北京漪林顺康科技发展有限公司

经颅直流电刺激（transcranial direct current stimulation，tDCS)是一种非侵入性的，利用恒定、低强度直流电调节大脑皮层神经元活动的神经调控技术。1998年Prior等发现，微弱的经颅直流电刺激可以引起皮层双相的、极性依赖性的改变，随后Nitsche的研究证实了这一发现，从而为tDCS的临床研究拉开了序幕。目前该技术已经成为认知神经科学、神经康复医学、精神病学的研究热点。本文主要介绍经颅直流电刺激（tDCS）的历史，电生理基础、作用机制、药理学相关研究、刺激相关参数等基础信息。

一．经颅直流电刺激（tDCS）历史简介

自古以来就有很多关于不受控电刺激对大脑进行调控的报告。Scribonius Largus(罗马皇帝克劳迪亚斯的医生)曾经描述了如何利用电鳐向颅骨释放电流来缓解头痛。古希腊名医加伦、老普林尼也都描述过类似的发现。2在11世纪,穆斯林名医Ibn-Sidah曾经建议使用活的电鲶治疗来治疗癫痫（epilepsy）。

随着18世纪电池的发明，对经颅直流电刺激进行系统评估成为可能。Walsh (1773), Galvani (1791, 1797), 以及Volta (1792) 都认识到不同时长的电刺激可以诱发不同的生理改变。事实上，第一个关于电流刺激临床应用的系统性报告也可以回溯到这一时期，意大利生理学家Giovanni Aldini（Luigi Galvani的侄子）等人采用经颅电刺激治疗抑郁症。在过去的两个世纪里，许多其他研究者 (see Zago et al.3 for further references)一直不断尝试利用电流治疗各种精神疾病，也产生了各种各样的结果。但是在最近的历史中，由于电休克（electroconvulsive therapy，ECT）及精神药物的使用以及可信神经生理学标志物的缺乏共同造成利用直流电对中枢神经系统（CNS）进行刺激不再被作为精神病学重要治疗和研究手段。而与此同时，电流刺激主要被用于治疗肌肉骨骼失调及外周疼痛。

事实上，经颅直流电刺激（tDCS）作为一种非侵入性脑刺激手段被重新认可和接受发生在本世纪初。Priori等人的开创性研究及Nitsche和Paulus等的后续研究证明了微弱直流电可以有效地透过颅骨进行传导并在皮层上诱发出双相的、极性相关的改变。具体而言，阳极的直流电刺激可以增加皮质兴奋性，而阴极的直流电刺激可以降低皮层兴奋性。此外,动物和人类研究也为经颅直流电刺激（tDCS）影响神经可塑性的机制及电流分布与刺激区域相关提供了证据。另外，还有研究正式tDCS可以引起神经心理学(neuropsychologic)、生理心理学(psychophysiologic)及刺激脑区相关的运动功能（motor activity)改变。此外,某些tDCS的技术特点（如无创、非侵入性、耐受较好、作用短暂、副作用轻微等）也点燃了临床应用研究的热情，相关研究大幅增加，特别是关于神经精神障碍如重度抑郁症、慢性和急性疼痛、中风康复治疗、药物成瘾等神经和精神疾病。尽管研究结果存在差异且都提出需要进一步的研究证实，但是绝大多数的研究结果都对tDCS寄予厚望。

随着tDCS逐渐走向临床应用，一系列新的问题也逐渐重要。如实验设计、方法学、伦理问题、安全性等。最新的问题是为什么要关注对tDCS的临床研究。三个主要的原因是： 

1. 理论上存在tDCS替代药物疗法的临床需求基础，如病人对药物耐受差或者病人存在严重的药物不良相互作用（如接受多种药物治疗的老人）。比如，患有单相抑郁的孕妇将可能从进一步的tDCS安全性研究中获益，因为目前对这类患者还没有可接受的药物。
2. 将tDCS作为一种辅助协同治疗手段，如tDCS和预防性治疗用于中风，tDCS和药物治疗用于慢性疼痛和重度抑郁。非侵入性和副作用轻微这两个特点使得tDCS成为一个辅助放大其它疗法作用的理想手段，而tDCS本身在改变膜静息电位阈值方面的神经生理效应也为此协同效应提供了生理基础。
3. tDCS性价比更高，因此对资源匮乏地区吸引力更大。如果证明有效，tDCS将可能成为发展中国家的一个引人注目的选择。 

