Drug-resistant epilepsy is one of the primary conditions treated with iVNS, which received FDA approval in 1997, and extensive clinical research has shown the effectiveness of iVNS in reducing seizure frequency in patients with drug-resistant epilepsy (DeGiorgio et al., 2000). L-VNS has been used to treat epilepsy in both pediatric and adult populations. In pediatric patients with medically refractory epilepsy, particularly those with atonic seizures, iVNS had a 68% clinical response rate (Patwardhan et al., 2000). Long-term studies support the effectiveness of iVNS in children with partial refractory epilepsy (Rychlicki et al., 2006) showing seizure reductions over 2 years. Additionally, a one-year follow-up study in pediatric patients with primary generalized epilepsy reported a 64% reduction in seizure frequency (Welch et al., 2018).

In adult patients, multiple cases have demonstrated iVNS can significantly reduce seizure frequency by 50 to 90% (García-Navarrete et al., 2013; Batson et al., 2022). Studies have also shown a progressive increase in iVNS clinical benefits over time, with a 46 and 62% decrease in seizure frequency after 3 months or 2 years, respectively (Englot et al., 2011). Long-term response rates in larger cohorts indicated a 63% reduction in seizure frequency after 2 years of treatment (Englot et al., 2015).

The mechanism of how L-VNS treats epilepsy involves multiple potential pathways. In humans, acute L-VNS enhances thalamic blood flow, with increased thalamic activity tied to fewer seizures, suggesting thalamic synaptic mediation (Henry et al., 1999). L-VNS also promotes EEG desynchronization particularly in theta and gamma bands, disrupting pathological neural synchrony (Sangare et al., 2020). A recent review of the literature suggests L-VNS modulates epileptic networks through a cascade beginning in the brainstem and extending to limbic and cortical regions, reducing hyperconnectivity and cortical excitability (Carron et al., 2023).

Several studies have explored the use of R-VNS as an alternative to L-VNS for treating epilepsy. An observational report described three children who benefited from L-VNS, but L-VNS was discontinued early due to infections, and R-VNS was applied. One child became seizure-free for over 2 years with R-VNS and experienced no postoperative cardiac side effects, although minor respiratory events, which are also common with L-VNS, were noted. Another child saw an improvement in seizure control, albeit less dramatic than with L-VNS. The third child experienced a cessation of generalized tonic–clonic seizures, with only transient respiratory issues after swimming (McGregor et al., 2005).

In another case, a 16-year-old boy with medically refractory psychomotor seizures initially responded to L-VNS but required removal of the pulse generator due to a deep wound infection which prevented left-sided surgery. R-VNS was therefore implanted, leading to seizure suppression, although with a delayed onset compared to L-VNS. However, stimulation of the right VN induced minor cardiac symptoms, necessitating ECG-guided placement and adjustment of the device to manage potential adverse effects on cardiac function (Spuck et al., 2008).

Two adult patients additionally underwent R-VNS following complications with L-VNS implantation. While one patient experienced significant improvements in seizure reduction with L-VNS, the stimulation device was removed due to mechanical malfunction and device reimplantation in the left VN was deemed too risky. The device was therefore placed in the right VN, and the subsequent R-VNS yielded a 95% seizure reduction without cardiac side effects. The utility of L-VNS for the second patient was halted due to significant bleeding, prompting a switch to R-VNS, which led to a 50% control of seizures without any cardiac complications (Navas et al., 2010).

In a medical series reported by Galbarriatu et al. (2015), one patient underwent R-VNS, which resulted in a seizure burden reduction comparable to that achieved with L-VNS. There were no significant cardiorespiratory events reported either in the immediate post-operative period or in the longer follow-up. Collectively, these cases highlight R-VNS as a viable alternative when L-VNS is unsuitable due to individual conditions or complications, underscoring the potential for off-label VNS applications to provide significant clinical benefits for epilepsy.

