沉浸式翻译·综述·
·Overview·
Theta爆发式经颅磁刺激治疗卒中后失语的研究进展
Research progress on theta burst transcranial magnetic stimulation in the treatment of post-stroke aphasia
沈康敏1 康晓宇2 刘丽旭1
Shen Kangmin 1 Kang Xiaoyu 2 Liu Lixu1
基金项目：国家重点研发计划（2022YFC3602802）
Fund project: National Key Research and Development Program (2022YFC3602802)
作者单位：325000 温州，温州医科大学第二临床医学院1；100068 北京，中国康复研究中心神经康复一科2
Author unit: The Second Clinical School of Medicine, Wenzhou Medical University, Wenzhou 325000 1 ; Department of Neurological Rehabilitation, China Rehabilitation Research Center, Beijing 100068 2
通信作者：刘丽旭，Email：liulixu2004@163.com
Corresponding author: Liu Lixu, Email: liulixu2004@163.com
【摘要】 随着卒中发病率的不断上升，患病人群逐渐呈现年轻化趋势。卒中后语言功能障碍不仅会影响患者和他人的交流，而且导致患者理解力下降、发音困难、情绪低落等，从而无法理解康复指令，难以配合康复训练，影响预后。Theta爆发式经颅磁刺激(TBS)作为一种新兴的经颅磁刺激模式，有助于卒中后失语患者语言能力的恢复，但其治疗方案却各不相同。本文围绕TBS的作用原理、不同刺激模式（如间歇性TBS和持续性TBS）的基本特征、改善失语的机制、治疗失语的不同刺激方案及目前国内外关于TBS治疗失语的相关研究所存在的局限性等方面展开综述，为卒中后失语的康复治疗提供新的临床参考和思路。
【Abstract】As the incidence of stroke continues to increase, the affected population is gradually becoming younger. Post-stroke language dysfunction will not only affect the patient's communication with others, but also lead to reduced understanding, difficulty in pronunciation, and depression, making it difficult for the patient to understand rehabilitation instructions and cooperate with rehabilitation training, which affects the prognosis. Theta burst transcranial magnetic stimulation (TBS), as an emerging transcranial magnetic stimulation mode, can help restore language ability in patients with post-stroke aphasia, but its treatment options vary. This article focuses on the principle of action of TBS, the basic characteristics of different stimulation modes (such as intermittent TBS and continuous TBS), the mechanism for improving aphasia, different stimulation schemes for treating aphasia, and the limitations of current domestic and foreign research on TBS for the treatment of aphasia. A review will be conducted on sexual and other aspects to provide new clinical references and ideas for the rehabilitation treatment of post-stroke aphasia.
【关键词】 卒中； Theta爆发式经颅磁刺激； 康复； 失语
【Key words】 Stroke; Theta burst transcranial magnetic stimulation; Rehabilitation; Aphasia
Research progress on the use of Theta burst stimulation for the treatment of post-stroke aphasia Shen Kangmin1, Liu Lixu2, Kang Xiaoyu2. 1The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325000, China; 2China Rehabilitation Research Centre, Beijing 100068, China.
Corresponding author: Liu Lixu, Email: liulixu2004@163.com
Fund program: National Key Research and Development Program (2022YFC3602802)
【Abstract】 Currently, the incidence of stroke is steadily increasing, and the patient population is gradually becoming younger. The resulting language impairments not only affect communication between patients and others, but also hinder the patient’s understanding of recovery instructions due to decreased comprehension, speech difficulties, and emotional depression, making it challenging to cooperate with rehabilitation training. This, in turn, affects the overall prognosis of the patient. Theta burst stimulation (TBS), as an emerging transcranial magnetic stimulation modality, aids in the recovery of language abilities in post-stroke aphasia patients, but the treatment protocols vary widely. This article provides a comprehensive review of the principles of TBS, the basic characteristics of different stimulation modes (such as intermittent and continuous TBS), the mechanisms for improving aphasia, and different stimulation plans for treating aphasia. It also discusses the limitations of current domestic and international research on TBS treatment for aphasia, aiming to provide new clinical references and insights for the rehabilitation treatment of post-stroke aphasia.
