The Brave Initiative: Bringing Rehabilitation to American Veterans in an Enriched Environment

The proposed project is a prospective, randomized, controlled, single-blind study comparing
the motor improvements resulting from Constraint-Induced Movement Therapy (CIMT) and
Lakeshore Enriched Fitness Training (LEFT) for traumatic brain injury (TBI) in veterans and
civilians. Over the course of two years, there will be a total of 80 subjects randomly
assigned to 4 conditions. Treatment, testing, and follow-up testing will be carried out in
the first 3 grant years and the 1-year follow-up will be completed in the fourth year.
Clinical testing will be conducted at pre-treatment, post-treatment, and 1-year follow-up.
Longitudinal neuroimaging studies to determine the treatment change in white matter, grey
matter, and functional brain connectivity will be carried out across the above-noted time
points by different diffusion tensor imaging (DTI) analysis variants, voxel-based morphometry
(VBM) analysis of structural magnetic resonance imaging (MRI) scans, analysis of resting
state functional MRI (fMRI), and analysis of fMRI during hand movement.

The 80 study participants will be randomly assigned in equal numbers to 1 of 4 arms: CIMT
with Standard Transfer Package (sTP), CIMT with Enhanced Transfer Package (eTP), LEFT with
sTP or LEFT with eTP. Forty volunteers will be tested on average per year. The patients will
be classified into mild/moderate (Grade 2) and moderate motor deficits (Grades 3); a
classification made at the impairment level based on standard active range of motion (AROM)
criteria (further elaborated in "Eligibility Criteria").

The primary clinical outcome will be pre- to post-treatment change in a measure of use of the
more-affected arm in daily life known as the Motor Activity Log. It is described in the
outcomes section. As noted above, the response of the brain to the interventions will be
examined using structural grey matter MRI analysis, DTI, and fMRI during resting state and
during arm movement.

Each participant will have the option of being accompanied by a caregiver (travel and living
expenses paid for by the project). The caregiver will be asked to complete the MAL
independently of the participant. The same questionnaire administered to the patient will be
administered to the caregiver. In addition, the caregiver will be shown how to help the
patient carry out the home practice exercises so that they can do this during treatment and
afterwards (if they remain in close contact with the participant).

Inclusion Criteria:

- Motor criteria will be made using an impairment-level system for characterizing the
severity of an upper-extremity (UE) motor deficit based on Active Range of Motion (AROM).
All UE motor criteria determinations will be made with the subject sitting. The
more-affected forearm will be resting on a supporting surface (e.g. arm of chair) to allow
for maximum wrist flexion with gravity. This study will treat patients at levels of Grade 2
(mild/moderate impairment) and Grade 3 (moderate impairment).

- The minimum motor criterion (MMC) for inclusion in Grade 3 (moderate impairment) will
be ability to:

- Extend against gravity at least 10 degrees at the wrist from a fully flexed
starting position

- Extend two or more fingers at least 10 degrees at the metacarpophalangeal (MP)
joint and either the proximal or distal interphalangeal (IP) joints

- Extend or abduct the thumb at least 10 degrees

- Extend the elbow at least 20 degrees from a 90 degree flexed starting position

- Flex and abduct the shoulder at least 45 degrees

- The MMC for inclusion in Grade 2 (mild/moderate impairment) will be ability to:

- Extend against gravity at least 20 degrees at the wrist from a fully flexed
starting position

- Extend all fingers at least 10 degrees at the MP joint and either the proximal or
distal IP joints

- Extend or abduct the thumb at least 10 degrees

- Extend the elbow at least 20 degrees from a 90 degree flexed starting position

- Flex and abduct the shoulder at least 45 degrees

- Additionally, subjects must have substantially reduced use of the extremity in the
activities of daily living as indicated by a score of less than 2.5 on the Motor
Activity Log (MAL).

Note: Each movement described above must be repeated 3 times in 1 minute.

Exclusion Criteria:

- Those < 3 months post-TBI.

- Excessive UE spasticity.

- Insufficient stamina to carry out the requirements of the therapy (based on clinical
judgment).

- Medication (including psychoactive substances) will not be exclusionary except in the
following cases: (If subjects are on other medications, the medications will be
recorded and the possible effect on treatment outcome will be analyzed separately)

- Participation in any experimental drug field study

- Botox injections to the more-affected UE less than 3 months prior to
participation

- Baclofen or Dantrium taken orally at the time of study

- Mini-Mental Status Exam (MMSE) score below 20.

- Concurrent participation in any formal physical rehabilitation program or clinical
trial.

- Excessive pain in any joint of the more-affected extremity that could limit ability to
cooperate with the intervention (based on clinical judgment).

- Serious, uncontrolled medical problems (e.g., cardiovascular, severe rheumatoid
arthritis, serious joint deformity of arthritic origin, symptomatic cancer or renal
disease, any kind of end-stage pulmonary or cardiovascular disease, uncontrolled
epilepsy) as judged by the Medical Director.

- Other neurological or musculoskeletal conditions affecting UE function.

- Unable to read or speak English.

- Inadequate communication skills, i.e., not able to reliably understand questions or
not able to express needs or report own behavior, to participate in study based on
clinical judgment.

- Substantial use of the more-affected arm in daily life as reflected by a Motor
Activity Log score > 2.5.

- Pain that interferes with use of the more-affected arm based on clinical judgment.

- A positive pregnancy test will exclude participants from MRI scanning, but would not
exclude them from clinical treatment.