A Prospective on Vagal Tone via Auricular Stimulation and Deep Breathing

The Vagal Nerve Complex and Its Role in Autonomic Regulation 

The vagal nerve, or the tenth cranial nerve, is a paramount component of the autonomic nervous system, playing a pivotal role in the regulation of various bodily functions. As one of the longest nerves in the body, it extends from the brainstem through the neck and into the abdomen, innervating multiple organs, including the heart, lungs, and digestive tract. This extensive reach positions the vagus nerve as a critical mediator in autonomic function, influencing processes such as heart rate, gastrointestinal peristalsis, sweating, and muscle movements in the mouth [1]. 

Heart rate variability (HRV), a measure of the variation in time between each heartbeat, is heavily influenced by the vagal nerve. HRV is an index of the autonomic nervous system's activity and an indicator of an individual's ability to adapt to stress and environmental demands. Higher HRV is associated with greater vagal tone, signifying a body’s efficient response to stressors, while lower HRV indicates reduced vagal activity and can be a predictor of poor cardiovascular outcomes [2]. 

Furthermore, the vagus nerve plays a vital role in modulating inflammation. Through the cholinergic anti-inflammatory pathway, it can inhibit the release of pro-inflammatory cytokines, thereby controlling inflammatory responses. This pathway is a part of the body's mechanism for controlling immune response and inflammation, with implications for diseases characterized by excessive inflammation [3]. 

Given its extensive influence on autonomic and immune function, the vagal nerve complex emerges as a critical area of study in understanding and potentially managing a range of conditions characterized by autonomic dysregulation and inflammatory processes (Figure 1). 

Figure 1: Generalized outline of relationship between the effects of the interventions on the vagal nerve, the influences throughout the autonomic system, the metrics used to determine the extent of change, and the disease burdens that may be affected.

Chronic Diseases Linked to Low Vagal Tone and High Inflammation 

Chronic diseases, characterized by prolonged duration and slow progression, pose significant challenges to healthcare systems globally. The rise in Non-Communicable Diseases (NCDs) such as cardiovascular diseases, diabetes, and various forms of cancer has been linked to systemic inflammation and autonomic imbalance, particularly low Heart Rate Variability (HRV) indicating reduced vagal tone. Systemic inflammation, a sustained, low-grade inflammation without overt symptoms, is increasingly recognized as a critical factor in the pathogenesis and progression of these chronic diseases [4]. 

HRV, as a non-invasive measure of autonomic nervous system function, particularly the balance between sympathetic and parasympathetic activity, is crucial in understanding the relationship between autonomic dysfunction and chronic diseases. Lower HRV has been associated with an increased risk of various health issues, including coronary artery disease, hypertension, diabetes, and metabolic syndrome. This association suggests that reduced vagal tone may predispose individuals to a host of pathophysiological conditions that underlie these diseases [5].

Furthermore, the growing prevalence of chronic, non-communicable diseases worldwide, often attributed to lifestyle factors such as physical inactivity, unhealthy diet, and tobacco use, is compounded by the challenge of managing systemic inflammation and autonomic dysregulation. Traditional pharmacological interventions often target specific symptoms or disease processes but may not adequately address the underlying autonomic and inflammatory dysfunctions. This gap highlights the need for novel, effective approaches to managing chronic diseases that can modulate autonomic function and reduce systemic inflammation, potentially through lifestyle and behavioral modifications [6]. 

Vagal Nerve Stimulation, Vagal Tone, and Their Relationship to Health

Vagal Nerve Stimulation (VNS) refers to a therapeutic modality involving the deliberate modulation of the vagus nerve's activity, often used to treat disorders such as epilepsy and depression. This technique can be invasive, involving surgical implantation of a device that electrically stimulates the vagus nerve, or non-invasive, using external devices to stimulate vagal nerve endings in the ear or neck (Ben-Menachem, 2002) [7]. VNS has been observed to affect various physiological parameters and has been researched for its potential in treating a variety of conditions beyond its original applications.

Vagal tone, an indicator of the activity of the vagus nerve, is closely associated with the parasympathetic nervous system's control over heart rate. Higher vagal tone is generally indicative of a body's capacity to regulate internal processes efficiently and adapt to stress. It is measured indirectly through Heart Rate Variability (HRV), where a high HRV is an indicator of good vagal tone and robust autonomic function, signifying a greater ability to adapt to stress [1].

The relationship between vagal tone and health is multifaceted. High vagal tone has been associated with improved cardiovascular health, lower levels of inflammation, better glucose regulation, and enhanced emotional regulation. In contrast, low vagal tone has been linked with health conditions such as chronic heart failure, depression, and inflammatory diseases [3].

Moreover, VNS, by improving vagal tone, has shown potential in managing these conditions. For example, in cardiovascular diseases, VNS has been found to reduce heart rate, lower blood pressure, and improve cardiac function. In the realm of mental health, VNS can modulate mood and emotional responses, offering a therapeutic avenue for depression and anxiety disorders [8].

In the context of metabolic disorders, the role of vagal tone is significant. The vagus nerve innervates many digestive tract organs and plays a critical role in regulating glucose metabolism and satiety signals. Studies have shown that VNS can influence eating behavior and energy metabolism, suggesting potential applications in obesity and diabetes management [9].

The broad influence of the vagus nerve on various physiological systems underscores its importance in maintaining health and homeostasis. The ongoing research into VNS presents a promising avenue for addressing a range of health conditions, highlighting the potential for novel therapeutic strategies centered around modulation of vagal activity.

Auricular Stimulation and Vagal Tone

Auricular stimulation, a form of therapy involving the stimulation of specific points on the ear, has garnered significant interest in the context of enhancing vagal tone. This therapeutic approach, rooted in principles of auricular acupuncture, leverages the rich innervation of the ear by several cranial nerves, including the vagus nerve. The external ear is mainly innervated by the Auricular Branch of the Vagus Nerve (ABVN), which provides a unique and accessible target for non-invasive vagal stimulation [10].

Biologically, auricular stimulation is thought to activate the ABVN, which then transmits signals to the nucleus of the solitary tract in the brainstem. This nucleus is a primary integration center for autonomic nervous system signals and plays a critical role in modulating cardiac and respiratory functions. Activation of this pathway through auricular stimulation can enhance vagal tone, as evidenced by increased heart rate variability [11].

Several studies have investigated the mechanisms through which auricular stimulation affects vagal tone. It has been suggested that the stimulation of specific auricular points can influence the autonomic nervous system, promoting a shift towards parasympathetic dominance. This shift is associated with a reduction in heart rate, lower blood pressure, and improved cardiac function, all indicative of enhanced vagal tone [12].

