The vagus nerve in psychiatry: From theories to therapeutic neurostimulation in neuropsychiatric disorders

INTRODUCTION

The vagus nerve (VN) (the 10^th cranial nerve [CN]) is the longest and probably the most versatile CN in our body.^[1] It may be the first to pick up physiological disturbances in the body through its afferent and efferent fibres and also the earliest to respond to the same. It affects the cardiovascular, respiratory, and gastrointestinal systems by innervating the visceral organs and regulating the autonomic nervous system (ANS). It regulates the inflammation cascade.^[2,3] The VN is often implicated in psychiatric conditions due to its wide range of functions.

Vagus nerve stimulation (VNS) has been used for treatment-resistant epilepsy and depression, chronic pain syndromes, and headaches. The VN can be stimulated in the traditional invasive VNS (iVNS) method through surgery. Recently, non-invasive or minimally invasive techniques such as percutaneous and transcutaneous VNS (tVNS) are becoming popular. tVNS is usually either cervical VNS (cVNS) or trans-auricular VNS (ta-VNS).^[4] Overall, tVNS provides a safe method to test the potential of VN neurostimulation as an investigative and therapeutic tool.^[5] At this juncture, we should look at what the VN has to offer to enhance our understanding of general health, particularly psychiatric disorders. Therefore, we believe that this review is essential and timely to provide an overview of these recent advances. Here, we briefly note the anatomy and physiology of the VN, discuss various VN-related theories on human health and psychology, and ways through which the VN may be related to psychiatric disorders. Finally, we briefly discuss the procedure of tVNS, its potential, and future directions.

BASIC ANATOMY AND PHYSIOLOGY

The VN has anatomically four nuclei of origin: the dorsal motor nuclei of the vagus (DMNV), the nucleus ambiguus (NA), the nucleus of the spinal tract of the trigeminal nerve (TN) and the nucleus of the solitary tract (NTS). These four nuclei have been classified as motor (NA), sensory (spinal tract of TN and NTS), and parasympathetic (DMNV) nuclei. The DMNV is paired, symmetrical, and predominantly made of parasympathetic preganglionic nuclei (80%). Its efferent fibres connect with the parabrachial nucleus, cerebellar nuclei, and cerebral cortex.^[6-8] The fibres from NA mainly control motor movements of swallowing and speech. Some of its fibres innervate the heart and regulate the parasympathetic.^[8-10] The spinal trigeminal nucleus contains afferent sensory fibres with cell bodies in the superior or jugular ganglion: The NTS forms general and special visceral afferent pathways (General visceral afferent [GVA] and special visceral afferent [SVA], respectively). The GVA component innervates the thorax, abdomen, and mucous membranes. The SVA component receives taste afferents.^[8,10] These are summarised in [Table 1]. Theories that explain the functions of the VN often give prime importance to these various nuclei of origins, proposing that the fibres from a specific nucleus may function differently than those from another.

After arising from the medulla, the VN leaves the cranium through the jugular foramen. It gives the auricular branch of VN (ABVN).^[8] This is the branch of the vagus that is targeted non-invasively through ta-VNS. The ABVN forms the rounded superior ganglion and cylindrical inferior ganglion (both sensory) at the jugular foramen. Here, it is also joined by the cranial root of the accessory spinal nerve. The VN remains in the carotid sheath in the neck thereafter, along with the internal jugular vein and the internal and common carotid arteries. This is the target region of cVNS. From here, the right and left VNS have slightly different paths, which may have clinical applications. Laterality becomes important for safety and effectiveness. Animal studies show that right-sided stimulation has stronger effects on the heart, and therefore, left-sided VNS is preferred in humans. However, safety concerns like arrhythmia are not higher in the right-sided VNS.^[4,5] The right side of the heart is also considered to contain more efferent vagal fibres, which can show differential effects of stimulation. Stimulating both sides may lead to a higher (‘summation’) effect as well. Again, these features have not been evaluated sufficiently.^[11]

