Mechanisms of Neuromuscular Fatigue Post Stroke

NCT01688570 | Completed Early Phase 1

• 1 other identifier: UL1RR031973-02
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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.

Conditions

Stroke

Keywords

neuromuscular fatigue; motor impairment

Outcome Measures

Primary Outcomes (1)

• Force generation

  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 Outcomes (1)

• Surface electromyography (EMG)of lower leg muscles.

  EMG measurements will be made during each of the four sessions.

Study Arms (3)

Duloxetine

ACTIVE COMPARATOR

Neuromuscular fatigue testing with duloxetine dose

Drug: duloxetine

Cyproheptadine

ACTIVE COMPARATOR

Neuromuscular fatigue testing with cyproheptadine dose

Drug: Cyproheptadine

Placebo

PLACEBO COMPARATOR

Neuromuscular fatigue testing with placebo dose

Drug: Placebo

Interventions

duloxetine DRUG

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.

Also known as: Cymbalta

Duloxetine

Cyproheptadine DRUG

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.

Cyproheptadine

Placebo DRUG

Single dose, orally, 6 hours prior to the start of the respective testing session. Subjects take a single dose once.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Medical College of Wisconsin: lead

Study Sites (1)

Medical College of Wisconsin

Milwaukee, Wisconsin, 53201, United States

Location

MeSH Terms

Conditions

Stroke

Interventions

Duloxetine Hydrochloride; Cyproheptadine

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dibenzocycloheptenes; Benzocycloheptenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperidines; Polycyclic Compounds

Study Officials

• Philip A. Nelson, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: September 12, 2012
• First Posted: September 20, 2012
• Study Start: August 1, 2011
• Primary Completion: May 1, 2015
• Study Completion: May 1, 2015
• Last Updated: November 5, 2015

Record last verified: 2015-11

Locations

US (1)