|Alternative Title||Physical and Mental Chatacteristics and Brain Imaging Study on Pain Pathways in Patients with Postherpetic Neuralgia|
疼痛是一种复杂的生理心理活动，是各种疾病中最为常见的临床症状之一，是继呼吸、脉搏、血压和体温之后人体的第五生命体征。国际疼痛研究学会(International Association for the Study of Pain, IASP)将疼痛定义为“与组织损伤或潜在组织损伤有关的不愉快的主观感觉和情绪体验”。慢性疼痛起源于急性疼痛，从急性疼痛到慢性疼痛的转变往往伴随着自主神经的功能紊乱以及各种生理心理问题，如焦虑和抑郁情绪等。带状疽疹后遗神经痛(Postherpetic Neuralgia, PHN)作为一种典型的慢性疼痛，通常是指带状疽疹粘膜皮疹消失后疼痛仍持续3个月以上的综合征。PHN患者往往伴随有异常疼痛，不仅严重危害了患者的健康，而且影响其正常生活和工作状态，给患者带来身心的双重痛苦。然而，影响PHN发生发展的因素众多，但就目前PHN的研究现状而言，仍缺乏对PHN的生理、心理及认知等相关因素的综合评价，PHN与各因素之间的关系尚不清楚; 再者，PHN对大脑疼痛通路的影响尚未明确，缺乏对PHN脑机制的理解。因此，本研究试图综合多方面因素(如感觉系统功能、心理状态、脑结构与功能等)对比PHN患者与对照组在疼痛多方面的差异，探究PHN与多维度因素之间的关系。
研究一采用皮质醇测试、躯体感觉定量测试(痛觉和触觉阂限)、简版麦吉尔疼痛问卷(Short-Form of the McGill Pain Questionnaire, SF-MPQ )、心理状态量表(焦虑自评量表和抑郁自评量表)、认知功能测试(纸笔测验和操作测试)对PHN患者及对照组进行多维度的生理心理测量。研究一包括23名PHN患者和23名健康被试。结果发现:(1) PHN患者的SF-MPQ总分及各分量表评分均显著高于对照组;(2) PHN患者与对照组的痛觉阂限无显著差异，PHN患者患病区与镜像区的触觉阂限无显著差异;(3) PHN患者的焦虑和抑郁评分均显著高于对照组;(4) PHN患者在信息处理速度(韦氏数字符号及连线测试)、选择性注意力(Stroop色词干扰测试)、工作记忆(N-back测试)及执行功能(Go/No-Go测试)方面出现明显的认知功能下降;(5)多元线性回归分析发现，PHN患者的疼痛评分与其对1-back相同条件的正确反应时呈显著的负相关。研究一结果表明:PHN是与生理心理等多维度的因素相关联的。
研究二我们将心理物理学与结构和功能磁共振成像(Magnetic Resonance Imaging, MRl)技术相结合，研究PHN对疼痛上行和下行调节通路的影响。研究二的被试同研究一。结果发现:(1)结构MRI数据表明，PHN患者的丘脑C Thalamus)和杏仁核(Amygdala)的体积显著小于对照组，并且，PHN患者的丘脑体积与其SF-MPQ疼痛评分呈显著负相关。(2)当丘脑和中脑导水管周围灰质(Periaqueductal Gray Matter，PAG)作为种子点时，静息态功能MRI结果显示:PHN患者疼痛上行和下行调节通路的功能连接异常，例如，丘脑和躯体感觉皮层之间的功能连接增强;PAG和前额叶皮层之间的功能连接性降低。(3)PHN患者的疼痛指数(Present Pain Index, PPI)及贝克抑郁量表(Beck DepressionInventory, BDI)的主观评分与PAG和初级躯体感觉皮层(Primary Somatosensory cortex, SI)间的功能连接呈显著的负相关，其中，BDI对PPI的影响受到PAG-SI功能连接的影响。总体而言，研究二的结果表明:PHN的上行和下行疼痛调节通路均存在异常，这与PHN患者的疼痛及情绪强度高度相关。
研究三将丘脑分为6个不同的亚区，对比PHN患者和对照组丘脑不同亚区与躯体感觉和认知相关脑区间连接的差异。研究三的被试与研究一相同。结果发现，PHN患者和对照组的丘脑亚区与躯体感觉和认知皮层间的连接均无显著差异。但结果提示，PHN患者的丘脑亚区(主要连接前额叶的区域)与后扣带回C Posterior Cingulate Cortex, PCC)间的连接有显著小于对照组的趋势。相关分析结果显示，PHN患者的丘脑亚区(主要连接前额叶的区域)与PCC之间的连接与其疼痛评分呈负相关。本研究通过对比PHN患者和对照组丘脑不同亚区与躯体感觉和认知皮层间连接的差异，为丘脑不同亚区在慢性疼痛中具有不同的功能作用提供了证据支持。
研究四采用弥散张量成像技术(Diffusion Tensor Imaging, DTI)研究PHN 患者和对照组的脑白质弥散束，被试与研究一相同。采用纤维素空间统计学C tract-based spatial statistics, TB S S)比较PHN患者与对照组白质微结构的差异。结果发现:(1) PHN患者存在局灶性的白质微结构的异常，主要集中在前扣带回(Anterior Cingulate Cortex, ACC)以及PCC。(2)PHN患者的平均弥散率(Mean Diffusion, MD)与状态焦虑评分呈显著正相关。(3 ) PHN患者的白质微结构的异常与其疼痛强度无显著相关。研究四的结果表明:PHN患者存在局部脑白质微观结构的异常，且白质弥散结构的异常与其焦虑评分密切相关。
研究五结合静息态功能MRI和任务态功能MRl，研究PHN的SI在感知自发性和诱发性疼痛中的功能可塑性。被试包括16名PHN患者和20名健康对照者。结果发现: (1) PHN患者和对照组对伤害性激光刺激的疼痛评分及BOLD激活均没有显著差异。对比PHN患者和对照组SI两侧的BOLD激活，2(组间:患者组与对照组)X2(组内:Sljeft VS SIRight)方差分析结果发现，组间因素的主效应不显著，组内因素的主效应显著，两因素间的交互作用显著。事后检验的结果显示，PHN患者SI双侧激活无显著差异;对照组SIRigh，激活显著大于Slleft VS SlRieft的激活PHN患者显著大于对照组; SIRigh，的激活两组间无显著差异。C2)在PHN患者和对照组中，与激光疼痛主观评分相关的大脑激活(疼痛编码区)属于SI不同的子区域。当以PHN患者疼痛编码的SI区域作为感兴趣区(Region of Interest, ROI)时，SI-ROI激活与PHN患者的激光疼痛评分呈显著正相关。当以对照组疼痛编码的SI区域作为ROI时，对照组的SI-ROI的激活与其激光疼痛评分呈显著正相关，但PHN患者的SI-ROI的激活与其SF-MPQ评分呈显著正相关; C3)在静息状态下，PHN患者在Sljeft和SIRigh，间的静息状态功能连接较对照组显著降低，此外，PHN患者Sljeft和SIRigh，间的功能连接与其SF-MPQ评分呈显著负相关;C4) PHN患者(SI疼痛编码区)SI-ROI的BOLD激活可以预测其对激光刺激的疼痛强度，对照组(SI疼痛编码区)SI-ROI的BOLD激活可以预测其对激光刺激的疼痛强度。另外，PHN患者Sljeft和SIRigh，间的静息态功能连接可以预测其SF-MPQ评分。总体而言，我们从任务态和静息态MRl两个角度强调了SI在编码PHN患者的自发性和诱发性疼痛中的功能可塑性。
