Mechanisms of Neuromuscular Fatigue Post Stroke

Sponsor

Medical College of Wisconsin (Other)

Overall Status

Completed

CT.gov ID

NCT01688570

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.6

Patients Per Site Per Month

Study Details

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

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 :

Aug 1, 2011

Actual Primary Completion Date :

May 1, 2015

Actual Study Completion Date :

May 1, 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 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.

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.

Outcome Measures

Primary Outcome Measures

Force generation [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

Surface electromyography (EMG)of lower leg muscles. [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

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.