Customized Cortical Stimulation Therapy in the Rehabilitation of Stroke Patients

• Sponsor: Emory University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02544503
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Neurological Disorders and Stroke (NINDS) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 100
• Locations: 3
• Arms: 2
• Actual Duration (Months): 67.2
• Patients Per Site: 33.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to identify and establish how the area of the brain that controls motor function (motor cortex) of the non-affected hemisphere after stroke might serve as a new target for therapeutic interventions to improve motor performance after stroke.

Condition or Disease	Intervention/Treatment	Phase
Stroke	Device: Single-pulse Transcranial Magnetic Stimulation (TMS); Device: Paired-pulse Transcranial Magnetic Stimulation (ppTMS); Device: Low-frequency Repetitive Transcranial Magnetic Stimulation (rTMS); Device: Sham Motor Cortex Stimulation	N/A

Detailed Description

It is well known that the motor area of one hemisphere of the brain (motor cortex) controls the movement of the opposite side of the body but the role of the motor cortex in the hemisphere spared by stroke (contralesional motor cortex) in motor performance during post stroke recovery is still unclear. It is also not clear whether the motor cortex of both hemispheres of the brain are involved, as movement becomes more complicated. Currently the role of the motor cortex on the same side of the body (referred to as ipsilateral motor cortex) in hand performance remains controversial. In most patients with stroke, only one side of the brain is affected by the stroke (affected hemisphere) resulting in weakness of half of the body opposite to the side of the stroke. Over the recent years, research has discovered that the side of the brain, that is spared by the stroke (non-affected hemisphere) may support recovery after stroke. However, there is also a question whether the non-affected hemisphere may interfere with the process of recovery. It is currently not known what factors influence the activity of non-affected hemisphere to either support or interfere with the recovery of stroke. A better understanding of those events is critical to development of optimal therapeutic strategies. For example, non-invasive stimulation of specific areas of the non-affected hemisphere may help to improve functional recovery following stroke. The objectives of this study are to define the factors that influence the activity in the non-affected hemisphere to either support or interfere with the recovery after stroke. The researchers will study the area of the brain that controls movements of the non-affected hemisphere as it relates to motor function post-stroke.

Transcranial magnetic stimulation (TMS) is a device that allows non-invasive stimulation of the brain. When the brain is stimulated repetitively at a very low rate and low intensity for about 15 minutes, the stimulated brain area becomes less active. This effect lasts 10 minutes and is called a "transient artificial lesion" as it mimics the effects of transiently interfering with the function of the stimulated brain area. The study includes experiments that first identify the extent of stroke and brain areas involved in a motor task using functional MRI of the brain and TMS. The researchers will then determine the functional role of the contralesional motor cortex by studying the effect of low frequency and high frequency repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex (M1) on interhemispheric inhibition (IHI) (resting and active) and motor cortex excitability (short interval intracortical excitability and corticospinal excitability) and behavior. The researchers will thereby also identify rTMS protocols that enhance motor performance in stroke patients.

