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VeRelief Reduces State Anxiety and Increases HRV in PTSD and Panic Dis – Hoolest Inc.
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VeRelief Reduces State Anxiety and Increases HRV in PTSD and Panic Disorder Patients

VeRelief Reduces State Anxiety and Increases HRV in PTSD and Panic Disorder Patients

Abstract

Background

Vagus Nerve Stimulation is a known technique to modulate autonomic function and is FDA approved for the treatment of certain diseases like depression and epilepsy. However, traditional stimulation methods are invasive, require an implant, and reserved for severe or drug-resistant cases and approval for use in anxiety related diseases has yet to be achieved.

Objective

The purpose of this study was to assess the safety and efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) compared to a sham taVNS in patients with PTSD and Panic Disorder using a the first generation VeRelief vagus nerve stimulation device.

Methods

A randomized, sham-controlled approach was used to investigate the effects of active or sham taVNS on state-anxiety in 24 participants as scored by the State-Trait Anxiety Inventory (STAI) with the use of a novel neurostimulation device. Participants completed a stress inducing task before and after using a sham or active neurostimulation device at a target site over the proximal lateral cervical region containing the auricular vagus nerve. A survey was used to measure anxiety before and after each stress-inducing task was completed. Upon completion of the tasks and treatment, the safety and tolerability of the device was assessed. Results were examined to compare the change in anxiety levels before and after stimulation as well as determine safety and tolerability of treatment with the P57 ONE.

Results

There was a significant qualitative difference between sham and active device users when asked if the experience was relaxing, where 100% of active device users found the experience relaxing when compared to 33% of sham device users. There was also a 31% increase in HRV in the active group, and no change in HRV in the sham group. Analyses for safety and tolerability ratings found no significant differences in safety responses nor reported adverse effects between active and sham users immediately after nor 24 hours after stimulation. Quantitative results suggest a beneficial effect of relaxation immediately after using the stimulation device where active users found the device more relaxing than sham users.

Conclusion

This study provides evidence in support of using taVNS to elicit a beneficial effect on relative anxiety via increased relaxation and decreased state-anxiety. Stimulation of the target site with the use of the VeRelief device was found to be both safe and tolerable. This technique of non-invasive stimulation could be a new effective method to quickly reduce anxiety without having to resort to pharmaceutical or invasive intervention. Future studies should include larger sample populations to better assess individual response variability and explore various parameters of stimulation to further optimize this novel method of neuromodulation for anxiety treatment.

Author Names and Affiliations:

Nicholas Hool ab, Andrea C. Carpentera abc

a, WearTech, 3110 N Central Ave UNIT 153, Phoenix, AZ 85012, USA

b, Hoolest Performance Technologies, Inc., 2398 East Camelback Road, Suite 1020, Phoenix, AZ 85016, USA

cMidwestern University Arizona College of Osteopathic Medicine, 19555 N 59th Ave, Glendale, AZ, 85308, USA

 

1. INTRODUCTION

    1.1 Anxiety

    Anxiety is one of the most prevalent psychiatric disorders in the world and has a lifetime prevalence of almost 30% (Moritz et al., 2017). Anxiety disorders are classified by the Diagnostic and Statistical Manual of Mental Disorders, which classifies different types of anxiety disorders. While personal experience varies, anxiety can be split into two different components: trait anxiety and state anxiety. Trait anxiety represents a person’s natural inclination to be anxious, while state anxiety represents a person’s anxiety level at any given moment and is transitory by nature (Endler and Kocovski, 2001; Moritz et al., 2017; Spielberger, 2012).

    1.2 Treatment Methods

    Pharmacological treatment of anxiety generally requires minimal effort for the patient and may provide acute or long-term relief, but comes with the risk of various negative side effects. Non-drug anxiety treatments, like cognitive behavioral therapy (CBT) or mindfulness and meditation, are often favorable treatments due to their holistic nature but require a substantial amount of time and discipline for individuals to reap the benefits (Teasdale et al., 2000; Kabat-Zinn et al., 1992; Pawlow et al., 2003).

