While baseline weakness is clearly an important factor that contributes to disability post
stroke, neuromuscular fatigue (the acute reduction in force production) of the paretic
musculature likely compounds strength deficits and further exacerbates disability. The
proposed study aims to improve our understanding of the mechanisms of neuromuscular fatigue
in people post stroke in order to optimize strength training. In healthy individuals, both
central (neural) and peripheral (muscle) factors are determinants of neuromuscular fatigue,
but preliminary data from our laboratory suggests a greater contribution of central
components to neuromuscular fatigue in the paretic musculature. Although cortical pathways
are clearly disrupted post stroke, it is likely that brainstem pathways, known to have
neuromodulatory effects on spinal motor circuitry, are more involved in the sustaining of
force in the paretic leg, compared to the non-paretic and control legs. Therefore, the
purpose of this proposal is to examine the role of descending neuromodulatory pathways of the
brainstem in neuromuscular fatigue post stroke (Aim 1) and to correlate brainstem-related
changes in neuromuscular fatigue to walking function (Aim 2). The investigators propose that
stroke survivors' decreased capability to sustain force overtime results from the diminished
ability of spinal motoneurons to respond to brainstem neuromodulatory inputs (serotonin
(5-HT) and norepinephrine (NE)). Aim 1 will quantify stroke-related decreases in motor output
sensitivity to a 5-HT and NE reuptake inhibitor (SNRI), serotonin antagonist, or placebo
during sub-maximal intermittent fatiguing knee extension contractions. If motoneurons are
desensitized to descending monoamines in chronic stroke patients, then they will be less
sensitive to the effects of drugs that increase monoamine levels. The investigators predict
that in response to the SNRI or serotonin antagonist, the paretic leg will show less change
in time to task failure and a smaller reduction in strength as compared to the non-paretic
and control legs. For Aim 2, the investigators predict that stroke subjects with the highest
walking function will demonstrate the greatest fatigue-related changes in response to the
SNRI. This proposal adopts an innovative model of motor impairment post stroke by including
the role of subcortical structures in neuromuscular fatigue.