While the focus has often been to stimulate the R-VNS due to its innervation to the SA node to stimulate heart activity, research has shown that L-VNS also provides significant cardiovascular benefits, in the management of heart failure.

In humans, the ANTHEM-HF study demonstrated that chronic iVNS in heart failure patients with reduced ejection fraction was safe, feasible, and associated with significant clinical benefits (Premchand et al., 2016). Sixty patients with symptomatic heart failure (LVEF ≤40%, NYHA Class II–III) were enrolled and randomized to receive either L-VNS or R-VNS. After six months of therapy, L-VNS led to an average increase in left ventricular ejection fraction from 32.0 to 37.2%. Both groups showed gains in six-minute walk distance, with the left-sided group improving by 58.4 meters. Heart rate variability also improved in both arms, and there were no device-related serious adverse events. There were no statistically significant differences in efficacy between L-VNS and R-VNS, and the data were pooled for extended analysis. However, in the larger ANTHEM-HFrEF trial of over 500 patients, iVNS did not significantly improve primary clinical endpoints, and outcomes were not reported separately by stimulation side, limiting conclusions about laterality (Konstam et al., 2019, 2024).

Clinical studies investigating R-VNS for cardiac regulation have yielded mixed results. The first human trial using the CardioFit system showed improvements in New York Heart Association class, quality of life, and left ventricular end-systolic volume in eight patients with heart failure (Schwartz et al., 2008). The NECTAR-HF trial found R-VNS did not significantly impact cardiac remodeling and functional capacity but did improve quality of life measures (Zannad et al., 2015). The INOVATE-HF trial reported that while R-VNS improved quality of life and functional class, it did not significantly reduce the rate of death or heart failure events in patients (Gold et al., 2016).

In the ANTHEM-HF patients receiving R-VNS experienced a mean increase in left ventricular ejection fraction from 32.9 to 39.0%, along with a 70.5-meter improvement in six-minute walk distance over 6 months. Heart rate variability improved, and importantly, device-related adverse events were significantly lower in the right-sided group, with a 4:1 ratio favoring R-VNS. The study indicated that autonomic regulation therapy via R-VNS was well-tolerated and maintained improvements in heart function and symptoms over a 12-month period (Premchand et al., 2016). However, the subsequent ANTHEM-HFrEF trial did not replicate these benefits and failed to show significant improvement in primary clinical outcomes (Konstam et al., 2019, 2024). Most recently, a sham-controlled, double-blind, randomized clinical trial demonstrated significant improvements in global longitudinal strain, inflammatory cytokines, and quality of life in patients with heart failure with preserved ejection fraction through taVNS (Stavrakis et al., 2022). Importantly, no device-related side effects were observed. These collective findings suggest that while R-VNS shows promise as a treatment for heart failure, further research is necessary to fully understand its efficacy and optimize its clinical application in humans.

L-VNS is an effective FDA-approved treatment for depression in patients who do not respond to conventional antidepressants. Initial studies by Rush et al. (2000) demonstrated that over 30% of participants experienced a positive response on the Hamilton Depression Rating Scale (HDRS) following L-VNS. A subsequent year-long clinical trial confirmed significant and sustained mood improvements (Rush et al., 2005). Additional longitudinal studies have also shown progressively improving response and remission rates in patients with chronic or recurrent major depressive episodes (Nahas et al., 2005; Schlaepfer et al., 2008). Significant reductions in additional clinical depression indexes, including Beck Depression Inventory (BDI) scores, have also been observed over time after iVNS administration with scores decreasing from a baseline mean of 37.8 to 24.6 at 12 months, along with a 28.6% response rate and 7.1% remission at 1 year (Cristancho et al., 2011).

Investigations into optimal iVNS dosages have shown 20% of participants responded positively during the acute phase, as assessed primarily using HDRS (Aaronson et al., 2013). Long-term benefits of iVNS in treatment-resistant depression were further substantiated with sustained positive outcomes on both HDRS and BDI scores in a five-year study (Aaronson et al., 2017). The durability of therapeutic effects of L-VNS was further supported by studies showing enhanced clinical outcomes and improved quality of life for patients over extended periods (Conway et al., 2018; Kumar et al., 2019). Additionally, explorations into left tcVNS have shown promising outcomes, with the potential for reversing neurobiological changes associated with PTSD (Wittbrodt et al., 2021).

