An interventional study of Transcranial Magnetic Stimulation (TMS) and Carbidopa-Levodopa in Stroke, sponsored by Emory University. Completed at 1 site in United States. Open to participants aged 18 Years to 80 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2017-10-16.
Sponsored by Emory University · Not applicable, Interventional, and Treatment
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.
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.
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Aims 1 and 2
Inclusion Criteria:
Exclusion Criteria:
Aim 3:
Inclusion Criteria:
Exclusion Criteria:
Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
Drug: Carbidopa-Levodopa · Drug: Methylphenidate · Drug: Amphetamine Sulfate · Drug: Placebo · Other: Transcranial Magnetic Stimulation (TMS) Training
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.
Other: Transcranial Magnetic Stimulation (TMS) · Other: 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.
Drug: Carbidopa-Levodopa · Drug: Methylphenidate · Drug: Amphetamine Sulfate · Drug: Placebo · Other: Sham Transcranial Magnetic Stimulation (TMS) · Other: Transcranial Magnetic Stimulation (TMS) Training
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.
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.
Also known as: Sinemet
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.
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.
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.
Sham TMS pulses will be randomly administered during TMS sessions.
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.
Aim 1: Mean Parameter Estimate for Maximal Motor Evoked Potential (MEPmax) Derived From Stimulus Response Curves (SRC)
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.
Time frame: Baseline, Post-Training 1 (Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Aim 1: Mean Peak Acceleration of Wrist Extension Movements
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.
Time frame: Baseline, Post-Training 1 (Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Aim 2: Mean Sum of Normalized Motor Evoked Potentials (MEPs) With Respect to Pulse
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.
Time frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Aim 2: Mean Peak Acceleration of Wrist Extension Movements With Respect to Pulse
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.
Time frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Aim 2: Mean Sum of Normalized Motor Evoked Potentials (MEPs) for rTMS Treatment With Respect to Frequency
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.
Time frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Aim 2: Mean Peak Acceleration for rTMS Treatment With Respect to Frequency
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.
Time frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Aim 3: Mean Parameter Estimate for Maximal Motor Evoked Potential (MEPmax) Derived From Stimulus Response Curves (SRC)
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.
Time frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Aim 3: Mean Peak Acceleration of Wrist Extension Movements
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.
Time frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes)
Participants were recruited between April 2007 and August 2013.
| Milestone | Aim 1 | Aim 2 | Aim 3 |
|---|---|---|---|
| Started | 20 | 10 | 3 |
| Completed | 10 | 9 | 1 |
| Not completed | 10 | 1 | 2 |
| Withdrew: Screen failure | 8 | 1 | 1 |
| Withdrew: Withdrawal by subject | 2 | 0 | 1 |
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.
| mV | Aim 1 |
|---|---|
| Baseline Placebo - MEPmax | 1.01 ± .13 |
| Post-Training 1 Placebo - MEPmax | 1.63 ± .33 |
| Post-Training 2 Placebo - MEPmax | 1.29 ± .05 |
| Baseline - Amphetamine Sulfate - MEPmax | .73 ± .10 |
| Post-Training 1 Ampletamine Sulfate - MEPmax | 1.22 ± .26 |
| Post-Training 2 Amphetamine Sulfate - MEPmax | 1.08 ± .04 |
| Baseline Methylphenidate - MEPmax | 1.04 ± .13 |
| Post-Training 1 Methylphenidate - MEPmax | 1.10 ± .12 |
| Post-Training 2 Methylphenidate - MEPmax | 1.22 ± .06 |
| Baseline Carbidopa-Levodopa - MEPmax | 1.81 ± .62 |
| Post-Training 1 Carbidopa-Levodopa - MEPmax | 1.41 ± .26 |
| Post-Training 2 Carbidopa-Levodopa - MEPmax | 1.53 ± .13 |
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.
