Managing MTBI-related Headaches With rTMS

Long Term Efficacy of rTMS in Managing MTBI-related Headache

Persistent headache is one of the most common debilitating symptoms in military personnel suffering from mild traumatic brain injury (MTBI). This study aims to assess the long-term effect of repetitive transcranial magnetic stimulation (rTMS) in managing MTBI related headaches for up to 2-3 months by comparing the treatment effect of active-rTMS to sham-rTMS.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury (TBI)
• Intervention / Treatment: Device: Transcranial Magnetic Stimulation; Device: Sham Transcranial Magnetic Stimulation

Detailed Description

Headache is one of the most common debilitating chronic pain conditions in either active or retired military personnel with MTBI. This high prevalence of persistent chronic headache is often associated with neuropsychological dysfunction in mood, attention, and memory, which casts a profound negative impact on patients' quality of life and increases stress in their caregivers. Unfortunately, as witnessed by the investigators in their clinical practices, conventional pharmacological treatments for MTBI related headache (MTBI-HA) has not been shown to be effective and drugs such as narcotics contain many long-term untoward psychosomatic and abusive side effects. This calls for an urgent need in developing alternate and innovative long-term headache management strategies for this rapidly increasing patient population.

Coinciding with other published treatment protocols related to traumatic brain injury and pain, this initial clinical evidence provides compelling support for the current proposal aiming to assess the effect of a longer duration of rTMS protocol in managing MTBI-HA for up to 10 weeks after the initiation of the treatment. Given existing treatment options for MTBI-HA are limited, validating such a non-pharmacological and non-invasive treatment option will significantly enhance the capability of the VA healthcare system in caring for this rapidly increasing patient population.

1. PRE-TREATMENT PHASE (weeks 1-2) consists of Visit 1 (Screening Visit) and Visit 2 (Pre-treatment Assessments);
2. TREAMENT PHASE (week 3-4) consists of Visits 3-12 (Neuronagvigation guided rTMS consisting of 10 weekday treatments at >24 and < 72 hours apart, weekends excluded, maximum 5 weeks for treatment completion) rTMS will take place in Building 23 Room 105 at the VASDHS; and
3. POST-TREATMENT PHASE (week 5-14) consists of two initial weekly visits (Visits 13&14) and two additional biweekly visits (Visits 15&16) and one monthly visit (Visit 17).

Brain anatomical and functional MRI will be performed within 72 hours after Visits 2 and 13. Subjects will be required to fill out headache diary between assessment visits. Headache assessments along with quality of life, mood and functions assessments will be carried out at Visits 1,2, and 13--17. This frequency of treatment and duration of follow-up is in line with recently published rTMS articles related to TBI, headache and pain, and also in accordance with the 3-month post treatment initiation follow-up guideline/recommendation [32; 55; 80].

• Study Type: Interventional
• Enrollment (Actual): 179
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Caleb T Lopez, BS; Phone Number: 2638 (858) 552-8585; Email: caleb.lopez@va.gov

Study Locations

• United States
  • California
    • San Diego, California, United States, 92161-0002
      • VA San Diego Healthcare System, San Diego, CA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• The following diagnostic criteria for MTBI based on the 1993 American Congress of Rehabilitation Medicine and recent recommendation from the DOD, and the current diagnostic criteria adopted by the VASDHS TBI Clinic will be used for the study. A traumatically induced physiological disruption of brain function, as manifested by at least one of the following:
• any loss of consciousness
• any loss of memory for events immediately before or after the accident

• any alteration in mental state at the time of the accident, e.g.:

  • feeling dazed
  • disoriented
  • confused)

• Focal neurologic deficit (s) that may or may not be transient but where the severity of the injury does not exceed the following:

  • loss of consciousness of approximately 30 min or less
  • after 30 min, an initial Glasgow Coma Scale score of 13-15
  • post-traumatic amnesia not greater than 24 hrs

• In addition, the following established diagnostic criteria for " Persistent headache attributed to mild traumatic injury headache" based on the International Classification of Headache Disorder (ICHD-3) will be applied to the study subjects:

  • A. Any headache fulfilling criteria C and D
  • B. Traumatic injury to the head has occurred
  • C. Headache is reported to have developed within 7 d after one of the following:
  • 1. injury to the head
  • 2. regaining of consciousness following the injury
  • 3. discontinuation of medication(s) that impairs the ability to sense or report headache following the injury
  • D. Headache persists for >3 mo after injury to the head
  • E. Not better accounted for by another ICHD-3 diagnosis

Additional Inclusion Criteria:

• no prior experience of TMS treatment
• average persistent headache intensity more than 30 on the 0-100 mechanical visual analog scale(M-VAS) at the screening visit (visit 1) and average persistent headache intensity score greater than 3/10 on a numerical rating scale (NRS) reported in the headache diary (between visits 1&2)
• no history of daily persistent headache prior to the MTBI incidence

Exclusion Criteria:

• pregnancy; To be eligible for the study and to ensure no pregnancy risk, you will need to utilize contraception or practice abstinence until your study participation is completed
• history of pacemaker implant

• any ferromagnetic material in the brain or body that would prohibit the patients from having a brain MRI, e.g.:

