脑皮层功能定位技术在临床研究中的应用发展

温建斌,李小俚

北京师范大学 认知神经科学与学习国家重点实验室,北京 100875

[摘 要]皮层功能定位对于保证神经外科手术的效果有重要作用,而皮层电刺激技术一直以来都被认为是临床皮层功能定位的“金标准”。随着神经成像技术和理论的发展,越来越多新的方法也开始被应用于神经外科皮层功能定位,包括皮层脑电图、正电子放射断层扫描、功能核磁共振成像、脑磁图、经颅磁刺激以及皮层光学成像等。本文对这些技术的原理分别作了简单介绍,并从临床可靠性、安全性、检测效率、成本以及应用现状等方面对它们进行比较。文章最后对临床皮层功能定位技术的未来发展状况作出了展望。

[关键词]皮层功能定位;神经外科;功能核磁成像;经颅磁刺激;皮层脑电图

引言

神经外科手术对于药物难治性癫痫[1]、脑血管疾病[2]以及脑肿瘤等[3]均有较好的治愈效果。但是,当大脑的重要功能区与病灶临近或重合时,便会受到损毁手术的影响,从而引起功能损伤。大部分术后功能区受损的病人会在3个月内得到恢复,但约有5%的病人会形成永久损伤[4]。因此,如何能准确地对大脑重要的功能区进行定位对手术方案的制定和病人的愈后有重要意义。皮层电刺激技术(Electrical Cortical Stimulation,ECS)一直以来被认为是临床上皮层功能定位的“金标准”,但随着神经信号采集以及神经成像技术和理论的发展,越来越多的新方法也开始被应用于神经外科皮层功能定位。除了皮层电刺激之外,目前可在临床上用于皮层功能定位的技术包括:皮层脑电图(Electrocorticography,ECoG)、正电子放射断层扫描(Positron Emission Tomography,PET)、功能核磁共振成像(Functional Magnetic Resonance Imaging,fMRI)、脑磁图(Magnetoencephalography,MEG)、经颅磁刺激(Transcranial Magnetic Stimulation,TMS)和皮层光学成像(Optical Cortical Imaging,OCI)等。

总的来说,皮层功能定位技术可采取的策略可大体分为两种:① 观测记录相关脑区在特定认知任务下的活动状态,如电/磁信号(ECoG和MEG)、光信号(OCI)或代谢强度(fMRI和PET)等指标。采用这种策略可以说明相关脑区参与了特定认知过程,但无法证明其充分性和必要性;② 对相关皮层区域施加刺激并考察引起的后果(ECS和TMS)。如果刺激引起抑制性的效果,则可以暂时造成目标皮层区域失活,从而直接模拟手术可能造成的认知损伤,验证了该皮层区域对于相关功能的必要性;反之,如果刺激是兴奋性的,则可以通过观察其是否能引起相关的预期反应而确定相关皮层区域的功能。除了总体技术策略,这些方法在原理上也各不相同,在临床可靠性、检测效率、安全性以及成本方面也存在差别,本文将分别对其作简单介绍,比较其应用现状,并就未来发展作出展望。

1 皮层功能定位技术简介

1.1 皮层电刺激技术

ECS的发展最早可以追溯到19世纪,于1910年前后开始作为一种稳定可靠的功能定位技术被应用于神经外科手术,一直至今。ECS需要开颅进行,通过直接放置在皮层表面的电极施加电流刺激而对相关皮层区域造成干扰,从而判断其功能。作为临床应用时间最长的皮层功能定位技术,ECS已经使无数病人免受外科术后的功能损伤,其可靠性也得到诸多系统研究的支持[5-6]。实际上,尽管有很长的历史,几十年来ECS本身并没有很多实质性的改变,临床上甚至没有一套严格的标准化操作规程[7]。由于是直接对皮层施加电刺激,在应用于癫痫病人时,ECS有诱发后放电甚至发作的风险,另外,在应用于儿科病人时,由于发育中的皮层对于电刺激的耐受性较差,往往不能取得理想效果。ECS的另外一个缺点是效率低,每个刺激点需要从弱电流开始,重复若干次后再逐步加强,且刺激间需要留有充分间隔。这样导致一个典型的术前硬膜下植入电极电刺激功能定位程序耗时经常长达数小时。尽管如此,ECS仍然是应用最为广泛的皮层功能定位技术,其也经常被用作标准来评估其他功能定位技术的效果。

