Vagus Nerve Anatomy

The vagus nerve, the tenth cranial nerve (CN X), is a large mixed nerve containing branchiomotor fibers, general visceral afferents, and preganglionic parasympathetic fibers. It has a more extensive course and distribution than any other cranial nerve, extending through the neck, thorax, and abdomen. Its intracranial segment originates from multiple small rootlets that converge laterally to the medulla and exit the skull via the jugular foramen accompanied by the accessory nerve (CN XI), with which it shares an arachnoid and a dural sheath. ^[1]

The CN X functions include motor, sensory, taste, and chemoreception roles across various organ systems, including the heart, pharynx, tongue, and gastrointestinal tract (where it may respond to stretch or contraction). It also plays an integral role in swallowing, cough, Hering-Breuer reflexes, and sensations related to hunger, and nausea. ^[1]

A thorough understanding of the regional anatomy, branches, and variations of the vagus nerve is critical for performing various surgical procedures without causing iatrogenic injury and subsequent sequelae.

However, apart from its neurosurgical significance, scientific studies have implicated the role of the vagus nerve in inflammation pathways via the hypothalamic-pituitary-adrenal (HPA) axis, cholinergic anti-inflammatory pathway (CAP), and vago-sympathetic pathway. ^[2] Studies on the "brain-gut axis" have shown a potential link between the emotional and cognitive brain regions and gut functions and gastrointestinal homeostasis, thereby offering a novel therapeutic target for gastrointestinal and psychiatric disorders. ^[3]

Embryology

Pharyngeal arches develop during the third and fourth weeks of embryonic gestation. As neural crest cells migrate around the pharynx to more caudal levels, five pairs of pharyngeal arches (also called branchial arches) are formed. ^[1]  They are classified into pharyngeal arches 1, 2, 3, 4, and 6 (arch 5 involutes during embryo development and does not give rise to an adult structure ^[4] ). Each arch is covered externally by ectoderm and internally by endoderm, with the mesenchyme primarily derived from neural crest cells. During embryogenesis, each layer differentiates to form various oropharyngeal structures, including pharyngeal epithelia, cartilage, muscles, vessels, and nerves. ^[4] Motor and sensory innervation is provided by arch-specific cranial nerves. ^[1]

The superior laryngeal branch of the vagus nerve (X) originates from the fourth pharyngeal arch that appears by stage 13 and its recurrent laryngeal branch originates from the sixth pharyngeal arch. ^[1]

The cranial sensory ganglia are partly derived from the neural crest and partly from cells of the ectodermal placodes. The jugular ganglion of the vagus nerve is derived from the neural crest, while the nodose ganglion of the vagus nerve is derived from placodal cells. ^[1]

Vagal Nerve Nuclei

The vagal nucleus in the medulla oblongata comprises four nuclei: the dorsal motor nucleus of the vagus nerve (CN X), nucleus ambiguus, nucleus solitarius, and spinal trigeminal nucleus (with minor vagal input). These nuclei collectively mediate the diverse functions of the vagus nerve (CN X) and influence other cranial nerves. ^[1]  (See Table 1.)

Table 1. The Vagal Nerve Nuclei: Location and Connections ^[1] (Open Table in a new window)

The nerve contains somatic and visceral afferent fibers as well as general and special visceral efferent fibers (see Table 2). 

Table 2. Summary of Central Connections, Components, Function, and Peripheral Distribution of the Vagus Nerve (Open Table in a new window)

Extracranial Course of Vagus Nerve

The vagus nerve exits from the medulla oblongata in the groove between the olive and the inferior cerebellar peduncle. It leaves the skull through the middle compartment of the jugular foramen, accompanied by the accessory nerve, with which it shares an arachnoid and a dural sheath. Both nerves lie anterior to a fibrous septum that separates them from the glossopharyngeal nerve. ^[1]  After emerging from the jugular foramen, the vagus bears two significant ganglionic swellings, which are the sensory ganglia of the nerve and contain somatic, special visceral, and general visceral afferent neurons. Both ganglia contain parasympathetic, and possibly some sympathetic fibers, but there is no evidence that vagal parasympathetic components relay within the inferior ganglion. ^[1]

