Feb 26, 2026

Public workspaceREVEAL Common Study Protocol

This protocol is a draft, published without a DOI.
  • John Osborn1,
  • Zohara Cohen1,
  • Roman Tyshynsky1
  • 1University of Minnesota
Zohara Cohen
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External link: https://classic.clinicaltrials.gov/ct2/show/NCT06143293
Protocol Citation: John Osborn, Zohara Cohen, Roman Tyshynsky 2026. REVEAL Common Study Protocol. protocols.io https://protocols.io/view/reveal-common-study-protocol-dd6x29fn
License: This is an open access protocol distributed under the terms of the Creative Commons Attribution License,  which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Protocol status: Working
We use this protocol and it's working
Created: May 22, 2024
Last Modified: February 26, 2026
Protocol Integer ID: 100279
Keywords: Vagus Nerve Stimulation, VNS, SPARC, VESPA, investigational vagus nerve stimulation parameter, chronic administration of investigational vagus nerve stimulation parameter, vagus nerve stimulation, effect of vagus nerve stimulation, chronic effects of vns stimulation, autonomic nervous system reflex assessment, vns stimulation, common study protocol the research evaluating vagal excitation, autonomic nervous system reflex assessments via physiological stimuli, research evaluating vagal excitation, invasive physiological recording, physiological stimuli, resistant epilepsy, common study protocol, study protocol, interventions for all study participant, various time points throughout the study, drug resistant epilepsy, primary treatment refractory focal epilepsy with seizure, clinical trial, focal epilepsy, acute testing phase, chronic testing phase, vns device, chronic effect, study intervention, generating study protocol
Funders Acknowledgements:
NCCIH
Grant ID: U54AT012307
Abstract
The Research Evaluating Vagal Excitation and Anatomical Links study is a multi-site, single-blind, cross-over, randomized clinical trial that is governed by a Common Study Protocol (CSP), meaning that all study sites will follow this same IRB protocol. The CSP is a hypothesis-generating study protocol resulting in a dataset that will enable the investigation and assessment of various hypotheses for the effect of vagus nerve stimulation on the autonomic nervous, cardiovascular, immune, and metabolic systems. The acute and chronic effects of VNS stimulation on these body systems are compared from noninvasive and minimally invasive physiological recordings and blood draws at various time points throughout the study. These interventions and assessments are performed in individuals 18 years of age and older who are implanted with a VNS device and who have been diagnosed with either drug resistant epilepsy or major depressive disorder.

Study interventions include the acute and chronic administration of investigational vagus nerve stimulation parameters, and the autonomic nervous system reflex assessments via physiological stimuli (such as the isometric handgrip exercise, post-exercise circulatory occlusion, and the passive head-up tilt test). The interventions for all study participants begin at Visit 1 and continue for 3 months through Visit 2. All participants are consented approximately two months before Visit 1.

The target sample size for the CSP is 144 participants with a diagnosis of primary major depressive disorder or with a diagnosis of primary treatment refractory focal epilepsy with seizures. There are six VNS parameter sets that are delivered in randomized order to all participants during the acute testing phase, such that each participant will receive all six parameters combinations across the two Study Visits. In addition, each participant are randomly assigned one of the six VNS parameter combinations that are applied for their chronic testing phase.

Species Used in the Study
  • Those participants with a diagnosis of Major Depressive Disorder (MDD) are implanted with the LivaNova Symmetry VNS device which is FDA approved to treat the condition.
  • Those participants with a diagnosis of drug resistant epilepsy are implanted with the LivaNova Sentiva VNS device which is FDA approved to treat the condition.
  • At-home BP are collected with a Spacelabs APBM portable arm-cuff system (Spacelabs Healthcare, Snoqualmie, WA, or similar system).
  • At-home ECG are collected with a Vivalink Multi-vital ECG patch applied to the skin of the chest (Vivalink, Campbell, CA or similar system).
Troubleshooting
Before start
Techniques and methods used in the study
The REVEAL CSP consists of four cohorts made up of two separate clinical indications requiring vagus nerve stimulation (VNS) therapy: depression and epilepsy. A subset of participants from each disease group are previously implanted (p-VNS) with a VNS device before enrolling in the study. The remaining participants are newly implanted (n-VNS) with the clinically-indicated VNS device after enrolling in the study and before attending Study Visits 1 and 2.
The target sample size for the pooled data analysis from REVEAL-CSP and REVEAL-AP3 and the estimated sample size for the individual cohorts is indicated in Table 1 below.

