Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (11): 1799-1804.doi: 10.3969/j.issn.2095-4344.3078
Wang Liqun1, Li Yuxi1, Jin Rongjiang1, Wang Wenchun2, Pang Richao2, Zhang Anren2
Received:
2020-04-07
Revised:
2020-04-13
Accepted:
2020-05-17
Online:
2021-04-18
Published:
2020-12-22
Contact:
Zhang Anren, Professor, Chief physician, Doctoral supervisor, Department of Rehabilitation Medicine, General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
About author:
Wang Liqun, Master candidate, College of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
Supported by:
CLC Number:
Wang Liqun, Li Yuxi, Jin Rongjiang, Wang Wenchun, Pang Richao, Zhang Anren. Application of functional near-infrared spectroscopy in the study of depression[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(11): 1799-1804.
2.1 抑郁症的临床诊断及治疗现状 抑郁症是一种高致残率的精神障碍。根据世界卫生组织的统计报告,全世界有超过3亿人患有抑郁症[5] ,抑郁症是导致世界范围内残疾的主要原因,是造成全球总体疾病负担的主要因素。同时,抑郁症的复发率很高,大多数患者甚至会遭受多次复发[6],更严重的是,抑郁症可能导致自杀。由于抑郁症是一种多维度的异质性疾病,不同个体之间的发病机制、临床表现、治疗及预后等方面都存在较大差异,目前对其病因和病理生理学知之甚少。当前抑郁症的诊断仍依赖于患者的自我报告和行为评估,缺乏明确的生物标志物或诊断的金标准[7]。抑郁症的治疗也主要集中于症状的缓解,没有取得实质性进展。因此,寻找高灵敏度和特异度的生物标记物,为临床个体化诊断和治疗提供相对精确的证据,已成为当务之急。 2.2 fNIRS的原理及优缺点 2.2.1 fNIRS的原理 近红外光在人体组织中能被特定的化合物吸收,这些化合物包括水、脂质、细胞色素、氧合血红蛋白、去氧血红蛋白等,它们均有自己特定的吸收波长,其中650-900 nm 波长的近红光对氧合血红蛋白和去氧血红蛋白较为敏感。人体的不同组织(皮肤、颅骨、血红蛋白等)对近红外光有不同程度的吸收。由于颅骨和皮肤相对固定,颅内光的衰减主要原因在于氧合血红蛋白和去氧血红蛋白对光的吸收。近红光可以穿透颅骨到达皮质 2.0-3.0 cm 。fNIRS通过测定大脑活动区域皮质散色光的强度,进而得知脑内氧合血红蛋白和去氧血红蛋白的相对浓度变化,从而获得大脑活动的相关信息。氧合血红蛋白的浓度在大脑活动时的变化尤为显著,是fNIRS 数据分析中最常用的指标之一[8]。