基于情感-认知环路的耳电针治疗难治性抑郁症神经影像学研究

In 2005, the US FDA approved the implantable vagus nerve stimulation (iVNS) for the treatment resistant depression (TRD). Because it needs surgery and it is expensive, it is difficult to be promoted in more patients. Otherwise, its neuromechanism is not clarified so far. Recently our team developed a new therapy named transcutaneous vagus nerve stimulation (taVNS)，which is based on the ear acupuncture theory of traditional Chinese medicine, anatomy and iVNS. Our previous study showed the following results. It was effective for depression in clinical trial. Further study showed that it modulated the rostal of anterior cingulate cortex, orbitofrontal cortex, amygdala, anterior insula and dorsal lateral prefrontal cortex, which are involved in emotion and cognition function. Furthermore the function connectivity changes of amygdala-dorsal lateral prefrontal cortex were correlated to the efficacy. In current study, two groups of TRD patients would receive taVNS or sham taVNS accompanied with treatment of Sertraline for 6 weeks respectively. Before and after treatment, functional magnetic resonance imaging (fMRI) scans would be performed. the brain functional network and the neurotransmitters are detected for TRD. The analysis of fMRI data are focused on observing TRD neural circuits dysfunction, and abnormal neurotransmitter GABA / Glu in rostal ACC, and then the correlation would be analyzed between the abnormality of TRD and the taVNS efficacy. The results would clarify the brain mechanism of taVNS in the treatment of TRD, and identify the hypothesis “ taVNS regulated the Emotion - Cognitive circuits. It would be explored the functional imaging biomark of taVNS on TRD in the early stage of treatment. This study will provide a neuroimaging basis for noninvasive, simple and inexpensive taVNS - a potential new therapy for TRD, and also enrich the theory of ear acupuncture.

美国FDA于2005年批准了植入式迷走神经刺激术（iVNS）用于难治性抑郁症（TRD），因其需手术，费用昂贵，难以推广，而且脑机制不明。我们团队基于耳针理论、解剖和iVNS原理研发了经耳甲迷走神经刺激技术（taVNS），前期发现对抑郁症有效，调制前扣带回、眶回、杏仁核、前脑岛、背侧额叶等情绪认知关键脑区，且杏仁核-背外侧前额叶网络与疗效相关。本研究真、假taVNS各加舍曲林两组，分别干预TRD 6周。治疗前后均行fMRI扫描，从脑功能成像观察TRD神经环路异常，从磁共振波谱探测神经递质γ-氨基丁酸与谷氨酸变化；提取多模态脑功能影像的共性特征，分析与疗效的相关性，阐明taVNS治疗TRD脑机制，验证假说：taVNS调节以前扣带回头部为关键节点的情感-认知环路；探寻预测taVNS疗效的早期脑影像标记。本研究将为无创、简便、价廉的taVNS新技术治疗TRD提供神经影像学依据，充实耳针理论的内涵。

背景：侵入性迷走神经刺激（iVNS）治疗难治性抑郁症（TRD）临床有效，因其有创，难以临床推广。前期本课题组发现经耳甲迷走神经刺激技术（taVNS）治疗抑郁症有效，其疗效与调制前扣带回、眶回、杏仁核等情绪认知关键脑区有关。因此，本研究通过观察taVNS治疗TRD、复发性抑郁症（RDE）、首发性抑郁症（FDE）临床疗效、神经环路异常以及磁共振波谱探测神经递质γ-氨基丁酸与谷氨酸的变化；分析差异脑区与临床疗效的相关性，进而阐明taVNS治疗TRD、RDE、FDE脑机制差异，验证假说：taVNS调节以前扣带回头部(rACC)为关键节点的情感-认知环路，探寻预测taVNS疗效的早期脑影像标记。.方法：本研究共纳入抑郁症患者134例，其中TRD 52例，RDE 52例，FDE 30例。连续8周taVNS治疗，每日2次，疏密波，5Hz/20Hz，每次刺激30min。同时纳入60例健康者，采集受试者抑郁、焦虑等临床量表以及fMRI成像数据。.结果及结论：在临床方面，taVNS均能改善TRD、RDE、FDE患者的抑郁、焦虑、失眠等临床症状。在脑机制方面，TRD患者默认网络及边缘系统-皮层-纹状体-苍白球-丘脑神经环路脑功能活动异常，其中认知及运动皮层相关脑区脑功能异常可能与负性情绪有关；从即刻效应上看taVNS可调节TRD患者的脑自发活动，涉及情感认知相关脑；从长期效应上看，taVNS能调制TRD患者的rACC与脑默认网络(DMN)重要脑区楔前叶及联合皮层舌状回FC，且与临床量表相关，这可能是taVNS调制TRD情感-认知环路的早期脑影像标记；taVNS对TRD患者的GABA、Glu值无显著差异，但GABA、Glu与TRD伴随症状焦虑、睡眠、冗思相关，推测它们也可能是taVNS治疗TRD的神经递质调节靶标。本研究实现了taVNS调控TRD的假说。.RDE存在DMN、视觉加工脑区功能异常，FDE患者存在执行控制网络(ECN)、DMN及奖赏网络等脑区功能活动异常。taVNS对这些脑区有即刻调节作用，这可能是其治疗RDE、FDE潜在的脑网络机制；.总之，taVNS可有效治疗多种抑郁症，调控情绪-认知等脑网络，是值得临床进一步深入研究和推广的针刺治疗抑郁症适宜技术。