ABCDEFG
CohortVNS implant indicationPreviously implanted (p-VNS) or newly implanted (n-VNS)?CSP target sample sizeAP3 target sample size1Total target sample sizeVNS Device Model
1aDepressionp-VNS20-24020-24LivaNova Symmetry
1bDepressionn-VNS18-303048-60LivaNova Symmetry and Microburst3
2aEpilepsyp-VNS20-24020-24LivaNova Sentiva
2bEpilepsyn-VNS36-56036-56LivaNova Sentiva
Total target enrollmentDepression and Epilepsyp-VNS and n-VNS11430144LivaNova Sentiva, Symmetry and Microburst3
Table 1: REVEAL Study Cohorts


Figure 1: Shown here is a high-level summary of the protocol that each cohort will follow.

Selection, Prescreening, and Enrollment
Participant Selection

For this study enroll between 48-60 participants with Major Depressive Disorder who will have a new VNS device implanted; 20-24 participants with MDD who have a previous VNS implant; 36-56 participants with epilepsy who have a new VNS device implanted; and 20-24 participants with epilepsy who have a previous VNS implant.

The REVEAL Common Study Protocol (CSP) described in this document study consists of four cohorts made up of two separate clinical indications requiring vagus nerve stimulation (VNS) therapy: depression and epilepsy. A subset of participants from each disease group will be previously implanted (p-VNS) with a VNS device before enrolling in the study. The remaining participants will be newly implanted (n-VNS) with the clinically-indicated VNS device after enrolling in the study and before attending Study Visits 1 and Study Visit 2.
Prescreening and Recruitment
Prescreening is performed by comparing the participant’s medical records alongside the study’s inclusion/exclusion criteria. Medical records may be reviewed electronically or obtained from the participant’s medical provider in the provider’s required format. Verbal medical history is not be used as the sole source to confirm inclusion/exclusion criteria.

All candidates who are identified as potential study participants are contacted to determine their interest in study participation. Prescreening activities may be conducted via phone or video meetings, in addition to in-person. If the candidate expresses interest, the study team will provide study materials to review (e.g. IRB-approved study handout(s) and informed consent materials). Informational videos may be shown to study candidates which give an overview of the study and demonstrate various study procedures. The informational videos may be used during prescreening, enrollment or during the study, and all videos are IRB-approved.

If they wish to continue with the prescreening process, candidates are asked for some basic information and whether they agree for the study team to review their medical records to fully assess eligibility.

Candidates are asked to sign a Unsecured Email Authorization form and Unsecured Text Authorization form which explains the risks of using their personal email/texting accounts for discussing personal health information to the study team. Participants may also choose to communicate via secure emails for private communications.

Participants are given the opportunity to ask questions about the study during screening, enrollment, and throughout their study participation. Their questions may be addressed in person or on a phone or video meeting. These calls to discuss the study details may be conducted with the local REVEAL site teams or with REVEAL teams at other participating study sites.

Finally, an in-person screening and enrollment visit is scheduled for those participants who wish to proceed with the final enrollment steps. The potential participant is provided a copy of the informed consent form to review.
Consent
Only trained members of the research team, documented with authority to conduct consent, will conduct consent conversations with all potential participants. The study will only enroll individuals who are able to consent for themselves.

