fMRI-neuronavigated rTMS Treatment for Symptoms of Depression Associated With Concussive TBI in the Military Population

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.

Inclusion Criteria:

1. Age 18-64

2. Current or former US military service member

3. Able to provide written, informed consent in English

4. History of concussive TBI:

1. >6 months prior to consent

2. Documented previously in medical records and/or as confirmed by the TBI Screener

5. Must meet Criterion A of the DSM-5 criteria for Major Depressive Disorder as
determined by a trained assessor

6. 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. History of TBI resulting in penetrating trauma or intraparenchymal hemorrhage

3. History of intracranial tumor

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. Life expectancy of less than 6 months

4. Presence of rapidly progressive illnesses such as late stage cancer, neurodegenerative
conditions, major organ failure, etc.