神经调控技术在阿尔茨海默病认知障碍研究中的应用

阿尔茨海默病（Alzheimer’s disease, AD）是发生于老年和老年前期的中枢神经系统退行性疾病，其临床主要表现为进行性认知障碍。目前针对AD尚无有效的治疗方法，药物治疗只能延缓其病情进展，治疗效果有限，且常伴随副作用。近些年，神经调控作为一种可以靶向刺激调节目标脑区活动的方法受到广泛关注，逐渐被应用于AD的治疗和研究，包括无创的经颅磁刺激、电刺激以及有创的脑深部电刺激、光遗传刺激等。本文从作用效果、作用机制、刺激脑区、刺激参数等方面对这四种典型的神经调控方法在AD的应用研究现状进行综述，为今后神经调控应用于临床治疗AD提供新思路。     

精准定位脑刺激对运动功能调控研究进展

脑刺激是神经科学研究的重要手段,传统的经颅磁刺激和经颅电刺激等脑刺激方法尽管能调控运动功能(包括减轻运动性障碍疾病的运动障碍、提高运动能力等),但存在空间分辨率低且无法刺激深部脑组织的局限性.近年来迅速发展的深部脑刺激(deep brain stimulation,DBS)、光遗传学、经颅超声刺激(transcranial ultrasound stimulation,TUS)、时间干涉(temporal interference,TI)等精准定位脑刺激方法,具有空间分辨率高、可聚焦深部脑组织等优点.本文综述了上述几种脑刺激方法的原理、特点,对运动功能调控的研究进展,以及面临的挑战和发展前景,从而为神经科学研究提供更好的研究工具,为临床实践提供更多的干预治疗手段.     

综述: 无创穿颅电刺激对人脑神经活动和认知功能的调控

穿颅电刺激被认为可以无创调节大脑的神经活动,为研究特定脑区与某一认知功能间的因果关系提供了可能.近些年,对穿颅电刺激作用机制和其对认知、运动功能调控的研究方面取得了很多重要进展.在这篇综述中,我们总结了以往关于穿颅直流电刺激、穿颅交流电刺激和穿颅随机噪声电刺激三种刺激方式的发展历史及其作用机制,同时总结了其对感知觉(主要是视觉知觉)、注意和记忆等认知功能的调控,并对未来的研究方向进行了展望.     

经颅磁刺激和经颅直流电刺激在调控大脑共情功能中的应用

共情可以帮助人们建立和谐的人际关系，更好地适应现实社会，是一种重要的社会认知功能。已有研究表明，诸多神经和精神类疾病的发生发展和复发与共情缺陷有关。非侵入性脑刺激技术（经颅磁刺激和经颅直流电刺激）可以通过调节大脑皮层兴奋性来调控个体的共情水平，缓解共情缺陷症状。针对健康群体使用该技术的现有证据显示：内侧前额叶、初级运动皮层、额下回、背外侧前额叶和颞顶交界处的活动有助于提升个体的认知共情水平，其中双侧背外侧前额叶的活动还有助于下调个体的情感共情水平，而右侧颞顶交界处的活动则可以增强自我表征从而支持个体在共情时进行自我和他人的区分。少数针对共情缺陷群体使用该技术的临床证据提示，增强左侧背外侧前额叶和内侧前额叶的活动可以分别提升精神疾病和神经退行性疾病患者的认知共情水平。未来的研究应探讨在统一的行为测量范式下针对不同刺激参数和刺激位点进行共情干预研究，通过融合其他神经生理技术进一步考察非侵入性脑刺激技术改善共情功能的作用机制，并考虑个体差异性对大脑共情功能干预效果的影响。     

综述与专论: 外源节律性脑刺激技术在精神神经类疾病治疗中的应用

神经振荡是中枢神经系统中一种节律性神经活动模式，研究发现精神神经类疾病患者存在神经振荡异常。外源节律性刺激能够通过“夹带”效应以及可塑性变化机制有效调节异常的神经振荡，具有治疗精神神经类疾病的潜在可能性。目前，外源节律性脑刺激技术主要包括经颅交流电刺激、经颅时间相干刺激、节律性感觉刺激等方式。本文从外源节律性脑刺激技术原理以及目前不同技术在临床上治疗精神神经类疾病的刺激策略、研究进展以及治疗效果等角度展开综述，提出这一类调控技术可能成为未来临床治疗精神神经疾病症状的无创高效新型治疗方案，并对其未来的发展方向进行展望。     

