Invasive Vagus Nerve Stimulation (iVNS) involves surgically implanting a vagus nerve stimulation device into the human body. The vagus nerve stimulator consists of stimulating electrodes implanted around the vagus nerve through a small cervical incision and a pulse generator implanted in the subclavian region (6, 7). The device delivers electrical stimulation every few minutes. Additionally, patients can use a wristband magnet to trigger the pulse generator, providing an extra dose of stimulation. Over several weeks following implantation, the current is gradually adjusted to the target level based on patient tolerability (7). The electrode types include helical electrodes that wrap around the vagus nerve and intravascular electrodes placed within the internal jugular vein. Helical electrodes are commonly used for broad nerve activation, while intravascular electrodes are designed to reduce off-target effects and enhance stimulation specificity (8). The complications of VNS include those related to surgery and those associated with the device and nerve stimulation. During VNS implantation, the implanted device is typically tested using one pulse train lasting 1 min with specific parameters (1 mA, 550 μs, 20 Hz). This phase may result in bradycardia or even cardiac arrest (6, 9). Surgical complications such as peritracheal hematoma, infection, and vagus nerve injury have also been reported (10). Complications associated with the device and nerve stimulation include delayed arrhythmias (bradycardia, cardiac arrest), laryngopharyngeal dysfunction (hoarseness, dyspnea, and coughing) due to stimulation of the recurrent laryngeal nerve, obstructive sleep apnea, phrenic nerve stimulation caused by proximity, tonsillar pain resembling glossopharyngeal neuralgia, and sternocleidomastoid muscle spasms (6, 11–13). The iVNS therapy system is indicated for stimulating the left vagus nerve located within the carotid sheath, specifically below the point where the superior and inferior cervical cardiac branches diverge from the vagus nerve (14). Typically, the left-sided cervical vagus nerve is chosen as the implantation site for the stimulating electrodes because stimulating the right-sided vagus nerve can lead to severe adverse reactions. The right vagus nerve innervates the sinoatrial node and parts of the myocardium, and nerve stimulation can cause various cardiac side effects, such as cardiac arrest. In comparison to the right-sided vagus nerve, the left-sided vagus nerve innervates the atrioventricular node, resulting in relatively milder adverse reactions (7). Furthermore, studies have shown that stimulation frequencies of 50 Hz or higher during VNS can cause significant and irreversible damage to the vagus nerve. To minimize adverse events associated with direct stimulation of the carotid sheath, stimulation frequencies were randomly selected within the range of 20–30 Hz (14, 15). AspireSR is a pulse generator that detects heart rate through specific detection algorithms, recommended for use in cardiac patients due to the cardiac side effects of VNS (16). Additionally, SenTiva VNS has a cardiac detection feature that not only detects heart activity but also allows for changes in VNS output parameters, making VNS therapy more tailored and safe. The SenTiva device is smaller in size compared to AspireSR. For pediatric patients whose development is not yet complete, having an appropriately sized implantable pulse generator is particularly crucial. Moreover, for those seeking smaller surgical incisions and aesthetic considerations, SenTiva represents a favorable choice. Despite being withdrawn from clinical use by the U.S. Food and Drug Administration in 2020 due to reset errors, SenTiva regained approval in 2022 (16, 17).

Invasive Vagus Nerve Stimulation requires surgical implantation, while non-invasive Vagus Nerve Stimulation avoids trauma and is more cost-effective. nVNS devices stimulate the VN at specific body surface sites to achieve therapeutic effects. nVNS comprises transcutaneous auricular Vagus Nerve Stimulation (taVNS) and transcutaneous cervical Vagus Nerve Stimulation (tcVNS), relying on the distribution of vagal afferents in the ear and neck, respectively (18). taVNS transmits signals by stimulating the auricular branch of the vagus nerve (ABVN). Peuker and Filler found anatomical structures in the ear—such as parts of the ear canal and auricle—that send their afferent information via vagal branches. The optimal site for stimulation is the cymba conchae, as ABVN primarily exists in the skin surrounding the cymba conchae (19, 20). tcVNS involves stimulation of the vagus nerve within the carotid sheath, with the stimulation signals activating the VN through the skin and other tissues near the carotid sheath, thereby inducing vagus nerve action potentials. tVNS can be administered using various devices, such as the transcutaneous Vagus Nerve Stimulation device NEMOS and the neck-stimulating gammaCore (21). The use of VNS is restricted to the left vagus nerve, while tVNS might not have this limitation. Research by Chen et al. suggests that unilateral VN stimulation transmits only on one side, while unilateral ABVN stimulation integrates within the nucleus tractus solitarii and then transmits bilaterally via the vagus nerve. Results indicate that right transcutaneous vagus nerve stimulation is as safe as left transcutaneous vagus nerve stimulation (22). Studies by He et al. and Hein E et al. respectively employed bilateral transcutaneous vagus nerve stimulation in clinical trials involving children and adults. No adverse cardiac-related reactions were observed in these experiments (23, 24). Although nVNS is relatively safe, it is not without side effects, which include localized skin irritation caused by electrode placement, headaches, nasopharyngitis, gastrointestinal reactions, palpitations, and vocal cord hoarseness (14). Different devices have varying stimulation methods, frequencies, durations, and other parameters. Currently, there are no standardized optimal stimulation parameters, nor is there literature establishing superiority between taVNS and tcVNS stimulation methods.