    Neuromodulation is a popular alternative treatment method for mental health due to its ability to directly affect neural activity and structures associated with the condition being treated without the use of medications. Transcranial magnetic stimulation (TMS) is one neuromodulation method that has been demonstrated to be effective for treating depression and anxiety, however it can be extremely expensive and often requires office visits for several weeks. Transcutaneous direct current stimulation (tDCS) is a relatively simple and inexpensive method that uses electricity to modulate brain activity for a variety of health purposes and has recently been shown to improve anxiety in a patient with COVID-19 (Shinjo et al., 2020). However, tDCS is often uncomfortable for the patient, can be difficult to use, and has an unclear mechanism of action due to non-precise stimulation locations on the cranium and inconsistent effects on neural firing rates (Chase et al., 2019).

    1.3 Transcutaneous Vagus Nerve Stimulation

    A particular neuromodulation method that has been identified as a potential treatment for anxiety is transcutaneous vagus nerve stimulation (tVNS). The vagus nerve is a major component in the autonomic nervous system (Tracy, 2009), and communicates with regions in the brain responsible for the regulation of neurotransmitters implicated in anxiety related disorders, such as post-traumatic stress disorder (PTSD) (Campanella & Bremner, 2016; Fang et al., 2016; Howland, 2014).  tVNS is similar to tDCS, but precisely stimulates branches of the vagus nerve in a manner shown to have similar effects to invasive vagus nerve stimulation (VNS) yet without the side effects associated with invasive procedures (Ben-Menachem et al., 2015), and typically uses an alternating current waveform, which is considered a safer and more tolerable form of stimulation than direct current stimulation (Antal et al., 2017).

    tVNS can be accomplished via cervical or auricular vagal nerve stimulation. Cervical tVNS is a method of stimulating a branch of the vagus nerve in the cervical region on the front side of the neck and has been demonstrated to be effective in reducing pain associated with episodic cluster headache and migraine in the PRESTO study run by Electrocore, Inc. (Tassorelli et al., 2018). Cervical tVNS has also been noted to decrease sympathetic tone, indicating it may be an effective treatment for patients with anxiety symptoms (Gurel et al., 2020). Auricular tVNS involves stimulating branches of the vagus nerve surrounding the external ear. Cranial Electrotherapy Stimulation (CES) is a neurostimulation method FDA-cleared to treat anxiety disorders and its anxiolytic mechanism of action has been hypothesized to be a result of auricular vagal nerve stimulation (Yakunina et al., 2017). Auricular tVNS has been shown to activate regions in the brain such as the nucleus of solitary tract (NTS) and the locus coeruleus (LC), regions which can produce norepinephrine, a neurotransmitter implicated in anxiety disorders such as PTSD and Panic Disorder (Kraus et al., 2007; Goddard et al., 2009). As Selective-Norepinephrine Reuptake Inhibitors may be used to treat anxiety by blocking the reuptake of norepinephrine by neurons (Strawn et al., 2018), taVNS may have positive effects on anxiety by increasing norepinephrine production through activating the locus coeruleus (Butt et al., 2019).

    Auricular tVNS is consistently well tolerated and has shown promising results in the treatment of anxiety disorders. One study tested tVNS with a custom electrode in 22 combat veterans with PTSD and found increased parasympathetic tone indicated by an increase in the high frequency (HF) component of Heart Rate Variability (HRV), and a decrease in sympathetic tone indicated by a decrease in electrodermal activity (Lamb et al., 2017). There have been several tVNS studies using custom ear clip electrodes for stimulation delivery which have shown an effect of reduced heart rate, increased parasympathetic activity evidenced by increased HRV, reduced muscle sympathetic nerve activity, and modulated salivary cortisol levels in healthy individuals, all of which suggesting tVNS as a potential stress and anxiety management method (Badran et al., 2018; Clancy et al., 2014; Warren et al., 2019).

    1.4 Safety and Tolerability

    Documented side effects of tVNS have been demonstrated to be low risk and similar to side effects of other standard non-invasive electrical stimulation devices. One study assessing how effectively the Cerbomed NEMOS taVNS device addresses pain evaluated treatment tolerability with the most common effects being feelings of slight pain, pressure, prickling, itching, or tickling at the site of the electrodes. No serious adverse events were found in the study and every participant completed the entire 1-hour stimulation session (Busch et al., 2013). Another study assessing pain and tolerability of the Cerbomed NEMOS device in healthy individuals found that 75% of patients who received active stimulation reported low pain levels (1 or 2 on a Likert-scale), and the stimulation was well tolerated by all participants (De Couck et al., 2016). However, there were no studies that could be found up to the date of this study which have assessed the safety and tolerability of auricular tVNS at the tympanomastoid fissure located on the upper-most lateral neck just inferior to the ear.