功能磁共振和脑电神经成像技术与大脑刺激相结合的研究进展

随着对神经机制问题阐述水平的迅速提高,所应用的神经成像技术、方法及各种工具的复杂程度也在不断提高．一方面是神经成像技术本身的不断发展,另一方面则是大脑直接刺激与神经成像技术同步记录方法的发展．经颅磁刺激-功能磁共振成像同步技术(TMS-fMRI)和经颅磁刺激-脑电技术(TMS-EEG)能为研究大脑网络的功能和有效连通性提供技术手段,该技术在多种认知领域的发展和应用,为神经科学、认知心理学、神经信息学等学科的研究者对人脑的研究开启了多条通道,更加有利于深入地理解人类大脑的工作机制．     

无创穿颅电刺激对人脑神经活动和认知功能的调控

穿颅电刺激被认为可以无创调节大脑的神经活动,为研究特定脑区与某一认知功能间的因果关系提供了可能.近些年,对穿颅电刺激作用机制和其对认知、运动功能调控的研究方面取得了很多重要进展.在这篇综述中,我们总结了以往关于穿颅直流电刺激、穿颅交流电刺激和穿颅随机噪声电刺激三种刺激方式的发展历史及其作用机制,同时总结了其对感知觉(主要是视觉知觉)、注意和记忆等认知功能的调控,并对未来的研究方向进行了展望.     

非侵入性电刺激神经调控技术：镇痛效果与镇痛机制

非侵入性电刺激神经调控技术是一种潜力巨大的非药物镇痛手段,具有经济、易操作、安全性高等优点,已被应用于各类临床疼痛的治疗。然而,目前仍缺乏对不同电刺激神经调控技术镇痛特性的深入理解。本文从镇痛效果和镇痛机制两个方面入手,评述非侵入性外周神经电刺激(经皮神经电刺激、经皮迷走神经电刺激)和中枢神经电刺激(经颅直流电刺激、经颅交流电刺激)在镇痛方面的研究结果,总结各技术在缓解急性疼痛和慢性疼痛中常用的刺激参数和其镇痛效果,探讨可能的镇痛机制。最后,本文对比和总结各技术的镇痛特点,讨论了现有研究的若干局限和未来的研究方向。克服这些局限将促进相关技术的临床应用,最终达到帮助患者缓解疼痛的目的,减轻疼痛对患者、其家庭和整个社会带来的健康和经济负担。     

脑深部电刺激的临床应用

脑深部电刺激(deep brain stimulation,DBS)是近20年来神经外科领域发展最迅猛的技术。DBS是通过刺激发生器发出的高频电脉冲信号刺激脑神经核团或神经传导束来调节异常的神经环路。DBS已经成为治疗特发性震颤、帕金森病、肌张力障碍等运动障碍病的常规手术方法。自1997年深部脑刺激通过美国FDA认证用于治疗特发性震颤以来,已有超过数万名运动障碍患者接受该疗法,而国内脑深部电刺激最早在1999年应用于帕金森病临床治疗,迄今也有数千例患者接受了植入手术。近年,脑起搏器的临床适应症不断扩大,从最初的运动障碍病逐渐发展到治疗其他神经和精神疾病,如抽动秽语综合征、强迫症、抑郁症、神经性厌食症、难治性疼痛、癫痫、植物状态和阿尔茨海默病等,虽然DBS的治疗机理还不很清楚,但可以预见未来DBS将成为众多神经和精神疾病的重要治疗方法。     

脑起搏器

脑起搏器在医学术语上称“脑深部刺激系统(DBS)”,其外形及工作原理与心脏起搏器类同。DBS由植入脑内的刺激电极、埋在胸部皮下的脉冲发生器和皮下导线组成。脑内电极质地柔软,直径1.2mm,电极头端有4个刺激触点,供刺激选用。脉冲发生器大小为6×6×0.5cm,为整个系统的核心部分,持续发出高频脉冲电刺激,通过皮下导线传递到脑内电极,抑制不正常的脑核团放电,消除帕金森病症状。整个刺激系统均埋在皮下,不影响日常工作和生活。可根据病情选择不同的刺激触点、频率、强度及脉宽等参数,通过体外电脑程控调节,以达到最佳刺激效果,调节时病人无…     

