A Review of Vagus Nerve Stimulation for Disease: Comprehensive Theory and Evidence for Mechanisms of Action.

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  FIGURE 1. Vagus nerve pathway from the brain through various organs and various vagus nerve stimulation (VNS) technologies. (A) Transcutaneous auricular VNS (taVNS) by Transtimulation Research (FDA‐cleared) and tVNS technologies (CE mark Approved) and typical settings of stimulation parameters. (B) Percutaneous auricular VNS (paVNS) devices and stimulation parameters, Drug Relief (FDA‐cleared) by DyAnsys and IB‐STIM (FDA‐cleared) by Innovative Health Solutions (now NeurAxis). (C) Transcutaneous cervical VNS (tcVNS) by GammaCore (FDA‐cleared) and its stimulation waveforms. (D) Invasive (iVNS) by LivaNova (FDA‐approved) and by SetPoint Medical (FDA‐approved) with programmable parameters. (E) Vagal‐blocking (vBloc) therapy by the MAESTRO Rechargeable system (FDA‐approved) and stimulation parameters. The device is discontinued in the U.S. market. (F) Focused ultrasound stimulation (FUS) by SecondWave Systems for noninvasive stimulation of anti‐inflammatory cellular pathways within the spleen and via feedback circuits to the brain for modulating immune function. (G) Optogenetic VNS (oVNS) uses laser light to activate genetically encoded light‐sensitive ion channels in preclinical studies. (H)…

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  FIGURE 2. (A) Vagus nerve cross‐sectional composition. (B) Illustration of the relationship between stimulation power and fiber activation of different vagal fibers.

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  FIGURE 3. Schematic illustration of VN pathways and their neuromodulatory effects in the brain. VNS initiates ascending afferent signals from the nodose ganglion to the nucleus tractus solitarius (NTS), subsequently activating critical brainstem nuclei including locus coeruleus (LC), dorsal raphe nucleus (DRN), ventral tegmental area (VTA), hippocampus, paraventricular nucleus (PVN), and nucleus basalis of Meynert (NBM). These nuclei release key neuromodulators—norepinephrine (NE), serotonin (5‐HT), dopamine (DA), brain‐derived neurotrophic factor (BDNF), corticotropin‐releasing hormone (CRH), and acetylcholine (ACh). Major target structures include the cerebellum, the parabrachial nucleus (PBN), the periaqueductal gray (PAG), the thalamus, the amygdala, the hypothalamus, the basal forebrain, the nucleus accumbens, the basal ganglia, the striatum, the prefrontal cortex, the anterior cingulate cortex (ACC), and the cerebral cortex, collectively orchestrating therapeutic effects of VNS across diverse conditions.

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  FIGURE 4. VNS‐mediated anti‐inflammatory and protective effects. Upon immune challenge, the activation of TLRs triggers activated macrophages and other immune cells to release inflammatory mediators, including cytokines. These cytokines subsequently activate vagal afferents, which modulate the hypothalamic–pituitary–adrenal (HPA) axis and stimulate cortisol release. This cascade ultimately suppresses proinflammatory cytokine production while promoting anti‐inflammatory cytokine secretion. Vagal efferent fibers exert anti‐inflammatory actions via the cholinergic anti‐inflammatory pathway. Within the spleen, norepinephrine (NE) released by the splenic nerve and acetylcholine (ACh) released by ChAT‐positive T cells inhibit macrophage activation via β‐adrenergic receptors (βAR) and α7 nicotinic acetylcholine receptors (α7nAChR), downregulating JAK2‐STAT3 and NF‐κB pathway, thereby shifting macrophages toward an anti‐inflammatory M2 phenotype. Hepatic and enteric neurons similarly reduce inflammation by ACh‐mediated modulation of Kupffer cells and resident immune cells. Additionally, VNS also directly influences microglia in the brain. NE and ACh release lead to activation of the cholinergic…

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  FIGURE 5. Mechanistic overview of the major effects of vagus nerve stimulation (VNS) on physiological systems. In the cardiovascular system, parasympathetic nerves release acetylcholine (ACh) onto the sinoatrial (SA) and atrioventricular (AV) nodes, resulting in decreased heart rate, while sympathetic nerves release norepinephrine (NE) and epinephrine (E), which increase heart rate and contractility. VNS promotes parasympathetic activity and suppresses sympathetic tone, thereby collectively reducing heart rate and enhancing baroreflex sensitivity, which promotes balanced autonomic regulation. In the pulmonary system, the intensity of VNS determines its effect: High‐intensity stimulation promotes bronchoconstriction, while low‐intensity stimulation supports bronchodilation. In the metabolic system, VNS reduces hepatic glucose production and differentially modulates insulin secretion, with afferent vagal activation suppressing insulin release and efferent vagal stimulation promoting insulin secretion. In the gastrointestinal system, VNS increases gastric receptive relaxation and enhances gastric emptying, while promoting microbial diversity and balance. In the renal system, VNS enhances…

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  FIGURE 6. Brain‐gut axis: vagal network in gastrointestinal function and inflammatory control. Vagal afferent fibers (yellow path) transmit mechanical and chemical stimuli from the gut to the nucleus tractus solitarius (NTS) in the brainstem, originating from terminals that include intraganglionic laminar endings (IGLE), intramuscular arrays (IMA), and mucosal afferents. These afferents interact with enteroendocrine cells, enterochromaffin cells, and neuropods, which release neurotransmitters like glutamate, serotonin (5‐HT), and gut hormones in response to luminal stimuli. The gastrointestinal tract also sends sensory afferents to the spinal cord via the dorsal root ganglia (pink path). Vagal efferent fibers (red path), terminating in the myenteric and submucosal plexi, modulate gastrointestinal motility, secretion, and immune function. Epithelial injury can activate the macrophage to release cytokines, which in turn activate the vagal afferent pathway. In response, vagal efferent modulates enteric neurons to release ACh, which binds to α7 nicotinic acetylcholine receptors (α7nAChRs) on immune cells, glia, and epithelial cells, suppressing proinflammatory cytokine release and supporting…

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  FIGURE 7. Schematic representation of closed‐loop autonomic neuromodulation paradigms. By definition, closed‐loop neuromodulation requires a continuous sensing modality that continuously modifies the stimulation parameter (yellow arrows = afferent sensing pathway; purple arrows = VNS device control, brown arrows = efferent regulation pathway). (A) Closed‐loop neuroplasticity‐inducing autonomic neuromodulation. VNS can be delivered through two triggering approaches: (1) physiologically triggered stimulation using real‐time biosignals including electroencephalograph (EEG), electrocardiography (ECG), and respiration patterns to initiate VNS based on detected physiological states automatically; or (2) manually triggered stimulation through patient self‐activated therapy or clinician‐administered in‐clinic training session. Both approaches aim to enhance neuroplasticity outcomes through precise timed vagal neuromodulation. (B) Closed‐loop cholinergic anti‐inflammatory autonomic neuromodulation. Future closed‐loop autonomic neuromodulation is under development, in which inflammation is sensed with Autonomic Neurography (ANG) that can then drive autonomic neuromodulation delivery or hone in on…