基于fMRI技术探讨电针结合帕罗西汀快速抗抑郁的脑功能机制

It’s extremely urgent to find the effective prevention methods and mechanism for depression, as its high burden of disease. It needs 2 weeks for SSRIs to work, with poor medication experience in the first week. In our previous RCTs, 1-week rapid onset of electro-acupuncture (EA) combined with paroxetine was observed on mild-to-moderate depression with significantly more effect and less adverse drug reaction. The previous fMRI research showed that, once EA could target on brain areas related with Depression. The delayed onset of SSRIs was considered to be associated with the negative feedback of the central 5-HT system. Brain Derived Neurotrophic Factor (BDNF) becomes hotspot of the rapid antidepressant-like effect recently. In consequence, we hypothesize that: the targeted brain regions of EA combined with paroxetine might not be simple superposition of EA’s and paroxetine’s targeted brain regions. The changes of neurotransmitter concentration in serum might be associated with the targeted brain regions. Therefore, after 1-week treatment of EA, EA with paroxetine, paroxetine on mild-to-moderate primary depression, clinical efficacy, fMRI and concentration of neurotransmitter in serum would be observed. "Related brain regions - neurotransmitters - clinical efficacy" would be analyzed by bioinformatics to reveal effictive mechanisms of rapid antidepressant of EA combined with paroxetine.

抑郁症的危害越来越重，其防治和机制研究迫在眉睫。SSRIs抗抑郁需要2周方能起效，且患者服药第1周体验较差。本项目前期RCTs表明电针结合帕罗西汀治疗轻中度抑郁症1周即可起效，效果显著且副作用明显减少。同期fMRI研究亦表明，单次电针能够靶向作用于抑郁症发病相关脑区，提示fMRI可以反映抗抑郁效果。目前多认为SSRIs起效延迟可能与中枢5-HT系统负反馈相关；而近期研究发现BDNF可能是快速抗抑郁样作用的靶点。因此本项目提出假说：电针结合帕罗西汀1周快速抗抑郁作用的靶向脑区可能不是电针靶向脑区与帕罗西汀靶向脑区的简单叠加；血清中神经递质含量的变化可能与靶向脑区相关。基于上述假说，本项目拟以电针、针药结合、西药治疗轻中度原发性抑郁症，观察治疗1周时临床疗效、fMRI变化及血清神经递质含量变化，应用生物信息学进行“相关脑区-神经递质-临床疗效”的整合分析，明确针药结合快速抗抑郁的疗效机制。

抑郁症的防治和机制研究迫在眉睫。SSRIs抗抑郁起效需2周，且第1周体验较差。本项目前期RCTs表明电针结合帕罗西汀治疗轻中度抑郁症1周可起效，且副作用明显减少。同期fMRI研究亦表明，单次电针能够靶向作用于抑郁症发病相关脑区，提示fMRI可以反映抗抑郁效果。目前多认为SSRIs起效延迟可能与中枢5-HT系统负反馈相关；而近期研究发现BDNF可能是快速抗抑郁样作用的靶点。.因此本项目以电针、针药结合、西药治疗轻中度抑郁症，基于fMRI数据的ALFF、ReHo及功能连接分析，观察与健康受试者比较轻中度抑郁症患者脑功能成像变化情况，首次电针治疗前后、治疗1周前后各组患者脑功能成像变化情况。同时通过动物实验，探索电针、针药结合、药物干预CUMS抑郁模型大鼠靶向脑区BDNF/TrkB受体表达情况，并采用iTRAQ技术探索靶向脑区的差异表达蛋白。.fMRI研究表明，轻中度抑郁症患者前额叶等脑区ALFF值显著减低，ReHo值变化则显示抑郁症患者右前额叶等脑区降低，扣带回等脑区升高；此外抑郁症患者双侧额、顶叶等脑区与左侧额中回（ROI）的功能连接显著升高。首次电针干预、针药结合、药物治疗前后，患者全脑ReHo值进一步改变，而额中回与相应脑区的FC值有所降低。.动物行为学实验表明，电针、药物、针药结合干预1周可显著改善抑郁模型动物的体重、糖水偏好率、中药区域停留时间、总活动路程，且针药结合干预优于单纯电针或药物。.电针、药物干预1周可上调海马BDNF受体mRNA的表达，针药结合干预1周时对其影响则是下调。电针、药物、针药结合干预1周均上调前额叶BDNF受体mRNA的表达，且不同干预措施之间有显著性差异。.iTRAQ差异蛋白定量分析表明，电针干预1周可上调前额叶蛋白Bassoon、离子型谷氨酸受体3（GluR3）、多巴脱羧酶（DDC）和酪氨酸羟化酶（TH），以及海马的纤调蛋白（Fibromodulin），富含半胱氨酸型酸性蛋白（SPARC）和突触体相关蛋白29（SNAP29）。.以上结果表明，表明针药结合干预CUMS模型效果优于单纯针刺或单纯药物，主要靶向脑区为前额叶、海马，可能是通过影响前额叶、海马BDNF/TrkB通路。