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Vagus nerve

The vagus nerve, designated as the tenth cranial nerve (CN X), is the longest cranial nerve in the , originating in the of the and extending through the , , and to innervate multiple organs, primarily serving as a key component of the to regulate involuntary functions such as , , and . Anatomically, the vagus nerve emerges from the and exits the skull via the , accompanied by superior and inferior ganglia that house sensory cell bodies; it then descends within the alongside the and , giving rise to branches including the pharyngeal nerve for swallowing, the superior and recurrent laryngeal nerves for voice production, and cardiac branches for heart modulation, before forming the esophageal and continuing to supply the lungs, heart, and up to the splenic flexure of the colon. Its structure comprises approximately 80% afferent (sensory) fibers that convey information from organs to the and 20% efferent (motor) fibers that control parasympathetic outflow, accounting for about 75% of the body's total parasympathetic innervation and enabling the "rest and digest" response in opposition to the sympathetic "fight or flight" system. Functionally, the vagus nerve modulates a wide array of visceral activities, including slowing the via inhibition, promoting gastrointestinal and through innervation of the smooth muscles and glands from the to the proximal colon, and influencing by affecting bronchial tone and receptors; it also plays roles in immune regulation by dampening through the pathway and in sensory feedback for , , and cardiovascular reflexes. Embryologically, it derives from the fourth , contributing to the of pharyngeal and laryngeal structures, which underscores its evolutionary across vertebrates for autonomic control. Clinically, the vagus nerve's integrity is assessed through tests like the gag reflex and deviation, with damage potentially leading to conditions such as , hoarseness from , gastroparesis due to impaired gastric (often linked to ), or vasovagal syncope from excessive parasympathetic activation causing and ; therapeutic interventions include (VNS), an FDA-approved implantable device that electrically activates the nerve to treat refractory and by modulating nuclei and release.

Anatomy

Nuclei and central connections

The vagus nerve, or cranial nerve X, originates from four principal nuclei within the , each contributing distinct efferent and afferent components essential for its central processing. These nuclei include the dorsal motor nucleus, , (also known as the ), and , collectively forming the central origins and integration points for vagal innervation. The dorsal motor , located in the dorsomedial medulla anterior to the , consists of preganglionic parasympathetic neurons that provide . These neurons are organized in a rostrocaudal column, with rostral portions targeting thoracic viscera and caudal segments innervating abdominal organs, and they connect bidirectionally with the nucleus of the solitary tract to facilitate arcs. Additionally, this nucleus links to the medullary , enabling coordination of autonomic outputs. The lies within the medullary , spanning from the level of the facial to the upper cord, and contains special visceral efferent (branchiomotor) neurons for innervating striated muscles of the and . Its neurons are somatotopically arranged, with rostral cells projecting to ambiguus-derived laryngeal muscles and caudal cells to pharyngeal ones, and it receives modulatory inputs from the for motor coordination. This also interconnects with adjacent structures, including the . The nucleus of the solitary tract forms a longitudinal column of in the dorsomedial medulla, divided into rostral (gustatory) and caudal (viscerosensory) divisions, serving as the primary site for general visceral afferent integration from the vagus nerve. It receives inputs via the solitary tract and contains multipolar neurons, including and noradrenergic types, that process chemoreceptive and mechanoreceptive signals. Projections from this nucleus extend to the parabrachial nucleus, , and dorsal raphe for relay, while ascending pathways connect to the (via the paraventricular nucleus) and limbic structures like the through the ventral amygdalofugal pathway, supporting autonomic and emotional regulation. The , extending from the caudal medulla to the upper cervical (C3 level), provides somatic afferent processing for the vagus nerve's minor sensory contributions, particularly , , and touch from the external auditory and . It receives vagal fibers alongside inputs from the trigeminal, , and glossopharyngeal nerves, with second-order neurons projecting via the trigeminothalamic tracts to the ventral posteromedial thalamic nucleus. This nucleus integrates with the adjacent for reflexive responses.