Since the 1990s, numerous studies have evidenced the favorable effects of VNS in reducing seizure frequency in epilepsy patients (25, 26). In 1997 and 1999, the American Academy of Neurology (AAN) Therapeutics and Technology Assessment Subcommittee conducted two evaluations of VNS therapy for epilepsy. The committee concluded that VNS is suitable for adults and adolescents aged 12 and above with refractory partial-onset seizures (excluding those suitable for potentially curative surgical resection) (27, 28). Due to the infrequent occurrence of complete seizure remission with VNS and its invasiveness and high cost, VNS is deemed more appropriate for individuals intolerant to or not benefiting from antiseizure medication (ASMs) (28). Subsequently, the feasibility and safety of VNS were further acknowledged, with observed reductions in seizure frequency over time (29, 30). Moreover, during the use of invasive VNS in epilepsy patients, the blood concentrations of ASMs remained unaffected by VNS and could even reduce the dosage of ASMs (31, 32). Currently, invasive Vagus Nerve Stimulation has been approved for epilepsy treatment in numerous countries and regions, including the European Union, the USA, Canada, China, and Japan (33). In recent years, although iVNS has shown promising results in the treatment of drug-resistant epilepsy, it is still chosen only after antiseizure medications and surgical options have been ruled out, primarily due to its invasive nature and cost-effectiveness concerns. This is largely due to its invasive nature and cost-effectiveness concerns. Studies on the cost-effectiveness of iVNS have demonstrated a significant reduction in epilepsy-related direct medical expenses following VNS implantation compared to pre-implantation costs (34–36). Evans et al. (37) included the cost of device implantation in their analysis and obtained similar results. However, the reduction in costs is observed only when the treatment is effective and not prematurely discontinued due to ineffectiveness or severe side effects. Additionally, surgical and other medical costs vary across countries, leaving the cost-effectiveness of VNS still uncertain (33).

Further research has found that VNS is effective for various types of epilepsy and can serve as an adjunctive therapy for both focal and generalized seizures. However, in clinical practice, iVNS is more commonly used for patients with focal seizures. Some researchers suggest this could be because focal seizures may develop a higher likelihood of drug resistance, or it might relate to the relatively lower incidence of refractory generalized seizures in adults (33). Recent studies have also discovered positive effects of VNS on drug-resistant generalized seizures, particularly in cases of genetic generalized epilepsy, significantly reducing seizure frequency and epilepsy-related hospitalizations among these patients (38).

Invasive Vagus Nerve Stimulation can also be used as adjunctive therapy for pediatric epilepsy, with abundant research confirming its effectiveness and safety (12, 39). Children’s response to invasive VNS (reduction in seizure rate by ≥50%) is similar to that of adults, and seizure frequency tends to decrease with prolonged treatment (12, 40). Besides reducing seizure rates, iVNS has shown favorable outcomes in seizure duration, severity, post-seizure severity, quality of life, and overall clinical improvement (39–41). iVNS is similarly effective for pediatric or adolescent epilepsy syndromes, including Dravet syndrome (DS), Lennox–Gastaut syndrome (LGS), hypothalamic hamartomas, epileptic encephalopathies, Rett syndrome, and tuberous sclerosis complex (TSC) (39, 42–49). Initially, the FDA approved iVNS for patients aged 12 and older. However, Elliott et al. found no significant differences in treatment efficacy or complications between children under 12 and older children (12 to under 18 years old) (50). The American Academy of Neurology guideline development subcommittee suggested that for children with partial and generalized seizures who are not suitable for brain surgery, iVNS could be considered (29). Subsequent clinical studies reported the use of iVNS in children around 5 years old, revealing more pronounced improvements in quality of life and cognitive outcomes in the younger age group (under 5 years old) (41). Thus, for children with drug-resistant epilepsy, considering VNS implantation early on could mitigate the adverse effects of epilepsy on their development.