二．经颅直流电刺激（tDCS）应用

本世纪以来经颅直流电刺激技术不断发展，并逐渐成为认知神经科学、神经康复医学、精神病学的研究热点，每年都有大量文章发表在包括《Nature》、《Science》、《NeuroImage》、《Neuroscience》、《Brain Stimulation》在内的相关领域顶级刊物上。主要应用领域涉及情绪调控、认知增强、脑功能调控、道德价值判断、决策研究等。

tDCS技术在神经康复领域中的应用也逐渐得到推广，研究发现，tDCS对于脑卒中后肢体运动障碍、认知障碍、失语症以及老年痴呆、帕金森病及脊髓神经网络兴奋性的改变都有不同的治疗作用，是神经康复领域一项非常有发展前景的无创性脑刺激技术。但到目前为止，尚未把tDCS作为一项常规的康复治疗技术使用。另有研究证实，tDCS联合康复治疗共同使用可以提高常规康复治疗的效果。近年来的研究也发现，tDCS对于纤维肌痛综合征、神经痛及下背痛等也有一定的治疗作用。

临床应用领域：

脑卒中后偏瘫、认知障碍、言语、吞咽障碍

老年痴呆症、帕金森病、脊髓损伤、疼痛（神经痛、偏头痛、纤维肌痛、下背痛）、癫痫、抑郁症

失眠、焦虑、孤独症、耳鸣

——

 三. 经颅直流电刺激电生理学基础 The electrophysiology of tDCS

1.  tDCS作用机制 Mechanisms of action

与其他非侵入性脑刺激技术如经颅电刺激和经颅磁刺激不同，经颅直流电刺激（tDCS）不是通过阈上刺激引起神经元放电，而是通过调节自发性神经元网络活性而发挥作用。在神经元水平， tDCS 对皮质兴奋性调节的基本机制是依据刺激的极性不同引起静息膜电位超极化或者去极化的改变。阳极刺激通常使皮层增强兴奋性提高，阴极刺激则降低皮层的兴奋性。动物研究表明兴奋性的变化反映在自发性放电率和对传入的突触输入的响应能力上。正是这种初级的极化机制成为了低强度直流电对人类大脑皮层兴奋性产生即刻作用的基础。

除了即刻作用外， tDCS 同样具有刺激后效应，如果刺激时间持续足够长，刺激结束后皮质兴奋性的改变可持续达 1 h 。因此，其作用机制不能单一的用神经元膜电位极化来解释。进一步的研究证实， tDCS 除了改变膜电位的极性外，还可以调节突触的微环境，如改变 NMDA 受体或GABA 的活性，从而起到调节突触可塑性的作用。tDCS也可以通过调节皮质内和皮质脊髓的神经元来调节大脑兴奋性。 tDCS 的后效应机制类似于突触的长时程易化，动物研究发现，以阳极刺激作用于运动皮层可观察到突触后兴奋性电位的持续增加。对周围神经和脊髓刺激的实验表明,tDCS刺激的效果也有非突触相关的，可能涉及到位于刺激电极下的蛋白质通道密度的瞬态变化。

鉴于恒定电场影响所有的极性分子，而大脑中大部分的神经递质和受体都具有电性质，tDCS也可能通过诱导长期的神经化学变化来影响神经功能。例如,核磁共振光谱显示阳极tDCS刺激后大脑肌醇显著增加，而N-乙酰天冬氨酸盐没有明显改变。

除了上述的"直接"tDCS效应，"非直接“效应也被观察到。这在相连的远隔皮层和皮层下区域都可观察到。有趣的是,tDCS不仅调节单一神经元活动、诱发神经活动，也诱发自发性神经振荡。Ardolino等发现在阴极电极下，EEG的theta和delat慢波增加。动物和计算机模拟研究提示，紧密耦合活动神经元网络(如振荡)可能比对独立的神经元施加刺激更敏感。

