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Chinese Journal of Alzheimer's Disease and Related Disorders

Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders      Editor in chief: Jun WANG

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Review

Research progress on transcutaneous auricular acupoint electrical stimulation (taVNS) for mild cognitive impairment

  • Qingyan CHEN 1, 2 ,
  • Shanshan GAO 1, 2 ,
  • Chunlei GUO 1, 2 ,
  • Hua YAN 3 ,
  • Ge YANG , 3 ,
  • Jiliang FANG , 1
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  • 1 Department of Radiology, Guang’anmen Hospital of Chinese Academy of Traditional Chinese Medicine, Beijing 100053, China
  • 2 China Academy of Chinese Medical Sciences, Beijing 100700, China
  • 3 Department of Geriatrics, Guang’anmen Hospital of Chinese Academy of Traditional Chinese Medicine, Beijing 100053, China

Received date: 2024-03-05

  Revised date: 2024-04-12

  Online published: 2024-04-26

Abstract

The treatment of mild cognitive impairment remains a challenging aspect of geriatric healthcare. Based on the theory of "treating brain disease through ear" in traditional Chinese medicine, a novel neural modulation technique known as transcutaneous auricular acupoint vagus nerve stimulation (taVNS) has emerged as a promising adjunctive therapy for a range of neurological and psychiatric conditions. Recently, research has demonstrated its effectiveness in mild cognitive impairment. This paper offers a comprehensive review of the current research status of taVNS in the treatment of mild cognitive impairment both domestically and internationally. It focuses on the therapeutic effects and mechanisms of taVNS, presenting its research achievements, and proposes further research directions in this field. This will provide a novel and referential approach for non-pharmacological therapies for MCI, offering a new technique to improve cognitive function and enhance the quality of life for a vast number of elderly patients.

Cite this article

Qingyan CHEN , Shanshan GAO , Chunlei GUO , Hua YAN , Ge YANG , Jiliang FANG . Research progress on transcutaneous auricular acupoint electrical stimulation (taVNS) for mild cognitive impairment[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2024 , 7(2) : 142 -146 . DOI: 10.3969/j.issn.2096-5516.2024.02.010

轻度认知障碍(mild cognitive impairment,MCI)是指记忆力和/或其他认知功能减退,但日常生活能力基本正常,且未达到痴呆的前期病理状态。痴呆的分型很多,如阿尔茨海默病、额颞叶痴呆、路易体痴呆病、帕金森病合并痴呆以及血管性痴呆等。阿尔茨海默病(Alzheimer's disease,AD)是常见的痴呆类型,其前期阶段亦表现为MCI。国内外研究表明,MCI向AD的近期转化率为20%~40%,5至10年后,其转化率增至60%~100%[1]。2020年贾建平团队[2]关于中国60岁以上成年人的痴呆症与MCI的全国性横向研究表明,中国的AD患病率为3.9%,MCI患病率为15.5%,达3877余万。MCI发病率高、病因复杂,如果能在MCI阶段及时对患者进行干预,降低其向AD的转化率,将极大减轻经济负担,给患者和社会带来福音。但目前MCI尚无明确公认的药物治疗方法。研究表明,针对MCI的胆碱酯酶抑制剂、非甾体类抗炎药、银杏制剂、壳聚糖卵磷脂及维生素E等,均有一定的疗效,但尚无满意的治疗方法[3-4]。近年来热门的用于治疗早期AD和MCI的单抗药,如Aducanumab、Donanemab等,存在价格高昂、疗效存疑等缺点[5]。因此,临床迫切需要开发新的有效、简便、安全的补充替代疗法。

1 MCI的中医病机及治疗

中医经典中未见MCI的明确病名,但其与“痴呆”关系密切,根据其记忆力障碍症状可将其归属于中医“健忘”“不慧”“脑髓消”等范畴。MCI病位在脑,病机总属本虚标实、虚实夹杂,本虚为藏腑气血亏虚,标实多为痰浊、瘀血。老年人多体弱,后天脾土不足,气血生化乏源,或久病多虚,耗伤气血,致使心之气血虚;心为神明之官,心气虚则神明失养,继而心神涣散,呆滞善忘。脑为髓海,肾主骨生髓而通于脑,年事高或久病,导致肾精亏损,脑失充养。或中阳不振,脾运失司,气化不利,水谷精微无法如常生化,聚湿凝痰,阻遏脉络,致血运不畅,形成瘀血。终致阴阳失司,神机失控而呆滞愚钝,动作笨拙。中医对MCI的治疗同样基于辨证论治。药物治疗方面包括单味中药和复方中成药。有研究表明银杏叶提取物对神经系统具有独特而广泛的药理作用[6],是治疗MCI最成熟的单味中药,可改善患者认知功能,提高其日常生活能力。石菖蒲、远志、淫羊藿、人参等也被用作改善认知功能的治疗。但由于单味中药作用靶点少,疗效弱,故临床使用还是以复方为主,例如开心益智饮[7]、复方菖蒲益智汤[8]、黄连温胆汤[9]、补肾健脾化痰方[10]、复方苁蓉益智胶囊[11]、参乌胶囊等[12]。针对MCI的非药物疗法有针刺[13]、灸法[14]、八段锦[15]、太极拳[16]等,耳穴针刺[17]、五音疗法[18]、瑜伽[19]、正念冥想等[20],对MCI均有一定效果,但循证的规范化临床及实验研究尚少[21]

