Abstract
Background: The vagus nerve, a key element of the parasympathetic nervous system, regulates vital processes such as heart rate, digestion, and immune function. Non-invasive Vagus Nerve Stimulation (nVNS) techniques, including transcutaneous auricular (taVNS) and cervical (tcVNS) methods, have emerged as promising alternatives to invasive stimulation. These approaches show potential in treating neurological, psychiatric, and inflammatory disorders. This scoping review evaluates the therapeutic potential of nVNS, synthesizing evidence on its efficacy, applications, and research gaps. In this scoping review, a systematic literature search was performed in PubMed, Scopus, Cochrane Library, and Google Scholar using terms like “non-invasive vagus nerve stimulation”, “taVNS”, and “tcVNS”. Studies exploring nVNS applications in psychiatric, neurological, and inflammatory disorders were included, focusing on clinical outcomes, protocols, and therapeutic impacts. nVNS demonstrates promise in autonomic modulation, reducing symptoms of treatment-resistant depression, anxiety, and inflammatory conditions like rheumatoid arthritis and Crohn’s disease. It also shows potential in managing migraines, cluster headaches, and aiding post-stroke rehabilitation. However, variability in study designs and stimulation protocols limits definitive conclusions.
Non-invasive vagus nerve stimulation is a promising non-pharmacological therapy with diverse applications. Standardized large-scale clinical trials are required to optimize stimulation parameters, ensure long-term safety, and develop robust therapeutic guidelines.
Keywords: Depression, Migraine disorders, Parasympathetic nervous system, Search engine, Stroke rehabilitation, Vagus nerve, Vagus nerve stimulation 

Introduction
The vagus nerve, a key component of the parasympathetic nervous system, plays a crucial role in regulating a wide range of physiological processes, including heart rate, digestion, respiratory rate, and inflammatory response. As such, Vagus Nerve Stimulation (VNS) has garnered significant interest in recent years for its potential therapeutic applications across various medical fields. Traditionally, VNS was administered through an invasive surgical procedure that involved implanting an electrode around the vagus nerve in the neck, which was primarily used for treating refractory epilepsy and depression (1). However, due to the invasive nature and associated risks of surgical VNS, recent advancements have led to the development of nVNS techniques that offer a safer, more accessible alternative (2). Non-invasive methods, which primarily include transcutaneous auricular Vagus Nerve Stimulation (taVNS) and transcutaneous cervical Vagus Nerve Stimulation (tcVNS), have shown promising results in a variety of conditions, expanding their potential use far beyond neurological disorders.
The mechanism of action behind VNS lies in its ability to modulate the Autonomic Nervous System (ANS) and influence neuroinflammatory processes (3). Stimulation of the vagus nerve activates afferent fibers that project to the nucleus tractus solitarius in the brainstem, which then interacts with several brain regions involved in mood regulation, pain processing, and inflammatory response (4). Through the cholinergic anti-inflammatory pathway, VNS has been shown to reduce the release of pro-inflammatory cytokines, which can be particularly beneficial in conditions characterized by chronic inflammation, such as rheumatoid arthritis, inflammatory bowel disease, and certain cardiovascular diseases (5). Additionally, by modulating ANS balance, VNS has demonstrated potential in managing conditions associated with autonomic dysfunction, including migraine, post-traumatic stress disorder, and even obesity (6,7).
Non-invasive VNS, with its ease of application and lower side-effect profile, has enabled researchers to explore the potential of VNS in a broader range of conditions, including psychiatric, neurological, and inflammatory disorders. In the realm of psychiatric applications, for example, studies have found that nVNS may help alleviate symptoms in patients with treatment-resistant depression and anxiety disorders by enhancing neuroplasticity and regulating mood-related brain circuits (8). Neurological applications have similarly expanded, with evidence suggesting that nVNS can serve as a non-pharmacological option for migraine and cluster headache management (9,10). Beyond these areas, nVNS is also being investigated for its potential role in modulating cognitive function and improving outcomes in post-stroke rehabilitation, where it could facilitate neurorehabilitation by promoting neurogenesis and motor recovery (11).
Despite the growing body of evidence supporting the efficacy of nVNS, there are several challenges and limitations associated with its application. The heterogeneity of study designs, variability in stimulation parameters, and differences in targeted patient populations have resulted in mixed findings and make it challenging to draw definitive conclusions about its clinical utility (12). Furthermore, while nVNS devices are generally well tolerated, some patients report discomfort, and optimal stimulation parameters are still under investigation (13). The need for standardized protocols and well-designed, large-scale clinical trials is crucial to establish the safety and efficacy of nVNS and to better understand its therapeutic mechanisms (14).
The present scoping review aims to synthesize current evidence on the therapeutic potential of non-invasive VNS across a range of medical conditions. By exploring recent studies and highlighting emerging trends, this review seeks to provide a comprehensive overview of the current landscape and to identify gaps in knowledge that warrant further investigation. Understanding the breadth and limitations of nVNS applications can guide future research efforts and inform clinical practice, potentially leading to more personalized and effective interventions (15).