Studies have suggested that Vagus Nerve Stimulation can serve as an adjunctive therapy to control seizures during pregnancy for women with epilepsy (51, 52). There are reported cases where expectant mothers undergoing iVNS treatment for epilepsy during pregnancy led to fetal anomalies, including unilateral congenital glaucoma, mild malformations, and heart murmurs (52, 53). However, in these cases of neonatal anomalies, these pregnant women were also on multiple antiseizure medications in addition to VNS therapy. Ding et al. (54) reviewed and analyzed past relevant literature, concluding that VNS during pregnancy is relatively safe and effective for both the fetus and the mother, suggesting there’s no need to deactivate VNS during pregnancy. However, clinical trials involving VNS therapy for pregnant women with epilepsy are scarce, and the sample sizes in existing case reports are small. Additionally, VNS is often used in conjunction with ASMs, making it challenging to distinguish whether adverse reactions are solely attributable to VNS as an isolated factor. Therefore, further relevant experiments are necessary to determine the suitability of VNS for pregnant women.

Determining the optimal stimulation parameters for patients of different ages and those with specific seizure types or syndromes remains uncertain. The side effects and stimulation levels in invasive Vagus Nerve Stimulation might be closely related. Higher stimulation levels tend to result in higher rates and severity of side effects compared to lower stimulation levels (32). The settings recommended by manufacturers for VNS therapy in epilepsy are typically 1.5–2.25 mA with a pulse width of 250 μs and a frequency of 20 Hz. However, manufacturers only provide recommendations for therapeutic dosing and titration rather than definitive guidelines (55). Fahoum et al. attempted to explore target dosing for drug-resistant epilepsy (DRE) and inferred overall target output current and duty cycle for VNS therapy in epilepsy to be 1.61 mA and 17.1% duty cycle, respectively. Their analysis suggested that patients with longer durations of VNS therapy were more likely to respond to treatment, implying that patients with inadequate sustained dosing might still benefit from achieving target dosing. Therefore, improvements in VNS outcomes might be achieved through appropriately implementing evidence-based dosing and titration guidelines (55). Additionally, rapid titration in DRE patients results in faster clinical benefits regardless of age, and children demonstrate greater tolerance to rapid titration (56, 57). However, most of these reports assess efficacy based on response rates. In practice, while considering efficacy, it’s essential to tailor parameters differently for individuals based on their unique constraints (such as age, physique, etc.) and side effects.

Based on existing clinical trials targeting transcutaneous Vagus Nerve Stimulation (tVNS) for treating drug-resistant epilepsy, the majority of scholars widely acknowledge tVNS as an effective, cost-efficient, and relatively safe adjunct therapy for such patients (58–63). These studies assessed the effectiveness of tVNS in terms of seizure frequency, severity, quality of life, and epilepsy rating scales. Additionally, compared to invasive Vagus Nerve Stimulation, research indicates that transcutaneous Vagus Nerve Stimulation exhibits milder adverse reactions (60, 61, 63, 64). tVNS has also shown positive clinical outcomes for post-stroke epilepsy (65). Furthermore, studies have clinically validated the safety and efficacy of transcutaneous auricular Vagus Nerve Stimulation in treating childhood epilepsy (24). These findings suggest that tVNS represents a highly promising adjunct therapy for drug-resistant epilepsy applicable to both adults and children. However, differences exist in the devices used, stimulation parameters, and duration of studies in these clinical trials, hence the optimal stimulation parameters for tVNS remain unclear (66, 67), necessitating further research and exploration. tVNS holds significant potential in epilepsy treatment, given its non-invasive nature and relatively high safety profile, making it more acceptable to patients. However, there is currently no research indicating how to choose between tVNS or iVNS for patients with drug-resistant epilepsy. Apart from their efficacy in treating epilepsy, the choice between iVNS and tVNS in practice also involves cost-effectiveness considerations, which require further supporting evidence.

