Neurobiological Principles Applied to the Rehabilitation of Stroke Patients

Not Applicable

Completed

Conditions: Stroke

Interventions: Drug: Carbidopa-Levodopa
Other: Transcranial Magnetic Stimulation (TMS)
Other: Sham Transcranial Magnetic Stimulation (TMS)
Drug: Methylphenidate
Drug: Amphetamine Sulfate
Drug: Placebo
Other: Transcranial Magnetic Stimulation (TMS) Training

Registration Number: NCT00715520

Lead Sponsor: Emory University

Brief Summary: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 33

Inclusion Criteria

Normal neurological examination
Ability to meet criteria of inclusion experiment
Ability to give informed consent.

Exclusion Criteria

History or neurological or psychiatric disease
Abnormal MRI of brain
Abnormal neuropsychological testing
Intake of CNS active drugs
History of seizure disorder
History of migraine headaches
History of anaphylaxis or allergic reactions
Contraindication to TMS

Aim 3:

Inclusion Criteria:

Cerebral ischemic infarction more than 6 months prior to entering the study
Single lesion as defined by MRI of the brain affecting the primary motor output system of the hand at a cortical (M1) level or subcortical level, or unilateral, and supratentorial in absence of history of a previous symptomatic stroke within 3 months of the current stroke
Dense paresis of the hand for more than three days after cerebral infarction (MRC of < 4- of wrist- and finger extension/flexion movements)
Good functional recovery of hand function as defined by MRC of 4 or 4+ of wrist- and finger extension/flexion movements
Ability to perform wrist extension movements
Ability to meet criteria of inclusion experiment
Ability to give informed consent
Ability of TMS to elicit a measurable MEP of > 100 μV and an increase in MEP amplitude with increasing stimulus intensity (up to 100% of MSO) of at least 20% over MEP amplitude at MT

Exclusion Criteria:

History or neurological or psychiatric disease, including bipolar disorder
Intake of CNS active drugs
History of seizure disorder
History of migraine headaches
History of anaphylaxis or allergic reactions
Contraindication to TMS

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Aim 1	Carbidopa-Levodopa	Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
Aim 1	Amphetamine Sulfate	Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
Aim 1	Placebo	Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
Aim 1	Transcranial Magnetic Stimulation (TMS) Training	Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
Aim 2	Transcranial Magnetic Stimulation (TMS)	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.
Aim 2	Sham Transcranial Magnetic Stimulation (TMS)	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.
Aim 3	Carbidopa-Levodopa	Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
Aim 3	Amphetamine Sulfate	Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
Aim 3	Placebo	Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
Aim 3	Sham Transcranial Magnetic Stimulation (TMS)	Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
Aim 3	Transcranial Magnetic Stimulation (TMS) Training	Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
Aim 1	Methylphenidate	Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
Aim 3	Methylphenidate	Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.

Primary Outcome Measures

Name	Time	Method
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)	Motor evoked potential (MEP) amplitudes were measured prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2), and 60 minutes after the treatment (post-training 3).The MEP is elicited by transcranial magnetic stimulation (TMS) at increased intensity. Its amplitude is measured from peak to peak and expressed in millivolts (mV). Measured MEP amplitudes were plotted against the intensity to create a stimulus response curve (SRC). SRCs were modeled by a 3- parameter sigmoid function and MEPmax was extracted. Long-lasting increases in MEP amplitude indicate increases in motor cortex excitability and are associated with motor learning.
Aim 1: Mean Peak Acceleration of Wrist Extension Movements	Baseline, Post-Training 1 (Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)	Mean peak acceleration was measured across study drug conditions prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning. Acceleration was measured in g; a symbol for the average acceleration produced by gravity at the Earth's surface.

Secondary Outcome Measures

Name	Time	Method
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)	Mean sum of normalized MEP for repeated TMS (rTMS) conditions with respect to the pulse (-100, +300, placebo, zero) prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Its amplitude is measured from peak to peak and expressed in mV. Long- lasting increases in MEP amplitude indicate increases in motor cortex excitability and are associated with motor learning.
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)	Mean sum of normalized MEP for the different frequencies of rTMS treatment (placebo at 0.1 Hz, 0.1 Hz, 0.25 Hz, 0.5 Hz) prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning.
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)	Mean peak acceleration of wrist movements for repeated TMS (rTMS) conditions with respect of the TMS pulse (-100, +300, placebo, zero) prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning. Acceleration was measured in g; a symbol for the average acceleration produced by gravity at the Earth's surface.
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)	Mean peak acceleration for the different frequencies of rTMS treatment (placebo, 0.1 Hz, 0.25 Hz, 0.5 Hz) prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning. Acceleration was measured in g; a symbol for the average acceleration produced by gravity at the Earth's surface.
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)	Motor evoked potential (MEP) amplitudes were measured prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2), and 60 minutes after the treatment (post-training 3).The MEP is elicited by transcranial magnetic stimulation (TMS) at increased intensity. Its amplitude is measured from peak to peak and expressed in millivolts (mV). Measured MEP amplitudes were plotted against the intensity to create a stimulus response curve (SRC). SRCs were modeled by a 3- parameter sigmoid function and MEPmax was extracted. Long-lasting increases in MEP amplitude indicate increases in motor cortex excitability and are associated with motor learning.
Aim 3: Mean Peak Acceleration of Wrist Extension Movements	Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)	Mean peak acceleration was measured across study drug conditions prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning. Acceleration was measured in g; a symbol for the average acceleration produced by gravity at the Earth's surface.