针刺持续性神经响应特性研究
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摘要
针刺医学是中华民族优秀传统文化的瑰宝,是我国医疗卫生事业中独具特色和优势的巨大卫生资源。随着全球性日益增长的医疗费用,特别是现代医学,在征服各种危害人类疾病的同时所带来的种种医源性和药源性的病症,促使医学界和患者对毒副作用小、经济、以调节见长的中医针刺产生浓厚兴趣。但由于中医针刺理论,本质上产生于实践又经过中国古典哲学的深加工,使得其与现代医学在很多方面难以相融,已逐渐成为制约中医针刺理论发展的桎梏。得益于现代医学影像特别是功能核磁共振成像技术的快速发展,使得探寻经穴-大脑-脏腑之间的相互作用关系成为可能。该技术以其无创、无辐射、图像分辨率高等优势,已经成为活体研究人脑高级皮层功能活动的重要手段。目前fMRI的针刺研究刚刚起步,研究方法学还有待进一步完善。
以往的针刺影像学研究,着重在探讨针刺特定穴位与大脑对应功能皮层的空间对应关系,即针刺机理的脑功能定位研究;而根据中国传统中医理论以及大量的临床报道,针刺治疗效应存在持续性,因此对于针刺中枢神经时间维度特征信息的考量在深入理解针刺作用机理方面具有重要的研究意义。本文以针刺持续性效应假说的验证为切入点,采用多组块实验设计结合逐段分析方法证明了针刺持续性效应存在的假说,指出以往基于模型的多组块分析由于忽略针刺的时间维度特征信息而违背了减法原理的基线选取原则,进而有可能导致实验结果产生偏差的事实;由于基于模型的多组块实验设计方法已不再适合fMRI针刺研究,本文又通过引入非重复事件相关的实验设计模式以及全新的动态检测算法初步构建了针刺中枢神经的动态响应模型,并推测针刺作用过程涉及多个神经脑网络的参与;为了进一步阐明针刺持续性效应对多个神经系统之间交互关系的调节作用,我们采用同步涨落脑网络分析方法对针刺大脑核团动态激活响应的协同加工作用机制进行了深入分析,提出了针刺具有反相关脑网络调节模式的神经表象,并对占针刺机理研究主导地位的负激活边缘系统理论提出质疑;最后,为了深入说明针刺持续性神经表象的具体生理加工机制,本文运用fMRI研究技术与生理行为指标相结合的分析方法,通过构建经典的恶心负性情绪模型,实现了对针刺持续性效应中枢神经调控机制及其对应生理机制的探索性研究。具体的实验设计及研究成果包括:
实验一:基于多组块实验设计的针刺持续性效应假说的验证。此实验通过对多组块实验设计各个阶段针刺神经响应模式的提取,验证了针刺持续性效应存在的假说;指出由于针刺持续性效应的存在,以往研究分析方法违背了减法原理基线的选取原则,从而可能导致分析结果的偏差。我们的研究结果表明,基于模型的多组块实验分析方法已不再适合fMRI针刺研究。
实验二:针刺持续性效应神经时变响应特征模型的初步建构。由于以往基于模型的多组块实验分析方法已不再适合针刺持续性效应的研究,该实验引入了非重复事件相关的实验设计以及基于指数加权的滑动平均检测算法,深入分析了针刺中枢神经的时间响应特征信息。我们的研究结果表明,针刺可引发大脑随时间变化的复杂动态响应模式,对针刺中枢神经响应的考察应综合其时空二维特征信息。
实验三:建立针刺反相关脑网络调节模式的假说。本实验采用非重复事件相关的实验设计模式以及同步动态脑网络分析算法,对针刺大脑核团动态激活响应的交互作用机制进行深入分析。研究结果表明,针刺持续性效应以大脑反相关组织形式实现其协同加工作用机制,而并非对大脑产生单向调节作用,我们对占针刺主导地位的负激活边缘系统理论提出质疑。
实验四:建构了针刺持续性效应神经调控途径以及生理加工机制的研究模型。针对现有针刺研究模式因为缺乏对实验因素的有效控制,从而可能导致结果一致性低,而且以往研究可能无法真正探明针刺具体调控途径这一研究现状。本实验通过构造恶心负性情绪模型,实现了对实验因素以及个体机能水平差异的有效控制;并运用生理行为指标与功能磁共振相结合的分析方法,不仅在针刺多个穴位上再次验证了针刺持续性效应存在的假说,而且深入分析了针刺不同穴位所引发的持续性效应对该模型的调节作用以及潜在的生理加工机制。研究结果表明,针刺不同穴位可引发对恶心负性情绪模型的选择性调节机制,并且与恶心生理指标以及焦虑水平的变化直接相关,据此得出针刺穴位发挥功能为导向的神经调节机制的结论。该研究不仅可以为解密针刺作用发挥复杂多系统效应提供全新的研究途径,而且为针刺神经影像学研究结果指导临床应用提供实证性理论依据。
Acupuncture, as a treasure of the splendid traditional culture of Chinese nations, possesses massive health resources with characters and advantages in Chinese medical and health care undertakings. Because of the globally increasing medical expenditure and the iatrogenic and drug-induced diseases caused by modern medication in conquering hazardous diseases, the medical community and patients are becoming very interested in the economic, low toxic and side-effect acupuncture subsectioned in Traditional Chinese Medicine good at regulation. The traditional Chinese Medicine of acupuncture theories, growing out of practices and deeply processed by Chinese classical philosophy, make it hard to reconcile with modern medicines in many aspects, which sets up shackles for the development of acupuncture theories. With the advanced development of the modern neuroimaging techniques, particularly the functional magnetic resonance imaging (fMRI), the exploration of the relations among acupoints, brain and viscera has become possible. The fMRI technique, with its non-invasive and higher resolution characterstics, has been widely applied in the detection of the brain functions. However, the fMRI acupuncture investigation is still in its early stage, and needs further improvements.
