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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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Chinese Journal of Alzheimer's Disease and Related Disorders >

2021 , Vol. 4 >Issue 4: 328 - 332

DOI: https://doi.org/10.3969/j.issn.2096-5516.2021.04.015

Review

Progress of transcranial magnetic stimulation on cognitive function in Alzheimer's disease

  • QIN Xiao-hong ,
  • JIANG Fu-gui ,
  • LIU Xue-mei ,
  • XIAO Jun
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  • Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of china, Neuropsychology Department, Chengdu, Sichuan 610000, China

Received date: 2020-11-16

  Revised date: 2020-01-04

  Online published: 2021-12-25

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Abstract

Alzheimer's disease (AD), a chronic progressive degenerative disease of the central nervous system, is the most common type of cognitive impairment in the elderly. As a safe and non-invasive brain stimulation technique, repetitive transcranial magnetic stimulation (TMS) has been proved to be effective in improving cognitive function of AD by a large number of studies.This paper reviews the mechanism and clinical studies of rTMS in the treatment of cognitive function of AD in the past decade.The rTMS on cognitive function in patients with AD is unclear, the mechanism of curative effect research mainly focus on regulating synaptic plasticity, regulate gene and protein expression, inhibition of cell apoptosis and regulate blood flow redistribution, etc., clinical research groups have focused on patients with mild-to-moderate and AD and MCI, through neuropsychological assessment scale to assess their language, memory and other cognitive changes.This paper made a review and found that high-frequency rTMS can improve the cognitive areas of AD, such as language, memory and learning ability. However, it is still necessary to expand the sample size, study population type and scope, and extend the follow-up time to further verify the effect of rTMS on the cognitive function of AD patients.

Key words： Alzheimer's disease; repetitive transcranial magnetic stimulation; cognitive function

Cite this article

QIN Xiao-hong , JIANG Fu-gui , LIU Xue-mei , XIAO Jun . Progress of transcranial magnetic stimulation on cognitive function in Alzheimer's disease[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2021 , 4(4) : 328 -332 . DOI: 10.3969/j.issn.2096-5516.2021.04.015

阿尔茨海默病(Alzheimer's disease, AD)是一种以认知障碍为特征的神经变性疾病,是老年人痴呆最常见的原因,也是公共卫生系统负担最重的疾病之一[1⇓⇓~4]。AD患者可发生进行性记忆减退、语言障碍、视空间障碍以及人格与行为障碍,中晚期可出现幻觉、冷漠等精神症状,严重影响患者及其照顾者的生活质量。现阶段主要通过药物治疗和非药物治疗暂时缓解AD患者的临床症状,但用于治疗AD的主流药物种类较少,且仅能有限缓解症状,对AD的病理过程没有逆转作用。近年来,重复经颅磁刺激(repetitive transcranial magnetic stimulation, rTMS)被认为是研究神经系统变性疾病进展的重要手段之一[5,6],也是改善AD患者认知功能的一种替代方法[7]。rTMS通过不同部位、不同频率、不同强度的磁刺激脉冲序列,能对脑组织产生持久的影响,如低频(≤1Hz)皮质兴奋性降低,高频(≥5Hz)皮质兴奋性增加[8,9]。随着皮层可塑性的改变,rTMS还可通过感兴趣的皮层区域来增强一种特定类型的认知或技能。目前虽然有大量研究证明rTMS对AD的认知功能有显著改善[10⇓⇓⇓⇓~15],但是仍有学者认为rTMS对AD的认知功能障碍的治疗机制尚不明确,故本文就此做一综述。

1 rTMS对AD认知障碍机制的研究

rTMS是由一个磁刺激器的设备运作的,该设备由一个高电流脉冲发生器组成,能够产生数千安培的放电电流,通过一个刺激线圈,产生一个磁场强度可达数特斯拉的短暂磁脉冲。将线圈放置在受试者的头部,磁场（很少被颅骨、脑膜、脑脊液等脑外组织衰减）能够诱导足够的电场去极化表面的轴突并激活皮层中的神经网络。其作用的效能取决于许多物理和生物参数：如线圈的类型和方向,线圈和脑区之间的距离,磁脉冲波形,强度,频率和刺激模式,进入大脑的电流线方向以及可兴奋的神经元细胞[16]。

