High Intensity Exercise in Incomplete SCI

Background/Readiness: The objective of this proposal is to maximize locomotor outcomes of
patients following incomplete spinal cord injury (iSCI) through identification of
rehabilitation strategies that maximize recovery. Specific training parameters, such as
provision of large amounts of stepping, appears to facilitate locomotor function in patients
with iSCI, although other factors may be critical. In this proposed phase II randomized
clinical trial, the overarching hypothesis is that the "intensity" of locomotor practice,
defined as power output and estimated using cardiopulmonary measures, is critical to
maximizing walking outcomes. Performance of high intensity locomotor training increases the
cardiovascular and neuromuscular demands, which results in physiological changes that
facilitate greater locomotor performance in individuals with and without neurological injury.
There are, however, limited data supporting its utility in patients with iSCI. Recent
findings suggest a role for high-intensity stepping training in variable contexts, with gains
in peak locomotor capacity as compared low-intensity variable training. Additional changes in
cardiopulmonary function and neuromuscular coordination provide a mechanistic rationale for
the utility of this strategy. Such changes are likely due to increased central (volitional)
activation, and are in sharp contrast to the long-standing notion that high intensity
training impairs motor function in neurological injury.

Despite these data, genotypic variations suggest specific caveats related to high intensity
training. For example, many patients possess a single nucleotide polymorphism (SNP) variation
in the brain derived neurotrophic factor (BDNF) gene that may impact the activity-dependent
BDNF expression thought to contribute to neuroplasticity underlying improved performance.
This single nucleotide polymorphism (SNP) can influential declarative memory, with recent
data suggesting a potential impact on motor recovery after neurologic injury. Previous
studies indicate limited BDNF increases in patients with this SNP during high intensity
exercise, although the effects of locomotor recovery with repeated high-intensity training is
unclear Hypothesis/Specific Aims: The primary hypotheses are that high intensity variable
stepping can markedly improve locomotor performance as well as neuromuscular and
cardiopulmonary function as compared to lower-intensity training in patients with chronic
motor iSCI. It is believed that genotypic variations in the ability to synthesis activity
dependent BDNF may modify the effects of high intensity training. Specific Aim 1: Test if
high intensity stepping training in variable contexts results in greater locomotor gains as
compared to lower intensity interventions. Specific Aim 2: Test the effects of these training
strategies on neuromuscular and cardiopulmonary impairments. Specific Aim 3: Test the effects
of the presence of the BDNF SNP on locomotor improvements in patients following
high-intensity activities Study Design: This phase II, stratified, assessor- blinded
randomized clinical trial will assess the effects 2 months (up to 30 sessions) of high- vs
low-intensity variable stepping training on ambulatory patients with chronic (> 1year) motor
iSCI. Participants referred from outpatient therapy settings will undergo evaluation of
locomotor performance, cardiopulmonary capacity, and neuromuscular coordination and
impairments prior to and following each training paradigm, with 2-month follow-up
assessments.

Clinical Impact: The application of high-intensity locomotor training in the clinical
rehabilitation of patients with iSCI is extremely limited, despite data regarding the
potential benefits in neurological intact individuals and patients with stroke. The clinical
application of high-intensity training represents a simple, readily modified training
parameter that can be readily implemented, and is in stark contrast to current clinical
practice and challenge traditional dogma in rehabilitation medicine.

Inclusion criteria

- Individuals with motor incomplete SCI (AIS C or D) > 12 mo. duration will be recruited
to participate in the study, with further criteria including anatomical lesions
between C1-T10..

- Participants will be between 18 and 75 years of age (note: while participants > 50 yrs
with subacute SCI have a reduced probability of functional ambulation 79, participants
will already be ambulatory with only minimal or no assistance and in the chronic phase
of rehabilitation, and prediction rules using age will not necessarily apply in this
study).

- All participants must be able to perform walking training with passive range of motion
within the limits of normal locomotor function, including: 0-30 degrees ankle
plantarflexion, knee flexion from 0 to 90 degrees, hip flexion to 0-90 degrees.

Exclusion criteria:

- Participants with body mass > 400 lbs will be excluded, which is the highest limit for
use of our motorized treadmill and safety harness systems.

- Participants 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 traumatic brain injury,
and history of pulmonary complications that limits exercise capacity, including
significant obstructive and/or restrictive lung diseases.

- Participants who are ventilator-dependent will be excluded secondary to severely
impaired respiratory capacity.

- Participants with substantial orthopedic bracing to stabilize the cervical or thoracic
vertebral column are not eligible due to safety concerns with harness supported
ambulation training..

- 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.

- Individuals who are undergoing concurrent physical therapy will be excluded from the
study population to eliminate confounding effects of additional physical
interventions, Other therapies, such as occupational or speech therapies, will be
allowed as prescribed by their physician. Individuals will be allowed and encouraged
to continue their normal exercise routines during the course of the intervention, with
activity monitors measuring stepping activity in all participants

- 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.

- All subjects prescribed oral anti-spastic medications will not be excluded, although
patients with intrathecal baclofen pumps or history of recent (< 3 months) botulinum
toxin injection in the lower extremities will be excluded due to potential increases
in weakness interfering with the effects of stepping training performance.

- Patients with a known history of autonomic dysreflexia will not be excluded, although
specific signs and symptoms of all patients with history of injury > T6 anatomical
level will be closely monitored throughout training.

Other criteria

- 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.

- 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% Asian. These populations closely resemble those at RHI and
in our previous studies in human SCI.