One potential mechanism behind the antidepressant effects of VNS may involve the upregulation of brain derived neurotrophic factor (BDNF) through noradrenergic signaling from the locus coeruleus, a mechanism shared with traditional antidepressants (Saarelainen et al., 2003; Follesa et al., 2007; Yang et al., 2020). Beyond its influence on BDNF, VNS also modulates several neurotransmitter systems that are critical for mood regulation. L-VNS has been shown to enhance serotonergic output from the raphe nuclei, increase dopaminergic activity in the ventral tegmental area, and promote neuroplastic remodeling in the hippocampus and cortex. It further reduces GABAergic inhibition and alters activity in key brain regions such as the insular cortex, anterior cingulate, and orbitofrontal cortex. These combined effects are thought to restore functional connectivity within mood-related networks and may underlie the antidepressant properties of VNS (Conway and Xiong, 2018).

L-VNS has shown promise in enhancing cognitive function in healthy individuals and patients with epilepsy. Following L-VNS administration, significant improvements in word recognition memory, figural recognition tasks, and verbal memory retention have been observed (Clark et al., 1999; Helmstaedter et al., 2001; Ghacibeh et al., 2006). Additionally, taVNS has also been shown to effectively reduce errors in working memory tasks among epileptic adults when administered before and during learning (Sun et al., 2017). In patients with Alzheimer’s disease, iVNS improved Alzheimer’s disease assessment scale-cognitive subscale and mini-mental state examination scores over 3 and 6 months, potentially enhancing cognitive functions and memory retention by decreasing tau protein accumulation and improving cerebral blood flow (Sjögren et al., 2002; Merrill et al., 2006).

Recent studies involving healthy populations have also demonstrated the potential of non-invasive L-VNS for cognitive enhancement. tcVNS increased associative memory performance in older adults when applied during and after learning (Jacobs et al., 2015). Additionally, tcVNS significantly increased performance in matrix reasoning tasks and reduced false negative errors in recognition tasks when administered before learning in healthy humans (Klaming et al., 2022). A recent review of the literature indicates VNS enhances memory by activating the NTS and subsequently the LC, increasing norepinephrine release and inducing hippocampal synaptic plasticity (Olsen et al., 2023). Collectively, these studies underscore L-VNS as a promising intervention for cognitive enhancement, highlighting its potential for broader applications in neurological therapy.

While research on R-VNS and cognition is less extensive than L-VNS, a notable study by McIntire et al. (2021) bridges this gap by applying tcVNS to the left and right sides of the neck in healthy military personnel during 34 h of sleep deprivation. Bilateral tcVNS enhanced multitasking and arousal performance, with a 5% throughput decline compared to 15% in the sham group, alongside reduced fatigue ratings. This suggests that combined L-VNS and R-VNS may offer robust cognitive benefits, potentially via synergistic activation of the locus coeruleus-norepinephrine system, warranting further exploration into the specific effects of R-VNS.