Informed consent is initiated before the individual agrees to participate in the study. Consent is conducted in person in a private room at one of the approved participating study sites. Only trained members of the research team conduct consent conversations with potential participants. We only enroll individuals who are able to consent for themselves.

An eligibility assessment is performed by comparing the participant’s medical records alongside the study’s inclusion/exclusion criteria. Each element of the inclusion/exclusion criteria are assessed and documented as part of the final eligibility screening for the study.

Participants receive a verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential risks of the study and of their rights as research participants. They have the opportunity to review the written consent form and ask questions prior to signing. They are informed that the study is completely voluntary and that their choice to participate, or not, will in no way affect the relationship with or the care they receive from their treating physician. They are also informed that they are able to withdraw consent at any time during the study without prejudice.

The participant signs the informed consent document prior to any procedures being done specifically for the study. If a participant withdraws from the study, their original clinical VNS settings are restored at their request, and the participant’s partial data may still be used for analysis.

The consent form may be in paper form, or electronic form. When electronic it is completed on the Part 11 and HIPAA compliant REDCap platform and participants are able to download, email themselves or print a copy of the signed forms.

Once an individual provides consent, a copy of the signed consent form is provided to the participant for their records. Paper consent forms are stored in a locked filing cabinet at the local study site and eConsent forms are stored securely in the HIPAA compliant REDCap platform. The consent forms are stored, at minimum of 10 years.
Enrollment Urinalysis
On the day of the screening and enrollment visit, a urine pregnancy test is administered for all candidates of childbearing potential. If a candidate is found to be pregnant, they will not be enrolled in the study. Pregnancy tests are repeated at the beginning of Visit 1 and Visit 2 and if a participant is found to be pregnant, they are administratively withdrawn from the study.

A nicotine/cotinine urine analysis is used to correlate study outcomes with nicotine use and is not used for study screening. The nicotine/cotinine may be performed at the enrollment blood draw, Study Visit 1 and Study Visit 2.
Four Cohorts
The REVEAL Common Study Protocol (CSP) outlined here study includes four cohorts made up of two separate clinical indications requiring vagus nerve stimulation (VNS) therapy: depression and epilepsy.

A subset of participants from each disease group will be previously implanted (p-VNS) with a VNS device before enrolling in the study. The remaining participants will be newly implanted (n-VNS) with the clinically-indicated VNS device after enrolling in the study and before attending Study Visits 1 and Study Visit 2. Select the cohort of interest here.
Step case

Participants w/ Depression, Previously Implanted
17 steps

Inclusion Criteria for Participants With Major Depressive Disorder That Have a Previously Implanted VNS Device
  1. Participant must be at least 18 years old.
  2. Participant must have the capacity to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization.
  3. Participant must be enrolled in an active health insurance plan that will cover the costs associated with standard health care services and injuries.
  4. Participant must have been previously implanted with a VNS device for the clinical indication of Major Depressive Disorder (MDD).
  5. Participant must be able and willing to complete the evaluations and procedures described in the study protocol.
  6. Participant must be able and willing to follow the stipulations regarding concomitant medications and excluded medications described in section 5.3 of the study protocol.
  7. Participant that is of childbearing potential must be adequately protected from conception or willing to use an acceptable method of birth control over the entire study duration (acceptable birth control includes abstinence, barrier methods, hormonal methods, sterilization and fertility awareness).