1. Superior ganglion (jugular): It is grayish, spherical, and about 4 mm in diameter. It connects to the inferior glossopharyngeal ganglion and the sympathetic trunk via a filament from the superior cervical ganglion. It is mainly somatic and most of its neurons enter the auricular nerve. ^[1]
2. Inferior (nodose) ganglion: It is larger, elongated, and cylindrical — about 2.5 cm long, with a maximum breadth of 5 mm. It lies 1 cm distal to the superior ganglion (see the image below). It connects to the hypoglossal nerve, the loop between the first and second cervical spinal nerves, and the superior cervical sympathetic ganglion.

                •  A majority of visceral afferent axons in the vagus nerve are peripheral processes of cell bodies in the nodose ganglion. ^[1]

                • Neurons in the inferior ganglion are responsible for visceral sensation from the heart, larynx, lungs, and the alimentary tract, spanning from the pharynx to the transverse colon. ^[1]

                • The vagus nerve is joined by the cranial root of the accessory nerve (CN XI), just below the inferior ganglion (see the images below). ^{[5, 6, 7, 8]}  

                • Preganglionic motor fibers from the dorsal vagal nucleus and special visceral efferents from the nucleus ambiguus descend to the inferior vagal ganglion, forming a visible band that likely provides motor innervation to the larynx via the recurrent and superior laryngeal nerves. ^[1]

Course of the vagus nerve

In the neck:

The vagus nerve descends vertically within the carotid sheath between the internal jugular vein and the internal carotid artery, to the upper border of the thyroid cartilage, and then passes between the vein and the common carotid artery to the root of the neck. ^[20]

In the thorax:

Right Vagus Nerve: The right vagus crosses in front of the first part of the subclavian artery and then travels into the fat behind the innominate vessels. It then reaches the thorax on the right side of the trachea, which separates it from the right pleura. It then inclines behind the hilum of the right lung and courses medially toward the esophagus to form the esophageal plexus with the left vagus nerve (see the image and Table 3 below).

Left Vagus Nerve: The left vagus crosses in front of the left subclavian artery to enter the thorax between the left common carotid and subclavian arteries. It descends the left side of the aortic arch that separates it from the left pleura and travels behind the phrenic nerve. It courses behind the root of the left lung and then deviates medially and downward to reach the esophagus and form the esophageal plexus by joining the opposite (right) vagus (see the image and Table 3 below).

Table 3. Thoracic Course of the Right and Left Vagus Nerves: Relations, Branches, Plexuses, and Trunks ^[1] (Open Table in a new window)

In the abdomen:

The vagus nerves provide parasympathetic innervation to the abdominal viscera up to the distal transverse colon (derivatives of the foregut and midgut, whereas the derivatives of the hindgut are supplied by parasympathetic fibers traveling via the pelvic splanchnic nerves). The anterior and posterior vagal trunks derived from their corresponding esophageal plexuses enter the abdomen via the esophageal hiatus closely related to the anterior and posterior walls of the abdominal part of the esophagus. They supply the abdominal part of the esophagus and stomach. ^[1]

1. The anterior vagal trunk is primarily derived from the left vagus nerve. It gives off a hepatic branch, innervating the liver, gallbladder, bile ducts, and structures in the free edge of the lesser omentum (hepatoduodenal ligament). ^[1]
2. The posterior vagal trunk is primarily derived from the right vagus nerve. It supplies branches to the coeliac plexus, contributing significantly to its fibers and synapsing in the myenteric and submucosal plexuses within the walls of the hollow viscera. ^[1]

The anterior and posterior gastric nerves are then formed from the esophageal plexus. The anterior gastric is formed mainly from the left vagus, but it contains fibers from the right vagus.

Similarly, the posterior gastric nerve is formed mainly from the right vagus but contains fibers from the left vagus nerve. The gastric nerves supply all abdominal organs and the gastrointestinal tract ending just before the left colonic (splenic) flexure (see the images below).