尽管大多数早期的tDCS研究集中在运动皮层，但是应该注意到，tDCS不仅引起运动诱发电位的长期的变化，也影响躯体感觉诱发电位和视觉诱发电位。这取决于于刺激的区域。Ferrucci等人和 Galea等人的研究提供证据表明tDCS可以影响人类小脑。Cogiamanian等人和Winkler等人的研究证明经皮的直流电刺激调节可沿着脊髓和节段性反射通路传导。

探讨tDCS作用机制时，在皮层所诱发出的电流的量级和位置是非常重要的因素，需要仔细考察。目前已经有一些关于这方面的建模研究。

最后，恒定电场还可以影响许多不同的组织(如血管、结缔组织)和病理生理机制(炎症、细胞迁移、血管运动性)，这些影响可以在众多细胞结构中观察到(细胞骨架、线粒体、膜)。按照这种说法,tDCS也可能影响l中枢神经系统的非神经元组织。支持这个理论的是在tDCS阳极刺激下可以观察到长时间的大脑血管舒张。

总之，tDCS的作用机制还有待完全阐明，这将对未来的临床应用产生重要影响。这些机制可能涉及不同对神经元细胞突触相关和非突触相关的影响，以及对中枢神经系统内的非神经元细胞和组织的影响。

2. tDCS药理学研究 Pharmacologic investigation of tDCS

在tDCS研究中，药理学研究通过使用不同药物阻止和/或增强神经递质及其受体的活性来观察tDCS是否能够诱发皮质兴奋性改变以及如何改变。因此,这样的研究旨在提高我们对tDCS在神经调节和神经可塑性活动方面作用机制的了解。

Evidence suggests that blocking voltage-gated sodium and calcium channels decreases the excitability enhancing effect of anodal tDCS. In contrast, cathodal tDCS-generated excitability reductions are not affected. These findings are in line with the assumption that tDCS induces shifts in membrane resting threshold of cortical neurons.

Regarding neurotransmitters, it has been shown that NMDA-glutamatergic receptors are involved in inhibitory and facilitatory plasticity induced by tDCS. Blocking NMDA receptors abolishes the after-effects of stimulation, whereas enhancement of NMDA receptor efficacy by d-cycloserine enhances selectively facilitatory plasticity. In contrast, GABAergic modulation with lorazepam results in a delayed then enhanced and prolonged anodal tDCS-induced excitability elevation.

Regarding the monoaminergic neurotransmitters, amphetamines (that increase monoaminergic activity) seem to enhance tDCS-induced facilitatory plasticity.For the dopaminergic system, tDCS-generated plasticity is modulated in a complex dosage- and subreceptor-dependent manner. Application of the dopamine precursor l-dopa converts facilitatory plasticity into inhibition, and prolongs inhibitory plasticity, whereas blocking D2 receptors seems to abolish tDCS-induced plasticity, D2 agonists, applied at high or low dosages, decrease plasticity. Furthermore, plasticity is restituted by medium dosage D2 agonists. Interestingly, the acetylcholine reuptake-inhibitor rivastigmine affects tDCS-induced plasticity in a similar fashion as l-dopa. For the serotoninergic system, the 5-HT reuptake-inhibitor citalopram enhances facilitatory plasticity and also converts inhibitory plasticity into facilitation.

From a clinical point of view, these results show that pharmacotherapy and tDCS interact, which might be an issue when studying clinical samples receiving both interventions. In fact, the complex nonlinear interaction makes it difficult to foresee the specific effects of pathophysiologic alterations or drug application on the amount and direction of tDCS-induced plasticity; thus demanding further empirical research on this topic.

四. 经颅直流电刺激（tDCS）相关参数

tDCS涉及参数可能相差很大，所以需要定义一些基本因素。这些参数主要包括电极尺寸和定位，电流强度，刺激持续时间，每天的刺激序列数量以及刺激序列间隔。通过改变这些参数，可以提供不同数量的电流刺激，从而产生不同的生理影响和副反应。

