Transcranial Magnetic Stimulation (TMS) to Treat mTBI and PTSD

The primary objectives of this study are:

1. To assess the change on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and
the PTSD Check List—Civilian Version (PCL-C) administered pre-treatment, then bi-weekly
(weeks 2, 4, 6) during a 7 week treatment course, then monthly for 3 months following
treatment.

Hypothesis: The addition of high frequency left pre-frontal and low frequency right
pre-frontal cortical stimulation will improve symptom reporting on the RPQ and PCL-C in
service members with mTBI and PTSD symptoms as compared to sham treatment.

2. To assess the tolerability of TMS in subjects as measured by side effects in active TMS
compared with sham treatment.

Hypothesis: TMS will prove safe and tolerable in service members with mTBI and PTSD.

The secondary objectives of this study are:

1. To assess whether TMS results in an improvement in mood as measured by the Quick
Inventory of Depressive Symptomatology - Self Report (QIDS-SR), general life
functioning (physical, cognitive, emotional, behavioral, and social problems) as
measured by the Mayo-Portland Adaptability Inventory - military (MPAI-m), life
satisfaction as measured by the Satisfaction With Life Scale (SWLS), and suicidality as
measured by the Beck Scale for Suicidal Ideation (BSS).

Hypothesis: TMS will result in an improvement in mood, general life functioning, and
life satisfaction, as well as a reduction in suicidality.

2. To assess the durability of any improvement realized by TMS over the course of three
months following the conclusion of sessions.

Hypothesis: The improvement realized by 7 weeks of TMS will prove stable, showing
effects up to 3 months after the conclusion of active treatment.

3. To assess structural neuronal changes over the course of active vs. sham TMS as
measured by MRI.

Hypothesis 1: Analysis of structural MRI (3D T1-weighted) will reveal increased volume
of the hippocampus and anterior cingulate cortex in service members who improve in PTSD
symptoms (as measured by the PCL-C).

Hypothesis 2: Microstructural MRI (DTI) will reveal FA increase in the corpus callosum
and the uncinated fasciculus in service members who improve in measures of mTBI (i.e.,
Rivermead Post Concussion Symptoms Questionnaire).

4. To assess metabolic neuronal changes that occur over the course of active vs. sham TMS
as measured by PET.

Hypothesis 1: TMS will result in increased glucose uptake in the ipsilateral and
contralateral cerebral hemispheres for those who show significant improvements in the
symptomatic measures of TBI (i.e. RPQ and MPAI-m).

Hypothesis 2: TMS will result in decreased glucose uptake in the dorsal anterior
cingulate/mid cingulate cortex (dACC/MCC) and in the bilateral amygdala for those
service members with significant improvements in the symptomatic measures of PTSD and
mood (i.e. PTSD Checklist and QIDS-SR).

5. To examine the mechanism of action of TMS through looking at the metabolic changes that
occur during a TMS session.

Hypothesis: There will be increased glucose uptake in the left prefrontal cortex and
decreased glucose uptake in the right prefrontal cortex immediately after active TMS as
compared to sham.

6. Exploratory: To assess biological changes that result from TMS therapy and to determine
how biomarkers relate to changes in PTSD symptoms.

7. Exploratory: To examine how single gene polymorphisms (SNPs) in serotonin genes may
relate to TMS response and symptom change.

Inclusion Criteria:

1. Military health care beneficiary for enrollment (loss of benefits will not require
separation from the study).

2. Over the age of 18 years.

3. Presence of mTBI (based on standard Veterans Affairs (VA)/ Department of Defense
(DoD) criteria).

4. Presence of PTSD symptoms (PCL score over 30).

Exclusion Criteria:

1. Evidence of moderate or severe TBI (based on standard VA/DoD criteria). Incidental
neuroimaging findings that may or may not be related to trauma (e.g. white matter
hyperintensities on structural MRI) are not sufficient to identify a subject as a
moderate TBI if other severity markers fall in the mild TBI range.

2. History of seizure, bipolar disorder, schizophrenia, or current dependence to
psychoactive substance(s).

3. History of severe or recent heart disease.

4. Vascular, traumatic, tumoral, infectious, or metabolic lesion of the brain.

5. Use of medications that potentially lower seizure threshold without concomitant
administration of anticonvulsant drugs which may protect against seizure occurrence.

6. Not a suitable candidate for the study as determined by the PI.

7. Pregnancy or plans to become pregnant during the course of the study (determined via
urine-pregnancy test).

8. Presence of metallic hardware in close contact to the discharging coil (e.g. cochlear
implants, internal pulse generator).

9. Presence of implanted brain electrodes (cortical or deep-brain electrodes).

10. MRI portion: Presence of metal fragments or devices (cardiac pacemaker, neural
stimulator, etc.), which are determined by a radiologist to contraindicate MRI (at 3
Tesla). Also, presence of metal (such as dental braces) which causes significant
degradation of the MRI signal.