In this study the researchers will conduct experiments using repetitive TMS to downregulate the activity of the motor area and measures its effect on activity of motor cortex of both hemispheres. In addition to enrolling participants who have had a stroke, the researchers will enroll healthy participants as this collected data will provide normative values for task related changes in M1s and their interactions - a prerequisite to studying abnormalities in stroke patients during motor recovery. The measurements and interventions will occur at two time points in all participants with stroke (1 and 6 months post-stroke). The data will be compared to the results of healthy age matched controls, assessed at a single time point.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Customized Cortical Stimulation Therapy in the Rehabilitation of Stroke Patients
• Actual Study Start Date: Jul 1, 2015
• Actual Primary Completion Date: Feb 4, 2021
• Actual Study Completion Date: Feb 4, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stroke Patients Subjects will undergo single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.	Device: Single-pulse Transcranial Magnetic Stimulation (TMS); Single-pulse Transcranial Magnetic Stimulation (TMS) is a brief magnetic pulse that is applied through a coil to the section of the head that overlays the motor cortex of the brain. Subjects will be comfortably seated in a dental chair surrounded by a frame that carries a coil holder to assist with the application of TMS to the brain. Single-pulse transcranial magnetic stimulation (TMS) will be administered at study visits.; Device: Paired-pulse Transcranial Magnetic Stimulation (ppTMS); Paired-pulse Transcranial Magnetic Stimulation (ppTMS) is two brief sequential magnetic pulses that are applied through a coil to the section of the head that overlays the motor cortex of the brain. Subjects will be comfortably seated in a dental chair surrounded by a frame that carries a coil holder to assist with the application of TMS to the brain. Paired-pulse transcranial magnetic stimulation (ppTMS) will be administered at study visits.; Device: Low-frequency Repetitive Transcranial Magnetic Stimulation (rTMS); Low-frequency Repetitive Transcranial Magnetic Stimulation (rTMS) is a sequence of brief magnetic pulses that are applied at 0.1 Hz frequency at low intensity through an air-cooled coil to the section of the head that overlays the motor cortex of the brain. Subjects will be comfortably seated in a dental chair surrounded by a frame that carries a coil holder to assist with the application of TMS to the brain. Low-frequency repetitive transcranial magnetic stimulation (rTMS) will be administered at study visits.; Device: Sham Motor Cortex Stimulation; Sham motor cortex stimulation will be applied at study visits.
Active Comparator: Healthy Controls Subjects will undergo single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months.	Device: Single-pulse Transcranial Magnetic Stimulation (TMS); Single-pulse Transcranial Magnetic Stimulation (TMS) is a brief magnetic pulse that is applied through a coil to the section of the head that overlays the motor cortex of the brain. Subjects will be comfortably seated in a dental chair surrounded by a frame that carries a coil holder to assist with the application of TMS to the brain. Single-pulse transcranial magnetic stimulation (TMS) will be administered at study visits.; Device: Paired-pulse Transcranial Magnetic Stimulation (ppTMS); Paired-pulse Transcranial Magnetic Stimulation (ppTMS) is two brief sequential magnetic pulses that are applied through a coil to the section of the head that overlays the motor cortex of the brain. Subjects will be comfortably seated in a dental chair surrounded by a frame that carries a coil holder to assist with the application of TMS to the brain. Paired-pulse transcranial magnetic stimulation (ppTMS) will be administered at study visits.; Device: Low-frequency Repetitive Transcranial Magnetic Stimulation (rTMS); Low-frequency Repetitive Transcranial Magnetic Stimulation (rTMS) is a sequence of brief magnetic pulses that are applied at 0.1 Hz frequency at low intensity through an air-cooled coil to the section of the head that overlays the motor cortex of the brain. Subjects will be comfortably seated in a dental chair surrounded by a frame that carries a coil holder to assist with the application of TMS to the brain. Low-frequency repetitive transcranial magnetic stimulation (rTMS) will be administered at study visits.; Device: Sham Motor Cortex Stimulation; Sham motor cortex stimulation will be applied at study visits.

Outcome Measures

Primary Outcome Measures

1. Motor Function Assessed by the Jebsen Test [1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)]

   The Jebsen Test assesses weighted and non-weighted hand function among participants who have had a stroke. Subjects are assessed through writing, turning over 3 by 5 inch cards, picking up small common objects, simulated feeding, stacking checkers, picking up large objects, and picking up large heavy objects. Patients are required to perform all of the subtests with both the right and left hands. Time to complete each task is recorded and normalized to healthy age and sex matched control subjects. The score ranges from 0 to 1 with 0 being normal.

2. Mean Motor Evoked Potential (MEP) Amplitudes Assessed by Stimulus Response Curve (SRC) of the Contralesional M1 [1 month post-stroke (subacute stroke) or single study visit for healthy controls, 6 months post-stroke (chronic stroke)]

   Change in mean motor evoked potential (MEP) amplitudes at each stimulus intensity will be calculated. The sum of these means is calculated as the area under the curve.

3. Presence of MEP in Response to TMS of the Ipsilesional M1 [1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)]

   The presence of motor evoked potential (MEP) in response to maximum TMS applied to ipsilesional M1 was determined in participants with stroke.

4. Lesion Volume [1 month post-stroke (subacute stroke)]

   Normalized stroke lesion volume was determined at the one-month time point using structural MRI of the brain.

5. Corticospinal Tract (CST) Lesion [1 month post-stroke (subacute stroke)]

   Corticospinal tract (CST) lesion load will be determined at the one-month time point using structural MRI of the brain. The lesion size is expressed as percentage of the entire CST.

