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综述
基于fMRI探讨针刺治疗失眠伴情绪障碍中枢机制的研究进展
王乙翔 孙曌 李豪 王静 康晓娜 冉彬艳 吴琼 黄禄宇 陈镒泽 沈巍

Cite this article as: WANG Y X, SUN Z, LI H, et al. Advances in fMRI-based research to explore the central mechanisms of acupuncture in the treatment of insomnia with mood disorders[J]. Chin J Magn Reson Imaging, 2023, 14(3): 144-148.本文引用格式:王乙翔, 孙曌, 李豪, 等. 基于fMRI探讨针刺治疗失眠伴情绪障碍中枢机制的研究进展[J]. 磁共振成像, 2023, 14(3): 144-148. DOI:10.12015/issn.1674-8034.2023.03.026.


[摘要] 失眠伴情绪障碍是一种身心疾病,以睡眠障碍、紧张恐惧、心悸不安、易激惹等一系列躯体和精神不适为特征,已严重影响人们的身心健康和生活质量。针刺在失眠伴情绪障碍防治方面具有安全无毒、效价比高的优势,但其中枢机制尚不明确。近年来,功能磁共振成像(functional magnetic resonance imaging, fMRI)的进步有助于客观评估针刺治疗失眠伴情绪障碍的疗效,并为探索针刺治疗失眠伴情绪障碍的中枢机制提供了时机。本文通过查阅近年来国内外相关文献,探索针刺对失眠伴情绪障碍患者脑结构和脑功能的中枢响应特征并进行综述,以期更好地了解针刺对失眠伴情绪障碍治疗机制的神经影像学研究现状,为今后研究提供参考和借鉴。
[Abstract] Insomnia with mood disorder is a physical and mental disorder characterized by a range of physical and mental discomforts such as sleep disturbances, nervousness and fear, palpitations and irritability.It has seriously affected people's physical and mental health and quality of life.Acupuncture has the advantage of being safe, non-toxic and cost-effective in the management of insomnia with mood disorders, but its central mechanism is not yet clear. In recent years, advances in functional magnetic resonance imaging (fMRI) have helped to objectively assess the efficacy of acupuncture in the treatment of insomnia with mood disorders.It has also provided an opportunity to explore the central mechanisms of acupuncture in the treatment of insomnia with mood disorders.In this paper, we review the relevant domestic and international literature in recent years to explore the central response characteristics of acupuncture on brain structure and brain function in patients with insomnia with mood disorders.To better understand the current state of neuroimaging research on the therapeutic mechanisms of acupuncture for insomnia with mood disorders, and to provide reference and input for future research.
[关键词] 针刺;失眠伴情绪障碍;中枢机制;脑功能成像;磁共振成像;功能磁共振成像
[Keywords] acupuncture;insomnia with mood disorders;central mechanism;functional brain imaging;magnetic resonance imaging;functional magnetic resonance imaging

王乙翔 1   孙曌 1   李豪 2   王静 3   康晓娜 1   冉彬艳 1   吴琼 1   黄禄宇 1   陈镒泽 1   沈巍 1, 4*  

1 海南医学院中医学院,海口 571199

2 海南省中医院眼科,海口 570203

3 海南省中医院推拿科,海口 570203

4 海南医学院第一附属医院针灸科,海口 570100

通信作者:沈巍,E-mail:hy0204033@hainmc.edu.cn

作者贡献声明:沈巍设计本综述的方案,对稿件重要的智力内容进行了修改;王乙翔起草和撰写稿件,获取、分析或解释本综述的数据/文献;孙曌、李豪、王静、康晓娜、冉彬艳、吴琼、黄禄宇、陈镒泽获取、分析或解释本综述的数据/文献,对稿件重要的智力内容进行了修改;沈巍获得了国家自然科学基金、海南省自然科学基金高层次人才项目、海南省卫生厅科研项目资助;王乙翔获得了海南医学院研创课题项目资助;孙曌获得了国家自然科学基金资助;全体作者都同意最后的修改稿发表,都同意对本综述的所有方面负责,确保本研究的准确性和诚信。


