Monoaminergic Modulation of Motor Function in Subacute Incomplete Spinal Cord Injury (SCI)

This is a phase I double blinded randomized control clinical trial. The procedures for
participation in both Aims of the study are described below in chronological order.

Aim 1 and 2: Explanation of the consent form and study procedures/protocol will be performed
in the Neurolocomotion laboratory (room 1382), with subjects and their families provided
ample time for questions. Subjects are provided substantial time to choose to participate,
and are provided the laboratory phone numbers/emails to contact the PI and research
personnel with any potential questions. In situations where the subject is unable to be
transported to the laboratory, the PI will explain the consent form at a time and location
convenient for the subject and/or their family. Subjects will then undergo a screening
procedure to determine if they are eligible to participate in the study based on
inclusion/exclusion criteria.

Aim 1:

Modified Ashworth scale (mod Ash, no units) will be used to detect velocity-dependent
resistance to passive muscle stretch/joint rotation. The modAsh will grossly assess
spasticity at bilateral knee extensors and knee flexors, with scores from 0-5 (1+ scores
will be converted to 2 and higher scores increased accordingly).

Spinal Cord Assessment Tools for Spasticity (SCATS, no units) will be employed to assess
flexor and extensor spasms and clonic activity of the plantarflexors (Benz et al. , 2005).

Independence in walking ability will be assessed at each assessment period using the Walking
Index for SCI II (WISCI II, which is a 21 point (0-20) ordinal scale which assigns a score
based on amount of physical assistance, bracing, and assistive device used to ambulate.
Notably, subjects will not be allowed to ambulate with braces extending above the knee. Six
minute walk test (m) will be assess walking around a continuous hall-way at subjects'
self-selected velocity, with distance determined each minute and summed over the entire six
minute duration (van Hedel et al. , 2005). Subjects will be asked to "walk at your (their)
normal, comfortable pace" with minimal physical assistance and bracing/devices as needed
This measure is significantly association with measures of community walking in subjects
with incomplete SCI (Saraf et al. , 2009).

BERG balance test will be administered. Gait Mat testing will be performed to guage
spatiotemporal aspects of walking. 6 minute walk test will be performed. Lower Extremity
Motor Score, Peak treadmill speed (m/s)

Aim 2:

Same as above including strength evaluations : Ankle, knee, hip flexors/extensors tested
bilaterally (Biodex®).

Subjects in Aim 2 will be tested at initial evaluation, after four weeks of initial
training, and will be repeated after each four weeks of training on either the placebo or
study medication.

Subjects in Aim 2 will additionally be requested to return for follow up testing after one
year.

Subjects will be offered to participate in audio, videotaping and/or photography.

Women who are of childbearing age and are contemplating becoming pregnant will be required
to submit a pregnancy test and must notify the principal investigator immediately.

Inclusion Criteria:

A) Subjects with motor incomplete SCI (AIS C or D) of 1-9 mo. duration will be selected,
with anatomical lesions between C1-T10.

B) Subjects will be between 18 and 75 years of age . Note: grant application states 16-75,
however, we will be only including subjects 18-75.

C) All subjects must be previously ambulatory with passive range of motion consistent with
normal walking, and must include: ankle dorsiflexion ankle to 10° and plantarflexion to
30°, knee flexion from 0 to 90°, hip flexion/extension to 90° - -10°.

D) Subjects will be medically stable with medical clearance to participate, with absence
of concurrent severe medical illness, including unhealed decubiti, existing infection,
significant cardiovascular or metabolic disease which limits exercise participation,
significant osteoporosis (as indicated by history of fractures following injury), active
heterotrophic ossification in the lower extremities, known history of peripheral nerve
injury in lower legs, history of known traumatic head injury, and history of pulmonary
complications, including significant obstructive and/or restrictive lung diseases.

E) Individuals who are undergoing concurrent physical therapy will not be excluded from
the study population, secondary to the use of the cross-over design. Physical therapy
records will be obtained to ascertain the amount and types of physical therapy services
being provided.

F) Women of childbearing potential will not be excluded, although women who are pregnant
or who are considering becoming pregnant will be excluded due to the trunk and pelvis
restraints required for use during locomotion, and secondary to the unknown effects of the
pharmacological agents on the developing fetus.

