The sympathetic nervous system is complexly connected to the VN, and its parasympathetic functions and regulation of the autonomic nervous system can lead to functional and structural changes in the CNS. Environmental factors, such as psychological stress, diet, infection, and pollution, can influence the function of the VN in neurodevelopment and cognitive processes. Stress, for example, is a major modulator of VN function and excessive stress can lead to epigenetic alterations in synaptic structure and function (Murphy and Heller, 2022). In response to stress, the body activates the autonomic nervous system – comprised of the sympathetic and parasympathetic branches (Murphy and Heller, 2022). The HPA axis is a primary component of the sympathetic nervous system – the “fight or flight” response – and stimulates the secretion of glucocorticoids and catecholamines (Murphy and Heller, 2022). These hormones influence changes in emotional and arousal states, increase heart rate and blood pressure, decrease gut motility and secretion, and decrease bronchi diameter (Murphy and Heller, 2022). Once stress has been mitigated, the body returns to its homeostatic functions, as mediated by the parasympathetic nervous system – the “rest and digest” condition – which is primarily controlled by the VN (Murphy and Heller, 2022). However, in rodent models exposed to chronic stress, the autonomic nervous system can become dysregulated, leading to elevated glutamate levels and dendritic shrinkage in the CA1, CA3 and dentate gyrus regions of the hippocampus, as well as in the medial amygdala and prefrontal cortex (McEwen, 2017; Chaouloff et al., 2007). To prevent excessive activation and maintain homeostasis, the autonomic nervous system meets at nerve junctions (plexuses) to bridge communication between the sympathetic and parasympathetic systems (Howland, 2014). The VN can also directly communicate with components of the sympathetic nervous system in the CNS, such as the HPA axis, and indirectly connect to the sympathetic preganglionic neurons in the upper spinal cord (Pavlov et al., 2003). These CNS communication lines are crucial for the sympathetic and parasympathetic systems to work synergistically in humoral and VN-mediated parasympathetic immune responses throughout the body (Pavlov et al., 2003).

The humoral immune pathway for immune-to-brain communication relies on the HPA axis as the major component to initiate immune response. This pathway involves circulating cytokines, including TNF and IL-1 β , that cross the BBB and act on surface receptors on the brain capillary endothelium to enhance the release of prostaglandins, whose diffusion into the parenchyma mediates fever response and triggers HPA axis activation (Pavlov et al., 2003). Furthermore, the AP is a circumventricular organ that acts as a transduction site, allowing direct systemic signaling to the NTS and RVM, which further synapse to the HPA axis and sympathetic nervous system (Pavlov et al., 2003). The VN-mediated activation of PVN cells causes CRH to be synthesized and enter the pituitary portal system, where it stimulates adrenocorticotrophin hormone synthesis in the anterior pituitary, which in turn stimulates the release of cortisol from the adrenal cortex (Pavlov et al., 2003). The HPA axis is regulated through multiple negative feedback loops, such as the inhibition of CRH by adrenocorticotrophin hormone, and modulation by neural ACh, GABA, and 5-HT (Pavlov et al., 2003). Cortisol influences the inflammatory response by binding intracellular receptors and suppressing nuclear factor κ B activity (NF- κ B) expression, which is linked to pro-inflammatory cytokine synthesis (Pavlov et al., 2003). The sympathetic nervous system plays a role in both pro-inflammatory and anti-inflammatory processes through the LC and RVM, which connect to the sympathetic preganglionic cholinergic neurons in the spinal cord (Pavlov et al., 2003; Elenkov et al., 2000). These neurons then synapse with the postganglionic neurons, using NE as their primary neurotransmitter (Pavlov et al., 2003; Elenkov et al., 2000). During early inflammatory stages, the sympathetic nervous system can activate the inflammatory response at a local level through stimulation of α ₂-ARs (Pavlov et al., 2003; Elenkov et al., 2000). Activation of β -ARs on lymphocytes and macrophages by NE inhibits pro-inflammatory cytokine production via the β ₂-AR-cAMP-protein kinase A pathway and elevate anti-inflammatory cytokine levels (Pavlov et al., 2003).

The inflammatory reflex is a VN-mediated response to immune challenge comprised of two arms: afferent and efferent (Pavlov et al., 2003; Pavlov and Tracey, 2012). Peripheral pro-inflammatory molecules are received by afferent VN fibers, and signals are sent to the NTS, where they synapse to interconnected brain regions, such as the hypothalamic nuclei, amygdala, and insular cortex, to coordinate autonomic and endocrine responses (Pavlov et al., 2003; Pavlov and Tracey, 2012). One study demonstrated that intraportal administration of IL-1 β results in a dose-dependent increase in afferent activity in the hepatic branch of the VN in rats, which was not observed following hepatic vagotomy, therefore suggesting the presence of IL-1 β receptors on VN afferents (Niijima, 1996). Furthermore, the administration of IL-1 β resulted in a reflex activation of the sympathetic splenic nerve, which was similarly lacking in vagotomised rats (Niijima, 1996). Further studies implicated the participation of IL-1 β receptors in VN afferents and chemosensory cells in the paraganglia surrounding the afferent endings of the VN (Goehler et al., 1999; Ek et al., 1998). However, studies using the inflammogen lipopolysaccharides (LPS) via intraperitoneal injection or using intraperitoneal injection of IL-1 β in vagotomised rodents found that high levels of circulating IL-1 β could produce fever and sickness behaviors by bypassing neuronal circuits and acting directly on the brain through circumventricular organs like the AP, or other humoral mechanisms. Therefore, VN-mediated responses work in a dose-dependent fashion and appear especially important at early stages of infection, when circulating IL-1 β levels are low (Goehler et al., 2000; Hansen et al., 2001). Additionally, endocrine processes can be slower in comparison to neural regulation, emphasizing the crucial role of the VN and sympathetic nervous system in eliciting a rapid initial immunoregulatory response (Pavlov and Tracey, 2004). Signal integration in the NTS and associated brain regions, such as the PVN, RVM, and LC, creates the substrate for the HPA axis and sympathetic nervous systems to interact with the VN playing a central immunomodulatory role (Pavlov et al., 2003).