In addition, auricular stimulation has been linked to changes in neurotransmitter levels, particularly acetylcholine, the primary neurotransmitter of the parasympathetic nervous system. Stimulation of the auricular branch of the vagus nerve can lead to increased acetylcholine release, thereby augmenting parasympathetic activity and enhancing vagal tone. This increased parasympathetic activity is crucial for maintaining homeostasis and has been implicated in the regulation of inflammatory responses, indicating potential therapeutic applications in conditions characterized by chronic inflammation [13].

Auricular stimulation's efficacy and the specificity of point selection have been subjects of ongoing research. Recent advancements in neuroimaging techniques, such as functional Magnetic Resonance Imaging (fMRI), have facilitated a deeper understanding of the neural pathways involved. These studies have shown that stimulation of specific auricular points can lead to activation of particular brain regions associated with autonomic regulation. For instance, activation of areas such as the prefrontal cortex and the insula, both linked to the autonomic control, has been observed during auricular stimulation. This activation suggests a central mechanism by which auricular stimulation can modulate autonomic functions and enhance vagal tone [14].

The application of auricular stimulation in clinical settings has also provided insights into its potential therapeutic benefits. Clinical trials have reported improvements in symptoms of conditions like migraine, anxiety, and hypertension, which are associated with dysregulated autonomic function and low vagal tone [15]. Auricular stimulation on the central nervous system, particularly the limbic system and brain regions, has also been associated with stress and emotional regulation. By modulating activity in these areas, auricular stimulation can potentially alleviate symptoms of stress, anxiety, and depression, further contributing to its effects on overall health and well-being [16]. These improvements further underscore the relationship between auricular stimulation and enhanced vagal activity.

Furthermore, auricular stimulation's role in pain management highlights its influence on the endogenous opioid system. The release of endorphins, triggered by auricular stimulation, can modulate pain perception, again implicating the vagus nerve and its role in pain regulation and stress response [17].

The relationship between auricular stimulation and vagal tone is grounded in a complex interplay of neural pathways, neurotransmitter release, and central and peripheral nervous system interactions. The convergence of evidence from neurophysiological, neuroimaging, and clinical studies underscores the potential of auricular stimulation as a non-invasive approach to enhance vagal tone and improve autonomic regulation, with broad implications for health and disease management.

Deep Breathing, Vagal Tone, and Respiratory-Gated Afferent Nerve Stimulation (RAVANS)

Deep breathing, or diaphragmatic breathing, is a practice that has been linked to improvements in vagal tone. The practice of deep breathing involves slow, intentional inhalation and exhalation, which can directly stimulate the vagus nerve and enhance parasympathetic nervous system activity, thereby increasing heart rate variability and improving vagal tone [18].

The physiological mechanisms underlying the relationship between deep breathing and vagal tone are multifaceted. During deep breathing, the diaphragm moves downward, causing the lungs to expand and the heart rate to slow down momentarily. This action activates the baroreflex, a physiological response that helps regulate blood pressure, and increases vagal activity. The subsequent increase in HRV during deep breathing is a manifestation of this enhanced vagal tone. This physiological response has been observed in various studies, indicating a consistent link between controlled breathing, vagal activation, and autonomic balance [19].

Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) is a novel technique that combines the principles of auricular stimulation with the benefits of controlled breathing. RAVANS specifically targets the auricular branch of the vagus nerve, synchronizing the stimulation with the respiratory cycle. The technique is based on the premise that the vagus nerve is more receptive to stimulation during the exhalation phase of breathing, thus potentially maximizing the therapeutic effects of vagal stimulation [20].

In RAVANS, stimulation is typically delivered to the ear, a region richly innervated by the vagus nerve, during the exhalation phase of deep breathing. This approach ensures that the timing of the stimulation coincides with the natural peak of vagal activity, potentially enhancing the efficacy of the intervention. Clinical studies have shown that RAVANS can lead to significant improvements in HRV and reductions in symptoms of conditions such as anxiety and depression, which are often associated with low vagal tone [21].

RAVANS has been previously explored for its potential in pain management and inflammation reduction. By modulating vagal activity, RAVANS can influence the body’s pain pathways and inflammatory responses, offering a non-pharmacological approach to managing chronic pain and inflammation-related disorders. The technique’s impact on the central nervous system, particularly in areas involved in pain and stress regulation, further substantiates its role in enhancing vagal tone and improving overall health outcomes [22].

The relationship between deep breathing and vagal tone is well-established, with deep breathing practices consistently shown to enhance parasympathetic activity and improve autonomic regulation. The advent of RAVANS as a technique that synergistically combines auricular stimulation with controlled breathing offers a promising avenue for non-invasively enhancing vagal tone and addressing a range of health conditions associated with autonomic dysfunction.

The Complementarity of Auricular Stimulation with Deep Breathing Practices like RAVANS

The convergence of auricular stimulation and deep breathing practices, particularly in the form of Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), presents a nuanced approach to autonomic regulation, specifically in enhancing vagal tone. This integrative method capitalizes on the unique strengths of each technique, potentially yielding a more profound impact on autonomic balance and health outcomes.

Auricular stimulation primarily targets the auricular branch of the vagus nerve, a mechanism that has been explored extensively in the realm of auricular acupuncture. The auricular branch is particularly accessible for non-invasive stimulation, making it an ideal site for modulating vagal activity. Deep breathing, on the other hand, influences vagal tone through respiratory and baroreceptor mechanisms. These techniques, when synchronized, as in the case of RAVANS, may lead to enhanced stimulation of the vagus nerve, potentially amplifying the benefits observed from each method individually. The synergy of these techniques could result in a more significant modulation of heart rate variability than either alone [19].

The timing of stimulation in RAVANS is crucial. By aligning auricular stimulation with the respiratory cycle, specifically during the exhalation phase, the method takes advantage of the naturally occurring peak in vagal activity. This optimized timing could enhance the efficacy of the intervention, particularly in reducing sympathetic arousal and improving HRV, which is beneficial for stress-related conditions and autonomic dysregulation [23].

The impact of RAVANS on the central nervous system is also noteworthy. Both deep breathing and auricular stimulation influence central nervous system functions, especially in regions associated with stress and emotional regulation, such as the prefrontal cortex and the limbic system. The combined effect of these modalities on these brain regions may be cumulative, potentially enhancing their capacity to modulate stress responses and emotional states [22].