Vagus nerve branches in the jugular foramen

The meningeal branch arises at the superior ganglion and reenters the cranium through the jugular foramen to supply the posterior fossa dura.

The auricular branch supplies sensations to the posterior aspect of the external ear (pinna) and the posterior part of the external auditory canal. It arises also from the superior ganglion and enters the mastoid canaliculus in the lateral part of the jugular foramen. It exits again through the tympanomastoid suture of the temporal bone to reach the skin. It communicates with branches of the seventh (facial) and ninth (glossopharyngeal) cranial nerves.

Vagus nerve branches in the neck

The branches in the neck consist of the following:

• Meningeal branch ^[1]
• Pharyngeal branches
• Superior laryngeal nerve
• Recurrent laryngeal nerve (RLN)
• Superior cardiac nerve

Meningeal Branch

It arises at the superior (jugular) ganglion and reenters the cranium through the jugular foramen to supply the dura mater of the posterior fossa. ^[1]

Auricular Branch

The auricular branch (Arnold's nerve) supplies sensations to the posterior aspect of the external ear (pinna) and the posterior part of the external auditory canal. It also arises from the superior ganglion and is joined by a branch from the inferior ganglion of the glossopharyngeal nerve. ^[1]  It passes behind the internal jugular vein and enters the mastoid canaliculus in the lateral part of the jugular fossa. It exits again through the tympanomastoid suture of the temporal bone and splits into two rami: one connects with the posterior auricular nerve and the other innervates the skin of part of the ear and the external acoustic meatus. ^[1]  It communicates with branches of the seventh (facial) and ninth (glossopharyngeal) cranial nerves.

Pharyngeal branch

It is the primary motor nerve of the pharynx, comprising axons originating from the nucleus ambiguus. The pharyngeal branch emerges from the upper part of the inferior ganglion and passes between the external and internal carotid arteries, reaches the middle pharyngeal constrictor. It divides into filaments that join rami from the sympathetic trunk and glossopharyngeal nerve to form the pharyngeal plexus. It also gives off a minute filament, the ramus lingualis vagi, which joins the hypoglossal nerve. It innervates all muscles of the soft palate (except tensor veli palatini, supplied by the mandibular division of the trigeminal nerve via the nerve to medial pterygoid) and the pharynx (except stylopharyngeus, supplied by the glossopharyngeal nerve). ^[1]

Branches to the carotid body

They vary in number, originating from the inferior ganglion, the pharyngeal branch, or the superior laryngeal nerve. They form a plexus with the glossopharyngeal rami and branches of the cervical sympathetic trunk. ^[1]  These vagal fibers and visceral afferents mediate impulses set up by the chemoreceptors in the carotid body.

Superior laryngeal nerve

The superior laryngeal nerve arises from the middle of the inferior vagal ganglion. It descends alongside the pharynx, at first posterior, then medial, to the internal carotid artery and passes between the external and internal carotid arteries at the level of crossing of CN XII. At the tip of the hyoid (about 1.5 cm below the ganglion), the superior laryngeal nerve divides into smaller external and larger internal branches.

           1. The internal laryngeal nerve pierces the thyrohyoid membrane above the superior laryngeal artery and divides into superior, middle, and inferior branches on entering the larynx. It is sensory to the laryngeal mucosa till the vocal folds and supplies most of the mucosa above the glottis. It also carries afferent fibers from the laryngeal neuromuscular spindles and other stretch receptors. The nerve terminates by piercing the inferior pharyngeal constrictor, joining an ascending branch from the RLN. As it ascends the neck, it supplies branches to the mucosa and tunica muscularis of the esophagus and trachea, as well as the inferior constrictor. ^[1]  It is divided into the following three divisions:

                   • Superior division – Supplies the mucosa of the laryngeal surface of the epiglottis and the piriform fossa ^[1]    

                   • Middle division – Supplies the mucosa of the true and false vocal folds, as well as the aryepiglottic fold. It also innervates the mucosa of the ventricle, specifically the quadrangular membrane, and therefore may participate as the afferent component of the cough reflex. ^[1]