Origin, course, and peripheral branches

The vagus nerve, designated as cranial nerve X, originates from a series of rootlets emerging at the pontomedullary junction in the , specifically from the and dorsal motor nucleus, forming a trunk that exits the through the alongside the glossopharyngeal (IX) and (XI) nerves. Upon exiting, it is joined by the superior (jugular) and inferior (nodose) ganglia, which house sensory cell bodies, before descending into the neck. In its cervical course, the vagus nerve travels within the carotid sheath, positioned posterior to the common carotid artery and medial to the internal jugular vein, with the right vagus curving anteriorly around the subclavian artery and the left descending between the carotid and subclavian arteries. Key cervical branches include the auricular nerve (also known as Arnold's nerve), arising from the superior ganglion to supply the external auditory canal and posterior auricle; the meningeal branch, which re-enters the cranium to innervate the dura mater; and the pharyngeal branches from the inferior ganglion, contributing to the pharyngeal plexus for pharyngeal muscle innervation. The superior laryngeal nerve branches off next, dividing into internal (sensory to the larynx above the vocal folds) and external (motor to the cricothyroid muscle) rami, while the recurrent laryngeal nerve loops inferiorly—the right around the subclavian artery and the left around the aortic arch—before ascending in the tracheoesophageal groove to supply intrinsic laryngeal muscles except the cricothyroid. Superior cervical cardiac branches also emerge here, directing toward the heart. Entering the thorax, the right vagus nerve courses posterior to the and right main , while the left parallels the and descends lateral to the , with both nerves contributing to the pulmonary and esophageal es. Thoracic branches encompass inferior and thoracic cardiac nerves targeting the ; bronchial branches forming anterior and posterior pulmonary es around the hila; and esophageal branches weaving into the esophageal along the esophageal walls. The nerves maintain close relations to the , , and throughout this segment. Upon piercing the diaphragm via the esophageal hiatus, the vagus nerves reorganize into anterior (primarily left) and posterior (primarily right) trunks that distribute along the stomach and abdominal viscera. Abdominal branches include gastric divisions from the anterior trunk innervating the stomach's anterior surface and pylorus; celiac branches extending to the celiac plexus for foregut derivatives like the liver, pancreas, and spleen; hepatic branches to the gallbladder and duodenum; with further extensions to the midgut via the superior mesenteric plexus. These trunks relate intimately to the stomach's curvature, celiac axis, and intestinal segments up to the splenic flexure.

Development

Embryonic formation

The vagus nerve, cranial nerve X, originates embryologically from the fourth during weeks 4 to 5 of , contributing to the of pharyngeal and laryngeal structures. This involves coordinated contributions from multiple embryonic tissues: the brainstem nuclei, including the dorsal motor nucleus of the vagus and the , arise from the of the alar and basal plates in the developing . In parallel, sensory ganglia associated with the vagus nerve—the jugular ganglion forms primarily from cells that migrate from the posterior , while the nodose ganglion derives from placodal . Sensory components of the vagus nerve develop from placodal , specifically the epibranchial placodes associated with the pharyngeal pouches, which delaminate to form neurons in the nodose . Motor elements, including branchial motor fibers innervating laryngeal muscles, derive influences from the branchial of the fourth arch, integrated with neuroectodermal precursors that migrate dorsally to establish vagal motor nuclei. Neural crest cells for the jugular originate from the posterior cephalic region and migrate ventrally, while placodal precursors for the nodose delaminate dorsally, ensuring topographic of sensory and autonomic pathways. The timeline of vagus nerve formation begins with initial axon outgrowth around embryonic day 28, corresponding to the end of week 4, as precursors extend fibers guided by signaling pathways like Netrin-DCC. formation follows by week 6, when vagal cells coalesce into the nodose and jugular ganglia, and parasympathetic innervation to target organs initiates. Genetic regulation is crucial for specifying vagal identity, with Hoxb1 expressed in rhombomere 8 of the hindbrain to delineate motor neuron domains and prevent anterior-posterior misspecification. The transcription factor Phox2b, expressed in nodose placodal neurons but absent in jugular crest-derived ones, drives autonomic differentiation and ganglion specification; mutations in Phox2b can lead to congenital vagal aplasia or related malformations like those in congenital central hypoventilation syndrome.