1.1 调节突触可塑性

Brehmer等人和Shen等人曾提出老年人群的中枢神经系统中潜伏的神经可塑性可以被重新激活,是晚年恢复认知功能的一种治疗手段[17,18]。Nam和Hernandez等人在老年小鼠中发现齿状回中pCREB蛋白（神经可塑性分子开关）和BDNF（分子神经营养因子,其降低常标志着神经变性疾病和神经元缺失）的显著增加与更好的学习和空间记忆有关[19]。BDNF与pCREB协同作用,对突触的结构和形态可塑性进行正反馈调节[20]。Ma等人发现在突触可塑性的相关基因谱可以被5 Hz HF-rTMS修饰[21],提示rTMS对正常衰老过程中发生的记忆损伤具有保护作用。

1.2 调节基因、蛋白表达,抑制细胞凋亡

过度磷酸化的tau蛋白是AD中神经原纤维缠结的主要蛋白亚基,清除脑内异常致病蛋白（沉积和磷酸化tau蛋白堆积）仍是AD治疗的首选方法。Chen等人发现2周的高频rTMS干预可通过下调APOE的表达和提高神经元的自噬能力[22],减少AD相关的致病标志物蛋白如A型蛋白、p-tau及其下游分子的表达,为早期预防和治疗AD提供了新的思路和实验依据。有学者提出通过抑制突变Tau表达可使转基因小鼠的记忆功能得到改善[23,24]。在Li等人的研究中[25],作者推测tau的过磷酸化促进了连环蛋白(β-catenin)的功能,从而使神经元从凋亡环境中逃脱,进而促进脑神经元的存活。然而Chen的研究证实[26],tau的磷酸化可以抑制β-catenin的水平,这与Li等人的结果相反。研究发现经过TMS治疗的老鼠,其凋亡细胞数量显著减少,凋亡相关细胞表达模式逆转,同时其脑内的BNDF、NGF两种神经营养因子的表达明显升高。此外,rTMS对AD症状和小鼠大脑分子水平的影响呈频率依赖性,表明rTMS具有更多的临床应用可能性。

1.3 调节脑血流再分布

Shang等人以20Hz rTMS刺激健康受试者的左侧前额叶背外侧皮质区(dorsolateral prefrontal cortex, DLPFC)[27],发现刺激后左侧颞叶内侧海马区的相对脑血流量(Relative CBF, rCBF)增加,而楔前叶和小脑的相对血流量降低。海马是与人类学习、记忆密切相关的脑区,推测高频rTMS的有益作用可能是通过rCBF在大脑网络内的再分配实现的。该研究还发现相对血流分布发生变化的区域数量都非常小,这可能是由于样本量相对较小、受试者之间的设计以及经颅磁刺激中已知的个体变异性造成的。目前这方面的研究相对较少,未来需要更大样本量的研究来证实rTMS对血流再分布的影响。