The efferent arm of the inflammatory reflex is constituted by the cholinergic anti-inflammatory pathway. When activated through the NTS-DMV synapse, the efferent signals travel to the celiac superior mesenteric ganglion complex, where they connect to the splenic nerve (Pavlov and Tracey, 2012). Stimulation of the splenic nerve by the efferent VN fibers leads to the release of NE in the spleen (Pavlov and Tracey, 2012). Splenic NE binds to β ₂-ARs found on the surface of memory CD4+ T cells expressing ChAT (Pavlov and Tracey, 2012). This subsequently triggers the synthesis and release of ACh from the T cells (Pavlov and Tracey, 2012). It was originally thought that ACh is directly released from the nerves, however studies found that the inflammatory reflex failed to inhibit TNF release in T cell-deficient nude mice, indicating that T cells play a role in the process (Rosas-Ballina et al., 2011). When T cells were repopulated in the T-cell deficient nude mice, the response was restored, suggesting direct signaling via NE due to the proximity of splenic lymphocytes to the adrenergic nerve endings (Rosas-Ballina et al., 2011). Together, these findings supported the role of ChAT T-cells in the ACh release required for the inflammatory reflex. Peripheral immune cells, such as macrophages, dendritic cells, and monocytes, are a major source of TNF, and the expression of α 7AChR in bone marrow-derived cells is essential for ACh regulation of TNF release (Pavlov and Tracey, 2012). The ChAT T-cell derived ACh binds α 7AChR to affect downstream signaling pathways, inhibiting NF- κ B nuclear translocation and activating the Janus kinase 2-signal transducer and activator of transcription 3 mediated signaling cascade (Pavlov and Tracey, 2012; de Jonge et al., 2005). This results in the inhibition of TNF transcription along with other pro-inflammatory mediators. A study using human macrophage cultures exposed to LPS demonstrated that ACh can inhibit pro-inflammatory cytokines without affecting the release of anti-inflammatory cytokines (Pavlov and Tracey, 2012; Borovikova et al., 2000). Electrical stimulation of the VN also effectively decreases serum TNF levels in wild-type mice, but is ineffective in mice lacking nicotinic receptors, further validating this important pathway (Pavlov et al., 2003).

One possible action of VNS in the brain is through the modulation of inflammation. Studies testing VNS for rheumatoid arthritis have shown that VNS inhibits joint inflammation and the release of inflammatory cytokines (Zhang et al., 2008). Clinical studies have also indicated that VNS might be beneficial against rheumatoid arthritis owing to a reduction of TNF- α release ex vivo and might lead to improvements in disease severity (Koopman et al., 2016; Genovese et al., 2020). In addition, the inflammation that underlies the pathogenesis of CNS diseases, such as multiple sclerosis, Alzheimer’s disease, epilepsy, and schizophrenia, is of great interest for VNS research (Kelly et al., 2022). Experimental studies in animal models have revealed that VNS plays a significant role in altering inflammatory responses (Howland, 2014). Additionally, a human trial in patients with refractory epilepsy found a decrease in IL-8 during long-term VNS (6 months), with no significant changes in the expression of IL-1 β , TNF- α , IL-6 or IL-10 (De Herdt et al., 2009). In a study of cerebral ischemia researchers also observed that VNS downregulated IL-1 β and IL-18 in brain tissues from the cortex, but the neuroprotective effects offered by VNS were reversed by the administration of an α 7nAChR antagonist (Tang et al., 2022). These results support a role of α 7nAChR in the anti-inflammatory action of VNS. Given the anatomical connections of the VN to the NB, the direct modulation of ACh levels may explain the link of this mechanism. A study on rats focused on depression and stress moreover revealed decreased IL-1 β , TNF- α , and IL-6 levels in hippocampal tissues after VNS, as well as morphological changes in hippocampal microglia, notably from amoeboid to surveillant states, with an increased expression of α 7nAChR (Namgung et al., 2022). In traumatic brain injury, VNS reduced TNF- α levels in the serum and brain tissue in a rabbit model (Zhou et al., 2014). Elsewhere, a study showed that VNS significantly reduced the release of pro-inflammatory cytokines such as TNF- α , IL-1 β , and IL-6 in the ischemic penumbra cortex 24-h after ischemia through α 7nAChR activation in microglia from mice subjected to vascular occlusion (Jiang et al., 2014).

Microglia hold a central place in VNS-induced cholinergic anti-inflammatory mechanisms. Numerous CNS conditions have been examined to determine the role of microglia in the actions of VNS, including epilepsy, stress, ischemic stroke and spinal cord injury (Namgung et al., 2022; Chen et al., 2022; Zhang et al., 2021). TLR4 is an important mediator in neuroinflammatory-related disease that is primarily expressed by microglia and has been demonstrated to have a role in traumatic brain injury and ischemic stroke (Yao et al., 2017; Tian et al., 2019). One study on rats found that VNS inhibited the TLR4/myeloid differentiation primary response 88/NF- κ B pathway in microglia, thereby reducing the release of the pro-inflammatory cytokines IL-1 β and IL-6 (Zhang et al., 2021). Activation of α 7nAChR stimulates adenylyl cyclase 6, promoting the degradation of TLR4, which is consistent with their findings of reduced TLR4 expression after VNS in rats (Zhang et al., 2021; Kim et al., 2014; Zhu et al., 2021). Additionally, VNS can increase ACh levels in the rat brain, thereby activating α 7nAChR in microglia after ischemic stroke, which inhibits the peripheral inflammatory response in part through the TLR4/NF- κ B pathway (Zhang et al., 2021; Kim et al., 2014). A study in mice subjected to transient middle cerebral artery occlusion also found that VNS treatment, given for 60 min before, during, and after the occlusion, preserved microglial α 7nAChR expression in the penumbra regions and inhibited NLRP3 inflammasome activation (Xia et al., 2024). Proposed mechanisms for the central reduction of inflammation involve the VNS-induced release of NE from the LC, which has been shown to be essential for the anti-convulsive effects of VNS, by activating β 2-ARs on microglia, astrocytes, and neurons to reduce inflammatory responses via the NF- κ B pathway (Krahl et al., 1998; Laureys et al., 2014). Additionally, activation of the NB triggers the release of ACh to target α 7nAChRs, which induce an anti-inflammatory response (Kaczmarczyk et al., 2018). Studies on spinal cord injury models and stress models in rats found similar results, with VNS downregulating pro-inflammatory cytokine release and promoting microglia to release anti-inflammatory mediators via α 7nAChR upregulation (Namgung et al., 2022; Chen et al., 2022).

Studies have shown evidence of anti-inflammatory effects in human rheumatoid arthritis upon treatment with VNS, as well in reducing the central inflammatory response in murine autoimmune encephalomyelitis (Koopman et al., 2016; Hao et al., 2011). One study, utilizing LPS in mice to induce increased pro-inflammatory cytokine levels found that the whole brain pro-inflammatory cytokine levels were significantly reduced after VNS, alongside a significant reduction in the percent of microglia (CD11b+/CD45^low) as seen by flow cytometry of whole brains (Meneses et al., 2016). Additionally, they found a decreased expression of the microglia/macrophage marker Iba1 in the hippocampus of VNS-treated mice, suggesting the treatment normalized microglial reactivity which could be linked to reduced CNS inflammation (Meneses et al., 2016). A study also tested VNS in a rat model of LPS-induced demyelination and found a reduced microglial response to inflammation and improved remyelination around the lesion border, indicated by a 57.4% reduction in demyelination compared to the sham (Bachmann et al., 2024). However, there was no preventative effect of VNS on demyelination (Bachmann et al., 2024). They suggest that VNS may enhance microglial clearance of debris to favor remyelination (Bachmann et al., 2024). Additionally, this study found a reduced Iba1 expression and cell count, without a reduction in surveillant microglia, indicating that VNS may reduce microglial reactivity and promote neuroprotective microglial populations (Bachmann et al., 2024). This is supported by a study that used a mouse model of maternal immune activation to study the effect of auricular VNS in the treatment of ASD-phenotypes in offspring (Zhang et al., 2024). Using Iba1 as a microglial marker and CD15, a marker found in immune cells and used as a marker for reactive microglia, they found 7 days of auricular VNS in adult maternal immune activation exposed mice decreased microglial proliferation and decreased the number of reactive microglia in the medial prefrontal cortex (Zhang et al., 2024). They additionally used an anti-IL17a model to compare against VNS treated mice and suggest the mechanism may be mediated through the IL-17a inflammatory pathway (Zhang et al., 2024).