1.2 皮层功能定位法-皮层脑电信号定位法

在颅骨打开的状态下,与皮层电刺激相反的策略是给予肢体某个部位物理刺激并观测记录大脑皮层的活动,即通过 体感诱发电位来定位功能区[8]。如果简单的物理刺激被替换成的认知任务,则通过记录事件相关电位就可以完成对高级认知功能的皮层定位,如语言等[9]。而随着信号采集和处理技术的发展,研究者们逐渐意识到神经电信号在时域和频域都含有丰富信息,其中高频伽马振荡活动被认为可以以很好的时间和空间特异性反映多种认知过程,包括体感运动、语言和记忆等[10-13]。因此,在该频段的事件相关同步化可以作为皮层功能定位的理想指标[14],其临床可靠性也得到了诸多研究的支持[15-17],有研究者甚至指出在某些情况下,它能够比皮层电刺激更好地避免手术后功能损伤[18]

相较而言,用皮层脑电定位重要功能区可以免除电刺激带来的风险,且能够同步处理所有电极通道来源的数据,提高了效率。而且由于其高信噪比和高时空分辨率,很多研究者开发出基于皮层高频伽马活动的快速或实时功能定位系统[19-22]。利用皮层脑电信号确定功能区的缺点在于,它不能够反映全脑的信息,也不能记录(或刺激)到大脑沟回里面和深部(如内侧颞叶和海马)皮层组织,电极之间的区域也可能被漏测,而这些也几乎是所有侵入性功能定位技术都面临的问题。

1.3 正电子放射断层扫描技术

PET技术发展于上世纪50年代,其基本原理是将能够被人体正常代谢的分子用能够进行正β衰变的同位素标记,然后在特定的时间窗口内,通过记录同位素衰变引起的物理效应来确定相关分子在空间中的密度分布,从而达到对人体组织进行结构成像和功能成像的目的。神经功能成像常用的标的物有15O标记的水分子和氟代脱氧葡萄糖(18F-FDG),前者通过皮层血流量来反映神经细胞的活动强度,后者与细胞对于葡萄糖摄取的情况相关,从而反映细胞活动水平。PET技术可以用于多种功能定位,如躯体感觉、运动和语言等[23-25]。但此项技术的缺点有很多,其空间分辨率最高仅能达到4 mm,而其信号本身也不能反映随时间变化的情况[26]。PET设备部署成本较高,图像采集时需要的放射性显像剂相对昂贵,并且显像剂的注射和在体内驻留都可能对人体造成不良影响。

1.4 脑磁图技术

MEG技术发展于上世纪60年代,其依靠探测由神经电活动引起的空间磁场变化来记录脑活动。由于神经电活动很微弱,产生的磁场变化也很难探测,因此MEG需要及其灵敏的超导量子干涉探头才能捕捉到有效信号。早期的MEG主要利用躯体感觉诱发磁场对躯体感觉区进行定位[27-28],随后类似的原理也被应用于运动和语言等[29-30]相关功能的定位。近年来也有许多研究者开始关注MEG记录到的不同频段的皮层活动与认知任务之间的关系[31-32]。MEG是一种非侵入性的脑成像设备,其空间分辨率可以达到毫米级,时间分辨率可以达到毫秒级,因此除了功能定位之外,在临床上也多用于记录分析某些异常放电活动,如癫痫[33]。但此种技术的缺点在于设备部署和采集成本很高,而其对于相关溯源算法的依赖也使其计算结果的可靠性一直受到争议,这也一直是该领域研究者们所关注的焦点[34]

1.5 功能核磁共振成像技术

MRI发展于上世纪70年代,其基本原理是通过在强梯度磁场下叠加一个高频激发磁场,使得特定原子(通常为氢原子或氧原子)能级状态发生变化,通过检测原子状态转换时以电磁波形式逸出的能量来获得该种类原子的空间密度分布,从而区分不同组织或活动状态。fMRI是基于MRI的脑功能定位技术,其主要观测指标血氧水平依赖(Blood-Oxygen-Level Dependent,BOLD)信号,与PET类似,都是利用了局部神经活动强度与代谢原料的需求关系。

随着fMRI在认知神经科学领域的普及,大量的研究也开始关注其在皮层功能定位中的应用。早期若干研究初步确认了fMRI在皮层运动及体感功能定位上的可行性[35-40]。随后有研究开始系统评估fMRI在临床应用效果,如Lee等[41]在其神经外科中心的病例回顾报告中指出,fMRI运动功能定位的结果对89%的肿瘤病人和91%的癫痫病人手术过程有贡献; Krishanan等[42]发现,手术切除部位如果在fMRI功能激活点10 mm范围以外则基本不会造成运动功能损伤,而在5 mm以内则有很可能造成术后运动功能损伤。fMRI在语言功能定位中得到结果则并不尽如人意,如 Giussani等[43]在一份文献总结中报道称,如果以术中皮层电刺激为标准的话,fMRI的语言功能定位结果敏感性为59%~100%,而特异性为0%~97%。造成这种现象的主要原因是语言功能本身的复杂性,但其也常受到病人病理状态[44]、任务设计[45]、磁场强度[46-47]以及采集参数的影响。