基金项目: 国家自然科学基金 81860880,82260966 海南省自然科学基金高层次人才项目 821RC567 海南省卫生厅科研项目 22A200035 海南医学院研创课题项目 HYYS2021A15
收稿日期:2022-10-28
接受日期:2023-03-02
中图分类号:R445.2  R749 
文献标识码:A
DOI: 10.12015/issn.1674-8034.2023.03.026
本文引用格式:王乙翔, 孙曌, 李豪, 等. 基于fMRI探讨针刺治疗失眠伴情绪障碍中枢机制的研究进展[J]. 磁共振成像, 2023, 14(3): 144-148. DOI:10.12015/issn.1674-8034.2023.03.026.

0 前言

       失眠伴情绪障碍是共病性失眠中的常见类型,患者以经常不能获得正常睡眠为主要特征,往往有入睡困难、多梦、易醒等临床症状,而伴随的情绪障碍一般指焦虑和抑郁,表现为紧张易激、烦躁、心悸不安、惊恐等焦虑障碍或处于情绪低落、易疲劳、食欲变化等抑郁引起的负面情绪,失眠与情绪障碍存在共同的病理生理机制且易“共病”[1, 2]。而在精神障碍的分类中,双相情感障碍表现为低落和情感高涨交替出现,属于情感障碍[3],而不是情绪障碍。

       一项流行病学调查显示,在普通人群中共病失眠和焦虑障碍的发生率为39%[4],而失眠和重性抑郁障碍和心境恶劣的发生率为17.3%[5]。回顾文献证据表明[6, 7],焦虑/抑郁是导致失眠迁延不愈的主要因素,而失眠患者新发焦虑的概率是无失眠患者的6倍,新发抑郁的概率高达3~4倍。然而在临床上失眠往往先于或者同步伴随焦虑/抑郁出现[8]。因此,准确诊断和治疗失眠伴情绪障碍需要进一步了解它们之间的复杂关系。目前功能磁共振成像(functional magnetic resonance imaging, fMRI)作为一种无侵入、无创伤、高时空分辨率的神经成像手段,已被成功应用于研究睡眠及情绪的中枢机制[9]。针刺作为重要的补充与替代医学疗法之一,多项研究[10, 11]证实针刺在治疗失眠伴情绪障碍的有效性,如JIANG等[12]通过选择失眠症患者情绪网络(emotional network, EN)内的大脑区域:杏仁核、内侧前额叶皮层、前扣带皮层等作为种子点进行脑功能连接(functional connectivity, FC)分析发现,与无效穴位针灸组相比,精神调节组在针刺后对中枢神经系统FC的积极影响更为一致,且显著缓解患者的失眠、焦虑和抑郁症状。然而目前有关针刺治疗失眠伴情绪障碍的研究较少且分散,仍有许多中枢机制尚待研究证实。因此,本文通过回顾国内外发表的文献,探索针刺对失眠伴情绪障碍患者脑功能和脑网络的调节特点并进行综述,为广大学者后续研究提供方向和借鉴。

1 失眠伴情绪障碍中枢机制的fMRI研究进展

1.1 失眠伴情绪障碍主要脑区和脑连接的异常

       神经影像学研究表明,失眠患者可见与情绪认知相关的脑区域受损,如睡眠不佳且情绪负面刺激反应增强的杏仁核[13]、灰质体积减小的右侧眶额叶皮层[14]、萎缩性海马亚结构[15]、功能失调的前额叶活动[16]、额纹状体网络(包括尾状核和额下回[17]及岛叶[18]等脑区域存在异常激活,而情绪调节系统(包括额叶皮层、杏仁核和前扣带回)的神经代谢发生改变[19, 20]。已有研究证实,睡眠深度减少或唤醒增加患者的杏仁核灰质体积减小[21],且该区域与抑郁严重程度相关的血浆皮质醇水平[22]、杏仁核血流量[23]存在显著正相关,而失眠和情绪压力可升高葡萄糖转运蛋白1[24]。背侧前扣带回体积减小[21]且该区域γ-氨基丁酸含量减低[25],可能与失眠患者情绪调节障碍及伴发的抑郁状态有关。LEERSSEN等[26]研究发现,重度抑郁症伴失眠患者皮质表面积较小,主要脑区(左侧额下回、左侧额极、右侧岛叶、右内侧眶额叶、右侧缘上回)均表现出显著的区域效应。WU等[27]研究发现,岛叶前部亚区域(左背侧无颗粒区和右腹侧无颗粒区)低频振幅(amplitude of low frequency fluctuations, ALFF)分数增加与情绪特质(抑郁、易怒、焦虑)呈正相关。