Other hypotheses implicate that the central role of α 7nAChR involves the expression of peroxisome proliferator-activated receptor γ (PPAR γ ), which is upregulated by α 7nAChR activation (Jiang et al., 2015). PPAR γ is a ligand-activated nuclear receptor that plays a role in adipocyte differentiation, lipid metabolism, and insulin resistance, as well as inhibits the synthesis and secretion of pro-inflammatory cytokines in the CNS (Jiang et al., 2015; Kapadia et al., 2008). Hypotheses stipulate that VNS may upregulate the expression of PPAR γ for participation during VNS-induced neuroprotection, while its activation can exert anti-inflammatory effects in both the periphery and CNS (Jiang et al., 2015). In line with this, studies using a rat model of right middle cerebral ischemia have demonstrated that VNS decreased pro-inflammatory cytokine expression and upregulated PPAR γ gene expression via activation of α 7nAChR (Jiang et al., 2015). Additionally, the authors found decreased neuronal damage, and improved neurofunctional recovery after ischemic stroke (Jiang et al., 2015).

The mechanisms underlying the anti-inflammatory effects of VNS occur through various pathways. Another possible pathway is the cholinergic anti-inflammatory pathway, where α 7nAChR in splenic macrophages inhibits the release of pro-inflammatory cytokines (Chen et al., 2018). The connection between the microbiota, gut, and brain, notably through the microbiota-gut-brain axis, can play an important role in modulating inflammatory responses via the VN and is associated with disorders, such as neurodevelopmental, neuropsychiatric and neurodegenerative conditions (Wang et al., 2021). The cells in the gut called enteroendocrine cells detect chemical signals and transmit them to the VN through the enteric neurons, triggering an anti-inflammatory response (Wang et al., 2021). Permeability in the BBB can allow for peripheral immune signaling that triggers an inflammatory response, which can be regulated by the VN. For example, neurodegenerative diseases and ischemic stroke are characterized by functional and structural changes in the BBB (Jin et al., 2023). When glial cells in the brain parenchyma bind to damage-associated molecular patterns, they undergo phenotypic changes leading to an increased release of pro-inflammatory mediators that affect BBB permeability (Jin et al., 2023). Besides, studies have shown that epilepsy is associated with structural and functional changes in the BBB (Kaya et al., 2008; Kaya et al., 2013). VNS treatments were shown to strengthen BBB integrity, likely through the modulation of α 7nAChR’s, notably improving the barrier’s structural and functional components (Kaya et al., 2008; Kaya et al., 2013). Specifically, VNS-mediated α 7nAChR-induced upregulation in splenic macrophages was shown to inhibit the release of pro-inflammatory factors, thereby protecting the initial degradation of the BBB (Chen et al., 2018). Additionally, VNS reversed BBB permeability and decreased pro-inflammatory microglial responses and TNF- α levels in mice with cerebral microinfarction and colitis (Chen et al., 2018). Under this model, the actions of the cholinergic anti-inflammatory pathway provide a possible route to influence CNS inflammation.

ACh and BDNF are both central neurotransmitters in neuronal plasticity and have been implicated in the mechanism of VNS-mediated plasticity modulation. Activation of the NB was found to be essential to the plasticity-enhancing effects of VNS in the motor cortex (Hulsey et al., 2016). For example, increased ACh release has been associated with increased visual cue detection in the prefrontal cortex and cognitive performance in learning and spatial memory tasks in the hippocampus in rats (Gombkoto et al., 2021). Nicotinic and muscarinic receptors can also modulate the release of other neurotransmitters, such as glutamate, DA, 5-HT, and NE (McGehee et al., 1995; Picciotto et al., 2012). The interaction of the cholinergic system with the dopaminergic pathway has led to suggestions that nAChRs and M1-muscarinic ACh receptors could be involved in dopaminergic dysregulation in patients with schizophrenia (Eickhoff et al., 2022). As previously discussed, ACh also ties into microglial modulation, which could also play important roles in increasing plasticity.

BDNF is another neurotransmitter that plays a crucial role in hippocampal neuronal plasticity. Activation of the TrkB receptor leads to activation of downstream pathways to recruit molecules like phosphoinositide 3-kinase, whose downstream pathways promote cell growth and proliferation (Yang et al., 2020). Studies in rat models have supported these connections through findings indicating that VNS influenced the expression of BDNF, 5-HT, NE, and inflammatory mediators involved in hippocampal neurogenesis (Manta et al., 2009a; Biggio et al., 2009; Follesa et al., 2007). One study observed reduced BDNF mRNA expression in the hippocampal CA1, CA3, and dentate gyrus of vagotomised rats and mice, as well as decreased adult hippocampal cell proliferation and decreased survival of newly born neurons in these animals (Andero et al., 2014; O’Leary et al., 2018). The gut has also been implicated in VN-mediated hippocampal plasticity. The VN facilitates bidirectional communication between the gut and the brain through complexly branching afferent fibers that extensively cover the stomach and receive substantial sensory data (Breit et al., 2018; O’Leary et al., 2018). Evidence from mouse studies support the role of the gut microbiota in influencing hippocampal neuronal plasticity, reducing depression-like behaviors, and altering protein expression in the hippocampus (O’Leary et al., 2018; Bravo et al., 2011). Additionally, the VN processes gut signals, such as mechanical distension and nutrient acquisition, which can, in turn, activate the hippocampus (Min et al., 2011; Wang et al., 2006). One study indicated that gut-derived VN afferent signaling enhanced hippocampus-dependent learning and memory functions in rat models and provided evidence of reduced BDNF in the hippocampus following VN signal loss (Suarez et al., 2018).

The neurotrophic hypothesis of depression and anti-depression action is backed by evidence of decreased BDNF concentrations in mood disorders, with chronic treatment of depression leading to increased BDNF expression (Karege et al., 2005). Early rodent studies found that VNS increased mRNA and protein levels of BDNF in the hippocampus through both acute and chronic stimulation (Biggio et al., 2009; Follesa et al., 2007). Studies using TrkB inhibitors also found that the anxiolytic and anti-depressant-like effects of VNS were inhibited, further suggesting a mechanism involving BDNF/TrkB (Shah et al., 2016). A study using a rat model has shown that chronic and acute VNS increases TrkB receptor phosphorylation in the hippocampus, even at similar TrkB protein levels, and noted increased activation of phospholipase C, gamma 1 and mitogen-activated protein kinase cascades activation/phosphoinositide 3-kinase signal transduction pathways (Furmaga et al., 2012). Treatment with VNS also caused increased phosphorylation of the downstream effector’s extracellular signal-regulated kinase and protein kinase B (Furmaga et al., 2012). Another study on rats found increased BDNF localized in the CA1 and CA2 hippocampal regions, as well as induction of BDNF protein translation after a single VNS session (Olsen et al., 2022). As previously noted, vagotomy, the surgical cutting of the VN, decreased BDNF expression in hippocampal regions, which supports a mechanism for VNS in regulating hippocampal neurogenesis (O’Leary et al., 2018). Overall, these studies strongly support a VNS-induced increase in BDNF/TrkB expression in the hippocampus as a possible mechanism for its anti-depressant action.