2 中医“脑病耳治”理论和耳穴治疗改善认知的应用

基于古代经典、基础研究及临床实践,荣培晶等[22]提出了中医“脑病耳治”理论,即应用耳穴刺激治疗精神神经疾病的新思路。黄帝内经中多个篇章记载了“脑病耳治”的相关内容。《灵枢·口问》曰:“耳者,宗脉之所聚也”,人体的经络、藏腑与耳有着密切的联系,“五藏六腑,十二经脉,有络于耳者”,耳通过经脉与五藏六腑建立了密切联系。同时,《灵枢•厥病篇》也谈到“耳聋无闻,取耳中”;《素问•缪刺论》云:“尸厥……不已,以竹管吹其两耳”,说明耳聋、中风可采用耳治法。《灵枢•厥论》亦云:“厥头痛,头痛甚,耳前后脉涌有热。泻出其血,后取足少阳。”记载了头痛与耳部疗法的关系。现代的耳穴贴压法对多种神经系统疾病有治疗作用[23-27]。耳穴贴压法通过刺激相应的穴位,可以活血通络,补肾填精,益气健脑,调节机体相应机能。例如:耳穴心具有宁心安神、调畅气血之功效;皮质下、额、枕耳穴具有调节大脑皮层的功效;耳穴肝具有疏肝理气、祛风除痰的功效;耳穴肾可补肾气、填肾精,肾生精,精生髓,脑为髓之海,肾精充足则脑髓充盈。陈士铎《辨证录-呆病门》“夫心肾交而智能生,心肾离而智能失……治法必须大补心肾”。既往研究表明,耳穴埋豆和耳穴磁疗等方法均能改善MCI患者的认知功能[23,28]。因此,中医“脑病耳治”思想指导MCI治疗具有较强的理论及实践基础。

3 神经调控技术治疗MCI

与传统非药物疗法相比,神经调控技术拥有一定的科技优势。近年来研究发现,给予40 Hz γ波频段刺激有助于改善AD和MCI。Murdock等[29]发现40 Hz声光刺激可促进多个脑区γ神经振荡的同步性,减轻AD小鼠大脑β淀粉样沉积,这种新疗法目前已进入临床试验阶段,在2023年公布的2期临床试验中取得了积极结果。Liu等[30]发现,40 Hz高频重复经颅磁刺激(transcranial magnetic stimulation,TMS)调制了左侧后颞顶叶区的γ波振荡,通过促进大脑内的局部和长期的动态连接,有效地改善AD患者的认知功能。Nissim等[31]总结既往研究发现,对左侧前额叶、背外侧前额叶等脑区靶向给予40Hz经颅交流电刺激(transcranial alternating current stimulation,tACS)对改善MCI和AD患者的情景记忆、关联记忆和工作记忆等认知功能有显著作用。
近年研究发现,神经调控技术—迷走神经刺激术(vagus nerve stimulation,VNS)可改善认知功能。早期VNS通过手术于颈部迷走神经处埋置电极产生电刺激,也称为侵入式迷走神经刺激术(implanting or invasive VNS,iVNS),美国食品与药品管理局(Food and Drug Administration,FDA)批准其用于治疗难治性癫痫(1997年)及难治性抑郁症(2005年)。后来,Merrill等[32]采用iVNS治疗17例AD患者6个月后发现,70%的患者认知功能未进一步损害。Sun等[33]进一步证实,iVNS可以提高工作记忆能力。Sjogren等[34]随后也证实iVNS改善了AD患者的认知功能。由于iVNS有创、费用较高、存在感染风险,限制了其临床应用。

4 耳甲电针与迷走神经刺激术结合治疗MCI

针对iVNS的缺点,朱兵、荣培晶及方继良团队历经二十余年研究,发现了耳甲内脏区与迷走神经耳支的联系,原创性研发了耳甲电针刺激术,又称为经皮耳穴迷走神经刺激术(transcutaneous auricular acupoint vagus nerve stimulation,taVNS),初步形成了结合传统中医耳针及现代神经科学原理的“脑病耳治”学术思想[22]。目前,taVNS已应用于治疗癫痫[35]、抑郁症[36]、失眠[37]等疾病,在临床上取得了与iVNS类似的疗效,并发表了系列相关研究成果。