近红外装置的主要组成部分有发射光源、检测器和数据处理系统。发射光源在人的头皮表面发射一束近红外光,光以“香蕉型”的弯曲路径传出头皮,被检测器接受并进行数据处理,最终获得检测脑区血红蛋白浓度变化情况。发射光源与检测器的距离即为一条通道[9],通道一般需要大于2.5 cm[10],见图2。 2.2.2 fNIRS的优缺点 fNIRS作为一种神经影像学技术,具有其独特的优势。近红外装置简单,轻巧便携;操作简单,操作者容易上手;无创且经济,受试者易于接受;可重复测量,时间分辨率高;受试人群范围广,对头动人群的相对高容忍度,适合婴幼儿、不自主运动的患者等,同时不受场地限制,适易于幽闭恐惧症、身体不易移动的人群;与其他脑功能影像技术兼容性好,如功能磁共振成像、脑磁图、脑电图、正电子发射断层扫描等。fNIRS也有其不可避免的缺点:探测深度较浅,仅能到达大脑皮质 2.0-3.0 cm ;相比功能磁共振成像的检测范围累及全脑且对软组织的对比度分辨率高,fNIRS的空间分辨率较低;目前fNIRS在技术、信号解读和数据分析等方面的差异使其难以标准化。 2.3 fNIRS在抑郁症研究中的应用 2.3.1 fNIRS应用于抑郁症的认知功能研究 认知功能障碍是抑郁症患者的核心特征之一[11],主要表现在执行功能、工作记忆、言语功能、注意力等方面的异常[12]。认知功能障碍主要与背外侧前额叶皮质、丘脑、背外侧尾状核等大脑区域的异常有关。影像学研究显示,抑郁症患者的额叶、颞叶、丘脑、前扣带皮质和杏仁核等大脑区域发生了明显变化[13]。fNIRS主要从额叶的血流动力学变化方面进行抑郁症的认知功能障碍研究。 言语流畅性任务(verbal fluency test,VFT)是指让受试者在规定时间内进行说、读、写的流畅性的词语记忆任务,主要分为音韵言语流畅性任务和语义言语流畅性任务。作为fNIRS在检查神经精神疾病患者时常用的激活任务,言语流畅性任务可以激活某些大脑区域,语义言语流畅性任务可激活左额叶,包括额下回和前额叶皮质等区域[14-15],音韵言语流畅性任务可激活背外侧前额叶皮质区域[16]。因此,言语流畅性任务常作为一种认知激活范式。认知激活期间血红蛋白变化的降低被认为是抑郁症潜在的生物标志物[17]。有学者指出,由于言语流畅性任务的认知需求和与抑郁相关的认知缺陷之间存在重叠,言语流畅性任务对抑郁症特别敏感[18]。因此,在通过fNIRS研究抑郁症的认知激活状态下皮质的血流动力学反应变化的研究中,言语流畅性任务的应用最多。多数研究表明,重度抑郁症患者在言语流畅性任务过程中,主要在前额叶区域的氧合血红蛋白减少。SUTO等[17]使用24通道近红外光谱技术检测重度抑郁症患者在言语流畅性任务期间额叶血红蛋白浓度变化发现,抑郁组的双侧额叶氧合血红蛋白的增加都比健康对照组小。OHTA等[19]也有类似结论,他们借助52通道fNRIS发现重度抑郁症患者在言语流畅性任务期间,双侧额叶区域氧合血红蛋白的增加减弱。另外有研究则发现抑郁症患者在进行认知任务过程中,存在半球差异。OKADA等[20]对缓解期重度抑郁症患者的双侧大脑皮质进行功能磁共振成像观测发现,与健康受试者相比,缓解期重度抑郁症患者的左侧前额叶皮质的激活明显减弱。随后,AKIYAMA等[21]利用fNIRS对抑郁症患者的双侧额叶皮质进行的研究也发现了类似结果,该研究将抑郁症患者定义为成两组:具有强制性症状(情绪低落、兴趣丧失或愉悦感超过2周)的组和没有强制症状的组(抑郁症状得到缓解但仍有残留)。研究结果显示,与没有强制症状的抑郁症患者相比,有强制症状的抑郁症患者的左侧背外侧前额叶皮质的激活明显减少。