| g | Aim 1 |
|---|---|
| Baseline - Placebo | 1.32 ± .35 |
| Post-Training 1 - Placebo | 1.33 ± .21 |
| Post-Training 2 - Placebo | 1.24 ± .30 |
| Baseline - Amphetamine Sulfate | 1.24 ± .33 |
| Post-Training 1 - Amphetamine Sulfate | 1.28 ± .31 |
| Post-Training 2 - Amphetamine Sulfate | 1.29 ± .39 |
| Baseline - Methylphenidate | 1.35 ± .30 |
| Post-Training 1 - Methylphenidate | 1.27 ± .16 |
| Post-Training 2 - Methylphenidate | 1.22 ± .25 |
| Baseline - Carbidopa-Levodopa | 1.22 ± .39 |
| Post-Training 1 - Carbidopa-Levodopa | 1.23 ± .27 |
| Post-Training 2 - Carbidopa-Levodopa | 1.37 ± .38 |
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.
| millivolts | Aim 2 |
|---|---|
| Baseline - Pulse (zero) | .39 ± .36 |
| Post-Training 1 - Pulse (zero) | .66 ± .74 |
| Post-Training 2 - Pulse (zero) | .63 ± .63 |
| Post-Training 3 - Pulse (zero) | .69 ± .76 |
| Baseline - Pulse (placebo) | .40 ± .38 |
| Post-Training 1 - Pulse (placebo) | .54 ± .57 |
| Post-Training 2 - Pulse (placebo) | .51 ± .59 |
| Post-Training 3 - Pulse (placebo) | .52 ± .59 |
| Baseline - Pulse (-100) | .39 ± .37 |
| Post-Training 1 - Pulse (-100) | .56 ± .54 |
| Post-Training 2 - Pulse (-100) | .60 ± .67 |
| Post-Training 3 - Pulse (-100) | .61 ± .63 |
| Baseline - Pulse (+300) | .38 ± .38 |
| Post-Training 1 - Pulse (+300) | .54 ± .51 |
| Post-Training 2 - Pulse (+300) | .48 ± .45 |
| Post-Training 3 - Pulse (+300) | .51 ± .50 |
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.
| g | Aim 2 |
|---|---|
| Baseline - Pulse (zero) | 1.33 ± .31 |
| Post-Training 1 - Pulse (zero) | 1.43 ± .30 |
| Post-Training 2 - Pulse (zero) | 1.51 ± .34 |
| Post-Training 3 - Pulse (zero) | 1.53 ± .37 |
| Baseline - Pulse (placebo) | 1.44 ± .25 |
| Post-Training 1 - Pulse (placebo) | 1.36 ± .24 |
| Post-Training 2 - Pulse (placebo) | 1.35 ± .24 |
| Post-Training 3 - Pulse (placebo) | 1.33 ± .30 |
| Baseline - Pulse (-100) | 1.51 ± .34 |
| Post-Training 1 - Pulse (-100) | 1.5 ± .30 |
| Post-Training 2 - Pulse (-100) | 1.46 ± .34 |
| Post-Training 3 - Pulse (-100) | 1.47 ± .27 |
| Baseline - Pulse (+300) | 1.40 ± .34 |
| Post-Training 1 - Pulse (+300) | 1.32 ± .35 |
| Post-Training 2 - Pulse (+300) | 1.38 ± .40 |
| Post-Training 3 - Pulse (+300) | 1.40 ± .43 |
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.
