Optimizing Transdiagnostic Non-invasive Vagus Nerve Stimulation to Enhance Learning
Phase: NA
Conditions: Learning, taVNS
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE: 
Optimizing Transdiagnostic Non-invasive Vagus Nerve Stimulation to Enhance Learning 
 
PRINCIPAL INVESTIGATOR: 
• 
Danielle Taylor, Ph.D. 
 
 
 
 

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1.0 
Objectives / Specific Aims 
Improving treatment for anxiety and related conditions is essential, as anxiety disorders, for example, 
have a lifetime prevalence of 16.6% (Remes et al., 2016) and remission rates at only 51% after frontline 
exposure therapy (Springer et al., 2018). Enhancing acceptability and improving treatment refractory rates 
are key. Transcutaneous auricular vagus nerve stimulation (taVNS) is a brain stimulation candidate for 
disorders characterized by sympathetic hyper-activity (i.e., fight-or-flight; Badran et al., 2018c), including 
but not limited to generalized anxiety disorder, social anxiety disorder, panic disorder, and posttraumatic 
stress disorder. In fact, taVNS is thought to target transdiagnostic mechanisms, those mechanisms which 
are not diagnosis specific and cut across psychiatric illnesses. These include inflexible stress responses, 
heightened anxious arousal, and impaired cognitive processing (Deuchars et al., 2018). There are many 
advantages to taVNS over other stimulation technology, as it is non-invasive, affordable, and safe enough 
to implement at home or in the cognitive-behavioral therapy (CBT) clinical setting, without immediate 
MD oversight. A major limitation to the development of therapeutic taVNS is a lack of evidence for the 
optimal stimulation intensity. Failing to fully assess dose responses and mechanisms of taVNS is a major 
barrier to implementation in transdiagnostic interventions. 
To establish the clinical viability of taVNS, it will be essential to determine optimal dosing to impact 
cognitive control and fear learning and associated biomarkers. Recent research suggests that there is a 
bidirectional relationship between sympathetic responses and cognitive control implicated in adaptive 
learning processes (Taylor et al., 2019; 2020). Also, anxiety is linked to heightened perception of heart 
rate changes (subjectively and neurally; Judah…Taylor & Grant, 2018), both factors which in turn 
influence cognitive functioning and learning processes, fear or otherwise, and this cascade may be 
modulated via vagal tone. Therefore, this study will determine the optimal taVNS dose and its influence 
on the course of fear learning and basic cognitive processes during goal-directed activity, while evaluating 
the psychophysiological profile in each context. 
In order to develop therapeutic taVNS for psychiatric problems, a necessary first step is to establish the 
appropriate parameters that will modulate cognitive and affective responses among healthy participants. 
We will first recruit 45 healthy participants (randomized to 9 different dose durations) to determine the 
dose-response curve for taVNS on a range of vagally-mediated physiological measures and subjective 
mood. At a single session, heart rate variability (HRV), skin conductance (SC), and 
electroencephalography (EEG) will be measured at baseline, concurrently with stimulation, during 
learning and cognitive tasks and finally during a recovery period. Utilizing rest, learning and recovery 
conditions concurrent with multiple physiological measures we will demonstrate whether there is process- 
or physiological modality-specific modulation or co-activation across domains and measures. Our team of 
experts in brain stimulation, neuroscience, and psychophysiology are uniquely suited to accomplish these 
tasks. After establishing the dose-response curve, the findings of our dosing may be evaluated an 
additional sample of 45 participants seeking treatment for anxiety or trauma related disorder. 
An additional goal of this study is to evaluate invasive vagus nerve stimulation (VNS) to determine how 
taVNS relates to other established forms of brain stimulation via the vagus nerve. VNS is currently FDA 
approved for depression and epilepsy, and research has indicated that patients also report decreased 
anxiety symptoms. Therefore, patients with previously implanted VNS, will be invited to complete this 
study. They will be administered similar tasks as participants who receive taVNS, and a full 
psychophysiological profile will be assessed. This study will only recruit individuals who currently have 
implanted VNS, given the invasive procedure. Although VNS is FDA approved, nearly 150,000 patients 
have received VNS worldwide over the past 25 years. Therefore, limited patients in the study area have 
received VNS, so this study expects to recruit <5 patients for this study goal. 

