rTMS调控阿尔茨海默病神经网络的“胆碱能-血管”机制研究

Repetitive transcranial magnetic stimulation (rTMS) is a newly developed non-invasive brain stimulation(NIBS) technology, which can improve the cognitive function in patients with Alzheimer's disease (AD) significantly, but the underlying mechanism is still unclear. In recent years, more and more evidences showed that AD is a disconnection syndrome, and the breakdown of cholinergic pathway from the basal forebrain to the microvascular network of frontal parietal cortex is a key factor leading to its cognitive decline. Our previous studies found that the CBF and functional connectivity in AD patients were significantly changed after rTMS treatment. Based on this and literature reports, we assumed that the regulation of neural network by rTMS in AD is achieved through the "cholinergic-vascular" pathway. To testify this hypothesis, this project intended to proceed from clinical and animal studies, to investigate the macroscopic changes of cholinergic pathway, brain network, and CBF from the perspective of neuroimaging, to explore the microscopic changes of the key neurotransmitter ACh, NGF/BDNF signaling pathway, and CBF from the perspective of neuropathology before and after rTMS treatment. By combining the neuroimaging and neuropathological results, we want to finally clarify the "cholinergic-vascular" mechanism underlying the regulation of neural network by rTMS in AD. The implementation of this project is expected to provide new evidence from the point of neural networks for understanding the mechanism of rTMS in improving cognition, and to provide theoretical support for the treatment of AD by rTMS.

重复经颅磁刺激（rTMS）是一种新兴的、无创性脑刺激技术，可显著改善阿尔茨海默病（AD）认知功能，但具体作用机制仍不明确。近年研究表明AD脑网络连接存在广泛异常，其中从基底前脑到额顶叶皮层微血管网的胆碱能通路障碍是导致其认知下降的一个重要因素。我们前期研究发现rTMS治疗后AD患者脑血流、功能连接显著改变，结合相关文献我们推测，rTMS对AD神经网络的调控是通过“胆碱能-血管”通路实现的。为了验证该假说，本课题拟从临床和实验研究两方面着手，从影像学角度探索rTMS治疗前后AD胆碱能通路、脑网络、脑血流的宏观变化，从神经病理学角度探索关键神经递质ACh、NGF/BDNF信号通路、脑血流微观变化，结合影像学和神经病理学的结果，阐明rTMS调控AD神经网络变化的“胆碱能-血管”机制。本研究的实施有望为rTMS改善AD认知的机制从神经网络变化层面提供新的思路和证据，为rTMS治疗AD提供理论支持。

本项目基于“胆碱能-血管”理论展开对阿尔茨海默病（AD）的重复经颅磁刺激（rTMS）治疗研究，为rTMS改善AD认知的机制提供了新证据。目前已经发表相关论文12篇。主要成果如下：（1）探索了AD患者rTMS治疗的刺激靶点、条件以及疗效，发现rTMS靶向刺激左侧背外侧前额叶（DLPFC）在改善AD临床和神经认知功能方面有一定的作用，左侧DLPFC是比左侧颞叶更佳的刺激靶点，为临床应用提供了指导；（2）明确了高频rTMS对AD患者刺激靶点脑区MRS代谢水平的影响，发现rTMS可提高刺激靶点脑区的NAA/Cr水平、同时降低Cho/Cr水平，且NAA/Cr水平升高与ADAS-cog评分降低（分数越低，认知功能越好）相关；(3) 采用静息态fMRI为研究手段，探索rTMS改善脑功能活动的神经基础，发现刺激靶点远隔脑区的分数低频振幅（fALFF）显著变化和功能连接（FC），主要包括右侧小脑半球、左侧舌/楔状回、左侧扣带回和左侧额中回等脑区，为rTMS调控神经网络变化提供了依据；（4）探索rTMS引起的脑血流变化是本项目的一个重要内容。基于体素的全脑CBF分析发现，rTMS治疗结束后随访4周，左侧海马旁回的脑血流量显著提高；基于ROI的分析显示，rTMS治疗结束时楔前叶CBF显著减低，且与患者的长期认知功能改善相关，可能代表了一种短暂的可塑性阶段。本部分内容为理解rTMS临床应用的潜在神经生物学机制提供了影像学证据；（5）初步探索了基于LDDMM算法的多图谱融合分割方法，并应用于AD患者基底核团的QSM定量分析。本课题对理解rTMS改善AD认知的神经网络机制提供了一定的客观依据及理论基础，并在课题进行中形成了新的研究问题和思路，协助培养了3名博士和硕士研究生。