                   • Inferior division – Supplies the mucosa of the ventricle and subglottic cavity. It also innervates the arytenoid mucosa, anterior wall of the hypopharynx, upper esophageal sphincter, and part of the subglottis (a major part of the subglottis is innervated by the ipsilateral recurrent nerve)

            2. The external laryngeal nerve passes inferiorly with the superior thyroid vessels to the inferior pharyngeal constrictor muscle. The cricothyroid muscle is supplied by the external branch of the superior laryngeal nerve. It also gives branches to the pharyngeal plexus and the inferior constrictor. Posterior to the common carotid artery, the external laryngeal nerve communicates with the superior cardiac nerve and superior cervical sympathetic ganglion. The external laryngeal nerve can be damaged during ligation of the superior thyroid artery in thyroid surgery. It is also at risk in parathyroidectomy, carotid endarterectomy, and anterior cervical spine procedures. ^[1]

Recurrent laryngeal nerve

RLN is also known as the inferior laryngeal nerve. It ascends within or adjacent to the tracheoesophageal groove on both sides. It maintains a close anatomical relationship with the medial aspect of the thyroid gland. The nerve then courses under the lower border of the inferior pharyngeal constrictor muscle, finally entering the larynx posterior to the articulation of the inferior thyroid cornu with the cricoid cartilage. ^[1]  (See Table 4.)

Table 4. Right and Left Recurrent Laryngeal Nerves; Origin, Course, and Relations ^[1] (Open Table in a new window)

As the RLN curves around either the subclavian artery or the aortic arch, it gives cardiac filaments to the deep cardiac plexus. ^[1]

The main trunk divides into two or more branches: anterior and posterior. The anterior branch is mainly motor (the inferior laryngeal nerve) that innervates the posterior cricoarytenoid, interarytenoid, lateral cricoarytenoid, and thyroarytenoid. The posterior branch of the RLN is mainly sensory. ^[1]  The main trunk of the recurrent lies in a triangle bound laterally by the common carotid artery, the internal jugular vein, and the vagus nerve and medially by the trachea and esophagus. The recurrent nerve passes under the posterior suspensory ligament of Berry (located on either side of the trachea, extending from the cricoid cartilage and the first two tracheal rings to the posteromedial aspect of the thyroid gland), before entering the larynx (see the image below). A few variations may occur in this area (see Natural Variants). The ligament of Berry (BL) is considered one of the most reliable landmarks in neck surgery. In most cases, the RLN courses superficially to the BL. However, instances have been reported where the RLN pierces the BL, becoming intricately intertwined with it, posing a unique hazard as fibers can be easily severed during thyroidectomy when the ligament is incised. ^[9]

All the intrinsic laryngeal musculature is supplied by the ipsilateral recurrent nerve except the cricothyroid muscle, which is supplied by the superior laryngeal nerve. The interarytenoid muscle is the only one that receives a bilateral supply (i.e., from the left and right RLNs). The RLN interacts with the internal laryngeal nerve, supplying sensory fibers to the laryngeal mucosa below the vocal cords, and carries signals from laryngeal stretch receptors. ^[1]

The ramus communicans, or nerve of Galen, connects the superior and the RLNs. It provides the tracheal and esophageal mucosa and smooth muscle with visceral motor input.

Laryngeal nerve anastomoses

The existence of anastomotic communications among the internal, external, and RLNs explains the preservation of normal or near-normal vocal function post-neck surgery or when one or more branches of these nerves are transected (see Table 5).

Table 5. Summary of Laryngeal Nerve Anastomoses: Location and Connections ^[1] (Open Table in a new window)

Superior cardiac nerve

The superior cardiac nerve is made up of 2-3 branches. They communicate with sympathetic fibers.

Pharyngeal plexus

It is constituted by the pharyngeal branches of the glossopharyngeal and vagus nerves, with additional input from the superior cervical sympathetic ganglion. This plexus is situated on the external surface of the pharynx, predominantly over the middle constrictor muscle. It provides nearly all the motor and sensory innervation to the pharynx. ^[1]

Vagus nerve branches in the thorax

Preganglionic parasympathetic axons from the dorsal motor nucleus of the vagus in the medulla oblongata travel through the pulmonary, cardiac, and esophageal branches, synapsing in the minute ganglia within target viscera.