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Aim 1. Establish the dose-response curve secondary to transauricular vagus nerve stimulation 
(taVNS) for vagally-mediated physiological indicators at rest. We hypothesize that a dose-response 
curve will be observed with higher doses than typically administered in taVNS protocols being more 
efficacious in affecting physiological responding. Exploratory Aim 1a. Examine whether dose-response 
curves vary as a function of physiological measure (e.g., EEG/HRV, etc.). Exploratory Aim 1b. Examine 
whether a dose-response curve emerges for state measures of mood and interoceptive sensitivity.   
Aim 2.  Establish the dose-response curve secondary to transauricular vagus nerve stimulation 
(taVNS) for vagally-mediated physiological indicators during fear and cognitive challenge. We 
hypothesize that higher doses than typically administered in taVNS protocols will be more efficacious in 
affecting physiological responding and performance. Exploratory Aim 2a. Examine whether dose-
response curves vary as a function of different physiological measures. Exploratory Aim 2b. Examine 
whether a dose-response curve emerges for cognitive and/or fear learning performance. 
Aim 3. Assess tolerability and feasibility among a sample of participants with anxiety and trauma 
related symptoms. We hypothesize that utilizing taVNS among participants with anxiety and trauma 
symptoms will be well tolerated and will modulate autonomic arousal and fear processes, as indicated in 
physiological indicators. 
Exploratory Aim 3. Examine whether invasive VNS and taVNS result in similar modulation of 
physiological measure (e.g., EEG/HRV, etc.), state measures of mood and interoceptive sensitivity, and 
across similar cognitive and affective tasks. 
2.0 
Background 
The vagus nerve is the longest cranial nerve and maintains parasympathetic control over the heart, lungs, 
and digestive track, while also providing the prefrontal cortex with somatic and visceral feedback 
(Chalmers et al., 2014; Porges, 2001). It contains a variety of fibers which provide sympathetic and 
parasympathetic innervation and carry somatic and visceral afferent and efferent information. Given the 
vagus nerve’s contributions to cardiac functioning, it is often indexed using heart rate variability (HRV; 
beat-to-beat changes in the heart rate), also referred to as vagal tone. Pharmacological blockade of the 
vagus results in increased heart rate suggesting that cardiac activity is regulated by inhibitory vagal 
control. Chronic stress, on the other hand, leads to protracted sympathetic disinhibition, inflexible 
parasympathetic activity, and maladaptive cognitive responses. In fact, low vagal tone and poor inhibition 
of sympathetic activity (i.e., fight-or-flight) is implicated in a range of psychiatric conditions and mental 
health problems, including emotion regulation difficulties, anxiety, depression, and PTSD. 
Aberrations in cardiac activity are central to both the state expression of anxiety, as well as its 
pathological form. During the acquisition of fear, the vagus nerve provides visceral feedback to the brain 
and during extinction, the vagus inhibits sympathetic responses 
such as heart rate (Pappens et al., 2014). This critical brain-
body communication which facilitates inhibitory fear 
extinction is hijacked in anxiety, as prolonged disinhibition of 
cardiac activity leads to persistent elevations in sympathetic 
responding regardless of the absence of threat. Thus, low vagal 
tone is considered a biomarker of anxiety and related 
psychopathology (Chalmers et al., 2014). Given that 
engagement in new learning (both reinforcement from positive 
feedback and inhibition of fear responses) are essential 
components to attain improvements via CBT and exposure 
Figure 1. Moderating effect of RSA on the relation 
between negative cognitions and ERP indicator of 
cognitive control (Taylor et al., 2020). 

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therapy (Craske et al., 2008; 2014), it is predictable that disorders characterized by low vagal tone show 
poor treatment responsivity. In fact, our research suggests that parasympathetic responses are protective 
against the otherwise harmful effects of repetitive negative thinking (RNT) on cognitive control (Taylor et 
al., 2020; see Figure 1). Thus, given the linkage between vagal tone and psychiatric problems, 
interventions that non-invasively target the vagus nerve to regulate inhibition of sympathetic activity may 
be therapeutic for psychiatric conditions characterized by inflexible parasympathetic responses such as 
anxiety disorders.   
Brain stimulation techniques have been used to identify mechanisms of action and treat mental health 
conditions, and evidence of afferent and efferent vagal contributions has been shown using a variety of 
stimulation techniques. In fact, vagal innervation of cardiac responses, observed via HRV, may be 
modulated using vagus nerve stimulation resulting in increases in parasympathetic activity (Zamotrinsky 
et al., 2001), providing additional support for this connection. Stimulating the vagus also is a therapeutic 
intervention approved for the treatment of depression and can be accomplished by implantation of 
electrodes. Studies investigating VNS show that it affects brain regions linked to mood regulation, and 
clinical trials using VNS for depression show efficacy in reducing depressive symptoms, as well as 
reduced anxiety symptoms. A potential mechanism for its anxiolytic effects is that VNS stimulates the 
locus ceruleus, a primary norepinephrine (NE) site, which is essential to regulating arousal and stress 
responses. Those with anxiety and other related problems tend to show greater NE reactivity, thus VNS 
may aid its down regulation (George et al., 2000).  
A draw back to administration of VNS is that it requires implantation, which reduces the feasibility of 
VNS as a tool for clinicians. Researchers have developed a safe, non-invasive, as well as easy to use 
stimulation technique, taVNS, which modulates afferent projections via stimulation of the vagus nerve 
through the human ear (Badran et al., 2018a; see Figure 2). Using conductive gel, an 
electrode is applied to the tragus cartilage of the left ear and pulsed electrical stimulation 
is delivered at a tolerable intensity for half hour to an hour, thus, stimulating the 
auricular branch of the vagus nerve (ABVN). This method has been shown to activate 
afferent vagal networks and early work shows promise for treatment of psychiatric 
conditions linked to overactive sympathetic responses (Badran et al., 2018c). Studies 
have recently demonstrated some efficacy for taVNS for reduction in symptoms of 
depression, including RNT, sleep disturbances and anxiety. However, mechanisms, 
parameters, and the neurobiological effects are not well established (Badran et al. 
2018b). Trials studying the efficacy of taVNS have shown inconsistent results, which 
are largely attributable to incomplete consideration of stimulation parameters and 
corresponding modulation in the psychophysiological profile taVNS purportedly targets. 
This study aims to parameterize, then employ this emerging form of stimulation and 
explore its effects on learning and cognitive control, while fully evaluating the 
physiological mechanisms which are affected during and after stimulation. 
3.0 
Intervention to be studied  
The stimulation system, custom developed at the MUSC Brain Stimulation Laboratory, consists of a 
commercially available, FDA-cleared (K172381) Digitimer DS7A constant current stimulator (Digitimer 
Ltd., USA) used with custom-built electrodes built by Dr. Bashar Badran in MUSC’s Brain Stimulation 
Lab. This is a safe, non-invasive, and easily implemented stimulation technique which does not require MD 
oversight. TaVNS modulates afferent projections via stimulation of the vagus nerve through the human ear 
(Badran et al., 2018a) and early work shows promise for treatment of psychiatric conditions linked to 
overactive sympathetic responses (Badran et al., 2018c). Studies have recently demonstrated some efficacy 
for taVNS for reduction in symptoms of depression, including RNT, sleep disturbances and anxiety. 
Figure 2. TaVNS active and 
sham stimulation electrode 
placement

