Molecular Markers of Neuroplasticity During Exercise in People With Incomplete Spinal Cord Injury

The protein brain-derived neurotrophic factor (BDNF) is known to promote cell survival,
improve synaptic function, and induce neuronal morphological changes. Consequently, BDNF
plays a major role in neuroplasticity and the ability of the central nervous system to adapt
and recover following injury. Regardless of the molecular mechanisms by which this occurs
(which are poorly understood), potentiating the expression of BDNF following spinal cord
injury has been shown to improve functional outcomes in animals.(1, 2) It is well documented
in both animal and human literature that the production BDNF increases with physical exercise
in healthy populations and individuals with chronic disease or disability. (3) The literature
suggests that this increase is proportional to the intensity of exercise, though the
parameters of exercise to maximize this effect are poorly understood. (2, 4-6) From animal
research, it has been postulated that serotonin (5HT) plays a role in the mechanism of
increase in BDNF expression, (7-9) with findings that specifically demonstrate potentiation
of the exercise-induced expression with antidepressant treatment(10)and a blunted response
when monoaminergic signaling is blocked.(11) A specific genetic variation in the BDNF gene,
found in approximately 30% of the population has also been noted as an important factor in
the proper release of BDNF with associated deficits in motor learning. (12, 13) Initial
evidence also suggests that this polymorphism may have an impact of the relationship between
exercise and BDNF. (14, 15) The objective of this study is the evaluate the response of serum
concentrations of brain-derived neurotrophic factor ([BDNF]s) to an acute bout of exercise in
ambulatory people with incomplete spinal cord injury; additionally, to examine the effect of
pharmacological agents that alter serotonergic (5HT) transmission on this exercise-induced
change in [BDNF]s. To achieve this objective we will investigate [BDNF]s during a treadmill
test alone and in combination with two commonly used medications; escitalopram oxalate , a
selective-5HT reuptake inhibitor (SSRI) and cyproheptadine (CYPRO), a 5HT antagonist.

Studies have also shown a relationship of BDNF to mood, in particular, depression. A
secondary study will be performed in parallel with the primary study with the purpose of
examining mood and how it correlates with the molecular markers for neuroplasticity as
individuals participate in the repeated exercise and the other stated interventions. As the
subjects progress over the course of the study time mood may change and may impact the
relationship of the BDNF to the primary interventions.

Inclusion Criteria:

- Must be motor incomplete spinal cord injury (ASIA C or D) of 1 year or greater
duration, with anatomical lesions between C1-T10

- Must be between 18 and 75 years of age

- Must be 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° to -10°.

- Must 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, mental
illness, history of pre-existing QT interval prolongation, congenital long QT
syndrome, and history of pulmonary complications, including significant obstructive
and/or restrictive lung diseases

- May be undergoing concurrent physical therapy

- May be of childbearing potential (for women)

- Men and women will be recruited for participation in the proposed study at rates
consistent with national and local average of gender disparities of SCI (80% male, 20%
women)

- 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.

Exclusion Criteria:

- Weighing more than 300lbs

- Ventilator-dependency

- Use of substantial orthopedic bracing to stabilize the cervical or thoracic vertebral
column

- Inability to tolerate 10 minutes of standing without orthostasis (decrease in blood
pressure by 20 mmHg systolic and 10 mmHg diastolic).

- 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

- Exhibiting symptoms suggestive of depression according to the Personal health
Questionaire (PHQ-9)

- Subjects who exhibit hemoglobin levels consistent with anemia (<13g/dL for men and
<12g/dL for women) will be excluded from the study.

- Currently taking prescribed anti-depressant medications, including specific
monoaminergic agents, their precursors or their agonists, antipsychotics, medications
known to prolong the QT interval, or other medications with known interactions to the
SSRIs. 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
Tizanidine will be utilized. Subjects will be financially responsible for the
physician visits necessary to wean from medication. Completion of appropriate and safe
weaning will be confirmed by the patients' physician.

- Currently taking prescribed anti-spastic medications. 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. 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. Subjects will be financially responsible for the physician visits necessary
to wean from medication. Completion of appropriate and safe weaning will be confirmed
by the patients' physician.

- Clinically diagnosed liver, renal, or other metabolic disease that may interfere with
drug action and/or clearance