        1. Cardiac branches: The inferior cardiac branch is also called the ramus cardiaci inferiors. On the right side, it arises from the trunk of the vagus as it lies beside the trachea. On the left side, it originates from the RLN. Cardiac branches join the cardiac plexuses, synapsing in ganglia across atrial regions (both atria, the interatrial septum, and peri-nodal subepicardial tissue). The postganglionic fibers from these synapses are distributed to the atria and the atrioventricular bundle, sinoatrial nodes, and atrioventricular nodes, influencing heart rate and contraction force. ^[1]

        2. Pulmonary branches: They contain axons that synapse in the ganglia of the pulmonary plexuses. These pulmonary branches are motor (bronchoconstrictor) to the circular nonstriated muscle fibers of the bronchi and bronchioles and are secretomotor to the mucous glands of the respiratory epithelium. ^[1]  The anterior and posterior bronchial branches are distributed as 2-3 branches on the anterior surface of the root of the lung.

                   • They form the anterior pulmonary plexus after joining branches from the sympathetic trunk.

                   • The posterior bronchial branches arise from the right and the left vagus nerves. They are larger than the anterior and lie on the posterior surface of the root of the lung. They unite with the corresponding rami from the second to fifth/sixth thoracic sympathetic ganglia to form the right and left posterior pulmonary plexuses, respectively. ^[1]

       3. The esophageal branches: The vagus nerve regulates the parasympathetic motor functions of the esophageal muscles and glands. It includes anterior and posterior branches, which form the esophageal plexus. The posterior surface of the pericardium is supplied by filaments from this plexus.

                   • The right posterior pulmonary plexus gives off two or three branches that join the left vagal branch on the posterior aspect of the esophagus to form the posterior esophageal plexus. ^[1]

                   • The left posterior pulmonary plexus gives off two or three branches that join a ramus from the right posterior pulmonary plexus on the anterior aspect of the esophagus to form the anterior esophageal plexus. ^[1]

Vagus nerve branches in the abdomen

The vagus nerve provides parasympathetic innervation to the abdominal viscera up to the distal transverse colon. Derived from the esophageal plexus, the vagal trunks enter the abdomen through the esophageal hiatus, closely associated with the anterior and posterior walls of the abdominal esophagus. ^[1] (See Table 6.)

Table 6. Anterior and Posterior Vagal Trunks: Origin and Structures Innervated ^[1] (Open Table in a new window)

The gastric branches (rami gastrici) supply the stomach. The right vagus forms the posterior gastric plexus and the left forms the anterior gastric plexus. The branches lie on the posteroinferior and the anterosuperior surfaces, respectively. The left vagus nerve supplies the anterior and superior parts of the stomach, and the right vagus nerve supplies the posterior and inferior surfaces. ^[1]  The celiac branches (rami celiaci) are derived mainly from the right vagus nerve. They join the celiac plexus and supply the pancreas, spleen, kidneys, adrenals, and intestine.

The recurrent and external branches of the superior laryngeal nerves carry parasympathetic fibers from the dorsal motor nucleus to the subglottis and supraglottic regions, respectively. The superior cervical ganglion sends sympathetic innervation. ^{[8, 10, 11]} Histologic sections have revealed the presence of Meissner's corpuscles, Meckel cells, and taste buds scattered in the larynx.

The mucosal surface sensory receptors are more numerous on the laryngeal surface of the epiglottis than on the true vocal folds. On the other hand, chemoreceptors are limited to the supraglottic mucosa.