The anti-inflammatory potential of this combined approach could also be significant. Activation of the cholinergic anti-inflammatory pathway through both auricular routes and deep breathing have been independently identified. This combined activation can lead to greater reductions in pro-inflammatory cytokines, offering a non-pharmacological approach to managing chronic inflammation, a common underlying factor in numerous health conditions [24].

The integration of these modalities also requires consideration of potential limitations and redundancies. Overstimulation of the vagus nerve, resulting from the combination of two potent vagal nerve stimulators, could lead to adverse effects like bradycardia or gastrointestinal disturbances. Thus, it is crucial to calibrate stimulation intensity and duration to mitigate such risks. Additionally, individual variability in response to vagal nerve stimulation necessitates personalized approaches to optimize outcomes and avoid habituation, where the response to stimulation diminishes over time [25].

The combination of auricular stimulation with deep breathing practices like RAVANS offers a potentially impactful and novel approach to enhancing vagal tone and autonomic regulation. This complementary method warrants further exploration to fully elucidate its therapeutic potential and optimize its application in clinical settings.

Auricular Stimulation Methods and Deep Breathing Techniques like RAVANS

Auricular stimulation methods and deep breathing techniques, particularly Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), represent a unique convergence of traditional and modern therapeutic practices. These methods, rooted in both ancient practices and contemporary scientific understanding, offer a non-invasive approach to enhancing vagal tone and autonomic regulation.

Auricular Stimulation Methods

Auricular stimulation involves the application of stimuli to specific points on the ear. The outer ear, or auricle, is innervated by several cranial nerves, including the vagus nerve, making it a strategic site for modulating autonomic functions.

• Manual Auricular Stimulation: This traditional method involves manual pressure or massage of specific auricular points. Historically linked to auricular acupuncture, it relies on the practitioner’s understanding of the ear’s reflexology map, where different regions correspond to various body systems and organs. Variations in pressure, duration, and specific points targeted can lead to differing outcomes, influencing factors such as stress response, pain perception, and heart rate variability [26 ].
• Electrical Auricular Stimulation: In this more modern approach, electrical impulses are delivered to auricular points via electrodes. The intensity, frequency, and duration of electrical stimulation can be precisely controlled, allowing for tailored treatment protocols. This method has been used in clinical settings for pain management, stress reduction, and treatment of various neurological conditions. Variations in the electrical parameters can yield different therapeutic effects, with higher frequencies often used for pain relief and lower frequencies for relaxation and mood regulation [27]. Limitations with electrical or transcutaneous stimulation include difficulties in placement, current, and personalization [28].

Deep Breathing Techniques

Deep breathing techniques, particularly those synchronized with vagal nerve stimulation, play a crucial role in enhancing parasympathetic activity and promoting relaxation and stress reduction.

• Diaphragmatic Breathing: This technique involves deep, rhythmic breathing using the diaphragm. It promotes a more efficient exchange of oxygen and carbon dioxide and stimulates the vagus nerve, enhancing vagal tone and HRV. Variations in breathing rate and depth can alter the impact on the autonomic nervous system, with slower, deeper breaths generally enhancing parasympathetic activity.
• RAVANS: This innovative technique combines auricular stimulation with controlled breathing. It involves the application of auricular stimulation, timed with the exhalation phase of deep breathing. This synchronization takes advantage of the natural increase in vagal activity during exhalation, potentially amplifying the therapeutic effects. Variations in the timing and intensity of stimulation during different phases of the respiratory cycle can lead to different outcomes in HRV and stress response [29].

Potential Differences in Results from Variations

The variations in auricular stimulation methods and deep breathing techniques can lead to different therapeutic outcomes. For instance, manual auricular stimulation, while less precise than electrical stimulation, offers the advantage of being easily self-administered and tailored to individual comfort levels. Electrical stimulation, on the other hand, allows for more controlled and consistent delivery of stimuli but requires specialized equipment and professional oversight.

Similarly, variations in deep breathing techniques can influence their effectiveness. For example, slower breathing rates are generally more effective in increasing HRV and enhancing relaxation. The incorporation of RAVANS, with its precise timing of stimulation, can potentially enhance these effects but requires careful coordination between the breathing pattern and stimulation delivery.

Effectiveness of Auricular Stimulation and Deep Breathing on Vagal Tone, HRV, and Inflammation

The efficacy of auricular stimulation and deep breathing in affecting vagal tone has been extensively researched. These methods, individually and in combination, have been shown to positively influence heart rate variability and modulate inflammatory responses, highlighting their potential therapeutic value.

Auricular Stimulation and Vagal Tone

Auricular stimulation’s effectiveness in enhancing vagal tone is well-documented. The auricular branch of the vagus nerve, accessible through the ear, provides a direct pathway for modulating autonomic functions. Studies utilizing various forms of auricular stimulation, including manual and electrical methods, have consistently demonstrated improvements in HRV, an indicator of enhanced vagal activity. La Marca et al., [11] observed significant increases in HRV following transcutaneous auricular vagus nerve stimulation, suggesting a direct influence on parasympathetic activity. Similarly, Sator-Katzenschlager and Michalek-Sauberer [27] reported improvements in pain and stress symptoms, which are often associated with low vagal tone, using auricular electrical stimulation.

Deep Breathing and Vagal Tone

Deep breathing practices, particularly diaphragmatic breathing, have been associated with increased vagal tone and improved HRV. Russo et al., [19] demonstrated that controlled deep breathing could significantly enhance HRV, indicating a shift toward parasympathetic dominance. These findings are supported by Lehrer et al. (2017), who noted that deep breathing techniques, through their physiological effects on the baroreflex and vagal nerve, result in improved autonomic regulation.

Vagal Tone, HRV, and Inflammation

The links between vagal tone, HRV, and inflammation are a critical area of investigation. High vagal tone, often reflected in higher HRV, has been associated with reduced levels of pro-inflammatory cytokines. Pavlov and Tracey [3] highlighted the role of the vagus nerve in the inflammatory reflex, which can inhibit cytokine production and thus reduce inflammation. This anti-inflammatory effect of vagal nerve stimulation provides a theoretical basis for using auricular stimulation and deep breathing to manage conditions characterized by chronic inflammation.

Kreuzer et al., [21] provided evidence supporting the use of transcutaneous vagus nerve stimulation in reducing inflammation markers. Further supporting this, Fallgatter et al., [22] observed significant decreases in inflammatory responses following auricular stimulation. These findings are corroborated by studies on deep breathing practices, where a reduction in stress-induced inflammatory markers was noted.

