Is Vagus Nerve Stimulation Brain Washing?

Abstract

Authors contributed equally to this work One Sentence Summary: Cervical vagus nerve stimulation using clinically derived parameters enhances movement of cerebrospinal fluid into the brain parenchyma presenting a previously unreported effect of vagus nerve stimulation with potential clinical utility.Abstract: Vagal nerve stimulation (VNS) is an FDA approved treatment method for intractable epilepsy, treatment resistant depression, cluster headaches and migraine with over 100,000 patients having received vagal nerve implants to date. 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 and an area of active research. In parallel, the glymphatic and meningeal lymphatic systems have recently been proposed and experimentally validated to explain how the brain maintains a healthy homeostasis 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 from the interstitium. Of note, clearance is sensitive to adrenergic signaling, and a primary driver of CSF influx into the parenchyma appears to be cerebral arterial pulsations and respiration. As VNS has well-documented effects on cardiovascular and respiratory physiology as well as brain adrenergic signaling, we hypothesized that VNS delivered at clinically derived parameters would increase CSF influx in the brain. To test this hypothesis, we injected a low molecular weight (3 kD) lysine-fixable fluorescent tracer (TxRed) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following VNS. We found that the clinical VNS group showed a significant increase in CSF dye penetrance as compared to the naïve control and sham groups. 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.

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“…Panel B is adapted from Jarczok et al 59 (e.g., during fasting 68 ), and to move fluid through brain waste clearance pathways. 69,70 As already mentioned, HRV declines dramatically with age, 1,71,72 while various indicators of sympathetic activity increase, including blood pressure, plasma noradrenaline, and sympathetic nerve activity. 12 Along with these opposing changes in parasympathetic versus sympathetic activity, aging dramatically reduces the dynamic ranges of these two branches of the autonomic nervous system during the daily circadian cycle (Figure 2C,D).…”

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“…However, in another smaller clinical trial of 18 patients' side effects it may have limited efficacy. Surprisingly, similar side effects are also observed in vagus nerve stimulation (23,24). Therefore, Dr. Ludwig proposed that identifying more anatomically relevant animal models, or using a computational platform pipeline (similar to Prof.…”

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“…These structures are associated with the regulation of mood and emotion, seizure activity, anxiety, intestinal activity, satiety, and pain perception ( 131 – 134 ). Other potential, centrally mediated mechanisms for VNS include elevation of gamma aminobutyric acid (GABA) levels in the brain stem ( 135 ), desynchronization of cortical and thalamocortical network activity ( 125 ), suppression of cortical spreading depression ( 136 ), altering expression of brain-derived neurotrophic factor and other growth factors and increasing norepinephrine in prefrontal cortex ( 137 ), and altering brain waste clearance dynamics ( 138 ).…”