【Key words】 Stroke; Theta burst stimulation; Rehabilitation; Aphasia
失语症（Aphasia）是言语获得后的障碍，是指患者意识清楚的情况下，由优势半球的语言中枢病变导致的语言表达或理解障碍，常表现为发音和构音正常但不能言语，肢体运动功能正常但不能书写，视力正常但不能阅读，听力正常但不能理解言语，即听、说、读、写、计算等方面的障碍[1]。目前卒中是引起失语的最常见原因，2020年我国40岁以上居民卒中患病率为2.6%，每年新发卒中340万人，其中38%的患者发生失语，且有12%的患者在发病６个月后仍然患失语[2-3]。长期的语言功能障碍将严重影响患者的交流和社会参与能力，因此如何帮助卒中患者恢复语言能力、缩短住院周期、改善生活质量，是亟待解决的问题。
Aphasia is a disorder after the acquisition of speech. It refers to language expression or understanding disorders caused by lesions of the language center in the dominant hemisphere when the patient is conscious. It often manifests as normal pronunciation and articulation but the inability to speak or move body parts. Normal functions but the inability to write, normal vision but the inability to read, normal hearing but the inability to understand speech, that is, impairments in listening, speaking, reading, writing, and calculation [1] . Stroke is currently the most common cause of aphasia. The prevalence of stroke among residents over 40 years old in my country in 2020 is 2.6%. There are 3.4 million new strokes every year, of which 38% suffer from aphasia, and 12% of patients suffer from aphasia within 6 years of onset. Still suffering from aphasia [2 - 3] months later. Long-term language dysfunction will seriously affect the patient's ability to communicate and participate in society. Therefore, how to help stroke patients recover their language ability, shorten their hospitalization period, and improve their quality of life is an urgent problem to be solved.
治疗卒中后失语尚无快速有效的方法，且当前治疗方案仍存在缺陷，例如药物治疗（如左旋多巴、多奈哌齐等）卒中后失语虽然有成功案例，但疗效通常较弱，此外不同类型的失语对药物治疗的敏感性不同，还有待进一步研究[4-5]。音乐疗法是一种实验性的方法，作为广泛治疗指导方法还需进一步研究证实[6]。国内外指南推荐言语－语言疗法（speech and language therapy，SLT）为卒中后失语治疗的金标准，治疗效果良好，但患者群体大、言语康复训练时间长，通常需要康复治疗师与患者进行一对一康复治疗，跟踪随访时间长，尤其是我国缺少受过专业培训的康复治疗工作者，因此无法满足广大失语患者群体的需求，而且SLT在卒中后失语的急性期和亚急性期（3周~12个月）的疗效证据仍然不足[7-9]。由此说明言语训练等行为学疗法治疗卒中后失语起效慢、效率低，对语言功能的提升作用有限，因此迫切需要语言康复训练辅助方法来提高临床康复疗效。近年来，非侵入性脑刺激（non-invasive brain stimulation，NIBS）技术作为新型的神经调控技术，具有无创、易耐受和不良反应小等特点，可以瞬时调节皮质兴奋性，诱导在刺激后产生更长远的疗效，被广泛应用于失语治疗，且疗效肯定。典型的NIBS方法包括经颅磁刺激（transcranial magnetic stimulation，TMS）和经颅直流电刺激（transcranial direct current stimulation，tDCS）等[10]。根据刺激释放的数目和频率，TMS分为单刺激、双刺激和重复刺激(repetitive transcranial magnetic stimulation，rTMS)[11]。Theta爆发式经颅磁刺激(theta burst stimulation，TBS)是一种新型的rTMS形式，可以促进失语的康复。本文围绕TBS在卒中后失语患者中应用的研究进展进行综述，以期为失语患者的康复治疗提供参考和思路。
There is no quick and effective method to treat post-stroke aphasia, and current treatment options still have shortcomings, such as drug treatments (such as levodopa, donepezil, etc.). Although there are successful cases of post-stroke aphasia, the efficacy is usually weak. In addition, different types of aphasia The sensitivity to drug treatment is different and needs further study [4 - 5] . Music therapy is an experimental method, and further research is needed to confirm it as a comprehensive treatment guidance [6] . Domestic and foreign guidelines recommend speech and language therapy (SLT) as the gold standard for post-stroke aphasia treatment. The treatment effect is good, but the patient group is large and the speech rehabilitation training time is long, which usually requires a rehabilitation therapist to conduct one-on-one sessions with the patient. Rehabilitation treatment requires a long follow-up time. In particular, my country lacks professionally trained rehabilitation workers, so it cannot meet the needs of the majority of aphasic patients. Moreover, SLT is not effective in the acute and subacute stages of post-stroke aphasia (3 weeks to 12 weeks). months) is still insufficient [7-9] . This shows that behavioral therapies such as speech training have slow onset and low efficiency in treating post-stroke aphasia, and have limited effect on improving language function. Therefore, there is an urgent need for language rehabilitation training auxiliary methods to improve clinical rehabilitation efficacy. In recent years, non-invasive brain stimulation (NIBS) technology, as a new neuromodulation technology, has the characteristics of being non-invasive, easy to tolerate, and having few adverse reactions. It can instantly regulate cortical excitability and induce the production of post-stimulation Long-term curative effect, it is widely used in aphasia treatment, and the curative effect is certain. Typical NIBS methods include transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) [10] . According to the number and frequency of stimulation release, TMS is divided into single stimulation, double stimulation and repetitive transcranial magnetic stimulation (rTMS) [11] . Theta burst transcranial magnetic stimulation (TBS) is a new form of rTMS that can promote aphasia recovery. This article reviews the research progress on the application of TBS in post-stroke aphasic patients, with a view to providing references and ideas for the rehabilitation treatment of aphasic patients.