The right VN enters the thorax contributes to the pulmonary plexus and oesophageal plexus, and then, through the diaphragm reaches the gastrointestinal and renal system through the celiac, superior mesenteric, and renal plexuses. The left VN reaches the thorax and reaches the aortic arch, contributes to the pulmonary plexus and oesophageal plexus, and then reaches gastrointestinal organs through the oesophageal opening of the diaphragm. Throughout this course, the VN gives several branches such as meningeal, auricular, pharyngeal, carotid, superior laryngeal, recurrent laryngeal, cardiac, oesophageal, pulmonary, and gastrointestinal.^[7,8,10]

Among the CNs (i.e., III, VII, IX, and X) that constitute a significant portion of the parasympathetic system, the VN makes the greatest contribution (i.e., about 75%). The VN is responsible for the regulation of cardiac relaxation, salivation and digestion, and the respiratory cycle.^[12,13] Thus, the vagal influence on the parasympathetic function is one of the factors that underlie its neuromodulatory effects through VNS. Moreover, the specific type of nerve fibre composition influences the effects of stimulation. The VN contains A, B, and C, fibre groups. These have different speeds of conduction and activation thresholds. The afferent, large and myelinated A-fibres may be relevant for reducing seizures; whereas the efferent, myelinated B-fibres may be responsible for cardiac functioning; both type B and afferent, unmyelinated C-fibres are related to inflammation.^[1,14,15] Stimulation of the B-type fibres may be essential to regulate the parasympathetic action of the VN.

However, the importance of the VN in the human body goes beyond the neuroanatomical and neurophysiological boundaries and fascinatingly extends to the social and evolutionary mechanisms. Below, we discuss several hypotheses relating to our general well-being and the pathological implications of VN dysfunction.

THEORIES RELATED TO VN AND HUMAN HEALTH

There are theories/concepts linking the VN, its effect on cardiovascular regulation, the ANS, cognition, and species evolution. These theories are important as they invariably link the VN to a diseased or dysfunctional state of the human body. Stress increases the heart rate, and therefore, a lower baseline heart rate is preferred. This lowering of the heart rate is predominantly brought about by the parasympathetic action, and therefore by the VN. This is measured through heart rate variability (HRV) and shows that a better HRV capacity is beneficial. However, lowering heart rate is also potentially fatal. Thus, the control of the cardiac rate at an optimum level is desired. The following theories propose and argue on how the VN nerve is regulated and, in turn, regulates the ANS, what may be the ideal range of cardiac and respiratory rates, the interaction between these parameters, and the mechanisms behind these. We briefly mention these below and also in [Table 2]:

The calming cycle theory

This handles the vagal paradox by introducing the mother of a neonate/foetus as the secondary control. It goes back to the intrauterine life of the foetus, and the coordination between the VNs of the foetus and the mother. Their ANS is thus co-ordinated even after birth, leading to attachment and thereafter social and emotional development. Healthy relationships, again, are denoted by a higher vagal tone.^[16]

While these hypotheses are based on proposed mechanisms of VN action, which may at times seem more theoretical, biological evidence to back these claims has gradually been accumulated. The VN has been implicated in the regulation of various neurochemicals in our body, along with its overall function in the autonomic and inflammatory systems [Figure 1]. We briefly discuss these two aspects in the following sections.

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Figure 1:

Impact of the vagus nerve on various neurophysiological processes. BDNF: Brain-derived neurotrophic factor, GABA: Gamma-aminobutyric acid, NGF: Nerve growth factor.