Postnatal maturation and variations

Following birth, the vagus nerve undergoes continued maturation, particularly in myelination and structural growth, which supports its role in autonomic regulation. Myelination of vagal s, initiated prenatally, progresses actively postnatally, with significant increases in the number and thickness of sheaths during the first year of life. The nerve contains a mix of fiber types: myelinated A- and B-fibers, primarily responsible for motor functions and some sensory afferents, alongside unmyelinated C-fibers that mediate parasympathetic efferents and most visceral sensory signals. Studies of vagus samples from term infants show a linear rise in total myelinated fiber counts from birth, with active myelination evident up to 9 months postpartum, marked by increased lamellae and a shift in g-ratio (myelin thickness relative to diameter), though average diameters remain stable. By , myelinated fiber counts and distributions approximate adult patterns, with no major further changes reported beyond . The vagus nerve's physical growth correlates closely with overall body size during childhood, involving elongation and increases in cross-sectional area (CSA) to accommodate somatic expansion. Nerve CSA expands gradually from infancy through adolescence, reaching adult dimensions around 15-17 years, influenced more by age and height than body mass index. This postnatal adaptation ensures the nerve's branches maintain effective innervation of growing thoracic and abdominal organs. In aging, a trend toward CSA reduction emerges, potentially linked to atrophy, though specific vagal data are limited and show no significant latency changes in evoked potentials with advanced age. Anatomical variations in the vagus nerve occur in up to % of individuals, often affecting branches and detected via preoperative for surgical planning. The non-recurrent laryngeal nerve (NRLN), a rare variant where the inferior laryngeal nerve arises directly from the vagus instead of looping around the subclavian or , has an incidence of 0.3-0.8% overall, predominantly right-sided (0.54% in surgical series) and left-sided (0.07%). Associated with vascular anomalies like arteria lusoria, NRLN increases iatrogenic injury risk during or carotid surgery. The branch, providing parasympathetic input to the and abdominal viscera, exhibits variations in origin and routing from the posterior vagal trunk, though complete absence is infrequently documented and may contribute to altered gastrointestinal motility if unrecognized. Bilateral anomalies, involving aberrant branching or positioning near the , are uncommon, potentially affecting and laryngeal sensation bilaterally. Imaging modalities like fused 3D- angiography and MRI effectively visualize vagus variations preoperatively, delineating its position relative to the and with high precision (detection time <60 minutes intraoperatively). High-resolution ultrasound also identifies cervical vagus CSA and branching anomalies non-invasively, aiding in procedures such as implantation. and MRI are particularly useful for confirming NRLN or branch variants, with contrast-enhanced sequences highlighting nerve fascicles against vascular structures.

Function

Parasympathetic regulation

The vagus nerve serves as the primary conduit for parasympathetic outflow from the central nervous system, comprising approximately 75% of the total parasympathetic innervation to the thoracic and abdominal viscera. This extensive parasympathetic contribution enables the nerve to orchestrate widespread visceral control, promoting restorative physiological processes during periods of low stress. Parasympathetic fibers within the vagus nerve are preganglionic neurons originating primarily from the dorsal motor nucleus of the vagus in the medulla oblongata, with additional contributions from the nucleus ambiguus for specific targets like the heart. These preganglionic fibers release acetylcholine, which binds to nicotinic receptors on postganglionic neurons located in terminal ganglia situated near or within the innervated organs. The postganglionic neurons, in turn, also release acetylcholine that acts on muscarinic receptors on the target tissues, facilitating localized inhibitory effects such as smooth muscle relaxation and glandular secretion. Vagal tone, representing the baseline level of parasympathetic activity, modulates key homeostatic functions by slowing and enhancing digestive , thereby supporting the "rest-and-digest" state characteristic of parasympathetic dominance. This tone is dynamically adjusted to counterbalance sympathetic activation, maintaining autonomic equilibrium; for instance, in the , increased vagal efferent activity in response to inputs from the and helps rapidly lower and during hypertensive episodes. Such integration ensures adaptive responses across organ systems, including cardiovascular and gastrointestinal regulation.