Exclusion Criteria for Participants With Major Depressive Disorder That Have a Previously Implanted VNS Device
  1. Participant has a prior implantable stimulation device, other than a VNS device for the clinical indication of Major Depressive Disorder (MDD).
  2. Participant currently uses or is expected during the study to use short-wave diathermy, microwave, diathermy, or therapeutic ultrasound diathermy.
  3. Participant is judged by the investigator to be acutely suicidal (e.g. has made specific plans or preparations to commit suicide or as indicated by the Sheehan Suicidality Tracking Scale) within the last 30 days prior to study enrollment.
  4. Participant has made a suicide attempt within the previous 6 months from study enrollment.
  5. Participant has a history of one or more schizophrenia-spectrum or other psychotic disorders including schizophrenia, schizoaffective disorder, delusional disorder, or a current or lifetime major depressive episode that includes psychotic features (commonly referred to as psychotic depression) according to the MINI criteria.
  6. Participant has a history of significant borderline or severe personality disorder as determined by clinical judgment.
  7. Participant has an active primary diagnosis of obsessive-compulsive, eating, or post-traumatic stress disorder based on the MINI criteria.
  8. Participant has a diagnosis of Substance Use Disorder as defined by DSM-5 without sustained remission of 12 months or longer.
  9. Participant has a presence of any type of dementia, major neurocognitive disorder, or cognitive or psychiatric deficit as determined by clinical judgment.
  10. Participant has a history of rapid cycling bipolar disorder I or II.
  11. Participant currently receives treatment with another investigational device or investigational drug other than the REVEAL study (or a REVEAL ancillary project or sub-study) or has participated in another drug or device trial within the preceding 30 days before enrollment.
  12. Participant is not able or willing to use their dominant arm, or either upper arm circumference is greater than 50 cm.
  13. Participant does not speak English.
  14. Participant is pregnant.
  15. Any other clinical reasons deemed by the investigators of the study for which the participant would not be an appropriate candidate for the study, such as peripheral vascular disease, Raynaud’s phenomenon, orthostatic hypotension (OH), postural orthostatic tachycardia syndrome (POTS), uncontrolled obstructive sleep apnea (OSA), chronic obstructive pulmonary disease (COPD), or uncontrolled diabetes.
Baseline and Study Preparation (pVNS - Depression)
Baseline Clinical Assessments and Surveys for Depression Cohort
For participants who have successfully been screened for eligibility and are enrolled into the study, we will collect information regarding their treatment history, symptoms, and quality-of-life factors. Assessments will be collected either by clinical staff, a blinded central rater, or via self-report by the participant. All assessments and self-report questionnaires have an allowance of ± 1 week for collection and may be performed remotely or in-person.
  1. ATHF: Antidepressant Treatment History Form
  2. MINI-7: Mini International Neuropsychiatric Interview
  3. CGI-C: Clinical Global Impression
  4. Sheehan-STS: Sheehan Suicidality Tracking Scale
  5. YMRS: Young Mania Rating Scale
  6. Berlin Questionnaire
  7. MADRS: Montgomery- Asberg Depression Rating Scale 
  8. QIDS: Quick Inventory of Depressive Symptomatology
  9. BAI: Beck Anxiety Inventory
  10. Q-LES-Q-SF: Quality of Life, Enjoyment and Satisfaction Questionnaire – Short Form
  11. A questionnaire called the “Motivations To Enroll Questionnaire” to better understand the reasons that the participant chose to join the study. 
VNS Washout
VNS devices are turned off for participants in this cohort for the 4 week period (± 1 week) after enrollment to allow for washout of any long-term effects of VNS.

During this VNS washout period, there are weekly calls made to the study participants for safety monitoring and AE documentation purposes. Participants are closely monitored for recurrence of their clinical symptoms during the change or cessation in their VNS therapy parameters.
Baseline Blood Tests - Metabolic and Immune Markers
Blood samples are collected to establish a baseline for metabolic and immune system biomarkers including:
  • plasma glucose levels, lipids panels
  • serum C-reactive Protein [CRP] levels
  • serum cytokine levels

The total blood collected from study participants for all study assays does not exceed 132 mL in a 24 hour period. Participants are asked to fast from food and drink (except water) for a minimum of 10 hours before all blood draws. If the phlebotomist is unable, for any reason, to draw enough blood for all assessments, the participant may continue participating in the study.
Titration
Titration is the gradual adjustment of VNS parameter settings for tolerability and takes place over the course of a minimum of three weeks. All study participants are titrated using standard VNS parameters: 30 Hz frequency, 1 min on + 5 min off duty cycle, and 0.25 ms pulse width. During titration, participants visit their clinician to have their VNS amplitude gradually increased over a minimum of three weeks, so that a comfortable and therapeutic VNS parameter set is attained (≥ 1.25 mA).