电极定位 Electrode positioning

尽管tDCS电场分布相对不集中属于非聚焦型，但是电极定位仍然至关重要。例如，先前的研究表明，将电极的参考位置从DLPFC移动到M1将会消除tDCS对工作记忆的影响。另有研究表明，仅在对枕叶（时间皮层）进行的tDCS刺激可以对对光幻视阈值产生调节作用。同样地，一项tDCS治疗重度抑郁症的试验显示，只有DLPFC刺激(而不是枕叶刺激)可以改善症状。尽管目前证据表明刺激效果是与位点相关，但是也有其它的问题有待探索，比如针对一个部位的刺激是如果影响毗邻脑区及更远区域的。

TDCS studies usually use one anode and one cathode electrode placed over the scalp to modulate a particular area of the CNS. Electrode positioning is usually determined according to the International EEG 10-20 System. Given the focality of tDCS, this appears appropriate. For instance, studies exploring the motor cortex place electrodes over C3 or C4; for the visual system, electrodes are typically placed over O1 or O2 (for a review of tDCS studies exploring different brain areas see Utz et al.).

In this study, some terms used to describe tDCS montages should be discussed: when one electrode is placed bellow the neck, the entire montage is usually described as “unipolar.” In contrast, montages with two electrodes on the head are termed usually “bipolar.” However, this nomenclature might be inaccurate as technically the DC stimulation is always generated via two poles (electrodes) generating an electric dipole between the electrodes. Therefore, an alternative nomenclature of “mono-cephalic” and “bi-cephalic” is proposed to differentiate between “unipolar” and “bipolar” setups, respectively. Researchers in the field also use the terms “reference” and “stimulating” electrode to refer to the “neutral” and “active” electrode, respectively. However, the term “reference” electrode may also be problematic, especially for bicephalic montages because the “reference” electrode is not physiologically inert and can contribute to activity modulation as well. This could be a potential confounder depending on the main study question. Nonetheless, researchers use these terms to highlight that (in their study) they are under the assumption that in their particular montage one electrode is being explored as the “stimulating,” whereas the other is the “reference.”

In contrast, having the possibility to increase and decrease activity in different brain areas simultaneously may be advantageous. For instance, this could be useful in conditions involving an imbalanced interhemispheric activity (ie, in stroke).64 In scenarios whether the reference electrode poses a confounding effect, an extracephalic reference electrode could theoretically aid in avoiding this issue. However, this might increase the risk of shunting the electric current through the skin (which would then not reach brain tissue) or displacing the current. Ultimately, the choice of montage will be application specific; for example, a recent study comparing different tDCS setups showed that, although bicephalic setups were effective, the monocephalic setup was no different than sham stimulation. Finally, in a monocephalic setup, using very high currents there is the potential risk of influencing brain stem activity, including respiratory control (note that this risk is theoretical and was only observed in one historical report). Nevertheless, in choosing the extracephalic position, the researcher must be confident that a significant electric field will be induced on the target brain area.

Moreover, because current flow direction/electrical field orientation relative to neuronal orientation might determine the effects of tDCS,7 it might be that the effects of an extracephalic electrode differs relevantly from that of a bipolar electrode arrangement. Alternatively, enhancing the size of one electrode, thus reducing current density, might enable functional monocephalic stimulation also with a bicephalic electrode montage.

Direct current stimulation can also be delivered over noncortical brain areas. Ferrucci et al. stimulated the cerebellum showing changes in performance in a cognitive task for working memory. Galea et al. explored the inhibitory effects of the cerebellum on motor-evoked potentials (MEPs) triggered by TMS over the motor cortex. This revealed that tDCS could modify MEPs in a polarity-specific manner. In addition, Cogiamanian et al. observed that cathodal transcutaneous DC over the thoracic spinal cord suppressed tibial somatosensory-evoked potentials. Furthermore, Winkler et al. observed that transcutaneous DCS over the spinal cord modulates the postactivation depression of the H-reflex. Preliminary data indicates spinal DCS also influences nociception suggesting that the spinal cord as a target for transcutaneous DCS. Challenges for stimulation in this area must be considered such as location of induced electrical fields.