In clinical trials of Vagus Nerve Stimulation for epilepsy treatment, an unexpected discovery emerged regarding VNS’s regulatory effect on human emotions, suggesting a sustained improvement in mood (68, 69). These studies revealed the potential of VNS in treating depression. Early studies predominantly involved treatment-resistant depression patients (those unresponsive to various antidepressant therapies, including medications and electroconvulsive therapy). Following VNS treatment, these patients exhibited notable improvements in their 28-item Hamilton Rating Scale for Depression (HRS-D-28), Montgomery-Åsberg Depression Rating Scale (MADRS), and Clinical Global Impression Improvement score (CGI-I1 or 2) (70, 71). Additionally, these patients showed good tolerance to the treatment (72, 73). In subsequent randomized controlled trials, treatment-resistant depression patients receiving adjunctive VNS showed better performance on depression-related assessment scales compared to those undergoing conventional therapy alone, indicating the positive effects of adjunctive VNS (74, 75). Furthermore, apart from clinical efficacy, VNS also enhanced their quality of life, reduced mortality, and suicide rates (5, 75, 76). However, John et al. found in their experiments that the short-term efficacy (10 weeks) of VNS as an adjunctive treatment for treatment-resistant depression was not significant (77). Moreover, other experiments have shown that VNS-induced improvement in symptoms of depression accumulates over time in the short term and persists (5, 75, 78), suggesting that longer treatment durations might be necessary to achieve the desired effects when using VNS for depression. In 2005, VNS was approved for depression treatment. The National Institute for Health and Care Excellence (NICE) released guidelines for the use of invasive Vagus Nerve Stimulation in treating treatment-resistant depression, suggesting its consideration when patients have failed multiple antidepressants and psychological therapies, including electroconvulsive therapy or other forms of neurostimulation, such as VNS. Current studies mostly demonstrate iVNS as an effective anti-depression treatment, although the evidence literature is limited and requires further substantiation of its efficacy and safety.

Additionally, VNS might offer promising prospects for pregnant women and children with depression. Antidepressants have a range of effects on pregnant women, such as miscarriage, premature birth, fetal malformations, and neonatal adaptation syndrome (79). In this context, VNS as a treatment approach provides a new avenue. A case report from 2005 detailed significant relief from pregnancy-related depression in a patient receiving a combination of antidepressants and VNS therapy (80). There have been noticeable improvements in emotional and depression-related assessment scores among pediatric patients as well (81). However, the effectiveness and safety of VNS therapy for treatment-resistant depression in children and pregnant women have not been well elucidated. Therefore, more research is needed to determine specific criteria for selecting candidates for iVNS treatment within depression.

Transcutaneous Vagus Nerve Stimulation is also effective in treating depression. Several clinical trials using tVNS for treatment-resistant depression have demonstrated its effectiveness and safety. Combining tVNS with standard treatment offers greater benefits to patients (23, 82–85). Furthermore, the efficacy of tVNS in treating depression is comparable to that of citalopram (an antidepressant), suggesting that tVNS could not only serve as an adjunctive therapy but also potentially as an alternative treatment (86). However, there is still a lack of high-quality evidence regarding the effectiveness of tVNS for different types and severity levels of depression (87).

Ischemic stroke and hemorrhagic stroke are two types of strokes, both with serious consequences that lead to a range of lingering effects impacting patients’ daily lives and social interactions. Vagus Nerve Stimulation serves as an auxiliary method in conventional rehabilitation treatments, displaying promising outcomes in the treatment of ischemic strokes. In recent years, there has been a growing number of animal experiments and clinical trials investigating VNS treatment for ischemic strokes. However, the application of VNS therapy is excluded for hemorrhagic strokes.

Disorders of consciousness (DOC) refer to impaired consciousness following severe brain or neurological injury. Based on their neurological behavioral functions, DOC can be classified into four categories: coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), and emergence from MCS to higher levels of consciousness (eMCS) (100). In recent years, the utilization of vagus nerve stimulation (VNS) techniques has sparked considerable interest among neuroscientists for treating disorders of consciousness. These techniques offer a promising neuroregulatory treatment method for the rehabilitation of DOC patients.