While the participant’s VNS settings are being increased in-person with the study team, a faster duty cycle of 1 min on + 30 seconds off may be used to gauge tolerability of the current intensity. However, participants will always be sent home with the standard titration VNS parameters described above (30 Hz frequency, 1 min on + 5 min off duty cycle, and 0.25 ms pulse width).

These clinical settings will continue during titration until Study Visit 1, at which point the clinical settings are turned off and the investigational settings will begin.

The following assessments will be administered at the titration visits
  1. CGI-C: Clinical Global Impression
  2. Sheehan-STS: Sheehan Suicidality Tracking Scale
  3. YMRS: Young Mania Rating Scale (bipolar depression only)
  4. MADRS: Montgomery- Asberg Depression Rating Scale 
  5. QIDS: Quick Inventory of Depressive Symptomatology
  6. BAI: Beck Anxiety Inventory
Study Visit 1
Biometric Recording Prior to Study Visit 1
Participants will have ambulatory biometrics collected within the window between 7 and 2 days prior to the Study Visit 1. See detailed information on the Ambulatory BP measurement in our REVEAL: Standard Operating Procedure for Ambulatory Blood Pressure Monitoring - Instrumentation, Collection, and Processing protocol; and detailed information on the Ambulatory ECG measurement in our REVEAL: Standard Operating Procedure for Ambulatory Electrocardiography Collection and Processing protocol.
Visit 1 Timeline

Visit 1 Timeline

Site Check-In
Study visits take place at one of three participating study sites: University of Minnesota; Mayo Clinic Rochester; and Monash University. Participants recruited at the the Medical University of South Carolina; Stanford University; and Washington University in St Louis will travel to the University of Minnesota for Study Visit 1 and Study Visit 2.

Participants arrive for Study Visit 1 in the morning in fasted state, and asked to abstain from exercise and caffeine for at least 12 hours prior to testing.

Pregnancy test is repeated and if a participant is found to be pregnant, they are administratively withdrawn from the study.
Questionnaires
After checking in to the study site, the participant responds to questions regarding their demographics; social history; general medical history; psychiatric history; epilepsy history; and current medications. They also respond to self-report questionnaires on food, activity, and alcohol use; and Quality-of-Life Surveys (Q-LES-Q-SF and QOLIE-89).

The following psychiatric assessments are collected either by clinical staff, a blinded central rater, or via self-report by the participant: CGI-C: Clinical Global Impression; Sheehan-STS: Sheehan Suicidality Tracking Scale; YMRS: Young Mania Rating Scale (bipolar depression only); MADRS: Montgomery- Asberg Depression Rating Scale; QIDS: Quick Inventory of Depressive Symptomatology; BAI: Beck Anxiety Inventory; and Q-LES-Q-SF: Quality of Life, Enjoyment and Satisfaction Questionnaire – Short Form

For depression participants, the Sheehan-STS is immediately reviewed for risk of suicidality by the administrator/rater, and if there are any concerns, the administrator/rater will contact the site PI or clinician for review. More details on this process are covered in our IRB-approved clinical protocol.
IV and Baseline Blood Draw
An intravenous (IV) line for blood draws is inserted by a trained clinical professional. A baseline blood sample is collected. The first blood draw of every blood draw collection day is targeted to be at 9am (and phlebotomy should be initiated within ± 1 hour of that target). If placing an IV line is not successful, a standard venipuncture may be used instead.
Acute VNS Stimulation
The experimental procedures during Study Visit 1 begin with the acute electrical vagus nerve stimulation (VNS) testing phase (Periods 1, 2 and 3). The VNS is turned on and off throughout the Study Visit procedures. The following signals are collected continuously during these periods: blood pressure (BP), electrocardiography (ECG), heart rate (HR), muscle sympathetic nerve activity recordings (MSNA), and the electric signal from a noninvasive adhesive-electrode that is placed over the skin of the participant’s neck to record the VNS pulses.