G) Patients with known liver, renal, or other metabolic disease that may interfere with
drug action and/or clearance will be excluded from the proposed study. These complications
will be partially obviated by requiring all patients to undergo specific medical
procedures (liver function tests, urinalysis) prior to admission.

H)Men and women will be recruited for participation in the proposed clinical trial at
rates consistent with national and local average of gender disparities of SCI (80% male,
20% women). Women of childbearing potential will not be excluded, although women who are
pregnant or who are considering becoming pregnant will be excluded due to the trunk and
pelvis restraints required for use during locomotion, and secondary to the unknown effects
of the test agent (SSRIs) on the developing fetus. Women who use oral contraceptives will
not be assessed for TIZ experiments and will be excluded from Aim 1.

I) Individuals of different ethnicities will be recruited at rates similar to the national
and local ethnicity rates. Current data since 2005 indicate that of the entire population
of SCI, 66.1% are Caucasian, 27.1% are African American, 6.6% are of Hispanic origin, and
2.0% are Asian. These populations closely resemble those at RIC and in our previous
studies in human SCI.

Exclusion Criteria:

A) Subjects who are ventilator-dependent will be excluded secondary to severely impaired
respiratory capacity.

B) Subjects with substantial orthopedic bracing to stabilize the cervical or thoracic
vertebral column and are unable to fit in the safety harness without increased risk of
injury are not eligible.

C) Patients will also be excluded if they are unable to tolerate 10 minutes of standing
without orthostasis (decrease in blood pressure by 20 mmHg systolic and 10 mmHg
diastolic); previous experience in the sub-acute population suggests that 10 minutes of
standing is more than sufficient for tolerating 45 minutes of walking secondary to
increased activity/muscle pump minimizing risk for orthostasis.

D) Women who are pregnant or who are considering becoming pregnant will be excluded due to
the trunk and pelvis restraints required for use during locomotion, and secondary to the
unknown effects of the pharmacological agents on the developing fetus.

E) Subjects with height and weight limitations which restrict participation in Lokomat
Training(LT) will be excluded. For height, subjects who are > 78 inches or < 60 inches
tall may present with thigh/shank lengths that may limit use of the Lokomat. If subjects
are not able to step independently on the treadmill and require use of robotic-assistance
during treadmill stepping, attempts to fit all subjects in the robotic orthosis prior to
enrollment and randomization. For weight, the maximum weight limit for use of the safety
harness/counterweight system is 300 lbs.

F) Individuals with concurrent severe medical illness, including unhealed decubiti,
existing infection, significant cardiovascular or metabolic disease which limits exercise
participation, significant osteoporosis (as indicated by history of fractures following
injury), active heterotrophic ossification in the lower extremities, known history of
peripheral nerve injury in lower legs, history of known traumatic head injury, and history
of pulmonary complications, including significant obstructive and/or restrictive lung
diseases will be excluded.

G) Patients prescribed other anti-depressant medications, including specific monoaminergic
agents, their precursors or their agonists, or other medications with known interactions
to the SSRIs or TIZ will be excluded. With consultation and supervision of the patients'
physician and the attending physicians for each individual patient, subjects will be
required to wean of their medications on an appropriate and safe dosing schedule to
minimize side effects of drug cessation or withdrawal. All subjects will be excluded from
participation unless both attending physician and patient agree to cease all such
medications during the evaluation and training period. A 14-day washout period for SSRIs
and a 72 hour washout for TIZ will be utilized.

H) All subjects prescribed anti-spastic medications will be excluded. Specific agents to
be excluded include baclofen (Lioresal®) and benzodiazepines (Diazepam®). Selected agents
used for pain modulation will be evaluated per subject to ascertain potential interactions
with test agent. With consultation and supervision of the patients' physician and the
attending physicians for each individual patient, subjects will be required to wean of
their medications on an appropriate and safe dosing schedule to minimize side effects of
drug cessation or withdrawal. All subjects will be excluded from participation unless both
attending physician and patient agree to cease all such medications during the evaluation
and training period. A 72-hour minimum washout period for all such medications will be
utilized. (Note: exception to use of TIZ during training - see above).

I) Women of childbearing potential will not be excluded, although women who are pregnant
or who are considering becoming pregnant will be excluded due to the trunk and pelvis
restraints required for use during locomotion, and secondary to the unknown effects of the
test agent (SSRIs) on the developing fetus. Women who use oral contraceptives will not be
assessed for TIZ experiments and will be excluded from Aim 1.