关于tDCS的建模研究 Modeling tDCS

在tDCS刺激过程中，电流流过大脑，不同的组合（montage）下通过大脑的电流路径也不同，因此通过调整组合的方式，可以为特定应用对tDCS方法进行定制和优化。尽管tDCS组合设计通常遵循基本假设(如“阳极增加皮层兴奋性/阴极抑制皮层兴奋性”)，tDCS刺激中的大脑电流路径的计算机模型(所谓的“forward”模型)可以为了解电流模式提供更准确的提示信息，并提示在某些情况下前述基本假设是无效的。当解释这种模拟的结果时，需要认识到任何特定的大脑区域的电流强度与大脑调控程度不存在任何简单的线性关联。尽管如此，通过这种方式做以下似乎可以合理地做出以下预测：存在更多电流的区域更可能受到电流刺激的影响，而没有或者受到很少电流影响的区域则几乎没有受到刺激的直接影响。

Computational models of tDCS range in complexity from concentric sphere models to individualized high-resolution models based an individual’s structural magnetic resonance imaging (MRI). The appropriate level of detail depends on the available computational resources and the clinical question being asked (see technical note below). Regardless of complexity, all models share the primary outcome of correctly predicting brain current flow during transcranial stimulation to guide clinical practice in a meaningful manner.

Most clinical studies use tDCS devices that apply direct electric currents via a constant current source, but even within this space there are infinite variations of dosage and montage that can be leveraged, with the help of models, to optimize outcomes. The current is sent through patch electrodes (surface areas typical range from 25 to 35 cm2 but can vary by an order of magnitude) attached to the scalp surface. Total current injected ranges in magnitude are typically from 0.5 to 2 mA. Steps taken to improve tDCS specificity (including the use of larger “return” sponges and extracephalic electrodes) have been proposed but more analysis is required to determine the role of electrode-montage in neuromodulation and targeting. Modeling approaches are instrumental toward this goal. For example, modeling studies have recently predicted a profound role of the “return” electrode position in modulating overall current flow including under the “active” (or “stimulating”) electrode. Specifically, for a fixed active electrode position on the head, changing the position of the return electrode (including cephalic and extracephalic positions) influences current flow through the presumed target region directly under the active electrode. Therefore, in addition to considering the role of scalp shunting and action on deep brain structures (see above) when determining electrode distance, the complete design of electrode montage may subtly modulate cortical current flow. Again, computer modeling can provide valuable insight into this process.

Recent modeling studies suggest that individual anatomical differences may affect current flow through the cortex. In comparison to TMS, which uses MEPs to index its potency, there is no similar rationale for titrating tDCS dosage. A related issue is the modification of tDCS dose montages for individuals with skull defects or stroke-related lesions. Such individuals may be candidates for tDCS therapy but defects/lesions are expected to distort current flow. For example, any defect/injury filled with cerebrospinal fluid (CSF), including those related to stroke of traumatic brain injury, is expected to preferentially “shunt” current flow. Ideally, tDCS would be adjusted in a patient-specific (defect/lesion specific) manner to take advantage of such distortions in guiding current flow to targeted regions, while simultaneously avoiding any safety concerns (such as current hot spots).

Evidence from modeling studies suggests that for typical tDCS significant amounts of current can reach broad cortical areas especially between and under the electrode surface. Modeling studies also show that electrode montage is critical to the amount of current shunted through the skin.

Electrode montage is critically associated to the amount of current being shunted through the skin, how much is delivered to the brain, and to what targets. The overall theme emerging from modeling efforts is that despite clinical success in applying simplifying rules in dose design, all the details and aspects of electrode montage design combine to influence current flow such that these simplifying rules are applicable but only within a limited parameter range. For example, average current density (total current/electrode area) at the “active” electrode may be a useful metric to normalize specific neurophysiologic outcomes (eg, TMS evoked MEPs), there is no universal relationship between current density and brain modulation when one considers the full spectrum of possible electrode montages.

Recent modeling data taking into consideration gyri and sulci geometry have shown that electric current can concentrate on the edge of gyri. Therefore, the effects might not be homogeneous throughout the stimulated area. Increased appreciation of the complexity of current flow through the head (reflecting the complexity of neuroanatomy), reinforces the use of applying computational models to assist in tDCS dose design rather than simply relying on some heuristic rules (eg, “increased excitability under the anode”).

