Clinically-derived vagus nerve stimulation enhances cerebrospinal fluid penetrance.

Author: Cheng KP1, Brodnick SK1, Blanz SL1, Zeng W2, Kegel J1, Pisaniello JA1, Ness JP1, Ross E3, Nicolai EN4, Settell ML4, Trevathan JK4, Poore SO5, Suminski AJ6, Williams JC6, Ludwig KA7
Affiliation:
1Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Drive, Madison, WI, 53706, USA.
2Department of Surgery, Division of Plastic and Reconstructive Surgery, School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI, 53706, USA.
3Mayo Clinic, Department of Neurologic Surgery, Rochester, MN, 55905, USA.
4Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Drive, Madison, WI, 53706, USA; Mayo Clinic, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, 55905, USA.
5Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Drive, Madison, WI, 53706, USA; Department of Surgery, Division of Plastic and Reconstructive Surgery, School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI, 53706, USA.
6Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Drive, Madison, WI, 53706, USA; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI, 53706, USA.
7Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Drive, Madison, WI, 53706, USA; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI, 53706, USA. Electronic address: kip.ludwig@wisc.edu.
Conference/Journal: Brain Stimul.
Date published: 2020 Mar 26
Other: Volume ID: 13 , Issue ID: 4 , Pages: 1024-1030 , Special Notes: doi: 10.1016/j.brs.2020.03.012. [Epub ahead of print] , Word Count: 311

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.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

KEYWORDS: Glymphatic; Lymphatic; Neuromodulation; Vagus; Vagus nerve stimulation

PMID: 32388045 DOI: 10.1016/j.brs.2020.03.012

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