Sensory and afferent roles

The vagus nerve serves primarily as an afferent pathway, with 80–90% of its fibers dedicated to sensory from visceral organs to the . These afferents convey critical interoceptive signals, enabling the to monitor and respond to internal physiological states. The majority originate from pseudounipolar neurons with cell bodies in the nodose (inferior) ganglion, which projects predominantly to the nucleus of the solitary tract (NTS) in the . This pathway facilitates rapid integration of sensory inputs, triggering essential arcs that maintain . Vagal afferents detect a range of stimuli, including chemosensory cues such as changes in , CO₂ levels (), and from structures like the carotid and aortic bodies; mechanosensory inputs from organ distension and stretch; and thermosensory information via receptors like , which respond to temperature variations and irritants. These signals support diverse reflexes, such as the gag reflex elicited by pharyngeal stimulation and the swallow reflex coordinated during esophageal transit, both mediated by NTS projections that activate protective motor responses. Polymodal nociceptors within the vagus, often C-fiber afferents expressing , respond to multiple noxious stimuli including inflammation-induced chemical mediators and ischemia, transmitting signals to the NTS and contributing to defensive behaviors. In the context of feeding and emetic responses, vagal afferents play key roles in and . Gut distension activates mechanoreceptors, such as intraganglionic laminar endings, which relay signals via the NTS to the , activating pro-opiomelanocortin neurons to suppress and promote meal termination. Similarly, chemosensory detection of toxins or irritants links to the in the , which integrates with vagal inputs at the NTS to evoke and initiate aversion or reflexes. These afferent mechanisms underscore the vagus nerve's bidirectional influence on autonomic regulation, complementing efferent outputs in overall visceral control.

Somatic motor functions

The somatic motor functions of the (cranial nerve X) are mediated by branchiomotor fibers, also known as , which originate from the in the . These fibers provide innervation to skeletal muscles derived from the fourth and sixth branchial arches, primarily in the , , and , enabling essential functions such as and . Unlike the more extensive parasympathetic components, these somatic contributions are limited to the head and . The branchiomotor fibers innervate specific muscles critical for upper airway and digestive tract mechanics. In the larynx, they supply the intrinsic laryngeal muscles, including the posterior cricoarytenoid, interarytenoid, lateral cricoarytenoid, and thyroarytenoid muscles, which control vocal cord movement for voice production and airway protection; the receives innervation via the external branch of the . Pharyngeal muscles, such as the constrictors, are targeted for coordinated constriction during swallowing via the , while the (derived from the third branchial arch) receives innervation from the (CN IX). Additionally, the vagus nerve innervates muscles, including the levator veli palatini, palatopharyngeus, salpingopharyngeus, and musculus uvulae, facilitating elevation and closure to prevent nasal regurgitation during deglutition (except for the tensor veli palatini, supplied by the ). These functions involve precise coordination with other to ensure effective reflexes. The vagus nerve collaborates with the (CN IX) through the to mediate the gag reflex and pharyngeal phase of , where sensory input from CN IX triggers motor responses via CN X. Integration with the accessory nerve (CN XI) supports broader head and neck movements that aid airway protection during and deglutition. The branchiomotor fibers are myelinated type A fibers that release at neuromuscular junctions, binding to nicotinic receptors to elicit contraction. This cholinergic transmission mirrors general motor pathways, ensuring rapid and reliable activation.

