[32]采用tVNS治療30例急性期腦卒中后吞咽障礙患者(參數(shù):脈沖寬度0.5 ms、頻率25 Hz,刺激強(qiáng)度根據(jù)患者耐受性在0~5 mA范圍內(nèi)調(diào)節(jié)、每次30 min),治療3周后,患者的滲漏-誤吸評(píng)分明顯改善,提示tVNS是急性腦卒中后治療吞咽障礙的一種有效、無創(chuàng)的治療方式。Marrosu等[33]對(duì)3例多發(fā)性硬化合并吞咽障礙患者進(jìn)行VNS治療后,患者的吞咽功能得到改善。在基礎(chǔ)研究中,Long等[34]采用tVNS治療大腦中動(dòng)脈閉塞后吞咽障礙大鼠模型(參數(shù):頻率20 Hz、強(qiáng)度2 mA,脈沖寬度0.5 ms,30 min/次),治療3周后,結(jié)果提示該干預(yù)方式可增加大鼠的髓鞘再生、誘導(dǎo)血管生成、抑制腦白質(zhì)的炎癥反應(yīng),從而改善吞咽障礙。
此外,tVNS還可能通過緩解吞咽肌肉肌張力異常、改善吞咽協(xié)調(diào)性、促進(jìn)吞咽感覺功能的恢復(fù)等發(fā)揮臨床療效[35-37],其潛在作用機(jī)制包括整合神經(jīng)傳導(dǎo)通路、抗炎與神經(jīng)保護(hù)、增強(qiáng)神經(jīng)可塑性和重組、調(diào)節(jié)血腦屏障通透性、直接調(diào)節(jié)咽肌功能等[38-40],然而,tVNS在吞咽障礙中的作用機(jī)制尚未完全明了。tVNS的療效與刺激參數(shù)密切相關(guān),其參數(shù)優(yōu)化需綜合考慮電流、頻率、脈寬、刺激周期、持續(xù)時(shí)間、介入時(shí)機(jī)等多因素,同時(shí)結(jié)合患者生理特征及動(dòng)態(tài)反饋實(shí)現(xiàn)個(gè)體化治療[41]。
近年來,呼吸門控迷走神經(jīng)電刺激(respiratory-gated auricular vagal afferent nerve stimulation,RAVANS)作為一種比較新的tVNS刺激方式,也逐漸在吞咽障礙領(lǐng)域得到應(yīng)用。這項(xiàng)技術(shù)能夠?qū)崿F(xiàn)呼吸同步化的迷走神經(jīng)精準(zhǔn)調(diào)控。其核心機(jī)制在于:首先,通過實(shí)時(shí)監(jiān)測(cè)呼吸周期,在特定的吸氣或呼氣時(shí)相精確觸發(fā)迷走神經(jīng)刺激;其次,基于呼吸波形變化的動(dòng)態(tài)分析,智能算法能自動(dòng)優(yōu)化刺激參數(shù);最后,系統(tǒng)能夠即時(shí)獲取生理反饋數(shù)據(jù),并據(jù)此調(diào)整下一輪刺激方案,從而構(gòu)建完整的“監(jiān)測(cè)-反饋-刺激”閉環(huán)系統(tǒng)。這種模式實(shí)現(xiàn)了刺激時(shí)相的精準(zhǔn)同步,通過持續(xù)的自適應(yīng)優(yōu)化確保了治療的安全性和有效性。研究顯示,RAVANS可能通過呼吸控制調(diào)節(jié)單胺能和γ-氨基丁酸(gama-aminobutyric acid,GABA)系統(tǒng)來增強(qiáng)孤束核和藍(lán)斑的激活,達(dá)到調(diào)控吞咽的目的[42]。然而,其在吞咽障礙領(lǐng)域的確切療效及作用機(jī)制還需要更多研究進(jìn)一步闡明。
2 中樞神經(jīng)調(diào)控的相關(guān)技術(shù)
2.1 經(jīng)顱磁刺激
重復(fù)經(jīng)顱磁刺激(repetitive transcranial magnetic"stimulation,rTMS)根據(jù)法拉第電磁感應(yīng)原理,利用交流電通過線圈產(chǎn)生磁場(chǎng),時(shí)變磁場(chǎng)再產(chǎn)生感應(yīng)電流作用于大腦皮層,神經(jīng)細(xì)胞發(fā)生去極化,產(chǎn)生運(yùn)動(dòng)誘發(fā)電位,從而調(diào)節(jié)神經(jīng)細(xì)胞興奮性[43]。已有大量文獻(xiàn)證實(shí)高頻 rTMS(≥ 5 Hz)會(huì)增加吞咽皮層興奮性,低頻 rTMS(≤ 1 Hz)則會(huì)產(chǎn)生抑制作用[44]。
