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通讯作者:

郑海荣(1977-),安徽长丰人,博士研究生,副院长。E-mail:hr.zheng@siot.at.cn

中图分类号:R445.1,R454.3

文献标识码:A

文章编号:62-1218(2020)01-0001-10

DOI:10.12287/j.issn.2096-8965.20200102

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目录contents

    摘要

    目前,医学超声技术正逐渐从传统的基于波动效应的组织器官结构成像,以及基于热效应和空化效应的病变组织毁损等治疗方式,逐步向多功能诊疗技术融合的方向发展。超声力学效应 (即声辐射力),作为其最重要的生物学效应之一,越来越受到科研和医疗工作者的关注和重视。受益于对超声力学效应理论和机制的不断深入了解,以及电子信息技术的快速发展,近年来涌现出多种基于声辐射力的超声诊疗新技术,如能够对组织力学参数进行定量测量的超声弹性成像技术,以及能够对脑部等神经细胞的活动抑制状态进行无创调节的超声神经调控技术,极大地拓展了超声在医学临床领域的应用,为肝硬化、乳腺癌等重大疾病的早期筛查,以及脑疾病治疗和脑科学研究提供了独特的方法和工具。本文将对这些基于超声力学效应的医学超声新技术近年来的代表性研究成果进行系统性介绍,并分析其未来的发展方向。

    Abstract

    At present, medical ultrasound technology is gradually developing from the traditional imaging of tissue and organ structure based on wave effect of ultrasound, and the treatment of diseased tissue based on thermal and cavitation effects, to the direction of multi-functional integration of diagnosis and treatment. Therefore, as one of the most important biological effects, the mechanical effect of ultrasound (i.e. acoustic radiation force) has attracted more and more attention from scientific researchers and medical staffs. Benefiting from the in-depth understanding of the theory and mechanism of ultrasonic mechanical effect, as well as the rapid development of information and electronic technology, a variety of new ultrasonic diagnosis and treatment technologies based on acoustic radiation force have emerged in recent years, which have greatly expanded the application of ultrasound in clinics. For example, ultrasound elastography that can quantitatively measure the tissue stiffness and image its distribution, which can provide early screening for liver cirrhosis and breast cancer; as well as ultrasound neuromodulation that can non-invasively regulate the state of nerve cells in the brain, which can provide unique tools for brain disease treatment and neuroscience research. This article will systematically introduce the representative achievements of these new medical ultrasound technologies based on the mechanical effect of ultrasound in recent years, and analyze their future development directions.

  • 1 超声在医学领域的应用概述

  • 超声成像是目前我国医学临床中应用最广泛最频繁的医学影像技术。相比计算机断层扫描成像(CT)、核磁共振成像(MRI)、正电子发射型计算机断层显像(PET) 等技术,其具有无创无辐射、 使用限制少、设备成本低、操作灵活和适用范围广等优势,在多种疾病的临床诊疗中发挥着越来越重要的作用,特别适合疾病早期阶段的大范围筛查, 实现早诊早治。

  • 超声波具有多种生物学效应,包括波动效应、 热效应、力学效应和空化效应等。传统超声成像技术主要利用其波动效应。超声波是一种压缩波,换能器将电信号转换为声信号,进入人体传播,由于组织中声阻抗分布不均匀,声波不断发生散射,其中一部分返回换能器,又被转换为电信号,称为回波信号。声阻抗的差异越大,回波信号越强,特别是在不同器官的分界面上,会产生较强的回波,因此可以从中解调出对应的结构信息,即常见的B超图像。

  • 除诊断外,超声也被用于疾病治疗。这些技术主要利用超声的热效应和空化效应。例如,高强度聚焦超声(HIFU) 通过长脉冲、高功率发射,使焦点附近组织温度瞬间升高到70℃以上,造成蛋白质变性坏死,具有无创、痛苦少、保形保肢和术后肿瘤不易转移复发等优点,已被广泛用于治疗各种恶性肿瘤。在这个过程中,空化作用引起的局部高温/高压和冲击波等现象,也会加速肿瘤组织的瓦解。超声空化效应还被用于冲击波碎石、血栓消融、声动力治疗、开启血脑屏障等。

