rTMS: A Treatment to Restore Function After Severe TBI

The specific aims (SA) of the CDMRP study are:

SA-1: To determine presence, direction and sustainability of rTMS induced neurobehavioral
effects using the DRS (lower scores indicate more function).

SA-2: To determine presence, direction and sustainability of rTMS-induced changes in
functional neural activation and whether these changes correlate with improving
neurobehavioral function.

SA-3: To determine the rTMS effect on white fiber tracts and whether rTMS-related effects
correlate with neurobehavioral gains. White fiber tracts will be examined according to
changes in Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD), and
Axial Diffusivity (AD).

SA-4: To confirm rTMS safety for severe TBI. The investigators hypothesize that there will
be no difference between active and placebo groups according to average number of research
related adverse events (AE) during treatment.

To accomplish these aims, the investigators will conduct a double blind, randomized, placebo
controlled clinical trial where 58 persons remaining in states of disordered consciousness
for 3 to 12 months after TBI are randomized to the active rTMS group or the placebo rTMS
group.

The primary outcome is neurobehavioral recovery slope as measured by the total Disability
Rating Scale (DRS), which will be collected weekly at bedside between Endpoints 1 (15th rTMS
Session) and 2 (30th rTMS Session). The DRS will be collected weekly via telephone interview
for the three weeks between Endpoint 2 and Endpoint 3 (3 weeks after 30th rTMS session).
Secondary outcomes include four measures of functional neural activation: task related
functional magnetic resonance imaging (fMRI), functional connectivity MRI (fcMRI), EEG-Rest
and EEG-Task. The functional neural activation measures will be collected at baseline,
Endpoint 2 and Endpoint 3. Motor Threshold Testing and Neurobehavioral measures in addition
to the DRS and physical measures will also be collected as secondary outcomes. Motor
Threshold testing, neurobehavioral and physical measures will be collected at baseline,
Endpoint 1, Endpoint 2 and Endpoint 3. The additional Neurobehavioral and physical measures
are the Disorders of Consciousness Scale-25 (DOCS-25), Coma Recovery Scale Revised (CRS-R),
Coma Near Coma Scale (CNC), Modified Tardieu Scale, Modified Ashworth Scale, Spaulding Limb
Movement Protocol and the Consciousness Screening Algorithm.

Inclusion Criteria:

- At study screening, persons have remained in states of Seriously Impaired
Consciousness (SIC) for at least 3 and up to 12 months after TBI

- 18 years of age or older

- Traumatic Brain Injury etiology

- Able to participate in all phases of study including follow-up re-admission

- Able to identify legally authorized representative/surrogate who is able to read and
understand informed consent document and provide written consent

Exclusion Criteria:

- Primary injury is a non-traumatic brain injury (and is not secondary to TBI) (e.g.,
inflammatory, infectious, toxic and metabolic encephalopathies, anoxia, cancer,
ischemic and hemorrhagic stroke)

- History of TBI, psychiatric illness (DSM criteria) and or organic brain syndrome
(e.g. Alzheimer's)

- Left dorsal lateral pre-frontal cortex (DLPFC) is not accessible (e.g., left frontal
lobectomy)

- Incurred large cortically based ischemic infarction subsequent to TBI (size is
determined collectively by neurosurgeon, neurologist, neuroradiologist and principal
investigator)

- At study screening, patient is receiving anti-epileptic medications to control active
seizures

- Have had a documented seizure within 3 months of study screening

- Are ventilator dependent at time of study screening

- Have recovered full consciousness at time of study screening as indicated by a Motor
Function scale score of 6 and/or a Communication scale score of 2 on the CRS-R

- Receiving central nervous system (CNS) stimulants that cannot be safely discontinued
via titration

- Patient did not speak English prior to injury (bedside testing is conducted in
English)

- Pregnant

- Have implanted cardiac pacemaker or defibrillator, cochlear implant or nerve
stimulator

- Have MRI or TMS contraindications such as pre-injury claustrophobia, metal in
eyes/face or brain

- Other medical conditions, that in investigator's opinion, would preclude subject from
completing study