Neurobiological Principles Applied to the Rehabilitation of Stroke Patients

Completed

Phase N/A Results

Trial Description

The purpose of this study is to use (Transcranial Magnetic Stimulation) TMS or drugs to improve learning of movement skills and the adaptation processes in patients after stroke. Once investigators have determined the improving effect of TMS and the drugs on learning of movement skills, the study team may be able to provide information that improves rehabilitative treatment and helps to improve recovery after stroke.

Detailed Description

Previous studies have shown, that when patients learn a new motor movement, it may cause a change in the way the nerves act in the area of the brain that controls movement. This change is called use-dependent plasticity. The ability of that part of the brain, called the motor cortex (M1), to reorganize plays a major role in the recovery of motor deficits post-stroke; hence the importance for further development of rehabilitative strategies that utilize this potential for recovery. In this proposed study, investigators will further examine influences of use-dependent plasticity in the non-injured M1 of healthy subjects and injured M1 of stroke subjects using a combination of non-invasive cortical stimulation, medication, and exercise techniques. In Aim 1, investigators will test the effect of drugs that interact specifically with different neurotransmitter systems on use-dependent plasticity in intact M1 of healthy humans. In Aim 2, investigators will identify the parameters for non-invasive transcranial magnetic stimulation (TMS) of M1 that are most effective to enhance use-dependent plasticity in intact healthy human M1. In Aim 3, investigators will test the drugs and rTMS protocols that were demonstrated to be most effective to enhance use- dependent plasticity in the Specific Aim 1 and 2 and apply them to participants who have experienced a stroke. Results from this study will help to inform future research about the efficacy of plasticity enhancing methods in injured M1 of stroke patients.