Monoaminergic neurotransmission of NE from the LC and basolateral amygdala has been hypothesized to be a mediator of VN effects in epilepsy and depression (Landau et al., 2015; Dorr and Debonnel, 2006). The monoamine hypothesis of depression postulates a deficit in NE and 5-HT in the brain, leading to depression (Landau et al., 2015; Moret and Briley, 2011). Therefore, the promotion of NE by VNS is likely associated with the reported antidepressant effects. Pharmacological treatment modalities link 5-HT and NE to the anti-depressant and anti-convulsive effects of VNS (Giorgi et al., 2004; Snead, 1983). Moreover, some recent studies on rodent models have revealed a role for altered serotonergic transmission in the pathogenesis of epilepsy (Bonnycastle et al., 1957; Zhang et al., 2018). The α 2 adrenergic autoreceptors that receive NE are located in the LC pre-synaptically to control the release of NE and are located post-synaptically in projection areas in the cortex to modulate signaling pathways (Shansky and Lipps, 2013). One study utilized positron emission tomography (PET) to measure changes in NE receptor binding in minipigs (Landau et al., 2015). It was observed that VNS reduced the selective α 2-AR antagonist binding potential in limbic, thalamic, and cortical brain regions, which is consistent with NE release (Landau et al., 2015). Furthermore, microdialysis studies in rats exposed to acute VNS demonstrated increased NE in the amygdala, hippocampus, and prefrontal cortex (Follesa et al., 2007; Hassert et al., 2004; Roosevelt et al., 2006). The LC is critically linked to seizure suppression in VNS, indicating the significance of the LC and NE release for the effectiveness of treatment (Krahl et al., 1998). Short exposures to VNS have been shown to activate the NTS, parabrachial nucleus, and LC, while chronic exposure additionally activates the cingulate cortex and DRN (Yuan and Silberstein, 2016). Chronic VNS increased DRN activity to nearly double, associated with increased levels of 5-HT in the brain, while acute VNS had no effect (Dorr and Debonnel, 2006). When the LC was lesioned, VNS did not affect DRN activity, suggesting the importance of the LC as a key mediator between the NTS and DRN for driving the outcome of VNS on 5-HT promotion (Manta et al., 2009b). This mechanism is very promising in explaining the effectiveness of VNS in epilepsy and depression treatments and implicates the modulation of NE and 5-HT release by the VN.

Additional signaling molecules potentially associated with the VN’s inflammatory response include ghrelin, oxytocin, GABA, and DA. Ghrelin is a growth hormone primarily associated with the stomach, which has receptors expressed on the DMV and can modulate inflammation and protect the BBB (Wang et al., 2021). A study has confirmed that VNS increases ghrelin expression and decreases TNF- α in patients with traumatic brain injury, supporting its role in the central anti-inflammatory response (Bansal et al., 2012).

Oxytocin, released by the posterior pituitary gland, plays an important role in the reproductive systems and exhibits central anti-inflammatory effects through inhibition of pro-inflammatory cytokine release (Wang et al., 2021). The PVN is the primary site of oxytocin production and receives projections from the NTS and projects to the DMV (Wang et al., 2021). Oxytocin is believed to be beneficial for disorders related to social interaction deficit, such as ASD, by activating higher cortical regions and the PVN, and through the rescue of synaptic plasticity in the ventral tegmental area, which is an important region for learning and memory (Sgritta et al., 2019; Hara et al., 2017). Stimulation of the VN increases oxytocin levels and thus may be a mechanism by which VNS exerts its protective effects (Wang et al., 2021).

GABA is an inhibitory neurotransmitter with receptors primarily found in the NTS, DMV, prefrontal cortex, amygdala, and hippocampus (Wang et al., 2021). Studies have found GABA to be important in VNS modulation of working memory, automatic movement inhibition, reduction of cortical excitability, and neuroprotective effects (Wang et al., 2021). Additionally, impairment of GABA_A-mediated inhibition of neuronal excitability is key to drug-resistant epilepsy (Marrosu et al., 2003; Keute et al., 2021). Application of a single photon emission computed tomography with benzodiazepine receptor inverse agonist, Iomazenil, showed that VNS significantly increased GABA_A receptor density and plasticity in human studies (Marrosu et al., 2003; Keute et al., 2021). This suggests that VNS may inhibit the development of epilepsy by reducing neuronal excitability in cortical brain regions associated with epilepsy. One study in rats found that subdiaphragmatic vagal deafferentation resulted in transcriptional changes in the brain associated with schizophrenia and DA alterations in the nucleus accumbens, as well as induced anxiety-like behaviors (Klarer et al., 2014). The behavioral changes were associated with alterations in GABA and NE levels in the limbic system, without functional changes to the HPA (Klarer et al., 2014). These studies support the role of VN afferents in the modulation of GABAergic signaling.

DA is a neurotransmitter and hormone associated with emotion, behavior, and movement, primarily produced by the ventral tegmental area and substantia nigra pars compacta and discharged into the prefrontal cortex and nucleus accumbens (Juárez Olguín et al., 2016). The formation of DA from L-DOPA is catalyzed by DOPA decarboxylase, but DA is also a precursor to NE through degradation by dopamine- β -hydroxylase in the presence of L-ascorbic acid and molecular oxygen (Juárez Olguín et al., 2016). Studies have shown that stimulation of the right VN neurons of the nodose ganglion activated the ventral tegmental area and substantia nigra pars compacta and were sufficient to induce DA release, implicating a role for the VN in DA manipulation (Han et al., 2018). Another study confirmed that stimulation of the VN at the cervical site stimulated the ventral tegmental area and substantia nigra pars compacta, but left VN stimulation did not activate these regions (Brougher et al., 2021). Alternatively, the VN may stimulate the production of DA to the prefrontal cortex through stimulation of the LC (Devoto et al., 2005). The consensus of DA manipulation by VNS is not well established, and future studies are warranted to establish a strong connection.