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However, mechanisms, parameters, and the neurobiological effects are not well established (Badran et al. 
2018b). Researchers on this study are experts in the development, application, and clinical use of brain 
stimulation techniques, and in particular are pioneers in the development and investigation of taVNS 
technology and its application for psychiatric treatments. 
Using conductive gel, an electrode is applied and pulsed electrical stimulation is delivered at a tolerable 
intensity for at least half an hour, thus, stimulating the auricular branch of the vagus nerve (ABVN). The 
active condition will be direct electrical stimulation delivered to the inner side of the left tragus (anode in 
the ear canal, cathode on the surface of the tragus) based on Dr. Bashar Badran and Dr. Lisa McTeague’s 
prior work. The left earlobe, used as control, has minimal ABVN innervation. The control stimulation 
condition will utilize identical stimulation parameters as the active condition.  
Stimulation parameters will consist of 500 μs pulse width and 10 Hz frequency. Stimulation current will be 
delivered at 200% of each participant’s individual perceptual threshold (PT) and repeated for each 
stimulation condition (tragus and earlobe). PT procedure entails single pulses of stimulation to the target 
area and obtaining verbal confirmation of stimulation perception while modulating the current intensity via 
parametric estimation by sequential testing (PEST) method. This allows for determination of the minimum 
current intensity perceived by the participant at a specific target location. 
Participants will be randomized to one of 9 dose durations with 5 participants per dose, increasing in 10 
minute increments of active stimulation, ranging between 10 and 90 minutes of stimulation. All active 
sessions per dose will be delivered contiguously and at the end of the stimulation period, and sham 
stimulation at the beginning. This is to ensure that all participants have the same lapse of time between pre- 
and post-stimulation recording. That is, if a participant is randomized to 60 minutes of active stimulation, 
the first 30 minutes would be sham stimulation. After establishing the optimal dose-duration a sample of 
treatment seeking individuals will be recruited. This dose will be administered to individuals with anxiety 
and trauma symptoms to ensure that effects are sustained and to determine feasibility and tolerability. 
An additional group of individuals with implanted VNS also will be evaluated after 30 minutes of 
stimulation. Patients at MUSC who participated in the Microtransponder Vivistim trial or other 
research/treatments involving VNS will be recruited to complete similar cognitive and affective tasks while 
psychophysiological responses are measured across 3 sessions: control (no stimulation), implanted VNS, 
and noninvasive taVNS. This will serve as a comparator for whether taVNS is activating similar brain and 
physiological regions as invasive forms of vagus nerve stimulation. This will also indicate whether 
mechanisms of taVNS and VNS are comparable. In order to truly determine comparability of these two 
forms of VNS, it is imperative to assess within subject brain, body, cognitive, and emotional responding 
across both implanted and non-invasive VNS. 
4.0 
Study Endpoints  
The following indices will be measured to assess modulation of resting and cognitive/emotional challenge 
via taVNS dose. Each will be processed and scored according to published guidelines (Blumenthal et al., 
2005; Boucsein et al., 2012; Gatchel et al., 1973; Keil et al., 2014). Biopac equipment will be used to 
continuously measure heart rate/ variability (HRV) and skin conductance (SC) to assess autonomic 
responses. SC increases are indicative of a sympathetically mediated orienting response (Dawson et al., 
2011; Bradley, 2009). Previous studies evaluating taVNS have employed the SC within the context of fear 
extinction, but have not demonstrated an effect (Burger et al., 2016; 2017), though faster rates of extinction 
were shown. HR deceleration also is indicative of the orienting response, while higher HR variability is 
indicative of regulated emotional responding (Appelhans & Luecken, 2006; Bradley, 2009). Decelerations 
in HR after taVNS have been demonstrated under certain parameters (Badran et al., 2018b). Pupillometry 

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will be assessed to determine anxious arousal and defensive responding as a function of taVNS. Pupil 
dilation will be measured with a Tobii eyetracker. Previous data has shown that taVNS modulates pupil 
dilation. Thus, this will be used to aid in determining the optimal dose duration of taVNS. 
EEG will be measured using a 32-channel BrainVision actiCHamp system. Data will be processed with 
BrainVision Analyzer software. Resting EEG will be measured pre-, post-, and concurrently with 
stimulation, and will be explored for taVNS dose dependent modulation in frequency bands and coherence 
of the EEG power spectrum. For data collected during the learning/attention task, multiple event-related 
potentials (ERPs) and steady-state visually evoked potentials (ssVEPs) will be assessed. A variety of 
ERPs indicative of attention (i.e., orienting, discrimination) will be evaluated across a variety of contexts 
after stimulation, including fear learning and extinction, and learning more broadly. Some studies have 
shown taVNS linked enhancements in the P300, an orienting response (Warren et al., 2020), whereas other 
studies have not (Warran et al., 2019; Keute et al., 2019). A recent evaluation found taVNS related ERP 
modulations indicative of enhanced cognitive control (i.e., N2; Pihlaja et al., 2020), which is typically 
increased during engagement of attention and is enhanced during cognitive conflict. Enhancements in the 
N2 are typically seen across internalizing disorders, and our previous work demonstrates that the N2 is 
modulated under internal and external threat (Taylor et al., 2020; Moran, Taylor, & Moser, 2012; White, 
Grant, Taylor et al., 2018). In addition, ssVEPs which are collected by flickering visual stimuli, may be 
assessed during stimulation. These potentials are modulated by attentional and motivational factors and will 
provide real-time dose-dependent data regarding taVNS related modulations in attention. Given the extant 
and emerging literature on the effects of taVNS on brain activity, these ERPs and other relevant ERPs will 
be explored.   
Participants will complete subjective measures of anxiety and depression and related difficulties as well as 
Self-Reported Units of Distress (SUDs) during stimulation and the tasks and acceptability/tolerability 
measures (see Section 10.0 Study Design/Methods for surveys and other measures).  
The above measures will also be assessed for participants with implanted invasive VNS and then 
subsequently with noninvasive taVNS. 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
This study seeks to recruit from a broad range of individuals ensure generalizability, though some 
exclusion criteria are necessary to ensure participant safety. Participants will call the lab and complete a 
phone screener which assesses for the following criteria. The recruited sample will be 50% female evenly 
counterbalanced across active stimulation duration and sham conditions. No racial or ethnic groups will 
be excluded during recruitment, nor will any other individuals with diverse backgrounds. However, 
participants must be English speaking, as the study consent and other tasks are presented in the English 
language. Risks of taVNS to a fetus are currently unknown. Thus, individuals identifying as having 
childbearing potential will be screened for pregnancy during the phone screener and will be provided a 
pregnancy test prior to stimulation to confirm they are not pregnant. 
Inclusion Criteria  
• 
Ages 18-65 years 
• 
English speaking 