Conditions

Interventions

  • Methylphenidate (Ritalin)Drug
    Intervention Desc: Participants will receive one oral dose of methylphenidate 40mg 2 hours prior to measuring wrist extension movements. The order in which Methylphenidate is given will be randomized per participant.
    ARM 1: Kind: Experimental
    Label: Aim 1
    Description: Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
    ARM 2: Kind: Experimental
    Label: Aim 3
    Description: Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
  • Placebo Drug
    Intervention Desc: Participants will receive one oral tablet of placebo 2 hours prior to measuring wrist extension movements. The order in which Placebo is given will be randomized per participant.
    ARM 1: Kind: Experimental
    Label: Aim 1
    Description: Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
    ARM 2: Kind: Experimental
    Label: Aim 3
    Description: Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
  • Transcranial magnetic stimulation (TMS) Other
    Intervention Desc: Each TMS training session will begin with a baseline measurement lasting about 30 minutes in which brief magnetic pulses will be generated by the single—pulse and paired pulse TMS stimulator and the responses are recorded with surface EMG electrodes. Participants will be instructed to move their wrist for up to ½ hour. After these measures, rTMS will be applied to the scalp during training. Stimulation will occur at a low rate of different frequencies and different times with respect to the training movement depending on the experimental condition. In the last phase of the session post—training measurements will be done using single TMS pulses. TMS pulses and intensity with be given in random order.
    ARM 1: Kind: Experimental
    Label: Specific Aim 2
    Description: Healthy adult female and male subjects, aged 55 to 80 years with no previous history of neurological or psychiatric diseases.
    ARM 2: Kind: Experimental
    Label: Aim 2
    Description: Healthy adult female and male subjects will receive repetitive TMS (rTMS) at different times or frequencies with respect to the training movement or sham stimulation.
  • Sinemet, ritalin, amphetamine, and placebo Drug
    Intervention Desc: Each subject will take a single dose of the following during Transcranial Magnetic Stimulation sessions: Ritalin: 40 mg dose taken 2 hours prior to the baseline measurement. Sinemet: 25/100 mg dose taken 1 hour prior to the baseline measurement. Amphetamine: 10 mg dose taken 2 hours prior to the baseline measurement. Placebo: 1 pill taken 2 hours prior to the baseline measurement.
    ARM 1: Kind: Experimental
    Label: Specific Aim 1
    Description: Healthy adult female and male subjects, aged 55 to 80 years of age with no previous history of neurological or psychiatric diseases.
  • Combined drug treatment and TMS Other
    Intervention Desc: Data analysis from the healthy adult subjects participating in Specific Aims 1 and 2 will provide the drug/TMS settings to be used in Specific Aim 3 (Stroke subjects)
    ARM 1: Kind: Experimental
    Label: Specific Aim 3
    Description: Female and male subjects, aged 55 to 80 years of age with cerebral ischemic infarction more than 12 months prior to entering into the study.
  • Sinemet, ritalin, amphetamine, and placebo Drug
    Intervention Desc: Each subject will take a single dose of the following during Transcranial Magnetic Stimulation sessions: Ritalin: 40 mg dose taken 2 hours prior to the baseline measurement. Sinemet: 25/100 mg dose taken 1 hour prior to the baseline measurement. Amphetamine: 10 mg dose taken 2 hours prior to the baseline measurement. Placebo: 1 pill taken 2 hours prior to the baseline measurement.
    ARM 1: Kind: Experimental
    Label: Specific Aim 1
    Description: Healthy adult female and male subjects, aged 55 to 80 years of age with no previous history of neurological or psychiatric diseases.
  • Sham Transcranial Magnetic Stimulation (TMS) Other
    Intervention Desc: Sham TMS pulses will be randomly administered during TMS sessions.
    ARM 1: Kind: Experimental
    Label: Aim 2
    Description: Healthy adult female and male subjects will receive repetitive TMS (rTMS) at different times or frequencies with respect to the training movement or sham stimulation.
    ARM 2: Kind: Experimental
    Label: Aim 3
    Description: Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
  • Carbidopa-Levodopa Drug
    Other Names: Sinemet
    Intervention Desc: Participants will receive one oral dose of carbidopa-levodopa 25mg one hour prior to measuring wrist extension movements. The order in which Carbidopa-Levodopa is given will be randomized per participant.
    ARM 1: Kind: Experimental
    Label: Aim 1
    Description: Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
    ARM 2: Kind: Experimental
    Label: Aim 3
    Description: Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
  • Amphetamine Sulfate Drug
    Intervention Desc: Participants will receive one oral dose of amphetamine sulfate 10mg 2 hours prior to measuring wrist extension movements. The order in which Amphetamine Sulfate is given will be randomized per participant.
    ARM 1: Kind: Experimental
    Label: Aim 1
    Description: Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
    ARM 2: Kind: Experimental
    Label: Aim 3
    Description: Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
  • Transcranial Magnetic Stimulation (TMS) Training Other
    Intervention Desc: TMS surface electromyographic activity will be recorded with surface electrodes mounted on the skin overlaying a forearm muscle. Single pulses of TMS at increasing intensity will be delivered to measure motor cortex excitability. Peak acceleration and TMS evoked responses in the muscle will be measured prior to the training, after completion of the training and again one hour after completion of the training.
    ARM 1: Kind: Experimental
    Label: Aim 1
    Description: Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
    ARM 2: Kind: Experimental
    Label: Aim 3
    Description: Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Investigator)
  • Purpose: Treatment
  • Endpoint: Efficacy Study
  • Intervention: Factorial Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Specific Aim 1: Increases of noradrenergic, dopaminergic and serotonergic transmission will enhance use-dependent plasticity in intact M1. Study Completion No
Primary Specific Aim 2: M1 Stimulation is most effective in increasing use-dependent plasticity when the stimulus occurs within 50 ms of M1 pyramidal tract neuron discharge with 0.1 to 0.3 Hx frequency (reminiscent of settings used for Hebbian-type stimulation). Study Completion No
Primary Specific Aim 3: Hebbian-type stimulation of M1 and increase of monoaminergic transmission facilitates training induced changes of motor representation in the lesioned hemisphere of patients post-stroke. Study Completion No
Primary Aim 1: Mean Parameter Estimate for Maximal Motor Evoked Potential (MEPmax) Derived From Stimulus Response Curves (SRC) Baseline, Post-Training 1 (Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Primary Aim 1: Mean Peak Acceleration of Wrist Extension Movements Baseline, Post-Training 1 (Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Secondary Aim 2: Mean Sum of Normalized Motor Evoked Potentials (MEPs) With Respect to Pulse Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Secondary Aim 2: Mean Peak Acceleration of Wrist Extension Movements With Respect to Pulse Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Secondary Aim 2: Mean Sum of Normalized Motor Evoked Potentials (MEPs) for rTMS Treatment With Respect to Frequency Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Secondary Aim 2: Mean Peak Acceleration for rTMS Treatment With Respect to Frequency Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Secondary Aim 3: Mean Parameter Estimate for Maximal Motor Evoked Potential (MEPmax) Derived From Stimulus Response Curves (SRC) Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Secondary Aim 3: Mean Peak Acceleration of Wrist Extension Movements Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)

Sponsors