Organ-specific effects

Cardiovascular system

The vagus nerve provides parasympathetic innervation to the heart through its superior and inferior cardiac branches, which arise from the cervical and thoracic portions of the nerve, respectively. These branches contribute to the cardiac plexus, a network of autonomic fibers located at the base of the heart, with postganglionic neurons forming ganglionated plexi around the sinoatrial (SA) node and atrioventricular (AV) node. The right vagus nerve predominantly targets the SA node, while the left vagus nerve primarily influences the AV node, enabling precise modulation of cardiac rhythm. Upon stimulation, these cardiac branches release () from postganglionic fibers, binding to muscarinic receptors on the and nodes to produce a negative effect, thereby slowing , and a negative effect, which delays conduction. This parasympathetic dominance helps maintain resting between 60-100 beats per minute in adults. However, during intense or prolonged vagal stimulation, a phenomenon known as vagal escape can occur, where the heart resumes beating due to intrinsic activity or sympathetic override, preventing sustained . Afferent fibers of the vagus nerve convey signals from the and to the tractus solitarius (NTS) in the , where they inhibit sympathetic outflow from the rostral ventrolateral medulla, thereby reducing and vascular tone to lower during . This arc is crucial for short-term cardiovascular . Additionally, vagal stimulation promotes coronary through the release of (VIP) from nerve terminals, enhancing myocardial blood flow, and modulates the release of (ANP) from atrial cardiomyocytes, contributing to and . Clinically, heart rate variability (HRV), particularly the high-frequency component, serves as a noninvasive measure of vagal tone, reflecting the balance between parasympathetic and sympathetic influences on the heart. Reduced HRV is associated with diminished vagal activity and is commonly observed during acute stress, correlating with increased cardiovascular risk due to impaired autonomic flexibility.

Respiratory and gastrointestinal systems

The vagus nerve innervates the primarily through its pulmonary branches, which carry parasympathetic efferent fibers that regulate bronchial tone, submucosal gland , and protective reflexes such as coughing. These efferents release onto muscarinic M3 receptors in airway , inducing to modulate airflow resistance, and on glandular cells to promote for airway lubrication and clearance. The , essential for expelling irritants, involves coordinated vagal efferent activation of laryngeal and bronchial muscles alongside glandular responses, forming a key component of airway defense mechanisms. In the upper gastrointestinal tract, the vagus nerve orchestrates the esophageal phase of swallowing by coordinating peristaltic waves that propel boluses toward the stomach. Efferent fibers originating from the nucleus ambiguus innervate striated muscles in the proximal esophagus, initiating pharyngeal-esophageal contraction, while those from the dorsal motor nucleus target smooth muscle in the distal esophagus via both direct preganglionic synapses and enteric neuron modulation, ensuring sequential peristalsis through central pattern generators in the brainstem. This dual innervation allows precise control of esophageal motility, preventing reflux and facilitating efficient food transit. Vagal efferents exert significant control over gastrointestinal secretory and motor functions, including stimulation of gastric acid production through co-release of (GRP) from nerve terminals, which binds to receptors on antral G cells to trigger secretion and subsequent activation via and pathways. In the intestines, the vagus modulates motility patterns such as the (MMC), a fasting-state cyclic activity that clears residual contents; while enteric circuits drive intestinal MMC propagation, vagal cholinergic input primarily regulates its gastric initiation and overall coordination to maintain interdigestive propulsion. Additionally, vagal stimulation induces pancreatic exocrine secretion, including for digestion, for protein digestion, and for lipid digestion, mediated by preganglionic fibers synapsing on intrapancreatic ganglia. Afferent vagal pathways provide critical sensory feedback integrating respiratory and gastrointestinal , including from pulmonary stretch receptors that detect inflation and elicit the Hering-Breuer to terminate inspiration and avert overdistension via inhibitory signals to the respiratory centers in the medulla. In the gut, vagal afferents incorporating chemoreceptors sense luminal toxins or changes, relaying emetic signals centrally to coordinate through activation of the tractus solitarius and efferent vagal outputs to abdominal muscles and sphincters.

