Closed Loop Vagal Nerve Stimulation for Patients With Posttraumatic Stress Disorder

NCT ID: NCT02992899

Last Updated: 2021-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-19
• Study Completion Date: 2019-09-21

Brief Summary

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.

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.

Conditions

PostTraumatic Stress Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: SINGLE

Study Groups

Vagal Nerve Stimulation

Participants randomized to this arm will receive stimulation of the vagus nerve in conjunction with stress exposure.

Group Type: EXPERIMENTAL

GammaCore/electroCore non-invasive VNS device

Intervention Type: 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.

O-15 water

Intervention Type: DRUG

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 Stimulation

Participants randomized to this arm will receive sham stimulation of the vagus nerve in conjunction with stress exposure.

Group Type: SHAM_COMPARATOR

Sham gammaCore/electroCore

Intervention Type: DEVICE

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.

O-15 water

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DEVICE

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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Georgia Institute of Technology

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: lead

Responsible Party

J. Douglas Bremner, MD

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

James D Bremner, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Locations

Emory University

Atlanta, Georgia, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34292205 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33344717 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32960179 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB00091171

Identifier Type: -

Identifier Source: org_study_id