RLN: The position of the RLNs is crucial for thyroid surgeons. ^{[12, 7, 13, 14]} The following are some anatomic variations:

The upper part of the RLN has a variable relationship with the inferior thyroid artery. On the right side, it can be anterior, posterior, or intermingled with the artery's branches. On the left, it is usually posterior, though sometimes anterior. ^[1]

The branching pattern of the RLN is highly variable as 89% of right RLNs and 74.6% of left RLNs demonstrated 2-5 extra-laryngeal branches. ^[15]  The main trunk of the recurrent nerve has been observed to branch into two nerves before entering the larynx. Most of the time, the branching occurs 0.6-3.5 cm below the lower border of the inferior constrictor, although branching may take place higher up. ^[1]  In rare instances, the recurrent nerve may have 4-6 branches. These may be esophageal branches, or they may supply the inferior pharyngeal constrictor. Any nerve in the surgical field should not be sacrificed unless it is invaded by malignancy.

A non-RLN is a rare and significant anomaly in laryngeal pathology and surgery. In this condition, the right RLN originates directly from the vagus nerve high in the neck, entering the larynx near the lower thyroid pole. This anomaly only affects the right side and is linked with an aberrant right subclavian artery arising from the aortic arch on the left. If not identified, the non-RLN is at risk for injury during surgery. It also carries a risk for compression by small thyroid tumors. ^[1]

Studies have shown that the left RLN branches less frequently and follows a more predictable path to the larynx than the right RLN. The oblique, anterolateral route and a higher number of branches of the right RLN increase the risk for iatrogenic injury during anterior cervical discectomy and fusion. The right RLN also exhibits greater variability in its relationship with the inferior thyroid artery and its anterolateral position compared to the left RLN. ^[15]  Typically, the right RLN passes anterior to the inferior thyroid artery in about two thirds of cases, while the left RLN posteriorly. ^[15]  In some cases, the right subclavian artery is retroesophageal and arises from the aorta distal to the ligamentum arteriosus. In these cases, the right recurrent nerve enters the larynx without looping around the artery.

The RLN passes under the BL before entering the larynx. In 0.25% of cases, it passes over the ligament.

A branch of the inferior thyroid artery may pass deep to the BL or along its inferior edge. Indiscriminate clamping of this artery could jeopardize the recurrent nerve.

A small portion of the thyroid gland may exist deep to the ligament and lateral to the recurrent nerve. This should be removed with great care, without injuring the nerve, during thyroidectomy because it may contain a carcinoma.

The types of fibers that constitute the vagus nerve perform different physiologic roles (see the image below as well as Table 7) as follows: ^{[16, 17, 18, 19, 20]}

The parasympathetic efferent fibers (general visceral efferent or visceral motor) are distributed to the smooth muscle of the thoracic and abdominal viscera; to the bronchial tree (bronchi, lungs); to the heart (inhibitory fibers); and to the esophagus, stomach, liver, pancreas, spleen, small intestine, and proximal part of the colon (motor fibers) and glandular epithelium. ^[1]  In addition, they are distributed as secretory fibers to the stomach and pancreas. They arise from the dorsal motor nucleus of the vagus.

The somatic motor fibers special visceral (efferent or branchial motor) arise from the cells of the nucleus ambiguus, which is the motor nucleus. Discrete groups of cells in the caudal region innervate specific laryngeal muscles. Neurons in the intermediate area innervate the pharynx, while those in the rostral area innervate the esophagus and soft palate. ^[1]  The nucleus ambiguus is adjacent to the respiratory motor neurons in the brainstem (see the image below).

Sensory fibers (general visceral afferent and special visceral afferent) arise from the cells of the jugular ganglion and ganglion nodosum (superior and inferior ganglia of the vagus, respectively). When traced into the medulla, they end by arborizing around the cells of the inferior part of a nucleus, which lies beneath the ala cinerea in the lower part of the rhomboid fossa. These are the sympathetic afferent fibers. A few of the taste fibers of the vagus nerve descend in the fasciculus solitarius and end around its cells. Neurons in the inferior ganglion transmit visceral sensation from the heart, larynx, pharynx, lungs, and the alimentary tract to the central nervous system. Some fibers transmit impulses from taste endings in the vallecula and epiglottis. ^[1] (See Table 7.)