Epilepsy is a neurodevelopmental disorder characterized by chronic, uncontrolled seizures affecting over 65 million people worldwide, with 10.5 million being children (Moshé et al., 2015; Guerrini, 2006). Chronic seizures are especially harmful to children, as they interfere with physical and mental growth and can lead to psychiatric comorbidities like depression, anxiety, and ADHD (Ji et al., 2019). When VNS was initially approved as a treatment for epilepsy in 1997, it was for refractory epilepsy in patients aged 12 years or older who failed other therapeutic approaches (Ji et al., 2019). However, in 2017, the common VNS system was approved for patients aged 4 years or older who exhibit epilepsy refractory to antiepileptic medication (Ji et al., 2019). This made the therapy more available to afflicted individuals and allowed researchers to study the effects of VNS in children as a possible treatment for other childhood neurodevelopmental disorders.

Treatment for epilepsy is based on many factors. Currently, there are over 40 antiseizure medications available that offer a wide variety of benefits and drawbacks, taking into account different lifestyle and condition characteristics (National Institute of Neurological Disorders and Stroke, 2024). However, one-third of epilepsy patients do not respond to antiseizure medications and are at higher risk of mortality (Ji et al., 2019; National Institute of Neurological Disorders and Stroke, 2024). This leads to considering other options, such as dietary changes, surgery, or stimulation devices (Ji et al., 2019; National Institute of Neurological Disorders and Stroke, 2024). A ketogenic diet reduces carbohydrate intake to allow the body to rely primarily on fats for fuel and has been particularly effective in reducing seizures in children (National Institute of Neurological Disorders and Stroke, 2024). However, it is a self-regulated diet that can be very challenging for patients to maintain long-term (National Institute of Neurological Disorders and Stroke, 2024). Surgery is a more extreme treatment for those who are unresponsive to other options and can be very risky and sometimes ineffective (National Institute of Neurological Disorders and Stroke, 2024). Alternatively, neurostimulation treatments are available for patients who do not respond to other treatment options and are categorized into three models: iVNS, responsive stimulation, and deep-brain stimulation (National Institute of Neurological Disorders and Stroke, 2024). VNS has been shown to have anticonvulsive effects as well as positive effects on mood, behavior, and cognition in patients with epilepsy (Aalbers et al., 2012). However, while VNS is an effective treatment, the underlying mechanisms are not fully understood, making it difficult to gauge who will be a responder and best benefit from the treatment (Table 1).

Seizures are defined as the manifestation of abnormal, excessive, and hypersynchronous discharges of cortical neurons (Bromfield et al., 2006). Epilepsy is a chronic CNS disorder characterized by recurrent and unprovoked seizures (Bromfield et al., 2006). Excessive electrical activity in neurons causes involuntary movements, sensations, behaviors, and emotions, as well as loss of awareness, with lingering effects lasting up to hours (National Institute of Neurological Disorders and Stroke, 2024). After-effects can include drowsiness, weakness, and confusion (National Institute of Neurological Disorders and Stroke, 2024). The initiation of a seizure is identified by concurrent high-frequency bursts of action potentials and hyper-synchronization of a neuronal population, causing sustained depolarization (Bromfield et al., 2006). Epileptic seizure severity is believed to be correlated to neurotransmitter and central inflammatory functions, such as the overstimulation of glutamatergic NMDA receptors by tryptophan metabolites, notably kynurenine, which is implicated in seizure generation (Majoie et al., 2011). The cause of epilepsy is unknown, but genetic factors, developmental brain abnormalities, infection, or trauma have been implicated (National Institute of Neurological Disorders and Stroke, 2024). Genetically induced epilepsy has been linked to hereditary and sporadic causes, with at least 500 identified genes estimated to be involved (National Institute of Neurological Disorders and Stroke, 2024; Hajtovic et al., 2022). For example, children with Lennox–Gastaut syndrome, Dravet syndrome, and Tuberous Sclerosis Complex (TSC) can be at risk for epileptic seizures (National Institute of Neurological Disorders and Stroke, 2024). Several genes implicated in epilepsy encode ion channels, and carboxylase or are associated with neuronal migration (National Institute of Neurological Disorders and Stroke, 2024; Hajtovic et al., 2022).

Proposed mechanisms for the action of VNS involve desynchronization of neuronal activity, hippocampal plasticity, anti-inflammation, and neurotransmitter modulation (the monoamine hypothesis), as previously mentioned in this review. In addition to these mechanisms, it is believed that upward activity induced by VNS affects the limbic system (e.g., hippocampus, amygdala, hypothalamus) and cortex, suppressing epileptic waves and cerebral blood flow (Fukuda et al., 2024). VNS is also believed to change GABA and NE nerve activity and amino acid metabolism, increasing GABA in the piriform cortex (Fukuda et al., 2024). Additionally, anti-inflammatory effects, such as reduced neurotoxin concentrations, normalized cortisol levels, and the regulation of cerebral blood flow allow to reduce seizures (Fukuda et al., 2024). Studies have also shown that VNS results in changes in tryptophan concentrations in the CNS, which would decrease the stimulation of NMDA receptors (Majoie et al., 2011). Overall, it is believed that VNS acts through multiple mechanisms to decrease seizure activity in patients.

In addition to these cellular mechanisms, VNS is also affected by genetic mutations linked to epilepsy. As a highly heterogeneous condition, the efficacy of VNS is variable, with different response rates based on the patient’s genetic mutations. A meta-analysis determined that pediatric patients with TSC exhibit a 68% rate of ≥50% seizure reduction. In comparison, patients with Dravet syndrome had a ≥ 50% seizure reduction rate in 41% of cases, with no patients achieving complete seizure-freedom (Hajtovic et al., 2022). Patients with Rett syndrome displayed an 86% response to VNS among 7 patients, while another meta-analysis of 11 patients showed that 82% of patients had a ≥ 50% reduction in seizure frequency (Hajtovic et al., 2022; Xie et al., 2022). In a study on Lennox–Gastaut syndrome, a pair of female monozygotic twins received VNS, with one experiencing a 60% reduction in seizure frequency while the other had no reduction (Xie et al., 2022). This suggests that the effectiveness of VNS may be influenced by environmental (including prenatal) factors in addition to genetic predisposition. However, further studies are required to validate this finding. Studies have also shown that the response to VNS tends to improve over time with chronic usage (Starnes et al., 2019). In addition, studies focusing on children have highlighted the importance of age in determining VNS efficacy, suggesting younger children tend to demonstrate more significant improvements (Ji et al., 2019). This paper provides a comprehensive review of previous data on the efficacy of VNS in children (Ji et al., 2019).