Endocrine and immune modulation

The vagus nerve exerts influence on endocrine functions through its renal and hepatic branches, as well as indirect effects on urogenital processes. Vagal afferents provide tonic restraint on renin release from the kidneys, thereby modulating the renin-angiotensin-aldosterone system (RAAS) to help regulate blood pressure and fluid balance. The hepatic branch of the vagus nerve plays a key role in regulating hepatic glucose production, including modulation of glycogenolysis during fasting states to maintain energy homeostasis. In the urogenital system, while direct vagal innervation is limited, evidence from injury models suggests potential sprouting of vagal fibers to the bladder, contributing to detrusor muscle contraction through neuroplastic adaptations. A prominent role of the vagus nerve in immune modulation is mediated by the pathway, discovered in the early , which involves efferent vagal signaling to peripheral immune cells. This pathway activates alpha-7 nicotinic receptors (α7nAChR) on macrophages, inhibiting the release of pro-inflammatory s such as tumor necrosis factor-alpha (TNF-α) and mitigating cytokine storms during conditions like . As of 2025, noninvasive and implantable (VNS) has been approved by the FDA for treating inflammatory disorders such as , harnessing this pathway to reduce without broad , with ongoing clinical trials exploring further applications. Through the gut-brain axis, vagal afferents detect and transmit signals from enteroendocrine cells in the intestine, particularly (GLP-1), which promotes and regulates by relaying metabolic information to the . This vagal signaling also links to gut microbiome modulation, as microbial metabolites can activate vagal pathways to influence host behavior and immune responses, fostering bidirectional communication between the and . Vagal tone further modulates the stress response by projecting to the hypothalamic-pituitary-adrenal (HPA) axis, where it helps regulate release to counteract excessive activation during . Reduced is associated with HPA axis dysregulation, contributing to elevated levels in conditions such as anxiety and , highlighting the nerve's role in psychoneuroimmunological balance.

Clinical significance

Disorders and pathology

Diabetic represents a key manifestation of vagal neuropathy in patients with long-standing diabetes mellitus, characterized by delayed gastric emptying without mechanical obstruction due to impaired vagal innervation of the . This condition arises from affecting the vagus nerve's parasympathetic fibers, leading to symptoms such as , , early satiety, and . Diagnosis is confirmed through gastric emptying scintigraphy, the gold standard test, which quantifies retention of a radiolabeled meal, with more than 10% retention at 4 hours indicating delayed emptying. Vagal preganglionic lesions resulting from strokes, particularly those involving the where vagal nuclei reside, can disrupt parasympathetic outflow and laryngeal/pharyngeal innervation. Such lesions often manifest as due to impaired swallowing coordination from involvement, affecting up to 47% of stroke patients. Additionally, loss of contributes to autonomic imbalance, including from unopposed sympathetic activity, as part of broader post-stroke . Congenital disorders like , caused by a 22q11.2 deletion, are associated with vagal hypoplasia stemming from disrupted cell migration during embryonic development. This vagal underdevelopment frequently leads to congenital heart defects, including conotruncal types such as or interrupted , occurring in approximately 75% of affected individuals, with conotruncal defects present in about 30-40%. Idiopathic vagal dysfunction may present as vagal , where altered vagal signaling contributes to recurrent headaches accompanied by autonomic features like and , potentially linked to vagus-mediated neuroinflammatory pathways. Another idiopathic form involves from vagal failure, characterized by a drop in systolic of at least 20 mmHg upon standing, leading to and syncope. of these conditions often employs tilt-table testing to assess vagal integrity, reproducing symptoms under controlled orthostatic stress to confirm autonomic impairment. Post-2020 research has highlighted links between (post-acute sequelae of infection) and involving reduced , evidenced by vagus nerve inflammation and decreased in affected patients. This manifests as persistent symptoms including fatigue, , and gastrointestinal dysmotility, with studies showing vagal impairment in up to 30-50% of cases through autonomic function tests.