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THE VN AND NEUROCHEMICALS

Various neurochemicals such as dopamine, glutamate, serotonin, gamma-aminobutyric acid (GABA), norepinephrine (NE), oxytocin, and acetylcholine (Ach) are hypothesised in the etiopathogenesis of psychiatric disorders; interestingly, these neurotransmitters are intricately linked with VN. The major insights come from VNS in animal studies as well as a handful of in vivo human studies. Relevant details are given in [Table 3]. Dopamine and the VN interactions relate to mesolimbic and mesocortical dopaminergic pathways and, therefore, affect reward processing and hyperactivity.^[37,38] Serotonin and the VN interaction may be of prime importance in regulating the gut-brain axis and, therefore, affect anxiety, mood, substance abuse, and psychotic disorders.^[39-41] The VN has modulatory effects on the ANS through parasympathetic outflow on organs in the neck, thorax, abdomen, and pelvis. A lower parasympathetic tone is considered to be present in schizophrenia, mood, and anxiety disorders.^[11] The VN seems to affect the ANS specifically through alpha-2 NE and Ach.^[11] NE is also implicated in the gut-brain axis.^[39,42] Moreover, the anti-epileptic effects of VNS may be NE-related.^[43] Ach is of relevance for cognitive functions. Nicotinic Ach receptor alpha7 subunit (α7nAChRs) are specifically implicated in the neuro-immune axis.^[11,44,45]

GABA plays a role in afferent information reaching the brain through the VN as well and may inhibit mechanoreception centrally.^[46] GABA-ergic neurons are modulated through the VN during stress to relay information through the gut-brain axis (Hou et al.).^[47] Some of the VN afferents projected to the NTS are glutamatergic. L-glutamate acts as a neurotransmitter in the afferent nerve groups of the VN.^[48,49] These afferents regulate the baroreceptors and more extensively the cardiovascular system and the gut-brain axis.^[11]

Oxytocin receptors are present in the DMNV and together with those in the hypothalamic paraventricular nucleus, interact through the ANS.^[50] The VN may have inhibitory effects on peripherally administered oxytocin in drug (opioid) withdrawal.^[51] The VN itself may contain opioid receptors, which have an inhibitory action on the cardiovascular system.^[52] Opioid receptors play a role in nociception and endogenous pain control through vagal afferents.^[53,54]

INFLAMMATION AND THE VN

The VN may serve as an important modulator of inflammation through the hypothalamus-pituitary-adrenal (HPA) axis, thoracolumbar sympathetic efferents, vago-sympathetic pathway, and central descending pathways. Especially, efferent cholinergic fibres of the VN influence the inflammatory responses through the inflammatory reflex.^[3,11] The activation of the HPA axis by proinflammatory cytokines results in the release of glucocorticoids, or through the cholinergic anti-inflammatory pathway, by decreased cytokine production mediated by the central muscarinic receptors and α7nAchR or through reduction of TNF-α by splenic T-lymphocytes. Interaction between the vagus and the sympathetic nervous system through NTS may also have anti-inflammatory effects. Neurotrophins (NT) such as nerve growth factor and brain-derived neurotrophic factor (BDNF) may also play a part.^[3] Vagotomy has been associated with reduced BDNF expression through messenger ribonucleic acid, specifically in the hippocampus in mice.^[67] BDNF may play a regulatory role in the immune system; conversely, inflammation may reduce BDNF expression.^[68] Further, VNS can induce plasticity in the hippocampal region, probably mediated by GABA and NT.^[69]

The anti-inflammatory action of VNS has even been considered to reduce cytokine in viral infections.^[70] The influence of VNS on cytokines is not restricted to inflammatory states. Even in healthy conditions, certain specifications of stimulus parameters may result in changes (even increases) in inflammatory markers.^[71]

With such significant physiological functions attributed to the VN, its dysfunction certainly plays a major role in our ill health. Below we try to discuss the basic dysfunctions proposed to be involved in neuropsychiatric disease states and their implications.

VNS IN NEUROPSYCHIATRIC DISORDERS [FIGURE 2]

VN dysfunction is implicated in several neuropsychiatric disorders [Figure 2]. VNS has been used for treatment-resistant epilepsy. It significantly reduces seizure episodes in this population, increases the quality of life, and is relatively safe.^[72] However, most iVNS has been used and, therefore, has surgery-related adverse effects. Increased cerebral blood flow in certain regions of the brain, modulation of NE and serotonin, ‘quenching kindling of seizures’, and anti-inflammatory effects have been hypothesised for its anti-epileptic effects.^[73]

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Figure 2:

Vagus nerve dysfunction and probable effects on psychiatric disorders.