Overall, VNS has proved its efficacy as a treatment modality for children and adults with refractory epilepsy. Future researchers should attempt to determine the mechanisms behind VNS’s therapeutic actions and analyze the role of genetic and environmental influences. This data could help determine markers for responders that could increase the specificity of its use. A review on the use of tVNS for epilepsy determined the need for a common protocol among studies to avoid underestimation of anti-convulsive effects, reporting a weekly seizure reduction variance of 12.5–50%, a monthly seizure reduction of 8.3–64.5%, and a study timeline-based reduction of 30–65% (Lampros et al., 2021). Additionally, the studies reviewed supported increased efficacy in chronic use, with one study reporting a 23% increase in seizure reduction from weeks 8–16, with diminishing increases after week 16 (Lampros et al., 2021). Of the studies analyzed, three reported no differences in response to tVNS between age or gender (Lampros et al., 2021). Regarding adverse effects of tVNS, common side effects included headaches, and ear pain in around 15–20% of patients, as well as skin irritation and rashes (Lampros et al., 2021). Other common symptoms include nasopharyngitis, gastrointestinal symptoms such as nausea and diarrhea, fatigue, and dizziness (Lampros et al., 2021). One study analyzed transcutaneous auricular VNS using the NEMOS device in epilepsy patients but could not draw conclusive results due to limitations related to the device’s usability (Sabers et al., 2021). While non-invasive VNS can be more accessible, it appeared to be limiting in its need for active participation by the patients and possible lifestyle disruptions, as the study required four hours to use the device daily, and issues with electrode connection exacerbated frustrations (Sabers et al., 2021). As tVNS is still a developing treatment option, it shows promise with efficacy and tolerability. Standard protocols are required to continue the advancement of studies and options to make the device more lifestyle friendly for epilepsy patients would be beneficial in broadening its usability.

Schizophrenia is a chronic psychiatric disorder represented by positive (e.g., delusions, hallucinations), negative (e.g., social withdrawal, apathy), and cognitive (e.g., learning and memory impairments) symptoms (DSM Library, 2024). According to the World Health Organization, about 24 million people, approximately 1% of the world’s population, are affected by schizophrenia globally, ranking the disease as a serious cause of disability worldwide (Li et al., 2023). Unfortunately, effective treatments for schizophrenia have remained limited, leading to increased disability due to comorbidities, chronic behavioral changes, and increased suicide rates (Laursen et al., 2012). Diagnosis of schizophrenia utilizes the identification of psychosis as a first step but requires additional factors, such as chronicity, dysfunction, and presence of depression or mania to differentiate it from other psychotic disorders (van Os and Kapur, 2009). Studies have determined that prenatal factors, such as maternal infection, stress, or malnutrition, contribute to some cases of schizophrenia (van Os and Kapur, 2009; Ben-Azu et al., 2022).

Pharmacological treatments for schizophrenia are designed to antagonize DA receptors (van Os and Kapur, 2009). The Texas Medication Algorithm Project has developed a six-stage pharmacotherapeutic algorithm for schizophrenia treatment that utilizes first-and second-generation antipsychotics, as well as electroconvulsive therapy (Haddad and Correll, 2018). However, these treatments are often associated with risks of motor, reproductive, and metabolic disorders, such as agranulocytosis, extrapyramidal symptoms, obesity, diabetes, and reproductive dysfunction (Haddad and Correll, 2018; Obukohwo et al., 2024). The specific mechanism behind antipsychotic drugs remains unclear, but they are believed to fall into three categories: high DA antagonism and low 5-HT inhibition, moderate-to-high DA antagonism and high 5-HT blockade, and low DA antagonism and high 5-HT antagonism (Haddad and Correll, 2018). The specific risks of weight gain, reproductive impairment, or extrapyramidal symptoms depend on the specific antipsychotic drugs involved, although they all convey low to high risk in one of these categories (Haddad and Correll, 2018). The response rate of antipsychotics is low, with the most effective treatment having a response rate of 33% after three months, but also being associated with severe side effects (Haddad and Correll, 2018). Also, antipsychotics are only clinically effective for positive symptoms, with unsatisfactory results for negative symptoms and cognitive symptoms (Haddad and Correll, 2018). This lack of effective and safe treatment options has led to the development of alternative therapies targeting the inflammatory pathways involved in the pathogenesis of schizophrenia, such as VNS.

The pathophysiology of schizophrenia is multifaceted and includes, but is not limited to, decreased gray matter, enlarged ventricles, and focal alteration of white matter tracts in patients (van Os and Kapur, 2009). The DA hypothesis of schizophrenia posits an increase in DA in the brain linked to the schizophrenia phenotypes, supported by studies finding increased DA synthesis and release in mesolimbic brain region (e.g., striatum) with decreased levels in mesocortical area (e.g., prefrontal cortex), supported by preclinical and clinical studies (van Os and Kapur, 2009; Ben-Azu et al., 2018). Functional MRI analyses have shown abnormal network response to DA, with areas of hyper-and hypoactivity across different brain regions (van Os and Kapur, 2009). The causes of disturbances in dopaminergic neurotransmission in schizophrenia have been unclear. However, inflammation has been considered a possible mechanism behind the neurochemical alteration (Müller and Bechter, 2013). The inflammatory cytokine IL-1 β , which converts rat mesencephalic progenitor cells to a dopaminergic phenotype, and IL-6, which decreases serotonergic neuron survival in the fetal brain, both influence the development of neurotransmitter systems, especially those involved in schizophrenia (Müller and Bechter, 2013). Rodent models of maternal immune activation support this, as they have been shown to contribute to increased mesencephalic dopaminergic neurons in the fetus, likely associated with the increased DA production seen in schizophrenia (Müller and Bechter, 2013). These maternal immune activation models and studies of human cases are linked to an increased risk of schizophrenia associated with respiratory and reproductive tract infections, specifically those linked to increases in maternal IL-8 (Müller and Bechter, 2013).

A different hypothesis linked to inflammatory responses is the microglial hypothesis of schizophrenia, which suggests that the release of pro-inflammatory cytokines, kynurenines, nitric oxide, and reactive oxygen species by microglia leads to neuronal degradation and white matter abnormalities (Busse et al., 2012). Studies on humans supporting this hypothesis have found increased levels of peripheral benzodiazepine receptor, notably expressed by reactive microglia, and HLA-DR+ microglia, a major histocompatibility complex (MHC) class II marker that may be linked to antigen presentation, in acute psychotic episodes early in the disease course, but another paper found this was not the case in patients with chronic schizophrenia, pointing to certain immune alterations occurring as a function of the disease course (Busse et al., 2012). One study found an increased density of HLA-DR+ microglia in the hippocampus in patients with positive symptoms (paranoid schizophrenia), which may be linked to increased IL-1 β and IL-2 secretion as well as complement-dependent pathways that regulate DA-related brain signaling to modulate monoaminergic neurotransmission (Busse et al., 2012). The impairment of microglial functions in schizophrenia pathology is supported by a variety of evidence, including behavioral and molecular enrichments, as well as post-mortem transcriptomic studies of patients (Zhuo et al., 2023; Ormel et al., 2020; Gober et al., 2022; Nguyen et al., 2023). Genetic studies have shown increased expression of well-known microglial genes, notably TREM2, APOE, CX3CR1, IRF8, P2RX7, and P2RY12 in schizophrenia patient-derived microglial cells (Ormel et al., 2020; Koskuvi et al., 2024). Additionally, increased expressions of IBA1, P2RY12, MHC class II, CD16, CD32a, CD64, and CD68 have been detected, which are considered motility and phagocytic markers of microglia, often associated with increased pro-inflammatory actions (Ormel et al., 2020; Koskuvi et al., 2024). However, it is worth noting that the expression of these markers may depend on age, brain region, and sex (Gober et al., 2022; De Picker et al., 2021).