多項(xiàng)薈萃分析顯示rTMS對(duì)吞咽功能有積極作用。最新發(fā)表的一篇綜述中納入了19項(xiàng)系統(tǒng)綜述和meta分析,結(jié)果顯示所有研究均報(bào)告rTMS刺激大腦半球至少具有中等程度的整體療效[45],該綜述也強(qiáng)調(diào)了研究之間的差異,特別是在刺激部位、頻率和刺激模式等因素方面。然而,也有研究表明從刺激部位來看,刺激不同半球時(shí)吞咽功能的改善程度均無統(tǒng)計(jì)學(xué)差異[46-47],此外,最新證據(jù)提示,與單純刺激患側(cè)或健側(cè)半球相比,雙側(cè)半球聯(lián)合刺激可能帶來更顯著的吞咽功能獲益[48-49]。
針對(duì)低頻與高頻rTMS的療效,現(xiàn)有研究結(jié)果存在分歧,有研究者認(rèn)為兩者療效無顯著差異,也有研究者分別支持低頻或高頻rTMS更具優(yōu)勢(shì)[50-51]。
小腦rTMS的應(yīng)用潛力近年來已成為研究的熱點(diǎn)。一項(xiàng)納入了5個(gè)隨機(jī)對(duì)照試驗(yàn)、包含673例吞咽障礙患者的meta分析表明,小腦rTMS對(duì)吞咽功能具有顯著改善效果,且在刺激部位(單側(cè)與雙側(cè)小腦)、刺激模式[rTMS與間歇性θ波爆發(fā)刺激(intermittent theta burst stimulation,iTBS)]以及刺激頻率(5 Hz與10 Hz)方面均未發(fā)現(xiàn)顯著差異[52]。然而,雙側(cè)小腦rTMS在治療后的大腦興奮程度方面,比單側(cè)小腦rTMS顯著增強(qiáng)[53]。針對(duì)大腦皮層的rTMS治療存在誘發(fā)癲癇發(fā)作的風(fēng)險(xiǎn),小腦rTMS雖在理論上也有可能引發(fā)治療后癲癇發(fā)作,但目前文獻(xiàn)中尚未有相關(guān)病例報(bào)告,推測(cè)小腦rTMS較大腦皮層rTMS具有更高的安全性[14]。
iTBS是一種在相對(duì)較短刺激時(shí)間內(nèi)可產(chǎn)生等效或更強(qiáng)神經(jīng)調(diào)控效果的磁刺激方法,相較于傳統(tǒng)rTMS具有更高的刺激效率。Rao等[54]通過對(duì)70例腦卒中后吞咽困難患者實(shí)施10次雙側(cè)小腦iTBS,隨訪4周后發(fā)現(xiàn)其吞咽功能評(píng)分明顯提升。另一項(xiàng)研究將90例腦卒中患者分為幕上組和腦干組,均予持續(xù)4周每日30 min的干預(yù)。結(jié)果顯示,iTBS可有效改善滲漏、誤吸及殘留現(xiàn)象,顯著提升患者的吞咽功能[55]。
動(dòng)物實(shí)驗(yàn)方面,Huang等[56]在帕金森病吞咽障礙小鼠模型中發(fā)現(xiàn),rTMS和左旋多巴(levodopa,L-Dopa)均可通過抑制NOD樣受體熱蛋白結(jié)構(gòu)域相關(guān)蛋白3(NOD-like receptor family pyrin domain containing 3,NLRP3)炎癥小體激活及Caspase-1依賴的細(xì)胞焦亡通路,有效改善吞咽功能。筆者團(tuán)隊(duì)采用吞咽造影“金標(biāo)準(zhǔn)”方法,評(píng)價(jià)不同頻率rTMS對(duì)腦卒中后吞咽障礙大鼠吞咽功能的影響,結(jié)果顯示,10 Hz 高頻rTMS不僅顯著增加大鼠體質(zhì)量(體重),在各項(xiàng)吞咽功能指標(biāo)的改善上也優(yōu)于5 Hz和20 Hz組,并能減輕肺炎,提高肺、血清及孤束核中P物質(zhì)、降鈣素基因相關(guān)肽和5-羥色胺的水平[57]。進(jìn)一步研究提示,10 Hz rTMS對(duì)PSD大鼠吞咽功能的改善,可能與調(diào)節(jié)腸道微生物群及糞便代謝物的協(xié)同作用有關(guān)[58]。
2.2 經(jīng)顱直流電刺激
