Alleviating Headache and Pain in GWI With Neuronavigation Guided rTMS

This study aims to assess the effect of repetitive transcranial magnetic stimulation (rTMS) on Gulf War illness related headaches and pain.

Study Overview

• Status: Completed
• Conditions: Headache; Gulf War Syndrome
• Intervention / Treatment: Device: Repetitive transcranial magnetic stimulation; Device: Repetitive transcranial magnetic stimulation (sham)

Detailed Description

Headaches (HA) and wide spread pain are some of the most common debilitating symptoms in Gulf War Veterans (GWV) with Gulf War Illness (GWI). Migraine like HA and diffuse body pain were detected in 64% of GWV with GWI. This high prevalence of chronic HA and diffuse body pain conditions are often associated with neuropsychological dysfunction in mood, attention, memory and other systemic symptoms, which cast a profound negative impact on patients' quality of life. Unfortunately, conventional pharmacological treatments for GWI related headaches and pain (GWI-HAP) has not been shown to be effective and drugs such as narcotics contain many long term untoward psychosomatic and abusive side effects. Therefore, developing and validating non-invasive and low risk innovative treatment for this patient population is warranted. Transcranial Magnetic Stimulation (TMS) is currently a US FDA approved treatment for major depression and migraine HA.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92134
      • Naval Medical Center San Diego
    • San Diego, California, United States, 92161
      • Veteran Affairs Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Criteria for veterans with Gulf War Illness headaches and pain:

Inclusion Criteria:

• Male or female between ages 18-65
• CDC Criteria for GWI
• Kansas Criteria for GWI
• International Headache Society Criteria for Migraine HA w/o aura
• Average Headache Exacerbation Intensity >3 on 0-10 NPRS
• Average Overall Daily Muscle Pain Intensity >3 on 0-10 NPRS
• Average Overall Daily Extremities Joint Pain Intensity >3 on 0-10 NPRS
• Headache Exacerbation/Attack ≥ 3 times/week, lasting >4 hrs in past 3 months

Exclusion Criteria:

• Pregnancy
• History of pacemaker implant
• Any ferromagnetic (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
• History of seizure
• Pending litigation
• Low back pain with mechanical origins such as lumbar radiculopathy or radiculitis or lumbar facet arthropathy
• Lack of ability to understand the experimental protocol and to adequately communicate in English
• History of Traumatic Brain injury
• Chronic Tension or Cluster Headache
• Ongoing Cognitive Rehabilitation or Treatment of PTSD

Criteria for healthy veterans without Gulf War Illness headaches and pain:

Inclusion Criteria:

• Male or female between ages 18-65
• Served at least 30 consecutive days in the Persian Gulf between 8/90-7/91

Exclusion Criteria:

• CDC Criteria for GWI
• Kansas Criteria for GWI
• International Headache Society Criteria for Migraine HA w/o aura
• Average Headache Exacerbation Intensity >3 on 0-10 NPRS
• Average Overall Daily Muscle Pain Intensity >3 on 0-10 NPRS
• Average Overall Daily Extremities Joint Pain Intensity >3 on 0-10 NPRS
• Headache Exacerbation/Attack ≥ 3 times/week, lasting >4 hrs in past 3 months
• Pregnancy
• History of pacemaker implant
• Any ferromagnetic (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
• History of seizure
• Pending litigation
• Low back pain with mechanical origins such as lumbar radiculopathy or radiculitis or lumbar facet arthropathy
• Lack of ability to understand the experimental protocol and to adequately communicate in English
• History of Traumatic Brain injury
• Chronic Tension or Cluster Headache
• Ongoing Cognitive Rehabilitation or Treatment of PTSD