Pain, as one of the most common clinical symptoms in various diseases, is deemed as the fifth vital sign of the human body equivalent to breathing, pulse, blood pressure and body temperature. The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage." Chronic pain originates from acute pain, and the transition from acute pain to chronic pain is often accompanied by autonomic dysfunction and various psychological problems. Postherpetic neuralgia (PHN) is a typical chronic pain, which develops after resolution of the herpes zoster mucocutaneous eruption. PHN patients are characterized by extreme pain, which not only seriously harms the health of patients, but also affects their normal living and working conditions, and brings physical and mental pain to patients. However, there are many factors that influence the occurrence and development of PHN, there is still a lack of comprehensive evaluation of the physiological, psychological and cognitive factors in PHN. Moreover, the effect of PHN on the pain pathways is unclear, and there is a lack of understanding of its brain mechanisms. Therefore, this study attempts to integrate multiple factors (such as sensory system function, mental state, brain structure and function, etc.) to explore the similarities and differences between PHN patients and healthy control (HC) on various factors and their interconnections.
This study is divided into five parts: Study 1 adopts the cortisol test, somatosensory quantitative tests (including pain and tactile threshold), Short-Form of the McGill Pain Questionnaire (SF-MPQ), psychological scales (State-Triat Anxiety Index and Beck-Depression Index), and cognitive tests to measure the physiological and psychological characteristics in PHN patients and HC. Study 1 included 23 PHN patients and 23 HC. Results indicated that: (1) There was no significant difference in the pain threshold between PHN patients and HC, and there was no significant difference in the tactile threshold between the affected area and the mirror area in PHN patients. (2) The subscale scores and total score of the SF-MPQ in PHN patients were significantly higher than in HC; (3) Anxiety and depression ratings in PHN patients were significantly higher than in HC; (4) Performance in information processing speed (Webster digital symbol test and TMT-A connection test), selective attention (Stroop color word interference test), working memory (N-back test), and executive function (Go/ No-Go test) showed significant decline in PHN patients. (5) Multiple linear regression analysis revealed that the correct response in PHN patients to the same conditions of 1-back was significantly negatively correlated with their pain scores. Study 1 showed that chronic pain in PHN is related to dynamic factors.