  • bullet fragment
  • shrapnel
  • device implant
• history of dementia, major psychiatric or life threatening diseases
• presence of any other chronic neuropathic pain states;
• history of seizure
• pending litigation
• lack of ability to understand the experimental protocol and to adequately communicate in English
• history of chronic headache diagnoses such migraine, tension or cluster headaches prior to the incidence of MTBI.
• history of chronic headache prior to the MTBI incidence at a frequency more than once a month lasting more than one hour.
• evidence in the chart of recent exacerbation of depressive or anxiety symptoms, active substance dependence, suicidal intent or attempt within the previous month, and/or current psychotic symptoms

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Transcranial Magnetic Stimulation; Active-repetitive transcranial magnetic stimulation (rTMS) at the left motor cortex.	Device: Transcranial Magnetic Stimulation; Active-repetitive transcranial magnetic stimulation (rTMS) at the left motor cortex.
Sham Comparator: Sham Transcranial Magnetic Stimulation; Sham rTMS will consist of the same parameters as active, however, the subject will not receive the actual magnetic stimulation to the left motor cortex.	Device: Sham Transcranial Magnetic Stimulation; Sham rTMS will consist of the same parameters as active, however, the subject will not receive the actual magnetic stimulation to the left motor cortex due to the use of a double sided Active/Sham coil used specifically for research studies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduce the intensity, frequency and duration of MTBI-headaches	The outcome measure will be quantified through the headache diary log that tracks the intensity, frequency and duration of MTBI-headaches (MTBI-HA)	The measure will be assessed daily from baseline to the 3-month post-treatment follow up visit.
Change from Baseline to Post-Treatment Quality of Life scores	The outcome measure will be quantified through the self-assessed short form impact on quality of life (SF-36). The SF-36 has eight scaled scores; the scores are weighted sums of the questions in each section. Scores range from 0 - 100 where Lower scores = more disability and higher scores = less disability The sections include: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health.	The measure will be assessed at the Baseline visit, 1-Week, 1-Month, 2-Month and 3-month post-treatment follow up visits.
Change from Baseline to Post-Treatment Depression scores	The outcome measure will be quantified through the administered Hamilton Scale for Depression. This contains 17 items to be rated (HDRS-17), but four other questions are not added to the total score and are used to provide additional clinical information. Each item on the questionnaire is scored on a 3 or 5 point scale, depending on the item, and the total score is compared to the corresponding descriptor.	The measure will be assessed at the Baseline visit, 1-Week, 1-Month, 2-Month and 3-month post-treatment follow up visits.
Change in attention scores from Baseline to Post-Treatment visits	The outcome measure will be quantified through the Connors continuous performance test for sustained and selective attention. This is administered on a laptop and is automatically scored.	The measure will be assessed at the Baseline visit, 1-Week, 1-Month, 2-Month and 3-month post-treatment follow up visits.
Change from Baseline to Post-Treatment Global Pain scores.	The outcome measure will be quantified through the self-assessed global pain inventory survey. Pain will be recorded at it's worst, it's best and on average over the previous 24 hours on a 0 to 10 scale. Then the pain's impact on general activity, mood, walking ability, normal work, relationships, sleep and enjoyment of life will be measured on a 0 to 10 scale and added together for an overall Global Pain score.	The measure will be assessed at the Baseline visit, 1-Week, 1-Month, 2-Month and 3-month post-treatment follow up visits.
Change from Baseline to Post-Treatment Post Traumatic Stress Disorder (PTSD) scores	The outcome measure will be quantified through the administered CAPS, a structured interview designed to make a categorical PTSD diagnosis, as well as to provide a measure of PTSD symptom severity. The symptoms are rated for both frequency and intensity; these two scores are summed to provide severity ratings.	The measure will be assessed at the Baseline visit, 1-Month, 2-Month and 3-month post-treatment follow up visits.
Change from Baseline to Post-Treatment memory scores	The outcome measure will be quantified through the Hopkins Verbal Learning Test (HVLT-R) for memory. When scoring the HVLT-R, the three learning trials are combined to calculate a total recall score and the delayed recall trial creates the delayed recall score.	The measure will be assessed at the Baseline visit, 1-Week, 1-Month, 2-Month and 3-month post-treatment follow up visits.
Change from Baseline to Post-Treatment Executive Functioning	The outcome measure will be quantified through the Trail Making Test A and B and Stroop Test for executive functioning. The Trail Making Test consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. And the Stroop Test is a demonstration of interference in the reaction time of a task.	The measure will be assessed at the Baseline visit, 1-Week, 1-Month, 2-Month and 3-month post-treatment follow up visits.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Explore the treatment effect on the pain related network of the brain	The outcome measure will be assessed through functional magnetic imaging scans and subsequent processing.	Subjects will have 2 functional magnetic imaging scans, at baseline and then at the 1-week post treatment follow-up.

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Albert Yick Leung, MD, VA San Diego Healthcare System, San Diego, CA

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Actual): September 30, 2023
• Study Completion (Actual): January 31, 2024

Study Registration Dates

• First Submitted: October 4, 2017
• First Submitted That Met QC Criteria: October 17, 2017
• First Posted (Actual): October 19, 2017

Study Record Updates

• Last Update Posted (Actual): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: TBI; traumatic brain injury; headache; transcranial magnetic stimulation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Headache
• Other Study ID Numbers: B2506-I; H170053 (Other Identifier: VA San Diego Healthcare System)

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