一、TBS的作用原理
1. How TBS works
（一）TMS基本原理
(1) Basic principles of TMS
TMS由Barker[12]于1985年首次提出的电生理技术，可利用置于颅骨表面的通电线圈产生交变磁场作用于皮层神经细胞，产生感应电流，从而改变细胞膜电位，影响皮层兴奋性，具有无创、无痛、安全、易操作等特点[13]。近年来，TMS被广泛应用于神经康复领域多种功能障碍的康复治疗，在刺激结束后，仍可诱导神经生理学变化，从而持续改变大脑皮层兴奋性[14]。
TMS is an electrophysiological technology first proposed by Barker [12] in 1985. It can use an energized coil placed on the surface of the skull to generate an alternating magnetic field that acts on cortical nerve cells, generating an induced current, thereby changing the cell membrane potential and affecting the cortex. Excitatory, non-invasive, painless, safe and easy to operate [13] . In recent years, TMS has been widely used in the rehabilitation treatment of various dysfunctions in the field of neurological rehabilitation. After the stimulation is completed, it can still induce neurophysiological changes, thereby continuously changing the excitability of the cerebral cortex [14] .
（二）TBS治疗方案
(2) TBS treatment plan
rTMS作为新兴的脑刺激技术，对大脑皮层有暂时性的抑制或兴奋作用，使其产生长时程的可塑性改变，治疗方式安全[15]。TBS是在rTMS的基础上加入了丛状节律式刺激，这一概念最初源于清醒的大鼠发生探索行为时从海马记录到的4~7 Hz爆发性放电，TBS模拟了这种独特的电生理活动，2005年首次应用于人体受试者的运动皮质[16]。TBS的治疗机制包括：（1）通过调节突触上各受体的活性，影响Ca2+内流，从而产生长时程增强（long-term potentiation，LTP）和长时程抑制（long-term depression，LTD)；（2）影响基因和蛋白的调节来产生治疗作用，有研究发现经TBS刺激后，c-fos、zif268等基因表达明显增加，而钙结合蛋白、小清蛋白等表达明显降低，这些基因和蛋白水平的变化都与脑损伤后大脑功能恢复有关[17]。TBS基本特征是每200 ms内发生3次爆发式脉冲，丛内频率通常为50 Hz。TBS根据递送的不同模式（连续与间歇）对刺激的运动皮层的突触效率产生相反的影响[18-19]。间歇性TBS（intermittent TBS，iTBS）产生持续的LTP样效应，提高皮质兴奋性，每刺激2 s，间歇8 s，重复20次，共计600个脉冲，刺激强度为80%运动阈值(active motor threshod，AMT)，持续刺激时间为191.84 s[20]；持续性TBS(continuous TBS，cTBS)产生持续的LTD样效应，降低皮质兴奋性，cTBS同样也是600个脉冲，但连续刺激40 s[16]。与临床上常用的rTMS相比，TBS具有刺激时间短､刺激强度小､后作用时间长､更接近神经活动生理状态等优势，近年来受到广泛关注[18]。Maizey（？？）等[13]比较了不同TMS刺激模式（单脉冲、双脉冲、rTMs、TBS）不良反应发生率的差异，结果显示TBS的不良反应发生率较其他刺激模式更低，原因可能与TBS的刺激强度较低有关。
As an emerging brain stimulation technology, rTMS has a temporary inhibitory or excitatory effect on the cerebral cortex, causing long-term plastic changes. The treatment method is safe [15] . TBS adds plexiform rhythmic stimulation on the basis of rTMS. This concept originally originated from the 4~7 Hz burst discharges recorded from the hippocampus of awake rats during exploratory behavior. TBS simulates this unique electrical discharge. Physiological activity, first applied to the motor cortex of human subjects in 2005 [16] . The therapeutic mechanisms of TBS include: (1) By regulating the activity of receptors on the synapse, affecting Ca 2+ influx, thereby producing long-term potentiation (LTP) and long-term Inhibition (long-term depression, LTD); (2) Affecting the regulation of genes and proteins to produce therapeutic effects. Studies have found that after TBS stimulation, the expression of genes such as c-fos and zif268 increased significantly, while calbindin, The expression of proteins and other proteins was significantly reduced. These changes in gene and protein levels are related to the recovery of brain function after brain injury [17] . The basic characteristic of TBS is that three burst pulses occur every 200 ms, and the frequency within the cluster is usually 50 Hz. TBS exerts opposite effects on the synaptic efficiency of the stimulated motor cortex depending on the different modes of delivery (continuous vs. intermittent) [18 - 19] . Intermittent TBS (intermittent TBS, iTBS) produces a sustained LTP-like effect and increases cortical excitability. Each stimulation is 2 s, with an interval of 8 s. It is repeated 20 times, with a total of 600 pulses. The stimulation intensity is 80% of the motor threshold (active motor threshold). , AMT), the continuous stimulation time is 191.84 s [20] ; continuous TBS (continuous TBS, cTBS) produces a sustained LTD-like effect and reduces cortical excitability. cTBS also has 600 pulses, but the continuous stimulation is 40 s [16] . Compared with rTMS commonly used in clinical practice, TBS has the advantages of short stimulation time, low stimulation intensity, long post-action time, and is closer to the physiological state of neural activity. It has received widespread attention in recent years [18] . Maizey (??) et al. [13] compared the differences in the incidence of adverse reactions between different TMS stimulation modes (single pulse, double pulse, rTMs, TBS). The results showed that the incidence of adverse reactions in TBS was higher than that of other stimulation modes. Low, the reason may be related to the low stimulation intensity of TBS.