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• 
Healthy, Non-treatment-seeking community members who do not have a 
mental health diagnosis and individuals seeking treatment for an anxiety, mood, 
trauma-related, or obsessive-compulsive disorder. 
• 
Treatment and non-treatment-seeking community members with anxiety, mood, 
trauma-related, or obsessive-compulsive disorder or symptoms. 
• 
Patients at MUSC who have received implanted VNS for depression or stroke 
recovery. 
Exclusion Criteria 
• Diagnosis of COVID-19 in the past 14 days 
• 
Facial or ear pain or recent ear trauma for the taVNS group only. 
• 
Metal implant devices in the head, heart or neck for the taVNS group only. 
• 
History of brain stimulation or other brain surgery for the taVNS group only. 
• 
History of myocardial infarction or arrhythmia, bradycardia for the taVNS 
group only. 
• 
Use of B-blockers, antiarrhythmic medication (sodium/potassium/calcium-
channel blockers), or blood pressure medications for the taVNS group only. 
• 
Active respiratory disorder for the taVNS group only. 
• 
Personal or family history of seizure or epilepsy or personal use of medications 
that substantially reduce seizure threshold (e.g., olanzapine, chlorpromazine, 
lithium). 
• 
Personal history of head injury, concussion, or self-report of moderate to severe 
traumatic brain injury for the taVNS group only.  
• 
Individuals suffering from frequent/severe headaches for the taVNS group only. 
• 
Individuals with lifetime evidence of severe psychiatric disorder (e.g., 
schizophrenia) or neurological disorder for the taVNS group only. 
• 
Moderate to severe alcohol or substance use disorder.  
• 
Pregnancy 
6.0 
Number of Subjects 
This study will recruit 90 community individuals who meet the above inclusion and exclusion 
criteria, 50% of which will be female. Participants (n = 45) who are healthy controls will be 
recruited to establish the dose response curve. Then this dose will be administered to 40 
individuals with anxiety and trauma related symptoms. Participants with implanted VNS (n = 5) 
will be recruited for similar procedures. 

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7.0 
Setting 
All participants will complete the study tasks in a dedicated research suite, the Psychophysiology Center, 
in the Brain Sciences Department within the IOP. The space to be used here is currently assigned to 
researchers on this study team and is well equipped for stimulus-controlled physiological recording. In 
addition, this space is used only for research protocols and thus is accessed at limited times. Studies assigned 
to this space may only enter during their assigned hours to ensure participant confidentiality and privacy. 
This also ensures COVID-19 related precautions may be taken: limiting use of space to no more than the 
participant and the study researcher and allowing time between participants for cleaning/sanitation, 
requiring the use of masks for researchers and participants. 
8.0 
Recruitment Methods 
Participants will be recruited from the Charleston community and from the population of individuals who 
present to IOP for mental health treatment. Potential participants will be recruited via flyers (see 
advertisements) placed at approved sites at MUSC’s library and hospital, as well as within the IOP; in 
addition, online advertisements will be placed on scra.org, on facebook.com, on researchmatch.org, and 
on nextdoor.com. Separate recruitment materials will either be targeted to adults seeking treatment for 
anxiety, mood, trauma-related or obsessive-compulsive disorder, or to the Charleston community at large. 
Appropriate approvals will be received prior to posting flyers. 
When a potential participant contacts about the study, trained research assistants will overview all 
procedures and specify the expected duration and compensation (see Phone Recruitment script). The PI 
and Co-I will train staff in answering questions related to study procedures. After providing information 
about the study, a phone screener will be completed. Participants will be asked to complete this portion in 
a private setting. Should participants meet for the inclusion/exclusion criteria, and they agree participate, 
subjects will be provided with available participation dates, an online consent form, and will be sent the 
study’s Redcap survey. They will also be provided with instructions on how to locate IOP and the lab 
space. Participants will be asked to refrain from alcohol use and intense physical activity 24 hours before 
the study, as well as refrain from caffeine 6 hours and tobacco 2 hours prior to the study. Participants will 
be encouraged to sleep as they usually do the night before the study. 
 
In order to recruit participants with implanted VNS, the principal investigator will contact clinicians at 
MUSC to disseminate information about this study to patients with VNS, including the MUSC Center for 
Rehabilitation Research and the MUSC Comprehensive Stroke Center. Clinicians and researchers will be 
provided a script (see VNS Recruitment Script). Clinicians will be asked to only invite patients: 1) who 
have completed VNS treatment/research or 2) whose VNS treatment/research protocol will not be 
affected by 30 minutes of stimulation. 
 
9.0 
Consent Process 
The consent form will be sent to participants via RedCap after the phone screen is complete and 
prior to being sent the RedCap surveys. Participants will be given ample time to read the consent 
form and a researcher will describe the content of the consent form to ensure understanding, 
including describing the laboratory measures, study duration, and equipment and materials. The 
researcher will describe confidentiality/privacy measures, participant right to withdraw, 
risks/benefits, and compensation. In addition, participants will be prompted to ask questions 
throughout consenting to further ensure understanding. After electronically signing the consent 
form, an electronic copy will be made accessible to the participant for their records. They will also 
be offered a hard copy which will be provided during the in-lab scheduled participation date. 