Efficacy of Auricular Stimulation with Deep Breathing

Auricular stimulation methods and deep breathing techniques like RAVANS represent a comprehensive approach to enhancing autonomic function and overall well-being. The variations in these practices offer a range of therapeutic possibilities, with the potential for tailored interventions based on individual needs and responses. The therapeutic efficacy of RAVANS may also be influenced by individual differences in physiological responsiveness. Factors such as baseline vagal tone, individual stress levels, and even genetic predispositions can modulate the effects of auricular stimulation and deep breathing practices. This variability necessitates a personalized approach to the application of RAVANS, ensuring that the timing, intensity, and duration of stimulation are optimally aligned with each individual’s unique physiological and psychological profile.

The potential of RAVANS and similar integrative techniques lies in their capacity to offer a non-pharmacological, low-risk intervention for enhancing autonomic balance and managing stress-related disorders. By combining the principles of auricular stimulation with the well-established benefits of controlled breathing, these methods present an avenue for future research and clinical application, particularly in populations with dysregulated autonomic function or heightened stress and anxiety levels.

The integration of auricular stimulation with deep breathing practices like RAVANS has shown promise in amplifying the effects of each intervention. By combining the direct vagal stimulation of auricular methods with the systemic effects of controlled breathing, a more profound impact on HRV and inflammation can be achieved. Sclocco et al., [23,29] discussed the potential of this integrative approach in enhancing autonomic regulation and reducing inflammation. However, individual responses to these interventions can vary based on factors such as baseline vagal tone and physiological responsiveness. Personalized approaches in applying these techniques are crucial for maximizing therapeutic outcomes [30].

Metrics and Underlying Mechanisms

The theoretical mechanisms underlying the efficacy of deep breathing and auricular stimulation in enhancing vagal tone involve a complex interplay of neurophysiological processes. These mechanisms form the basis for proposing specific metrics to measure improvements in vagal tone, particularly focusing on heart rate variability and inflammatory biomarkers.

Mechanisms Underlying Deep Breathing

Deep breathing practices, particularly diaphragmatic breathing, have been shown to stimulate the vagus nerve, thereby increasing parasympathetic activity and enhancing vagal tone. The physiological basis for this involves several mechanisms:

• Respiratory Sinus Arrhythmia (RSA): RSA refers to the natural increase in heart rate during inhalation and decrease in heart rate during exhalation, mediated by vagal activity. Deep breathing amplifies RSA, thereby enhancing vagal tone [31].
• Baroreflex Sensitivity: Deep breathing can improve baroreflex sensitivity, a mechanism through which the body maintains blood pressure stability. Enhanced baroreflex sensitivity is associated with increased vagal tone [32].
• Central Nervous System Regulation: Controlled breathing influences the central nervous system, particularly the limbic system, which is involved in emotional regulation and the stress response. Vagal tone occurs through both neural and non-neural tissue which synchronizes neural elements in the heart, lungs, limbic system and cortex [33].

Mechanisms Underlying Auricular Stimulation

Auricular stimulation targets the auricular branch of the vagus nerve, stimulating the parasympathetic nervous system and enhancing vagal tone. Key mechanisms include:

• Direct Vagal Stimulation: Auricular points linked to the vagus nerve, when stimulated, can directly enhance vagal activity, which is seen in increased HRV [11].
• Neurotransmitter Release: Auricular stimulation can modulate neurotransmitter levels, particularly acetylcholine, the primary neurotransmitter of the parasympathetic nervous system. This modulation can enhance vagal tone [13].
• Inflammatory Reflex Modulation: The vagus nerve plays a crucial role in the inflammatory reflex. Stimulation of the vagus nerve can inhibit pro-inflammatory cytokine production, potentially improving disease burdens for a wide range of inflammatory disorders [34].

Proposed Metrics for Measuring Improvements in Vagal Tone

• Heart Rate Variability (HRV): HRV, particularly metrics like the high-frequency (HF) component, is a direct indicator of vagal tone. Increased HF-HRV suggests enhanced parasympathetic activity [35].
• Inflammatory Biomarkers: Markers such as cortisol, alpha amylase (AA), C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) can indicate changes in inflammatory status. Reductions in these markers suggest improved vagal modulation of inflammation [36].

Necessity of Identifying Corroborating Markers

To ascertain whether the effects of deep breathing and auricular stimulation are synergistic or redundant, it is essential to identify corroborating markers:

• Comparative Analysis of HRV and Inflammatory Markers: By analyzing changes in both HRV and inflammatory biomarkers, it is possible to determine if these methods work synergistically to enhance vagal tone or if their effects are redundant.
• Longitudinal Monitoring: Long-term monitoring of these markers can provide insights into the sustainability of the effects and any cumulative benefits or diminishing returns over time.
• Individual Variability: Considering individual variability in response to these interventions is crucial. Metrics like HRV can be particularly sensitive to individual differences in baseline autonomic function [5].

This comprehensive approach, incorporating both HRV and inflammatory biomarkers, aligns with the growing emphasis on holistic health measures in medical research. The integration of these metrics provides a more nuanced understanding of how auricular stimulation and deep breathing practices can synergistically or redundantly affect autonomic function and inflammatory processes. Such detailed exploration is critical in advancing the use of these non-pharmacological interventions in clinical and therapeutic settings, offering potential benefits for a wide range of conditions associated with dysregulated vagal tone and chronic inflammation.

Need for Further Research

While numerous papers referenced in this article have independently tracked the efficacy and mechanisms behind auricular stimulation and deep breathing practices, studies that approach a combination treatment as an integrative whole are rare and have been repeatedly requested. Similarly, while the effects of these interventions on vagal tone have been studied separately, there is a lack of literature tracking patterns and relationships between heart rate variability and inflammation in response to the interventions.

The potential complementarity of auricular stimulation and deep breathing requires a comprehensive, multi-pronged investigation. In order to overcome limitations related to isolated interventions or metrics, a holistic approach that tracks the breadth of changes in response to combined treatments is appropriate.

Study Design for Assessing the Effects of Manual Auricular Stimulation and Deep Breathing Practices

The proposed study aims to investigate the effects of manual auricular stimulation combined with deep breathing practices on heart rate variability and contemporary inflammatory levels. The study design involves a large cohort of participants engaging in self-administered interventions, with measurements taken through wearable devices and serological samples.
Study Population and Sampling

The study will recruit a diverse group of adult participants, ensuring a wide representation in terms of age, gender, and ethnicity. The inclusion criteria will focus on adults aged 18-65, with no existing cardiovascular or neurological conditions that could affect autonomic function. The exclusion criteria will include individuals with known inflammatory diseases, those currently on medications affecting the autonomic nervous system, and individuals with a history of ear disorders.

