Machine Learning in Guiding rTMS Treatment for GWI-Related Headaches and Body Pain (SVM - GWI)

The goal of this clinical trial is to create a machine learning algorithm to improve active repetitive transcranial magnetic stimulation (rTMS) treatments for veterans and/or active military personnel by alleviating Gulf War Illness related headaches and body pain (GWI-HAP). This study aims to develop and validate a Support Vector Machine (SVM) model that could replace the trial-and-error process by assessing functional connectivity provided by resting state functional magnetic resonance imaging (rs-fMRI) data to predict the most effective rTMS protocol for each person. All participants will be receiving active rTMS treatment.

The main questions it intends to answer are:

1. Does the SVM model predict a more effective treatment response rate for predicted respondents undergoing active rTMS at the left dorsolateral prefrontal cortex (DLPFC) compared to predicted non-respondents?
2. Does the SVM model predict a more effective treatment response rate while undergoing active rTMS at the left dorsolateral prefrontal cortex (DLPFC) and left motor cortex (LMC) in predicted respondents compared to predicted non-respondents?

Participants will undergo the following:

1. Receive a total of 13 active rTMS treatment sessions over 3-4 months.
2. Visit the clinic for a total of 15 visits for assessments, check ups, and treatments.
3. Keep a daily log of their headaches, muscle and joint pain throughout the study.

Study Overview

• Status: Recruiting
• Conditions: Headache; Gulf War Illness; Muscle and Joint Pain
• Intervention / Treatment: Device: Active Repetitive Transcranial Magnetic Stimulation; Device: Active Repetitive Transcranial Magnetic Stimulation

Detailed Description

This study aims to enroll a total of 140 veterans and/or active military personnel over the 4-year study period at the VA San Diego Healthcare System (VASDHS). Participants will be randomized into receiving treatments at the left DLPFC or left DLPFC and LMC, then placed into predicted respondent or non-respondent groups. They will be assigned to 1 of 4 groups:

Group A: Predicted Respondent at Left DLPFC Group B: Predicted Non-respondent at Left DLPFC Group C: Predicted Respondent at Left DLPFC and LMC Group D: Predicted Non-respondent at Left DLPFC and LMC

Participation in this study will require 15 total visits to the VASDHS over the course of 3-4 months. The visits will be separated in the following phases:

1. Pre-Treatment Assessments Phase (Weeks 1-2): Visit 1 (Screening) and Visit 2 (Baseline Assessments)
2. Induction Treatment Phase (Weeks 2-4): Visits 3-12 (Weekday active rTMS sessions at >24 hours and <72 hours apart)
3. Follow-Up and Maintenance Phase (Weeks 5-10): Visit 13 (1 week follow-up); Visit 14 (1 month follow-up); Visit 15 (2 months follow-up); All maintenance visits follow the final treatment of the induction phase.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Albert Y Leung, MD; Phone Number: 3866 8585528585; Email: ayleung@health.ucsd.edu
• Study Contact Backup: Name: Caleb Lopez, BS; Phone Number: 2638 8585528585; Email: caleb.lopez@va.gov

Study Locations

• United States
  • California
    • San Diego, California, United States, 92161
      • Recruiting
      • Jennifer Moreno Department of Veterans Affairs Medical Center
      • Contact: Caleb Lopez, B.S.; Phone Number: 2684 8585528585; Email: caleb.lopez@va.gov
      • Principal Investigator: Albert Leung, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female
• Veteran or active military personnel
• Between the ages of 18 and 65 years old
• Served in the Persian Gulf region for at least 30 consecutive days between August 1, 1990, and July 31, 1991
• Meets the CDC Criteria for GWVI (GWI), with symptoms starting during or after the 1990-1991 Persian Gulf deployment. Symptoms must be present for at least 6 months prior to enrollment in the study. Symptoms must be present in at least 2 of the 3 categories of fatigue, musculoskeletal, and mood cognitive.
• Meets the Kansas Criteria for GWVI (GWI), with symptoms starting during or after the 1990-1991 Persian Gulf deployment. Symptoms must be present for at least 6 months prior to enrollment in the study. Qualifying symptoms must be at least moderate in severity and/or multiple symptoms must be present within at least 3 of 6 categories consisting of fatigue/sleep, neurological/cognitive/mood, pain, respiratory, gastroenterological, and dermatological symptomology.
• Average Overall Daily Muscle Pain Intensity ≥3 on a 0-10 NPRS, present for at least 6 months
• Average Overall Daily Extremities Joint Pain Intensity ≥3 on a 0-10 NPRS, present for at least 6 months
• Average Headache Exacerbation Intensity ≥3 on a 0-10 NPRS, with headaches occurring for at least 6 months
• Headache Exacerbation/attack ≥ 1 time per week with the average intensity ≥3 on a 0-10 NPS, lasting > 1 hour in the past three months
• International Headache Society Criteria for Migraine Headache without aura