More information in the instrumentation can be found in the REVEAL Standard Operating Procedure for Microneurography Instrumentation protocol.

During the acute testing, all participants are stimulated at least once with each of the six different stimulus combinations: investigating four frequencies (1, 5, 10, and 30 Hz) and three different duty cycles (1 min on 5 min off, 1 minute on 1.1 min off, and 1 min on 0.2 min off) as shown in the table below. The 1-minute stimulus on-time used for all participants includes a 2s ramp-up period and 2s ramp-down period. These six stimulus combinations are conducted in randomized orderings over the two visits, with three combinations tested during SV1 (link to randomization protocol). The stimulation amplitude is ≥ 1.25 mA which is titrated to the patient comfort thresholds. The pulse width of 0.25 ms is used for all VNS combinations.

Signal Frequency (Hz)Duty cycle (1 min on)*Output current (mA)Pulse width (ms)**
10.2 m off≥ 1.250.25
50.2 m off≥ 1.250.25
105 m off≥ 1.250.25
101.1 m off≥ 1.250.25
305 m off≥ 1.250.25
301.1 m off≥ 1.250.25
Table with six possible VNS stimulation parameters.

Participants are blinded from the VNS stimulation parameters that are delivered (link to the blinding protocol). These VNS parameters are set wirelessly and will not be shown to the study participants. The programming devices are distributed to the study team by the VNS device manufacturer, LivaNova, and consist of a tablet/computer and a programming wand. The VNS parameters are input on a tablet/computer that is connected to a programming wand, which is waved in the air over the participant’s implanted device to modify the parameters. The programming wand communicates with the pulse generator, which enables functional assessments (device diagnostics), noninvasive programming, and data retrieval. The VNS system may be interrogated by the study team to review and document VNS device diagnostics, device usage including VNS-off times, and to program the VNS settings.

More details on the acute VNS testing testing can be found in REVEAL: Standard Operating Procedure for Muscle Sympathetic Nerve Activity Analysis and REVEAL: Standard Operating Procedure for Muscle Sympathetic Nerve Activity - Blood Pressure and Heart Rate Analysis.

At the end of each acute stimulation period, blood samples are collected to assess the effects of VNS on the immune system and the metabolic system, including: Standard clinical metabolic assays (e.g. plasma glucose levels, lipids panels, etc.); Standard clinical immunological assays (e.g. serum C-reactive Protein [CRP] levels, etc.); Serum cytokine levels; Advanced immunological assays (e.g. Single-cell cytometry by time of flight [CyTOF], RNA sequencing, etc.); and Advanced metabolic assays (e.g. gut hormone levels, adipokine levels, multidimensional serum and PBMC deep metabolomics, etc.).

During each Study Visit, the goal is to obtain successful blood draws and MSNA recordings during VNS stimulation and Autonomic Nervous System Reflex Assessments. In rare cases, a blood collection timepoint or MSNA recording may be unsuccessful due to challenges drawing blood from some participants or challenges placing a successful microelectrode into the nerve in some participants. A Study Visit are considered a failed visit if both of these conditions are met: (1) the baseline blood draw from a Study Visit (the first blood draw of that day) is unable to be completed, and (2) the MSNA recording is unable to be completed. If one of the described conditions is met but not both, the visit will continue as planned. Investigator discretion are used to determine if sufficient blood has been drawn and if the MSNA placement/recording is of sufficient quality to be deemed successful. Any data collected during a failed Study Visit may still be included in the pooled-data of the study for further analysis.
Chronic Stimulation Settings and ANS Reflex Testing
The acute testing periods of Study Visit 1 are followed by randomization to the chronic stimulation parameter set. This is the beginning of chronic testing which assesses the ANS reflexes prior to 12 weeks of chronic VNS stimulation. The amplitude of the randomly assigned chronic stimulation parameter is also ≥ 1.25 mA and is carefully increased in a gradual manner to the participant’s highest tolerability level (similar to the titration visits during the titration period).