  • 长期以来,与其他生物学效应相比,超声力学效应在医学临床中的应用比较薄弱。这一方面是因为缺乏准确的、能与具体场景紧密配合的声辐射力理论,另一方面也因为需要突破传统成像模式的束缚,引入高性能的新算法和新技术,才能充分发挥超声力学效应独特机制的效果,实现具有特殊功能的临床诊疗技术。近年来,随着相关理论方法的突破,基于声辐射力的超声剪切波弹性成像技术已经趋于成熟,相关产品在多种疾病的筛查诊断中发挥巨大作用;超声力学效应在神经调控和脑科学研究方面也表现出独特优势和重大潜力(图1,坐标为估算范围)。

  • 图1 超声的三大基本物理效应和可能的生物医学应用[1]

  • 2 超声辐射力理论

  • 声辐射力是声场与物体之间动量传递产生的, 而如何计算复杂声场环境下任意结构物体受到的声辐射力是超声弹性成像、声操控技术推向应用系统亟待解决的声学问题[2]。声场形态是决定操控效果的关键因素,此前声操控一般利用超声换能器直接产生的聚集场或驻波场等,其声场分布固定,形式单一,焦点范围窄,具有衍射极限,很难大范围、 连续地操控颗粒,也难以操控尺寸远小于波长的颗粒[3]。因此,声学换能器直接产生的声场在自由调控和设计优化方法上存在的不足,是该技术进一步发展和应用的瓶颈。

  • 首先,针对复杂声场环境下声辐射力计算的难题,郑海荣等提出声辐射力离散表达框架和计算理论[4],如式(1) 和(2) 所示,通过在声波波动方程中引入动量流密度张量,使精确求解目标周围总场诱导的动量流密度张量的时空分布变成可能,实现了复杂声场环境下任意结构、形状、性质的目标所受声辐射力的定量计算;该理论克服了20 世纪60 年代以来经典多重散射波方法仅能处理球或柱状散射体在理想声源中所受声辐射力的局限[5]

  • 声辐射力:

  • F=-A<Π>dA(1)

  • 动量流密度张量:

  • <Π>=12ρ0c02<p2>-ρ02<|v|2>+ρ0<vv
    (2)
  • 其中,dA=ndAn为物体表面法向方向,dA为面积微元,pv是微粒周围一阶声压和速度场,ρ0c0是周围流体密度和声速,<> 表示时间平均。

  • 郑海荣团队所提出的计算理论解决了长期以来声辐射力精准计算和弱散射介质中如何产生可控声辐射力的问题,研究了声辐射力场诱导剪切波的产生机理与控制方法,解决了剪切波与生物组织微形变及其生物力学特性的量化关系等核心问题,在此基础上研发了超声弹性成像系统,并实现产业化, 成为进入医学临床的专用超声弹性成像产品,形成了良好的社会和经济效益。

  • 3 超声弹性成像技术及应用

  • 弹性成像技术是近年来飞速发展的一类功能性成像方法。它通过测量生物组织力学参数,根据其数值和空间分布诊断病变,对某些疾病的早期诊断具有明显优势,目前已有超声弹性成像、磁共振弹性成像、光学弹性成像等多种技术。传统超声结构成像反映人体组织的声阻抗(密度乘以声速)差异, 相对变化范围通常只有其中间值的20%左右。而反映组织硬度的弹性模量,其相对变化范围最大能达到其中间值的500%以上[6](见图2)。因此,对于某些疾病,超声弹性成像具有更高的敏感性,能在发病早期实现精准诊断,或对其病情进行准确分期。 发展超声弹性成像技术和设备,已成为医学临床的迫切需求。

  • 图2 人体软组织弹性模量相对动态变化范围远大于声阻抗(等于体积模量除以声速)[6]

  • 超声弹性成像技术已发展出多种模式,主要包括:准静态应变成像[7]、瞬时弹性成像[8]、声辐射力脉冲成像[9]、实时剪切波成像[10] 等(见图3)。其中,准静态应变成像是一种非定量技术,反映组织在外力下的应变分布,一定程度上可以近似组织的相对硬度。但由于缺乏量化指标,易受医生手法和主观判断的影响,因此在临床中受到较大限制。而后三者都是通过测量组织中剪切波的传播速度,根据其与组织弹性模量间的量化公式(E=3ρc2E 杨氏弹性模量,ρ密度,c剪切波传播速度),可以计算出组织杨氏弹性模量值。

  • 图3 超声弹性成像发展历程及不同超声弹性成像技术的基本原理示意图[11]

