耳甲-迷走神经刺激治疗失眠症的临床及机制研究

Insomnia is a common and clinically refractory disease but testified as a disorder that can be treated with acupuncture. Insomnia is related to a decreased secretion of melatonin and a down regulated expression of melatonin receptor type 1 (MT1) in the central nervous system. Our preliminary results show that there are vagal innervations in the auricular concha area and transcutaneous vagus nerve stimulation (ta-VNS) which can promote the melatonergic system, as demonstrated by the facts that ta-VNS acutely elevated the concentration of melatonin in rats, and significantly up-regulated the expression of melatonin receptor type 1 (MT1). In this application we would further 1) explore the involvement of the promoted /restored melatonergic system in the mechanism of the therapeutic effectiveness of ta-VNS on insomnia in experimental animal model of insomnia, and 2) verify the therapeutic effectiveness of ta-VNS in clinical insomnia patients. The project would be able 1) to clarity the promoting effect of ta-VNS on the melatonergic system in rodent insomnia model, including the secretion amount, rhythm, sources of melatonin and its up-regulating effect on the MT1 expression; and 2) to evaluate the effectiveness of ta-VNS on the quantity and rhythm of melatonin secretion, and its therapeutic effect in insomnia patients. The outcome from this project will help us to understand the mechanism of the acupuncture effectiveness and to provide scientific evidence of the therapeutic effectiveness of ta-VNS on insomnia and other diseases with low circulating melatonin level implicated.

失眠症是一种临床常见的难治性疾病，与褪黑素分泌减少相关。失眠症是针灸治疗的优势病种。前期研究表明，耳甲区有迷走神经分布，耳甲区电刺激（经皮迷走神经刺激，Transcutaneous vagus nerve stimulation，ta-VNS ）能够促进褪黑素分泌，引起大鼠血浆褪黑素水平显著增加，上调褪黑素一型受体MT1的表达。本课题通过动物实验研究进一步阐明ta-VNS对失眠模型大鼠褪黑素能系统的调节效应，包括褪黑素分泌和对MT1表达的调节作用；通过临床随机对照试验明确ta-VNS治疗失眠症的疗效；通过脑功能磁共振研究探索ta-VNS治疗失眠症的中枢效应机制，证实我们的假说：耳甲区电针通过体表迷走神经刺激调制边缘叶-觉醒脑功能网络（特别是松果体、下丘脑、孤束核及杏仁核等结构）调节褪黑素能系统调整睡眠，为临床应用ta-VNS治疗失眠症提供有力的科学依据。

失眠症是一种临床常见的难治性疾病，与褪黑素分泌减少有关。前期研究表明，耳甲区电刺激（Transcutaneous vagus nerve stimulation，taVNS）能够促进褪黑素分泌，引起大鼠血浆褪黑素水平显著增加。本课题通过动物实验研究进一步阐明taVNS对失眠模型大鼠褪黑素能系统的调节效应；通过临床随机对照试验明确taVNS治疗失眠症的疗效；通过脑功能磁共振研究探索taVNS治疗失眠症的中枢效应机制，证实我们的假说：耳甲区电针通过体表迷走神经刺激调制边缘叶-觉醒脑功能网络（特别是松果体、下丘脑、孤束核及杏仁核等结构）调节褪黑素能系统调整睡眠，为临床应用taVNS治疗失眠症提供有力的科学依据。. 动物实验研究发现：与模型组相比，耳甲电针组大鼠体重明显升高，水平运动和垂直运动得分明显下降；模型组和耳甲电针组血浆褪黑素浓度与空白组相比显著下降，电针后，与空白组相比，模型组明显下降；与模型组相比，耳甲电针组明显升高，且耳甲区电针可引起血浆褪黑素呈节律性升高。对大鼠脑电进行监测发现安静状态下，耳甲电针组与耳缘电针组的主要频率分布于频率较低的δ和θ频段。δ频段中，耳甲电针组较模型组有较明显提高，能达到正常组的85.6%。相应在θ、α和β频段，耳甲电针组较模型组频率百分比下降；而耳缘电针组无明显差别。临床研究发现：与基线相比，taVNS组显著降低第四周（治疗后）PQSI、FFS、ESS、HAMD和HAMA评分，并显著提高第四周（治疗后）SF-36评分，但与tnVNS相比，在降低ESS、FFS、HAMD、HAMA、SF-36评分以及血清褪黑素水平方面无显著性差异。脑功能磁共振研究结果显示：以丘脑为感兴趣做全脑功能连接分析，经耳甲电针治疗后，患者前额叶、右侧杏仁核、孤束核、枕叶、松果体、颞叶出现功能连接增强；与耳缘电针组比较，耳甲电针组患者在海马、脑岛、楔前叶的功能连接增强。这些脑区大多属于边缘叶和觉醒系统的相关脑区。安全性评估：心电图、血尿常规及血生化等指标在两组治疗前后比较及组间比较均无显著性差异。. 本研究证实了耳甲电针治疗原发性失眠有效性和安全性，其疗效机制可能与对褪黑素能系统的调节密切相关。