fMRI在时空分辨率和信噪比上都优于PET,几乎不会对人体造成损伤,其信号采集基本亦不需要额外的成本,而且随着技术的推广,部署成本也显著降低。fMRI的空间分辨率可随着外部梯度磁场强度的提高而提高,但也受限于其信号本身的属性,因为产生BOLD信号的微动脉和微静脉与活动的神经元之间约有1 mm的误差。类似的,由于神经活动与血氧信号之间的延迟关系,其时间分辨率最短也只能以秒计。

fMRI在应用中最大的挑战是其信号极易受到运动干扰,有研究表明受试者头部不到1 mm的位移就会对成像结果产生显著影响[48],而病人又常常比正常人更易出现不自主的运动,为此很多研究者着力于发展新的固定或监测设备[49]和头动矫正算法[50]。此外,也有很多研究者致力于将fMRI纳入标准化的操作流程,为此他们提出针对整套的多种皮层功能定位的任务方案,这些整套任务可以迅速完成包括语言、运动、视觉甚至情感等功能的皮层定位[51-53]。另外值得一提的是,与功能定位密切相关的白质纤维追踪也只能靠以MRI为基础的弥散张量成像技术(Diffusion Tensor Imaging,DTI)来实现,鉴于此,fMRI和DTI的联合应用有望被纳入神经外科手术的标准规程[54]

fMRI在临床皮层功能定位方面近来有两个方面的发展值得关注,实时功能核磁成像(Real-time fMRI,Rt-fMRI)和静息态功能核磁成像(Resting-state fMRI,Rs-fMRI)。自Cox等[55]最早实现了Rt-fMRI以来,随着图像采集技术,计算机计算能力以及算法的提高和改进,其可靠性和实用性都大大提高。目前Rt-fMRI主要基于回波平面成像,它能够最大限度的提高图像采集速率。Rt-fMRI的数据处理可以在一个滑动时间窗里进行,也可以是对之前全部数据进行计算形成积累统计量。Rt-fMRI已经被成功应用于包括运动、躯体感觉和语言等多种功能的皮层定位[56-58]。尽管其相对于传统方法在噪声去除和分辨率上有所欠缺,有效性也缺少大样本数据支持,但其时效性在临床环境下无疑具有很大的优越性。

Biswal等[59]首次发现低于0.1 Hz的自发fMRI信号中也有重要信息,即低频皮层活动信号在互相关联的区域呈现出很高的相关性,这构成了Rs-fMRI技术的理论基础[60]。在方法上,Rs-fMRI可以用解剖位置较为明确的种子点感兴趣区来定位相关联的其他功能区,如被肿瘤影响的运动区可以通过计算与对侧未受影响的运动区的相关性而得到定位[61];还可以通过独立成分分析(Independent Component Analysis,ICA)自动提取各功能网络[62]。相较而言,种子点分析得到的结果较为准确,但长距离功能连接尤其是两半球之间的连接很容易受到影响,因此有得出错误结论的风险;ICA不需要确定种子点,也较少受连接缺失影响,因为其可以将被隔开的功能网络呈现为两个独立部分,但ICA的缺点在于得到的结果很多是无意义或噪音成分,其需要经过人为挑选来确定重要功能。

总体而言,Rs-fMRI的优点在于其适用于很多不能配合认知任务的病人群体,如运动或认知功能受损的患者和低龄儿童等,其也能够在睡眠甚至麻醉状态下进行,此外其利用同一批数据即可定位所有功能网络,这大大提高了效率。

1.6 经颅磁刺激技术

1985年,Barker等[63]首次实现了用磁脉冲对人脑运动皮层的非侵入性刺激,即TMS。TMS的基本原理是通过放置在头部上方的电磁线圈快速充放电,在线圈下方空间产生聚焦于某一点并快速变化的磁场,进而在目标区域产生电场刺激神经组织。近来,随着依据个体核磁成像数据的导航系统被引入TMS系统[64]以及刺激线圈及参数的优化,TMS的空间分辨率大大提高,其在实质上已经成为最接近皮层电刺激的技术,而其本身具有的无创性更使得其在临床上得到迅速普及[65-66]。很多研究者[67-70]都论证了TMS在运动功能和语言功能定位中的有效性。TMS在临床应用的安全性也得到了大样本数据的支持[71]。最近有一些回顾性报道指出,TMS应用于术前功能评估可以减小开颅面积,缩短手术时间,以及更好地避免术后功能损伤[72-74]

1.7 皮层光学成像技术

神经元活动同样可以改变大脑皮层的光学特性,如对特定波长光线的吸收率和散射率等等,以此作为基础的光学成像技术也可以用来进行皮层功能定位[75]。目前临床研究较多的OPI都是以血红蛋白相关信号为基础,因此其与BOLD信号的机制类似,但在时空分辨率上能高一到两个数量级[76]。OPI应用于外科手术皮层功能成像已有若干报道[77-85],包括躯体感觉、运动和语言等,其可靠性也得到了较为系统的验证。光学信号的采集也需要在开颅条件下进行,而且其需要额外的数据采集分析设备,因此临床推广程度并不高。