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10.0 Study Design / Methods 
After completing the phone screener, participants will be invited to in-lab participation: they will 
be provided available times and instructed on how to locate IOP and the laboratory space. They 
will be asked to refrain from the following prior to the study: Tobacco use within 2 hours, 
Caffeine within 6 hours, Alcohol within 24 hours, and intense physical activity within 24 hours. 
Participants will be asked to sleep as they usually do the night before the study.  The study will 
take up to two hours and thirty minutes. 
Prior to arrival to the research space, after phone screening, participants will be provided online 
informed consent (see Section 9.0). After participants have been informed of the nature of the 
study and consent to the study procedures, they will be sent a series of questionnaires to be 
completed online using the RedCap survey platform. They will be asked to complete these 
questionnaires in a private setting to ensure their confidentiality. None of the items on these 
questionnaires address suicidality. However, surveys will be monitored for extreme scores 
indicating severe mental health issues or indication of suicidal or homicidal ideation/risk, and 
those participants will be contacted immediately via phone to assess for safety. Several attempts 
will be made to reach at risk participants. They will be assessed for safety again, upon arrival to 
the lab. Questionnaires will include a measure of demographics, Penn State Worry Questionnaire 
(PSWQ; Meyer et al., 1990), the Attentional Control Scale (ACS; Derryberry & Reed, 2002), the 
Childhood Trauma Questionnaire (CTQ; Bernstein & Fink, 1998), Connor Davidson Resiliency 
Questionnaire (Connor & Davidson, 2003), Contrast Avoidance Questionnaire (CAQ; Llera & 
Newman 2017), PTSD Symptom Scale – Self-Report (PSS-SR; Falsetti et al., 1993), the 
Perseverative Thinking Questionnaire (Ehring et al., 2011), the Social Interaction Anxiety 
Inventory/Social Phobia Scales Short forms (SIAS-SPS; Fergus et al., 2012), the Intolerance of 
Uncertainty Scale (Carleton et al., 2007), Difficulties with Emotion Regulation Scale (Gratz & 
Roemer, 2004), and the Generalized Anxiety Disorder 7-item scale (GAD-7; Spitzer, 2006). 
Once participants have arrived to the laboratory, if they identify as an individual of childbearing 
potential, they will be provided with a pregnancy test strip to take in privacy. They will be 
provided instructions on how to use the test, as well. After completing the pregnancy test, 
participants with negative results will be asked to continue to the remaining study procedures, 
whereas those with a positive result will be debriefed, compensated for their time, and released. 
Next, electrodes will be attached which will measure a variety of responses, including 
electroencephalography, electrocardiography, electrooculography, electromyography (startle 
reflex), and electrodermal activity. Tobii eye tracker software will be set-up to monitor and record 
pupil dilation and eye tracking. TaVNS electrodes (active and sham) will be attached to 
participants who do not have implanted VNS. A computer monitor will be adjusted for appropriate 
eye level. Peripheral physiology (e.g., heart rate) data will be collected using a Biopac MP150 
hardware and amplifier along with AcqKnowledge software, and brain activity will be collected 
using an Actichamp active sensor cluster and amplifier. Stimuli (e.g., learning tests) will be 
presented using Presentation software. The following questionnaires will be administered during 
electrode set up: Positive and Negative Affect Schedule – Short Version (PANAS; Thompson, 
2007), the Beck Depression Inventory- II, (BDI-II; Beck et al., 1996), State Trait Anxiety 
Inventory (STAI; Spielberger et al., 1983), the Anxiety sensitivity index (ASI-3; Taylor et al., 
2007). Participants will be asked when they last used Tobacco, Caffeine, Alcohol, engaged in 
intense physical activity, and when they last took medication, along with what those medications 
include. They also will be asked to report on their typical sleep habits and sleep from the night 
before – these will be asked in the Health Behaviors Survey. A measure of tolerability for 

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stimulation will be administered periodically throughout the study. Responses (particularly those 
on the BDI-II (Item #9 – suicide ideation) will be monitored for endorsements of suicidal ideation. 
See section 13 for study team response to suicidal ideation. 
After all electrodes are attached, a 1) baseline (5-10 min) physiology measurement will be taken. Then 
stimulation will begin. See additional information in Section 3.0 (Intervention to be Studied). Participants 
in the taVNS group (not having implanted VNS) will be randomized to one of 9 doses with 5 participants 
per dose, increasing in 10 minute increments of active stimulation. All active sessions per dose will be 
delivered contiguously and at the end of the stimulation period, and sham stimulation at the beginning. 
This is to ensure that all participants have the same lapse of time between pre- and post-stimulation 
recording. That is, if a participant is randomized to 60 minutes of active stimulation, the first 30 minutes 
would be sham stimulation. 
For participants with previously implanted vagus nerve stimulation devices, stimulation will be delivered 
for 30 minutes. They will subsequently be invited to revisit the lab to receive non-invasive taVNS 
delivered in a comparable manner to the healthy subjects for 30 minutes. 
Additional physiology measurements will be taken 2) concurrent with stimulation and during a final 
recovery measurement (5-10 mins) after stimulation has concluded.  
During the base, recovery, and during 3 time points during the 90-minute stimulation period (i.e., 30 
minutes, 60 minutes, and 90 minutes), a Passive Auditory Oddball Task will be administered. During this 
task a relaxing movie (i.e., silent sand art film) is presented concurrent with standard and deviant tones; 
MMN task from the ERP Compendium of Open Resources and Experiments - ERP CORE; Kappenman et 
al., 2020; Eriksen & Eriksen 1974).  
For participants with previously implanted VNS devices, the same Passive Auditory Oddball task will be 
administered. Additional tasks will be administered, including a visual search task, during which an array 
of shapes are presented on a computer screen. Participants must identify and click on a target shape (N2pc 
task from the ERP Compendium of Open Resources and Experiments - ERP CORE; Kappenman et al., 
2020). A cued picture viewing task will be administered consistent with other research at MUSC 
department of psychiatry studies. Cues (shapes) are presented followed by either an unpleasant, pleasant, 
or neutral picture. Pictures are from the International Affective Picture System (Lang et al., 2005). Similar 
research is being conducted at MUSC by co-investigator Christopher Sege using these pictures and task 
design. Finally, a fear learning and extinction task will be administered. Participants will see different 
shapes/colors appear on the computer screen. Some of the shapes/colors will be paired with the sound of a 
person screaming (Glen et al., 2012). White noise bursts will be played during these tasks at random 
times.  
During the physiology/task assessment participants will be provided with a brief break from computer 
tasks. During this time, the Montreal Cognitive Assessment (MOCA; Nasreddine, 2004) will be 
administered to ensure there is no major cognitive decline. 
Then a 3) finally during a recovery period (5-10 min) resting physiology measurement will be taken. 
After all the tasks are completed, participants will be debriefed about the purpose of the study, 
compensated for their time, and released. Participants will be reimbursed using a Clincard with the 
amount of $100. They will be provided with the ClinCard along with relevant information (e.g., ATM 
withdrawal fees, how to use) prior to leaving the in-lab procedures. 
Participants with implanted VNS will be asked to return for a second visit, during which they will receive 
no stimulation, but will be asked to complete the same tasks. The order of stimulation versus no 