Materials and Methods
Study design
This scoping review followed the methodological framework outlined by Arksey and O’Malley for conducting scoping studies, with enhancements proposed by Levac et al, to explore the therapeutic potential of nVNS. The review aimed to map the current evidence, identify key areas of application, and highlight gaps in research, consistent with the exploratory nature of scoping reviews (16,17).

Literature search strategy
The review was conducted, and the study included data from the past 10 years, covering the period from 2012 to 2023, utilizing a comprehensive search across PubMed, Scopus, Cochrane Library, and Google Scholar to identify relevant peer-reviewed and gray literature. The search employed keywords such as “non-invasive vagus nerve stimulation”, “transcutaneous auricular vagus nerve stimulation (taVNS)”, “transcutaneous cervical vagus nerve stimulation (tcVNS)”, “neuroinflammation”, “autonomic regulation”, and “cholinergic anti-inflammatory pathway”. Boolean operators like “AND” and “OR” and truncation techniques were applied to refine the search strategy. Studies published in English involving human participants were included, while conference abstracts, editorials, and opinion pieces were excluded to maintain the review’s focus and rigor (18).

Inclusion criteria
Studies were included if they examined the therapeutic applications of nVNS across various conditions, including psychiatric, neurological, inflammatory, and cardiovascular disorders. Eligible studies focused on key outcomes such as symptom alleviation, modulation of the autonomic nervous system, reduction of inflammatory markers, and functional improvements. Additionally, they provided detailed descriptions of nVNS protocols, including the type of device used, stimulation parameters, and the application site (auricular or cervical). The study designs considered for inclusion encompassed Randomized Controlled Trials (RCTs), cohort studies, case-control studies, and case series that employed robust methodologies (19,20).

Exclusion criteria
Studies were excluded if they focused exclusively on invasive VNS techniques, did not report on the therapeutic outcomes of interest, lacked sufficient methodological detail or outcome measures, or were non-human studies. Additionally, publications in languages other than English were also excluded (21,22).

Bias mitigation
To reduce potential bias, studies with possible conflicts of interest—particularly those funded by manufacturers of nVNS devices—were carefully assessed for transparency and methodological rigor. Priority was given to independent, peer-reviewed research, while studies lacking clear or adequate control mechanisms were excluded from the analysis. Table 1 presents the Cochrane Risk of Bias assessment for the included studies.

Data extraction
Comprehensive data were systematically extracted from each selected study to facilitate a thorough evaluation and synthesis of findings. This included detailed information on the study design (e.g., RCTs, observational studies), methodological approach, and total sample size. In addition, participant demographics were carefully recorded, encompassing variables such as age, gender distribution, and specific medical conditions or diagnoses relevant to the study population.
Critical aspects of the nVNS protocol were meticulously documented. These included the type and model of the stimulation device, the anatomical site of stimulation (e.g., cervical or auricular branches of the vagus nerve), stimulation parameters (such as pulse width, frequency, and intensity), treatment frequency (number of sessions per day or week), and overall duration of the intervention period.
Furthermore, outcome measures were extracted with a focus on both efficacy and safety. This involved recording primary and secondary clinical endpoints, such as symptom improvement scores, functional outcomes, quality-of-life measures, and the incidence and severity of any reported adverse events. These results were analyzed in the context of the conclusions drawn by the original study authors, with particular attention to the demonstrated therapeutic potential of nVNS across different patient populations and clinical settings (23).
Table 2 provides a comprehensive overview of the key characteristics of the included studies, while table 3 details participant enrollment numbers, retention rates, and any reported attrition, thereby supporting the evaluation of study quality and the reliability of findings.

Review registration and ethical approval
The review was not prospectively registered, as is typical for scoping reviews. Ethical considerations were adhered to, focusing solely on publicly available data (24).