Intervention Protocol

Participants will be instructed in manual auricular stimulation techniques, targeting specific auricular points linked to vagal nerve activation. This non-invasive method will involve gentle massage or pressure on these points. Alongside auricular stimulation, participants will practice diaphragmatic breathing exercises, focusing on slow and deep breaths to enhance parasympathetic activity. The combination of these techniques is expected to synergistically enhance vagal tone and reduce inflammation.

Measurement of Heart Rate Variability

HRV will be continuously monitored using wearable devices capable of recording electrocardiogram (ECG) data. These devices will provide real-time, high-resolution insights into autonomic nervous system activity. Participants will be instructed to wear these devices throughout the study duration, ensuring a comprehensive dataset of HRV metrics, including time-domain (e.g., RMSSD, SDNN) and frequency-domain (e.g., LF, HF) measures. This continuous monitoring approach allows for the assessment of HRV changes in response to the intervention over time [35].

Serological Sample Collection and Analysis

Saliva samples will be collected from participants to assess contemporary inflammatory levels. These non-invasive samples will be used to measure biomarkers such as IL-6, cortisol, CRP, alpha-amylase (AA, and tumor necrosis factor-alpha (TNF-α). Saliva collection will be scheduled at specific times throughout the study to capture any fluctuations in these markers correlated with the intervention, improving understanding of the gap between up-regulators/down-regulators and inflammatory responses [37].

Data Analysis and Expected Outcomes

The data analysis will involve comparing pre- and post-intervention HRV and inflammatory marker levels. The primary hypothesis is that manual auricular stimulation combined with deep breathing will lead to an increase in HRV (indicating enhanced vagal tone) and a decrease in inflammatory biomarkers. Statistical methods, including mixed-effects models and repeated measures ANOVA, will be used to analyze the data, accounting for individual variations and potential confounding factors.

Ethical Considerations and Study Limitations

Ethical approval from a relevant Institutional Review Board (IRB) will be obtained, and informed consent will be required from all participants. Potential limitations of the study include the self-administered nature of the intervention, which may lead to variability in technique and adherence. Additionally, the subjective experience of participants and the placebo effect must be considered when interpreting the results.

Synopsis

This prospective study aims to provide valuable insights into the efficacy of manual auricular stimulation combined with deep breathing practices in enhancing vagal tone and reducing inflammation. The findings may offer a foundation for developing non-pharmacological interventions for conditions associated with dysregulated autonomic function and chronic inflammation.

Assessing HRV and Inflammatory Markers in Auricular Stimulation and Deep Breathing

The approach of measuring heart rate variability and inflammatory markers to evaluate the effects of auricular stimulation and deep breathing encompasses a detailed understanding of their impact on autonomic and immune functions. This method provides a holistic assessment of health, which is crucial in understanding the broader implications of these interventions.

HRV offers significant insights into the body’s response to stress-relieving techniques as an indicator of autonomic nervous system function. Continuous monitoring of HRV provides valuable real-time data on autonomic function, especially in response to auricular stimulation and deep breathing practices. This method is advantageous due to its non-invasive nature and it offers a direct measure of the balance between sympathetic and parasympathetic activities. This is essential to understand the body’s stress response and relaxation states and the role in reducing systemic inflammation and managing chronic diseases characterized by inflammation.

In addition to HRV, the analysis of inflammatory markers such as IL-6, CRP, and TNF-α gives an objective measure of the body’s inflammatory response. These biomarkers are pivotal in determining the effectiveness of auricular stimulation and deep breathing in modulating immune responses. The simultaneous measurement of HRV and inflammatory markers allows for an exploration of the interrelation between the autonomic and immune systems. This dual assessment is vital for a comprehensive understanding of the health impacts of auricular stimulation and deep breathing practices, revealing how they may improve both autonomic function and inflammatory status.
Such an approach also has significant implications for personalized health interventions. The variability observed in HRV and inflammatory responses among individuals underscores the need for personalized approaches in healthcare. Customizing these practices to suit individual physiological responses can optimize therapeutic benefits, aligning with the emerging focus on personalized medicine. Furthermore, evidence of improvements in autonomic balance and reductions in inflammation could expand the therapeutic applications of these practices. Conditions such as stress-related disorders, chronic pain, and autoimmune diseases could potentially benefit from tailored auricular stimulation and deep breathing techniques.

However, this approach is not without its limitations. The accuracy of HRV as an autonomic function measure can be influenced by various external factors, including physical activity and mental state. Likewise, the interpretation of inflammatory markers must consider external influences such as diet, lifestyle, and concurrent medications. Additionally, the correlation between changes in HRV and inflammatory markers and their clinical significance in various health conditions needs further exploration.

Evidence supports the premise that measuring HRV and inflammatory markers to assess the effects of auricular stimulation and deep breathing provides a holistic view of their impact on autonomic and immune functions. This method offers significant benefits in understanding and optimizing these interventions for various health conditions, paving the way for more personalized and effective therapeutic strategies.

Public Health Benefits and Biomedical Implications of Auricular Stimulation and Deep Breathing Practices

The potential public health benefits and biomedical implications of the study focusing on auricular stimulation combined with deep breathing practices are substantial, particularly in the context of chronic disease management and behavioral medicine. This research could pave the way for accessible, non-pharmacological interventions to alleviate the burden of diseases exacerbated by stress and autonomic imbalance.

Chronic Disease and Behavioral Medicine

Chronic diseases, such as cardiovascular disorders, diabetes, and mental health conditions, pose a significant challenge to public health systems worldwide. The World Health Organization (WHO) reports that Non-Communicable Diseases (NCDs) account for 71% of all deaths globally, with cardiovascular diseases being the leading cause (31% of all global deaths). Moreover, the global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014 (World Health Organization, 2018). Mental health disorders, including depression and anxiety, have also seen an increase, with the WHO estimating that depression affects 264 million people worldwide [38].

This study’s focus on enhancing vagal tone through non-invasive methods could offer significant benefits in managing these conditions. Enhanced vagal tone is associated with better cardiovascular health, improved glucose regulation, and reduced stress and anxiety levels. For instance, a review by Lehrer and Gevirtz demonstrated that HRV biofeedback, which primarily focuses on enhancing vagal tone, could effectively reduce blood pressure in patients with hypertension—a major risk factor for cardiovascular disease [39].

Accessibility and Treatment Burden

The accessibility of auricular stimulation and deep breathing practices stands out as a key advantage. Unlike many conventional medical treatments, these interventions do not require expensive equipment or medications, making them potentially accessible to a wider population, including those in low-resource settings. This aspect is crucial, considering that the WHO has highlighted the lack of access to treatment as a significant barrier to managing NCDs. This is especially relevant in low- and middle-income countries, which bear a disproportionate burden of inflammatory diseases [40].

