Mechanisms of Neuromuscular Fatigue Post Stroke

Completed

Phase 0 Results N/A

Trial Description

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.

Conditions

Interventions

  • Placebo Drug
    Intervention Desc: Single dose, orally, 6 hours prior to the start of the respective testing session. Subjects take a single dose once.
    ARM 1: Kind: Experimental
    Label: Duloxetine
    Description: Neuromuscular fatigue testing with duloxetine dose
    ARM 2: Kind: Experimental
    Label: Cyproheptadine
    Description: Neuromuscular fatigue testing with cyproheptadine dose
    ARM 3: Kind: Experimental
    Label: Placebo
    Description: Neuromuscular fatigue testing with placebo dose
  • Duloxetine Drug
    Other Names: Cymbalta
    Intervention Desc: Single dose, orally (pill), 30 mg, taken 6 hours prior to start of the testing session. Subjects will only take a single dose of duloxetine once.
    ARM 1: Kind: Experimental
    Label: Duloxetine
    Description: Neuromuscular fatigue testing with duloxetine dose
    ARM 2: Kind: Experimental
    Label: Cyproheptadine
    Description: Neuromuscular fatigue testing with cyproheptadine dose
  • Cyproheptadine Drug
    Other Names: cyproheptadine hydrochloride USP; cyproheptadine HCl; Periactin
    Intervention Desc: Single dose, orally, 8 mg, 6 hours prior to the start of the respective testing session. Subjects will take a single dose of cyproheptadine once.
    ARM 1: Kind: Experimental
    Label: Duloxetine
    Description: Neuromuscular fatigue testing with duloxetine dose
    ARM 2: Kind: Experimental
    Label: Cyproheptadine
    Description: Neuromuscular fatigue testing with cyproheptadine dose

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Investigator)
  • Purpose: Basic Science
  • Intervention: Crossover Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Force generation At time of each of 4 testing sessions (all sessions within a 2 year period). No
Secondary Surface electromyography (EMG)of lower leg muscles. EMG measurements will be made during each of the four sessions. No

Sponsors