Vagus Nerve Stimulation

Disambiguation

The process of stimulating the Vagus Nerve with micropulses of electrical current is referred to in a number of different ways.

Vagus Nerve Stimulation (VNS) - Typically refers to stimulation of the nerve with a surgically implanted device and electrode.

Non-invasive Vagus Nerve Stimulation (tVNS, taVNS, nVNS, LLTS) - Refers to stimulation of the vagus nerve without penetrating the skin using an external device and surface electrode. ‘tVNS’ stands for Transcutaneous Vagus Nerve Stimulation and this is the terminology Parasym uses.

Vagus Nerve Stimulation 

The vagus nerve provides a unique entrance to the brain via its auricular branch, where electrical stimulation allows direct modulative access to subcortical brain areas which interface with several neurophysiological and neuroinflammatory restorative pathways.

The development of vagus nerve stimulation (VNS) as therapy began with the investigations of James Corning who developed the first basic functioning VNS device. In the late 1990's, after the success of several clinical trials illustrating the beneficial use of VNS for treatment resistant epilepsy and depression, the FDA approved its use for these applications. This illustrated the safe and effective use of this treatment modality. Uptake of VNS as a treatment method was still limited by the need for surgical implantation. This ultimately restricted access geographically (centres specialising in the procedure), by condition severity (to warrant surgery), and financially (those who could afford the procedure).

In the last decade however, great advances have been made in the field of vagus nerve stimulation. Through greater anatomical understanding and applied research, it is possible to stimulate the vagus nerve without the need for a surgical procedure. This is possible by utilising the auricular branch of the nerve which runs past the tragus of the outer ear, where this method is known as transcutaneous vagus nerve stimulation (tVNS). This method has now been shown to activate vagal pathways in the same way as with the surgical (VNS) procedure, making it an accessible, low risk and lower cost route to stimulating the vagus nerve. This has fueled an already growing field bioelectric medicine, where the scope for neuromodulation via the vagus nerve is vast.

Why is stimulating the vagus nerve beneficial?

Stimulation of the vagus utilises several modulatory actions in the nervous, immune, autonomic, endocrine, cardiorespiratory, and gastrointestinal systems. The exact mechanisms of action in VNS are still being theorised however this has not hindered its ability to demonstrate safe and effective use for individuals suffering from conditions which interface vagal pathways.   

Vagus nerve stimulation therapies have already been approved by regulatory bodies for applications such as mood enhancement, pain relief, improving sleep and reducing anxiety; with investigations underway in assessing the cardiac and inflammatory modulation properties as well as those utilising effects of neuroplasticity.

Vagus nerve stimulation - Mechanism of Action

Autonomic Modulation

The vagus nerve is the main nerve of the parasympathetic division of the autonomic nervous system, which regulates unconscious processes in the body. The Parasympathetic Nervous System (PNS) is often referred to as the ‘rest and digest’ system, whereas the Sympathetic Nervous System (SNS) is thought of as the ‘fight or flight’ system. Stimulation of the vagus nerve has been shown to increase PNS activity/decrease SNS activity. Further through this regulation of metabolic homeostasis, the vagus nerve also controls heart rate, where increasing vagal activity has been associated with decreases in heart rate. This is significant as autonomic dysfunction, as characterised by an overactive SNS response, is thought to underpin serval high impact chronic conditions, illustrating the value of an intervention which can modulate this.

Neurotransmitters

Neurotransmitters are chemical substances released by nerve fiber impulses to surrounding areas of this electrical activity. Examples of neurotransmitters are Serotonin, Noradrenaline/Norepinephrine and Gamma-Aminobutyric acid (GABA). Research in this area indicates stimulating the vagus nerve can influence the release of neurotransmitters in the brain. Clinical studies indicate that VNS likely results in changes in serotonin (Ben-Menachem et al 1995), norepinephrine (Krahl et al 1998), GABA, and glutamate (Walker et al 1999), these are all neurotransmitters implicated in the pathogenesis of major depression. This influence on neurotransmitters, along with a number of other theorised mechanisms, are thought to explain the mood enhancing effects arising from stimulation of the vagus nerve.

Inflammatory Modulation

It is now understood that the nervous system reflexively regulates the inflammatory response in real time, in much the same way that it controls heart rate and other vital functions. This is thought to occur via the vagus nerve through a neural reflex mechanism known as the ‘inflammatory reflex’. The brain receives signals from the immune system for the purposes of optimally controlling inflammation in the body, however, dysfunction in these signals can lead to excess inflammation. It was observed that without vagus nerve activity (either due to a vagotomy or neural lesions) there was an absence of the inflammatory reflex which resulted in excessive innate immune responses and cytokine toxicity (excessive inflammation). This led to clinical study and demonstration that stimulation of the vagus nerve can lead to decreases in inflammatory cytokines. The anti-inflammatory properties of (stimulating) the vagus nerve are thought to be through the Cholinergic Anti-inflammatory Pathway (CAP) as well as mediated through the Hypothalamic pituitary adrenal (HPA) axis. These insights have led to new opportunities in the treatment of inflammation through these selective and reversible ‘hard-wired’ neural systems.

Neuroplasticity

Research towards the end of the 20th century has shown that many aspects of the brain can be altered, or are ‘plastic’, even through adulthood. Neuroplasticity is the brain's ability to restructure itself by generating new neural connections. It allows the neurons or nerve cells in the brain to compensate for injury or disease and amend their processes in response to new situations or environmental changes. The promotion of neuroplastic effects from tVNS/VNS through alterations in central nervous system neurotransmitter levels and/or processing have led to greater focus on the use of tVNS as therapy for tinnitus and stroke rehabilitation. It is now theorised that a significant number of Tinnitus cases arise or are disproportionality contributed by maladaptive plasticity of the auditory cortex. These applications utilise the mechanisms of ‘targeted plasticity’, by stimulating the vagus to promote neuroplasticity and pair this with a specific stimulus, eg. sound therapy (for tinnitus) or rehabilitative exercise (for stroke recovery), which targets this effect of plasticity in the specific region of the brain associated with each condition. This has led to outcomes such as accelerated and improved recovery from stroke and reductions in the symptoms of tinnitus.

Pioneering a new field

At Parasym we have developed an innovative tVNS device and are investigating how stimulation of the vagus nerve can be harnessed to increased patient outcomes in several applications where pathogenesis involves mechanisms interfacing with key vagus nerve processes.

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