Exclusion Criteria:

• Children under the age of 18
• Pregnant women
• Individuals with cognitive/decisional impairment
• Non-English speaking individuals
• Prisoners of War
• Incarcerated individuals
• VA employees - including VA paid, IPA, or WOC
• Students of the institution or of the investigator
• Patients with cancer
• History of pacemaker implant
• Presence of ferromagnetic material (e.g., bullet fragment, shrapnel, device implant) in the brain or body that will prohibit the patients from having a brain MRI
• History of dementia, major psychiatric diseases, or life-threatening diseases
• Presence of any other chronic neuropathic pain states such as Complex Regional Pain Syndrome or Painful Peripheral Neuropathy
• Known diagnosis of moderate to severe osteoarthritis and/or rheumatologic joint pain prior to the GWI deployment
• Low back pain with mechanical origins such as lumbar radiculopathy or radiculitis or lumbar facet arthropathy
• Concurrent conditions, like lupus, that can produce symptoms compatible with GWVI
• History of seizure
• Pending litigation
• History of Traumatic Brain Injury-related headaches
• Chronic Tension or Cluster Headache. However, subjects with occasional tension headaches (less than once every three months and lasting no more than 24 hours) will not be excluded from the study.
• Ongoing Cognitive Rehabilitation or Treatment of PTSD
• Recent exacerbation of anxiety disorder symptoms, active substance dependence, and/or current psychotic symptoms
• Ongoing suicidal/homicidal ideation or recent (in the past 6 months) suicidal attempts
• Patients who receive any narcotic-based analgesic, topical analgesics over the affected site, steroid and local anesthetic injection, anticonvulsants, and antipsychotic medications less than 7 days prior to the pretreatment assessment
• Patients who do not agree to avoid use of non-pharmacologic treatments, including but not limited to, transcutaneous electrical nerve stimulation unit (TENS), acupuncture, acupressure, and therapeutic massage during the entire study.
• Patients who do not agree to use additional acetaminophen (up to a maximum total of 3g per day) as the only rescue medication
• Patients who have received rTMS within the past 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A: Predicted Respondent at LDLPFC	Device: Active Repetitive Transcranial Magnetic Stimulation; rTMS will be administered to the LDLPFC with an active coil.; Device: Active Repetitive Transcranial Magnetic Stimulation; rTMS will be administered to the LDLPFC and LMC with an active coil.
Active Comparator: Group B: Predicted Non-respondent at LDLPFC	Device: Active Repetitive Transcranial Magnetic Stimulation; rTMS will be administered to the LDLPFC with an active coil.; Device: Active Repetitive Transcranial Magnetic Stimulation; rTMS will be administered to the LDLPFC and LMC with an active coil.
Active Comparator: Group C: Predicted Respondent at LDLPFC and LMC	Device: Active Repetitive Transcranial Magnetic Stimulation; rTMS will be administered to the LDLPFC with an active coil.; Device: Active Repetitive Transcranial Magnetic Stimulation; rTMS will be administered to the LDLPFC and LMC with an active coil.
Active Comparator: Group D: Predicted Non-respondent at LDLPFC and LMC	Device: Active Repetitive Transcranial Magnetic Stimulation; rTMS will be administered to the LDLPFC with an active coil.; Device: Active Repetitive Transcranial Magnetic Stimulation; rTMS will be administered to the LDLPFC and LMC with an active coil.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Intensity - Mechanical Visual Analogue Scale (M-VAS)	A scale that ranges from 0 to 10 ("No pain" to "Worst possible pain").	From baseline to the end of treatment at 16 weeks
Mood - Hamilton Rating Scale for Depression (HRSD)	This scale is a well-established questionnaire which consists of twenty-one questions and rates the severity of symptoms observed in depression such as low mood, insomnia, agitation, anxiety and weight loss. Only the first 17 items are used for the overall scoring. A score between 14 and 18 represents a moderate form of depression and a score greater than 19 represents severe depression.	From baseline to end of treatment at 16 weeks