    This present study aims to assess the safety and efficacy of the VeRelief auricular tVNS device on the lateral neck over the tympanomastoid fissure, a region containing the auricular branch of the vagus nerve (ABVN) and the great auricular nerve (GAN) (Tekdemir et al., 1998; Kiyokawa et al., 2014). The GAN synapses in similar regions in the brainstem as the ABVN and has been shown to produce similar results as tVNS when electrically stimulated (Shu et al., 2004; Liu & Hu, 1988; Ginsberg & Eicher, 2000). fMRI studies indicate that stimulation of the GAN at the earlobe resulted in deactivation in the hippocampus, posterior cingulate gyrus, parahippocampal gyrus, and the amygdala, all regions associated with fear and anxiety (Yakunina et al.,2017). Few studies have investigated how stimulating the GAN at the earlobe affects state anxiety, and the results are mixed. One study found that 60 minutes of electrical stimulation at the earlobe in young, healthy adults did not effect state-anxiety levels between baseline and post-treatment time periods (Hill, 2015), while another study found that only 20 minutes of electrical stimulation at the earlobe caused a clinically meaningful improvement of state-anxiety levels in people with impulse control disorders (Voris, 1995).

    While these studies looked at stimulation of the GAN at the earlobe, there are no studies that have reported how stimulating both the GAN and the ABVN at the tympanomastoid fissure affects state-anxiety. Due to the common connections of the vagus and great auricular nerves in brain regions associated with anxiety states, stimulating both the GAN and the ABVN together may be a more effective method of providing fast-acting state anxiety relief than other available methods. This study aimed to assess the safety and tolerability of electrical stimulation at this region on the side of the neck, as well as assessing the effects on state-anxiety in a group of patients with self-diagnosed PTSD and Panic Disorder.

    1.5 Hypotheses

    Active stimulation at the target region was hypothesized to be safe and tolerable compared to a sham treatment and was hypothesized to show a statistically significant change in state-anxiety level compared to a sham treatment. 

     

    2. METHODS

    2.1 Subjects

    Informed consent was obtained from 24 participants who were all screened prior to starting the experiment using three surveys to determine eligibility, two of which measured state and trait anxiety using Spielberg’s State-Trait Anxiety Inventory (STAI) questionnaires. All participants were between the ages of 18-69 and scored at least 30 points on each STAI questionnaire. The third survey checking for exclusion criteria ensured that none of the participants had a medical implant, debilitating migraines or frequent headaches, experienced frequent feinting or vaso-vagal or neurocardiogenic syncope, Raynaud’s disease, temporomandibular joint disorder or other facial neuropathy, history of significant face/head injury or cranial or facial metal plate or screw implants, recent hospitalization for surgery/illness in the last three months, vision or hearing that is uncorrectable, knowledge of current pregnancy, recent drug or alcohol treatment in the last three months, or high blood pressure, heart disease, or diabetes.

    2.2  Device

    The neurostimulation device used in the study was the first generation VeRelief device built by Hoolest Performance Technologies, Inc. It uses a custom pair of dry hydrogel electrodes to deliver electrical stimulation therapy in the target region on the side of the neck that contains the auricular branch of the vagus nerve and great auricular nerve. The stimulation output was a biphasic pulse train waveform of 100Hz, a pulse width of 500µs, and a maximum current output of 8mA. The device was designated a Non-Significant Risk device for this study by Solutions IRB.

    Figure 1: The neurostimulation device developed by Hoolest Performance Technologies. The device contains four buttons to control the stimulation output and LED lights to indicate the stimulation output.

    Figure 2: Target region of stimulation

    2.3  Protocol

    Participants were randomized into active or sham experimental groups using a tiered system based on mild/moderate/severe anxiety STAI results during screening. STAI scores between 0-38 were considered Mild, 39-44 were considered Moderate, and 45-80 were considered Severe. The investigator was unaware of control versus experimental group assignment until the participant arrived. The participant was kept blind throughout the duration of the study. 