       CHEN等[28]研究发现失眠症患者的岛叶在显著网络的FC激活增强,岛叶血氧水平依赖成像信号与脑电图高频γ-功率具有相关性,且与负面情绪有关。ZHANG等[29]发现,睡眠剥夺会增强奖赏系统的敏感性,而不良情绪体验与奖赏网络的激活有关,如与静息清醒相比,右侧伏隔核和右侧额下回之间的FC降低,伏隔核和前扣带回与情绪体验评分呈负相关。LI等[30]研究表明,失眠症患者左侧小脑前叶的局部一致性(regional homogeneity, ReHo)值与汉密尔顿抑郁量表(Hamilton Depression Scale, HAMD)评分的变化呈正相关,右侧辅助运动区的ReHo值与汉密尔顿焦虑量表(Hamilton Anxiety Scale, HAMA)评分呈显著正相关。另有研究证实[31],失眠症患者的左侧岛叶ReHo值升高与焦虑自评量表(Self-Rating Anxiety Scale, SAS)评分、右侧中扣带皮层ReHo值降低与抑郁自评量表(Self-Rating Depression Scale, SDS)和SAS评分以及右侧中央前回ReHo值升高与SDS评分呈负相关。

       因此,失眠伴情绪障碍患者存在多个脑区的异常,同时涉及与情绪相关的局部脑区可能存在皮质体积减小或代偿性ALFF、ReHo值增强或减弱,这种现象可能与其相应神经元连接通路的脑区发生改变有关。同时亦提示失眠通过大脑中负责情绪和奖励积极情绪刺激的区域敏感性来降低潜在机制诱发的情绪功能障碍,且呈现出显著效应的脑区表面积与失眠严重程度之间的关联对失眠伴情绪障碍患者具有特异性,这可能是导致失眠合并情绪障碍的原因之一。

1.2 失眠伴情绪障碍脑网络的异常

       默认模式网络(default mode network, DMN)被认为与自我加工和情绪调节有关[32],且静息态fMRI(resting-state fMRI, rs-fMRI)研究发现其与抑郁症、失眠患者的情绪认知功能障碍显著相关[33],主要涉及前扣带皮层和后扣带皮层、顶叶下皮层、腹内侧前额叶皮层、楔前叶和海马体[34, 35]。fMRI研究证实[36],前扣带回和杏仁核被认为是构成显著网络(salience network, SN)的关键节点,其功能包括情绪和生理状态的整合等。同时,岛叶皮层及DMN在SN中的连接可能起着特别重要的作用[37]。岛叶是显著性网络的关键枢纽,在情绪中起重要的作用[38],而在CHEN等[28]研究中发现,失眠者的焦虑和抑郁评分虽然增加,但低于临床阈值,可能归因于这种亚阈值的焦虑、担忧等情绪或者fMRI环境刺激的感觉门控不足[39]。另有WASSING等[40]行MRI来确定新情绪和重温自我意识情绪之间的大脑激活有何不同,结果发现与正常睡眠者相比,中性经历的失眠障碍患者边缘区域在新的羞耻经历中被激活,且失眠障碍患者在新的和重温的羞耻经历中边缘回路出现重叠部分,特别是背侧前扣带皮层。这就提示由于边缘回路的强烈参与,其被认为在编码和检索新的情绪记忆中起着至关重要的作用,特别是前扣带皮层,失眠患者对重温遥远过去的情绪困扰更加强烈。