Pain Severity - Brief Pain Inventory-Short Form (BPI-sf)	This is a self-administered questionnaire developed to assess the severity of pain and the impact of pain on daily functions during the 24-hour period prior to evaluation. The BPI-sf consists of five questions. Four items measure pain on 11-point response scales from 0 to 10 ("No Pain" to "Pain as bad as you can imagine"). Another item, containing 7 sub-questions, evaluates the level of pain interference with daily functioning on 11-point response scales from 0 to 10 ("Does not interfere" to "Completely interferes"). Items 3-6 are summed together for a total average pain severity score.	Baseline, 1-week, 1-month, 2-months
Pain Severity - Brief Pain Inventory-Short Form (BPI-sf)	This is a self-administered questionnaire developed to assess the severity of pain and the impact of pain on daily functions during the 24-hour period prior to evaluation. The BPI-sf consists of five questions. Four items measure pain on 11-point response scales from 0 to 10 ("No Pain" to "Pain as bad as you can imagine"). Another item, containing 7 sub-questions, evaluates the level of pain interference with daily functioning on 11-point response scales from 0 to 10 ("Does not interfere" to "Completely interferes"). Items 9A-9G are summed together for a total pain interference score.	Baseline, 1-week, 1-month, 2-months
Pain Quality and Intensity - Short Form McGill Pain Questionnaire (SF-MPQ)	This is a self-report questionnaire that allows individuals to describe the quality and intensity of pain they are experiencing. This will be used to assess the sensory and affective aspects of muscle pain. The SF-MPQ consists of fifteen questions; items 1-11 are measured on a 4-point response scale ranging from 0 to 3 ("None" to "Severe"). Items 12-15 include a visual analogue scale (VAS) from "No pain" to "Worst possible pain" and Present Pain Intensity (PPI) ranging from 0 to 5 ("No pain" to "Excruciating") ranking overall pain intensity for a total average muscle pain score. This is calculated via the average VAS scores (0-100) with 0 indicating no pain and 100 equivalent to the worst pain possible.	Baseline, 1-week, 1-month, 2-months
Pain Quality and Intensity - Short Form McGill Pain Questionnaire (SF-MPQ)	This is a self-report questionnaire that allows individuals to describe the quality and intensity of pain they are experiencing. This will be used to assess the sensory and affective aspects of joint pain. The SF-MPQ consists of fifteen questions; items 1-11 are measured on a 4-point response scale ranging from 0 to 3 ("None" to "Severe"). Items 12-15 include a visual analogue scale (VAS) from "No pain" to "Worst possible pain" and Present Pain Intensity (PPI) ranging from 0 to 5 ("No pain" to "Excruciating") ranking overall pain intensity for a total average joint pain score. This is calculated via the average VAS scores (0-100) with 0 indicating no pain and 100 equivalent to the worst pain possible.	Baseline, 1-week, 1-month, 2-months
Functionality - Revised Fibromyalgia Impact Questionnaire	A questionnaire to evaluate the function, overall impact and symptoms of Fibromyalgia. The 3 categories are calculated by the sum of the scores to produce a total score. Each item ranges from 0-10 and the total score is 0-100 with high scores indicating more severe impact.	Baseline, 1-week, 1-month, 2-months
Pain Intensity - New Clinical Fibromyalgia Diagnostic Criteria - Part 1	Patients will be asked to rate the average (over the past week) intensity of muscle pain up to 12 locations of the body. This is calculated by the Widespread Pain Index (WPI) total score ranging from 0 to 19 and a marker visual analogue scale (MVAS) ranging from 0 to 100.	Baseline, 1-week, 1-month, 2-months
Pain Severity - Headache Impact Test (HIT-6)	This test measures how impact headaches affect the individual's ability to function in different domains. This six question test evaluates the severity of headache pain from "Never" to "Always" with a total range between 36-78, higher scores indicating greater impact on functionality.	Baseline, 1-week, 1-month, 2-months
