rTMS to Improve Cognitive Function in TBI

The goal of the present study is to evaluate the efficacy and durability of benefits of
repetitive Transcranial Magnetic Stimulation (rTMS) as a promising non-invasive therapeutic
treatment for executive function deficits reported in Veterans with mild to moderate
Traumatic Brain Injury (TBI) patients. Although much progress has been made towards
understanding the various deficits following TBI, progress has yet to be made towards
identifying and assessing therapeutic treatment options that are responsive to TBI symptoms.
Many returning OEF/OIF Veterans with concussion histories report cognitive symptoms that may
last for months or years, and affect every day function. Symptoms faced by Veterans with mild
to moderate TBI include executive function deficits such as impaired attention (including
shifting sets), verbal fluency, poor planning, reduced working memory, and mental
flexibility. The primary objective is to assess the efficacy of rTMS in Veterans with mild to
moderate TBI in improving executive functioning.

A recent VA study reported improvements in PTSD and related symptoms in Veterans with PTSD
who received rTMS (Watts et al., 2012). Repetitive TMS is a method of delivering therapeutic,
non-invasive brain stimulation that is currently being used at the VA Palo Alto and Stanford
University in a number of clinical trials.

For this pilot study the investigators propose to enroll 40 Veterans diagnosed with mild to
moderate TBI (age range 20-65). Inclusion Criteria: mild and moderate TBI will be defined as:
post-traumatic amnesia (PTA < 1 day for mild; 1 day> x < 7days for moderate). Because of the
extensively documented co-occurrence of TBI with PTSD, (Veterans with TBI with and without
PTSD will be enrolled). PTSD will be assessed using standard clinical measures. Exclusionary
criteria: patients will be screened for TMS and MRI safety. The duration of the study will be
two years, with a 1.5 year enrollment period, and a final half-year of follow-up completion.
Following a preliminary telephone screen, Veterans will be scheduled for onsite informed
consent, screening, and baseline assessments. Using an electronic randomization form,
participants will be enrolled into two groups: active rTMS or sham rTMS. As this is a double
blind placebo controlled study, only the subject ID number is provided to the nurse
administrating the rTMS treatment. After randomization, the rTMS nurse will test the motor
threshold (MT) for rTMS. Each participant will be in the trial for a total of approximately
(28) weeks: 1-2 weeks screening, (2) weeks acute treatment phase (including MRI pre and post
rTMS) and 24 weeks (6 month) follow-up phase (with MRI, neuropsychological testing and
self-report measures). Left Dorsolateral Prefrontal Cortex (DLPFC) will be the stimulation
site as it is shown to be affective in treatment of depression and approved by FDA. All
participants will receive a minimum of 20 treatments before being evaluated for change in
executive function (primary outcome measure).

The primary hypothesis is that Veterans receiving active rTMS will show improvement more than
sham treated Veterans in (performance between baseline and last assessment of >1 SD on either
the Trail Making Test part B, Delis-Kaplan Executive Function System [D-KEFS] Verbal Fluency
and/or D-KEFS Color-Word Interference Test). Additional analysis will include: Sustained
Improvement on executive function composite score; secondary consequences of TBI scores on
Quality of Life (QOL) scale, moderators of response such as age, severity of symptoms at
baseline, type of comorbidity (e.g., PTSD); and, functional brain activity changes with rTMS
treatment. This pilot study will be one of the first to demonstrate rTMS as a treatment for
executive function deficit in Veterans with mild to moderate TBI. Additionally, it would also
report on the efficacy of using functional MRI (fMRI) as a biomarker to capture this
improvement in executive function.

Inclusion Criteria:

- Veteran of any combat era

- Both Genders

- 20-65years

- (History of (Post Traumatic Amnesia < 1 day for mild TBI; 1 day> x < 7days for
moderate TBI))

- Ability to obtain a Motor Threshold (MT) will be determined during the screening
process.

- If on a psychotropic medication regimen, that regimen will be stable for at least 4
weeks prior to entry to the study and patient will be willing to remain on a stable
regimen during the acute treatment phase.

- Has an adequately stable condition and environment to enable attendance at scheduled
clinic visits.

- For female participants, agrees to use one of the following acceptable methods of
birth control: abstinence, oral contraceptive; Norplant

- Able to read, verbalize understanding, and voluntarily sign the Informed Consent Form
prior to participating in any study-specific procedures or assessments.

Exclusion Criteria:

- Pregnant or lactating female.

- Unable to be safely withdraw, at least two-weeks prior to treatment commencement, from
medications that substantially increase the risk of having seizures

- Have a cardiac pacemaker or a cochlear implant

- Have an implanted device (deep brain stimulation) or metal in the brain (see standard
MRI exclusion criteria including metal screening section in telephone screen, Appendix
A).

- Have a mass lesion, cerebral infarct or other active central nervous system (CNS)
disease, including a seizure disorder.

- Known current psychosis as determined by DSM-IV coding in chart (Axis I, psychotic
disorder, schizophrenia) or a history of a non-mood psychotic disorder.

- Diagnosis of Bipolar Affective Disorder (as determined by chart review and intake
interview)

- Current amnesic disorders, dementia, mini mental state examination (MMSE) 24 or
delirium.

- Current substance abuse (not including caffeine or nicotine) as determined by positive
toxicology screen, or by history via AUDIT, within 3 months prior to screening

- Prior history of seizures

- Severe TBI or open head injury

- TBI within last two months or in acute stage

- Participation in another concurrent clinical trial

- Patients with prior exposure to rTMS/ECT

- Active current suicidal intent or plan. Patient at risk for suicide will be required
to establish a written safety plan involving their primary psychiatrist and the
treatment team before entering the clinical trial