二、TBS治疗卒中后失语的研究进展
2. Research progress of TBS in treating post-stroke aphasia
经统计，超过95%的右利手者和60%~70%的左利手者的优势语言区在左侧大脑半球，因此大多数患者的语言中枢位于左侧大脑半球[21]。生理情况下语言功能的运行机制和功能分区是双侧大脑半球相互影响、相互调节的结果；卒中后大脑优势半球语言控制中枢受累，导致两半球失衡，通过胼胝体的作用，健侧的功能反而增强，抑制患侧相关的区域激活[22-24]。因此大部分TMS都是通过修复双侧半球的兴奋性平衡机制、重组被破坏的语言网络达到治疗效果[25]；TBS治疗也是如此，即将iTBS应用于患侧半球提高皮质兴奋性，或将cTBS应用于健侧半球来抑制皮质兴奋性，间接提高患侧皮质兴奋性[26]。但Heikkinen等[27]用TMS（1 Hz rTMS，右侧Broca）抑制了健侧，并未改善言语功能，所以目前左右侧大脑半球对语言恢复过程的影响仍是争论的热点[28]。
According to statistics, more than 95% of right-handers and 60% to 70% of left-handers have their dominant language area in the left cerebral hemisphere, so the language center of most patients is located in the left cerebral hemisphere [21] . The operating mechanism and functional division of language function under physiological conditions are the result of the mutual influence and mutual regulation of the two cerebral hemispheres. After stroke, the language control center of the dominant hemisphere of the brain is affected, resulting in an imbalance between the two hemispheres. Through the action of the corpus callosum, the function of the unaffected side is enhanced. , inhibiting the activation of regions related to the affected side [22-24] . Therefore, most TMS achieves therapeutic effects by repairing the excitability balance mechanism of both hemispheres and reorganizing the damaged language network [25] ; the same is true for TBS treatment, that is, iTBS is applied to the affected hemisphere to improve cortical excitability. , or cTBS is applied to the unaffected hemisphere to inhibit cortical excitability and indirectly improve the cortical excitability of the affected side [26] . However, Heikkinen et al. [27] used TMS (1 Hz rTMS, right Broca) to suppress the healthy side, but did not improve speech function. Therefore, the impact of the left and right cerebral hemispheres on the language recovery process is still a hot topic of debate< b5>.
（一）cTBS
rTMS可促进卒中后失语患者的语言康复，不良反应少，安全性高，在卒中失语临床专家共识中为强推荐[29]。cTBS与低频rTMS相似，可能对所刺激皮层兴奋性产生抑制作用，且cTBS的干预时间仅为40 s，可对皮层兴奋性产生长达60 min的抑制作用，相对于20 min的低频rTMS而言更加简便易行且后作用时间更长（？？），目前有关cTBS干预脑卒中失语患者的研究尚较少。有研究通过个体化功能区剖分技术（personalized brain functional sectors，pBFS)对患者的大脑进行了个体化功能剖分，并以此为基础将45例患者分为左脑兴奋性刺激组（iTBS组)、右脑抑制性刺激组(cTBS组)及假刺激组，治疗3周，iTBS组和cTBS组患者的语言能力评分显著提升，且大多患者在治疗1周后就出现了显著改善，而且研究证实了言语功能恢复的机制即“半球间抑制理论”[30]。但cTBS对失语患者语言功能的恢复作用目前还存在争议。胡瑞萍等[22]对21例病程1~12个月的卒中后失语患者进行cTBS干预，并借助功能磁共振进行右侧额下回三角部的体表定位，随机分为cTBS组和对照组，对照组仅接受语言训练，cTBS组在对照组基础上进行cTBS干预，结果表明cTBS组和对照组患者在治疗后失语商均有所提高，提示cTBS结合语言训练和单独的语言训练均能改善脑卒中失语患者的语言障碍，表明应用个体化精准靶点的刺激方法可明显提升治疗效果；但2组比较差异无统计学意义，考虑原因可能是研究样本量偏少或cTBS治疗可能不足以带来比语言训练更强的临床疗效，而且纳入患者的病程跨度相对较大，cTBS的治疗效果也不同。Kindler等[31]研究发现cTBS组的命名性能优于假刺激组，命名潜伏期明显更短，反应最好的患者处于卒中后的亚急性期，表明cTBS对亚急性期失语患者治疗效果最佳，进一步证实了上述结论。Georgiou等[32]研究对不同发病时期的脑卒中后失语患者进行功能影像学扫描发现，非优势侧半球在失语恢复中的作用随脑卒中发病时间的不同而不同，这可能是cTBS治疗效果不同的原因之一。由于卒中后失语存在自发恢复的可能，亚急性期和急性期患者可因处在自发恢复期，加强了TMS的疗效，使语言功能得到更加明显的改善，因此，治疗介入的时机也是需要考虑的因素之一，同时由于半球优势的动态变化，治疗模式也需要随之调整[33]。
rTMS can promote language recovery in patients with post-stroke aphasia, has few adverse reactions, and is highly safe. It is strongly recommended in the consensus of clinical experts on stroke aphasia [29] . cTBS is similar to low-frequency rTMS and may have an inhibitory effect on the stimulated cortical excitability. The intervention time of cTBS is only 40 s and can inhibit cortical excitability for up to 60 min. Compared with 20 min of low-frequency rTMS, It is simpler and easier to perform and has a longer after-action time (??). There are currently few studies on cTBS intervention in patients with stroke aphasia. A study conducted personalized functional segmentation of patients' brains through personalized brain functional sectors (pBFS), and based on this, 45 patients were divided into left brain excitatory stimulation group (iTBS group). ), right brain inhibitory stimulation group (cTBS group) and sham stimulation group, after 3 weeks of treatment, the language ability scores of patients in the iTBS group and cTBS group significantly improved, and most patients showed significant improvement after 1 week of