Mechanisms of Neuromuscular Fatigue Post Stroke

November 4, 2015 updated by: Phillip Nelson, MD, Medical College of Wisconsin
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

27

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53201
        • Medical College of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: DOUBLE

Arms and Interventions

Participant Group / 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 Names:
  • 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
At time of each of 4 testing sessions (all sessions within a 2 year period).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
EMG measurements will be made during each of the four sessions.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical College of Wisconsin

Investigators

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2011

Primary Completion (ACTUAL)

May 1, 2015

Study Completion (ACTUAL)

May 1, 2015

Study Registration Dates

First Submitted

September 12, 2012

First Submitted That Met QC Criteria

September 16, 2012

First Posted (ESTIMATE)

September 20, 2012

Study Record Updates

Last Update Posted (ESTIMATE)

November 5, 2015

Last Update Submitted That Met QC Criteria

November 4, 2015

Last Verified

November 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UL1RR031973-02 (NIH)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Stroke

Clinical Trials on duloxetine

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Colombia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe