Understanding the Effects of Non-Invasive Transauricular Vagus Nerve Stimulation on EEG and HRV

Published: January 19, 2024

doi:

Anna Carolyna Gianlorenco², Kevin Pacheco-Barrios³, Lucas Camargo, Elly Pichardo, Hyuk Choi⁵, Jae-Jun Song⁶, Felipe Fregni

¹Neuromodulation Center and Center for Clinical Research Learning,Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, ²Physical Therapy Department,Federal University of Sao Carlos, ³Vicerrectorado de Investigación,Universidad de Investigación para la Generación y Síntesis de Evidencia en Salud, Universidad San Ignacio de Loyola, ⁴Department of Medical Sciences, Graduate School of Medicine,Korea University, ⁵Neurive Co., Ltd., ⁶Department of Otorhinolaryngology-Head and Neck Surgery,Korea University Medical Center

Summary

This protocol provides information on how to apply transcutaneous auricular vagus nerve stimulation (taVNS) in a clinical trial, including potential biomarkers such as EEG metrics and heart rate variability (HRV) to measure the effect of this treatment on the autonomic nervous system.

Abstract

Several studies have demonstrated promising results of transcutaneous auricular vagus nerve stimulation (taVNS) in treating various disorders; however, no mechanistic studies have investigated this technique’s neural network and autonomic nervous system effects. This study aims to describe how taVNS can affect EEG metrics, HRV, and pain levels. Healthy subjects were randomly allocated into two groups: the active taVNS group and the sham taVNS group. Electroencephalography (EEG) and Heart Rate Variability (HRV) were recorded at baseline, 30 min, and after 60 min of 30 Hz, 200-250 µs taVNS, or sham stimulation, and the differences between the metrics were calculated. Regarding vagal projections, some studies have demonstrated the role of the vagus nerve in modulating brain activity, the autonomic system, and pain pathways. However, more data is still needed to understand the mechanisms of taVNS on these systems. In this context, this study presents methods to provide data for a deeper discussion about the physiological impacts of this technique, which can help future therapeutic investigations in various conditions.

Introduction

Transauricular vagus nerve stimulation (taVNS) is a recent neuromodulation technique that does not require surgery and utilizes a non-invasive stimulation device placed at the concha or tragus of the ear. Consequently, it is more accessible and safer for patients¹. In recent years, the taVNS field has rapidly expanded, primarily focusing on clinical trials demonstrating potential therapeutic advantages for various pathological conditions, including epilepsy, depression, tinnitus, Parkinson’s disease, impaired glucose tolerance, schizophrenia, and atrial fibrillation². There is much to discuss about taVNS and its effects on biological processes in the central and peripheral systems. Ideally, a biological marker might demonstrate that the auricular branch of the vagus was stimulated, affecting intracranial structures and allowing researchers to analyze how taVNS affects physiological function. Nevertheless, without a trustworthy biomarker, it is not easy to understand what the taVNS data mean and how to interpret them effectively.

Electroencephalography (EEG) is an encouraging imaging tool to provide biomarkers for taVNS. It is a non-invasive, reliable, inexpensive approach to measure and quantify cortical activity³^,⁴. Following this process, our group performed a systematic review, demonstrating elementary details that taVNS could influence cortical activity, mainly increasing EEG power spectrum activity in lower frequencies (delta and theta). However, diverse results in higher frequencies (alpha) and changes in early ERP components related to inhibitory tasks were also detected. High heterogeneity between the studies was found; therefore, more homogeneous, more significant, and well-planned studies are essential to make more robust conclusions about the effects of taVNS on brain activity measured by EEG³. Assessing EEG during taVNS could advance future research on integrating the two techniques for a mobile, closed-loop, monitoring, and non-invasive stimulation tool to affect brain oscillatory activity⁴.

Alpha asymmetry, which assesses the relative alpha band activity between the brain hemispheres, particularly at frontal electrodes, is a frequently researched EEG biomarker. Previous literature has used this biomarker to analyze the approach-withdraw hypothesis⁵^,⁶, which holds that the right frontal side of the brain is associated with withdrawal behaviors. In contrast, the left frontal side is associated with approach behaviors. Since alpha is associated with low brain activity, an increase in alpha on the left side of the brain suggests lower activity and may show a lack of approach behavior. This concept helps to explain some results in the alpha band at the left side hemisphere in depressed patients⁷. Additionally, EEG electrodes record the activity of neuronal populations, examining Functional Connectivity (FC) or changes in large-scale brain networks, such as the default mode network (DMN)⁷^,⁸.

