穴位埋线调节围绝经期惊恐障碍患者脑神经活动Glutamate-GABA机制的在体研究

Previously, we showed that metabonomic analysis revealed efficient ameliorating effects of acupoint catgut embedding on the Ovariectomized rats in amino acids alterations in terms of emotional regulation (Zhang liming,et al. Scientific Reports 2014). It's well known that losing equilibrium between Glutamate and GABA(overactivation of glutamatergic system) is the fundamental cause of panic disorer. Together, these two neurotransmitters constitute to more than 90% of all neurotransmissions, creating excitatory/inhibitory forces in the brain. Perimenopausal panic disorder (PPD) is a typical psychosomatic disease during climacteric period wich attracts great concern in terms of its prevention and treatment at present. Clinically, we found that catgut embedding in points has anxiolytic effect in PPD,which is probably relative to balance the brain neural activation.However, The underlying molecular mechanism of PPD and its interaction between catgut embedding in acupoints still remain unknown. Thus, we propose to use functional Magnetic Resonance (fMRI) and Proton Magnetic Resonance Spectroscopy(1H-MRS) to investigate the status of brain equilibrium, excitation and inhibition. A randomized clinical trial comparing healthy control of childbearing women with PPD is done to examine changes in clinical outcomes and brain neural activations. Changes in brain neural activation and Glutamate-GABA concentration in amygdala and insula is also explored with the intervention of catgut embedding in points in comparison with Alprazolam. Besides, the free amino acid of peripheral blood is checked to probe the biomarker of PPD and its interactive underpinning of catgut embedding in points. It's an innovative research in translational medicine which has clinical significance in exploring innovative treatment.

前期研究表明,穴位埋线能够调节OVX大鼠与情绪相关的氨基酸（发表于2014年Nature子刊Scientific Reports）。已知，Glutamate-GABA介导了脑的90%以上的信号转导，是脑神经活动最重要的神经递质，抑制性GABA减少导致Glutamate-GABA平衡失调是惊恐障碍（PD）产生的根本原因。围绝经期惊恐障碍（PPD)的防治是当前值得重视的一大课题。临床研究表明，穴位埋线可以改善PPD的焦虑症状，考虑与脑神经活动有关，但是，机制不清。本实验采用磁共振（fMRI、1H-MRS）技术，以围绝经女性为研究对象，遵循随机对照原则，比较健康志愿者与PPD患者恐惧网络fMRI特征及杏仁核、岛叶Glutamate-GABA含量，对比穴位埋线与阿普唑仑的疗效,结合游离氨基酸的变化，探索PPD的生物标记物及穴位埋线的干预机制，是向临床转化的创新性研究，对创新治疗手段具有重要的意义。

前期临床研究表明，穴位埋线可改善PPD的焦虑症状，考虑与脑神经活动有关，但机制不清。本实验采用多模态fMRI（VBM、BOLD、DTI以及1H-MRS技术，以围绝经期女性为研究对象，比较健康志愿者与PPD患者恐惧网络fMRI特征及杏仁核、岛叶Glutamate-GABA含量，系统观察穴位埋线的临床疗效，结合PPD患者相应脑区变化，探索PPD的生物标记物及埋线作用机制。. 结果：（1）埋线组治疗后各量表评分显著下降（P<0.05）；（2）A.VBM-DTI：PPD患者额中回、额下回的灰质降低,边缘叶、扣带回、颞叶等的灰质增加；PPD患者的胼胝体膝、眶额回、扣带回的FA值较低；B.BOLD-fMRI：穴位埋线治疗后增加了枕中叶的视觉处理和丘脑对情绪的处理，提高背外侧额上回、眶部额下回对惊恐的抑制，出现扣带回、边缘叶、海马旁回、颞下回、顶叶的负激活，降低了额中回静息态下的神经元活性，增加了楔前叶及中央旁小叶静息态下的神经元活性；C.1H-MRS：埋线组治疗后右侧杏仁核、右侧前岛叶、右侧后岛叶的Glu/Cr 浓度均较治疗前显著降低（P＜0.05），右侧杏仁核NAA/Cr浓度则显著增高（P＜0.05）。（3）脑电图：PPD患者的脑电图α波绝对功率降低（P＜0.05），β波绝对功率值升高（P＜0.05）；（4）肠道菌群：PPD患者拟杆菌门所占比例升高，厚壁菌门比例下降，埋线治疗后拟杆菌门/厚壁菌门比例降低，菌群数量发生显著变化（P＜0.05）。. 结论：补肾益髓埋线法有明确临床疗效，可改善PPD患者相关临床症状、情绪状态和疾病程度，其作用机制：穴位埋线能下调异常高浓度Glu，以减轻杏仁核与岛叶的兴奋神经毒性作用，升高神经元代谢物NAA含量，促进神经细胞功能恢复，从而降低PPD患者大脑皮层的兴奋性，改善额叶与丘脑、杏仁核等脑区之间的信息传导；能调节丘脑核-边缘系统-眶部额下回、背外侧额上回-小脑后叶环路平衡，抑制边缘系统对惊恐的激发，双向调控“恐惧环路”，从而在一定程度上改善脑内白质纤维束完整性。研究亦发现，穴位埋线能调控PPD患者异常脑电波及肠道微生物群落结构。进一步印证了假说：PPD主要发病原因在于氨基酸代谢失调，进而造成脑功能兴奋与抑制失衡，穴位埋线能够纠正恐惧中枢代谢缺陷，促进恐惧网络的恢复，从而调节脑神经活动。