非侵入性脑刺激应用于创伤后应激障碍和物质滥用障碍的记忆干预

记忆是进行思维、想象等高级心理活动的基础，是累积经验、促进个体生存的重要功能。然而，创伤后应激障碍和物质滥用障碍具有某种非适应性记忆过强的特征，不利于个体生存。因此，以病理性改变的记忆为靶点，通过削弱或更新非适应性记忆，可以达到缓解症状甚至治愈的目的。记忆并非是对经验的刻板记录，而是对经验不断更新整合的过程，因此记忆有被干预的可能。记忆的再次激活可能会诱发记忆消退和再巩固，这为记忆相关精神疾病的干预提供了思路和启发。非侵入性脑刺激（noninvasive brain stimulation,NIBS）技术作为一种时间、空间分辨率较高的无创神经调控技术，近年来开始被结合运用到记忆干预研究中。不同刺激参数的NIBS （如频率、极性，以及受刺激区域的初始神经激活状态）应用于特定大脑皮质区域，可以调节神经可塑性，增强或降低靶点脑区的兴奋性，从而削弱或增强行为表现，实现记忆消退增强或在再巩固时间窗内干预记忆。本文首先介绍了记忆相关的脑功能基础研究与局部脑区干预方案的理论联系，继而回顾了近年来NIBS与记忆干预相结合应用于创伤或物质滥用相关障碍的临床干预研究，为精神疾病临床诊疗提供理论依据和启发。     

太赫兹刺激听神经的测试平台搭建

目的 近年来，用于脑功能调控的神经调控技术蓬勃发展，很多方法已在临床上被推广应用，主要包括电极深部脑刺激、经颅磁刺激、光遗传技术、超声深脑刺激等。但是这些调控技术存在刺激靶点改变灵活性差、空间分辨率不足、需要注射病毒转染等问题。与这些技术相比，太赫兹波调控则能以较高的时空分辨率、无需引入外源基因的方式对神经活动进行干预。激光神经刺激是一种具有较明确靶向性的刺激方法，可以通过调整不同激光参数（激光波长、脉冲能量等）控制引起神经兴奋或者抑制。但是由于该研究方向的实验手段和实验平台的缺乏，相关研究开展较少。方法 针对这个问题，从听觉神经入手，在分子、细胞和在体不同层面为相关领域的研究搭建了不同的测试平台。结果 实验结果表明，这些系统在时间和空间上具有良好的耦合性和靶向性，测得的信号受噪音干扰小。结论 这些系统可以有效测试神经系统对太赫兹刺激的响应并精确控制刺激时间和位置。     

Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent

Cortical oscillations play a fundamental role in organizing large-scale functional brain networks. Noninvasive brain stimulation with temporally patterned waveforms such as repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) have been proposed to modulate these oscillations. Thus, these stimulation modalities represent promising new approaches for the treatment of psychiatric illnesses in which these oscillations are impaired. However, the mechanism by which periodic brain stimulation alters endogenous oscillation dynamics is debated and appears to depend on brain state. Here, we demonstrate with a static model and a neural oscillator model that recurrent excitation in the thalamo-cortical circuit, together with recruitment of cortico-cortical connections, can explain the enhancement of oscillations by brain stimulation as a function of brain state. We then performed concurrent invasive recording and stimulation of the human cortical surface to elucidate the response of cortical oscillations to periodic stimulation and support the findings from the computational models. We found that (1) stimulation enhanced the targeted oscillation power, (2) this enhancement outlasted stimulation, and (3) the effect of stimulation depended on behavioral state. Together, our results show successful target engagement of oscillations by periodic brain stimulation and highlight the role of nonlinear interaction between endogenous network oscillations and stimulation. These mechanistic insights will contribute to the design of adaptive, more targeted stimulation paradigms.     

Transcranial alternating current stimulation enhances individual alpha activity in human EEG

Non-invasive electrical stimulation of the human cortex by means of transcranial direct current stimulation (tDCS) has been instrumental in a number of important discoveries in the field of human cortical function and has become a well-established method for evaluating brain function in healthy human participants. Recently, transcranial alternating current stimulation (tACS) has been introduced to directly modulate the ongoing rhythmic brain activity by the application of oscillatory currents on the human scalp. Until now the efficiency of tACS in modulating rhythmic brain activity has been indicated only by inference from perceptual and behavioural consequences of electrical stimulation. No direct electrophysiological evidence of tACS has been reported. We delivered tACS over the occipital cortex of 10 healthy participants to entrain the neuronal oscillatory activity in their individual alpha frequency range and compared results with those from a separate group of participants receiving sham stimulation. The tACS but not the sham stimulation elevated the endogenous alpha power in parieto-central electrodes of the electroencephalogram. Additionally, in a network of spiking neurons, we simulated how tACS can be affected even after the end of stimulation. The results show that spike-timing-dependent plasticity (STDP) selectively modulates synapses depending on the resonance frequencies of the neural circuits that they belong to. Thus, tACS influences STDP which in turn results in aftereffects upon neural activity.The present findings are the first direct electrophysiological evidence of an interaction of tACS and ongoing oscillatory activity in the human cortex. The data demonstrate the ability of tACS to specifically modulate oscillatory brain activity and show its potential both at fostering knowledge on the functional significance of brain oscillations and for therapeutic application.     