       此外,LI等[41]研究发现,原发性失眠患者在右额顶网络(frontoparietal network, FPN)区域的连接性降低,右侧颞中回和右外侧枕叶皮层与FPN的连接性降低,分别与失眠持续的时间和SAS呈显著正相关。GONG等[42]采用基于种子点的FC分析构建失眠患者的蓝斑-去甲肾上腺素系统(locus coeruleus noradrenergic, LC-NE),结果显示左侧LC和左侧枕中回之间的FC与失眠持续的时间有关,而右侧LC和左背侧前扣带皮层之间的异常FC与失眠患者的焦虑评分相关。

       基于此,可知失眠伴情绪障碍主要与DMN、SN、EN、奖赏网络、边缘网络、FPN和LC-NE等脑网络活动受到异常影响相关,而更多脑网络的研究举证仍需广大学者不断进行临床循证医学研究加以证实。

2 针刺治疗失眠伴情绪障碍中枢机制的fMRI研究进展

2.1 基于穴位特异性的单穴

       GAO等[43]采用一般线性模型分析fMRI数据,结果表明睡眠剥夺患者针刺三阴交穴后显著激活前扣带皮层、双侧岛叶、左侧基底神经节及丘脑;而假针刺组中双侧丘脑和左侧小脑被激活。提示针刺在不同的激活模式下针刺组激活的脑区更广泛,促睡眠、调节情绪的效果更佳。

       NING等[44]通过fMRI探索神门穴对急性睡眠剥夺患者的影响发现,与睡眠剥夺24小时后相比,针刺神门穴后背侧注意网络(dorsal attention network, DAN)-腹侧注意网络(ventral attention network, VAN)的网络间FC减少、体感运动网络(somatomotor network, SMN)-VAN的网络间FC增加。一项关于重性抑郁障碍的研究表明[45],DAN和VAN的聚类系数和小世界性增加,而SMN在空间区域上与DAN、VAN相邻且执行任务期间具有相关性[46]。研究证明[47],与睡眠和觉醒相关的大脑网络受到来自SMN感觉输入的调节,同时,感觉信息和剥夺都可能诱发相对于睡眠和醒来的大脑网络的变化。YANG等[48]研究发现,针刺神门穴能够增强对情绪刺激的自我控制。因此,推测针刺可能通过调节急性SD患者网络内部和网络之间的异常FC,来改善其认知障碍和情绪反应[44]。此外,多项研究[49, 50]表明,针刺神门穴参与情绪加工相关脑区的变化,主要改变以DMN和边缘叶-旁边缘叶-新皮层系统为主的脑网络FC。

       ZHENG等[51]选取右脑颞叶作为种子点,分析其FC发现针刺太冲穴可调节健康者右侧颞叶与左侧颞下回、前额叶等脑区FC,且可以激活内侧前额叶皮质和前扣带回、左侧颞叶等脑区。另有研究[52]证实针刺单侧太冲穴主要激活包括腹内侧前额叶、左侧额中回、左侧脑干、左侧颞下回等对侧的多个脑区。这些脑区与负性情绪管理、奖赏价值评估、决策及认知等方面密切相关[53]

       上述研究表明,三阴交穴、神门穴和太冲穴虽然不属于同一神经节段,其针刺促睡眠、改善情绪的作用可能是通过脑区的边缘系统/默认网络等区域协同来参与“睡眠-觉醒-情绪回路”的调控,但所涉及多个脑区的激活亦有差异,从而说明了穴位的特异性,也为今后解释临床针刺单穴治疗疾病作用机制提供一定的理论依据。