    The experiment consisted of participants performing a baseline computerized survey intended to induce anxiety, and would then complete the STAI survey to assess state-anxiety. The computerized task was a paced visual serial addition task used in several past studies as a technique to induce anxiety in participants (Starcke et al., 2016; Tanosoto et al., 2012; Tanosoto et al., 2015; Vanderploeg et al., 2005; Wills & Leathem, 2004). The task consisted of a time-constrained set of 100 simple numerical addition problems. Throughout the task, numbers were presented on a screen for four seconds and the participant was tasked with adding the current number shown to the previous number shown. Participants were given a short practice trial before the task began to ensure understanding of the rules. The task took approximately 10 minutes to complete.

    Participants then received 10 minutes of active or sham transcutaneous auricular vagal nerve stimulation (taVNS) over the tympanomastoid fissure using the VeRelief device. Both groups self-applied the treatment to each side of their necks for a total of 10 minutes, with 5 minutes on each side of the neck and starting with the right side first. The active stimulation setting used a 100Hz biphasic electrical stimulation waveform with custom dry electrodes. The sham stimulation had zero output current but was otherwise identical to the active device.

    Participants were asked to sit in a comfortable position with minimal interaction while receiving 10 minutes of either active or sham stimulation. Intensity was adjusted using the method of limits where participants were instructed to increase the stimulation intensity (by intervals of 0.25mA up to a maximum possible output setting of 8mA in the active group) until a comfortable setting was reached. Active participants were told the intensity level was appropriate when a comfortable tingling sensation was reached that was above the subject’s perception threshold but below the pain threshold. Sham participants were told they may or may not feel any sensations during treatment but were instructed to turn the output up as high as they could tolerate.

    After the treatment, participants performed the same paced visual serial addition task and then completed the STAI survey once more. The STAI is based on a 4-point Likert scale and consists of 40 total questions on a self-reporting basis for two distinct concepts of anxiety: state anxiety and trait anxiety. In this study, we assessed trait anxiety (20 questions) once to screen applicants and assessed state anxiety (20 questions) during screening and after each serial addition task (pre and post stimulation).

    Safety and tolerability data were collected immediately after completing the last stimulation task. An online survey assessing stimulation protocol safety and tolerability was taken on SurveyMonkey. The questions consisted of yes/no, 10-point Likert scale, and open-ended questions asking patients to subjectively assess their level of comfort or discomfort, dizziness, blurred vision, headache, distraction, and skin irritation during stimulation. Participants took another 12-question online survey assessing stimulation protocol safety and tolerability 24 hours after participating in the study similar to the survey given immediately after the stimulation.

    2.4 Data Analysis

    A Fisher’s Exact test was used to quantify the relationship between immediately after and 24 hours after safety reports (yes or no) of discomfort, dizziness, blurred vision, headache, skin irritation, relaxation, and distraction from the stimulation protocols (sham vs. stimulation). An unpaired t-test was used to compare average levels (1-10) of comfort, discomfort, dizziness, blurred vision, headache, skin irritation, relaxation, and distraction ratings immediately after stimulation and at least 24 hours after stimulation between each protocol group.

    An unpaired two-tailed t-test was used to compare average levels of state-anxiety between active and sham stimulation groups for both pre and post-stimulation points in time. An α level of 0.005 was used to determine significance in variables recorded. A lower α level than the typical 0.05 was selected due to a small sample size and was an attempt to improve reproducibility while maintaining an acceptable statistical power (Benjamin et al., 2018). 

     

    3. RESULTS

    3.1 Subjects

    The final sample included 24 participants. One of the 25 accepted participants withdrew due to an overactive vaso-vagal response citing lightheadedness and diaphoresis. Two participants, both in the active group, were unable to complete the safety and tolerability surveys due to connectivity issues. The demographic information of the participants in this study are described in Table 1.

    Table 1

    Demographic Information

    Stimulation Type

    N

    Gender

    Age

     

    Male

    Female

    Minimum

    Maximum

    Mean ± SD

     

    Active (100 Hz)

    15

    4

    12

    18

    69

    35.40 ± 14.01

     

    Sham (0 Hz)

    9

    5

    4

    18

    55

    44.11 ± 16.70

     

    Total

    24

    9

    16

    18

    69

    38.67 ± 15.33

     

    Of the 24 participants, 15 participants were in the active group and 9 participants were in the sham stimulation group. There was a total age range between 18 and 69 years for participants in the study. The mean age in the active group was 35.40 ± 14.01 years and the mean age in the sham group was 44.11 ± 16.70 years. The statistical differences between age and gender were not computed.

