基于多模态磁共振技术研究五行徵调音乐治疗GAD的中枢响应机制

Five elements music therapy is a kind of distinctive traditional Chinese medicine therapy, which can improve people’s emotion significantly. Five elements music therapy has been a research focus in psychological disease, however the central neural mechanism of its therapeutic effects has not been clear. Our previous clinical research has confirmed that five elements music therapy can improve the symptoms of anxiety exactly. In this new study we will research the central neural mechanism of five elements music therapy though its application in patients with generalized anxiety disorder (GAD). 90 GAD patients will be chosen as the research object, the TCM diagnose of those must be deficiency of xinyin. Its already been proved that the loop of amygdala-frontal and the loop of frontal lobe –basal ganglia-thalamus play an important role in the central nervous pathological changes in GAD patients. Our research will be carried out under the direction of a basic theory of TCM, which is the theory of“heart governing the mind”，the research hypothesis is , the therapeutic mechanism of five elements music therapy in GAD treatment has characteristic of multimodal neural information response. In this randomized controlled trial, the multimodal magnetic resonance (MMR) technology such as BOLD-fMRI, VBM will be used to check the functional and structural changes of brain. Both the changes between different interventions (five elements music therapy, neutral music stimulation and psychological regulation) and the changes between different status（healthy volunteers and GAD patients）will be checked in this study. Besides the changes of peripheral blood contents, such as NA, 5-HT, DA, BDNF, ACTH, EPH, will be measured too. This research has scientific significance and clinical practical value，it can provides theoretical basis as well as practical experience for the further application and popularization of five elements music therapy.

五音疗法是独具特色的音乐疗法，改善情绪疗效确切，已成为研究热点，其调节情绪的中枢神经机制尚未阐释清楚。我们前期临床研究证实五音疗法改善焦虑疗效确切。在“心主神明”理论的指导下，以常见的广泛性焦虑（GAD）心阴亏虚证90例患者为研究对象，以在GAD患者中枢神经病理改变中起重要作用的杏仁核-额叶环路、额叶-基底神经节-丘脑环路为研究重点，紧密围绕“五音治疗GAD具有多模态神经信息响应特征”这一假说，采用随机对照试验，运用BOLD-fMRI、VBM多模态磁共振技术对比不同干预方式（五行音乐、中性音乐和认知行为疗法）、不同状态（健康受试者和GAD患者）脑功能、结构和脑网络变化，同时采用ELISA测定外周血NE、5-HT、DA、BDNF、ACTH、EPH、皮质醇含量。从外周、中枢两层次深入阐释五音治疗GAD的中枢响应机制具有重要的科学意义和临床实用价值，为五音干预情志的进一步推广运用提供理论依据。

五行音乐疗法是独具祖国传统特色的音乐疗法，改善情绪疗效确切，其调节情绪的中枢神经机制尚未阐释清楚。本项目以广泛性焦虑（GAD）为研究载体，在五音疗法干预焦虑症状疗效确切的基础上，采用分子生物学、神经影像学等多学科技术手段开展基础研究、临床应用基础研究和临床研究。①首次构建了GAD心阴亏虚病证结合动物模型：采用不确定性空瓶应激法成功复制大鼠GAD疾病模型；创新性改良水环境小站台睡眠剥夺实验构建大鼠心阴亏虚证侯模型。分别采用了高架十字迷宫、旷场实验、OE%等评价疾病模型；基于文献、专家意见评价证候模型；天王补心丸以方验证。全面证实了GAD心阴亏虚病证结合动物模型稳定、可控、造模理念符合中医病因病机，为中医病证结合动物模型的构建提供方法学借鉴。②深入阐释了五行音乐干预GAD大鼠的神经内分泌作用机制和关键分子靶点：从动物实验角度验证了“心主神明”理论指导的五行音乐疗法可有效改善GAD大鼠焦虑行为；通过降低大鼠下丘脑CRH、血清ACTH、CORT浓度，下调下丘脑CRHRI mRNA表达水平，增加海马GR mRNA表达量，增强海马-HPA轴负反馈调节、抑制HPA轴过度亢进发挥抗焦虑效应。为临床进一步验证提供了重要依据。③整合临床疗效、递质激素、神经响应三者信息，从中枢、外周两层次全面阐释了五音疗疾的中枢神经机制：采用随机对照科研设计，共纳入90例GAD患者（随机数字表分为五行音乐干预组、西洋音乐干预组和CBT治疗组），同期纳入30例健康受试者作为对照。五音疗法能有效改善GAD患者焦虑症状，提高生活、睡眠质量，降低疾病负担。关注GAD患者外周血ACTH和5-HT浓度有助于病情诊察，五行音乐疗法可通过降低外周血5-HT以及增加BDNF浓度发挥抗焦虑效应。结合静息态BOLD-fMRI技术，揭示了GAD患者杏仁核-枕叶功能连接增强；杏仁核-额中回连接减弱可能是GAD产生的中枢病理机制。五行音乐疗法可能通过调节杏仁核-颞上极、杏仁核-枕下回、杏仁核-小脑改善GAD临床症状，且五行音乐疗法与西洋音乐疗法干预差异存在的网络连接可能为杏仁核-顶上回；与CBT干预差异则为杏仁核-小脑。本项目开展为五行音乐疗法推广运用奠定了扎实的理论和实证基础。