Table 7. Major Organs Innervated by Vagal Afferents and Their Functions ^[1] (Open Table in a new window)

Abdominal vagal afferents include mucosal mechanoreceptors, chemoreceptors, and tension receptors located in the esophagus, stomach, and proximal small intestine and sensory endings located in the liver and pancreas. ^[3]

The somatic sensory fibers (general somatic afferent) are only a few in number. From the posterior aspect of the external auditory canal and the back of the external ear, they join the spinal tract of the trigeminal nerve as it descends in the medulla. They have connections with the thalamus, sensory cortex, and medullary and spinal nuclei (see Table 8).

Table 8. The Pathway According to the Type of Nerve Fibers of the Vagus Nerve (Open Table in a new window)

The vagus nerve comprises fibers of various sizes and neurochemical phenotypes, including cholinergic, monoaminergic, glutamatergic, and peptidergic types. These fibers travel within fascicles, forming branches to innervate and regulate target organs. Recent animal studies have shown a complex, non-uniform anatomical organization of fibers in the cervical and thoracic vagus nerve, highlighting organ- and function-specific arrangements in both transverse and longitudinal orientations. These findings can play a key role in designing and testing selective vagus neuromodulation bioelectronic therapies such as vagus nerve stimulation (VNS) targeting specific organs and functions in humans. ^[21]

Cough is a very common symptom for physician visits all over the world. It serves to protect the respiratory tract from exogenous organic, thermal, and chemical irritants. It is triggered when mechanically and chemically sensitive vagal afferent fibers, which innervate airways from the upper respiratory tract to the terminal bronchioles and lung parenchyma, are activated. ^[1]

According to its characteristics, cough can be split into two distinct types, aspiration cough, which is loud and involuntary and is caused by mechanical laryngeal stimulation that induces an immediate expiratory reflex to prevent aspiration, and urge-to-cough sensation, which describes an irritant, scratchy, and controlled cough of slowly increasing intensity.

Acute cough mostly develops due to infection of the respiratory system and ends after approximately 1 month. In contrast to this, bacterial infection with pathogens such as Adenovirus, Bordetella pertussis (whooping cough), or Mycoplasma can last up to 2 months. Chronic dry cough can result from any of these etiologies: ^[1]

1.  Lesions that compress the upper airway, including arteriovenous malformations and retro tracheal masses
2. Tracheobronchomalacia
3. Obstructive lung disease in patients with a history of tobacco smoking
4. Irritation of the external acoustic meatus by foreign bodies or cerumen. The "ear cough" (otorespiratory) reflex is triggered by the auricular branch of the vagus nerve (Arnold's nerve).

The cough reflex is initiated by different receptors. Dinh et al (2013) summarized the cough reflex and receptors as being divided into the following groups: ^[22]

1. Two Aδ-fiber types

             • Rapid-adapting mechanoreceptors - They are dynamic receptors that respond to changes in airway mechanical properties (e.g., diameter, length, and interstitial pressures). They show rapid adaptation (in 1-2 seconds) to sustained lung inflation. Although they are active throughout the respiratory cycle, their activity gets enhanced in response to an increase in the rate and volume of lung inflation which initiates reflex bronchospasm and mucus secretion through parasympathetic pathways. ^[1]

             • Slow-adapting mechanoreceptors - They are found mostly in alveoli and bronchioles. Their activity increases during inspiration and peaks just before the initiation of expiration. Their activation causes a central inhibition of respiration and inhibition of the cholinergic drive to the airways, leading to decreased phrenic nerve activity and decreased airway smooth muscle tone. ^[1]

      2. Bronchopulmonary unmyelinated C-fiber receptor: They are slow-conducting fibers that are insensitive to mechanical stimulation and lung inflation and generally remain quiescent throughout the respiratory cycle. ^[1]

      3. Airway receptors in the external acoustic meatuses (external auditory canals), tympanic membranes, paranasal sinuses, pharynx, respiratory diaphragm, pleura, pericardium, and stomach are probably mechanoreceptors, stimulated by triggers such as touch or displacement. ^[1]

The stimulus is detected by cough receptors that conduct the signal to the cerebral cough center via vagal-sensory neurons. The cough itself is mediated by efferent motoneurons.