  • 要测量剪切波速度,必须先在组织内产生剪切波。瞬时弹性成像采用机械振荡器,从体表形成剪切波向体内传播。这种波幅度较大,较容易探测, 但在传播过程中易受外部干扰,造成测量失准。针对上述问题,郑海荣团队发明了一种超声换能器与低频振动源相对独立的新型结构,解决了振动源干扰造成回波信号质量严重下降的问题,并通过整合B超引导,实现对肝脏内不规则结构的手动规避。 此外,还通过建立激励源尺寸对测量结果影响的数学模型,配合自适应误差补偿算法,实现了对弹性测量值的高精度校正。上述成果成功转换为肝硬化检测仪(ET-CD系列)产品,填补了我国在超声专科影像诊断设备领域的空白,并取得国家三类医疗器械注册证和欧盟认证,形成了突出的经济效益和社会效益。

  • 声辐射力脉冲成像和实时剪切波成像技术都是利用超声辐射力产生剪切波,这已被证明是在体内产生剪切波的最佳方式。只要在待测区域施加较长时间的聚焦波束,就可以“隔空”推动组织形变, 回弹后成为剪切波源。这种方式产生的剪切波波阵面更整齐,更易得到精确追踪结果。而且,超声追踪组织运动的能力与其方向相关,当剪切波传播方向与超声入射方向垂直时灵敏度最高。在声辐射力脉冲成像中,力作用于一点,剪切波波阵面近似球面,在部分位置测量会有误差[9]。而在实时剪切波成像中,力的作用点自上而下等间隔分布,快速连续激发。当作用点移动速度远大于剪切波传播速度时,剪切波会发生相干叠加,最终形成传播方向与超声入射方向接近垂直的线形波阵面。该方法降低了单次声辐射力发射功率,确保了安全性,并可同时测量多点剪切波速度,使实时弹性模量分布成像成为可能[10]

  • 剪切波弹性成像的另一个关键是利用信号处理方法,从超声射频回波信号中计算组织位移,其准确性对最终测量精度至关重要。常规时域互相关法更适于幅度较大的位移[12],如瞬时弹性成像,但计算量过大,影响测量速度也提高了硬件成本。郑海荣团队发明了同样适于估计较大位移的追踪尺度不变特征点法,大幅提高了计算速度,并将动态范围提高20%[13]。相对而言,基于多普勒效应的相位估计法,更适合对幅度较小(低于采样点间隔) 的位移进行计算。目前基于声辐射力的弹性成像方法基本上都使用该方法。声辐射力产生的位移非常小, 仅有数微米,且会随剪切波传播快速衰减,若算法灵敏度不足,则难以捕捉[14]。针对该问题,郑海荣团队发明了利用Hilbert变换构建解析信号,再利用其自相关相位进行精细位移估计的新方法,进一步提高了计算的准确性[15](见图4)。

  • 图4 声辐射力脉冲成像过程示意图(左);剪切波侧向传播的组织位移图(右上) 和在4个位置得到的“时间-位移”曲线(右下)

  • 由于探头宽度通常只有几厘米,而声辐射力激发位置通常在其中央,因此,剪切波从被激发到传出可测范围只有几毫秒;若考虑剪切波幅度快速衰减,这一时间可能更短。这就对成像帧频提出了极高要求,传统的逐线扫描模式帧频只能达到数百帧每秒,难以满足需要。为此,基于平面波发射的超快超声成像方法被提出,发射时所有阵元一起激励且不设延时(波阵面为平面),再接收所有通道的回波信号,重建出一幅图像。由于每次成像只需一次发射接收,因此可以实现极高帧频,随成像深度不同,达到5 000~20 000 帧/秒[16]。如此高的成像帧频给后续波束合成计算造成很大压力。为解决该问题,郑海荣团队发明了利用大规模图形处理器(GPU) 并行加速计算的新方法,整体效率提高约20 倍。该方法不仅可以应用于剪切波弹性成像, 还可以进一步用于超声超分辨成像和超声脑功能成像,具有极大的应用潜力。

  • 超声弹性成像在临床上主要应用于乳腺肿瘤良恶性辨别[17]、肝纤维化/肝硬化早期筛查和分期[18]、 HIFU消融治疗的监控与疗效评估等领域,均取得了良好效果。世界医学超声联合会、中华医学会等组织先后发布了针对超声弹性成像的临床指南。在肝脏疾病诊断方面,郑海荣团队的研究成果被欧洲医学超声联合会发布的“肝脏超声弹性成像临床指南(2017 版)”引用[18]。在恶性乳腺肿瘤辨别方面, 团队率先发现了恶性肿瘤周边硬度增高的现象,并命名为“硬环征”[17]。相关成果已转化到高端弹性彩超(DC8及Resona系列)产品中(见图5),先后取得国家医疗器械注册证、美国FDA认证和欧盟CE认证,在临床上表现良好,将乳腺肿瘤诊断特异性从原来的50%~60%提高到80%~90%,实现了从普通彩超向高端弹性彩超的重大跨越,表现出强劲的市场竞争力。

