VNS mTBI: Vagal Nerve Stimulation in mTBI

Sponsor

VA Office of Research and Development (U.S. Fed)

Overall Status

Recruiting

CT.gov ID

NCT04437498

Collaborator

Atlanta VA Medical Center (U.S. Fed)

100

Enrollment

Location

Arms

46.7

Anticipated Duration (Months)

2.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are important conditions for the Veterans Administration (VA) that frequently occur together in combat Veterans from the conflicts in Afghanistan and Iraq. In many Veterans these become chronic, raising the risk the burden of neurotrauma can worsen over time. This study will examine a new intervention called non-invasive Vagal Nerve Stimulation (nVNS) and its effects on memory and symptoms of PTSD and mTBI as well as brain and physiology in Veterans with mTBI and PTSD.

Condition or Disease	Intervention/Treatment	Phase
PTSD mTBI	Device: sham stimulation Device: nVNS	Phase 4

Detailed Description

This projects will assess the effects of non-invasive Vagal Nerve Stimulation (nVNS) on neurobiology and cognition in combat Veterans with mild Traumatic Brain Injury (mTBI) and co-morbid posttraumatic stress disorder (PTSD) during the performance of stressful tasks (traumatic scripts, mental arithmetic) and verbal declarative memory tasks using measurement of memory performance, peripheral inflammatory markers in blood (IL6) and cardiovascular responses using wearable gated sensing devices and electro- and seismocardiography, as well as brain response (anterior cingulate, hippocampus) measured with High Resolution Positron Emission Tomography (HR-PET) and radiolabelled water (15O[H2O]). The investigators hypothesize that nVNS but not sham control will result in enhanced memory, and hippocampal activation with memory encoding, and reduced cardiovascular, sympathetic, and inflammatory responses to stress. The investigators will also assess the effects of nVNS and sham on memory retention when applied to the encoding phase of a declarative memory learning task repeated daily over a four day period and on ratings of PTSD and pain in Veterans with mTBI and co-morbid PTSD and repeat assessments after three months of twice daily treatments.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Veterans are randomized to double blind treatment with active non-invasive Vagal Nerve Stimulation (nVNS) or a sham control.Veterans are randomized to double blind treatment with active non-invasive Vagal Nerve Stimulation (nVNS) or a sham control.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

code for active and sham devices kept by non study personnel.

Primary Purpose:

Treatment

Official Title:

Non-Invasive Vagal Nerve Stimulation in Veterans With Mild Traumatic Brain Injury (mTBI)

Actual Study Start Date :

Feb 25, 2021

Anticipated Primary Completion Date :

Sep 20, 2024

Anticipated Study Completion Date :

Jan 15, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: nVNS non invasive vagal nerve stimulation	Device: nVNS active vns stimulation
Sham Comparator: sham sham stimulation	Device: sham stimulation non invasive vagal nerve stimulation

Arm

Intervention/Treatment

Experimental: nVNS

non invasive vagal nerve stimulation

Device: nVNS

active vns stimulation

Sham Comparator: sham

sham stimulation

Device: sham stimulation

non invasive vagal nerve stimulation

Outcome Measures

Primary Outcome Measures

CAPS [three months]
The Clinician Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS) is a measure of PTSD symptoms with a range of 0-80 and higher score indicating more severe PTSD symptoms. We will compare change from baseline to post treatment with active vagal nerve stimulation (VNS) or sham stimulation twice daily.
insula [10 minutes]
Blood flow in the insula is measured with positron emission tomography (PET) and radiolabelled water during the performance of stress tasks. We compare blood flow in the insula to whole brain blood flow ratio during stress tasks (listening to personalized traumatic scripts) versus control tasks in the VNS versus sham groups with hypothesis of blocked insula blood flow with VNS
HVLT-R % retention [baseline versus three months]
The Hopkins Verbal Learning Test-Revised (HVLT-R) is a test of declarative memory learning that involves the learning of 12 nouns, four from each of three semantic categories, learned over three learning trials, followed 20 minutes later by a delayed free recall trial and recognition trial composed of 24 words with 12 false positives. The percent (%) retention is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3. HLVT-R % retention has a range of 0-100 with 100 being best and 0 worst performance. Baseline and three months post treatment paired with sham or active stimulation are compared.
Change in IL6 Concentration in Blood with Stress [Baseline to 120 minutes after stress]
Interleukin-6 (IL6) response to stress paired with active or sham stimulation. IL6 is an inflammatory biomarker measured in blood. We compare IL6 response to stress in VNS versus sham treated groups.
hippocampal activation [10 minutes]
Blood flow in the hippocampus is measured with positron emission tomography (PET) and radiolabelled water during the performance of declarative memory tasks. We compare blood flow in the hippocampus to whole brain blood flow ratio during memory tasks versus control tasks in the VNS versus sham groups with hypothesis of increased hippocampal blood flow with VNS

Secondary Outcome Measures

PPG amplitude [Change from baseline to 5 seconds after the termination of stimulation paired with stress]
Photoplethysmography (PPG) amplitude is a measure of peripheral vasoconstriction which is a marker of sympathetic response to stress with active or sham. PPG amplitude is the diameter of the blood vessel in the finger, we measure change from baseline to post active vagal nerve stimulation versus sham stimulation with stress.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Veterans with mTBI and PTSD

Exclusion Criteria:

amnesia for the inciting event lasted longer than 24 hours
Glasgow Coma Scale Score after 30 minutes was less than 13
loss of consciousness more than 30 minutes
positive pregnancy test
meningitis or other neurological disorder other than mTBI
alcohol or substance abuse use disorder based on the SCID within the past 12 months
current or lifetime history of schizophrenia, schizoaffective disorder, bipolar disorder, anorexia nervosa or bulimia, based on the SCID
active suicidal ideation based on criteria outlined below
a history of serious medical or neurological illness, such as cardiovascular, gastrointestinal, hepatic, renal, neurologic or other systemic illness
active neuroleptic, opiate, or benzodiazepine treatment
structural abnormality on brain MRI or CT