Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA; Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA.
Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA.
Brain Stimul. 2019 Jan-Feb;12(1):19-29. doi: 10.1016/j.brs.2018.10.005. Epub 2018 Oct 9.
The vagus nerve is involved in regulating immunity and resolving inflammation. Current strategies aimed at modulating neuroinflammation and cognitive decline, in many cases, are limited and ineffective.
We sought to develop a minimally invasive, targeted, vagus nerve stimulation approach (pVNS), and we tested its efficacy with respect to microglial activation and amelioration of cognitive dysfunction following lipopolysaccharide (LPS) endotoxemia in mice.
We stimulated the cervical vagus nerve in mice using an ultrasound-guided needle electrode under sevoflurane anesthesia. The concentric bipolar needle electrode was percutaneously placed adjacent to the carotid sheath and stimulation was verified in real-time using bradycardia as a biomarker. Activation of vagal fibers was confirmed with immunostaining in relevant brainstem structures, including the dorsal motor nucleus and nucleus tractus solitarius. Efficacy of pVNS was evaluated following administration of LPS and analyses of changes in inflammation and behavior.
pVNS enabled stimulation of the vagus nerve as demonstrated by changes in bradycardia and histological evaluation of c-Fos and choline acetyltransferase expression in brainstem nuclei. Following LPS administration, pVNS significantly reduced plasma levels of tumor necrosis factor-α at 3 h post-injection. pVNS prevented LPS-induced hippocampal microglial activation as analyzed by changes in Iba-1 immunoreactivity, including cell body enlargement and shortened ramifications. Cognitive dysfunction following endotoxemia was also restored by pVNS.
Targeted cervical VNS using this novel percutaneous approach reduced LPS-induced systemic and brain inflammation and significantly improved cognitive responses. These results provide a novel therapeutic approach using bioelectronic medicine to modulate neuro-immune interactions that affect cognition.
迷走神经参与调节免疫和炎症的消退。目前，许多旨在调节神经炎症和认知能力下降的策略都存在局限性和无效性。
我们试图开发一种微创、靶向的迷走神经刺激方法（pVNS），并在 LPS 内毒素血症后，通过检测小胶质细胞的激活和认知功能障碍的改善，来测试其疗效。
我们在七氟醚麻醉下使用超声引导的针电极刺激小鼠的颈迷走神经。同心双极针电极经皮放置在颈动脉鞘附近，并通过心动过缓实时验证刺激。通过免疫染色在相关脑干结构（包括背侧运动核和孤束核）中确认迷走神经纤维的激活。在 LPS 给药后评估 pVNS 的疗效，并分析炎症和行为的变化。
pVNS 可刺激迷走神经，表现为心动过缓的变化和脑干核 c-Fos 和胆碱乙酰转移酶表达的组织学评估。在 LPS 给药后，pVNS 可显著降低注射后 3 小时的血浆肿瘤坏死因子-α水平。pVNS 可防止 LPS 诱导的海马小胶质细胞激活，表现为 Iba-1 免疫反应性的变化，包括细胞体增大和分支缩短。内毒素血症后的认知功能障碍也通过 pVNS 得到恢复。
使用这种新的经皮方法靶向颈 VNS 可减少 LPS 诱导的全身和脑炎症，并显著改善认知反应。这些结果为使用生物电子医学调节影响认知的神经免疫相互作用提供了一种新的治疗方法。