Secondary Outcome Measures

1. Motor Function Assessed by Time to Complete the Wolf Motor Function Test (WMFT) [1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)]

   Upper extremity motor ability among participants who had a stroke was evaluated with the Wolf Motor Function Test (WMFT). The test consists of 17 items (6 joint-segment movements, 9 integrative functional movements and 2 strength items). The items are rated on a 6-point functional ability scale (FAS) where 0 is "no attempt is made to use the more affected arm and 5 is a normal appearance of movement execution. The time taken to complete each task will be recorded up to 120 seconds. The mean time to complete all tasks will be used to evaluate motor ability.

2. Motor Function Assessed by Grip Strength During the Wolf Motor Function Test (WMFT) [1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)]

   During the grip strength assessment of the WMFT, participants grip a dynamometer with as much strength as possible. There are three trials of gripping with a minute rest interval between trials. The mean kilograms of strength exerted during the three trials is calculated.

3. Use of Paretic Arm Assessed by the Motor Activity Log (MAL) [1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)]

   In stroke patients, the everyday use of the paretic (the more affected) arm will be measured using the Motor Activity Log (MAL). The MAL is a subjective measure of semi- structured interview to examine a) how much and b) how well the subject uses their more-affected arm outside of the laboratory setting. Total scores range from 0 (no use of the more-affected arm) to 5 (use is as good as before stroke).

4. CST Subpathway Originating in M1 Lesion Load [1 month post-stroke (subacute stroke)]

   CST sub M1 lesion volume will be determined at the one- month time point using structural MRI of the brain. The lesion load is expressed as percentage of the entire CST.

5. Primary Motor Cortex (M1) Activity, Assessed by Functional Magnetic Resonance Imaging (fMRI) [1 month post-stroke (subacute stroke) or single study visit for healthy controls, 6 months post-stroke (chronic stroke)]

   Functional Magnetic Resonance Imaging (fMRI) will be used to determine hand movement related activity in the motor cortex of the brain in all subjects. Blood oxygenation level dependent (BOLD) response during execution of the motor task will be compared to rest. The subacute stroke and chronic stroke time points are compared to single study visit of healthy controls.

6. Short Interval Cortical Inhibition (SICI) Measured by Repeated Transcranial Magnetic Stimulation (rTMS) [1 month post-stroke (subacute stroke) or single study visit for healthy controls, 6 months post-stroke (chronic stroke)]

   SICI in the contralesional M1 will be measured using paired pulse TMS at an interstimulus interval (ISI) of 2 milliseconds (ms). Cortical stimulation intensity was delivered at 60% and 80% of the motor threshold (MT). SICI is expressed as the ratio between the mean MEP amplitude in response to a single TMS and the mean MEP amplitude in response to a paired pulse TMS. A ratio of 1 means no inhibition, a ratio smaller than 1 means inhibition, and a ratio greater than 1 means facilitation.

7. Peak Velocity During Wrist Extension Movement [1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)]

   Stroke patients are asked to rapidly execute 7 ballistic wrist extension movements following an auditory cue. A 2-dimensional gyrometer is mounted on the dorsum of the hand to measure wrist extension movements. Electromyography (EMG) activity will be recorded on the extensor carpi ulnaris (ECU) muscle, a muscle that supports wrist extension movements.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria for all Participants

• The ability to provide informed consent

• Ages 40 to 80 years old

• Male or female

Additional Inclusion Criteria for Stroke Patients:

• One cerebral ischemic infarction less than 1 month affecting the primary motor output system of the hand at a cortical (M1) level as defined by magnetic resonance imaging (MRI) of the brain

• Paresis of the hand for more than 3 days after their cerebral infarction

Additional Inclusion Criteria for Healthy Subjects:

• Normal MRI of the brain

• Normal neuropsychological testing

• Normal neurological examination

Exclusion Criteria for Stroke Patients:

• Neurological disorders other than stroke

• Aphasia that prevents following instructions or inability to communicate effectively with the study team

• Dementia

• Moderate or severe depression

• Contraindication to transcranial magnetic stimulation (TMS) and/or MRI

• Use of central nervous system (CNS) active drugs that block plasticity

Exclusion Criteria for Healthy Subjects:

• Neurological Disease

• Psychiatric Disease

• Use of CNS active drugs

• Contraindication to transcranial magnetic stimulation (TMS) and/or MRI

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Center for Rehabilitation Medicine	Atlanta	Georgia	United States	30322
2	Emory University Hospital	Atlanta	Georgia	United States	30322
3	Emory University School of Medicine	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University
• National Institutes of Health (NIH)
• National Institute of Neurological Disorders and Stroke (NINDS)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Cathrin Buetefisch, MD, PhD, Emory University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 1, 2019
• Informed Consent Form - Oct 1, 2019

More Information

Publications

None provided.

