Closed Loop Vagal Nerve Stimulation for Patients With Posttraumatic Stress Disorder

Closed Loop Vagal Nerve Stimulation in Patients With Posttraumatic Stress Disorder

The tasks of the project are to map the potency and kinetics of the neurologic, autonomic peripheral, inflammatory, and behavioral responses to vagal nerve stimulation (VNS) vs. sham treatment, at baseline and in response to stressful traumatic scripts related to personal traumatic events, as well as a series of other stressors.

Study Overview

• Status: Completed
• Conditions: PostTraumatic Stress Disorder
• Intervention / Treatment: Device: GammaCore/electroCore non-invasive VNS device; Drug: O-15 water; Device: Sham gammaCore/electroCore

Detailed Description

The purpose of this project is to develop the fundamental physiological understanding of feedback controlled vagal nerve stimulation (VNS) using positron emission tomography (PET) brain imaging and blood biomarker measurement with stress in healthy individuals and individuals with PTSD. Healthy human subjects with a history of psychological trauma but without the diagnosis of a psychiatric disorder (Phase 1), and human subjects with a history of PTSD (Phase 2), undergo PET imaging of the brain in conjunction with VNS or a sham treatment during exposure to neutral scripts and scripts of personal traumatic events. Blood is drawn simultaneously for measurement of a variety of stress responsive biomarkers, including inflammatory markers and neurohormones. A second PET scan with biomarkers assesses the delayed effects of VNS. On two other days subjects undergo exposure to random stressors with VNS or sham in conjunction with measurement of stress biomarkers.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Phase 1:

• Do not meet criteria for post traumatic stress disorder (PTSD) or other major mental disorder as determined by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5 SCID) interview for PTSD
• Have a history of psychological trauma as defined by DSM-5.

Phase 2:

- Meet criteria for PTSD as determined by the Structured Clinical Interview for DSM-5 (SCID) interview for PTSD.

Exclusion Criteria:

• Positive pregnancy test
• Meningitis
• Traumatic brain injury
• Neurological disorder or organic mental disorder
• History of loss of consciousness greater than one minute
• Alcohol abuse or substance abuse or dependence based on the SCID within the past 12 months
• Positive toxicology screen
• Current or lifetime history of schizophrenia, schizoaffective disorder, or bulimia, based on the SCID
• A history of serious medical or neurological illness, such as cardiovascular, gastrointestinal, hepatic, renal, neurologic or other systemic illness
• Evidence of a major medical or neurological illness on physical examination or as a result of laboratory studies (complete blood count (CBC), blood urea nitrogen (BUN), creatinine, blood sugar, electrolytes, liver and thyroid function tests, urinalysis, and EKG)
• Active implantable device (i.e. pacemaker)
• Carotid atherosclerosis
• Cervical vagotomy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Vagal Nerve Stimulation; Participants randomized to this arm will receive stimulation of the vagus nerve in conjunction with stress exposure.	Device: GammaCore/electroCore non-invasive VNS device; Vasal nerve stimulation (VNS) is self-administered using the electroCore non-invasive VNS device. The intensity of the stimulus (the current amplitude) is adjusted by the user, to the maximum tolerable level to ensure VNS without causing excessive pain (typically 10-30 V), the burst frequency to 5 kilohertz (kHz), and the envelope frequency to 25 Hz. These are the standard frequency settings that electroCore has demonstrated to be most effective in capturing the vagus nerve based on evoked potential studies. The duration of delivery is 2 minutes, one minute into which the high-resolution positron emission tomography (HR-PET) scan is conducted; following an additional 8 minutes, a second VNS delivery is administered, after which another scan is obtained.; Drug: O-15 water; Oxygen-15 labelled water is a radioactive variation of regular water, in which the oxygen atom has been replaced by oxygen-15 (15O), a positron-emitting isotope. 15O-water is used as a radioactive tracer for measuring and quantifying blood flow using positron emission tomography (PET) . H2[15O] will be prepared on-site in the Emory PET Center cyclotron. During the hours of the test, an intravenous infusion of normal saline will be started to permit the bolus injection of H2[15O]. Subjects will receive a 20 mCi intravenous bolus of H2[15O] for each of the 14 scans during exposure to neutral and traumatic scripts.
SHAM_COMPARATOR: Sham Stimulation; Participants randomized to this arm will receive sham stimulation of the vagus nerve in conjunction with stress exposure.	Drug: O-15 water; Oxygen-15 labelled water is a radioactive variation of regular water, in which the oxygen atom has been replaced by oxygen-15 (15O), a positron-emitting isotope. 15O-water is used as a radioactive tracer for measuring and quantifying blood flow using positron emission tomography (PET) . H2[15O] will be prepared on-site in the Emory PET Center cyclotron. During the hours of the test, an intravenous infusion of normal saline will be started to permit the bolus injection of H2[15O]. Subjects will receive a 20 mCi intravenous bolus of H2[15O] for each of the 14 scans during exposure to neutral and traumatic scripts.; Device: Sham gammaCore/electroCore; Sham vasal nerve stimulation (VNS) is self-administered using the electroCore non-invasive VNS device. The device is programmed such that no actual stimulation is given to the vagus nerve. The duration of delivery is 2 minutes, one minute into which the HR-PET scan is conducted; following an additional 8 minutes, a second sham VNS delivery is administered, after which another scan is obtained.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of Interleukin-6 (IL6)	IL6 level will be collected via blood draw. Change is defined as the difference in IL6 level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of Tryptophan	Tryptophan level will be collected via blood draw. Change is defined as the difference in tryptophan level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Kynurenine	Kynurenine level will be collected via blood draw. Change is defined as the difference in kynurenine level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Kynurenic Acid	Kynurenic acid level will be collected via blood draw. Change is defined as the difference in kynurenic acid level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of 3-3 Hydroxykynurenine	3-3 hydroxykynurenine level will be collected via blood draw. Change is defined as the difference in 3-3 hydroxykynurenine level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Anthranilic Acid	Anthranilic Acid level will be collected via blood draw. Change is defined as the difference in anthranilic acid level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Tumor Necrosis Factor (TNF)-Alpha	TNF-alpha level will be collected via blood draw. Change is defined as the difference in TNF-alpha level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Interferon-Gamma	Interferon-Gamma level will be collected via blood draw. Change is defined as the difference in Interferon-Gamma level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Interleukin-1 Beta	Interleukin-1 Beta level will be collected via blood draw. Change is defined as the difference in Interleukin-1 Beta level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Interleukin-2 (IL2)	IL2 level will be collected via blood draw. Change is defined as the difference in IL2 level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Interleukin-4 (IL4)	IL4 level will be collected via blood draw. Change is defined as the difference in IL4 level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Interleukin-8 (IL8)	IL8 level will be collected via blood draw. Change is defined as the difference in IL8 level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Interleukin-10 (IL10)	IL10 level will be collected via blood draw. Change is defined as the difference in IL10 level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Interleukin-12p70 (IL12p70)	IL12p70 level will be collected via blood draw. Change is defined as the difference in IL12p70 level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Interleukin-12p (IL12p)	IL12p level will be collected via blood draw. Change is defined as the difference in IL12p level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Interleukin-13 (IL13)	IL13 level will be collected via blood draw. Change is defined as the difference in IL13 level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Macrophage Migration Inhibitory Factor	Macrophage migration inhibitory factor will be collected via blood draw. Change is defined as the difference in factor level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of High-Mobility Group Protein B1	High-mobility group protein B1 level will be collected via blood draw. Change is defined as the difference in high-mobility group protein B1 level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Adrenocorticotropic Hormone	Adrenocorticotropic hormone level will be collected via blood draw. Change is defined as the difference in adrenocorticotropic hormone level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Cortisol	Cortisol level will be collected via blood draw. Change is defined as the difference in cortisol level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Epinephrine	Epinephrine level will be collected via blood draw. Change is defined as the difference in epinephrine level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Dopamine	Dopamine level will be collected via blood draw. Change is defined as the difference in dopamine level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)
Level of Norepinephrine	Norepinephrine level will be collected via blood draw. Change is defined as the difference in norepinephrine level from baseline to post emotional stress testing.	Baseline, Post Stress Testing (Up to 4 Hours)