經(jīng)顱直流電刺激(transcranial direct current stimulation,tDCS)是一種通過將陽(yáng)極和陰極電極放置于頭皮特定部位,持續(xù)給予微弱電流(通常為1~2 mA),以調(diào)節(jié)大腦皮層興奮性的神經(jīng)調(diào)控技術(shù)。tDCS可通過調(diào)節(jié)神經(jīng)元?jiǎng)幼麟娢话l(fā)放頻率,使靶區(qū)皮層興奮性發(fā)生相應(yīng)變化,陽(yáng)極刺激可增強(qiáng)、陰極刺激可降低皮層興奮性[59-60],從而改善與吞咽相關(guān)的神經(jīng)功能。作為一種非侵入性神經(jīng)調(diào)控手段,已有多項(xiàng)研究和系統(tǒng)評(píng)價(jià)證實(shí),tDCS在卒中后吞咽障礙的治療中具有一定療效,但其治療效果受刺激部位、刺激強(qiáng)度、卒中類型及病程等多種因素影響。
研究顯示,tDCS能顯著縮短口腔期和咽期食物運(yùn)送時(shí)間,有效降低滲漏與誤吸的發(fā)生率,且其治療效果可持續(xù)1至3個(gè)月,進(jìn)一步亞組分析結(jié)果顯示,單側(cè)刺激(無論健側(cè)還是患側(cè)半球)或雙側(cè)交替刺激的效果優(yōu)于雙側(cè)同時(shí)刺激,后者與單獨(dú)常規(guī)吞咽訓(xùn)練相比并未顯示出優(yōu)勢(shì)[61]。然而,Li等[62]的研究證實(shí),單側(cè)及雙側(cè)大腦半球陽(yáng)極tDCS聯(lián)合常規(guī)吞咽訓(xùn)練均有助于改善卒中后吞咽障礙患者的吞咽功能,其中雙側(cè)陽(yáng)極tDCS效果更為顯著。在刺激方案的選擇方面,20 min的1.4 mA
陽(yáng)極tDCS為目前最優(yōu)刺激方案,此外,20 min的1.2 mA、1.5 mA、1.6 mA、2 mA及30 min的2 mA陽(yáng)極刺激,同樣優(yōu)于常規(guī)治療或假刺激,亞組分析進(jìn)一步顯示刺激初級(jí)感覺運(yùn)動(dòng)皮層的效果優(yōu)于刺激緣上回,這可能與初級(jí)感覺運(yùn)動(dòng)皮層在吞咽運(yùn)動(dòng)調(diào)控中的核心作用相關(guān)[63]。目前,tDCS治療仍存在刺激參數(shù)不統(tǒng)一、樣本量偏小等局限,未來亟需開展大樣本、長(zhǎng)期隨訪、設(shè)計(jì)科學(xué)的隨機(jī)對(duì)照研究以進(jìn)一步優(yōu)化刺激參數(shù),并驗(yàn)證tDCS在神經(jīng)源性吞咽障礙治療中的長(zhǎng)期安全性及療效。
3 結(jié)語(yǔ)與展望
中樞神經(jīng)系統(tǒng)的神經(jīng)可塑性機(jī)制已成為當(dāng)前神經(jīng)科學(xué)領(lǐng)域的研究熱點(diǎn)。借助神經(jīng)調(diào)控技術(shù),精準(zhǔn)誘導(dǎo)并增強(qiáng)吞咽相關(guān)腦神經(jīng)環(huán)路的可塑性,為吞咽障礙患者的神經(jīng)功能康復(fù)提供了全新思路。本文系統(tǒng)闡述了目前吞咽障礙治療中常用神經(jīng)調(diào)控技術(shù)的臨床應(yīng)用進(jìn)展、作用機(jī)制及其局限性。該領(lǐng)域仍面臨諸多挑戰(zhàn),包括刺激參數(shù)標(biāo)準(zhǔn)化不足、針對(duì)帕金森病、肌萎縮側(cè)索硬化和頭頸部腫瘤等特定病因吞咽障礙的研究證據(jù)有限,以及在個(gè)體差異基礎(chǔ)上優(yōu)化治療方案的難題。此外,盡管現(xiàn)有神經(jīng)調(diào)控技術(shù)多樣、機(jī)制各異,但針對(duì)不同臨床分型、病程階段及個(gè)體生理特征,如何選擇最優(yōu)干預(yù)方案仍有待深入探索。展望未來,需依托醫(yī)工交叉融合,不斷深化神經(jīng)可塑性機(jī)制的相關(guān)研究,并推動(dòng)多模態(tài)神經(jīng)調(diào)控技術(shù)的協(xié)同整合,以更有效地激活感覺-運(yùn)動(dòng)神經(jīng)環(huán)路網(wǎng)絡(luò)。這不僅有望顯著提升吞咽障礙患者的康復(fù)效率和生活質(zhì)量,降低誤吸及吸入性肺炎等并發(fā)癥的發(fā)生風(fēng)險(xiǎn),也將成為該領(lǐng)域未來的重要發(fā)展方向。
利益沖突聲明:本研究未受到企業(yè)、公司等第三方資助,不存在潛在利益沖突。
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