treatment, and research The mechanism of speech function recovery, namely the "interhemispheric inhibition theory", was confirmed [30] . However, the role of cTBS in restoring language function in aphasic patients is still controversial. Hu Ruiping et al. [22] performed cTBS intervention on 21 post-stroke aphasic patients with a duration of 1 to 12 months, and used functional magnetic resonance to perform body surface positioning of the triangular part of the right inferior frontal gyrus, and randomly divided them into the cTBS group. And the control group, the control group only received language training, and the cTBS group received cTBS intervention on the basis of the control group. The results showed that the aphasia quotient of patients in the cTBS group and the control group improved after treatment, suggesting that cTBS combines language training with separate language training. Both can improve the language impairment of patients with stroke aphasia, indicating that the application of personalized precise target stimulation methods can significantly improve the treatment effect; however, there is no statistically significant difference between the two groups. The reason may be the small sample size of the study or the possibility of cTBS treatment. It is not enough to bring a stronger clinical effect than language training, and the disease course span of the included patients is relatively large, and the therapeutic effects of cTBS are also different. Kindler et al. [31] found that the naming performance of the cTBS group was better than that of the sham stimulation group, and the naming latency was significantly shorter. The patients with the best response were in the subacute phase after stroke, indicating that cTBS is effective in treating patients with aphasia in the subacute phase. The best effect further confirmed the above conclusion. Georgiou et al. [32] studied functional imaging scans of post-stroke aphasia patients at different onset stages and found that the role of the non-dominant hemisphere in aphasia recovery differs with the onset time of stroke. This may be due to One of the reasons for the different therapeutic effects of cTBS. Since there is a possibility of spontaneous recovery of aphasia after stroke, patients in the subacute and acute phases may be in the spontaneous recovery phase, which strengthens the efficacy of TMS and improves language function more significantly. Therefore, the timing of therapeutic intervention also needs to be considered. One of the factors, and due to the dynamic changes in hemispheric dominance, the treatment model also needs to be adjusted [33] accordingly.
NIBS的刺激部位选择至关重要，经典的“语言区”是治疗卒中后失语最常见的刺激部位，如Broca区或其右同源区（即右额下回）。近年来有研究发现小脑的cTBS对言语/语言产生也有调节作用，如Zheng等[34]研究证明了右小脑可能是治疗慢性卒中后失语的潜在最佳刺激靶点，并辅以功能磁共振成像技术表明右小脑的cTBS可能是通过改变大脑-小脑功能网络的连接来达到治疗效果。众所周知，脑卒中后病变的位置和大小使在皮层水平上确定最佳刺激脑区更加复杂，而小脑可作为单一的刺激靶点且安全可靠、不良反应小，这为失语患者的语言功能恢复提供了新的思路[35]。
The choice of stimulation site for NIBS is crucial. The classic "language area" is the most common stimulation site for the treatment of post-stroke aphasia, such as Broca's area or its right homologous area (i.e., right inferior frontal gyrus). In recent years, some studies have found that cTBS of the cerebellum also has a regulatory effect on speech/language production. For example, Zheng et al. [34] have proven that the right cerebellum may be the potential best stimulation target for the treatment of chronic post-stroke aphasia, supplemented by Functional magnetic resonance imaging technology shows that cTBS of the right cerebellum may achieve therapeutic effects by changing the connection of the brain-cerebellar functional network. It is well known that the location and size of post-stroke lesions make it more complex to determine the optimal brain area for stimulation at the cortical level. However, the cerebellum can be used as a single stimulation target with safety, reliability, and minimal adverse effects, which provides opportunities for the recovery of language function in aphasic patients. Got new ideas [35] .