More information on the Autonomic System Reflex testing can be found in the REVEAL Standard Operating Procedure for Autonomic Testing.
Echocardiogram
Routine echocardiography (echo) is performed with the VNS stimulation turned on and off.
To increase echo image quality, a contrast agent is sometimes administered intravenously (DEFINITY contrast agent manufactured by Lantheus, N. Billerica, MA, Optison contrast agent manufactured by GE Healthcare, Westborough, MA, or similar contrast agent may be used). Participants may opt out of the use of contrast agents on the day of echocardiography if they do not wish to have them used. The echo is performed last during the Study Visit day, and can be conducted any time after the acute VNS testing and chronic VNS testing (with ANS reflex testing) have been completed. For Study Visit 1, the echocardiogram may be performed up to 48 hours after Study Visit 1.

More details on the echocardiography protocol are provided on Protocols.io at REVEAL: Transthoracic Echocardiogram (TTE)
Conclusion of Study Visit 1
After the (ANS) reflex testing and echocardiography are completed, Study Visit 1 is concluded and the participant keeps their assigned chronic VNS settings over the next 12-weeks (the Chronic Phase) of the study. In this way, the long-term effects of the chronic VNS settings are analyzed by comparing the study outcomes before and after the 12-week Chronic Phase between Visit 1 and Visit 2.
Chronic Phase
Week 4 and Week 8 Visits
At Week 4 and Week 8 (± one week) of the 12-week chronic phase interim period, the participant has blood drawn at their local site. Some of the samples are assayed locally and others are sent to the University of Minnesota for analysis at research labs.

At the Week 4 and Week 8 visits, the participant also undergoes clinical assessment and completes surveys. At those visits, the following are completed: CGI-C: Clinical Global Impression; Sheehan-STS: Sheehan Suicidality Tracking Scale (optional for epilepsy cohort); YMRS: Young Mania Rating Scale (bipolar depression only); MADRS: Montgomery- Asberg Depression Rating Scale (depression cohort only); QIDS: Quick Inventory of Depressive Symptomatology; BAI: Beck Anxiety Inventory
Study Visit 2
Biometric Recording Prior to Study Visit 2
Participants will have ambulatory biometrics collected within the window between 7 and 2 days prior to the Study Visit 2. See detailed information on the Ambulatory BP measurement in our REVEAL: Standard Operating Procedure for Ambulatory Blood Pressure Monitoring - Instrumentation, Collection, and Processing protocol; and detailed information on the Ambulatory ECG measurement in our REVEAL: Standard Operating Procedure for Ambulatory Electrocardiography Collection and Processing protocol.
Visit 2 Timeline
The same clinical assessments are conducted and the same surveys completed by the participant at the start of Visit 2 as at Visit 1.

Visit 2 Timeline
The primary difference between Visit 1 and Visit 2 is that the ANS reflex testing using the chronic VNS settings will occur at the end of the VNS testing in Visit 1, but at the beginning of VNS testing in Visit 2. After the chronic parameter testing in Visit 2, the final three acute VNS stimulus settings are tested. As noted earlier, across the acute testing at Visits 1 and 2, all participants are stimulated at least once with each of the six different stimulus combinations . These six stimulus combinations are conducted in a randomized order over the two visits. Therefore, during Visit 2, each participant will receive the three VNS stimulus parameters that they did not receive during Visit 1.
Conclusion of Visit 2
After Visit 2 is concluded, the participant is re-programmed to standard clinical VNS settings. The default for participants who had a VNS implant prior to enrolling are the settings that they had before enrollment. The default for new VNS participants are the settings from their titration period. Different clinical VNS settings may also be chosen in coordination with the participant’s treating provider.