Pain Severity - Neurobehavioral Symptoms Inventory (NSI)	This twenty-two self-report questionnaire on the severity of each symptom is measured using a 5-point response scale ranging from 0 to 4 ("None - Rarely if ever present; not a problem at all" to "Very Severe - Almost always present and I have been unable to perform at work, school or home due to this problem; I probably cannot function without help"). It asks the subjects to indicate the extent to which each symptom has disturbed them. The total score ranges from 0 to 88 with a higher score indicating very severe symptom disruption.	Baseline, 1-week, 1-month, 2-months
Sleep Quality - Pittsburgh Sleep Quality Index (PSQI)	This index has nineteen individual items which are used to generate 7 composite scores on: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The 7 components measure sleep habits and sum together to measure global sleep quality with a high score of 0-21 with a higher score indicating worse sleep quality.	Baseline, 1-week, 1-month, 2-months
Sleep Severity - Insomnia Severity Index	This index consists of seven questions that depict the severity of sleep difficulties within the past 2 weeks on a 5-point response scale that rates satisfaction, noticeability, distress, and interference with daily functioning. A score between 15 and 21 suggests moderately severe clinical insomnia. A score of 22 or greater represents severe clinical insomnia.	Baseline, 1-week, 1-month, 2-months
Quality of Life - Veteran RAND 36-item Health Survey (VR-36+PCS and MCS)	A patient-reported survey of patient health. It is a measure of health status and quality of life in regards to eight main areas: vitality, physical functioning, bodily pain, health perceptions, physical, emotional, and social role functioning and mental health.	Baseline, 1-week, 1-month, 2-months
Multidimensional Fatigue Inventory	A twenty item self-report instrument with 4 categories total designed to measure fatigue level (24-96) with a higher score indicating more severe fatigue.	Baseline, 1-week, 1-month, 2-months
Chronic Fatigue Severity Scale	A Likert scale consisting of nine items that assess fatigue severity and functionality. The sum of all questions provides total fatigue level 8-63 with a higher score being more severe. A score over 36 indicates patient may be suffering from fatigue.	Baseline, 1-week, 1-month, 2-months
Headache and Pain Log	A personal daily log is used to track the subject's headaches, muscle and joint pain throughout the course of the study based on a range of 0 to 10, with higher scores indicating more severe pain.	From enrollment to the end of treatment at 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opiate/Medication Assessment	This assessment evaluates opiate consumption over the duration of the study. Opioids and narcotics are converted to their morphine equivalent value on a daily basis. Values during each measurement period are added up and divided by the number of weeks to determine weekly usage.	From the baseline to the end of treatment at 16 weeks

Collaborators and Investigators

• Sponsor: Veterans Medical Research Foundation
• Collaborators: Congressionally Directed Medical Research Programs; San Diego Veterans Healthcare System

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2026
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: January 6, 2026
• First Submitted That Met QC Criteria: January 6, 2026
• First Posted (Actual): January 8, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Headache; Machine Learning; Repetitive Transcranial Magnetic Stimulation (rTMS); Support Vector Machine (SVM); Muscle and Joint Pain
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Musculoskeletal Diseases; Joint Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Headache; Arthralgia
• Other Study ID Numbers: H2500180; CDMRP-TX240370 (Other Grant/Funding Number: Congressionally Directed Medical Research Programs (CDMRP))

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: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No