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: Georgia Institute of Technology

Publications and helpful links

General Publications

• Wittbrodt MT, Gurel NZ, Nye JA, Shandhi MMH, Gazi AH, Shah AJ, Pearce BD, Murrah N, Ko YA, Shallenberger LH, Vaccarino V, Inan OT, Bremner JD. Noninvasive Cervical Vagal Nerve Stimulation Alters Brain Activity During Traumatic Stress in Individuals With Posttraumatic Stress Disorder. Psychosom Med. 2021 Nov-Dec 01;83(9):969-977. doi: 10.1097/PSY.0000000000000987.
• Gurel NZ, Wittbrodt MT, Jung H, Shandhi MMH, Driggers EG, Ladd SL, Huang M, Ko YA, Shallenberger L, Beckwith J, Nye JA, Pearce BD, Vaccarino V, Shah AJ, Inan OT, Bremner JD. Transcutaneous cervical vagal nerve stimulation reduces sympathetic responses to stress in posttraumatic stress disorder: A double-blind, randomized, sham controlled trial. Neurobiol Stress. 2020 Oct 20;13:100264. doi: 10.1016/j.ynstr.2020.100264. eCollection 2020 Nov.
• Gazi AH, Gurel NZ, Richardson KLS, Wittbrodt MT, Shah AJ, Vaccarino V, Bremner JD, Inan OT. Digital Cardiovascular Biomarker Responses to Transcutaneous Cervical Vagus Nerve Stimulation: State-Space Modeling, Prediction, and Simulation. JMIR Mhealth Uhealth. 2020 Sep 22;8(9):e20488. doi: 10.2196/20488.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 19, 2017
• Primary Completion (ACTUAL): September 21, 2019
• Study Completion (ACTUAL): September 21, 2019

Study Registration Dates

• First Submitted: December 12, 2016
• First Submitted That Met QC Criteria: December 12, 2016
• First Posted (ESTIMATE): December 14, 2016

Study Record Updates

• Last Update Posted (ACTUAL): June 14, 2021
• Last Update Submitted That Met QC Criteria: May 20, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: PTSD; posttraumatic stress disorder; vagal nerve; stress disorders, post-traumatic
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Trauma and Stressor Related Disorders; Disease; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
• Other Study ID Numbers: IRB00091171

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes