Abstract
BackgroundElectrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation.MethodsHere, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice.ResultsSurprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor (TNF), while other parameters selectively lowered serum TNF levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others.ConclusionsThese results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes.
Highlights
Electrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy
Mice were euthanized after 2 h, and blood was collected (Fig. 1a)
We found electrically stimulating the vagus nerve with specific parameters results in increased circulating levels of tumor necrosis factor (TNF) and IL-10, cytokines known to be involved in inflammatory responses
Summary
Electrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Because diverse fiber types in the peripheral nervous system innervate different target organs and exhibit distinct functions, this fiber recruitment principle is important to achieve the desired physiological changes from activating nerves (Gorman and Mortimer, 1983) Electrical stimulation parameters such as output frequency, current, duration, and amplitude, are important determinants for achieving selective and efficient nerve activation (Grill, 2015). A large body of preclinical studies and emerging clinical evidence indicates that electrical stimulation at the cervical vagus nerve is able to change the body’s immune response to injury or infection, by reducing the levels of certain serum cytokines that are important mediators of inflammation in the body (Andersson and Tracey, 2012; Borovikova et al, 2000) This stimulation of the vagus nerve regulates cytokine release from the spleen through activation of the inflammatory reflex, thereby protecting against lethality in models of systemic inflammation (Borovikova et al, 2000; Chavan et al, 2017; Tracey, 2002). The antiinflammatory effects of vagus nerve stimulation have been attributed to A- and B-fiber activation, while the cardioinhibitory effects are thought to be mediated by only B-fibers (Huston et al, 2007; Olofsson et al, 2015; Yoo et al, 2016)
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