    3.2 Safety and Tolerability

    Table 2

    Safety and Tolerability Analysis of Subjective Yes/No Answers: Fisher's Exact

    Active (n=13)

    Sham (n=9)

     

    Question

    Events n

    Patients %

    Events n

    Patients %

    P-Value

    Did you find the experience comfortable?

    Did you experience any discomfort or pain?

    2

    15

    0

    0

    0.494

    Did you experience any dizziness?

    1

    8

    0

    0

    1

    Did you experience any blurred vision?

    0

    0

    1

    11

    0.409

    Did you experience any headache?

    1

    8

    2

    22

    0.544

    Did you find the experience relaxing?

    13

    100

    3

    33

    0.001

    Did you find the experience distracting?

    1

    8

    0

    0

    1

    Did you experience any skin itching or irritation?

    0

    0

    0

    0

    Did you experience any discomfort or pain after 24 hours?

    0

    0

    1

    33

    0.231

    Did you experience any dizziness after 24 hours?

    0

    0

    0

    0

    Did you experience any blurred vision after 24 hours?

    0

    0

    0

    0

    Did you experience any headache after 24 hours?

    1

    10

    1

    33

    0.423

    Did you experience any skin itching or irritation after 24 hours?

    0

    0

    0

    0

    Table 3

    Safety and Tolerability Question Analysis of Ratings

    Question

    Immediately After (n = 22)

    ≥24 Hours After (n=13)

    Mean Rating

    (1-10)

     

     

    Mean Rating

    (1-10)

     

     

    Active (n=13)

    Sham (n=9)

    |difference|

    p-value

    Active (n=10)

    Sham (n=3)

    |difference|

    p-value

    Level of comfort

    7.58

    6.89

    0.69

    0.33

    Level of discomfort/pain

    2.00

    1.67

    0.33

    0.61

    1.10

    1.67

    0.57

    0.15

    Level of Dizziness

    1.69

    1.00

    0.69

    0.16

    1.10

    1.00

    0.1

    0.61

    Level of Blurred vision

    1.08

    1.22

    0.14

    0.49

    1.00

    1.00

    0

    Level of Headache

    1.31

    1.33

    0.02

    0.93

    1.22

    2.00

    0.78

    0.26

    Level of Skin irritation

    1.15

    1.33

    0.18

    0.45

    1.00

    1.00

    0

    Level of relaxation

    6.77

    3.56

    3.21

    0.002

    Level of distraction

    2.92

    3.00

    0.08

    0.94

     

    Results of the yes or no safety questions were analyzed by a Fisher’s Exact test due to the low n of the study and the subjective ratings were analyzed by unpaired t-tests. Several participants did not complete the 24-hour post-study safety and tolerability survey due to non-responsiveness once leaving the study.  It is notable that the sham participants did not respond more often, with a 33% post-study response rate in the sham group and 77% post-study response rate in the active group non-inclusive of those with connectivity issues. The Fisher’s Exact test revealed that there was no significant difference in presence of adverse effects found between active and sham stimulation. There was only a significant difference between sham and active device users when asked if the experience was relaxing, where 100% of active users found the experience relaxing compared to 33% of sham device users (p = 0.001). Analyses by t-test for safety and tolerability ratings found no significant differences in levels of adverse effects between active and sham users immediately after nor 24 hours after stimulation. There was a significant difference found for the beneficial effect of relaxation immediately after using the stimulation device where active users found the device more relaxing than sham users (p = 0.002).

    3.3 Efficacy

    Figure 3: comparing STAI scores (state anxiety) following the completion of a standardized stress task both before and after stimulation using a sham or active device. ***: p = 8*10-6

    Table 4

    STAI Scores

     

     

     

     

     

     

    Active

    Sham

     

    Pre

    Post

    p-value

    Pre

    Post

    p-value

    STAI

    43.2 ± 7.6

    32.7 ± 7.2

    <0.001

    45.7 ± 10.1

    36.6 ± 8.4

    0.01

     

    Results of the STAI state anxiety surveys were analyze using two-tailed paired t-tests. The t-tests revealed that there was no significant difference between the means of the state anxiety levels before and after stimulation for the group using the sham stimulation device. However, there was a significant difference between the means of the state anxiety levels before and after stimulation for the group using the active device (p = 8*10-6). There were no significant differences in the means found between active and sham devices in the time before stimulation or the time after stimulation when analyzed using the unpaired t-test as shown in table 4 below.