Improvement in Disease Outcomes

The implications of this study could extend to the burden of diseases linked to autonomic dysregulation and chronic inflammation. Chronic inflammation is a known contributor to the pathogenesis of several NCDs. By potentially reducing inflammation, as indicated by markers like CRP and IL-6, the interventions studied could improve outcomes in diseases where chronic inflammation plays a crucial role. For example, elevated levels of CRP are associated with an increased risk of diabetes and cardiovascular disease. Reducing CRP and other inflammatory markers through non-pharmacological means could therefore contribute significantly to disease management and prevention [41].

Economic and Healthcare System Implications

Furthermore, the economic implications of such interventions are noteworthy. Chronic diseases are not only a health issue but also a significant economic burden. The Centers for Disease Control and Prevention (CDC) report that 90% of the United States’ $3.5 trillion in annual healthcare expenditures are spent on people with chronic and mental health conditions [42]. By providing cost-effective and accessible alternatives or adjuncts to traditional treatments, the interventions investigated in this study could alleviate some of this economic burden.

A prospective study investigating the effects of auricular stimulation combined with deep breathing on vagal tone and inflammation holds significant promise for public health and biomedical applications. Its potential impact on chronic disease management, behavioral medicine, and healthcare accessibility could address some of the most pressing challenges in contemporary healthcare. The projected outcomes from this research align with the urgent need for innovative, cost-effective, and accessible healthcare solutions. By leveraging non-pharmacological interventions like auricular stimulation and deep breathing, there is potential for a paradigm shift in managing chronic diseases, particularly those exacerbated by stress and inflammation. This shift could significantly impact public health, not just through improved health outcomes but also by reducing the economic burden associated with chronic disease management. The study’s findings could be instrumental in guiding healthcare policies and practices, emphasizing preventive and integrative approaches to health and well-being.

Comparisons and Context

The proposed study on the effects of auricular stimulation and deep breathing on HRV and inflammation levels stands on the shoulders of extensive existing research while carving out its unique niche. This section will compare the proposed study with existing literature, highlighting its unique benefits and discussing various potential outcomes, including both expected improvements and possibilities of conflicting or inconclusive results.

Comparison with Existing Literature

A key aspect that differentiates the proposed study from existing research is its integrated approach to combining auricular stimulation with deep breathing practices. While there is ample research focusing on each of these interventions individually, studies exploring their combined effect on HRV and inflammation are sparse. For instance, existing literature on HRV biofeedback and its effects on cardiovascular health [39] provides a foundation for understanding the role of vagal tone in health and disease. Similarly, studies on the anti-inflammatory effects of vagus nerve stimulation [36] illuminate the pathway through which such interventions could influence inflammatory markers. However, the proposed study aims to bridge these two areas by investigating the combined impact of auricular stimulation and deep breathing on both autonomic function and inflammation, providing a more holistic view of these interventions’ health benefits.

Expected Improvements in HRV and Inflammation

The expected outcome of the study is an improvement in HRV and a reduction in inflammatory markers. HRV is a well-established marker of autonomic nervous system balance, with higher HRV indicating greater parasympathetic (vagal) activity and resilience to stress [5]. By enhancing vagal tone, the combined intervention of auricular stimulation and deep breathing is hypothesized to increase HRV. Furthermore, the anti-inflammatory effects of vagus nerve stimulation, documented in studies such as those by Pavlov and Tracey [3], suggest that the study could observe reductions in inflammatory markers such as CRP, IL-6, and TNF-α. These outcomes would align with the growing body of research advocating for non-pharmacological approaches to manage chronic diseases and stress-related conditions.

Potential for Conflicting or Inconclusive Results

While the study is designed to test specific hypotheses, the possibility of conflicting or inconclusive results should be considered. Individual variability in response to auricular stimulation and deep breathing practices could lead to a wide range of outcomes. Factors such as baseline vagal tone, psychological state, and lifestyle factors (such as diet and exercise) might influence both HRV and inflammatory markers, potentially leading to results that do not align with the initial hypotheses. The subjective nature of self-administered interventions might introduce variability in the adherence and technique of the practices, further contributing to heterogeneous outcomes. It could also be possible that the combined intervention may not produce an additive effect, but rather result in outcomes similar to those achieved by each practice individually. This would suggest redundancy rather than synergy between auricular stimulation and deep breathing, a finding that would still contribute valuable insights into the mechanisms underlying these interventions.

Context

The proposed study, through its innovative approach, has the potential to contribute significantly to the fields of behavioral medicine and chronic disease management. By comparing its methodology and outcomes with existing literature, the study not only validates its findings but also identifies its unique contributions to the broader understanding of non-pharmacological interventions in healthcare. Regardless of whether the results align with the expected outcomes, the study promises to advance our understanding of the interplay between autonomic function, inflammation, and non-pharmacological interventions, offering potential benefits for both clinical practice and public health.

Implications for Health and Disease Management and Potential Limitations

The implications of the proposed research on auricular stimulation and deep breathing for health and disease management are far-reaching, particularly concerning chronic diseases and lifestyle adjustments. Understanding these implications, along with acknowledging the potential limitations of the study, is crucial for framing future research directions.

Implications for Chronic Disease and Lifestyle Adjustment

Chronic diseases such as cardiovascular disorders, diabetes, and mental health conditions are major contributors to global morbidity and mortality. The application of non-pharmacological interventions like auricular stimulation and deep breathing could play a significant role in managing these conditions. For instance, the American Heart Association has recognized stress, lifestyle, and chronic inflammation as modifiable risk factors for heart disease [43]. By reducing stress and enhancing autonomic balance measured by improvements in HRV, the interventions studied could mitigate risk factors for cardiovascular disease.

Similarly, the anti-inflammatory effects observed through reductions in biomarkers like CRP and IL-6 could be beneficial for managing numerous conditions where chronic inflammation plays a key role [44]. Additionally, these interventions could complement lifestyle adjustments by providing easily accessible tools for individuals to manage their stress and overall health, thereby promoting a holistic approach to chronic disease management.

Mental health, particularly conditions like anxiety and depression, also stands to benefit from these interventions. The modulation of the autonomic nervous system and the stress response could provide a non-invasive option for managing mental health conditions, aligning with the growing emphasis on integrative approaches in psychiatry [45].