但OPI几乎是目前神经科学领域发展最快的技术[86],多光子显微成像已经可以实现以单细胞甚至亚细胞级的空间分辨率和10 kHz的时间分辨率对脑皮层进行在体记录[87]。由于目前在神经科学领域应用的OPI多依赖于转基因荧光蛋白或外部荧光标记物质,且成像的视野范围受限于镜头尺寸而十分有限,因此较少在临床应用。但笔者认为安全有效的荧光活性物质的开发和成像范围的扩大都是可以逐步解决的问题,因而将高分辨率光学成像用于OPI研究具有很好的发展应用前景。

2 皮层功能定位技术间的比较和联合应用

实际上,每一种单独的技术方案都有其自身的诸多限制,无法实现对大脑皮层功能的充分精确定位。因此,应用多种技术联合施测将有助于直接比较不同方法间的差异,进而得到更为准确的结果。皮层功能定位技术间的比较结果,见表1。

表1 皮层功能定位技术比较

早在1995年,Morioka等[88]就联合使用MEG、fMRI、运动诱发电位和TMS来定位一名癫痫病人的运动皮层,并获得一致性较好的结果。Shinoura等[89]经过比较指出定位躯体感觉皮层时,fMRI比体感诱发电位更为可靠。Roberts等[90]比较了fMRI和TMS在运动皮层定位上的结果,发现两者误差在5 mm以内,但Lotze等[91]发现两者在3D空间里误差达13.9 mm,并认为其与两种技术原理的差异有关。Forster等[92]发现,以皮层电刺激为标准的话,TMS的误差为(10.5±5.67)mm,而fMRI的误差为(15.0±7.61)mm,Coburger等[93]也得到类似的结论。

但同样以皮层电刺激为标准, Babajani-Feremi等[94]于最近的一项研究中指出fMRI的定位准确度虽然不及ECoG,但优于TMS。造成这种差异的原因可能是多方面的,这也从另外一个角度说明fMRI于TMS在准确度上基本相当。为了弥补fMRI时间分辨率低的问题, Dale等[95]开发了一种将fMRI和MEG结合应用的方法,并将其应用于语言功能定位,得到高时空分辨率的结果,这一技术随后得到了ECoG的验证[96]。这表明联合应用无创技术可以达到与颅内皮层直接检测技术相当的结果。

3 总结与展望

综合而言,fMRI和TMS在目前的无创功能定位技术中最适用于临床环境。fMRI设备近来在国内的普及程度大幅提高,技术和理论的发展也已经相对成熟,而其与DTI技术结合能够为神经外科手术提供非常有价值的信息。TMS操作简单,且其能够解决fMRI不能确定的必要性的问题,但TMS的效率不高,因此其适合在fMRI的定位结果的基础上进行验证性施测,以节省时间。术前无创功能定位技术目前尚无法取代术中直接皮层定位,因此皮层电刺激仍然是神经外科手术功能定位的标准流程操作,但术中ECoG具有诸多方面的优势,也正在受到越来越多的重视。然而,笔者认为在未来10~20年的时间内,光学成像将发展成为临床术中皮层活动记录的主要技术。

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本文编辑 刘峰

Application and Development of Functional Cortical Mapping in Clinical Research

WEN Jian-bin, LI Xiao-li

State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China

Abstract:Electrical cortical stimulation (ECS) was considered as the “gold standard” of functional cortical mapping, which played an important role in the effect of neurosurgery surgery. With the development of neuroimaging technology and theory, more and more new methods were used in functional cortical mapping of neurosurgery, for example electrocorticography (ECoG), positron emission tomography (PET), functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), and optical cortical imaging (OCI). The principle of these technologies were brief l y introduced in this paper, and we compared the present situation of the application of these technologies from clinical reliability, security, detection efficiency, cost and application status respectively. Finally, we made the outlook for the future development of clinical functional cortical mapping technology.

Key words:functional cortical mapping; neurosurgery; functional magnetic resonance imaging; transcranial magnetic stimulation; electrocorticography

[中图分类号]R44

[文献标识码]A

doi:10.3969/j.issn.1674-1633.2017.05.031

[文章编号]1674-1633(2017)05-0116-07

收稿日期:2017-03-16

修回日期:2017-03-30

基金项目:国家自然科学基金面上项目“经颅磁刺激诱导的脑节律挖掘和分析”(61273063)。

通讯作者:李小俚,教授,主要研究方向为神经工程。

通讯作者邮箱:xiaoli@bnu.edu.cn