Mechanisms of Neuromuscular Fatigue Post Stroke

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

Study Description

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

Study Design

• 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

Arms and Interventions

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.

Outcome Measures

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.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

General

• 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:

General

• 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.

Contacts and Locations

Locations

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53201

Sponsors and Collaborators

Medical College of Wisconsin

Investigators

• Principal Investigator: Philip A. Nelson, MD; Medical College of Wisconsin

More Information

• 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
• 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:

Stroke; Fatigue; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Cyproheptadine; Duloxetine Hydrochloride; Serotonin and Noradrenaline Reuptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Antidepressive Agents; Psychotropic Drugs; Dopamine Agents; Antipruritics; Dermatologic Agents; Gastrointestinal Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Serotonin Antagonists; Serotonin Agents