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VNS is effective in treating pain syndromes, migraines, cluster headaches, trigeminal neuralgia, and fibromyalgia.^[4] Chronic high level of stimulation reduces nociception. Here, the recruitment of unmyelinated C fibres and the intensity of the stimulation may be essential. Anti-nociception through the VNS also depends on the cognitive and affective components of the individual.^[69] Functional connectivity between the amygdala, thalamus, hypothalamus, nucleus accumbens, basal ganglia, and insula regulate pain anticipation and experience, particularly from the viscera. Activation of these areas is seen with VNS and this may also be responsible for nociception.^[74,75]

The impetus for using VNS in depression came when those with epilepsy who were treated with VNS reported better moods. VNS may influence neurochemical expression (NE, serotonin, and BDNF) in key brain regions and increase hippocampal neurogenesis. It may also affect the quality of functional connectivity along the cortical-limbic-thalamicstriatal neural circuit.^[2] tVNS is found to significantly increase the functional connectivity between the nucleus accumbens, basal ganglia, and medial PFC. These areas are related to motivation and reward processing and thus, better functional connectivity may help to reduce depression.^[76,77] In treatment-resistant depression, reduced blood flow to the limbic system and the frontal cortex was important for the therapeutic effects of iVNS.^[69,78]

The VNS has been used to treat opioid withdrawal syndrome. The major benefit is obtained through modulation of the dysfunctional ANS in the withdrawal states.^[53] Decreased VN activity may predict tobacco use, especially during stressful conditions.^[79]

The VNS has been used in post-traumatic stress disorder by increasing the process of extinction of conditioned fearful stimuli. Its effects on the ANS may also play a part in fear conditioning and expressions.^[80] Using a similar rationale, VNS has also been proposed for therapeutic benefits in anxiety disorders and obesessive-compulsive disorder (OCD).^[81] Further, panic disorders are predominantly related to interoceptive disturbances which may be regulated by the VN. VNS also shows potential usefulness in eating disorders and schizophrenia, through its modulation of interoception, autonomic and inflammatory systems.^[82,83] VNS is hypothesised to be beneficial in autism spectrum disorder by modulation of emotional social interaction, facial recognition, and facial expression processing.^[84] It may also reduce temper tantrums and anger outbursts in neurodegenerative conditions and Prader–Willi syndrome.^[85] Finally, VNS has been proposed to have beneficial effects on disorders of consciousness after brain injury. This is probably through the modulation of brain circuit networks such as the upper and lower brainstem, thalamus, and cortico-striatalthalamic-cortical loop.^[86,87]

The next important step is joining the bridges and understanding the gaps between the physiological and pathological interaction of VN functioning. To do so, we need to empirically test hypotheses and make scientific progress that can support integrated hypotheses and illness models – this is discussed in detail below.

TRANSLATING THEORIES TO EMPIRICAL TESTING

[Table 2] summarises the VN-related theories and links these with probable psychophysiological disturbances, ways to empirically test it, and possible psychiatric disorders due to malfunction. Parts of these hypotheses can be empirically tested by well-designed research. tVNS allows doing so; with direct ways to stimulate and therefore manipulate the VN, a causal relationship can be teased out. These experiments will lay the foundation of evidence for VN-related theories.^[4,88,89] Supplemented with basic sciences related to animal experiment models, dysfunctions of the ANS and emotional/cognitive reactions can have a neurochemical scaffolding. This will translate to the current neurochemical-based understanding of psychiatric disorders. This will also help in developing new paradigms, similar to those inspired by other neuro-modulatory interventions.^[90]