Recent human studies have shown that R-VNS does not inherently pose a greater risk of cardiac side effects compared to L-VNS in epilepsy treatment. This is in contrast to outcomes in animal models and are likely due to significant anatomical differences. For instance, in dogs, pronounced cardiac effects like bradycardia or asystole may arise when stimulation occurs proximally because of more distally originating cervical cardiac nerves (Schuessler et al., 1986). Individual anatomical variations in humans can inadvertently stimulate cardiac fibers, causing bradycardia during both R-VNS and L-VNS; however, these effects are infrequent and often detected during intraoperative testing (Cantarín-Extremera et al., 2016). Cardiac side effects during VNS in humans can also result from improper electrode placement, stimulation parameters, device malfunctions, and polarity reversal. This may lead to erratic stimulation intensities or enhanced cardiac responses (Frei and Osorio, 2001; Amark et al., 2007; Spuck et al., 2008; Iriarte et al., 2009). Furthermore, rare respiratory side effects like dyspnea and worsening asthma observed with both R-VNS and L-VNS may result from the stimulation of capsaicin-sensitive afferent fibers (Undem et al., 1990; McGregor et al., 2005). A recent multicenter review further supports these findings, reporting slightly lower tolerability in epilepsy patients receiving R-VNS, with adverse effects including dyspnea, hoarseness, and sleep-related symptoms (Zanello et al., 2025). Furthermore, MRI studies suggest that the cardiac effects observed may result from long-term VNS-induced changes in the NTS and its projections to other brain nuclei, impacting higher autonomic functions (Narayanan et al., 2002; Amark et al., 2007). These findings emphasize that both R-VNS and L-VNS can be administered safely under controlled conditions with careful attention to technical and anatomical considerations.

Initial concerns about potential cardiac complications from R-VNS have not been substantiated in clinical trials and animal studies. For instance, the ANTHEM-HF trial demonstrated R-VNS maintains a good safety profile and improves the quality of life in patients with heart failure, showing no significant differences in efficacy between R-VNS and L-VNS (Premchand et al., 2016). Importantly, device-related adverse events were lower in the right-sided group, suggesting favorable tolerability. Further research into the effects of R-VNS and L-VNS on cardiac repolarization and hemodynamics in a porcine model found both methods equally increased action potential duration (APD) across various heart regions. There was no significant laterality in their effects with greater prolongation of APD at the heart’s apex than at the base and similar impacts on the anterior, posterior, and lateral walls of both ventricles (Yamakawa et al., 2014). Hemodynamic responses, including left ventricular end-systolic pressure and the rate of pressure development, showed no differences between L-VNS and R-VNS, indicating a lack of functional laterality. Additionally, studies with hypertensive rats have shown L-VNS induced more pronounced bradycardia, hypotension, and tachypnea compared to R-VNS (Stauss, 2017). These differences in cardiovascular and respiratory responses were influenced by stimulation parameters: lower frequencies and shorter pulse durations activated larger A-fibers, while longer pulse durations recruited smaller B-fibers. These findings collectively suggest that R-VNS and L-VNS can be safely and effectively used in heart failure treatment, emphasizing the importance of careful attention to stimulation parameters to optimize outcomes.

Recent findings in rodents have revealed a compelling advantage in targeting the right cervical VN, especially in activating the dopaminergic midbrain and noradrenergic neurons in the LC. A study in Long-Evans rats tested the differential effects of VNS when self-administered to the right or left cervical VN, providing the first evidence that R-VNS reinforces learned behaviors, which was absent with L-VNS (Brougher et al., 2021). The enhanced behavior correlated with a significant rise in c-Fos expression within tyrosine hydroxylase-positive (TH+) neuronal populations in the ventral tegmental area and substantia nigra pars compacta, suggesting R-VNS may enhance therapeutic outcomes for diseases like Parkinson’s by more effectively engaging the dopaminergic pathways. Additionally, R-VNS led to a higher percentage of TH + cells in the LC, corroborating previous research indicating the right cervical branch of the VN possesses significantly more TH + nerve fibers than the left cervical branch (Verlinden et al., 2016). The increased number of TH + cells is associated with greater availability of catecholamines, such as dopamine, norepinephrine, and epinephrine, as well as elevated levels of neurotrophic factors like BDNF (Weihe et al., 2006; Farrand et al., 2020). While L-VNS has been shown to exert its beneficial effects by activating noradrenergic neurons and promoting the release of norepinephrine and BDNF (Bonaz et al., 2019; Berger et al., 2021; Olsen et al., 2023), the greater potential for norepinephrine and BDNF production with R-VNS suggests it could offer similar or even superior clinical benefits. However, how these findings translate to humans has yet to be determined.