In addition to predicting brain current flow, modeling studies also provide insight into electrode design by predicting current flow patterns through the skin. Modeling studies has reinforced that current is not passed uniformly through the skin but rather tends to concentrate near electrode edges or skin inhomogeneities. Electrode design can be simple saline-soaked cotton or sponge pads or specifically designed patches with unique shapes and materials to maximize stimulation magnitude and focality. Modeling confirms that decreasing the salinity of the pads reduces peak current concentration at the edges (even as the total current applied and average current density is fixed).

计算机建模研究预计将在下一代经颅直流电刺激（tDCS）技术的发展中起到一个重要作用。值得注意的是，现有tDCS设备还没有彻底改变自电池首次被发明时的形制。因此,传统技术有一定的局限性，包括刺激的聚焦性，影响深度及定位控制。为了克服这些局限性，不断有新的技术被提出，如采用电极阵列（如所谓高分辨率经颅直流电刺激HD-tDCS），在经颅直流电刺激（tDCS）过程中同步采集EEG信号以实时调整tDCS剂量和参数。最终，通过将多种现代科技与经颅刺激技术相结合，tDCS技术的临床控制和有效性无疑将得到不断的提高。 

On a final technical note: Though there has been a recent emphasize to develop increasingly accurate and complex models, certain universal technical issues should be considered for high-precision models, beginning with: (1) high-resolution (eg, 1 mm) anatomic scans so that the entire model work flow should preserve precision. Any finite-element human head model is limited by the precision and accuracy of tissue dimensions (masks) and conductivity values incorporated (inhomogeneity and anisotropy). One hallmark of precision is the cortical surface used in the final finite-element mask solver should represent realistic sulci and gyri; (2) Simultaneously, a priori knowledge of tissue anatomy and factors known to shape current flow are applied to further refine segmentation. Particularly critical are discontinuities not present in nature that result from limited scan resolution; notably both unnatural perforations in planar tissues (eg, holes in cerebrospinal fluid where brain contacts skull) and microstructures (eg, incomplete or voxelized vessels) can produce significant aberrations in predicted current flow. Addition of complexity without proper parameterization can evidently decrease prediction accuracy. An improper balance between these factors can lead to distortions in brain current flow of an order of magnitude or more—uncontrolled additional complexity can in fact induce distortion. We thus emphasize that the most appropriate methodology (ranging from concentric spheres to individualized models) ultimately depends on the clinical question being addressed.

五．经颅直流电刺激（tDCS）安全性

至今为止，尚未有tDCS诱发癫痫的报道。有研究应用MRI 成像观察安全模式下tDCS刺激30 min 和1 h后大脑的变化，发现大脑并没有出现组织水肿、血脑屏障失衡及脑组织结构改变等现象，认为tDCS是一种安全的经颅刺激方式。同样的结论也在其他研究中得到证实。

电极的放置位置对于电流的空间分布及电流方向至关重要，决定刺激的有效性。常用的刺激电极面积为20–35mm2，其目的为尽量使刺激局限化、聚焦于需要治疗的部位。另一方面，较大面积的电极可以使电流密度下降，从而保证刺激的安全性。虽然tDCS的刺激参数标准还没有完全确定，但一般认为刺激持续时间跨度8-30 min，电流1.0~2.0 mA 的直流电是安全有效的。约有45%的电流被传送至颅骨并到达皮层表面。另外，tDCS治疗时电流强度应缓升缓降，避免造成患者不适。

六. 经颅直流电刺激装置 tDCS Device

        德国NeuroConn公司作为tDCS技术的引领者，为众多神经反馈和非侵入式大脑刺激中心提供仪器设备，产品全部通过欧洲CE认证，可以在欧盟面向临床销售。DC-STIMULATOR系列是世界范围内首款取得欧盟CE认证获准上市的经颅电刺激产品。该系列产品于2008年一经推出就广受好评，当年即被"Neurotech Reports" 选为年度最佳产品而荣获“Gold Electrode Award “。目前该系列产品已经成为经颅直流电刺激tDCS研究领域的标准配置，成为全球近千家研究机构和临床机构的首选。2009年。此后国际上发表的一系列关于tDCS，tRNS，tACS，fMRI-tDCS的论文主要都是采用该系列产品。它的某些硬件参数甚至被作为该技术领域的划分标准。如论文中常常看到的关于tRNS刺激Noise HF和Noise LF的划分即是按照DC-Stimulator系统刺激器的滤波设置。