Another mechanism of schizophrenia may be the lack of glutamatergic neurotransmission caused by NMDA receptor hypofunctionality, as well as disinhibition of GABAergic system and serotonergic impairments (Müller and Bechter, 2013). The glutamatergic hypothesis of schizophrenia is supported by studies showing altered NMDA receptor expression levels in patients with schizophrenia, and the mimicking of psychotic-like behaviors in healthy subjects and experimental animals given NMDA receptor antagonists (Espana et al., 2021; Ben-Azu et al., 2023). The body’s endogenous NMDA antagonist, kynurenic acid, is produced during inflammatory immune responses when the enzyme indoleamine 2,3-dioxygenase gets inhibited, and acts as a natural mediator of NMDA receptor activity (Müller and Bechter, 2013). Additionally, a recent study found that NMDA receptor surface trafficking was altered in patients with schizophrenia (Espana et al., 2021).

So far, there have been few studies exploring VNS as a treatment modality for schizophrenia. One study using tVNS found no differences in schizophrenia symptoms between tVNS-treated and sham groups over a 26-week trial (Hasan et al., 2015). However, the results remained inconclusive due to poor patient adherence to the treatment protocol (Hasan et al., 2015). Another study in rodent models found that chronic VNS can effectively reverse hyperactivity of the hippocampal and ventral tegmental area, mesolimbic dopaminergic dysfunction, and positive schizophrenia-associated symptoms (Perez et al., 2014). Furthermore, studies combining VNS with neuroimaging techniques observed that VNS decreases hippocampal activity, possibly through increased GABAergic signaling (Capone et al., 2015; Smucny et al., 2015). Moreover, improved cognition in domains responsible for attention, memory consolidation, and executive function has been linked to VNS in patients with epilepsy, Alzheimer’s disease, and depression (Smucny et al., 2015). The mechanisms of VNS that are relevant to schizophrenia include increases in NE, ACh, and 5-HT, as well as the manipulation of GABAergic signaling (Smucny et al., 2015). α 7nAChRs are believed to have reduced expression in patients with schizophrenia, leading to hippocampal hyperactivity (Smucny et al., 2015). Therefore, the increased release of ACh by VNS could stabilize this function (Smucny et al., 2015). Similarly, increases in 5-HT may also decrease hippocampal hyperactivity by modulating GABAergic signaling through the 5-HT2, 3, and 4 receptors (Smucny et al., 2015). Activation of the 5-HT1 receptor has been associated with hippocampal neurogenesis, acting as a possible mechanism to restore pattern separation deficits, while 5-HT3 receptors could relieve inhibition of ACh release (Smucny et al., 2015).

The modulation of the immune system may be another way by which VNS affects schizophrenia. Previous studies have shown that the expression of α 7nAChR is reduced in patients with schizophrenia and animal models of schizophrenia (Corsi-Zuelli et al., 2017; Freedman et al., 1995; Leonard et al., 2000). α 7nAChR plays a role in NMDA and GABA receptor activity. Altered α 7nAChR activity has been linked to altered NMDA/GABA receptors and related neuronal functions (Corsi-Zuelli et al., 2017). Of note, kynurenic acid, a popular NMDA receptor inhibitor and a non-competitive α 7nAChR-antagonist, is associated with decreased glutamatergic and cholinergic neurotransmission (Corsi-Zuelli et al., 2017). Different studies have shown that targeting α 7nAChR could lead to beneficial outcomes for schizophrenia patients. A study has shown that the administration of nicotine reversed hypofrontality, a state of decreased cerebral blood flow in the prefrontal cortex, through inhibitory neurons in experimental animal models of addiction and schizophrenia (Koukouli et al., 2017). Another study used a nicotinic agonist known to modulate α 7nAChR and they found significant improvements in the negative symptoms in patients with schizophrenia (Freedman et al., 2008). Indeed, it is estimated that around 70% of people with schizophrenia smoke cigarettes, a fact that is believed to be unknowingly associated with the benefits of α 7nAChR activation (Tregellas and Wylie, 2018). However, since nicotine has side effects such as anxiety, nausea, and mood changes, and is difficult to turn into therapy, VNS may be a feasible alternative to target α 7nAChRs, being well tolerated (Tregellas and Wylie, 2018).

ASD is a neurodevelopmental disorder best characterized by poor social interaction and communication, limited interests, and stereotypical behavior (Shivaswamy et al., 2022). Other impairments can include increased anxiety and fear responses, leading to behaviors such as tantrums, aggression, and phobias (Shivaswamy et al., 2022). It affects approximately 1 in 36 children (around 2% of the population), with an increasing prevalence (Shivaswamy et al., 2022; Jin and Kong, 2017). ASD is four times more prevalent in males, as shown by an earlier age of onset and poor response to treatment compared to females, suggesting a sex-related difference (Marotta et al., 2020). Cognitive behavioral therapies are an effective approach for treating anxiety in individuals with ASD and depend on extinction learning for the treatment of ASD-related phobias (Shivaswamy et al., 2022). Intensive behavioral therapies can promote adaptive plasticity and can lead to significant improvements in intelligence, communication, and social skills in individuals with ASD, but are also very time-consuming and expensive (Engineer et al., 2017). Furthermore, a significant number of children do not respond to these therapies, thereby limiting the treatment’s usefulness (Engineer et al., 2017).

Neuroimaging techniques have found abnormalities in the grey and white matter with regional differences in individuals with ASD compared to their typically developing counterparts (Ha et al., 2015). Total brain volume in children with ASD was also determined to be accelerated at around 2–4 years of age, with enlargement of the frontal and temporal lobes, but it tends to be decreased or present no difference in older individuals (Ha et al., 2015). Additionally, studies have identified an accelerated expansion of the cortical surface area, but not thickness, before 2 years of age, which may be associated with the impaired maturation of cortical white matter (Ha et al., 2015). Numerous studies have made a clear connection between the development of ASD and genetic factors, as siblings have a 100-fold increased risk compared to the general population, and monozygotic twins have a 36 to 91% concordance rate, although this does not take into account the effects of the shared maternal and postnatal environment (Marotta et al., 2020).