Potential Limitations and Suggestions for Future Research

Despite its potential, the proposed study has limitations that must be acknowledged. One major limitation is the variability in individual responses to auricular stimulation and deep breathing, which could lead to a wide range of outcomes. Factors like baseline vagal tone, psychological state, lifestyle, and adherence to the intervention protocol can influence the effectiveness of the interventions.

Furthermore, the self-administered nature of the interventions may introduce variability in the techniques used by participants, potentially affecting the outcomes. The study’s reliance on wearable devices for HRV measurement and self-collected saliva samples for inflammation marker analysis also poses challenges in ensuring consistent and accurate data collection.

To address these limitations, future research could explore more controlled intervention protocols, perhaps in clinical settings, to standardize the application of auricular stimulation and deep breathing techniques. Additionally, longitudinal studies would be beneficial to understand the long-term effects of these interventions on HRV and inflammation, as well as their sustained impact on health outcomes.

Future research could also expand to include more diverse populations including individuals with existing chronic conditions to evaluate the effectiveness of these interventions across different demographic and health status groups. Investigating the mechanisms underlying individual variability in response to the interventions could provide insights into tailoring these practices to maximize their therapeutic benefits.

The study’s proposed approach underscores the potential of combining traditional and modern practices to create interventions that are not only effective but also accessible and adaptable to individual needs. The exploration of these interventions in the context of chronic diseases and lifestyle modifications holds the promise of a paradigm shift in disease management. By addressing both physiological and psychological aspects of health, the study could contribute significantly to an integrated model of healthcare, emphasizing prevention and holistic well-being. Further research, taking into account the limitations and suggestions outlined, could validate and expand upon these findings, ultimately leading to more comprehensive and personalized healthcare solutions.

The intricate relationship between the vagus nerve, vagal tone, auricular stimulation, and deep breathing forms the foundation of a potentially transformative approach to health management. The vagus nerve, as a critical component of the autonomic nervous system, plays a pivotal role in maintaining physiological homeostasis. Vagal tone, which is directly associated with the activity of the vagus nerve, serves as an indicator of the body’s ability to respond to stress and maintain internal balance. Enhanced vagal tone, typically reflected in improved heart rate variability, is linked to better cardiovascular health, lower levels of inflammation, and improved emotional regulation. 

Auricular stimulation, involving the targeted application of pressure or stimulation to specific points on the ear, capitalizes on the auricular branch of the vagus nerve. This non-invasive method of stimulating the vagus nerve has shown promise in enhancing vagal tone, thereby influencing various physiological processes including the modulation of heart rate and the reduction of inflammation. On the other hand, deep breathing practices, particularly diaphragmatic breathing, have been known to naturally stimulate the vagus nerve, enhancing parasympathetic activity and consequently increasing HRV.  

The integration of auricular stimulation with deep breathing practices offers a novel and synergistic approach to augmenting vagal tone. This integrated intervention leverages the direct stimulation of the vagus nerve through auricular points in conjunction with the systemic enhancement of vagal activity through controlled breathing. The combined effect of these interventions could potentiate the individual benefits of each, potentially leading to more significant improvements in HRV and reductions in inflammation. 

The prospective research outlined above, exploring this integrated approach, holds substantial promise for health and disease management. By potentially improving autonomic balance and reducing inflammation, this intervention could be particularly beneficial for individuals with or at risk for chronic diseases, including cardiovascular disease, diabetes, and various stress-related conditions. The feasibility of this approach lies in its non-invasive low-cost nature making it accessible to a wide range of populations. 

In clinical settings, the practical application of this integrated treatment could offer a complementary or alternative option to traditional therapies, especially for conditions where autonomic dysregulation or chronic inflammation is a concern. For effective implementation, clinicians could consider individualizing the treatment protocols based on each patient’s specific needs, health status, and response to the intervention. Additionally, integrating this approach into holistic care models could enhance its effectiveness, especially when combined with other lifestyle interventions such as diet and exercise modifications. 

Moreover, the prospect of integrating such non-pharmacological interventions into mainstream healthcare presents an opportunity for a more holistic approach to health management. It aligns with the growing emphasis on preventive healthcare and the need for interventions that not only address specific health conditions but also improve overall well-being.  

The integration of auricular stimulation and deep breathing as a means of enhancing vagal tone represents an innovative approach in the realm of health and disease management. Its potential to improve autonomic balance and reduce inflammation could have far-reaching implications, offering a viable, non-invasive, and cost-effective treatment option. The practical application of this integrated treatment in clinical settings, tailored to individual patient needs, could significantly contribute to the advancement of holistic and preventive healthcare practices.

PMD has received research grants and advisory fees from several health/pharma/tech companies; PMD owns stock in several companies whose products are not discussed here; PMD serves on coporate and non-profit boards; PMD is coinventor on several patents unrelated to this paper