Results
The process of literature search and study selection was systematically documented using the PRISMA flow diagram. This diagram outlines the number of records identified, screened, assessed for eligibility, and ultimately included in the review, with reasons for exclusion noted at each stage. Extracted data were synthesized and organized into tables that summarize key aspects of each study, including design, intervention protocols, outcome measures, and main findings.
Figure 1 presents the PRISMA flow diagram illustrating the selection process. The final set of included studies encompassed a range of research designs: three randomized controlled trials (RCTs), four randomized crossover design studies, one randomized placebo-controlled crossover trial, two crossover studies, and one open-label pilot study.

Table 1. Cochrane risk of bias table of included studies

 +: Low risk of bias, -: High risk of bias, ?: Unclear risk of bias.

Table 2. Characteristics of the included studies

Table 3. Study participant enrollment and retention details

 Discussion
The findings of this scoping review highlight the therapeutic potential of nVNS across a range of applications, including autonomic modulation, inflammatory response attenuation, and mental health improvement. By synthesizing results from studies spanning over a decade, key insights into the mechanisms, clinical applications, and research gaps have been identified.

Mechanisms of action and physiological impact
The physiological basis of nVNS has been extensively investigated, with key contributions from Clancy et al and Antonino et al. Clancy and colleagues examined how nVNS modulates Heart Rate Variability (HRV), demonstrating its potential to influence the autonomic nervous system by enhancing parasympathetic activity and reducing sympathetic overdrive. This modulation of autonomic tone is crucial for various conditions, including cardiovascular disorders, where maintaining a balanced autonomic function is vital. Antonino et al further confirmed these findings, highlighting transcutaneous Vagus Nerve Stimulation (tVNS) and its ability to strengthen parasympathetic activity. By reducing sympathetic dominance, tVNS offers therapeutic potential for conditions such as anxiety and stress, which are often linked to autonomic dysregulation. Additionally, nVNS and tVNS have shown promising effects in treating migraine and cluster headaches, providing a non-pharmacological option for managing these debilitating conditions that involve altered autonomic regulation (25,26).

Applications in neurology and psychiatry
The potential for nVNS to influence brain function has been explored in depth, particularly in the context of neurological and psychiatric disorders. Sclocco et al utilized advanced neuroimaging techniques to investigate the effects of nVNS on brain regions responsible for pain processing. Their study identified significant changes in activity within the anterior cingulate cortex and insula, areas known to play pivotal roles in pain perception and emotional regulation. These findings suggest that nVNS could be an effective intervention for managing chronic pain conditions such as migraines and fibromyalgia, where traditional treatment options often fall short (27).
Additional studies by De Couck et al and Nagai et al expanded on these findings by examining the interaction between nVNS and the Hypothalamic-Pituitary-Adrenal (HPA) axis. Their research revealed that nVNS not only reduces sympathetic activity, but also helps regulate the HPA axis, a critical system involved in stress response and inflammatory processes. By attenuating overactivation of the HPA axis, nVNS demonstrates the potential to alleviate stress-induced physiological damage and control inflammatory pathways. These findings highlight nVNS as a promising approach to managing systemic inflammatory diseases and stress-related disorders, such as chronic inflammation, anxiety, and Post-Traumatic Stress disorder (PTSD) (28,29).
In the realm of psychiatry, Stowell et al explored the impact of nVNS on mood regulation. Their work demonstrated how nVNS influences neural circuits involved in emotional processing, providing evidence for its application in mood disorders like depression and anxiety. This aligns with the findings of Garcia et al, who emphasized the role of nVNS as an adjunctive therapy for depression. The study highlighted how nVNS complements conventional pharmacological treatments by modulating neural pathways associated with emotional dysregulation, thereby offering potential benefits for patients with treatment-resistant depression. This ability to target specific neural networks highlights the versatility of nVNS in addressing psychiatric conditions where therapeutic needs remain unmet (30,31).

Anti-inflammatory and immunomodulatory effects
The anti-inflammatory properties of nVNS have been extensively investigated, with studies by Fisher et al and Staley et al shedding light on its mechanisms. These studies highlight the activation of the cholinergic anti-inflammatory pathway by nVNS, which plays a pivotal role in modulating the immune response. Through this pathway, nVNS effectively reduces the release of pro-inflammatory cytokines, including Tumor Necrosis Factor-alpha (TNF-alpha) and Interleukin-6 (IL-6). Such findings underscore the therapeutic potential of nVNS in managing chronic inflammatory conditions such as rheumatoid arthritis and Crohn’s disease, where inflammation is a central pathological feature (32,33).