    Table 5

    STAI analysis

     

    t-test comparison

    p-value: two-tail

    active vs sham: pre stimulation

    0.5

    active vs sham: post stimulation

    0.2

    pre vs post: active stimulation

    8*10-6

    pre vs post: sham stimulation

    0.01

     

    The minimum clinically important difference (MCID) for the STAI questionnaire has been proposed to be 10 (Corsaletti et al., 2014; Taghizadeh et al., 2019). The average change in STAI scores in the active group was -10.5 ± 7.2 points which is considered a clinically meaningful improvement in state-anxiety. The average change in the sham group was -9.1 ± 9.3 which is not considered a clinically meaningful improvement in state-anxiety scores. In the active group, 67% of participants experienced a clinically meaningful improvement in state-anxiety scores, while in the sham group 33% of participants experienced a clinically meaningful improvement. 

     

    Table 6

    Heart Rate Analysis

     

     

     

     

     

     

    Active

    Sham

     

    Pre

    Post

    p-value

    Pre

    Post

    p-value

    HRV Amplitude

    10.6

    13.2

    0.1

    11.3

    10.5

    0.7

    HRV - RMSSD

    51.5

    67.3

    0.2

    50.1

    50.0

    0.9

    Resting Heart Rate 77.6 75.1 <0.05 77 76 0.5

    Heart rate metrics were also measured. Resting heart rate was significantly reduced after stimulation in the active group alone. There was no significant change in resting heart rate in the sham group. While not statistically significant, there was a clear trend in increasing heart rate variability (HRV) in the active group alone. In the active group, HRV Amplitude increased by 24% and RMSSD increased by 31%, where there was no change in the sham groups. 

     

    4. DISCUSSION

    4.1 Aim of the Study

    In this study, we aimed to demonstrate the safety and efficacy of the VeRelief neurostimulation device in decreasing anxiety when targeting an auricular branch of the vagus nerve at a novel location over the tympanomastoid fissure. Most notably, VeRelief device was found to be safe, tolerable, and effective in decreasing state-anxiety for participants. We found a significantly higher level of relaxation in participants and a significantly larger reduction in state-anxiety in patients. Due to this being a novel device, evaluation of safety and tolerability was done following similar device studies (Tassorelli et al., 2018) and adherence to current standards for pharmacologic trials via the use of 24-hour side effect analysis as the primary end point which is less susceptible to the sham effect (Tassorelli et al., 2018; Tfelt-Hansen, 2010; Voss et al., 2016).

    4.2 Safety and Tolerability

    As a novel device, careful assessment of the safety and tolerability demonstrated positive results, supporting that the device is both safe and tolerable for users. There was no significant difference in negative effects inquired upon between active and sham device users when working to determine adverse effects for both short term (directly after) and long term (>24 hours after) use.  Only slight discomfort claims were found which were reported in both the active and sham groups.

    This was found to be in line with previous studies on tVNS. In a study on pain perception done using tVNS by Busch et.al. no serious adverse events were observed during 1 hour of continuous stimulation in the left concha with an average intensity of 1.6 mA used in a sample of 48 volunteers. In this present study however, we use a set of proprietary dry electrodes designed to comfortably deliver 10 minutes of stimulation at the tympanomastoid fissure region on each side of the neck rather than direct external ear stimulation. In another study investigating tVNS for the treatment of epilepsy using 25 Hz active stimulation and 1 Hz sham stimulation, tVNS treatment was well tolerated in both groups with the most common side effect reported being headache in both groups without clinical significance between groups (Bauer, 2016).  

    In many previous tVNS clinical trials and studies, stimulation frequency is arbitrarily set between 20-30 Hz to avoid causing irreversible damage to the nerve as seen in past invasive VNS studies using 50 Hz stimulation (Agnew & McCreery, 1990; Wild et al., 2005; Yap et al., 2020). However, there have been additional tVNS studies that have used frequencies of 100 Hz and above and were found safe and tolerable (Laqua et. al., 2014; Trevizol et. al. 2016).  We believe this present study provides further support of the safety of using a frequency of 100 Hz for tVNS.

