双向干预对AD源性MCI患者执行-吞咽功能的影响及其神经网络连通性机制

Impairment in executive and swallowing function has been commonly found in patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD). Until now, no effective treatment has been identified yet. In a pilot study, we developed and applied a novel dual-stream method, that is, combing intermittent theta burst stimulation (iTBS) on the dorsal lateral prefrontal cortex (DLPFC) and stimulation on lingual gustatory receptor using personalized favorite taste. A small cohort of patients were treated and showed promising recovery of swallowing function. However, the mechanism underlying this recovery is not clear. We hypothesize that this dual-stimulation method may facilitate recovery of two specific neural networks related to executive and swallowing function where MCI due to AD patients showed reduction in connection strength. In particular, we are interested in two networks, one related to executive function and the other swallowing. Previous research identified abnormalities associated with both of them in AD/MCI patients suffering dysphagia.In this study, we will use both fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and resting-state functional connectivity and task related MRI (fMRI) in both MCI due to AD patients suffering dysphagia and age-gender-matched control subjects before and after applying the dual-stream stimulation method. Using these two imaging techniques together, we will identify the normal structures of these two executive and swallowing related networks and how they interact with each other in controls, and how they are impaired in patients and how they recover after treatment. In addition, we will collect endpoints before and after treatment, effective function by cognitive tasks, swallowing function by videofluroscopic imaging of swallowing and perioral muscles sEMG. We will examine the relationship between neural network signatures identified via neuro-imaging and these clinical endpoints to further clarify the neural pathway underlying the functional recovery of swallowing. Together, we believe this study would help to build a novel therapy for AD/MCI patients suffering dysphagia and provide a better understanding on the neural mechanisms underlying the loss and recovery of swallowing.

执行功能障碍合并吞咽障碍是AD源性MCI患者常见的临床症状，目前很多干预治疗效果不佳。我们应用iTBS定位刺激左侧前额叶背外侧区，配合个人喜爱口味的舌味觉刺激训练取得较好疗效。据此，我们假设这种双向干预对执行功能与吞咽功能的中枢神经网络重组具有易化作用，前额叶背外侧区是两个神经网络连通的主要调控节点之一，但涉及的神经通路及相互影响的机制还不清楚。为此，本研究采用18F-FDG-PET结合基于功能连接密度图方法的fMRI分析技术、吞咽造影及口周肌群表面肌电图量化检测、临床执行功能亚成分评分等方法，评价AD源性MCI患者与正常配对老年人比较，在双向干预4周前后执行功能伴吞咽功能障碍两个神经网络的变化及其通路间康复代偿的途径，明确执行功能障碍及亚成分与口咽吞咽功能的相互影响，探讨执行-吞咽功能脑神经网络连通性及其关键神经节点调控机制，为AD/MCI患者临床开展创新性的康复评估与治疗提供理论依据。

安全有效的吞咽需要外周神经和中枢神经系统的精确调控。研究显示吞咽困难（或吞咽障碍）在健康老年人也可能发生，如果合并认知障碍，吞咽障碍发生率会随之增加。阿尔茨海默病是一种发生于老年人的认知功能进行性下降的退行性疾病。先前研究发现在AD的中晚期认知障碍明显减退，此时合并吞咽障碍发生率更高。.实验的第一阶段是建立正常老年人的认知、吞咽常模。我们招募了24名健康老年人，完成认知执行功能评估和功能磁共振（functional MRI，fMRI）检查，其中13人完成了吞咽和认知任务态fMRI。结果显示吞咽任务和认知任务共同激活了多个脑区，包括：双侧的小脑、枕叶、中央前回、中央后回、舌回、额中回、下顶叶、梭状回，还有左侧下额叶。我们还发现双侧的前额叶脑区在吞咽任务中兴奋性活动是相左的，即右侧前额叶表现为兴奋性增加，左侧前额叶兴奋活动受抑制，而在认知任务中表现为双侧前额叶均为兴奋性增加。此外我们还发现吞咽任务中感觉区激活体素多于运动区，左侧中央后回、中央前回分别激活了141 、99体素，右侧中央后回、中央前回分别激活了107 、67体素。分析发现额-顶环路在共同激活脑区中起到了重要的连接作用，且右侧前额叶（额中回）在认知及吞咽任务中均为正性激活。.基于此，本研究入组轻度认知障碍合并吞咽障碍患者iTBS刺激位点选择为右侧前额叶背外侧区。共纳入了26名患者，随机分为两组：真刺激组和假刺激组，均刺激治疗10次。研究结果表明iTBS治疗后MoCA评分改善；治疗后10ml食物口腔运送时间减少，咽腔收缩率（pharyngeal contraction rate，PCR）降低，咽腔残留减少；真刺激组治疗后右侧前额叶同全脑功能连接（functional connectivity，FC）增加。结合第一阶段研究发现，本阶段结果提示iTBS刺激右侧前额叶背外侧区同时激活了认知和吞咽神经网络，改善了认知功能和吞咽功能，功能改善是通过刺激位点引起了整个脑网络的功能连接变化。.本研究初步证明了健康老年人的认知、吞咽脑功能之间存在网络分布，两任务之间的功能网络存在交叉重叠，iTBS刺激右侧前额叶背外侧区治疗的有效性，也提示了右侧前额叶是认知和吞咽功能的神经节点之一。本研究探讨了认知、吞咽功能的大脑皮层调控，但是皮层同脑干的相互作用以及小脑在认知、吞咽中的作用还需要在在未来的研究中进一步明确。