Optogenetic Functional MRI

The investigation of the functional connectivity of precise neural circuits across the entire intact brain can be achieved through optogenetic functional magnetic resonance imaging (ofMRI), which is a novel technique that combines the relatively high spatial resolution of high-field fMRI with the precision of optogenetic stimulation. Fiber optics that enable delivery of specific wavelengths of light deep into the brain in vivo are implanted into regions of interest in order to specifically stimulate targeted cell types that have been genetically induced to express light-sensitive trans-membrane conductance channels, called opsins. fMRI is used to provide a non-invasive method of determining the brain''s global dynamic response to optogenetic stimulation of specific neural circuits through measurement of the blood-oxygen-level-dependent (BOLD) signal, which provides an indirect measurement of neuronal activity. This protocol describes the construction of fiber optic implants, the implantation surgeries, the imaging with photostimulation and the data analysis required to successfully perform ofMRI. In summary, the precise stimulation and whole-brain monitoring ability of ofMRI are crucial factors in making ofMRI a powerful tool for the study of the connectomics of the brain in both healthy and diseased states.     

Synaptic Plasticity in Neurodegenerative Diseases Evaluated and Modulated by In Vivo Neurophysiological Techniques

Several studies demonstrated in experimental models and in humans synaptic plasticity impairment in some neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and schizophrenia. Recently new neurophysiological tools, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, have been introduced in experimental and clinical settings for studying physiology of the brain and modulating cortical activity. These techniques use noninvasive transcranial electrical or magnetic stimulation to modulate neurons activity in the human brain. Cortical stimulation might enhance or inhibit the activity of cortico?Csubcortical networks, depending on stimulus frequency and intensity, current polarity, and other stimulation parameters such as the configuration of the induced electric field and stimulation protocols. On this basis, in the last two decades, these techniques have rapidly become valuable tools to investigate physiology of the human brain and have been applied to treat drug-resistant neurological and psychiatric diseases. Here we describe these techniques and discuss the mechanisms that may explain these effects.     

Noninvasive brain stimulation with transcranial magnetic or direct current stimulation (TMS/tDCS)—From insights into human memory to therapy of its dysfunction

Noninvasive stimulation of the brain by means of transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) has driven important discoveries in the field of human memory functions. Stand-alone or in combination with other brain mapping techniques noninvasive brain stimulation can assess issues such as location and timing of brain activity, connectivity and plasticity of neural circuits and functional relevance of a circumscribed brain area to a given cognitive task. In this emerging field, major advances in technology have been made in a relatively short period. New stimulation protocols and, especially, the progress in the application of tDCS have made it possible to obtain longer and much clearer inhibitory or facilitatory effects even after the stimulation has ceased. In this introductory review, we outline the basic principles, discuss technical limitations and describe how noninvasive brain stimulation can be used to study human memory functions in vivo. Though improvement of cognitive functions through noninvasive brain stimulation is promising, it still remains an exciting challenge to extend the use of TMS and tDCS from research tools in neuroscience to the treatment of neurological and psychiatric patients.     

Noninvasive brain stimulation with transcranial magnetic or direct current stimulation (TMS/tDCS)-From insights into human memory to therapy of its dysfunction

Noninvasive stimulation of the brain by means of transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) has driven important discoveries in the field of human memory functions. Stand-alone or in combination with other brain mapping techniques noninvasive brain stimulation can assess issues such as location and timing of brain activity, connectivity and plasticity of neural circuits and functional relevance of a circumscribed brain area to a given cognitive task. In this emerging field, major advances in technology have been made in a relatively short period. New stimulation protocols and, especially, the progress in the application of tDCS have made it possible to obtain longer and much clearer inhibitory or facilitatory effects even after the stimulation has ceased. In this introductory review, we outline the basic principles, discuss technical limitations and describe how noninvasive brain stimulation can be used to study human memory functions in vivo. Though improvement of cognitive functions through noninvasive brain stimulation is promising, it still remains an exciting challenge to extend the use of TMS and tDCS from research tools in neuroscience to the treatment of neurological and psychiatric patients.