Clinical trial NCT03523507: fMRI-neuronavigated rTMS Treatment for Symptoms of Depression Associated With Concussive TBI in the Military Population
Official title: A Randomized, Sham-controlled, Double-blinded Study of Bilateral Prefrontal Individual Connectome-targeted Repetitive Transcranial Magnetic Stimulation to Treat the Symptoms of Depression Associated With Concussive Traumatic Brain Injury.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Traumatic Brain Injury
Concussion, Mild
Depressive Symptoms
Keywords: Repetitive Transcranial Magnetic Stimulation
Military
Lead sponsor: Henry M. Jackson Foundation for the Advancement of Military Medicine
Sponsor class: OTHER
Collaborators: name: Center for Neuroscience and Regenerative Medicine (CNRM)
First posted: 2018-05-14
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to investigate the efficacy and tolerability of fMRI-targeted repetitive transcranial magnetic stimulation (rTMS) in the treatment of depressive symptoms in service members with a history of concussive traumatic brain injury (TBI).

Up to ninety participants will be randomized to active or sham treatment. Participants randomized into the active group will receive 20 sessions of left-sided dorsolateral prefrontal cortex (DLFPC) high-frequency rTMS, followed by right-sided DLFPC low-frequency rTMS. The DLPFC treatment area will be identified by using individual subject-level resting state network estimation (Hacker et al., 2013). Participants randomized into the sham treatment group will receive 20 sham treatments designed to have similar sound and tactile sensation, without producing active treatment. Participants will also be asked to complete regular follow-up evaluations for up to a total of six follow-up sessions. Those who do not respond to the treatment will have the option to receive active treatment through this study regardless of group assignment to active or sham.

Detailed description: This study aims to investigate the efficacy and tolerability of individual connectome-targeted repetitive transcranial magnetic stimulation (ICT-rTMS) treatment to enhance the rehabilitation of service members with symptoms of depression and history of concussive traumatic brain injury (TBI).

This will be a multi-site, double-blinded, sham-controlled, prospective, randomized interventional trial. Up to ninety participants will be block randomized to active (ICT-rTMS) or sham treatment. Participants will receive 20 sessions of ICT-rTMS over approximately 5 weeks.

Resting-state functional magnetic resonance imaging (rsfMRI) and structural MRI will be obtained at baseline to allow for the calculation of connectome-targeted treatment coordinates and ensure the absence of structural abnormalities. The rsfMRI scan at baseline will also be used to establish the baseline for the secondary imaging outcome measures.

Treatment sessions will consist of high-frequency left dorsolateral prefrontal cortex (DLPFC) stimulation for 4,000 pulses followed by low-frequency right DLPFC stimulation for 1,000 pulses for a total stimulation time of approximately one hour per session. This protocol was chosen based on a recent meta-analysis (Brunoni et al., 2017) indicating that amongst the various treatment protocols, priming the low frequency right hemisphere stimulation with a high frequency left hemisphere stimulation led to the greatest efficacy for treatment of Major Depressive Episodes. Additionally, the overwhelming majority of the literature in TMS for depression targets the stimulation to DLPFC and the FDA has approved repetitive transcranial magnetic stimulation (rTMS) to DLPFC for the treatment of medication-resistant major depressive disorder (MDD).

The primary outcome will be change in depression severity from baseline to post-treatment. The primary analysis will be a comparison between the ICT-rTMS and sham groups. Secondary outcome measures utilized will include cognitive, quality of life, and emotional regulation measures, as well as imaging changes. Additional analyses will include durability of effects during the 6 months following treatment.