Studies investigating the use of vagus nerve stimulation in treating disorders of consciousness have explored various etiologies, including traumatic brain injury (TBI) (101), stroke (102), hypoxic–ischemic encephalopathy (HIE) (103), and intracerebral hemorrhage (104). Vagus nerve stimulation, whether invasive VNS (105) or non-invasive VNS (101, 103, 106), has shown favorable outcomes in treating DOC. In these studies, assessment of consciousness disorders includes behavioral assessment and brain function evaluation. Behavioral assessment of DOC patients primarily utilizes the revised Coma Recovery Scale-Revised (CRS-R). Nearly all studies using CRS-R as a primary outcome measure reported significant improvements in scores post-intervention (101, 103, 105–107), except for Wang et al.’s study (which did not find significant changes in the scale) (108). Additionally, efficacy might increase over extended periods of time (109). Brain function assessment via scale scoring includes electroencephalograms (EEG) (105), positron emission tomography (PET) (105), and functional magnetic resonance imaging (observed changes in default mode networks and cerebral blood flow) (103, 104), providing evidence of cerebral changes post-stimulation. Yu et al. (104) found that individuals who responded to auditory stimulation (RtAS) had demonstrated better therapeutic outcomes following tVNS compared to those who did not respond, suggesting that preserved auditory function might be a key preexisting factor for tVNS responders among DOC patients.

Research on VNS has primarily focused on patients classified as VS/UWS or MCS. Wang observed significant alterations in cortical connectivity in specific brain regions through electroencephalographic observation in MCS patients, with noticeable changes in interbrain connectivity in MCS patients (108). Noe et al. also found a significant improvement in CRS-R scores in MCS patients with tVNS, while VS/UWS patients did not significantly benefit (101). However, other studies have indicated that VS/UWS patients also benefit from vagus nerve stimulation (104). In summary, the specific target population for the application of VNS in DOC remains inconclusive. In a review of VNS treatment for DOC, the author concluded that existing studies had insufficient sample sizes, low quality (lack of strict adherence to methodology, inadequate sample size selection, reliance on single outcome indicators to assess consciousness levels, and short monitoring follow-up), thus preventing definitive conclusions or recommendations (110).

Alzheimer’s disease (AD) typically starts subtly and gradually progresses, manifesting as declining cognitive abilities and memory impairments, eventually affecting normal life (111). There is not extensive research on iVNS (implantable vagus nerve stimulation) for treating Alzheimer’s disease, but the existing reports show promising outcomes. Two reports involving 27 AD patients revealed improvements or stability in Alzheimer’s disease assessment scales such as the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC+) (112, 113). Additionally, patients did not experience a significant decline in mood, behavior, or quality of life 1 year post-treatment (113). Apart from enhancing cognitive capabilities, iVNS demonstrates a positive impact on memory loss, effectively ameliorating Alzheimer’s disease symptoms. Studies indicate that iVNS enhances word recognition memory, working memory, and memory retention in language learning (114, 115). In summary, iVNS may delay AD progression and improve its symptoms. However, reports on iVNS treatment for AD are limited and have garnered little attention. This might be attributed to the fact that AD patients are mostly elderly, and the high risk of invasive vagus nerve stimulation in the elderly population cannot be overlooked.

The impact of tVNS on Alzheimer’s disease is currently under exploration in human trials (NCT04908358, NCT04877782). One study involving 140 elderly individuals will divide participants into tVNS and sham stimulation groups, receiving percutaneous vagus nerve stimulation-breathing controlled auricular electrical stimulation for 10 min (twice, with a 4-week interval). The efficacy of VNS will be determined through the Face-Name Associative Memory Exam (FNAME) and Alzheimer’s disease-related biomarkers in blood. Another study aims to explore the impact of tVNS on memory and attention by monitoring its effects on Alzheimer’s disease.

Research on the effects of tVNS on memory has also emerged. Early findings suggested that tVNS could alter associative memory performance in older individuals (116). In an experiment involving 60 healthy volunteers, tVNS did not impact word processing or overall emotional memory recognition. However, compared to sham stimulation, tVNS increased the hit rate percentage for high confidence memory words, suggesting an impact on recollective memory performance (117). Sun et al. proposed that tVNS has beneficial effects on offline working memory in healthy individuals (118). Mertens attempted to replicate the positive effects of iVNS on word recognition memory using tVNS but found no improvement in word recognition memory in healthy individuals (119). Researchers speculated that this outcome might be related to the parametric design of the stimulation. Mariana compared Mertens’ parameter settings with those used in other papers that measured successful memory outcomes, indicating that the standard “off” interval length might be critical for modulating successful memory (120). Recent studies also suggest that tcVNS can improve attention, performance, and working memory (121).