    Electrode design is a key component to comfort during stimulation treatment and important so a patient can complete a full stimulation protocol with minimal irritation. The dry electrodes used in this study were uniquely designed by Hoolest Performance Technologies, Inc. to improve the stimulation experience by optimizing impedance and current distribution and eliminating the need to soak the electrodes in a gel or saline solution before use. The electrodes also negate the discomfort of mechanical pinching and unintentional movement by the user observed in studies using ear clip electrodes (Badran et al., 2019). Other devices use electrodes made of stainless steel resulting in high current densities or made with high impedance conductive silicone or rubber which may require coating or soaking in a solution to decrease impedance but cannot ensure an evenly distributed current and requires significant preparation before the device can be used (Warren et al., 2019; Cartledge et al., 2019).

    It is also notable that the taVNS location over the tympanomastoid fissure in this study introduces another potential site to target the ABVN (Tekdemir et al., 1998; Kiyokawa et al., 2014) and have resulting therapeutic effects as measured subjectively in our study. In prior studies using tVNS, target stimulation areas have focused on either a cervical site over the sternocleidomastoid muscle which targets the vagus nerve within the carotid sheath, or various external ear sites targeting the auricular branch of the vagus nerve (Butt et al., 2019; Yap et al., 2020). Cervical tVNS comes with the risk of damaging the carotid artery, and tVNS in the external ear is often uncomfortable and requires custom electrodes for each patient to maximize comfort. tVNS over the tympanomastoid fissure reduces the risk of damaging the carotid artery, is more comfortable than external ear tVNS, and can be done with a one-size-fits-all electrode.  

    Additionally, the device used was a hand-held self-applied stimulation device, similar to the device used by Tassorelli et al. The user placement of electrodes can be beneficial in that a single device, when used properly, allows for easy anatomical adjustment to better fit the individualized anatomy of any user.

    4.3 Efficacy

    The efficacy of the device was measured primarily with reliance upon the reported state anxiety by participants before and after the received stimulation treatment. taVNS using this novel neurostimulation device was found to be superior to sham in reducing state anxiety as active users experienced a 24% clinically meaningful reduction and sham users experienced a 20% reduction that was not clinically meaningful after only 10 minutes of treatment. Even though the baseline anxiety levels were not significantly different between active and sham groups, the active group had a lower baseline anxiety level than the sham group and experienced a state-anxiety reduction 1.4 points larger than the sham group (effect size: 0.5). taVNS treatment with this novel neurostimulation device was demonstrated to provide similar results to other stimulation methods, medications, and alternative treatment methods.

    Cranial Electrotherapy Stimulation (CES) devices are neurostimulation devices that apply electrical stimulation to the head and/or neck areas and are FDA cleared for the treatment of anxiety, insomnia, depression, and pain. These devices are meant to be used daily for weeks at a time before anxiety relief can be felt by the patient. Few studies have looked at the effects of CES on fast-acting anxiety relief, but the results vary dramatically. In one study, CES was applied to the earlobes of patients with impulse control disorders for 20 minutes. In the active group, patients experienced a 32% reduction in state anxiety (Pre: 50±8.1, Post: 34±7.3). In the sham group, patients experienced a 2% decrease in state anxiety (Pre: 51±8.6, Post: 50±8.4). The average change in STAI scores was 15 points greater in the active group than in the sham group, and the active group demonstrated a clinically meaningful improvement in state-anxiety (Voris, 1995). In another study however, CES was applied to the earlobes of younger patients with mild anxiety for one hour during a stressful computer task, and results showed that CES caused an increase in state-anxiety. In the active group, patients experienced a 12% increase in state anxiety (Pre: 34.8±6, Post: 38.9±9.1). In the sham group, patients experienced a 10% increase in state anxiety. Neither group in this study demonstrated a clinically meaningful improvement in state-anxiety (Hill, 2015). It is difficult to conclude whether neurostimulation at the earlobes is an effective method for fast-acting anxiety relief, but it appears baseline state anxiety levels play a major role in the effect of neurostimulation treatment, where the higher the baseline anxiety levels, the greater the improvement in anxiety symptoms from the treatment.

