Cranial Electrotherapy Stimulation and Brain Imaging for Gulf War Syndrome

Emory University

Status: Enrolling

Conditions: Gulf War Syndrome

Treatments: Device: Sham Cranial electrical/electrotherapy stimulation (CES); Device: Cranial electrical/electrotherapy stimulation (CES)

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT07151248

GRANT14297332 (Other Grant/Funding Number)

GRANT14297241 (Other Grant/Funding Number)

2025P011630 (Other Identifier)

STUDY00009810

Details and patient eligibility

About

The main goal of the proposed study is to critically evaluate a nonpharmacological and readily available therapy, cranial electrical stimulation (CES) using Alpha-Stim™, and to discover the brain function mechanisms underlying Gulf War Illness-related Headache and Pain (GWI-HAP) and treatment response to CES.

For this objective, the investigators will employ an adaptive trial design as well as a neuroimaging technique using MRI, which has become the pre-eminent technique for assessing the integrity of brain function, connectivity, and organization in healthy brain and pathology.

Full description

Gulf War Veterans are disproportionately plagued by fibromyalgia-like symptoms including headaches, joint, and muscle pain, known as gulf war illness pain or GWI-HAP. Treatment options are limited, and the neurobiology of these symptoms is poorly understood.

In this population, the investigators plan to test a portable, non-pharmacological, non-invasive therapy (Alpha-Stim™) that is FDA-cleared for anxiety, insomnia, and pain, and readily available for widespread implementation in the United States. This cranial electrical stimulation (CES) device has shown promising, though limited results for anxiety, insomnia, and pain. They also plan to employ magnetic resonance spectroscopy (MRS) to evaluate neuroinflammation.

Subjects will be male and females, age 40-80 years old, with a diagnosis of Gulf war illness. Subjects will be recruited by referral and posted flyers on Emory campus, ResearchMatch, the Gulf War Registry, and the Wounded Warriors' Program. The research team will not approach vulnerable populations including minors, prisoners, pregnant persons, neonates or human fetuses, wards of the state, or cognitively impaired persons. Recruitment, screening and enrollment will occur at the Emory clinics (EUHM and EUH) and the Human Subjects Research Building II.

This randomized, double-blind, sham-controlled study will compare the efficacy of "active" or true CES therapy to "sham" CES therapy. Participants will be randomized in a 1:1 ratio to true or sham CES (n=104 total; 52 true, 52 sham). Up to 130 subjects will be enrolled to achieve 104 treated subjects. Baseline assessments including quality of life questionnaires and pain assessments, in addition to MRI will be obtained prior to initiation of the intervention.

The participant will be trained in device usage and instructed to use the device each evening around the same time for 60 minutes (timer will be pre-set). They will also be provided detailed instructions.

The intervention (both sham and true CES) will occur over the course of 6 weeks, and participants will be assessed again post-treatment. To assess our neuroimaging outcomes, MRI will also be obtained at 6 weeks post-treatment, to assess for changes in connectivity and neuroinflammation. The total time commitment for most subjects will be 7 weeks.

Participants who are initially randomized to sham and are determined to be non-responders (<2 point decrease on DVPRS) will be offered the opportunity to utilize the true CES therapy with additional reimbursement and follow-up periods. They will use the device for an additional 6 weeks and return for post-treatment follow up at that time (12 weeks after initial therapy) that will include additional MRI and the original baseline and 6-week assessments. The total time commitment for these subjects will be 13 weeks.

A verbal prescreening consent will be used to confirm eligibility. Informed consent will be conducted in person with the participant and written, or over the telephone or zoom with consent signed using Hipaa Part 11 compliant DocuSign. Participants may also consent to be contacted for future research.

Enrollment: 130 estimated patients

Sex: All

Ages: 40 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Subjects must be male and female age 40-80 years old

2. Meet criteria for GWVI based on the CDC and Kansas Criteria for GWVI.

   • CDC: 1 or more from at least 2 of the following categories for ≥ 6 months): 1) fatigue 2) mood and cognition (symptoms of feeling depressed, difficulty in remembering or concentrating, feeling moody, feeling anxious, trouble in finding words, or difficulty in sleeping) 3) musculoskeletal (symptoms of joint pain, joint stiffness, or muscle pain
   • Kansas: 3 of 6 domains: 1) fatigue and sleep problems 2) pain symptoms 3) neurologic, cognitive, or mood symptoms 4) gastrointestinal symptoms 5) respiratory symptoms 6) skin symptoms chronic since 1990. Symptom reporting must be in the absence of diagnosed exclusionary conditions; only respondents who have at least 1 moderately severe symptom or 2 or more symptoms within a group were considered to have a high level of symptoms in the group.

3. Subjects must self-report consistent, daily pain (greater than or equal to 4 on the DVPRS) >90 days (prior to enrollment)

4. Subjects must have intact skin free of infection at the site of electrode placement (earlobe).

5. Subjects must be willing to participate and understand the consent.

6. Subjects must be right-handed to provide consistency in brain structure and function.

Exclusion criteria

1. Subjects must not be currently pregnant since effects of fMRI and electrical current on the developing fetus are not well-known.
2. Subjects must not have a history of drug abuse or severe, uncontrolled psychiatric illness such as schizophrenia or major depressive disorder with suicidal ideation.
3. Subjects must not have psoriasis vulgaris or other skin conditions that may increase the risk of infection at the implantation site.
4. Subjects must not introduce new medications or treatments for symptoms during the study to prevent confounding results.
5. Subjects must not have severe anxiety, claustrophobia, or other conditions that may prevent their ability to lie at rest in an MRI scanner. This will be determined after discussion with the patient regarding their own perceived ability to lie at rest in an MRI scanner without the use of additional sedating medications.
6. Subjects must not have an implanted electrical device such as a surgically placed vagal stimulator, pacemaker, or spinal pain pump, which are not compatible with MRI.
7. Subjects must not have a history of seizures or neurologic conditions that may alter the structure of the brain.
8. Subjects must not be allergic to the metals used in electrodes for CES stimulation.
9. Subjects must not have a diagnosed autoimmune disease that better explains pain symptoms.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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130 participants in 3 patient groups

True CES therapy

Experimental group

Description:

The participant will be trained in device usage and instructed to use the device each evening around the same time for 60 minutes (timer will be pre-set). The intervention (true CES) will occur over the course of 6 weeks.

Treatment:

Device: Cranial electrical/electrotherapy stimulation (CES)

Sham CES therapy

Sham Comparator group

Description:

The participant will be trained in device usage and instructed to use the device each evening around the same time for 60 minutes (timer will be pre-set). The intervention (sham CES) will occur over the course of 6 weeks.

Treatment:

Device: Sham Cranial electrical/electrotherapy stimulation (CES)

True CES therapy for non-responders

Experimental group

Description:

For the non-responders (\<2 point decrease on DVPRS), the blind will be broken, and those non-responder participants who were initially assigned to sham placebo CES during the first 6 weeks of the intervention, now will be offered the opportunity to utilize the true CES device in a modified sequential parallel comparison design for an additional 6 weeks.

Treatment:

Device: Cranial electrical/electrotherapy stimulation (CES)