There’s substantial research on the effects of tVNS on cognition, demonstrating that electrical stimulation can enhance cognitive abilities and increase cognitive control in healthy volunteers (122–124). Studies found that tVNS modulates conflict-induced cognitive control and action execution in behavioral and electroencephalogram data (125). There are varying perspectives on the impact of tVNS on cognitive flexibility. Tona et al. suggested that tVNS does not influence working flexibility (126). However, Borges remains optimistic about the potential of tVNS to influence cognitive flexibility. In his study, he compared the effects of tVNS on core executive functions, including inhibitory control and cognitive flexibility, and suggested that tVNS might have a stronger impact on cognitive flexibility than on inhibitory control (127). In recent research, tVNS has shown promising implications for neurocognitive functional recovery in elderly patients, effectively reducing the occurrence of delayed neurocognitive recovery (dnCR) after total joint arthroplasty (TJA) in the elderly (128). Effective results were observed in cognitive impairment patients by stimulating two ear acupoints related to the heart (auricle CO15) and kidney (CO10) (129). This provides evidence for tcVNS in slowing cognitive decline in the elderly and preventing dementia.

As Alzheimer’s disease is common among the elderly, the risk of carotid atherosclerotic plaques is relatively higher due to its specific nature (111). Vargas-Caballero et al. (120) mentioned in their article that the surgical implantation of iVNS devices into the cervical vagus nerve would involve manipulating the carotid arteries, increasing the risk of plaque rupture and leading to severe complications like cerebrovascular disease. While invasive vagus nerve stimulation and its potential for greater closed-loop interventions might be preferable clinically, non-invasive vagus nerve stimulation may be a better choice for treating Alzheimer’s disease (120). tVNS demonstrates certain effects on memory capabilities and cognition, has low costs, and high safety, making it a very promising treatment for Alzheimer’s disease, which mainly affects elderly patients. However, the effectiveness of tVNS as a treatment method requires further clinical trials.

VNS has been shown to alleviate anxiety symptoms, a finding initially observed in epilepsy patients. In addition to improving epilepsy and depression, iVNS has been found to significantly reduce anxiety levels (130). George et al. (131) reported that iVNS demonstrated notable efficacy in treatment-resistant obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder (PTSD) based on Hamilton Anxiety Rating Scale (HAM-A) scores. Furthermore, OCD patients showed significant improvements in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores. Additionally, iVNS has been found beneficial in alleviating PTSD symptoms, effectively enhancing the extinction of conditioned fear (132, 133). The anxiolytic effects of iVNS appear to be frequency-dependent (134). In studies by Burger et al. (135), tVNS also accelerated fear extinction but did not lead to better retention of extinction memory after 24 h. However, Genheimer et al. (136) presented contrasting findings, as her study did not observe significant anxiety reduction with tVNS. Therefore, further research is necessary to clarify these effects.

Initially, VNS was found to alter the behavior of children with epilepsy and ASD, including changes in alertness, mood, and communication styles. It also significantly improved various aspects of quality of life (137–139). Moreover, these behavioral and developmental improvements were found to be independent of epilepsy control, further demonstrating the potential of VNS in treating ASD (140). However, research related to ASD remains highly limited, and whether VNS provides benefits for children with ASD is still an open question.

In a study using nVNS to treat gait disturbances associated with Parkinson’s disease (PD), tcVNS improved gait parameters and alleviated freezing of gait (FOG) symptoms in PD patients. Significant reductions were observed in UPDRS III scores, with notable improvements in gait parameters such as walking speed, stride length, and step velocity (141). The number of steps required for turning was particularly reduced. Additionally, Farrand et al. (142) found that higher VNS frequencies contributed to behavioral improvements and attenuation of pathological markers in PD models. These findings suggest that VNS may be a potential therapeutic option for PD, although further studies are required to validate and optimize its application in PD treatment.