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Repetitive TMS; Subjects will receive the repetitive transcranial magnetic stimulation study procedure.	Device: Repetitive transcranial magnetic stimulation; A non-invasive method of brain stimulation that emits a magnetic pulse.
Placebo Comparator: No (blocked) repetitive TMS; Subjects will not receive the repetitive transcranial magnetic stimulation study procedure by blocking the stimulation between the coil and the head, but the audiovisual conditions will be mimicked.	Device: Repetitive transcranial magnetic stimulation (sham); No brain stimulation will be administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily Headache and Pain Log	This is a daily self-reporting log that tracks headache, muscle pain, and joint pain levels. The pain levels are scored from 0-10 with 10 being the worst possible pain.	2 months for each subject (11 visits)
Headache Impact Test 6 (HIT-6)	This 6-question form assesses the severity of headache pain and is scored with a range of 36-78. The higher score, the higher the impact of headaches on functional ability.	2 months for each subject (11 visits)
2 months for each subject (11 visits)	This assessment has 9 questions about pain level, relief, and interference. Pain level and interference questions range from 0-10, with 10 being the worst. Level of relief has a range of 0-100%, with 100% being complete relief.	2 months for each subject (11 visits)
Opioid Medication Assessment	This is a self-reporting log that tracks opioid medication usage. Average daily dosages are converted to equal-potent oral Morphine Sulfate dosage and reported in milligrams.	2 months for each subject (11 visits)
Mechanical-Visual Analogue Scale	This scale measures the level of headache, muscle, and joint pain at each visit. This ranges from 0-100, with 100 being the worst possible pain.	2 months for each subject (11 visits)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurobehavioral Symptom Inventory (NSI)	This is a 22-question self-report assessment that tracks symptoms over time. Each question ranges from 0-4, with 4 being very severe. The total NSI score ranges from 0-88.	2 months for each subject (11 visits)
Short-Form McGill Pain Questionnaire (SF-MPQ)	This self-reporting survey contains 15 questions that describe the type of pain. Each descriptor is scored between 0-3, with 3 being severe pain. The total score then ranges from 0-45. This questionnaire is filled out one each for joint pain and one for muscle pain.	2 months for each subject (11 visits)
New Clinical Fibromyalgia Diagnostic Criteria	This form contains a checklist of 19 possible areas for muscle pain. The checkmarks are tallied to give the Widespread Pain Index score, which ranges from 0-19. A score of 19 would suggest muscle pain in all 19 possible locations.	2 months for each subject (11 visits)
Revised Fibromyalgia Impact Questionnaire (FIQR)	This 3-part questionnaire measures the level of interference the pain causes, the overall impact of the pain, and intensity of the symptoms. There are a total of 21 questions, each with a range of 0-10, with 10 being either "very difficult" or "always." The FIQR total has a range of 0-210.	2 months for each subject (11 visits)
Conners Continuous Performance Test 2 (CPT2)	This is a 15-minute attention task administered on a laptop. The subject is prompted to press the spacebar as quickly as possible after every letter that appears on the screen except for the letter X. The exam is automatically scored by the program and reports omission rate and response latency. The attentional cognitive function is tracked by their change in these scores over time.	2 months for each subject (11 visits)
Hopkins Verbal Learning Test (HVLT)	This is a memory and recall task that requires the subject to memorize a list of 10 words and recall them. There are 3 trials and they are scored just by the number of words that can be recalled each time, which can be from 0-10 for a total range of 0-30 words. The second part of this test rates their recognition discrimination index by asking if certain words were on the original list. This is scored by taking the number of true positives and subtracting the false positives. The range for this is from 0-12, with 12 indicative of better discrimination within memory.	2 months for each subject (11 visits)
Trailmaking Test A&B	This is a timed test that is administered to assess executive function. Both tests have a series of numbers or numbers and letters that are to be connected in sequential order. The faster the completion time, the better the executive function.	2 months for each subject (11 visits)
This is a timed test that is administered to assess executive function. Both tests have a series of numbers or numbers and letters that are to be connected in sequential order. The faster the completion time, the better the executive function.	This is an administered IQ test that is designed to measure intelligence and cognitive ability in adults and older adolescents. There are several parts to the test, with each response being scored from 0-2 or 0-4 based on the quality of the answer or the completion time. The raw scores are then converted to scaled scores and summed to give the Full Scale score. The higher the Full Scale score, the higher the IQ classification.	2 months for each subject (11 visits)
Hamilton Rating Scale for Depression	This questionnaire rates the severity of depression in 21 questions. Each question either ranges from 0-2 or 0-4. The sum of the scores would give the total score, where a higher score would mean more severe depression.	2 months for each subject (11 visits)
36-Item Short Form Survey Instrument (SF-36)	This is a 38-question survey that assesses physical function, physical health limitations, emotional problem limitations, fatigue, emotional well-being, social functioning, pain, and general health. The scoring follows the official guidelines by RAND, where certain questions determine each health aspect. The questions are rated from 1-5, and then scored from 0-100. Each health aspect will have a range of 0-100, with 100 suggesting a more favorable health state.	2 months for each subject (11 visits)
Sleep Quality Assessment (PSQI)	This is self-reporting survey has 9 questions and determines the quality and patterns of sleep. Questions are either free-response or have a range from 0-3, with 3 being "more frequent" or "very bad." The responses will be scored based on the guidelines at the bottom of the page. The global PSQI score then has a range of 0-21, with 21 indicative of poor sleep quality.	2 months for each subject (11 visits)
Insomnia Severity Index	This survey has 7 questions that rate the severity of insomnia problems. All questions range from 0-4 and the sum of the answers would give the total score. The total score range from 0-28, with 28 being severe clinical insomnia.	2 months for each subject (11 visits)
Flinders Fatigue Scale	This questionnaire contains 7 questions in order to determine the level of fatigue one is experiencing. The questions range from 1-5, with 5 being "extremely" or "entirely." The higher one scores, the more severe the fatigue.	2 months for each subject (11 visits)

Collaborators and Investigators

• Sponsor: Veterans Medical Research Foundation
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Albert Leung, M.D., VA San Diego Health Care System

Publications and helpful links

General Publications

• Leung A, Donohue M, Xu R, Lee R, Lefaucheur JP, Khedr EM, Saitoh Y, Andre-Obadia N, Rollnik J, Wallace M, Chen R. rTMS for suppressing neuropathic pain: a meta-analysis. J Pain. 2009 Dec;10(12):1205-16. doi: 10.1016/j.jpain.2009.03.010. Epub 2009 May 23.
• Leung A, Shukla S, Fallah A, Song D, Lin L, Golshan S, Tsai A, Jak A, Polston G, Lee R. Repetitive Transcranial Magnetic Stimulation in Managing Mild Traumatic Brain Injury-Related Headaches. Neuromodulation. 2016 Feb;19(2):133-41. doi: 10.1111/ner.12364. Epub 2015 Nov 10.
• Lei K, Kunnel A, Metzger-Smith V, Golshan S, Javors J, Wei J, Lee R, Vaninetti M, Rutledge T, Leung A. Diminished corticomotor excitability in Gulf War Illness related chronic pain symptoms; evidence from TMS study. Sci Rep. 2020 Oct 28;10(1):18520. doi: 10.1038/s41598-020-75006-8.

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: January 4, 2017
• First Submitted That Met QC Criteria: January 20, 2017
• First Posted (Estimate): January 25, 2017

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 13, 2020
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Headache; Gulf War Illness; TMS; Muscle Pain; Joint Pain
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Occupational Diseases; Headache; Persian Gulf Syndrome
• Other Study ID Numbers: H160047

Plan for Individual participant data (IPD)

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