Previous neuroimaging acupuncture studies have mainly focused on the correlations between acupuncture at certain acupoint and the functional brain cortice, as the spatially localized studies. According to the Traditional Chinese Medicine and abundant clinical evidence, the effect of acupuncture can sustain beyond the needle manipulation period. Therefore, the consideration of temporal information of the central nervous system in acupuncture bears vital theoretical importance in the deep understading of acupuncture mechanism. This paper, with the verification of acupuncture sustained effect hypothesis as the breakthrough point and through the multi-block design, confirmed the existence of the prolonged effects of acupuncture, demonstrated the fact that previous model-based multi-block studies violated the baseline princinple in the substracte technique reckoning without temporal information, and caused the errors of experiment results; next, the article adopted the new non-repeted event-related experiment paradigm and dynamic detection algorithm to construct the dynamic neutral response to acupuncture, and then the author speculated that acupuncture action involved participation of multi-neuro brain networks; further, we employed the spontaneous oscillation network analysis to investigate the intergrated mechanism of these dynamic nuclei responses induced by acupuncture, and advanced the nervous representation of the anti-correlated brain networks to doubt the dominant decreased limbic-system theory of acupuncture; finally, for the purpose of explaination about the real physiological mechanism of the nervous representation of sustained effects of acupuncture, we constructed the disgust affective model and combined the fMRI data with physiological indices to explore both the neural modulatory and the potential physiological mechanism underlying the longer-lasting effects of acupuncture. The details of the design paradigms and corresponding results are listed as follows:
The first experiment“the validation of the sustained effects of acupuncture by the multi-block design”aimed to validate the hypothesis about the sustained effects of acupuncture. To achieve this goal, we designed separate models to evaluate the baseline activities (prior to stimulation) and neural activities in sequential epochs via the block-designed paradigm to confirm the existence of the prolonged effects of acupuncture. This finding indicated that previous studies violate the baseline princinple in the substracte technique and may cause errors of experiment results, which make the model-based multi-block designed analysis improper in acupuncture studies.
The second experiment“the construction of the time-varying neural responses model of the sustained effects of acupuncture”attempted to construct the time-varying neural responses to the sustained effects of acupuncture. We introduced the non-repeated event-related design and hierarchical exponentially weighted moving-average method to investigate the temporal characteristics of neural responses to acupuncture. Resullts showed that acupuncture can evoke the complex time-dependent neural responses, and an accurate interpretation of acupuncture actions depended on how effectively we can characterize the nature of temporal variations underlying neural activities that give rise to hemodynamic responses, rather than simply detect the occurrence of such changes.
The third experiment“the proposed hypothesis of the anti-correlated brain networks following acupuncture and the doubt of the hypothesis of the dominant decreased limbic-system theory”, employed the non-repeated event-related design and spontaneous oscillation network analysis to investigate the intergrated processing mechanism of the dynamic neural responses induced by acupuncture. Its findings demonstrated the sustained effects of acupuncture can achieve the intergrated processing mechanism through the anti-correlated organization mechanism of brain networks, rather than exert unidirectional modulatory effects on human brain. Therefore, we made concluded doubt of the dominant theory of decreased limbic-system following acupuncture.
