fMRI-neuronavigated rTMS for the Treatment of Major Depression Associated With TBI

rTMS is an FDA-approved treatment for major depressive disorder, but its utility has not yet
been investigated for major depression associated with traumatic brain injury.

This will be a prospective double-blind randomized sham-controlled crossover study. Patients
in the treatment group will receive 20 sessions of high-frequency rTMS over the left
dorsolateral prefrontal cortex (DLPFC) and low-frequency rTMS over the right DLPFC. The DLPFC
will be identified as target by using individual subject-level resting state network
estimation (Hacker et al, 2013). Patients in the control group will receive 20 sham
treatments designed to be visibly indistinguishable from active treatment, and will
subsequently have the option to be crossed over to receive active treatment with the
aforementioned protocol. A subgroup of patients in each group will receive more detailed
diffusion imaging (diffusion tensor and diffusion kurtosis imaging) and resting state fMRI
scans before and after the treatment in order to assess for changes in white matter integrity
and functional connectivity associated with the treatment.

Inclusion criteria:

- Adults age 18 to 65

- History of traumatic brain injury (TBI) at least two weeks prior to study initiation

- Presence of an active major depressive episode as defined by DSM-5 criteria, including
depression secondary to traumatic brain injury

- Baseline score of 10 or greater on Montgomery-Asberg Depression Rating Scale (MADRS)

- Failure of at least one prior antidepressant trial after the traumatic brain injury

Exclusion criteria

History of:

- Moderate or severe substance use disorder in the past six months as defined by DSM-5
criteria, with the exception of cannabis and nicotine use disorders.

- Dementia, as defined by treating neurologist

- Moderate or severe autism spectrum disorder

- Bipolar disorder

- Schizophrenia spectrum disorders

Current evidence of:

- Substance-induced mood disorder

- Active psychotic symptoms

- Depression secondary to a general medical illness, with the exception of TBI

- Dysphoria better explained by a baseline personality disorder than a major depressive
episode

- Dysphoria better explained by a baseline anxiety disorder (including post-traumatic
stress disorder) rather than a major depressive episode

- Active suicidal ideation

Contraindications to rTMS treatment:

- Seizure disorder

- Significantly elevated seizure risk, as determined by clinician assessment

- TBI associated with elevated seizure risk, including penetrating injury and/or
cortical intraparenchymal hemorrhage

- Presence of metallic objects within the head

- Presence of an implanted neurostimulation device within the head

Contraindications to MRI

- Severe claustrophobia

- Severe pain/illness exacerbated by lying prone in the scanner

- Presence of non-MRI compatible metal foreign bodies or implants

- Weight in excess of 350 lbs

- Shoulder width in excess of maximum tolerable width for scanner