脑深部电刺激对阿尔茨海默病脑网络的调控作用及机制研究

Alzheimer’s disease (AD) has been increasingly considered as a large-scale network disconnection syndrome. Currently, Alzheimer’s disease remains unchecked, and the economic burden on society is huge. Recently, deep brain stimulation (DBS) engaging circuits and networks in brain regions of individuals with AD are proved potentially therapeutic. DBS of the bilateral hypothalamus/fornix has been trialed in 5 patients suffering from AD in our pilot study. The results of our early studies suggested that DBS therapy in AD patients could improve the cognitive functions and reverse the abnormal glucose metabolism in several brain regions. In this study, we aim to further investigate the effect of DBS on large-scale networks in AD brain activity and its relationship to cognition. We recruit AD patients and perform multimodal neuroimaging scans and cognitive tests before and after 6 months and 12 months of treatment with DBS. Healthy controls (HCs) and matched AD patients not receiving DBS are also scanned 3 times with a 6-month interval. Firstly, we intend to evaluate how DBS influences the cognitive functions and brain structure as well as glucose metabolism in AD patients. Second, we use the method of imaging connectomics to understand how the human brain networks in vivo are topologically organized in AD patients before and after DBS treatment. Finally, we will map the DBS-target-related brain’s structural and functional circuits. The features of these circuits enable us to build machine-learning models to predict the individual patient’s cognitive functions following DBS. The project will elucidate the underlying mechanism of DBS treatment for AD, which in turn, may facilitate advances in management and intervention.

阿尔茨海默病（Alzheimer’s disease, AD）是一种大尺度脑网络疾病，至今尚无有效治疗方法，对社会产生严重负担。脑深部电刺激（deep brain stimulation，DBS）可调控靶点相关的脑网络，为AD的治疗带来希望。课题组前期完成5例AD的下丘脑/穹窿DBS治疗，发现DBS能改善认知功能，恢复局部脑区的异常糖代谢。本研究拟入组重度AD进行DBS治疗，完成治疗前和治疗后半年、一年的多模态神经影像及多维度认知评估，并匹配正常对照组和疾病相当的AD患者，评价不同组别人群在纵向上的认知及脑代谢、结构变化差异；基于脑连接组学研究AD患者接受治疗前后脑网络拓扑属性的变化及其和认知功能改善的关系；以DBS靶点进行种子点功能和结构连接，利用这些环路水平的特征和机器学习模型预测DBS治疗AD的效果。本研究可为阐明DBS治疗AD的作用机制提供了理论基础，有助于解决AD这一世界性难题。

阿尔茨海默病（Alzheimer’s disease, AD）是一种大尺度脑网络疾病，至今尚无有效治疗方法，对社会产生严重负担。脑深部电刺激（deep brain stimulation， DBS）可调控靶点相关的脑网络，为AD的治疗带来希望。按照研究计划，本研究团队注册了世界上第一个针对重度AD患者的穹窿-DBS治疗的临床试验（NCT03115814），完成国内前9例AD病例的下丘脑/穹隆核DBS治疗，建立机器人下电极植入手术技术流程及效果评价体系，在该手术流程下，9例患者的DBS手术均成功，手术时间为6.0～8.5h，平均为7.0±1.0h；住院时间为12～32d，平均为26.0±7.3d。术后无一例发生颅内出血、脑梗塞、电极连接异常及伤口感染等围手术期并发症。术后复查颅脑MRI、CT以及X线平片显示9例患者的电极均植入预设靶点位置；其次，本项目在国内首次报道了DBS治疗重度AD的术后程控方案，术后4周进行开机测试，电刺激方式为单极刺激，频率为130Hz、脉宽为90μs、电压3V。根据电极触点所在位置的相应功能，节选量表分项检测患者的情绪、记忆、计算、语言或交流及定向力，以判断最佳触点，根据随访结果优化电极的刺激参数；此外，本项目完成DBS治疗前和治疗后半年、一年的多模态神经影像及多维度认知评估，并匹配正常对照组和疾病相当的AD患者，评价不同组别人群在纵向上的认知及脑代谢、结构变化差异，发现电刺激下丘脑/穹窿能改善AD患者的部分日常行为能力，提高患者的注意力，改善患者的淡漠状况，促进患者参与日常生活的能力，患者家属的照料困难程度也较手术前有明显的改善；最后，基于纵向的多模态神经影像和人脑连接组学分析，发现DBS能恢复AD患者局部脑区的异常糖代谢，DBS可以调控包含海马在内的Papez环路以及靶点相关的默认网络、凸显网络等高级认知相关网络。本课题研究目标已达标，长期随访数据仍在挖掘，拟进一步申请项目，为阐明DBS治疗AD的作用机制提供了理论基础，最终有望推进AD的个体化DBS治疗。