Since some epilepsy patients also experience migraine symptoms, iVNS was initially found to improve migraine symptoms while alleviating epilepsy (143). Hord et al. (144) followed up with epilepsy patients undergoing iVNS treatment and similarly received positive feedback regarding iVNS’s efficacy in relieving migraine. Subsequently, iVNS was further demonstrated to be effective in alleviating chronic refractory migraine and cluster headache, although these studies involved small sample sizes (145, 146). Compared to iVNS, nVNS has attracted more attention. Both tcVNS and taVNS have been found to significantly relieve acute migraine, reduce headache days and attack frequency, lower pain intensity, and improve pain-free rates (147, 148). Studies on chronic cluster headache have shown that tcVNS can terminate pain within 11 ± 1 min (149). Additionally, nVNS has shown promising results in relieving acute cluster headaches, with sustained treatment potentially providing further benefits. However, in chronic cluster headache cohorts, tcVNS has not demonstrated significant advantages (150). Although increasing evidence suggests that VNS could bring significant benefits to patients with migraine or cluster headache, further high-quality studies are urgently needed.

Inflammation is a protective response of the body to external stimuli; however, excessive inflammation can lead to structural damage in brain function. Neuroinflammation is triggered by activated and proliferating microglia, astrocytes, and other myeloid cells, which produce pro-inflammatory cytokines, chemokines, and other inflammatory mediators, ultimately leading to neuronal damage (153). When a stroke occurs, a severe inflammatory response in the central nervous system damages neurons, and VNS’s central anti-inflammatory mechanism can alleviate this process. Several central nervous system diseases are closely associated with the occurrence of excessive inflammation, such as epilepsy and depression (154–156). The central anti-inflammatory effect of VNS has drawn significant attention and research from many scholars, with abundant and compelling evidence demonstrating its inhibitory role in inflammation. Its mechanisms primarily encompass three aspects (Figure 2): firstly, it can alter the phenotype of microglia cells; secondly, it reduces the secretion of inflammatory cytokines by activating the widespread α7nAchR receptors present in the CNS; and finally, it maintains the integrity of the blood–brain barrier, preventing inflammatory factors from damaging the central nervous system. The α7nAchR receptor is a crucial anti-inflammatory participant in the human body and is extensively expressed in the brain, including neurons, neuroglial cells, and endothelial cells. Activation of these receptors enhances the neurons’ resistance to ischemic or other types of injuries (157). Moreover, research indicates that VNS can induce an endogenous cholinergic anti-inflammatory pathway by increasing acetylcholine release through vagus nerve activation, subsequently activating α7nAchR receptors upon binding with acetylcholine (158).

Previous research indicates that the vagus nerve plays a significant role in neuroprotection (Figure 3). Various neuroprotective pathways of Vagus Nerve Stimulation (VNS) have been discovered, including the release of neurotrophic factors, modulation of neurotransmitters, and improvement in cerebral vascular regeneration.

Vagus nerve stimulation has been confirmed to produce widespread excitatory effects in various cortical regions, prompting exploration into induced cortical neuroplasticity. In the sensory and motor systems, temporarily pairing VNS with sensory stimulation or movement reorganizes neural circuits associated with sensation and movement networks (214). The cholinergic system in the basal forebrain (214, 215) and activation of the noradrenergic system in the locus coeruleus (216) may play important roles in this neural circuitry reshaping. This involves increased activity in noradrenergic neurons in the LC and cholinergic neurons in the basal forebrain (BF), which are a source of cortical-projecting cholinergic neurons (198, 217). VNS induces acetylcholine release in the basal forebrain and modulates neural activity in the BF, playing a critical role in the cortex (215). Impaired cholinergic projection in the basal forebrain cortex leads to a loss of motor network plasticity (218), while excitability and synchrony in the auditory cortex are disrupted upon blocking muscarinic receptors in the auditory cortex (219).

The sensory system comprises two pathways: the feedback (FB) and feedforward (FF) pathways. The superficial layers of the primary sensory cortex act as the hub for the feedforward (FF) pathway, while the deeper layers serve as the hub for the feedback (FB) pathway. Acetylcholine and norepinephrine, respectively, modulate the FF and FB pathways (220, 221). In the study by Kumagai et al. (199), VNS primarily activated the FF pathway within the sensory system rather than the FB pathway. This indicates that VNS-induced neural regulation can alter the FF-FB balance in the auditory cortex, known as neural gain, and the regulation of FF-FB balance induced by VNS may contribute to various clinical outcomes.