The fourth experiment“the construction of neural pathways and physiological mechanism of the prolonged effects of acupuncture”constructed the novel disgust affective model and realized the effective control of experimental factors and individual functional differences,with respect of the deficient control of experimental factors, low consistency of analysis results, and lack of real understanding of acupuncture modulatory pathways; it also validated the existence of sustained effects of acupuncture, and investigated the modulatory mechanism on this disgust affective model and the potential physiological mechanism, after acupuncturing at different acupoints,by ways of combined method of fMRI data and physiological indices. Our findings indicated that acupuncture at different acupoints can cause selective modulatory effects on the disgust affective model, which have high relations to the changes of physiological disgust and anxiety indices. According to these observations, we inferred that acupuncture can exert the function-guided neural modulatory mechanisms. This investigation can not only disclose the complex multiple system effects underlying the acupuncture, but also provide meaningful theoretical evidence for the clinical applications of acupuncture neuroimaging.
以往的针刺影像学研究,着重在探讨针刺特定穴位与大脑对应功能皮层的空间对应关系,即针刺机理的脑功能定位研究;而根据中国传统中医理论以及大量的临床报道,针刺治疗效应存在持续性,因此对于针刺中枢神经时间维度特征信息的考量在深入理解针刺作用机理方面具有重要的研究意义。本文以针刺持续性效应假说的验证为切入点,采用多组块实验设计结合逐段分析方法证明了针刺持续性效应存在的假说,指出以往基于模型的多组块分析由于忽略针刺的时间维度特征信息而违背了减法原理的基线选取原则,进而有可能导致实验结果产生偏差的事实;由于基于模型的多组块实验设计方法已不再适合fMRI针刺研究,本文又通过引入非重复事件相关的实验设计模式以及全新的动态检测算法初步构建了针刺中枢神经的动态响应模型,并推测针刺作用过程涉及多个神经脑网络的参与;为了进一步阐明针刺持续性效应对多个神经系统之间交互关系的调节作用,我们采用同步涨落脑网络分析方法对针刺大脑核团动态激活响应的协同加工作用机制进行了深入分析,提出了针刺具有反相关脑网络调节模式的神经表象,并对占针刺机理研究主导地位的负激活边缘系统理论提出质疑;最后,为了深入说明针刺持续性神经表象的具体生理加工机制,本文运用fMRI研究技术与生理行为指标相结合的分析方法,通过构建经典的恶心负性情绪模型,实现了对针刺持续性效应中枢神经调控机制及其对应生理机制的探索性研究。具体的实验设计及研究成果包括:
实验一:基于多组块实验设计的针刺持续性效应假说的验证。此实验通过对多组块实验设计各个阶段针刺神经响应模式的提取,验证了针刺持续性效应存在的假说;指出由于针刺持续性效应的存在,以往研究分析方法违背了减法原理基线的选取原则,从而可能导致分析结果的偏差。我们的研究结果表明,基于模型的多组块实验分析方法已不再适合fMRI针刺研究。
实验二:针刺持续性效应神经时变响应特征模型的初步建构。由于以往基于模型的多组块实验分析方法已不再适合针刺持续性效应的研究,该实验引入了非重复事件相关的实验设计以及基于指数加权的滑动平均检测算法,深入分析了针刺中枢神经的时间响应特征信息。我们的研究结果表明,针刺可引发大脑随时间变化的复杂动态响应模式,对针刺中枢神经响应的考察应综合其时空二维特征信息。
实验三:建立针刺反相关脑网络调节模式的假说。本实验采用非重复事件相关的实验设计模式以及同步动态脑网络分析算法,对针刺大脑核团动态激活响应的交互作用机制进行深入分析。研究结果表明,针刺持续性效应以大脑反相关组织形式实现其协同加工作用机制,而并非对大脑产生单向调节作用,我们对占针刺主导地位的负激活边缘系统理论提出质疑。
实验四:建构了针刺持续性效应神经调控途径以及生理加工机制的研究模型。针对现有针刺研究模式因为缺乏对实验因素的有效控制,从而可能导致结果一致性低,而且以往研究可能无法真正探明针刺具体调控途径这一研究现状。本实验通过构造恶心负性情绪模型,实现了对实验因素以及个体机能水平差异的有效控制;并运用生理行为指标与功能磁共振相结合的分析方法,不仅在针刺多个穴位上再次验证了针刺持续性效应存在的假说,而且深入分析了针刺不同穴位所引发的持续性效应对该模型的调节作用以及潜在的生理加工机制。研究结果表明,针刺不同穴位可引发对恶心负性情绪模型的选择性调节机制,并且与恶心生理指标以及焦虑水平的变化直接相关,据此得出针刺穴位发挥功能为导向的神经调节机制的结论。该研究不仅可以为解密针刺作用发挥复杂多系统效应提供全新的研究途径,而且为针刺神经影像学研究结果指导临床应用提供实证性理论依据。
Acupuncture, as a treasure of the splendid traditional culture of Chinese nations, possesses massive health resources with characters and advantages in Chinese medical and health care undertakings. Because of the globally increasing medical expenditure and the iatrogenic and drug-induced diseases caused by modern medication in conquering hazardous diseases, the medical community and patients are becoming very interested in the economic, low toxic and side-effect acupuncture subsectioned in Traditional Chinese Medicine good at regulation. The traditional Chinese Medicine of acupuncture theories, growing out of practices and deeply processed by Chinese classical philosophy, make it hard to reconcile with modern medicines in many aspects, which sets up shackles for the development of acupuncture theories. With the advanced development of the modern neuroimaging techniques, particularly the functional magnetic resonance imaging (fMRI), the exploration of the relations among acupoints, brain and viscera has become possible. The fMRI technique, with its non-invasive and higher resolution characterstics, has been widely applied in the detection of the brain functions. However, the fMRI acupuncture investigation is still in its early stage, and needs further improvements.