Device innovation and technological advances
The advancements in device technology have been instrumental in enhancing the accessibility and effectiveness of nVNS therapies. Sinkovec et al highlighted significant progress in the development of wearable nVNS devices, which prioritize user-friendliness and improved therapeutic efficacy. These devices are designed to increase patient compliance by offering non-invasive, portable, and easy-to-use options that can seamlessly integrate into daily routines (34).
More recently, Kaduk et al expanded the understanding of nVNS by examining its role in metabolic regulation. Their findings demonstrate a connection between vagus nerve stimulation and metabolic homeostasis, suggesting that nVNS may influence weight management and other metabolic processes. This integrative approach broadens the applicability of nVNS, emphasizing its potential to address both inflammatory and metabolic disorders through non-invasive means (35).
Kaduk et al further explored innovations in device safety and functionality, introducing designs optimized for long-term use across diverse patient populations. These improvements address concerns about prolonged stimulation and potential adverse effects, thereby making nVNS more practical for chronic use in clinical and home settings. Together, these advancements pave the way for broader adoption of nVNS in clinical practice, particularly in managing conditions that require ongoing therapeutic interventions (35).

Research gaps and future directions
Despite significant progress in understanding and implementing nVNS, several critical gaps remain. A recurring limitation in the literature, including studies by Fisher et al and Garcia et al, is the focus on short-term outcomes. While these studies provide valuable insights into the immediate benefits of nVNS, the long-term sustainability and safety of these effects remain unclear. This lack of longitudinal data limits the ability to fully assess the durability of therapeutic benefits over extended periods (31,32).
Another challenge lies in the variability of stimulation parameters used across studies, such as frequency, intensity, and duration. This inconsistency complicates the establishment of standardized treatment protocols, hindering widespread clinical adoption. Comparative studies examining the efficacy of auricular vs. cervical stimulation are also limited, leaving room for ambiguity about which method is more effective for specific conditions.
To address these gaps, future research should prioritize longitudinal studies to evaluate the sustained effects and safety of nVNS over extended periods, spanning months or years. Comparative trials are also essential to determine the relative effectiveness of auricular versus cervical stimulation, which could guide the selection of the most appropriate application for different patient populations. Additionally, expanding the application of nVNS to underserved therapeutic areas, such as pediatric populations and neurodegenerative conditions, holds the potential to uncover new opportunities for its use. By tackling these challenges, future studies can build upon existing evidence to optimize the therapeutic potential of nVNS and broaden its scope in medical practice.

Conclusion
The findings from this scoping review underscore the significant therapeutic potential of nVNS across multiple clinical domains, including autonomic regulation, mental health management, and the modulation of inflammatory responses. The ability of nVNS to influence autonomic nervous system activity presents promising applications in the management of cardiovascular conditions, anxiety, and stress-related disorders. Its positive effects on mental health, particularly in mood disorders such as depression, have been increasingly recognized in recent research. Additionally, the observed anti-inflammatory properties suggest potential benefits in addressing chronic inflammatory conditions.
For allied health professionals, these findings hold practical relevance in broadening therapeutic strategies and integrating nVNS as a complementary modality within multidisciplinary care. 
Physiotherapists, occupational therapists, and other allied health practitioners can consider the use of nVNS in rehabilitation programs aimed at enhancing autonomic balance, improving mental well-being, and reducing systemic inflammation. Its non-invasive nature makes it an attractive option for long-term management and patient compliance.
However, the current variability in stimulation parameters—including frequency, intensity, and duration—poses a challenge to widespread clinical adoption. Thus, allied health professionals should advocate for and participate in the development of standardized protocols and clinical guidelines. Furthermore, long-term and large-scale studies are needed to validate the sustained benefits of nVNS and establish its role within routine clinical practice.

Limitations
This scoping review provides an overview of nVNS but has several limitations. The included studies exhibit heterogeneity in design, sample sizes, and methodological quality, complicating definitive conclusions. Variations in stimulation parameters (e.g., frequency, intensity, and duration) further hinder result comparisons. Additionally, many studies lack long-term follow-up, limiting the assessment of sustained effects and safety. The absence of comparative trials between different nVNS techniques and the exclusion of non-English studies may have omitted relevant research. These factors highlight the need for more rigorous, large-scale, long-term studies.

Acknowledgement
The authors would like to thank all researchers whose published work contributed to this scoping review. We also acknowledge the support and guidance provided by colleagues and faculty members during the preparation of this manuscript. No specific funding was received for this study.

Conflict of Interest
Authors declare no conflict of interest.