    We found that taVNS with the study device provided similar relief compared with current mainstay fast-acting treatments like benzodiazepines or meditation techniques. One 398-patient study assessing the effects of lorazepam introduced intravenously to patients just before a surgical operation found that state-anxiety decreased 16% from 38.6 pre-surgery to 32.3 post-surgery (Mijderwijk et al., 2013). In that same study, the placebo group saw a 22% decrease in state-anxiety from 37.6 pre-surgery to 29.3 post-surgery. These results suggest that intravenously introduced lorazepam is not necessarily as effective for fast-acting anxiety relief as a placebo and not as effective as the neurostimulation treatment used in our study.  

    Meditation is the most popular form of drug-free anxiety treatment methods and is consistently demonstrated to be clinically effective. One study testing the effects of a 20-minute mindfulness technique on state-anxiety in 20 patients demonstrated a 41% reduction the active group and only a 1% reduction in the sham group (Pawlow et al., 2003). Another study testing the effects of a 30-minute mindfulness exercise in 24 patients found a 27% reduction in state anxiety in the active group and a 20% reduction in the sham group (Knowlton et al., 2006). Meditation practices are popular because they are low cost and have no side effects, but they require large amounts of time, mental energy, and practice to best reap the benefits. Mindfulness and meditation paired with neurostimulation may be more effective at quickly reducing anxiety than meditation practices alone, and would be a safe and effective alternative to medications like benzodiazepines. 

    4.4 Study Limitations and Future Directions

    This study assessed taVNS in a rather small, relatively healthy patient population. To better support the conclusions of this study, additional future studies will need to be done with much larger sample sizes with clinical populations varied across age, gender, and both mental and physical health. Additionally, subjects given the sham treatment did not feel any physical sensation like subjects in the active group did. Although sham participants were told to expect no physical sensation and the sham device was similar in appearance and made to have audio and visual cues, this may have made participants doubtful of the device having any effect at all. This could be better addressed in the future with the use of an active control, either in a different neutral location or in the same location but set at a minimal frequency shown to have no stimulating effect; the latter proposed method could also help with blinding. Measuring stress and anxiety levels is another relative limitation due to the subjectivity of responses, how the treatment may be perceived in control vs trial groups, and how individuals vary in what may trigger and how they may recognize such feelings.

    Additionally, engagement of the targeted ABVN could not be directly validated and was entirely based upon previous literature describing the pathway of the targeted nerve (Tekdemir et al., 1998; Kiyokawa et al., 2014). Even with the use of the active device, assuring use at the appropriate stimulation location to hit the intended target nerve without outside guidance or an effective Instructions-For-Use manual may be difficult. Validation of this target stimulation technique should be done in the future to verify activation of the intended nerve structure and more accurately define the most effective external target stimulation area. Conducting further safety studies investigating stimulation at unintended tangential locations may help provide further insight on necessary user direction to ensure accurate stimulation and avoid potential unintended side effects. Future studies should also be done with singularly controlled stimulation parameters, clinical conditions, and participant groups to further validate efficacy and help determine optimal stimulation location for tVNS, especially now that this study has introduced an additional potential location for safe and effective neurostimulation for fast-acting treatment of anxiety. 

     

    5. CONCLUSION

    Our findings have shown that using taVNS via electrical stimulation over the tympanomastoid fissure located on the upper-most lateral neck just inferior to the ear has a beneficial effect on relative anxiety in a manner that is both safe and tolerable. We have demonstrated a significant increase in level of relaxation and a significant decrease in state anxiety levels using the neurostimulation method as measured by the accepted STAI surveys compared to using a sham device.  Although more research must still be done on the topic with further trials in both healthy individuals and patients with anxiety related diagnoses to more precisely investigate the impact of varied frequencies and treatment duration, directly compare with existing anxiety reducing treatment, and explore additional potential therapeutic properties, clinically, this device may become a valuable, efficient, non-invasive, non-pharmaceutical answer for patients suffering from anxiety related disorders.

     

    6. ACKNOWLEDGEMENTS

    Thank you to all the volunteers who took part in this study. We would also like to thank Dr. Karen Gallagher of Arizona State University in the Department of Military Veteran Research for providing guidance and input on the protocol design.

     

    7. FUNDING

    This work was supported by Hoolest Performance Technologies Incorporated.

     

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