2 rTMS对改善AD认知障碍的临床应用

Wu等人对52例AD患者在常规抗精神病药物（低剂量利培酮）治疗的基础上[15],干预组（真实刺激组）在左侧DLFPC用静息运动阈值的80%,20Hz rTMS治疗,每周五天,共四周;而对照组采用伪磁刺激治疗。采用阿尔茨海默病行为病理学评定量表 (Behavioral Pathology in Alzheimer's Disease Rating Scale, BEHAVE-AD)、阿尔茨海默病评估量表-认知分量表(Alzheimer's Disease Assessment Scale- Cognitive, ADAS-Cog)和副反应量表(Treatment Emergent Symptom Scale, TESS)对患者分别在4周治疗期前后进行盲法评估。研究发现干预组和对照组患者的BEHAVE-AD总分的均值（标准差）和 ADAS-Cog总分的均值与基线相比均显著降低,且干预组的BEHAVE-AD总分较对照组降低更明显。其中,BEHAVE-AD中的活动障碍、昼夜节律、攻击性、情感障碍、焦虑和恐惧,ADAS-Cog 中4个因子分（记忆、语言、结构性练习、注意力）较对照组有明显改善。证明相较于单纯低剂量抗精神病药物治疗,高频rTMS 辅助低剂量抗精神病药物治疗能更显著地改善AD患者的认知功能和精神行为症状。
Koch等人通过随机、假对照、双盲试验的方法将经颅磁刺激结合脑电图(TMS-EEG)检测脑连通性的变化[28],对14例AD早期患者的左侧楔前叶区域进行了20Hz rTMS, 静息运动阈值为100%（两周10次）,通过临床前AD 认知负荷量表(Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, ADCS-PACC)测试评估认知功能的改善。通过TMS-EEG的方法,研究发现了楔前叶的神经活动增加,β节律活动的增强,默认网络中内楔前叶和内侧额叶之间的功能连接的改变,由此改善AD患者的记忆功能障碍。
Alcalá在5Hz的安全频率下,将19名患者随机分配至单一刺激点组（左侧DLPFC的rTMS）和多点位刺激组（6个不同区域的刺激）[29],使用3周的rTMS,其中每个疗程包括30组刺激,每次持续时间为10秒,中间有1分钟的休息时间,静息运动阈值为100%。结果发现两组的临床改善指标（ADAS-Cog和MMSE）基本一致,且其效果能持续至rTMS干预后4周。 Alcalá等人认为通过rTMS可调节病理大脑活动模式和诱导改善活动模式,直接调节皮层区域或网络,从而提高大脑处理效率。rTMS模式之间的差异可能是由于两者的DLPFC受到刺激所致。DLPFC可能作为认知和行为的网络整合的重要枢纽,而这在AD患者中是中断的。因此,在该区域使用rTMS可能会提高网络的活性和整合性,这可能与临床症状改善直接相关。
Lee等人通过随机、双盲方式对26例疑似的AD患者（18例治疗组,8例假治疗组）进行持续6周[30]、每周接受5次rTMS联合主动认知刺激训练(rTMS combined with cognitive training, rTMS-COG)。rTMS刺激频率为10Hz, 90~110%强度,每次刺激均使用图像导航系统在三个不同的大脑皮层区域进行。因此,每隔一天,Broca's 区、Wernicke's区和右侧DLPFC（第1天、第3天和第5天）或左侧DLPFC和两个顶叶躯体感觉联合皮质（第2天和第4天）都会受到刺激。在rTMS结合认知训练(rTMS combined with cognitive training, rTMS-COG)治疗前、治疗后及治疗结束后6周,采用AD评估量表-认知分量量表(ADAS-cog)、临床总体变化印象量表(Clinical Global Impression of Change, CGIC)和简易智力状态检查量表(Mini-mental State Examination, MMSE)进行神经心理评估。研究发现治疗组ADAS-cog评分明显改善,MMSE、CGIC评分均有一定程度的改善。亚组分析表明,rTMS-COG在轻度组的效果优于全部患者,尤其是在记忆和语言方面。该研究认为rTMS有可能通过靶向作用于对执行或学习技能至关重要的皮质区域来加速学习技能,特别是当经rTMS与专门的技能训练或练习结合治疗时,增加了皮质的可塑性,改善AD患者的临床症状。在2014年的另一项RCT中[31],研究者同样运用rTMS-COG治疗AD患者,定期间歇刺激上述6个部位,5天/周,连续6周,在维持阶段,参与者接受为期3个月的双周治疗。治疗后4.5月随访发现ADAS-Cog评分明显升高,临床整体印象改变(CGIC)在治疗组有轻微改善,在假治疗组有轻微恶化。Zhao等人研究时也采用定期间歇刺激多部位[11],发现rTMS可以改善AD患者的认知功能如记忆和语言水平,尤其是在AD的轻度阶段。
Sabbagh等学者纳入了131例MMSE 18~26分[32],ADAS-Cog>17分的AD患者进行一项前瞻性、随机、双盲、假对照、多中心临床试验。将受试者随机分为积极治疗组和假治疗组。这项研究主要刺激6个与AD的认知功能密切相关不同的大脑区域和网络：Broca's 区、Wernicke's区和左右背外侧前额叶皮层、左右顶叶下小叶。每个参与者的头颅MRI被用于标记个人大脑区域,通过投射相关的大脑区域（由解剖标志确定）到头皮。利用系统集成的红外/光学神经导航单元,对TMS相对于靶点脑区域的精确位置进行连续监测。每日刺激三个目标区域,共计1300次rTMS脉冲,频率为10Hz,rTMS强度设置为受试者静息运动阈值的110%。通过对基线阿尔茨海默病评估量表-认知(ADAS-Cog)和临床整体印象变化进行评估。结果发现在7周时,积极治疗组和假治疗组的ADAS-Cog差异无统计学意义。然而,在第12周,假治疗组的ADAS- Cog恢复到基线水平,而积极治疗组的症状表现出持续的改善,研究证实对于ADAS-Cog<30分的AD患者,rTMS是相对来说低风险的治疗手段。