以上研究结论虽未统一,但都为抑郁症的额叶功能障碍提供证据,进而促进认知功能障碍的相关研究进展。 工作记忆是许多认知任务和日常活动执行的基础,其完整性对于日常工作至关重要。神经心理学研究表明抑郁症患者的工作记忆受损[22-23]。众多学者通过对执行工作任务的抑郁症患者进行功能磁共振成像研究,发现工作记忆的损伤是由左侧前额叶皮质、左侧中央前回、左侧岛叶、右侧颞叶和额上皮质等大脑区域的异常介导的[24-26]。利用fNIRS检测抑郁症患者工作记忆任务期间血流动力学特征的研究相对较少。SCHECKLMANN等[27]采用fNIRS对16例抑郁症患者和14例双相情感障碍患者(躁郁症)以及15例健康受试者进行工作记忆任务的研究,与健康对照组相比,两组患者的背外侧和腹外侧前额叶皮质均表现出较低的氧合血红蛋白浓度变化,但抑郁症组与躁郁症组之间差别无统计学意义。PU等[28]使用52通道近红外光谱仪测量了重度抑郁症患者执行工作记忆任务过程中前额叶和颞叶的血红蛋白的浓度变化,与健康对照组相比,重度抑郁症患者的工作记忆任务表现较差,他们的外侧前额叶和上颞叶皮质激活的增加幅度较小,这一结果与先前在重度抑郁症患者的工作记忆缺陷和前额叶皮质功能障碍方面的发现相一致,但与一些功能磁共振成像研究相矛盾,这些研究表明抑郁症患者在工作记忆任务期间皮质活动增加[29-31]。这可能与重度抑郁症患者的神经响应与认知需求之间的倒U型关系有关,即在较低的认知要求条件下,重度抑郁症患者的神经反应较低,在较高的认知负荷条件下,神经反应增强,但随着认知负荷不断增加并超过一定范围,神经反应减弱。因此,使用不同难度的工作记忆任务,重度抑郁症患者的大脑皮质会呈现不同的血流动力学变化。 2.3.2 fNIRS应用于抑郁症的其他功能研究 抑郁症除了存在认知功能障碍,还具有认知、知觉和行为异常等综合导致的功能障碍,这些功能障碍表现为情绪低落、思维迟缓、睡眠障碍、自杀观念或行为等症状。由于目前临床诊断仍较依赖这些临床表现,探究其发生机制成为研究的重点。 情绪调节是一种在行为和生理层面上增加、减少或维持情绪的能力。抑郁症患者的核心症状之一是情绪调节能力受损。研究表明,情绪调节的关键结构位于边缘系统,除此之外,前额叶皮质也参与情绪处理[32]。fNIRS最早应用于研究健康人的情绪诱导,研究者以国际情感图片系统(IAPS)的图片作为情绪诱导材料来评估前额叶皮质激活中的性别差异[33],图片被分为2组:一组是中性的图片(家庭用品),另一组是负面的图片(血腥、残缺不全的尸体等),结果发现,与中性情绪刺激相比,负面情绪刺激对男性的额叶氧合血红蛋白反应没有显著差异,但是对女性的反应显示出明显的增强。这表明在遇到负面的生活事件时,女性可能比男性容易情绪失调并患上抑郁症。GLOTZBACH等[34]以20名健康女性作为研究对象,通过fNIRS来区分情绪诱导和调节。他们将中性图片作为参考基线,恐惧图片视为情绪诱导条件,同时将重新评估的恐惧图片(观看过的恐怖图片以随机顺序第2次出现)视为情绪调节条件,最终他们没有发现诱导条件与调节条件下大脑激活的显著差异,但是与基线条件相比,诱导条件下双侧前额叶的氧合血红蛋白浓度显著升高,调节条件下仅激活左侧前额叶皮质。据文献报道,MANELIS等[35]是首次使用fNIRS来探究健康受试者与抑郁症患者面部情绪表达识别过程中前额叶皮质激活差异的研究,实验结果发现,相较于健康对照组,抑郁症组在识别中性的面部情绪表情时更慢,也更不准确,这可能与面部情绪处理过程中背外侧前额叶皮质激活的异常减少有关。 睡眠改变在抑郁症患者中经常被观察到,并构成诊断标准的关键部分。