Previous neuroimaging acupuncture studies have mainly focused on the correlations between acupuncture at certain acupoint and the functional brain cortice, as the spatially localized studies. According to the Traditional Chinese Medicine and abundant clinical evidence, the effect of acupuncture can sustain beyond the needle manipulation period. Therefore, the consideration of temporal information of the central nervous system in acupuncture bears vital theoretical importance in the deep understading of acupuncture mechanism. This paper, with the verification of acupuncture sustained effect hypothesis as the breakthrough point and through the multi-block design, confirmed the existence of the prolonged effects of acupuncture, demonstrated the fact that previous model-based multi-block studies violated the baseline princinple in the substracte technique reckoning without temporal information, and caused the errors of experiment results; next, the article adopted the new non-repeted event-related experiment paradigm and dynamic detection algorithm to construct the dynamic neutral response to acupuncture, and then the author speculated that acupuncture action involved participation of multi-neuro brain networks; further, we employed the spontaneous oscillation network analysis to investigate the intergrated mechanism of these dynamic nuclei responses induced by acupuncture, and advanced the nervous representation of the anti-correlated brain networks to doubt the dominant decreased limbic-system theory of acupuncture; finally, for the purpose of explaination about the real physiological mechanism of the nervous representation of sustained effects of acupuncture, we constructed the disgust affective model and combined the fMRI data with physiological indices to explore both the neural modulatory and the potential physiological mechanism underlying the longer-lasting effects of acupuncture. The details of the design paradigms and corresponding results are listed as follows:
The first experiment“the validation of the sustained effects of acupuncture by the multi-block design”aimed to validate the hypothesis about the sustained effects of acupuncture. To achieve this goal, we designed separate models to evaluate the baseline activities (prior to stimulation) and neural activities in sequential epochs via the block-designed paradigm to confirm the existence of the prolonged effects of acupuncture. This finding indicated that previous studies violate the baseline princinple in the substracte technique and may cause errors of experiment results, which make the model-based multi-block designed analysis improper in acupuncture studies.
The second experiment“the construction of the time-varying neural responses model of the sustained effects of acupuncture”attempted to construct the time-varying neural responses to the sustained effects of acupuncture. We introduced the non-repeated event-related design and hierarchical exponentially weighted moving-average method to investigate the temporal characteristics of neural responses to acupuncture. Resullts showed that acupuncture can evoke the complex time-dependent neural responses, and an accurate interpretation of acupuncture actions depended on how effectively we can characterize the nature of temporal variations underlying neural activities that give rise to hemodynamic responses, rather than simply detect the occurrence of such changes.
The third experiment“the proposed hypothesis of the anti-correlated brain networks following acupuncture and the doubt of the hypothesis of the dominant decreased limbic-system theory”, employed the non-repeated event-related design and spontaneous oscillation network analysis to investigate the intergrated processing mechanism of the dynamic neural responses induced by acupuncture. Its findings demonstrated the sustained effects of acupuncture can achieve the intergrated processing mechanism through the anti-correlated organization mechanism of brain networks, rather than exert unidirectional modulatory effects on human brain. Therefore, we made concluded doubt of the dominant theory of decreased limbic-system following acupuncture.
The fourth experiment“the construction of neural pathways and physiological mechanism of the prolonged effects of acupuncture”constructed the novel disgust affective model and realized the effective control of experimental factors and individual functional differences,with respect of the deficient control of experimental factors, low consistency of analysis results, and lack of real understanding of acupuncture modulatory pathways; it also validated the existence of sustained effects of acupuncture, and investigated the modulatory mechanism on this disgust affective model and the potential physiological mechanism, after acupuncturing at different acupoints,by ways of combined method of fMRI data and physiological indices. Our findings indicated that acupuncture at different acupoints can cause selective modulatory effects on the disgust affective model, which have high relations to the changes of physiological disgust and anxiety indices. According to these observations, we inferred that acupuncture can exert the function-guided neural modulatory mechanisms. This investigation can not only disclose the complex multiple system effects underlying the acupuncture, but also provide meaningful theoretical evidence for the clinical applications of acupuncture neuroimaging.
引文
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