（二）iTBS
有研究显示，在语言任务执行过程中右半球语言功能镜像区兴奋性增强可能是一种代偿反应，是神经活动效率低下、功能重组无效的表现，可导致失语状加重，从而阻碍了语言的恢复[36]；而功能神经影像学研究则表明，在左半球语言区损伤后，残留语言区的细胞再激活可能更有助于失语患者语言功能恢复[37]。iTBS短时间内可诱导稳定的长时程兴奋，提高左侧皮质的兴奋性，增强大脑可塑性。大量研究已经证实低频rTMS在治疗卒中后失语方面显示出了巨大前景，iTBS和高频rTMS都具有皮层兴奋作用，但其疗效尚待确定。Chou等[38]对卒中后非流畅性失语的研究显示，iTBS（额下回）组在简明汉语失语测试总分、匹配和听力理解方面显著优于低频rTMS（1 Hz ，右侧Broca）组，说明iTBS可以增强慢性卒中后非流畅性失语患者的语言恢复。与低频rTMS相比，iTBS更优先改善听觉理解。蒋孝翠等[39]采用iTBS治疗22例病程2周至6个月的失语患者，研究证实刺激左额下回可以改善脑卒中后非流畅性失语患者的言语功能，包括听理解、复述、命名、朗读等方面，并推测言语功能改善机制可能与脑源性神经营养因子含量升高有关。该研究再次证明iTBS对患者左半球额下回后部语言残存区兴奋性刺激可促进卒中后失语患者语言恢复，但由于纳入患者的病程较短，不能排除自发恢复的可能。而Szaflarski等[40]采用iTBS治疗12例发病1年以上的失语患者，治疗靶点为左额下回残存语言区，治疗1次/d，连续10 d，2周后波士顿命名测试成绩显著提高，研究纳入患者病程均为1年以上，可排除自发恢复的可能。
Studies have shown that the increased excitability of the language function mirror area of the right hemisphere during the execution of language tasks may be a compensatory response, a manifestation of inefficient neural activity and ineffective functional reorganization, which can lead to aggravation of aphasia, thus hindering language development. Recovery [36] ; and functional neuroimaging studies show that after damage to the language area of the left hemisphere, reactivation of cells in the residual language area may be more conducive to the recovery of language function in aphasic patients [37] . iTBS can induce stable long-term excitation in a short period of time, increase the excitability of the left cortex, and enhance brain plasticity. A large number of studies have confirmed that low-frequency rTMS shows great promise in treating post-stroke aphasia. Both iTBS and high-frequency rTMS have cortical excitatory effects, but their efficacy has yet to be determined. Chou et al [38] 's study on post-stroke non-fluent aphasia showed that the iTBS (inferior frontal gyrus) group was significantly better than low-frequency rTMS (1 Hz, right) in terms of total score, matching and listening comprehension of the Brief Chinese Aphasia Test Broca) group, indicating that iTBS can enhance language recovery in patients with chronic post-stroke non-fluent aphasia. Compared with low-frequency rTMS, iTBS prioritizes improving auditory understanding. Jiang Xiaocui et al. [39] used iTBS to treat 22 patients with aphasia whose illness lasted from 2 weeks to 6 months. The study confirmed that stimulating the left inferior frontal gyrus can improve the speech functions of patients with post-stroke non-fluent aphasia, including listening comprehension and repetition. , naming, reading, etc., and it is speculated that the mechanism of improvement of speech function may be related to the increased content of brain-derived neurotrophic factor. This study once again proves that iTBS's excitatory stimulation of the language residual area in the posterior inferior frontal gyrus of the left hemisphere can promote language recovery in patients with post-stroke aphasia. However, due to the short duration of the disease in the included patients, the possibility of spontaneous recovery cannot be ruled out. Szaflarski et al. [40] used iTBS to treat 12 aphasic patients with onset for more than 1 year. The treatment target was the residual language area of the left inferior frontal gyrus. The treatment was once/d for 10 consecutive days. Boston naming was performed after 2 weeks. The test scores improved significantly, and the disease duration of the patients included in the study was more than 1 year, which can rule out the possibility of spontaneous recovery.