| millivolts | Aim 2 |
|---|---|
| Baseline - Placebo | .67 ± .79 |
| Post-Training 1 - Placebo | .93 ± 1.00 |
| Post-Training 2 - Placebo | .94 ± 1.09 |
| Post-Training 3 - Placebo | 1.02 ± 1.19 |
| Baseline - .1 Hz | .71 ± .83 |
| Post-Training 1 - .1 Hz | 1.06 ± 1.15 |
| Post-Training 2 - .1 Hz | 1.06 ± 1.23 |
| Post-Training 3 - .1 Hz | 1.14 ± 1.24 |
| Baseline - .25 Hz | .67 ± .84 |
| Post-Training 1 - .25 Hz | .90 ± 1.03 |
| Post-Training 2 - .25 Hz | .90 ± 1.08 |
| Post-Training 3 - .25 Hz | .98 ± 1.15 |
| Baseline - .5 Hz | .64 ± .74 |
| Post-Training 1 - .5 Hz | .92 ± 1.11 |
| Post-Training 2 - .5 Hz | .90 ± .99 |
| Post-Training 3 - .5 Hz | .84 ± 1.00 |
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.
| g | Aim 2 |
|---|---|
| Baseline - Placebo | 1.44 ± .25 |
| Post-Training 1 - Placebo | 1.36 ± .24 |
| Post-Training 2 - Placebo | 1.35 ± .24 |
| Post-Training 3 - Placebo | 1.33 ± .30 |
| Baseline - .1 Hz | 1.33 ± .31 |
| Post-Training 1 - .1 Hz | 1.43 ± .30 |
| Post-Training 2 - .1 Hz | 1.50 ± .34 |
| Post-Training 3 - .1 Hz | 1.53 ± .37 |
| Baseline - .25 Hz | 1.38 ± .26 |
| Post-Training 1 - .25 Hz | 1.35 ± .44 |
| Post-Training 2 - .25 Hz | 1.40 ± .37 |
| Post-Training 3 - .25 Hz | 1.34 ± .47 |
| Baseline - .5 Hz | 1.32 ± .23 |
| Post-Training 1 - .5 Hz | 1.29 ± .30 |
| Post-Training 2 - .5 Hz | 1.25 ± .29 |
| Post-Training 3 - .5 Hz | 1.29 ± .31 |
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
Collected over Adverse events were collected throughout the duration of the study (6 years, 6 months).. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Aim 1 | 0/10 (0%) | 0/10 (0%) | 5/10 (50%) |
| Aim 2 | 0/9 (0%) | 0/9 (0%) | 0/9 (0%) |
| Aim 3 | 0/1 (0%) | 0/1 (0%) | 1/1 (100%) |
| Event | Aim 1 | Aim 2 | Aim 3 |
|---|---|---|---|
| DysarthriaNervous system disorders | 0/10 | 0/9 | 1/1 |
| Facial EdemaGeneral disorders | 0/10 | 0/9 | 1/1 |
| SomnolenceNervous system disorders | 5/10 | 0/9 | 0/1 |
| DizzinessNervous system disorders | 3/10 | 0/9 | 0/1 |
| NauseaGastrointestinal disorders | 2/10 | 0/9 | 0/1 |
| VertioEar and labyrinth disorders | 1/10 | 0/9 | 0/1 |
| Increased Blood PressureVascular disorders | 1/10 | 0/9 | 0/1 |
| Dry MouthGastrointestinal disorders | 1/10 | 0/9 | 0/1 |
| ParathesisNervous system disorders | 1/10 | 0/9 | 0/1 |
Participants included in the baseline analysis received a study intervention and completed all study procedures.
| Age, Categorical(Participants) | Aim 1 | Aim 2 | Aim 3 | Total |
|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 7 | 7 | 1 | 15 |
| >=65 years | 3 | 2 | 0 | 5 |
| Sex: Female, Male(Participants) | Aim 1 | Aim 2 | Aim 3 | Total |
|---|---|---|---|---|
| Female | 5 | 6 | 1 | 12 |
| Male | 5 | 3 | 0 | 8 |
| Race and Ethnicity Not Collected(Participants) | Aim 1 | Aim 2 | Aim 3 | Total |
|---|---|---|---|---|
| Count of participants | — | — | — | 0 |
| Region of Enrollment(Participants) | Aim 1 | Aim 2 | Aim 3 | Total |
|---|---|---|---|---|
| United States | 10 | 9 | 1 | 20 |
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Emory University