Study 2 we combined psychophysics with structural and functional magnetic resonance imaging (MRI) techniques to investigate the brain alternations associated with ascending and descending pain modulations in PHN patients. Participants in Study 2 were the same as Study 1 .Structural MRI data indicated that PHN patients had significant smaller gray matter volumes of the thalamus and amygdala than HC, and the thalamus volume was negatively correlated with pain intensity in PHN patients. When the thalamus and periaqueductal gray matter (PAG) were used as the seeds, resting-state functional MRI data revealed abnormal patterns of functional
connectivity within ascending and descending pain pathways in PHN patients, e.g., increased functional connectivity between the thalamus and somatosensory cortices and decreased functional connectivity between the PAG and frontal cortices. In addition, subjective ratings of both present pain index (PPI) and Beck Depression Inventory (BDI) were negatively correlated with the strength of functional connectivity between the PAG and primary somatosensory cortex (SI), and importantly, the effect of BDI on PPI was mediated by the PAG-SI functional connectivity. Study 2 provided evidence suggesting deficits in ascending and descending pain modulation pathways, which were highly associated with the intensity of chronic pain and its emotional comorbidities in PHN patients.
Study 3 divided the thalamus into six sub-regions, and we compared the connectivity between the thalamus sub-regions and somatosensory and cognitive-ralated cortex in PHN patients and HC. Participants in study 3 were the same as Study 1 .Results indicated that there were no significant differences in connectivity between thalamus sub-regions and cortex in PHN patients and HC. However, the results suggest that the connectivity between thalamus sub-region (mainly connected to the prefrontal lobe) and posterior cingulate cortex (PCC) in PHN patients has a significantly smaller trend than in HC. Further correlation analysis found that the connectivity between thalamus sub-region and PCC was negatively correlated with pain ratings in PHN patients. In this study, we provided a new evidence for the functional role of different thalamus sub-regions in chronic pain.
Study 4 using diffusion tensor imaging (DTI) to study the white matter diffusion in PHN patients and HC, and participants were the same as study 1 .The tract-based spatial statistics (TBSS) was used to compare the white matter microstructure differences between PHN patients and HC. Results showed that: (1) The focal white matter microstructures abnormals were mainly concentrated in anterior cingulate cortex (ACC) and PCC in PHN patients. (2) The mean diffusion (MD) was significantly positive correlated with the SAI ratings in PHN patients. (3) Abnormal white matter microstructures were not significantly related to the pain intensity ratings in PHN patients. Results indicated that there were local brain white matter microstructure abnormalities in PHN patients, and the abnormal microstructures was closely related to the anxiety ratings in PHN patients.
Study 5 we combined task functional MRI with resting-state functional MRI data to determine whether SI functional plasticity occurs in PHN patients compared to matched HC. This study included 16 PHN patients and 20 HC. We observed (1) There were no significant differences in perceived intensity ratings and BOLD responses to nociceptive laser stimuli between PHN patients and HC. Two-way ANOVA analysis revealed that HC exhibited a significant activation focus in SIRight; while PHN patients showed a significant activation in SILe}; (2) Nociceptive activated brain regions associated with subjective ratings in PHN patients and HC showed different cerebral patterns in SI, and there was no overlap. SI-ROI (at nociception encoded voxels in PHN patients) activity in PHN patients was positively correlated with its ratings of laser pain. SI-ROI (at nociception encoded voxels in HC) activity in HC was strongly correlated with its ratings of laser pain as expected; while SI-ROI activity in PHN patients was not correlated with ratings of laser pain, but with spontaneous pain accessed by SF-MPQ. (3) At resting state, PHN patients exhibited weaker resting state FC between SILeft and SIRight than HC, further, the weaker FC between SILeft and SIRighr was negatively correlated with SF-MPQ ratings in PHN patients; (4) Multivariate pattern analyses demonstrated that SI-ROI activity was able to predict laser pain intensity ratings in PHN patients and HC; resting state functional connectivity bilaterally at SI in PHN patients was able to predict its MPQ ratings. Study 5 emphasized the functional plasticity of SI in encoding spontaneous and evoked pain perception in PHN patients.
To sum up, this study confirmed that PHN is associated with a variety of complex brain-physio-psychological factors. Behavioral studies have found that patients' anxiety and depression increase, and cognitive functions such as information processing speed and selective attention are impaired. MRI studies combined structural MRI and functional MRI demonstrated that PHN patients have deficits in both ascending and descending pain modulation pathways, and pioneeringly confirmed that SI in PHN patients has functional plasticity, providing evidence support for studying the peripheral and central nervous mechanism of chronic pain. Elucidating the brain-physiological-psychological mechanism of PHN could enable us to better understand the pathological mechanism of PHN, and provide scientific evidence and theoretical support for scientific prediction and treatment of PHN.
|Keyword||带状疽疹后遗神经痛 生理一心理 磁共振 疼痛通路|
|Place of Conferral||中国科学院心理研究所|
|李宏. 带状疱疹后遗神经痛的身心特征及其疼痛通路的脑影像研究[D]. 中国科学院心理研究所. 中国科学院心理研究所,2020.|
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