上述研究均刺激经典脑区“额下回”，但近年来也有研究认为刺激该脑区容易产生疼痛感等不良反应，患者的耐受度低；近年来新靶点刺激成为了研究的热点，Ren等[30]研究表明，额上回不仅包含了语言功能区，并位于颅顶附近，操作便利且患者耐受度高，这为失语的治疗提供了一种新思路。Yang等[41]对16例卒中后失语患者进行左侧M1区iTBS刺激，结果表明左侧M1区iTBS刺激可引起卒中后失语患者语义系统中功能连接的变化。Ding等[42]采用iTBS刺激15例卒中后上肢运动功能障碍患者的初级运动皮层，并借助静息状态脑电图来评估大脑功能网络的活动，结果显示iTBS可使大脑半球间功能连接和整体效率增加，表明iTBS有可能使脑卒中后的脑网络功能正常化，可用于脑卒中康复。该研究为iTBS改善卒中后失语提供了进一步的证据支持，但由于仅测量了iTBS后6 min的静息状态脑电图，缺少随访结果，后期需要进一步研究来监测iTBS后多个时间点的脑电图变化。上述研究表明兴奋左侧初级运动区（即M1）也可以改善卒中后患者的语言能力。综上，iTBS可以有效改善卒中后失语患者的语言功能，且具有高效率，这可能会使其成为未来失语治疗的主流方向，与此同时探索新的刺激靶点也将为临床治疗提供更多的选择。
The above-mentioned studies all stimulated the classic brain area "inferior frontal gyrus", but in recent years, some studies have suggested that stimulating this brain area is prone to produce pain and other adverse reactions, and patients have low tolerance. In recent years, new target stimulation has become a hot spot in research. Ren et al.'s [30] study showed that the superior frontal gyrus not only contains the language functional area, but is also located near the skull top. It is easy to operate and has high patient tolerance. This provides a new idea for the treatment of aphasia. Yang et al. [41] performed iTBS stimulation of the left M1 area on 16 patients with post-stroke aphasia. The results showed that iTBS stimulation of the left M1 area can cause changes in functional connections in the semantic system of patients with post-stroke aphasia. Ding et al. [42] used iTBS to stimulate the primary motor cortex of 15 patients with post-stroke upper limb motor dysfunction, and used resting-state electroencephalography to evaluate the activity of brain functional networks. The results showed that iTBS can stimulate interhemispheric changes in brain function. The increase in functional connectivity and overall efficiency indicates that iTBS has the potential to normalize brain network function after stroke and can be used for stroke rehabilitation. This study provides further evidence support that iTBS improves post-stroke aphasia. However, because it only measured the resting state EEG 6 minutes after iTBS, there is a lack of follow-up results. Further research is needed to monitor the brain at multiple time points after iTBS. Electrical diagram changes. The above-mentioned studies show that stimulating the left primary motor area (i.e., M1) can also improve speech ability in post-stroke patients. In summary, iTBS can effectively improve the language function of post-stroke aphasic patients with high efficiency, which may make it the mainstream direction of aphasia treatment in the future. At the same time, exploring new stimulation targets will also provide more opportunities for clinical treatment. s Choice.
（三）双侧大脑联合治疗
(3) Bilateral brain combined treatment
随着近年来对语言中枢传导通路及无创神经调控技术研究的深入，单用iTBS或cTBS治疗卒中后失语取得了可靠疗效，然而不同频率的双侧刺激对卒中后失语症的恢复疗效如何值得探讨。研究发现两侧半球联合应用不同模式TBS也可有效改善非流畅性失语患者的语义流畅度；Vuksanović等[43]将TBS应用于1例发病17个月的基底节区受损的非流畅性失语患者的双侧大脑，即iTBS刺激左侧语言区联合cTBS刺激右侧语言镜像区，连续刺激5 d后发现患者介词短语、词汇记忆等语言功能显著提高，语言的流畅性也显著提高，2周后随访表明患者的语言功能有明显改善。但目前关于iTBS联合cTBS治疗卒中后失语的相关文献报道较少，上述研究为单病例个案研究，其实验的准确性及是否有临床应用价值仍需要进一步扩大样本量、多中心、随机对照及更长随访时间的研究来探讨。此外，该研究中采用TBS联合刺激双侧大脑，尚无法确定在改善语言功能中何种刺激方式占据主导地位，也无法肯定双侧刺激方式是否优于单刺激模式[13]。但一项关于tDCS联合cTBS刺激双侧大脑语言通路的研究发现其能显著改善脑卒中后非流畅性失语患者的语言功能[44]。与此同时，Ren等[30]首次确认了cTBS对右脑语言区的抑制性刺激疗效与对左脑语言区兴奋性iTBS刺激相似，也进一步证实双侧大脑同时治疗的可行性，这为将来进一步探索左右脑联合治疗打下了基础。总之，双侧刺激的效果仍需要更多研究进行论证，且应注意与单侧刺激对比，同时需考虑刺激顺序是否会对研究结果产生不同的效果。
With the in-depth research on language central conduction pathways and non-invasive neuromodulation technology in recent years, iTBS or cTBS alone has achieved reliable efficacy in the treatment of post-stroke aphasia. However, the efficacy of bilateral stimulation with different frequencies in the recovery of post-stroke aphasia deserves discussion. . Research has found that the combined application of different modes of TBS on both hemispheres can also effectively improve the semantic fluency of patients with non-fluent aphasia; Vuksanović et al [43] applied TBS to a patient with damage to the basal ganglia 17 months after onset. In the bilateral brain of patients with non-fluent aphasia, iTBS stimulated the left language area combined with cTBS to stimulate the right language mirror area. After 5 days of continuous stimulation, it was found that the patient's language functions such as prepositional phrases and vocabulary memory were significantly improved, and the language fluency was also significantly improved. Improvement, follow-up after 2 weeks showed that the patient's language function had been significantly improved. However, there are currently few relevant literature reports on iTBS combined with cTBS for the treatment of post-stroke aphasia. The above-mentioned studies are single-case studies. The accuracy of the experiments and whether they have clinical application value still need to further expand the sample size, multi-center, randomized control and more. study with long follow-up time. In addition, TBS was used to jointly stimulate both sides of the brain in this study. It is not yet certain which stimulation method is dominant in improving language function, nor is it certain whether bilateral stimulation is better than single stimulation [13] . However, a study on tDCS combined with cTBS to stimulate bilateral brain language pathways found that it can significantly improve the language function of patients with post-stroke non-fluent aphasia [44] . At the same time, Ren et al. [30] confirmed for the first time that the inhibitory stimulation effect of cTBS on the right brain language area is similar to the excitatory iTBS stimulation on the left brain language area, and further confirmed the feasibility of simultaneous treatment of both sides of the brain. , which lays the foundation for further exploration of combined treatment of left and right brains in the future. In short, the effect of bilateral stimulation still needs more research to demonstrate, and attention should be paid to comparison with unilateral stimulation. At the same time, it is necessary to consider whether the order of stimulation will have different effects on the research results.