1. Thayer JF, Lane RD (2007) The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol 74: 224-242.
2. Mensah GA, Mokdad AH, Ford ES, Greenlund KJ, Croft JB (2005) State of disparities in cardiovascular health in the United States. Circulation 111: 1233-1241.
3. Pavlov VA, Tracey KJ (2012) The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nature Reviews Endocrinology 8: 743-754.
4. Libby P (2006) Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr 83: 456-460.
5. Thayer JF, Ahs F, Fredrikson M, Sollers JJ 3rd, Wager TD (2010) A meta-analysis of heart rate variability and neuroimaging studies: Implications for heart rate variability as a marker of stress and health. Neurosci Biobehav Rev 35: 747-756.
6. Fuster V, Kelly BB (Eds.) (2010) Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health. National Academies Press, USA.
7. Ben-Menachem E (2002) Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol 1: 477-482.
8. George MS, Sackeim HA, Rush AJ, Marangell LB, Nahas Z, et al. (2000) Vagus nerve stimulation: A new tool for brain research and therapy. Biol Psychiatry 47: 287-295.
9. Val-Laillet D, Aarts E, Weber B, Ferrari M, Quaresima V, et al. (2015) Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and obesity. Neuroimage Clin 8: 1-31.
10. Peuker ET, Filler TJ (2002) The nerve supply of the human auricle. Clin Anat 15: 35-37.
11. La Marca R, Nedeljkovic M, Yuan L, Maercker A, Elhert U (2010) Effects of auricular electrical stimulation on vagal activity in healthy men: Evidence from a three-armed randomized trial. Clin Sci (Lond) 118: 537-546.
12. Streitberger K, Steppan J, Maier C, Hill H, Backs J, et al. (2007) Effects of verum acupuncture compared to placebo acupuncture on quantitative EEG and heart rate variability in healthy volunteers. J Altern Complement Med 13: 427-434.
13. Bell GD, Gochenouer K, Altschuler EL (2014) Acetylcholine release by transcutaneous electrical nerve stimulation. Journal of Rehabilitation Research and Development 51: 533-541.
14. Breit S, Kupferberg A, Rogler G, Hasler G (2018) Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Front Psychiatry 9: 44.
15. Corrêa FI, Souza PHL, Uehara L, Ritti-Dias RM, Oliveira da Silva G, et al. (2022) Transcutaneous Auricular Vagus Nerve Stimulation Improves Inflammation but Does Not Interfere with Cardiac Modulation and Clinical Symptoms of Individuals with COVID-19: A Randomized Clinical Trial. Life (Basel) 12: 1644.
16. Rong PJ, Fang JL, Wang LP, Meng H, Liu J, et al. (2014) Transcutaneous vagus nerve stimulation for the treatment of depression: A study protocol for a double-blinded randomized clinical trial. BMC Complement Altern Med: 14: 255.
17. Usichenko T, Hacker H, Lotze M (2017) Transcutaneous auricular vagal nerve stimulation (taVNS) might be a mechanism behind the analgesic effects of auricular acupuncture. Brain Stimul 10: 1042-1044.
18. Lehrer PM, Vaschillo E, Vaschillo B (2017) Resonant frequency biofeedback training to increase cardiac variability: Rationale and manual for training. Appl Psychophysiol Biofeedback 25: 177-191.
19. Russo MA, Santarelli DM, O'Rourke D (2017) The physiological effects of slow breathing in the healthy human. Breathe 13: 298-309.
20. Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, et al. (2019) Current Directions in the Auricular Vagus Nerve Stimulation II – An Engineering Perspective. Front Neurosci 13: 772.
21. Kreuzer PM, Landgrebe M, Husser O, Resch M, Schecklmann M, et al. (2020) Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. Frontiers in Psychiatry 4: 173.
22. Fallgatter AJ, Neuhauser B, Herrmann MJ, Ehlis AC, Wagener A, et al. (2003) Far field potentials from the brain stem after transcutaneous vagus nerve stimulation. Journal of Neural Transmission 110: 1437-1443.
23. Sclocco R, Garcia RG, Gabriel A, Kettner NW, Napadow V, et al. (2017) Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) effects on autonomic outflow in hypertension. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference 2017: 3130-3133.
24. Garcia RG, Cohen JE, Stanford AD, Gabriel A, Stowell J, et al. (2021) Respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) modulates brain response to stress in major depression. Journal of psychiatric research 142: 188-197.
25. Garcia RG, Staley R, Aroner S, Stowell J, Sclocco R, et al. (2022) Optimization of respiratory-gated auricular vagus afferent nerve stimulation for the modulation of blood pressure in hypertension. Frontiers in neuroscience 16: 1038339.
26. Gori L, Firenzuoli F (2007) Ear acupuncture in European traditional medicine. Evidence-Based Complementary and Alternative Medicine 4: 13-16.
27. Sator-Katzenschlager SM, Michalek-Sauberer A (2007) P-Stim auricular electroacupuncture stimulation device for pain relief. Expert Review of Medical Devices 4: 23-32.
28. Butt MF, Albusoda A, Farmer AD, Aziz Q (2020) The anatomical basis for transcutaneous auricular vagus nerve stimulation. Journal of anatomy 236: 588-611.
29. Sclocco R, Garcia RG, Kettner NW, Isenburg K, Fisher HP, et al. (2019). The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study. Brain stimulation 12: 911-921.
30. Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, et al. (2014) Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain stimulation 7: 871-877.
31. Grossman P, Taylor EW (2007) Toward understanding respiratory sinus arrhythmia: relations to cardiac vagal tone, evolution and biobehavioral functions. Biological psychology 74: 263-285.
32. Bernardi L, Porta C, Gabutti A, Spicuzza L, Sleight P (2001) Modulatory effects of respiration. Autonomic neuroscience: basic & clinical 90: 47-56.
33. Jerath R, Edry JW, Barnes VA, Jerath V (2006) Physiology of long pranayamic breathing: neural respiratory elements may provide a mechanism that explains how slow deep breathing shifts the autonomic nervous system. Medical hypotheses 67: 566-571.
34. Tracey KJ (2009) Reflex control of immunity. Nature reviews. Immunology 9: 418-428.
35. Shaffer F, Ginsberg JP (2017) An Overview of Heart Rate Variability Metrics and Norms. Frontiers in public health 5: 258.
36. Kox M, Eijk LT, Zwaag J, Wildenberg J, Sweep FC, et al. (2014) Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. Proceedings of the National Academy of Sciences 111: 7379-7384.
37. Rohleder N (2019) Stress and inflammation - The need to address the gap in the transition between acute and chronic stress effects. Psychoneuroendocrinology 105: 164-171.
38. World Health Organization (2018) Noncommunicable diseases. World Health Organization, Geneva, Switzerland.
39. Lehrer PM, Gevirtz R (2014) Heart rate variability biofeedback: how and why does it work? Frontiers in psychology 5: 756.
40. Castle R, Bushell WC, Mills PJ, Williams MA, Chopra D et al. (2021) Global Correlations Between Chronic Inflammation and Violent Incidents: Potential Behavioral Consequences of Inflammatory Illnesses Across Socio-Demographic Levels. International journal of general medicine 14: 6677-6691.
41. Castle RD, Williams MA, Bushell WC, Rindfleisch JA, Peterson CT, et al. (2021) Implications for Systemic Approaches to COVID-19: Effect Sizes of Remdesivir, Tocilizumab, Melatonin, Vitamin D3, and Meditation. Journal of inflammation research 14: 4859-4876.
42. Centers for Disease Control and Prevention (2019) Health and economic costs of chronic diseases. Centers for Disease Control and Prevention, USA.
43. Cen M, Song L, Fu X, Gao X, Zuo Q, et al. (2023) Associations between metabolic syndrome and anxiety, and the mediating role of inflammation: Findings from the UK Biobank. Brain, behavior, and immunity 116: 1-9.
44. Bushell W, Castle R, Williams MA, Brouwer KC, Tanzi RE, et al. (2020) Meditation and Yoga Practices as Potential Adjunctive Treatment of SARS-CoV-2 Infection and COVID-19: A Brief Overview of Key Subjects. Journal of alternative and complementary medicine 26: 547-556.
45. Hofmann SG, Asnaani A, Vonk IJ, Sawyer AT, Fang A (2012) The Efficacy of Cognitive Behavioral Therapy: A Review of Meta-analyses. Cognitive therapy and research 36: 427-440.