Therapeutic stimulation

Vagus nerve stimulation (VNS) involves the electrical activation of the vagus nerve to treat various neurological and inflammatory conditions, primarily through implanted or non-invasive devices that target afferent pathways to modulate brain activity and systemic responses. Implanted VNS devices, first approved by the U.S. Food and Drug Administration (FDA) in 1997 as an adjunctive therapy for reducing seizure frequency in adults and adolescents over 12 years with drug-resistant epilepsy, consist of a pulse generator implanted in the chest that delivers intermittent electrical pulses to the left cervical vagus nerve. Standard stimulation parameters include a frequency of 20-30 Hz, pulse width of 250-500 microseconds, and a duty cycle of 30 seconds on followed by 5 minutes off, with current output adjusted to 0.25-2.5 mA based on patient tolerance. In clinical trials, approximately 50% of responders achieve at least a 50% reduction in seizure frequency after one to two years, attributed to desynchronization of cortical epileptiform activity via brainstem projections. The FDA expanded approval in 2005 for the adjunctive long-term treatment of chronic or recurrent depression in adults aged 18 and older who have not responded to at least four adequate antidepressant trials, with sustained response rates of 20-40% observed in open-label extensions. VNS is also FDA-approved for heart failure in patients with NYHA class III (since 2015) and under investigation for conditions like inflammatory bowel disease and stroke recovery as of 2025. Non-invasive transcutaneous VNS (tVNS) targets the auricular branch of the vagus nerve, accessible via the , using handheld devices that deliver low-level electrical pulses without surgical implantation. The gammaCore device received FDA clearance in 2017 for the acute treatment of pain associated with episodic in adults, and subsequently for acute and preventive treatment of in patients aged 12 and older. Emerging evidence supports its use for anxiety disorders, with randomized controlled trials demonstrating reductions in generalized anxiety symptoms through twice-daily 2-minute sessions at 25 Hz, though full FDA approval for anxiety remains pending as of November 2025. The therapeutic effects of VNS primarily arise from afferent fiber activation, which projects to the nucleus tractus solitarius and subsequently influences key brainstem nuclei, leading to increased norepinephrine release and serotonin modulation that enhance mood regulation and thresholds. Additionally, efferent pathways activate the , suppressing pro-inflammatory cytokines such as tumor factor-alpha via alpha-7 nicotinic receptors on immune cells, thereby mitigating without . As of 2025, ongoing clinical trials are investigating VNS for neurodegenerative and autoimmune diseases. In , preliminary evidence from trials suggests enhancements in through locus coeruleus-norepinephrine signaling, with reports of improved scores in patients after 12 weeks of stimulation. For , the RESET-RA trial demonstrated that implanted VNS reduced disease activity scores by 40% and lowered serum levels (e.g., interleukin-6 and ) in treatment-resistant patients, supporting its potential as a non-pharmacologic therapy.

Surgical interventions

Surgical interventions involving the vagus nerve primarily focus on procedures, which sever specific branches or trunks of the nerve to reduce secretion in the treatment of . Historically, emerged as a key surgical approach in the mid-20th century; the first truncal was performed by Latarjet in 1921, but it gained widespread adoption following Dragstedt's work in 1943, becoming a standard treatment for intractable duodenal ulcers by the . This procedure interrupts parasympathetic innervation to the , thereby decreasing acid production and promoting ulcer healing. Vagotomy is classified into three main types based on the extent of nerve disruption. Truncal vagotomy involves complete transection of the anterior and posterior vagal trunks at the , affecting innervation to the entire abdominal viscera and requiring a drainage procedure like to prevent . Selective vagotomy targets only the gastric branches, sparing the hepatic and celiac divisions to preserve innervation to the liver, , and intestines, thus reducing some postoperative complications. Highly selective (or ) vagotomy, developed in the 1970s, denervates only the branches supplying the acid-secreting in the gastric fundus and body, leaving the nerves of Latarjet intact to maintain pyloric and antral function without needing drainage. Despite its efficacy in reducing ulcer recurrence rates to below 10% in early studies, vagotomy has become rare since the 1990s due to the advent of inhibitors (PPIs), which effectively manage acid hypersecretion medically. Common complications include , characterized by rapid gastric emptying leading to gastrointestinal and vasomotor symptoms, with an incidence of 20-50% among patients reporting symptoms and up to 14% experiencing significant cases after truncal vagotomy with drainage. Other risks encompass , gallstone formation, and nutritional deficiencies from altered motility. In contemporary practice, vagus nerve interventions emphasize preservation rather than severance. During for , surgeons aim to maintain vagal integrity to support postoperative gastrointestinal function and potentially improve long-term outcomes, as vagal transection has been associated with increased dysmotility despite similar compared to preservation techniques. Intraoperative nerve monitoring is routinely employed in to safeguard the , a vagal , reducing risk from 5-10% in visual identification alone to about 2-5% with electromyography-based monitoring, thereby preventing vocal cord . Surgical techniques for vagotomy have evolved from open to minimally invasive approaches. Laparoscopic vagotomy, introduced in the 1990s, uses small incisions and endoscopic tools for truncal or highly selective procedures, offering reduced postoperative pain, shorter hospital stays, and equivalent efficacy to open while minimizing complications. Nerve integrity monitoring, involving electrodes on the vagus or , provides real-time feedback during dissection to enhance precision and safety across both open and laparoscopic methods.