（四）TBS
(4) TBS
TBS具有刺激时间短、脉冲数少及治疗强度低等优势，可用于卒中后失语的治疗，疗效确切。但大量研究表明卒中发病时长、失语类型以及是否为单一治疗，甚至年龄、性别和基因均会影响TBS的临床效果，而且大部分研究未将失语患者进行分类甚至进一步亚分类，且无论是iTBS刺激优势半球还是cTBS刺激右侧同源区或者是刺激“非经典”脑区，都缺乏大样本、多中心的随机对照研究和长期随访证实。关于刺激部位的精准定位，目前已有TBS附带导航定位系统辅助，但因成本高昂且定位方法操作难度高，限制了其在临床应用中推广。此外，由于语言网络的位置、大小和形状均展现出较大的个体差异，大部分研究忽视了个体化精准识别才是提升效果的关键点[30]。
TBS has the advantages of short stimulation time, low number of pulses, and low treatment intensity. It can be used to treat post-stroke aphasia with definite efficacy. However, a large number of studies have shown that the duration of stroke, the type of aphasia, whether it is a single treatment, and even age, gender and genes will affect the clinical effects of TBS, and most studies do not classify or even further subclassify aphasia patients, and whether it is iTBS stimulation Whether it is the dominant hemisphere or cTBS to stimulate the right homologous area or the "non-classical" brain area, there is a lack of large-sample, multi-center randomized controlled studies and long-term follow-up confirmation. Regarding the precise positioning of the stimulation site, TBS currently has navigation and positioning system assistance, but its high cost and difficulty in positioning method have limited its promotion in clinical applications. In addition, since the location, size, and shape of language networks show large individual differences, most studies ignore individualized and accurate recognition as the key to improving results [30] .
三、小结与展望
3. Summary and Outlook
近年来，以TMS为代表的非侵入性脑刺激，通过外加磁场对大脑特定脑功能区进行精准调控，可实现对特定神经回路的精准靶向治疗，是脑疾病治疗的前沿方向，也展现出了治疗卒中后失语的巨大潜力。TBS作为一种新型的TMS，目前国内外对于其用于失语的康复研究较少，但在改善语言功能方面显示出了巨大前景；无论是对右侧半球语言镜像区进行抑制性磁刺激以及左侧半球进行兴奋性磁刺激，均能改善卒中失语患者的语言功能。如何控制影响语言恢复复杂多变的因素（失语的类型、病程、病情的严重程度、病灶大小）以制定出最佳的治疗方案，以及卒中后失语患者两侧大脑半球之间的相互影响与关联的具体机制，仍需进一步探索[28]。近年来，功能影像学技术联合TMS为探索TBS治疗卒中后失语提供了更加强而有力的客观检测手段，有望成为未来的发展方向。
In recent years, non-invasive brain stimulation, represented by TMS, uses external magnetic fields to precisely regulate specific functional areas of the brain, enabling precise targeted treatment of specific neural circuits. It is the forefront of the treatment of brain diseases and has also demonstrated It has great potential to treat post-stroke aphasia. As a new type of TMS, there are currently few studies on its use in aphasia rehabilitation at home and abroad, but it shows great promise in improving language function; whether it is inhibitory magnetic stimulation of the language mirror area of the right hemisphere and left Excitatory magnetic stimulation of the lateral hemisphere can improve the language function of patients with stroke aphasia. How to control the complex and changeable factors that affect language recovery (type of aphasia, course of disease, severity of disease, size of lesions) to formulate the best treatment plan, and the mutual influence and correlation between the two cerebral hemispheres of patients with post-stroke aphasia The specific mechanism still needs further exploration [28] . In recent years, functional imaging technology combined with TMS has provided a more powerful and powerful objective detection method for exploring TBS treatment of post-stroke aphasia, and is expected to become the future development direction.
参 考 文 献
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