Eligibility criteria: Inclusion Criteria:

1. Age 18-64
2. Current or former US military service member
3. Eligible for care at DoD facilities
4. Able to provide written, informed consent in English
5. History of concussive TBI:

   1. \>6 months prior to consent
   2. Documented previously in medical records and/or as confirmed by the TBI Screener
6. Must meet Criterion A of the DSM-5 criteria for Major Depressive Disorder as determined by a trained assessor
7. Baseline MADRS \>10

Exclusion Criteria:

1. Elevated risk of seizures:

   1. Prior history of unprovoked seizures other than within 24 hours of concussive TBI
   2. Family history of seizures
   3. History of TBI resulting in penetrating trauma based on the TBI Screener
   4. Presence of intracranial tumor or intraparenchymal hemorrhage based on the structural MRI scan
   5. Heavy alcohol consumption within 48 hours, prior to any treatment session
   6. Receiving tricyclic antidepressants or neuroleptics at doses that lower seizure threshold
2. Contraindications to awake 3T MRI without contrast:

   1. Ferromagnetic implants or metallic shrapnel
   2. Severe claustrophobia
   3. Unable to lie awake, supine, stationary, with reasonable comfort in the scanner for approximately 45 minutes
   4. Markedly distorted functional brain anatomy such that rsfMRI targeting cannot be performed
3. History of severe or recent uncontrolled heart disease
4. Presence of a cardiac pacemaker or intracardiac lines
5. Implanted neurostimulators and medication pumps
6. Presence of rapidly progressive illnesses such as late stage cancer, neurodegenerative conditions, major organ failure, etc.
7. History of Bipolar Disorder, Schizophrenia Spectrum Disorders, or Moderate/Severe Substance Use Disorders, with the exception of nicotine use disorders
8. Increased risk of suicide as clinically evaluated
9. Current evidence of substance-induced mood disorder, active psychosis, and/or depression secondary to general medical illness (other than TBI)
10. Concomitant or previous history of receiving open-label TMS, other neurostimulatory treatment, or electroconvulsive therapy
11. Pregnancy

    a. Female participants of childbearing potential must agree to use an effective method of birth control during the course of the study, or to remain abstinent from sex, to ensure they do not become pregnant during the course of the study
12. Unilateral or bilateral upper extremity amputation or other condition precluding motor threshold calibration
13. Any considerations that, in the opinion of the investigator, may adversely affect patient safety, participation, or the scientific validity of the data being collected (e.g., planned hospitalization halfway through the initial treatment period, limited life expectancy, etc.)

Primary outcomes:
measure: Improvement in Depressive Symptoms
timeFrame: Change between baseline, post-treatment (i.e., within 10 days of treatement completion), and 6-month follow-up
Secondary outcomes:
measure: Changes in Cognitive Function
timeFrame: Change between baseline, post-treatment (i.e., within 10 days of treatement completion), and 6-month follow-up
measure: Changes in TBI-related Symptoms
timeFrame: Change between baseline, post-treatment (i.e., within 10 days of treatement completion), and 6-month follow-up
measure: Changes in PTSD-related Symptoms
timeFrame: Change between baseline, post-treatment (i.e., within 10 days of treatement completion), and 6-month follow-up
measure: Changes in Tinnitus-related Symptoms
timeFrame: Change between baseline, post-treatment (i.e., within 10 days of treatement completion), and 6-month follow-up
measure: Frequency of Adverse Effects
timeFrame: Change between baseline, post-treatment (i.e., within 10 days of treatement completion), and 6-month follow-up
measure: Changes in Psychotherapeutic Changes
timeFrame: Change between baseline, post-treatment (i.e., within 10 days of treatement completion), and 6-month follow-up
measure: Changes in Resting-state fMRI
timeFrame: Change between baseline, post-treatment (i.e., within 10 days of treatement completion), and 6-month follow-up
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Fort Belvoir
country: United States
facility: Fort Belvoir Community Hospital
state: Virginia
Study officials:
affiliation: Center for Neuroscience and Regenerative Medicine (CNRM)
name: David L Brody, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hacker CD, Laumann TO, Szrama NP, Baldassarre A, Snyder AZ, Leuthardt EC, Corbetta M. Resting state network estimation in individual subjects. Neuroimage. 2013 Nov 15;82:616-633. doi: 10.1016/j.neuroimage.2013.05.108. Epub 2013 Jun 2.
citation: Brunoni AR, Chaimani A, Moffa AH, Razza LB, Gattaz WF, Daskalakis ZJ, Carvalho AF. Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes: A Systematic Review With Network Meta-analysis. JAMA Psychiatry. 2017 Feb 1;74(2):143-152. doi: 10.1001/jamapsychiatry.2016.3644.