4.1 taVNS治疗MCI的疗效观察

taVNS可以通过调节耳部的迷走神经增强或者改善认知功能。既往研究发现,taVNS可增强健康人的工作记忆[38]、联想记忆和执行功能[39-40]。临床上,taVNS也被证实对抑郁症[36]、术后认知障碍和癫痫患者的认知功能有改善作用[41-42]。在动物实验方面,Yu等[43]发现40 Hz taVNS可以提高小鼠的空间记忆和学习能力。2022年Wang等[44]首次将taVNS引入对MCI的临床治疗观察。使用了20/100 Hz的疏密波刺激耳穴心、肾穴,对52例MCI患者进行一项假针对照的随机双盲临床试验,发现24周的taVNS治疗显著提高了MCI的MoCA-B和AVLT-H的N5、N7评分。在另一项研究中,郭春蕾[45]同样使用20/100 Hz的疏密波taVNS刺激耳穴心、肾穴,通过对36例MCI患者taVNS临床疗效及脑机制观察发现,24周的taVNS治疗有效改善MCI患者的情景记忆和执行功能,量表评分主要表现在MoCA-B、AVLT-H的N5评分提高以及STT-A用时减少。基于以上临床证据,taVNS可通过刺激耳穴心、肾穴,宁神益智,改善MCI症状。

4.2 taVNS治疗MCI的脑网络机制研究

目前,国内外关于taVNS治疗MCI的机制研究较少。2022年,Murphy等[46]发现taVNS在磁共振实时扫描期间对MCI患者多个脑网络产生了一定影响,改变了患者与语义网络和突显网络相关的颞叶和顶叶区域内的连通性,以及左侧海马与多个皮质、皮质下脑区的功能连接,主要表现为左侧海马与前额叶和扣带回的连通性增加,包括颞叶在内的前颞叶前内侧的连通性降低,右侧海马与左侧前颞叶,与ROI功能连接显著下降。郭春蕾[45]发现24周taVNS治疗增强了MCI患者左侧前扣带-右侧中扣带功能连接(functional connectivity,FC)。说明taVNS可以通过调节边缘系统改善认知功能,这可能是taVNS的作用靶点。
额皮质、基底节和小脑之间存在平行的直接和间接投射,形成皮质-基底节-小脑环路[47]。前额叶联合区既与注意、记忆、问题解决等高级认知功能有密切关系,也与人格发展有密切关系[48]。基底节与认知存在密切联系,参与记忆、注意力、语言等多个方面[49]。近年来发现,除了参与运动,小脑在工作记忆、语言、社会和情绪处理方面也发挥重要作用[50]。Fastenrath等[51]研究发现小脑和皮质-小脑连接参与情绪记忆增强,活动增加的集群包括枕叶、颞叶、顶叶和额叶以及杏仁核/海马体、扣带回和丘脑。

4.3 taVNS治疗MCI的炎症机制探讨

近年来研究发现大脑中持续存在的免疫炎症反应已成为AD的第三个核心病理特征。大量研究表明,AD患者大脑中持续的免疫炎症反应不仅与神经退行性变有关,而且还促进和加剧了Aβ和神经元纤维缠结病理[52],噬菌斑和早期的可溶性Aβ能够触发小胶质细胞的活化并促进炎性细胞因子(包括IL-1β)和肿瘤因子的释放[53]。Gulen等[54]通过小鼠实验验证,炎症可能才是导致神经变性疾病的更深层次根源。血液炎症标记物(如IL-1β、TNF-α等)在AD和MCI的研究中逐渐得到重视[55]。Li等[56]的研究发现,血浆炎症因子在预测MCI转化方面具有良好的潜力。Wang等[57]研究发现,taVNS可以通过海马α7nAchR/NF-κB信号通路对抑郁模型大鼠发挥抗炎作用,从而达到“抗抑郁效应”,也可以通过外周抗炎作用和调节脑肠肽异常分泌来降低功能性消化不良模型大鼠的胃敏感性[58],但taVNS是否能调节MCI患者的血液炎症因子尚需深入研究。

5 结论

目前临床及基础初步研究发现,非药物疗法的taVNS可改善MCI的认知功能。taVNS作为神经调控的新技术,其中枢机制可能与调节大脑皮质(前额叶)、基底节和小脑之间的脑网络功能有关。taVNS对MCI多方面临床症状的疗效,尚需多中心随机双盲对照循证研究提供高级证据,其疗效机制方面,尚未阐明疗效与脑结构、脑功能、脑血流与血液炎症因子等之间的关系,值得深入探索。这些研究将为taVNS在MCI中的临床应用打下科学基础,促进其临床转化,为广大患者提供一种有效、安全、便携的非药物治疗新技术。
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