What do you know about the vagus nerve? 

Vagal tone, the activity level of the vagus nerve, is a strong indicator of emotional resilience and stress vulnerability.¹ Despite playing a quiet role in basic physiological regulation, vagal maintenance is essential for health and healing. Suppressed vagus nerve causes stress and over time leads to major chronic illness or psychiatric disorders.² Therefore, the vagus nerve is crowned the superpower of the body.³

Manual activation of the vagus nerve is the new anti-depressant strategy. This treatment called vagus nerve stimulation (VNS) can potentially cure various chronic diseases including major psychiatric disorders. 

What are the superpowers of the vagus nerve? And how is VNS used in mental health applications? This article will briefly introduce this new therapy and discuss its mental health application.  

What is vagus nerve stimulation?

Vagus nerve stimulation (VNS) is an electrostimulation therapy. An intermittent impulse with low frequency is induced in the left vagus nerve and signals a wide range of brain regions through its connection to the locus coeruleus and the nucleus tractus solitarius.^4,5

VNS has developed into an established and evidence-informed therapy and has become FDA-approved to be used clinically for refractory (treatment-resistant) epilepsy (1997), unipolar and bipolar major depression disorders (2005) and more recently as an adjunct for stroke rehabilitation (2019). 

Oftentimes, VNS refers to the invasive VNS (iVNS), which requires surgically implanting a pulse generator in the left thoracic region under the skin.⁶ The stimulation device and implantation procedure resembles that of a cardiac pacemaker.⁷ The stimulation takes place intermittently at the cervical level of the left vagus nerve, where electrodes are cuffed around the nerve.⁴ Alternative stimulation methods have emerged, which will be discussed later. 

Application in mental health

VNS effectively eased the drug-resistance and symptom recurrence challenge in clinical depression. On average, 40% of treatment-resistant depression (TRD) VNS receivers display significant clinical improvement even after 1 year,^9,12 with that percentage increasing to 60% after 2 years of continuous VNS treatment.¹⁰ The effect of VNS is cumulative but long-lasting, making it the perfect bypass to recurrence and drug-resistance problems. 

The anti-depressant property can be broken down into different aspects:

1. Reducing deep thought through modulating functional connectivity in the default mode network¹³
2. Redirect attention from negative subjects (reduce emotion bias) through enhancing interoception and reward response^14,17
3. Reducing anhedonia by improvement of interoceptive feedback and inducing invigoration for effort¹⁸

In addition, VNS also demonstrates effects that reduce anxiety in the body and the mind:

• Increases parasympathetic and suppresses sympathetic neurons, freeing the body from a frozen state induced by sympathetic fight-or-flight response¹⁹
• Remedies declined projection from the ventromedial prefrontal cortex to the amygdala for emotion regulation,(20) leading to inhibition of fearful thoughts²¹
• Enhances extinction of memory, unpairing or generalising conditioned fear in trauma-induced stress response^22,23

Last but not least, the vagus nerve maintains vital functions (sleeping, eating, breathing, excretion, blood flow) and regulates metabolism. For instance, stimulation increases neurotransmitters that facilitate sleeping and activates fibres projecting to brain structures involved in sleep.²⁴ Sleep and diet quality and exercise amount are highly associated with mental health quality.²⁵

In contrast to traditional psychiatric treatment, VNS seems to induce holistic effects on both the body and the mind. 

How does VNS influence the nervous system?

The Vagus nerve provides a bidirectional connection between the brain and the gut coordinated via acetylcholine.⁴

The Vagus nerve not only modulates the peripheral nervous system but also regulates emotion, motor functions, and even cognition & memory. 

The full molecular pathway of vagal modulation in the brain (the central nervous system) remains mostly unveiled. What’s consistently shown in the molecular studies are suppressed neuroinflammation, increased neurogenesis, and promoted neuroplasticity,^{26, 27} accompanied by alteration of neurotransmission.²⁸ Vagal signals influence the release of dopamine, acetylcholine and noradrenaline.^29,30

Brain imaging studies revealed alterations in volume, structure of brain regions and circuit connectivity after VNS administration. 

Particularly, vagal signals could travel long distances to a myriad of core cortical and sub-cortical brain areas involved in emotional reasoning, processing, interpretation and reaction:

• Insula – for Interoceptive awareness (self-awareness)¹⁶
• Default mode network – for self-reflection and self-directed thinking³¹
• Hippocampus – learning and memory²⁷
• Thalamus and hypothalamus – wakefulness, alertness and arousal⁵
• Striatum, mesolimbic dopaminergic pathway – motivation and reward³¹
• Prefrontal cortex& amygdala – stress response³²

These discoveries confirmed the biological basis of emotion and validity of mental health beneficiaries from VNS.