The event of coughing can be divided into phases. The first phase consists of fast inspiration with an opened glottis, followed by compression with a closed glottis. This is accompanied with rapid generation of intrapulmonary pressure and the sudden opening of the glottis and contraction of intercostal and abdominal wall muscles. These events generate a high-velocity flow of expired air which propels irritant material toward the pharynx in a forceful exhalation, resulting in a cough. ^[1]

Cough Reflex:

Neurologically, the cough reflex consists of five sequential parts: (1) the cough receptors; (2) the primary afferent fibers of the vagus, trigeminus, and glossopharyngeus CNs; (3) the cough center in the medulla (nucleus tractus solitarius); (4) the efferent fibers of the phrenic, accessory, and the RLNs; and (5) the diaphragm, the abdominal wall, and intercostal and laryngeal musculature. Laryngeal branches of the vagus nerve carrying general visceral afferent information (with cell bodies in the inferior vagal ganglion) terminate in the nucleus tractus solitarius. Second-order neurons from this nucleus terminate on respiratory-related regions of the pons, medulla, and spinal cord. Efferent impulses travel via the vagus, phrenic, and spinal motor nerves to the inspiratory and expiratory muscles, larynx, respiratory diaphragm, and abdominal wall muscles. ^[1]

Beaumont et al ^[23] found that chronic VNS mitigates myocardial infarction-induced remodeling of the intrinsic cardiac nervous system along with the cardiac tissue it regulates in guinea pigs.

Lagae et al published a study on the efficacy of VNS therapy in a highly drug-resistant childhood epilepsy patient group. They confirmed the efficacy of VNS in children. A larger study is required to determine the contribution of different factors (such as age at implantation, etiology, and epilepsy duration) associated with this therapy. ^[24]  

Apart from the  anti-inflammatory effects via the HPA axis and the CAP, there is a vago-sympathetic pathway, wherein the vagus nerve and the sympathetic nervous system (via the splenic nerve) act synergistically to suppress inflammation and involve both vagal afferent and efferent fibers. Thus, targeting the vagus nerve presents novel therapeutic avenues for gastrointestinal inflammatory diseases (inflammatory bowel disease [IBD], postoperative ileus, irritable bowel syndrome) and other tumor necrosis factor α-mediated conditions (rheumatoid arthritis, psoriasis). ^[2]

The brain-gut axis encompasses bidirectional communication between the brain and gastrointestinal tract, involving the vagus nerve; sympathetic pathways (prevertebral ganglia); endocrine, immune, and humoral connections; and gut microbiota. This system regulates gastrointestinal homeostasis and connects emotional and cognitive brain regions with gut functions. Preliminary evidence suggests that VNS is a promising adjunct therapy for treatment-resistant depression, post-traumatic stress disorder, and IBD. VNS treatments enhance vagal tone and reduce cytokine production, both of which are crucial for resilience. Stimulating vagal afferent fibers in the gut affects monoaminergic brain systems in the brainstem, which play a vital role in psychiatric conditions such as mood and anxiety disorders. ^[3]

Recent case studies have localized cardiac parasympathetic fibers within human vagus nerve rootlets. This new insight into the distribution of vagus nerve rootlets' fibers — pure sensory (most rostral), motor/sensory (more caudal), and parasympathetic (most caudal) — enhances our understanding and diagnosis of vagal rhizopathies. The findings elucidate the pathophysiology of bradycardia in rare cases of vago-glossopharyngeal neuralgia, potentially mediated reflexively through the brainstem with afferent impulses in CN IX and efferent impulses in CN X. ^[25]

Intraoperative neuro monitoring during thyroid or parathyroid surgery is now recognized as an adjunct to visual nerve identification. It improves the outcomes among patients undergoing these types of surgeries. ^{[26, 27]}  Laryngeal electromyography is effective in determining the origin of unilateral vocal-fold paralysis. It also has an important therapeutic and prognostic role if a lack of reinnervation potential is noted, which is a possible indication for early medialization laryngeal surgery.