Alterations in GABAergic and glutamatergic systems are believed to be potential pathological mechanisms for ASD (Marotta et al., 2020). Magnetic resonance spectroscopy has shown reduced glutamate concentrations in the striatum of adults with ASD and reduced GABA levels in the motor, visual, auditory, and somatosensory areas (Marotta et al., 2020). Furthermore, plasma levels of GABA and glutamate are altered in children diagnosed with ASD, leading to an imbalance in excitatory and inhibitory mechanisms (Marotta et al., 2020). Glutamate and its NMDA and AMPA receptors have also been implicated in ASD (Marotta et al., 2020). Rodent models have shown overexpression of NMDA receptor subunits, leading to enhanced synaptic currents and amplified postsynaptic plasticity (Marotta et al., 2020). Meanwhile, AMPA receptors displayed significant decreases in their GluA2 subunit in the hippocampus (Marotta et al., 2020). 5-HT is another neurotransmitter that has been implicated in the development of ASD during early neonatal brain development (Marotta et al., 2020). Studies have shown higher levels of 5-HT transporter or 5-HT in children with ASD and in animal models, while post-mortem studies showed reductions in 5-HT receptor binding (Marotta et al., 2020). Additionally, children with ASD were found to have significantly lower levels of serotonin at the ages of two and five, with a slight increase with age, while healthy children showed elevated 5-HT at this age, with a decline after puberty (Marotta et al., 2020). It is hypothesized that dysfunctional DA level plays a role in the development of ASD, as individuals with ASD demonstrate reduced DA release in the prefrontal cortex and reduced neural response in the nucleus accumbens (Marotta et al., 2020). Some other neurochemicals implicated in the development of ASD include ACh, N-acetyl aspartate, oxytocin, and melatonin (Marotta et al., 2020).

VNS has been proposed as a treatment for ASD due to the unpredictable response to medication and the potential limitations of behavioral therapies (Black et al., 2023). One study investigated the use of auricular tVNS in patients with ASD and found that it was well-tolerated, with high completion rates, tolerability, and delivery of intended stimulation (Black et al., 2023). The study also observed an improvement in anxiety and sleep scores in a small cohort of children after a 2-week period (Black et al., 2023). Another study indicated that VNS improved the recognition of emotion and salient social cues, which are commonly impaired in individuals with ASD (Colzato et al., 2017). However, a separate study involving a small group of patients (n = 7) with both refractory epilepsy and ASD found no significant effects on quality of life, cognitive abilities, or reduction in seizure frequency two years after undergoing iVNS implantation (Danielsson et al., 2008). This highlights the need for further research on the effectiveness of VNS, especially in patients with multiple health conditions. Since this study was published, other studies have tested VNS in children with ASD and have yielded promising results. One study included children with both epilepsy and ASD and found that two of four children who achieved seizure control also had changes in their autism diagnosis, from autism to suspected autism (Wang et al., 2022). This study also observed a significant reduction in autistic behaviors related to language, social skills, and self-help, indicating the possible effects of VNS on neurocognitive function (Wang et al., 2022). However, it is important to consider the potential influence of a child’s age and previous interventions on these results (Wang et al., 2022).

The mechanisms of VNS that may support its usage in ASD involve the modulation of the glutamatergic system, 5-HT, and DA. One study found that VNS activated NDMA receptor-and AMPA receptor-mediated TrkB in the NTS, without changes in BDNF concentration (Liu et al., 2024). Therefore, VNS may be able to modulate glutamate concentrations through the NTS in the CNS. Furthermore, studies support the modulation of 5-HT by chronic VNS (Liu et al., 2024). Children exposed to VNS may be able to express normalized levels of 5-HT through the critical developmental period (Liu et al., 2024). The role of the VN in DA production is less well established, but studies support that the VN can stimulate DA production in the ventral tegmental area and substantia nigra pars compacta or through the LC, which project to the prefrontal cortex (Liu et al., 2024). Overall, while further studies are needed for clarification, these studies support the notion that VNS may have positive effects on mood regulation and could potentially be a promising therapy for ASD.

ADHD is a neurodevelopmental disorder characterized by hyperactivity, impulsivity, and attentional difficulties (Zaehle and Krauel, 2021). Most individuals show symptoms in childhood, with a prevalence of about 5% in school-aged children ( ≥ 18 years old) worldwide, and 2.5% in adults (Cortese et al., 2018). Memory performance, encoding, and consolidation can be affected, and the ability to adjust behavior to situations and anticipate outcomes (Zaehle and Krauel, 2021). While not associated with increased mortality, ADHD in children can accumulate additional financial costs, with studies finding families in the United States with children diagnosed with ADHD spend an additional $15,000 per year (Sciberras et al., 2022). Individuals with ADHD are at higher risk of anxiety, depression, and overall report a lower quality of life (Kosse et al., 2017).

Pharmacological treatment options for ADHD include psychostimulant and non-psychostimulant medications, though clinical guidelines and efficacy and safety are still in debate (Cortese et al., 2018). A meta-analysis examined the available medications and found that while all but one were generally effective compared to placebo, they were also more efficacious in children than adults (Cortese et al., 2018). They also determined that amphetamines were more effective at all ages, but had varied effects across ages (Cortese et al., 2018). Overall, their results supported the use of methylphenidate for children and adolescents, and amphetamines for adults as the primary pharmacological choice (Cortese et al., 2018). These treatments can be highly effective initially for the majority of patients, but over time the side effects and low treatment acceptance may lead to the discontinuation of treatment (Biederman et al., 2019). Side effects can moreover include decreased appetite and sleep problems, as well as rarer cases of cardiac complications (Kosse et al., 2017). In children and adolescents, the non-adherence rate varies from 10 to 64% (Kosse et al., 2017).

ADHD is largely genetic, with a hereditability of 70–80%, and a smaller environmental risk factor (Demontis et al., 2019). There are also consistent structural and functional alterations related to ADHD symptoms in various brain regions, including the prefrontal cortex, basal ganglia, cerebellum, parietal cortex, and anterior cingulate cortex (Zaehle and Krauel, 2021). Neurochemically, individuals with ADHD have reduced levels of DA, NE, and GABA (Zaehle and Krauel, 2021). One study found that GABA concentrations were significantly lower in female and male children with ADHD compared to their typically developing counterparts (Edden et al., 2012). However, this study did not determine whether this reduction in GABA was due to the reduced density of GABAergic neurons or a reduced concentration of GABA with a normal neuronal density (Edden et al., 2012). Dopaminergic dysfunction in ADHD has been supported through animal studies and pharmacological treatments, like methylphenidate that blocks DA transporters at therapeutic doses, which could be linked to why ADHD patients are vulnerable to drug dependence (Véronneau-Veilleux et al., 2022).

The benefits of VNS for ADHD have not been experimentally explored, but its potential lies in its ability to increase NE and GABA concentrations in the brain. Studies have shown that VNS can have a protective effect on GABAergic neurons, as well as increased GABA transmission in the NTS in traumatic brain injury models (Zaehle and Krauel, 2021). In epilepsy patients, chronic VNS increases GABA receptor density in the frontal and temporal brain regions (Zaehle and Krauel, 2021). However, the main effects of VNS are believed to be mediated through the LC-NE system discussed in this review. It is known that NE can facilitate aspects of cognition that are lacking in individuals with ADHD, such as attention and behavioral flexibility (Zaehle and Krauel, 2021). Thus, modulation of NE by VNS may improve these behavioral and cognitive deficits. Furthermore, unlike currently approved pharmacological treatments, VNS is a well-accepted treatment modality with few side effects. The implementation of iVNS would remove the non-adherence component but add surgical risks and higher costs. Alternatively, non-invasive methods of VNS may be more practical and could provide a treatment that reduces the risk of drug dependence. Future studies should evaluate the efficacy of VNS in reducing ADHD symptoms to determine how patients may benefit.