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stimulation lab visits will be randomized. They will be reimbursed using a Clincard with the amount of 
$180 for the first 2 lab visits and surveys. Should participants with implanted devices agree to a third in-
lab visit for 2.5 hours, they will be reimbursed with an additional $80.00 to their ClinCard. 
Several procedures will be taken to minimize risks over the course of the study: 
Physiology: For sensors that are attached to skin there is some risk for mild local irritation or 
redness, thus adhesives are removed with caution/gently. Participants are informed that EEG 
involves the use of a water based gel during the consent process as some participants report they 
dislike having the gel in their hair. There are rare instances of static shock during EEG. Thus 
participants are seated in non-metal chairs and experimenters use caution so as to not increase risk 
of electrical shock, such as using a grounded EEG system.  
TaVNS: The taVNS stimulation administered during the study is non-invasive but includes some risk. 
Participants will be screened for potential contraindications to taVNS prior to invitation to the lab (see 
Section 5.0 for exclusion criteria; e.g., ear trauma/pain, metal implants). The device has safety 
mechanisms to prevent electrical surges. Skin will be prepared using 70% alcohol swabs prior to electrode 
attachment to ensure sanitation and stimulation power is safe. Metal jewelry also will be removed from 
the head. Stimulation is applied using similar electrodes to those used in EEG and a water based 
conductive gel, and participants will be assessed after application/prior to stimulation for discomfort 
related to the electrode. Participants will be assessed during stimulation for discomfort or adverse events 
over the course of stimulation, though studies have demonstrated few concerns of safety. Participants are 
encouraged to share report of discomfort and are reminded prior to the study they may discontinue at any 
point. The ear also will be cleaned and inspected for irritation/redness after stimulation. The ear 
stimulation delivered during the study is includes some risk. Participants in previous research using this 
stimulation describe the feeling as a “tickle” or “pricking” sensation. Some report mild irritation. Our 
researchers will inspect the ear after stimulation given previous research has documented some redness 
from the stimulation.  
 
VNS: Participants being recruited to complete this study with VNS, will include subjects with previously 
implanted devices and who have been given permission by their physician to activate their own stimulator 
without health risks. These participants who may administer their own stimulation have been given a 
“magnetic wand” or button to activate their stimulator in order to encourage post-stroke motor function. 
No severe adverse effects have been reported with implanted devices after implantation. However, mild 
discomforts/risks have been reported including nausea and dysphagia (swallowing difficulties) which 
resolve by the end of the day after stimulation. Participants will be encouraged to report discomfort and 
will be assessed periodically for these discomforts. To ensure that ongoing VNS treatment is not affected, 
only those who have completed VNS treatment/research or whose VNS treatment/research will not be 
affected by 30 minutes of stimulation will be recruited for the study. 
 
 
Surveys: Some report mild discomfort when reporting on these topics, so study staff, including the PI and 
Co-I, will be available to debrief participants in distress, if needed. The PI will be available to provide 
counseling resources if participants are interested, and in the case of suicidal ideation and intent (see 
Section 13.0) immediate and appropriate response will be provided, including encouraging the participant 
to remain with experimenters (even if study is terminated) to ensure the participant is in a safe location. 
The study personnel are clinically trained to identify participants in distress. However, these surveys 
involve minimal and low-base rate for risk.  

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Tasks: The tasks involve no more than minimal risk. The scenes and tones played during the study 
are not distressing in nature. To ensure comfort, participants will be allowed to adjust to the tones 
starting the task. Participants will be monitored for distress. For participants with implanted VNS 
who complete the fear learning task, the screaming sounds can generate mild temporary distress. 
Studies show that this mild temporary distress typically dissipates by the end of the task, as it 
includes a phase of “fear extinction” where symbols are presented unpaired with a feared stimulus. 
The picture viewing task, used in several studies here and at other research labs, consists of some 
unpleasant pictures, which can evoke sadness or fear. However, these feelings do not persist 
beyond the picture viewing task and participants who report sadness or fear indicate the emotions 
are of a manageable intensity. Participants will be assessed for these discomforts throughout, and 
will be monitored for extreme discomfort. Should participants indicate the discomfort is of 
extreme intensity, the tasks will be discontinued. Participants may discontinue at any point without 
consequence. 
Confidentiality: To protect confidentiality of study-specific measures, only the participant code, 
and no potentially identifying information (e.g., name, date of birth) will ever be associated with 
these measures. In addition, self-report data will not include identifiable information. Self-report 
data are in Likert format and will be linked only to a participant code. Thus, no data will be 
identifiable. However, there is still a small risk of loss of confidentiality of participant information 
in this study. Steps taken to protect confidentiality are described further in the Data Management 
section. 
12.0 Data Management  
Power: Dose-response studies are not powered in the traditional manner. To resolve the shape of 
the continuous dose response function, it is statistically more efficient to select more doses as 
opposed to more participants (O’Quigley & Conaway, 2010; Kuljus et al., 2006). The number of 
observations within each dose primarily accounts for sampling variability, which could be 
achieved with 2-3 observations. Capturing variability is essential to the planned analyses, which 
underweight the points of greatest variability in estimating the response curve. Thus, the sample 
size of N = 45 was determined sufficient to accomplish Aim 1 to establish a dose-response curve. 
Of note, Dr. McTeague is running three funded projects with these dose-response techniques in 
optimizing repetitive transcranial magnetic stimulation (rTMS). An additional, sample of 45 
participants are included in the case of data loss and to replicate dose-response findings/assess 
feasibility/tolerability on participants with anxiety or trauma related disorder or symptoms. 
Analyses: The psychophysiological data will be processed using standard protocols which have 
previously been used in this lab and in various other studies (Sege et al., 2017, 2018, Taylor et al., 
2020; Grant et al., 2015), and according to published guidelines (Blumenthal et al., 2005; 
Boucsein et al., 2012; Gatchel et al., 1973; Keil et al., 2014). 
Dose-response relationships will be assessed using the multiple comparisons procedure with 
modeling (MCP-Mod) approach pre- to post-stimulation changes in physiology and behavior. To 
determine the reliability of a dose response, MCP-Mod fits a set of pre-specified candidate dose-
response curves to the data using a multiple-comparisons technique. The pre-specified dose-
response curves to be tested would be Emax, logistic, and linear. Significant curves would then be 
used to develop inferences on optimal doses for a follow-up adaptive-dosing design, with doses 
more finely resolved around the probable point of maximal efficacy as determined in this project.  