  • 图5 肝硬化检测仪产品及肝组织瞬时弹性成像图(左);高端弹性彩超产品及其乳腺恶性肿瘤呈现“硬环征”图(右)

  • 超声弹性成像技术的发展趋势将是专科化和多样化,例如针对动脉壁和骨骼肌等具有各向异性的器官,研究更精确的物理模型;针对仅靠弹性模量无法实现准确诊断的情况,对粘性系数等参数同步测量;针对胰腺等深部器官,开发基于内窥超声的定量弹性成像技术等。有理由相信,超声弹性成像技术在医学临床上将发挥越来越重要的作用。

  • 4 超声神经调控技术及应用

  • 发展无创精准的新型神经调控技术一直是神经科学和脑疾病领域的迫切需求。超声波作为一种机械波,其力学效应控制神经元电活动的新机制的发现(见图6),使无创地开展神经刺激成为可能。研究发现超声波可以诱发神经元动作电位以及神经元和胶质细胞的钙活动[19, 20],激活线虫多模感受神经元ASH,产生回避的行为学反应[21]。最近,郑海荣团队、李月舟团队及孙雷团队,将超声辐射力和机械敏感性离子通道结合起来,首次在神经元上通过超声刺激激活机械敏感性离子通道,并进而精确控制神经元的兴奋性[22, 23]。该成果开拓了超声在脑科学研究中的新方向,为超声遗传学技术的进一步发展奠定了基础,具有重要的理论意义和应用价值。

  • 图6 超声诱发神经电活动

  • 超声对神经电活动的作用可能为神经环路调控和深部脑刺激提供革命性的新技术(见图7)。早在1929年,Harvey就初步发现超声可刺激神经纤维与肌纤维[24]。此后,20世纪60年代,应用超声通过颅骨窗实现了猫的视觉皮层和听觉神经刺激,引起体感诱发电位的可逆性抑制[25]。但是在其后几十年内,由于神经科学工具的缺乏和超声与神经学科交叉学科的缓慢发展,相关研究一直未有新的突破。 2008 年,Tyler团队通过小鼠海马脑片实验证明了低强度超声波诱发神经活动,而且也提出可能的调控机制,即超声波影响电压门控的钠离子和钙离子通道[19]。2010年,Tyler团队在Neuron杂志上发表文章首次在分子水平和小动物水平证明了利用低强度超声波实现神经调控[26],其调控作用是双向的,可逆的[27]。同时,Yoo教授在活体动物实验中利用超声调控兔子的躯体运动区域和视觉区,说明了超声调控是双模态的—大脑活动可以被刺激或者选择性抑制[28]。在非人灵长类动物水平上,2013 年Thomas团队将超声聚焦于眼球运动皮层,改变了猴子眼动的方向,证实超声可以调节非人灵长类动物的神经活动[29]。此外,2018 年Yang团队结合MRI引导技术和功能磁共振成像技术(fMRI),使超声准确聚焦到猴子大脑3a/3b区域,观察到刺激靶点和下游神经环路的激活[30]。2019 年Folloni团队利用MRI的引导,对深部脑区进行超声刺激,通过fMRI观察到脑功能网络的活动,同时,观察到仅40 秒的超声刺激可以引起长达1小时的神经活动[31]。更为惊喜的是,2014 年低强度超声人脑神经调控也取得了重要突破: Legon等在Nature Neuroscience杂志上的研究将低强度超声波直接作用于人脑初级躯体感觉皮层,实现了神经刺激和调控,改变了人脑对触觉的分辨能力[32]。2020年Science文章指出: “超声波可用于改变大脑活动和治疗脑疾病”[33](见图7)。