2.2 基于穴位协同增效的组穴

       WU等[54]以针刺干预组行fMRI检查,主穴选取百会、四神聪、安眠、肝俞、膈俞、太冲以疏肝调神,结果发现针刺干预组可能通过调节前额叶皮层与杏仁核连接刺激中枢整合神经信号来抑制围绝经期失眠症患者的负面情绪及改善睡眠。WANG等[55]研究发现,经组穴(神门、三阴交、百会)电针治疗5周后行rs-fMRI检查,失眠症患者的额中回、前扣带回、缘上回、楔前叶等脑区的分数ALFF增加。另有一项研究[11]证实,失眠患者左侧脑岛与右侧前扣带回的连接增强,相关分析显示,失眠患者的连接性增强与SDS和SAS得分呈显著负相关。ZHAO等[56]通过针刺失眠症患者的百会、四神聪、风府、风池、强间、枕上旁线、安眠、翳明、大椎后行fMRI发现,左腹侧尾状核与岛叶的FC强度与HAMD评分呈负相关,左腹侧尾状核与前扣带回的FC强度与HAMA评分呈负相关。另有学者[50]通过利用度中心度(degree centrality, DC)方法研究发现,对失眠患者行2周针刺百会、四神聪、神门、三阴交等穴位后,与健康组相比,失眠患者DC值减低的脑区包括双侧海马旁回、左侧楔前叶、右侧豆状核、右侧海马及右侧颞中回等区域,且颞叶皮层及楔前叶的DC值与自我意识和认知信息自我加工密切相关,表明针刺可有效降低失眠患者因睡眠障碍引起的不良情绪反应。

       在有关穴位配伍的研究中,不管采用手针还是电针的干预方式,不难看出穴位配伍产生了协同效应,其机制并不是简单地在针刺单穴上脑激活区的叠加[57],而是神经功能重新整合或协同后激发了特定的功能区域。

3 问题与展望

       从目前研究中总结出的问题如下:(1)国外学者的研究大部分集中于失眠症或合并焦虑/抑郁,而国内学者注重针刺穴位配伍和穴位特异性作用于失眠伴焦虑/抑郁的研究;(2)多数招募的受试对象符合流行病学调查中的失眠伴情绪障碍,患者女性多于男性且呈年轻化的特征;(3)临床主要结局指标的相关性分析方法和试验样本量少,不足以论证针刺治疗失眠伴情绪障碍只引起脑功能改变而脑结构没有异常变化;(4)因针刺干预方式、腧穴的选择及感兴趣种子点的选取等多方面因素影响,可能导致针刺疗法的脑功能研究结果不尽相同;(5)针刺治疗失眠伴情绪障碍的脑结构是否产生病理性改变仍未可知,且有关机器学习或机器学习整合多模态成像技术的针刺脑结构和脑功能研究也未见报道,这些方面均尚缺相关研究证实。

       在未来的研究中需考虑上述影响针刺的脑功能研究因素,包括在病理状态下大样本、多中心随机对照试验来进行前期穴位配伍基础上的进一步深化研究,设定在不同的针刺干预条件下单穴和组穴的差异对照量化参数以及范式化的结局指标相关性分析,以期得到更加严谨合理、可靠的结论以阐明针刺治疗失眠伴情绪障碍的中枢机制。同时,基于目前穴位特异性的研究,除了加大样本量,还应进一步规范针刺时间窗、证候特征的数据化等,增设非经非穴组以及假针刺组为对照参考,在手针或电针不同的刺激频率和波形下,发挥其神经整合或协同调节“睡眠-觉醒-情绪网络”效应关联的差异变化。此外,失眠伴情绪障碍的中枢病理改变及针刺疗法的中枢机制效应有待更多深入探讨,以便以严谨合理的方式方法在针刺研究及临床上推广运用。

4 小结

       针刺不仅可以改善睡眠质量,缓解白天嗜睡,而且还可以降低HAMA、HAMD-17和SDS评分[58]。在fMRI技术应用中,ALFF、FC、ReHo作为神经影像学的生物指标,可以更加直观、可视化地体现出针刺对失眠伴情绪障碍的相关脑区、脑FC、脑网络等产生的神经功能重新整合或协同的调节作用,且这些脑区涉及与负性情绪管理、奖赏价值评估、决策及认知等方面,为明确针刺效应与中枢机制存在关联性奠定了理论基础,同时也说明了针刺是治疗失眠伴情绪障碍的有效方法。

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