Development directions

Wider clinical implication

For psychiatric treatment

Vagal signals brings calmness, making VNS a potential option for conditions with psychosis:

• Post-traumatic stress disorders (PTSD)³³
• Borderline personality disorders (BPD)³⁴
• Bipolar disorder³⁵
• Schizophrenia³⁶

Anxiety management and anxiety symptoms

The anxiolytic effect of VNS can be exploited to reduce anxiety in psychiatric patients which could accelerate and ease the therapy process while enhancing the therapeutic effect.²³

Curing dementia and improve cognition

Memory formation is the main regulator of cognition. The Vagus nerve is seen to restore the structure and volume of the hippocampus and targets several regions involved in the memory formation pathway.^5,27

VNS improves memory recall in mild cognitive injury, implying its role in curing dementia, but further research is required for confirmation.³⁷

VNS as an adjunctive treatment

Compared to solo VNS, a combined treatment regime with VNS is shown to enhance the therapeutic effects. Some examples are:

1. VNS with exposure therapy for PTSD treatment³⁸
2. VNS with cognitive behavioural therapy (CBT) for autistic population
3. VNS with antidepressant treatment for major depressive disorders and bipolar disorders³⁹

In this context, what VNS seems to do is enhancement.

A PTSD clinical trial revealed that the addition of VNS as adjunctive treatment with exposure therapy showed quicker and more stable extinction of conditioned fear, compared to VNS and exposure therapy alone.³⁸

Sensory overload in autistic individuals makes exposure therapies such as CBT difficult to go through. VNS makes the therapy more tolerable for autistic patients to achieve therapeutic goals.²³

Non-invasive options

Emerging non-invasive stimulation techniques are in demand to bypass the surgery complications and high costs that come with the invasive method. 

Popular  non-invasive methods are:

• Transcutaneous VNS
• Ultrasound stimulation headset

The site for stimulation is tricky, for it needs to have a superficial vagus nerve branch running under the skin. Transcutaneous auricular stimulation of the vagus nerve (taVNS) is the most popular non-invasive choice, where stimulation occurs in the cymbal conchae of the ear lobe (figure3).⁴⁰ taVNS is the most studied and comparatively established non-invasive method.

Up-to-date research results show that taVNS exerts equivalent efficiency and safety as invasive VNS in treating both mood and physiological disorders.^{13, 41, 42} Meanwhile, the ultrasonic VNS method is still undergoing evaluation for clinical performance.⁴³

Both taVNS and ultrasound stimulation were seen to decrease inflammation which is propagated through a cholinergic mechanism (driven by neuromodulator acetylcholine) and stimulates the same range of key brain structures (e.g. hippocampus).^46-50

Therefore, the non-invasive VNS does not only have the same clinical outcome but probably works through the same mechanism as iVNS, making it a promising replacement.

The advantage of non-invasive methods is avoiding open surgery and complications following that. Despite not being approved by any health organisation officially, the product is available commercially and some people have used it for their mental health. 

Summary

VNS is an adaptable treatment. As soon as the therapeutic effects are established, treatment outcome can be achieved by adjusting the amperage, frequency and duration of the stimulation.⁵⁴

VNS modulates brain structure which is accompanied by changes in neuroinflammation, neurogenesis and neuroplasticity. Through these mechanisms, it brought on mental health benefits in cognition & memory, physiological well-being and mood regulation. 

The therapy demonstrated efficiency and safety while side effects exist and precautions need to be taken during the process. 

Other psychiatric applications are possible but require further analysis. 

Overall, this article highlighted the significance of the vagus nerve in psychiatric health. 

Frequently asked questions

When should a patient consider VNS as an anti-depressant treatment?

VNS is used for patients with treatment-resistant unipolar or bipolar depression, which is defined by evidence of failure to respond to at least four types of established anti-depressant therapies. Plus, VNS is not suitable for severe cases of clinical depression, as the treatment is only effective in mild or moderate cases. 

Are there any risks or adverse effects of taking VNS treatment?

The side effects from VNS treatment could be the result of the surgical procedure or the electric stimulation.

Side effects sustained from the surgery:^{35, 51}

• Soreness at the incision site
• Infection around the surgical cut 
• Difficulty swallowing
• Vocal cord paralysis

Side effects sustained from electrical stimulation:^{35, 51}

• Voice change, usually becomes hoarse
• Throat pain
• Cough
• Headaches
• Difficulty with swallowing 
• Tingling or pricking of the skin
• Insomnia 
• Sleep apnea

Notably, the most common side effect is hoarseness or voice alteration. More than half (55%) of the participating population experienced voice change after the treatment and the intensity of voice change is correlated to stimulation intensity.⁵² 

Patients with a medical history concerning anatomical regions connected to the vagus nerve may be more likely to experience mild adverse effects. For example, there is a case report on mild adverse reactions for the first week after termination of taVNS treatment in a patient with a tympanic membrane perforation history.³⁷

Apart from physical side effects, it’s also suggested that VNS can cause emotional bluntness, similar to selective serotonin reuptake inhibitors (SSRIs), in that the treatment can lead to the reduction of negative emotions (such as sadness and anger) as well as positive ones (happiness).¹⁷

What are the precautions that need to be taken while undergoing VNS treatment?

During the treatment period, patients should strictly adhere to medical advice and should not make any changes without consulting with the medical care providers who prescribed the treatment first. These include:

1. The amplitude of the stimulation, i.e. the strength of the stimulation should not be adjusted based on personal preference. Some patients adjusted to stronger stimulation for a sooner or better clinical outcome, but only caused mild side effects, e.g. tinnitus⁵³
2. The treatment should not be stopped without consulting with the physician, as this sudden cease of treatment would lead to a serious relapse of depression symptoms and re-establishment of remission may be difficult after the stopping³⁹