  • 图7 超声神经调控技术发展历程

  • 超声神经调控技术在脑疾病的干预与治疗方面也取得了一系列成果(见图8)。在脑缺血疾病方面,利用超声刺激脑动脉栓塞鼠的脑缺血区域, 结果显示超声刺激后通过调节炎症或BDNF(BrainDerived Neurotrophic Factor) 等相关通路,缓解了脑损伤后的缺血性症状[34, 35]。在精神神经疾病方面,童善保团队、王刚团队和郑海荣团队利用超声刺激抑郁症模型大鼠的前额叶皮质,结果表明超声能够提高脑源性营养因子的表达,并有改善大鼠抑郁症状的作用[36, 37]。2020 年,Sanguinetti团队利用超声刺激右前额皮质可以改善情绪,有望消除消极情绪[38]。在帕金森疾病方面,郑海荣团队利用超声刺激帕金森病小鼠运动皮层或丘脑底核,结果表明超声刺激缓解了帕金森病小鼠的运动症状,并且对多巴胺能神经元有神经保护作用[39, 40]。2020年,李小俚团队利用低强度超声刺激帕金森小鼠,发现局部场电位中beta(13~30 Hz)频段的功率谱强度显著降低,beta和high-gamma(55~100 Hz)、ripple(100~200 Hz)之间的相位幅值耦合强度显著下降。证实了低强度经颅超声刺激可以显著降低帕金森小鼠运动皮层中的与帕金森相关的神经电活动[41]。Wei Wu团队利用超声刺激帕金森小鼠,发现超声的力学效应提高细胞膜通透性,增加多巴胺的释放,从而改善运动症状[42]。在阿尔茨海默症(Alzheimer Disease, AD)方面,2020 年,Bobola等采用超声刺激阿尔兹海默症模型小鼠的海马,结果显示超声可以减低淀粉样蛋白的聚集[43]。同年, Beisteiner团队通过单一脉冲超声刺激一名AD患者的右侧感觉皮层后,神经心理学评分显著提高,改善效果持续长达三个月,并利用fMRI分析发现超声作用与记忆网络的上调相关[44]。在药物成瘾方面,郑海荣团队与袁逖飞团队合作,利用吗啡成瘾小鼠模型,发现超声刺激能有效且迅速降低吗啡导致的行为偏好,其持续效应可以改变小鼠的戒断后复吸行为[45]。本研究展现了新型超声神经调控技术在药物成瘾治疗领域的巨大潜力。在癫痫方面,在啮齿类动物水平,发现超声刺激可以减低癫痫的脑区异常放电[46, 47]。最近,郑海荣团队发现超声神经调控技术可安全有效地调控脑内神经元电活动,抑制癫痫病人脑组织神经元的异常放电和改善癫痫猴子的行为[48, 49],为癫痫疾病的临床干预治疗提供了重要的技术转化前景(见图8)。

  • 图8 超声神经调控技术在脑疾病干预与治疗方面的应用

  • 上述超声神经调控技术研究成果证实超声作为一种新型无创的神经刺激与调控技术在脑科学研究和脑疾病干预方面展示了光明前景。在国家自然科学基金委国家重大科研仪器研制项目支持下,中科院深圳先进院郑海荣团队开发了跨尺度、动态多焦点的超声神经调控装置,涵盖了细胞、小动物、灵长类大动物研究的多个仪器,并已经成功开发了万阵元的磁共振兼容超声神经调控系统,为多点动态脑深部刺激研究提供了仪器基础(见图9)。目前微/小动物神经调控设备已经成功应用到了包括浙江大学、清华大学、上海交通大学、香港理工大学、美国南加州大学、中科院昆明动物所、上海神经所和心理所等十多个国内外神经生物学与脑科学实验室,在超声神经调控及声感基因(声遗传) 等关键技术研究中发挥关键作用。 2017年Nature杂志在“未来用于大脑的超声技术”综述论文中引用报道了郑海荣团队研制的超声神经调控仪器并称之为神经科学和脑疾病研究带来了新武器[50]。2018 年,绿谷制药公司与中国科学院深圳先进技术研究院在上海签署战略合作协议,共同推动国家重大科研仪器研制专项——“基于超声辐射力的深部脑刺激与神经调控技术”的科技成果转化,助力这项在全球具有领先技术优势、核心技术首创的成果可以快速驶入产业化的快车道。

  • 图9 跨尺度超声神经调控仪器

  • 目前,国际上在脑科学领域的新方法和新工具的研究竞争异常激烈,各国政府均投入巨资开展角逐,形势紧迫。2013 年,美国启动“创新神经技术的脑研究计划”,其核心是发展新方法新工具研究脑科学问题。 另外, 美国国家卫生研究院(NIH) 主任弗朗西斯·柯林斯(Francis Collins) 表示,未来10 年美国计划投入40 亿美元资助加速 “旨在了解大脑工作方式的、令人兴奋的新工具和新技术的研发工作”。美国“脑计划”确定的关键技术领域之一就是研发精准调控大脑神经元的新技术和新方法。欧盟、日本近年也启动了相应的脑科学研究专项,我国的“脑计划”专项也将呼之欲出。超声作为一种新型、无创的神经调控方式,相比现有的神经刺激与调控技术具有独特的优势(见图10),在脑疾病干预和治疗方面展示出特殊的优势和巨大的应用前景。

  • 图10 各类神经调控技术[51]

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    • [33] SERVICK K.Hope grows for targeting the brain with ul-trasound[J].Science,2020,368(6498):1408.

