INTRODUCTION Vagus nerve stimulation (VNS) is an FDA-approved neuromodulatory treatment used in the clinic today for epilepsy, depression, and cluster headaches. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood. In parallel, the glymphatic and meningeal lymphatic systems have recently been described as methods by which the brain maintains a healthy homeostasis and removes waste without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins. OBJECTIVE/HYPOTHESIS As VNS has well-documented effects on many of the pathways recently linked to the clearance systems of the brain, we hypothesized that VNS could increase CSF penetrance in the brain. METHODS We injected a low molecular weight lysine-fixable fluorescent tracer (TxRed-3kD) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following an application of a clinically-derived VNS paradigm (30 Hz, 10% duty cycle). RESULTS We found that the clinical VNS group showed a significant increase in CSF tracer penetrance as compared to the naïve control and sham groups. CONCLUSION (s): This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.

中文翻译：

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临床衍生的迷走神经刺激增强脑脊液渗透

介绍 迷走神经刺激 (VNS) 是 FDA 批准的神经调节疗法，目前用于临床治疗癫痫、抑郁症和丛集性头痛。此外，文献中的证据导致了越来越多的可能的临床适应症，一些小型临床试验将 VNS 应用于治疗从神经退行性疾病到关节炎、焦虑症和肥胖症的各种疾病。尽管治疗应用越来越多，但人们对 VNS 实现其有益效果的基本机制知之甚少。与此同时，淋巴系统和脑膜淋巴系统最近被描述为大脑维持健康稳态和清除废物的方法，而无需传统定义的淋巴系统。特别是，淋巴系统涉及脑脊液 (CSF) 和间质液 (ISF) 的交换，其净效应是冲洗脑实质，去除代谢废物和错误折叠的蛋白质。目标/假设由于 VNS 对许多最近与大脑清除系统相关的通路有充分记录的影响，我们假设 VNS 可以增加大脑中的脑脊液外显率。方法我们将低分子量赖氨酸固定荧光示踪剂 (TxRed-3kD) 注射到带有颈迷走神经袖带植入物的小鼠脑脊液系统中，并在应用临床衍生的 VNS 范式（30 Hz）后测量脑脊液外显量, 10% 占空比）。结果我们发现，与初始对照组和假手术组相比，临床 VNS 组的 CSF 示踪剂外显率显着增加。结论 (s)：这项研究表明，今天已经在临床中应用的 VNS 治疗策略可能会通过改变大脑中的 CSF/ISF 交换来引起预期的效果和/或不需要的副作用。这可能对治疗各种中枢神经系统疾病具有广泛的影响。