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Confidentiality and Quality Control: All study personnel will complete Social-Behavioral-
Educational research CITI training, and also complete in-lab training regarding data security 
practices. Study personnel will be trained in the IRB protocol. The investigator, and co-
investigators will be available to monitor data collection to ensure quality, confidentiality, and 
adherence to the IRB protocol. 
 
The majority of this study's procedures will take place in the study's research suite, which is a 
private room with limited access. Regarding documentation, participant names will appear only on 
the IRB-approved Consent, HIPAA, and payment forms. After the participant electronically signs 
the consent form on HIPAA-compliant RedCap, a random identification code will be assigned to 
the individual, and all data collection will be referenced to the code rather than name or other 
identifying information. Questionnaires will be completed in a HIPAA-compliant RedCAP 
interface. There is some risk to loss of confidentiality due to the remote nature of consent and 
questionnaires. It cannot be guaranteed that participants will complete these study portions in 
private spaces, though they will be encouraged to do so for their protection. Payment forms will be 
collected and stored separately from data in a locked cabinet for up to 6 years. 
 
After participation, RedCAP data will be downloaded in excel format to the secure MUSC server. 
Finally, physiology data files will also be linked only to participant code; these data will be 
recorded on password-protected local drives at the IOP. 
 
In terms of publication, data will be published in aggregate form, so invidual participants will not 
be identifiable in the final manuscript. No identifying information will be published. 
13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
The PI and co-Is will be responsible for monitoring the data collection and safety of participants. 
This study involves some risk, though previous research at MUSC using the same stimulation 
parameters has demonstrated no major or minor adverse events during or after stimulation when 
assessing skin discomfort, irritation, headache, facial pain and dizziness, heart rate, respiration, 
and self-reported pain (Badran et al., 2018). Researchers identified redness at stimulation location 
and pain ratings in this study were means of 2.1 and 1.2 (out of 10) for the tragus and the ear lobe, 
respectively. Of the MUSC patients with implanted VNS, only those who have been provided 
clearance from their doctors to deliver 30 minutes of stimulation at home and unmonitored by 
physicians as part of their treatment protocol will be recruited. The stimulation parameters used in 
this study are the same stimulation parameters that participants self-administer at home. However, 
Brain Stimulation Lab physicians will be readily available should adverse events occur. 
The questionnaire, experimental, and physiological data will be monitored to ensure the safety of 
subjects. During the study participants will be inquired about their comfort with regard to the 
stimulation and will be informed (prior to stimulation) that they may terminate at any point. 
Participants will be assessed for adverse events in the current study, including skin discomfort, 
irritation, headache, facial pain and dizziness.  
Quality Control: Regular data verification meetings will take place weekly with the PI, co-Is, and 
the study personnel to ensure proper procedures are followed (consenting, data collection and de-
identification), ensure study/experimental protocol adherence, and to assess for adverse events. In 
addition, study personnel will be trained to contact the PI immediately, in the case of an adverse 
event. Events determined by the PI to be unanticipated problems involving risks to subjects or 
others, or to be an adverse event, in accordance with HRPP guideline 4.7, will be reported by the 