    • [34] GUO T,LI H,LV Y,et al.Pulsed transcranial ultrasound stimulation immediately after the ischemic brain injury is neuroprotective[J].IEEE Transactions on Biomedical Engineering,2015,62(10):2352-2357.

    • [35] WU S,ZHENG T,DU J,et al.Neuroprotective effect of low-intensity transcranial ultrasound stimulation in endothelin-1-induced middle cerebral artery occlusion in rats[J].Brain Research Bulletin,2020,161:127-135.

    • [36] ZHANG D,LI H,SUN J,et al.Antidepressant-like effect of low-intensity transcranial ultrasound stimulation[J].IEEE Transactions on Biomedical Engineering,2019,66(2):411-420.

    • [37] ZHANG J,ZHOU H,YANG J,et al.Low-intensity pulsed ultrasound ameliorates depression-like behaviors in a rat model of chronic unpredictable stress[J].CNS Neuroscience & Therapeutics,2020:1-11.

    • [38] SANGUINETTI J L,HAMEROFF S,SMITH E E,et al.Transcranial focused ultrasound to the right prefrontal cortex improves mood and alters functional connectivity in humans[J].Frontiers in Human Neuroscience,2020,14(52):

    • [39] ZHOU H,NIU L,XIA X,et al.Wearable ultrasound improves motor function in an mptp mouse model of parkinson's disease[J].IEEE Transactions Biomedical Engineering,2019,66(11):3006-3013.

    • [40] ZHOU H,NIU L S,MENG L,et al.Noninvasive ultrasound deep brain stimulation for the treatment of Parkinson's disease model mouse[J].Research,2019,2019:1748489.

    • [41] XU T,LU X X,PENG D H,et al.Ultrasonic stimulation of the brain to enhance the release of dopamine-A potential novel treatment for Parkinson's disease[J].Ultrasonics Sonochemistry,2020,63:104955.

    • [42] WANG Z T,YAN J Q,WANG X R,et al.Transcranial ultrasound stimulation directly influences the cortical excitability of the motor cortex in Parkinsonian mice[J].Movement Disorders,2020,35(4):693-698.

    • [43] BOBOLA M S,CHEN L,EZEOKEKE C K,et al.Transcranial focused ultrasound,pulsed at 40 Hz,activates microglia acutely and reduces Aβ load chronically,as demonstrated in vivo[J].Brain Stimulation,2020,13(4):1014-1023.

    • [44] BEISTEINER R,MATT E,FAN C,et al.Transcranial Pulse Stimulation with ultrasound in alzheimer's diseasea new navigated focal brain therapy[J].Advanced Science,2020,7(3):1902583.

    • [45] NIU L L,GUO Y C,LIN Z R,et al.Noninvasive ultrasound deep brain stimulation of nucleus accumbens induces behavioral avoidance[J].Sci China Life,2020,63(9):1-9.

    • [46] BYOUNG KYONG M,BYSTRITSKY A,KWANG I K J,et al.Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity[J].BMC Neuroscience,2011,12(1):23-34.

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    • [48] LIN Z,MENG L,ZOU J,et al.Non-invasive ultrasonic neuromodulation of neuronal excitability for treatment of epilepsy[J].Theranostics,2020,10(12):5514-5526.

    • [49] ZOU J,MENG L,LIN Z,et al.Ultrasound neuromodulation inhibits seizures in acute epileptic monkeys[J].iScience,2020,23(5):101066.

    • [50] LANDHUIS E J N.Ultrasound for the brain[J].2017,551(7679):257-259.

    • [51] DARROW D P.Focused ultrasound for neuromodulation[J].Neurotherapeutics,2019,16(1):88-99.

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    • [51] DARROW D P.Focused ultrasound for neuromodulation[J].Neurotherapeutics,2019,16(1):88-99.

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