History and nomenclature

Etymology

The term "vagus" for the tenth cranial nerve originates from the Latin adjective vagus, meaning "wandering" or "vagrant," a designation that reflects the nerve's extensive and meandering distribution throughout the body. This nomenclature was introduced by the English anatomist in his seminal 1664 work Cerebri anatome, where he described the nerve as the "vagus" due to its far-reaching branches from the to the viscera. Willis's choice of term, drawn from vocabulary denoting mobility and diffusion, marked a shift toward more descriptive anatomical naming conventions in the . Historically, the vagus nerve was also known as the pneumogastric nerve, a name emphasizing its innervation of the lungs (pneumo-) and (gastric-), particularly in earlier before the adoption of Willis's terminology. In modern , it is designated as cranial X (CN X), following the standardized numbering system established in the based on its sequential emergence from the . The Latin vagus itself traces etymologically to Proto-Italic wagos, likely derived from the Huog-o- (suggesting bending or turning), which influenced related terms in denoting straying or unsteady motion, such as Old Norse vakka ("to stray"). This linguistic heritage underscores the term's aptness in for a characterized by its broad, irregular .

Historical discoveries

The vagus nerve's anatomical features were first described in detail by the physician in the AD, who noted its extensive branching to the viscera, including connections to the that suggested a role in digestive functions, earning it an early association as the "nerve of the ." Galen's observations, based on dissections of animals like pigs, highlighted the nerve's path from the through the and to abdominal organs, laying foundational knowledge for its visceral innervation despite limitations in human access. During the , advanced this understanding through precise illustrations in his 1543 work De humani corporis fabrica, depicting the vagus nerve's cranial origins and branching patterns among the , including its separation from the glossopharyngeal and contributions to laryngeal and pharyngeal structures. 's drawings corrected some of Galen's animal-based interpretations by emphasizing human-specific anatomy, such as the recurrent laryngeal branches, which influenced subsequent neuroanatomical studies. In the 19th century, Claude Bernard's experimental physiology in the 1850s elucidated the vagus nerve's functional roles, demonstrating through animal vivisections that sectioning the nerve led to disruptions in visceral regulation, including gastric motility changes like dilation due to loss of parasympathetic tone. Bernard's work, including vagotomy experiments on rabbits and frogs, showed the nerve's excitatory effects on digestion and inhibitory influence on the heart, establishing it as a key component of autonomic control. Building on this, William Bayliss and Ernest Starling's 1902 experiments on pancreatic secretion revealed a humoral mechanism via secretin, independent of direct vagal innervation, though they acknowledged the nerve's modulatory role in enhancing digestive responses to neural stimuli. The 20th century brought insights into the vagus nerve's neurotransmitter-mediated effects, with Otto Loewi's 1921 frog heart experiments identifying "Vagusstoff" (later acetylcholine) as the substance released upon vagal stimulation to slow heart rate, confirmed through bioassays linking electrical nerve activity to cardiac inhibition. This discovery, bridging neural signaling and electrocardiographic observations, underscored the nerve's parasympathetic dominance in cardiovascular regulation. In the early 21st century, Kevin Tracey's 2002 identification of the "inflammatory reflex" demonstrated that efferent vagal signaling inhibits cytokine release via the cholinergic anti-inflammatory pathway, offering a neural basis for modulating systemic inflammation in conditions like sepsis. Recent 21st-century research has emphasized the vagus nerve's role in the gut-brain axis, particularly its interactions with the ; studies from the 2010s onward show that vagal afferents transmit microbial metabolite signals (e.g., ) to the , influencing , , and , as evidenced in models of transplantation altering vagal-dependent behaviors. These findings, integrating metagenomic and neurophysiological data, highlight the nerve's bidirectional communication in -gut-brain signaling, with implications for disorders like and .