抑郁症患者经常难以入睡,并且在夜间频繁觉醒[36]。流行病学研究表明,抑郁症患者的睡眠异常频率增加,甚至在缓解期间仍持续存在,同时发现持续失眠但无抑郁的患者比正常睡眠者患上抑郁症的风险更高[37]。一项针对于40名健康志愿者的fNIRS研究报道[38],前额叶皮质区域的反应性降低与白天的轻度嗜睡有关。为了探究抑郁症患者的睡眠障碍是否与前额叶皮质功能受损有关,研究者使用多通道fNIRS研究重度抑郁症住院患者大脑皮质氧合血红蛋白变化与睡眠障碍之间的关系[39],实验期间要求在家中的健康对照者遵守与住院患者相似的睡眠时间表,并使用了腰部记录仪来记录受试者晚上睡眠参数。结果表明,在左侧前额叶皮质和颞叶区域,重度抑郁症患者在言语流畅性任务诱导的平均氧合血红蛋白水平变化明显小于正常对照组,提示左侧前额叶皮质区域的反应性受损与重度抑郁症患者睡眠障碍的严重程度有关。但是由于严重抑郁症状和治疗睡眠障碍的药物可能会影响血液动力学反应,且难以客观评估抑郁症患者的白天嗜睡问题,因此有必要对抑郁症患者的睡眠障碍问题进行更加深入的研究。 自杀意念是抑郁症的常见症状。神经影像学研究表明,自杀意念与执行功能受损有关,执行功能障碍与前额叶皮质的结构和功能变化有关[40]。据所查资料,第一个报道fNIRS和抑郁症自杀意念之间联系的研究是PU等[41],他们纳入了67例重度抑郁症患者和67例在年龄、性别和智力方面与重度抑郁症患者相匹配的健康志愿者,通过使用汉密尔顿抑郁量表(HAMD)中的自杀项目来衡量自杀意念。结果发现,与健康对照组相比,重度抑郁症患者在言语流畅性任务诱导下的平均氧合血红蛋白的变化要小得多;另外,在重度抑郁症患者中,言语流畅性任务激活引起右侧的背外侧前额叶皮质、眶额叶皮质和额极皮质等区域平均氧合血红蛋白水平的变化与HAMD中自杀意念项目得分之间存在显著的负相关;同时,在有和没有自杀意念的重度抑郁症患者中,上述3个大脑皮质区域的平均氧合血红蛋白水平的变化存在显著差异。这些结果表明,背外侧前额叶皮质,眶额叶皮质和额极皮质(区域的功能与重度抑郁症患者的自杀意念相关。最近一项研究以53例重度抑郁症患者的前额半球不对称性为切入点,通过在认知任务期间使用48通道的fNIRS测量氧合血红蛋白浓度变化探究抑郁症严重程度与自杀意念之间的关系。结果表明,与健康对照组相比,重度抑郁症患者在言语流畅性任务期间左侧前额叶氧合血红蛋白的变化相对减少,这种额叶不对称减轻了抑郁症严重程度与自杀意念之间的关系[42]。具体来说,当左侧前额叶皮质激活较高时,抑郁严重程度对自杀意念的影响更强。虽然fNIRS应用于抑郁症患者自杀观念方面的研究较少,但是上述研究表明fNIRS是一种有效的医疗监测工具。 2.3.3 fNIRS用于抑郁症的鉴别诊断 研究发现,通过fNIRS测量皮质血流动力学反应,可以将抑郁症与双相情感障碍、精神分裂症、边缘型人格障碍等精神疾病进行鉴别。 双相情感性障碍患者既有躁狂症状发作,又有抑郁发作,因此很难从症状上区分双相情感性障碍的抑郁发作与抑郁症。KAMEYAMA等[43]通过fNIRS发现,由于抑郁症和双相情感障碍患者的额叶功能存在差异,前者在言语流畅性任务期间主要表现为额叶氧合血红蛋白反应减弱,后者表现为额叶氧合血红蛋白反应延迟。有研究团队利用fNIRS开发出一种在临床上适用的神经影像引导诊断支持系统,通过fNIRS检测到的额叶血流动力学模式可较准确地区分重度抑郁症、双相情感障碍和精神分裂症[44]。精神分裂症也是一类常见的精神疾病,需要与抑郁症进行鉴别。