Skeletal Muscle Properties and the Metabolic Cost of Walking Post-stroke

A guiding principle of the proposed research is that skeletal muscle is the building block of
all movement and, as such, muscle dysfunction can ultimately limit the gains possible from
rehabilitation intervention. Therefore, maximal gains will be made only when central nervous
system adaptations access peripheral muscle that is fully capable of supporting the increased
activity.

The primary hypothesis is that in persons with hemiparesis following stroke, alterations in
the metabolic properties of peripheral skeletal muscles, in combination with greater
mechanical work, contribute to the increased metabolic cost of walking. A secondary
hypothesis is that locomotor training induces adaptations in lower extremity skeletal muscle
resulting in improved mechanical and metabolic efficiency. In order to test these hypotheses,
the following three specific aims will be addressed:

Aim 1: Determine the in-vivo metabolic characteristics of the ankle plantar flexor muscles in
persons with chronic post-stroke hemiparesis and neurologically healthy individuals. In-vivo
muscle metabolic properties will be assessed via phosphorous magnetic resonance spectroscopy
(31P-MRS). Specifically, we will measure the resting phosphorylation potential as well as the
in-vivo oxidative capacity of the ankle plantar flexor muscles. We hypothesize that
individuals with chronic hemiparesis will exhibit reductions in oxidative capacity as well as
an increased resting phosphorylation potential relative to age-, gender-, height- and
weight-matched control subjects. We suggest these adaptations, which are characteristic of a
less energetically efficient muscle, contribute to an increased metabolic cost beyond that
resulting from potential increases in mechanical work performed by locomotor muscles.

Aim 2: Quantify metabolic cost as well as muscle mechanical energy expenditure during walking
in persons with chronic post-stroke hemiparesis and neurologically healthy individuals.
Post-stroke hemiparesis is associated with a variety of motor control problems that include
abnormal synergistic organization of movement as well as altered temporal sequencing of
muscle activity 5,10,11. Since muscle excitation during normal walking is believed to be very
efficient 8,9,33 it is likely that altered muscle coordination post-stroke, reflected in
increased mechanical work, is one factor contributing to the increased metabolic cost of
walking. We hypothesize that the metabolic cost of walking post-stroke will be elevated
relative to controls at matched speeds. Additionally, a measure of mechanical work, muscle
mechanical energy expenditure (MMEE), will be elevated post-stroke, reflective of
mechanically inefficient movement strategies and causal to a portion of the increased
metabolic cost of walking.

Aim 3: Determine the impact of 12 weeks of locomotor training on in-vivo muscle metabolic
properties, the metabolic cost of walking as well as MMEE in persons with chronic post-stroke
hemiparesis. There is emerging evidence that chronic neurologic deficits due to stroke can be
improved through intensive, repetitive task-oriented motor training (e.g. locomotor
training). The basis for locomotor training (LT) improvements is thought to involve
mechanisms of central neuroplasticity that are responsive to fundamental principles of motor
learning 37,38,39. In addition, our pilot data demonstrate that LT may also result in
peripheral adaptations in the plantar flexor muscles. Thus, the potential seemingly exists to
induce both central and peripheral adaptations with this intervention strategy. We expect
that LT will attenuate existing deficits, resulting in an increased oxidative capacity and a
decreased resting phosphorylation potential in ankle plantar flexor muscles. In addition, LT
will result in a reduced MMEE and a reduced metabolic cost of walking, reflective of improved
mechanical and metabolic efficiency. We believe it will prove important to describe
adaptations in walking mechanics as well as within peripheral muscle that occur following LT
and relate them to the metabolic cost of walking. In addition, continued deficits will
reflect a need for additional or adjunctive intervention strategies, thus providing
information on how to modify or augment future rehabilitation interventions in order to
improve individual outcomes.

Inclusion Criteria:

- age 18-80;

- stroke within past 6 months - 5 years;

- residual paresis in the lower extremity (LE) (Fugl-Meyer motor score <34);

- ability to sit unsupported for 30 sec;

- ability to walk at least 10 ft with maximum 1 person assist;

- self selected 10 meter gait speed < 0.8 m/s; and

- provision of informed consent.

Exclusion Criteria:

- Unable to ambulate at least 150 feet prior to stroke, or experienced intermittent
claudication while walking < 200 meters;

- history of congestive heart failure, unstable cardiac arrhythmias, hypertrophic
cardiomyopathy, severe aortic stenosis, angina or dyspnea at rest or during activities
of daily living;

- History of chronic obstructive pulmonary disease or oxygen dependence;

- Preexisting neurological disorders, dementia or previous stroke;

- History of major head trauma;

- Legal blindness or severe visual impairment;

- history of significant psychiatric illness;

- Life expectancy <1 yr;

- Severe arthritis or orthopedic problems that limit passive range of motion (ROM);

- post-stroke depression (PHQ-9 10);

- History of deep vein thrombosis (DVT) or pulmonary embolism within 6 months;

- Uncontrolled diabetes with recent weight loss, diabetic coma, or frequent insulin
reactions;

- Severe hypertension with systolic >200 mmHg and diastolic >110 mmHg at rest;

- Previous or current enrollment in a clinical trial to enhance motor recovery;

- Presence of non-magnetic resonance (MR) compatible implants or devices, pregnancy or
severe claustrophobia.