3 安全性

rTMS治疗的优点之一即为安全性高,治疗中出现的副作用少,仅有少部分出现头痛不适[29,33],WU等人报告rTMS干预组轻度锥体外系反应4例[15],短暂性头痛4例,但与假手术组比较差异无统计学意义。Lee等人报道一名假治疗组受试者因出现轻度头痛和疲劳退出试验[30],此外还有其他部分报道有类似表现[34]。Sabbagh等人研究中发生了4例严重不良反应[32]：1例死亡,1例尿潴留,1例肢体无力,1例颈椎骨折,但所有这些严重的不良反应都被主管医生和独立的医学审查委员会确定为与研究程序或设备无关。除此之外,该研究还发现常见的诸如头痛、头皮/皮肤不适、颈部疼痛/僵硬和疲劳等不适。此外,还有报道称rTMS可能引发癫痫发作和听力损害等副作用[35]。

4 展望

目前,关于rTMS对AD认知功能的疗效研究多集中在轻中度患者,在重度AD患者中,严重的脑萎缩和皮质兴奋性降低,其运动阈值降低,可能会改变rTMS对皮质的影响,从而降低其疗效,这可能提示治疗时相对于病情严重程度可能需要更高的rTMS运动阈值强度来提高疗效,这些问题有待于进一步研究。很多研究中观察到rTMS的神经调节干预的治疗效果可能需要一定的时间才能完全发展并转化为临床效益[13,14,32]。对此有必要进一步研究其疗效的时间过程和疗效的寿命,而这可以通过对患者进行长时间的随访来实现（如在干预疗程结束后随访长达12个月或更久）。在研究的其他方面还可以利用其他标准化的测量方法（例如,冷漠量表）或目标达成量表来获取一些临床益处,从而用更高的刺激和更具挑战性的认知训练来治疗患者。相信对受益于这种治疗的人群进行为期一年的或更进一步的研究,将有助于更好地了解rTMS的治疗效果,为医生提供更多循证依据。
rTMS作为治疗AD的一种干预手段,虽然目前还没有足够的证据支持广泛用于rTMS的AD临床治疗,但是通过未来更多的标准化的、明确靶点的、纵向随访的大型、特征良好的队列研究,相信rTMS将会成为一个治疗AD的重要手段,与智力训练和药物干预措施一起,改善AD患者认知功能,提高AD患者的生活质量,减轻AD患者的家庭及社会负担。

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