So far, among psychiatric disorders, tVNS has been tried primarily on depression. Although stimulation parameters, site, and duration vary greatly, 2–4 weeks of tVNS may reduce the severity of depression. In epilepsy, about 5–12 months of tVNS have been required to decrease seizure frequency. Furthermore, tVNS has been shown to improve quality of life, mood, sleep, autonomic functioning, systolic blood pressure, headache, and tinnitus.^[4] These results are encouraging to further probe tVNS in psychiatric disorders.

tVNS

VNS is of three types: iVNS, percutaneous, and non-invasive/ transcutaneous.^[4] In iVNS, an electrode, the battery, and the pulse generator are placed inside an implantable device, which is surgically attached to the left VN. The device can be controlled from the outside.^[88] In percutaneous VNS, minimally invasive needle electrodes are fixed at areas around the ear that are innervated by the VN. It has been used mainly in pain-related syndromes.^[91] The tVNS uses the cutaneous nerves at the cervical region or the ABVN at the ear to be electrically stimulated. For cervical tVNS, the sternocleidomastoid muscle is targeted for the stimuli to reach through the skin, fascia, and muscular structures to the VN. About 80% of the vagal fibres at the cervical region are unmyelinated type C fibres. However, these may not be stimulated during tVNS as painful sensations are not associated during tVNS.^[1,14] The control over whether it stimulated the afferent or efferent fibres is thus lost, making it less precise.^[92,93] The stimulation site for ABVN is debated between cymba concha and tragus, with most using the ear lobe for sham stimulation.^[4,89,91]

The parameters of stimulation of tVNS are not yet well formulated.^[4,89,92] Most tVNS studies use parameters ranging between 1.5 Hz and 30 Hz of frequency (although as high as 120 Hz frequency has also been used), around 0.25–1 microsecond wave width, intensity within 2–6 mA, based on the subject’s tolerability, for various lengths of time from 20 min to few hours and alternative on and off time of stimulations. The devices used are mostly handheld for cervical tVNS and attached to the ear for ABVN.^[4,5,94-96]

It is important to note that the impact of tVNS should be physiologically informed, for example, cVNS targets efferent fibres, whereas ta-VNS targets afferent fibres exclusively.^[4,91] Likewise, stimulating the afferent or efferent fibres in animal models has shown distinguishably differential effects on inflammatory systems, ANS and oxytocin release.^[64,65] However, more electrophysiological studies are required to tease out fibre-specific effects of tVNS to fully understand the required stimulation parameters and their utility in clinical psychiatric conditions. The significant advantage of tVNS over iVNS is the safety and tolerability profile.^[5] Overall, iVNS implantation is a safe minor surgical procedure and surgery-related risks are seen in about 8% of procedures.^[89] Serious complications such as post-operative infection, hematoma and vocal cord palsy are <2%. The left side is generally favoured, as the right side innervates the sinoatrial node and can theoretically cause arrhythmias. However, iVNS also has about 4% of hardware-related problems such as lead fracture, malfunction, or disconnection.^[97] Common side effects unrelated to the surgical procedure and hardware are coughs, hoarseness, change in voice, pain, and paraesthesia.^[88] Although not shown to be harmful in tVNS, the left VN is still preferred. The most common side effect of tVNS is local skin irritation, headache, and nasopharyngitis. In trials, <3% of the subjects drop out due to complications.^[5] Cervical tVNS may lead to temporary painless, mild facial twitching.^[91]

FUTURE DIRECTION

The current availability and increasing use of tVNS should be utilised in future studies to test its effects on overall well-being, cognition, inflammatory system, ANS, brain circuits, and psychiatric disorders. It can probably be safely used in investigational and therapeutic studies and may help to determine the causal role of VN in neuropsychiatric disorders. This will enrich our knowledge regarding psychophysiology and will help to bridge the gap between theoretical foundations and the clinical utility of this neuromodulation technique in psychiatry.

CONCLUSION

The VN plays a vital role in neuropsychiatric disorders. Newer tVNS techniques provide opportunities to explore the etiopathological and therapeutic role of the VN in these disorders. Neurophysiologically-oriented research, therefore, can inform clinical decision-making to delineate the potential uses of VNS.