SUTO等[17]发现抑郁症患者的特征是在认知任务期的前半部分出现了小幅度的氧合血红蛋白升高,而精神分裂症患者在任务期的开始时出现了小幅度的氧合血红蛋白升高,在任务期结束后氧合血红蛋白再次升高。另外,精神分裂症和重度抑郁症患者在言语流畅性任务期间前额叶皮质活动降低也存在不同,精神分裂症患者主要集中在额极区域,而重度抑郁症患者主要在背外侧前额叶皮质区域[45]。最近一项针对重度抑郁症患者和边缘型人格障碍患者的研究显示[46],可能由于边缘型人格障碍患者的额叶皮质功能的破坏没有重度抑郁症患者那样广泛,在执行言语流畅性任务过程中,重度抑郁症患者右侧额叶皮质的血流动力学反应明显低于边缘型人格障碍患者。以上发现表明,fNIRS相对较高的时间分辨率对于研究不同情感障碍的患者具有潜在的优势,可能为神经精神疾病的鉴别诊断提供新的机会。 2.4 fNIRS与其他技术的结合 2.4.1 fNIRS与重复经颅磁刺激技术 随着fNIRS技术的不断发展,研究者开始将fNIRS与其他技术相结合用于抑郁症的研究。ESCHWEILER等[47]首次尝试在抑郁症研究中将fNIRS与重复经颅磁刺激技术相结合,他们使用fNIRS测量了抑郁症患者重复经颅磁刺激技术治疗前左侧背外侧前额叶皮质区域的血流动力学反应,结果发现重复经颅磁刺激技术对抑郁症状的改善与患者在治疗前镜像绘制任务期间左侧背外侧前额叶皮质较低的血流反应有关。由于只进行了重复经颅磁刺激技术治疗前的任务测量,尚不清楚重复经颅磁刺激技术的治疗可能对fNIRS的活动有何影响,但是这项研究开创了利用fNIRS进行重复经颅磁刺激技术靶向背外侧前额叶皮质治疗的先例[48]。SHINBA等[49]对15例耐药性抑郁症患者的左侧背外侧前额叶皮质使用重复经颅磁刺激技术治疗方案(刺激强度为10 Hz,每周进行5 d,共6周),在治疗第1天(开始)和最后一天(结束)的重复经颅磁刺激技术刺激过程中,利用fNIRS监测抑郁症患者的额叶血红蛋白浓度变化,使用蒙哥马利抑郁量表(MADRS)评估抑郁症状的严重程度。研究结果显示多数患者在重复经颅磁刺激技术刺激时的额叶血红蛋白浓度反应持续增加(额叶血红蛋白浓度增加组,n=9),少数患者的额叶血红蛋白浓度反应下降(额叶血红蛋白浓度降低组,n=6);与额叶血红蛋白浓度降低组相比,额叶血红蛋白浓度增加组在治疗结束时的MADRS得分明显降低。以上研究表明在重复经颅磁刺激技术刺激过程中,fNIRS能为重复经颅磁刺激技术的治疗提供有效指标。 2.4.2 fNIRS与经颅直流电刺激 最近一项研究使用fNIRS研究了经颅直流电刺激治疗脑卒中后抑郁症的神经机制,研究者将26例脑卒中后抑郁症患者随机分为接受经颅直流电刺激的实验组和接受假刺激的对照组,在患者经颅直流电刺激治疗前后记录了情绪面部性别判断任务(识别不同面部情绪和性别)和工作记忆任务期间前额叶氧合血红蛋白的反应时间和相对浓度变化。结果发现,与对照组相比,接受经颅直流电刺激治疗后的脑卒中后抑郁症患者对积极面部情绪反应时间明显缩短,处理负性情绪面孔时前额叶皮质的氧合血红蛋白浓度变化相对较大;同时,实验组的工作记忆任务反应时间缩短,双侧前额叶皮质的氧合血红蛋白浓度变化显著增加。提示经颅直流电刺激可通过激活前额叶来改善脑卒中后抑郁症患者的负性情绪处理和工作记忆,从而改善抑郁症状[50]。将fNIRS与其他技术(如重复经颅磁刺激技术、经颅直流电刺激、功能磁共振成像、正电子发射断层扫描等)相结合可以更加全面有效地研究抑郁症的生理病理机制,但是不同技术的信号融合仍存在很多挑战。 "
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