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Mechanisms of Neuromuscular Fatigue Post Stroke

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ClinicalTrials.gov Identifier: NCT01688570
Recruitment Status : Completed
First Posted : September 20, 2012
Last Update Posted : November 5, 2015
Information provided by (Responsible Party):
Phillip Nelson, MD, Medical College of Wisconsin

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Stroke Drug: duloxetine Drug: Cyproheptadine Drug: Placebo Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Mechanisms of Neuromuscular Fatigue Post Stroke
Study Start Date : August 2011
Actual Primary Completion Date : May 2015
Actual Study Completion Date : May 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fatigue

Arm Intervention/treatment
Active Comparator: Duloxetine
Neuromuscular fatigue testing with duloxetine dose
Drug: duloxetine
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.
Other Name: Cymbalta

Active Comparator: Cyproheptadine
Neuromuscular fatigue testing with cyproheptadine dose
Drug: Cyproheptadine
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.

Placebo Comparator: Placebo
Neuromuscular fatigue testing with placebo dose
Drug: Placebo
Single dose, orally, 6 hours prior to the start of the respective testing session. Subjects take a single dose once.

Primary Outcome Measures :
  1. Force generation [ Time Frame: At time of each of 4 testing sessions (all sessions within a 2 year period). ]
    Sub-maximal and maximal force measurements will be made during brief contractions during each of the four testing sessions. All sessions will occur at least one week apart and within a total time span of 2 years.

Secondary Outcome Measures :
  1. Surface electromyography (EMG)of lower leg muscles. [ Time Frame: EMG measurements will be made during each of the four sessions. ]
    Sessions will occur at least a week apart and within a 2 year time span.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:


  • be at least 18 years of age
  • Cognitively able to give informed consent Stroke

    -≥ 6 months post diagnosis of unilateral cortical stroke

  • residual leg paresis

Exclusion Criteria:


  • chronic low back or hip pain
  • major psychiatric disorders (e.g. depression
  • substance abuse
  • head trauma
  • neurodegenerative disorder
  • any uncontrolled medical disorder (e.g. hypertension)
  • taking any medication or supplement (e.g. St. John's Wort) that has 5-HT or NE mechanisms of action(including Monoamine oxidase inhibitors (MAO) inhibitors)
  • narrow angle glaucoma
  • chronic liver or kidney disorders Stroke
  • history of multiple strokes
  • people who are unable to follow 2 step commands
  • people who cannot walk ≥ 10 ft without physical assistance.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01688570

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United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53201
Sponsors and Collaborators
Medical College of Wisconsin
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Principal Investigator: Philip A. Nelson, MD Medical College of Wisconsin
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Responsible Party: Phillip Nelson, MD, Assistant Professor, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT01688570    
Other Study ID Numbers: UL1RR031973-02 ( U.S. NIH Grant/Contract )
First Posted: September 20, 2012    Key Record Dates
Last Update Posted: November 5, 2015
Last Verified: November 2015
Keywords provided by Phillip Nelson, MD, Medical College of Wisconsin:
neuromuscular fatigue
motor impairment
Additional relevant MeSH terms:
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Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Duloxetine Hydrochloride
Serotonin and Noradrenaline Reuptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Antidepressive Agents
Psychotropic Drugs
Dopamine Agents
Dermatologic Agents
Gastrointestinal Agents
Histamine H1 Antagonists
Histamine Antagonists
Histamine Agents
Serotonin Antagonists
Serotonin Agents