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PI to the IRB as soon as possible and after no later than 10 working days, per IRB policy 
described in guideline 4.7. 
Access & Safety Training: Research staff assisting with physiological data collection will receive first aid 
and CPR certification to assess and respond to participant emergencies during the study. The PI and Co-I 
each have expertise in physiological and clinical data collection, and will be responsible for training any 
additional research staff in proper procedures for sensor use/ placement and handling of data.  
Suicidal Intent: Suicidal ideation, intent or planning will be screened as part of this study. The PI and Co-I 
are trained in clinical psychological interview techniques and suicide risk and safety interventions. The PI 
or Co-I will be completing study procedures or will be immediately available (in the study building) in the 
case suicidal or other safety concerns are identified. Any participants disclosing suicidal intent or planning 
will be assessed immediately for safety and will be referred to clinical staff within the IOP for further 
evaluation. For participants at imminent risk, this will include arrangement of an emergency outpatient 
appointment or an in-house consult with a psychiatrist to determine need for hospitalization, as well as 
notification of campus police in the event that a participant deemed to be imminently at risk refuses to 
cooperate with a hospitalization plan. 
14.0 Withdrawal of Subjects 
Participants will be informed during consenting that they are free to withdraw from the study at 
any time. They will be informed that they are not obligated to participate once the study is initiated 
and in particular will be reminded prior to taVNS/VNS stimulation they may discontinue 
stimulation and/or the experiment at any point.  
Study advertisements will not state the amount of compensation to be provided, so as to prevent 
potential subjects from participating out of need. Study personnel will not pressure any participant 
to engage in the study or in parts of the study. Research personnel may choose to end participation 
early if the subject appears or expresses distress by the study procedures. 
15.0 Risks to Subjects 
Physiology: The study procedures may involve non-invasive recording of EEG, EMG, and ECG, 
so the risk with this is minimal. For external sensors used for ECG and EMG, adhesive disks are 
used. Removal of these adhesives may result in mild local irritation or redness. For EEG 
measurement, little to no risks are involved. A water soluble gel which contains sodium is used, 
but this gel does not cause irritation. This gel rinses easily with water, though some participants 
report they dislike having the gel in their hair. Participants are informed of the gel prior to arrival 
at the lab. EEG does not transmit any electrical signals and only measures electrical activity 
naturally produced in the human body. The electrode cap fits comfortably and participants are 
assessed throughout setup procedures to ensure their comfort.  
TaVNS: The taVNS stimulation administered during the study is non-invasive but includes some risk – 
similar to that of EEG or other physiological recording. Our system is a commercially available, FDA-
cleared Digitimer DS7A constant current stimulator (Digitimer Ltd., USA; for additional information see 
https://www.digitimer.com/product/human-neurophysiology/peripheral-stimulators/ds7a-ds7ah-hv-
current-stimulator/). Several research groups at MUSC and elsewhere have demonstrated the safety and 
tolerability of taVNS (Kreuzer et al., 2012; Badran et al., 2019; Clancy et al., 2014). Participants will be 
screened for potential contraindications to taVNS prior to invitation to the lab (see Section 5.0 for 
exclusion criteria; e.g., ear trauma/pain, metal implants). The device has safety mechanisms to prevent 

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electrical surges. Skin will be prepared using 70% alcohol swabs) prior to electrode attachment to ensure 
sanitation and stimulation power is safe. Metal jewelry also will be removed from the head. Stimulation is 
applied using similar electrodes to those used in EEG and a water based conductive gel, and participants 
will be assessed after application/prior to stimulation for discomfort related to the electrode. Perceptual 
Threshold (PT) will be determined (see 3.0 Intervention to be studied for details; Badran et al., 2019) 
using a step-up/step-down parametric search. Stimulation will be applied at the level of 200% of PT. 
Participants will be assessed during stimulation for discomfort or adverse events over the course of 
stimulation, though studies have demonstrated few concerns of safety. The ear also will be cleaned and 
inspected for irritation/redness after stimulation. The ear stimulation delivered during the study is includes 
some risk. Participants in previous research using this stimulation describe the feeling as a “tickle” or 
“pricking” sensation. Some report mild irritation. Our researchers will inspect the ear after stimulation 
given previous research has documented some redness from the stimulation. Because dose duration of 
taVNS is being investigated and this treatment is still experimental there is chance unknown risks may 
occur, though the likelihood of these risks occurring is low. 
 
VNS: Although implantation of VNS involves an invasive procedure, this study will only recruit 
individuals with previously implanted VNS. Thereafter, stimulation may be delivered noninvasively via 
remote access/computer/external button or via magnetic wand. In safety studies of the Microtransponder 
VNS system that was researched at MUSC, some patients report nausea or difficulties swallowing the day 
of stimulation. Some report neck tingling and/or hoarseness. The full publication on safety can be found 
here: https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.115.010477  
 
Surveys: During the questionnaire portion of the study, participants will be asked to report on personal 
experiences and symptoms. Some report mild discomfort when reporting on these topics, but that risk is 
low. Again, it will be ensured that study staff, including the PI and Co-I, will be available to debrief 
participants in distress, if needed. If adverse effects occur during the study, researchers will terminate the 
study, provide debriefing, and contact the PI or Co-I for further assistance. Study personnel will be trained 
to identify participants in distress. However, these procedures involve minimal and low-base rate for risk. 
Tasks: The tasks involve no more than minimal risk. The loud noises which may be played and 
some of the pictures which may be shown during the study may result in momentary mild distress. 
However, several studies have used similar procedures, and the risk of this is low, with 
participants reporting mild, temporary distress. To ensure comfort, participants will be allowed to 
adjust to the noises starting the task and will be reminded of their right to withdraw at any point. 
Confidentiality: Because physiological recordings are generally non-sensitive, risk of disclosure of 
these data is very minimal. This study does involve risk of disclosure of sensitive information 
(e.g., self-report of mental health symptoms) collected during study-specific assessment. To 
protect confidentiality of study-specific measures, only the participant code, and no potentially 
identifying information (e.g., name, date of birth) will ever be associated with these measures. In 
addition, self-report data will not include identifiable information. Self-report data are in Likert 
format and will be linked only to a participant code. Thus, no data will be identifiable. However, 
there is still a small risk of loss of confidentiality of participant information in this study. Steps 
taken to protect confidentiality are described further in the Data Management section. 
16.0 Potential Benefits to Subjects or Others 
There are no direct benefits to subjects for participating. Participants may learn about the procedures 
involved in psychological research. Benefits to society include knowledge about how physiology is linked 
to attention and learning. Such basic knowledge may ultimately lead to establishing more effective ways 

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of helping people who suffer from problems related to their mood or anxiety. The main aim of this project 
is to establish the dose-response curve for taVNS, a necessary first-step to implement taVNS in the 
clinical setting and assess potential mechanisms of action. The data collected in this pilot project will be 
used to inform larger scale research aimed at assessing taVNS paired exposure therapies for anxiety and 
trauma-related disorders. 
17.0 Sharing of Results with Subjects 
Physiological results collected in this study are currently useful at the group, not individual, level; 
as such, results will not be shared with subjects. Participants will be given the opportunity to be 
debriefed regarding the purpose and hypotheses of the study after it is completed. 
18.0 Drugs or Devices  
The Digitimer DS7A Constant Current Stimulator is FDA cleared (K051357), is non-invasive, and 
has an excellent safety profile. However, limited use of the device will nonetheless be maintained. 
The research space is locked with limited access to only trained researchers. 
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