Based on that, quantitative electroencephalography can be employed to assess the effects of taVNS on brain activity; however, more studies are required to systematically demonstrate the specific metrics and effects that would highlight the non-invasive stimulation through the auricular branch of the vagus nerve.

Peripherally, the vagus nerve and sympathetic nervous system mediate the heart’s contractile and electrical function⁹. This regulation promotes the heart’s pacemaker ability and controls it through physiological manifestations of the body, known as sinus depolarizations. Heart rate variability (HRV) records the changes per beat of sinus depolarization, thus non-invasively describing vagal influences on the sinus node¹⁰. Given this function, HRV has been seen and studied as a prominent neurocardiac function biomarker associated with an individual’s well-being and the likelihood of morbidity, mortality, and stress¹¹^,¹².

In the context of taVNS, HRV has been recorded in many trials, and stimulation has been thought to modulate HRV⁹^,¹¹^,¹². Considering that decreased HRV has been related to the morbidity and mortality of different diseases through mechanisms such as over-activity of the sympathetic nervous system, inflammatory response, and oxidative stress, the vagal nerve modulation of taVNS is thought to directly impact HRV and its sinus regulation¹³^,¹⁴. In fact, some trials have already indicated that taVNS can increase HRV in healthy subjects, thus supporting this hypothesis¹⁵^,¹⁶. However, there is still a need to understand better whether different taVNS parameters can affect HRV differently.

Currently, no mechanistic studies have investigated the taVNS neural network and autonomic nervous system effects of this technique together. Therefore, this protocol aims to assess how taVNS can affect EEG metrics and HRV and evaluate its safety. Additionally, this also aims to identify predictors that can influence the response to taVNS. Understanding the variables associated with the response to taVNS can help design future clinical trials to maximize the effects of this intervention.

Protocol

All study procedures were performed at the Spaulding Neuromodulation Center/Spaulding Cambridge Hospital. Ethical approval for this protocol was obtained from Mass General Brigham IRB (Number Protocol #:2022P003200). Informed consent was obtained from all subjects using the encrypted Research Electronic Data Capture (REDCap) platform (see Table of Materials). Trial registration number: NCT05801809. 1. Subject selection and screening Identify potent…

Representative Results

We performed a preliminary descriptive analysis of the first randomized subject without unblinding the study. For this reason, which arms this subject was allocated to is unknown. The first subject is a 69-year-old woman, non-Hispanic, Caucasian, with a college degree, who did not report any adverse event during or after the stimulation session. The clinical data are displayed in Table 2. Besides, a topographic distribution of scalp plots was created in resting-state EEG for t…

Discussion

Transauricular Vagus Nerve Stimulation (taVNS) is emerging as a promising therapeutic avenue for addressing several neuropsychiatric conditions. Mood disorders, such as depression and anxiety, pose a significant global health burden, especially after the COVID-19 pandemic¹⁹. Recent studies exploring taVNS have exhibited the potential to alleviate symptoms associated with these disorders.

The vagus nerve plays a pivotal role in the brain-gut axis and the regulation of e…

Disclosures

The authors have nothing to disclose.

Acknowledgements

The author is grateful to the research team (Maria Fernanda Andrade, Allison Kim, Robin Heemels).

Materials

Articulated arm	Electrical Geodesics, Inc.	20090645
Baby shampoo	Dynarex	1396
Charge Cable	NEURIVE Co.	HV12303003
Computer	Apple	YM92704U4PC
Condutive eartip	NEURIVE Co.	HV12303003
Earset	NEURIVE Co.	HV12303003
EEG 64-channel cap	Electrical Geodesics, Inc.	H11333
Heart rate sensor	Polar	M311370175396
Monitor	Dell	REVA01
Net Amps 300	Electrical Geodesics, Inc.	A09370244
Peltier thermode	Advanced Medical Systems, Ramat Yishai, Isreal
Potassium Chloride (dry)	Electrical Geodesics, Inc.	820127755
Rally	Mass General Brigham Research		online platform
Research Electronic Data Capture (REDCap)	Vanderbilt		web-based software platform
Thermosensory Stimulator	Medoc Ltd	1241
Transauricular vagus nerve stimulator	NEURIVE Co.	HV12303003

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