• Responsible Party: Cathrin Buetefisch, Professor, Emory University
• ClinicalTrials.gov Identifier: NCT02544503
• Other Study ID Numbers: IRB00081238; R01NS090677
• First Posted: Sep 9, 2015
• Last Update Posted: Aug 23, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by Cathrin Buetefisch, Professor, Emory University: Subacute stroke; Chronic stroke
• Additional relevant MeSH terms: Stroke

Study Results

Participant Flow

Recruitment Details

Participants were recruited at Emory University in Atlanta, Georgia, USA. Participant enrollment began in July 2015 and all follow-up assessments were completed by February 4, 2021.

Pre-assignment Detail

Individuals provided consent to participate and were enrolled into study arms based on their health status (prior stroke or health control). After enrolling, 24 individuals with stroke and 3 healthy controls did not meet eligibility criteria and did not participate in any study assessments. Participants with stroke were assessed one and six months after their stroke, while healthy controls participated in a single assessment.

Arm/Group Title	Stroke Patients	Healthy Controls
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.	Healthy control participants underwent MRI, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS).
Period Title: Overall Study
STARTED	66	34
Completed First Study Assessment	42	31
Stroke Patients Who Completed the 6 Month Post-stroke Assessment	32	0
COMPLETED	32	31
NOT COMPLETED	34	3

Baseline Characteristics

Arm/Group Title	Stroke Patients	Healthy Controls	Total
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.	Healthy control participants underwent MRI, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS).	Total of all reporting groups
Overall Participants	42	31	73
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.83 (9.43)	61.68 (8.65)	60.94 (9.21)
Age, Customized (Count of Participants)
Less than 40	0 0%	0 0%	0 0%
40 - 80	42 100%	31 100%	73 100%
Sex: Female, Male (Count of Participants)
Female	23 54.8%	17 54.8%	40 54.8%
Male	19 45.2%	14 45.2%	33 45.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 4.8%	0 0%	2 2.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	24 57.1%	8 25.8%	32 43.8%
White	14 33.3%	4 12.9%	18 24.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 4.8%	19 61.3%	21 28.8%
Region of Enrollment (Count of Participants)
United States	42 100%	31 100%	73 100%

Outcome Measures

1. Primary Outcome

Title	Motor Function Assessed by the Jebsen Test
Description	The Jebsen Test assesses weighted and non-weighted hand function among participants who have had a stroke. Subjects are assessed through writing, turning over 3 by 5 inch cards, picking up small common objects, simulated feeding, stacking checkers, picking up large objects, and picking up large heavy objects. Patients are required to perform all of the subtests with both the right and left hands. Time to complete each task is recorded and normalized to healthy age and sex matched control subjects. The score ranges from 0 to 1 with 0 being normal.
Time Frame	1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment at the indicated study visit.

Arm/Group Title	Stroke Patients
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.
Measure Participants	32
More affected hand - subacute stroke	0.49 (0.32)
Less affected hand - subacute stroke	0.14 (0.10)
More affected hand - chronic stroke	0.35 (0.31)
Less affected hand - chronic stroke	0.11 (0.09)

2. Primary Outcome

Title	Mean Motor Evoked Potential (MEP) Amplitudes Assessed by Stimulus Response Curve (SRC) of the Contralesional M1
Description	Change in mean motor evoked potential (MEP) amplitudes at each stimulus intensity will be calculated. The sum of these means is calculated as the area under the curve.
Time Frame	1 month post-stroke (subacute stroke) or single study visit for healthy controls, 6 months post-stroke (chronic stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants completing the assessment at the indicated time point.

Arm/Group Title	Stroke Patients	Healthy Controls
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.	Healthy control participants underwent MRI, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS).
Measure Participants	35	12
Subacute stroke or single visit for healthy controls	0.67 (0.75)	0.63 (0.85)
Chronic stroke	0.39 (0.63)

3. Primary Outcome

Title	Presence of MEP in Response to TMS of the Ipsilesional M1
Description	The presence of motor evoked potential (MEP) in response to maximum TMS applied to ipsilesional M1 was determined in participants with stroke.
Time Frame	1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed the assessment at the indicated time point.

Arm/Group Title	Stroke Patients
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.
Measure Participants	35
Not Present	11 26.2%
Present	24 57.1%
Not Present	3 7.1%
Present	22 52.4%

4. Primary Outcome

Title	Lesion Volume
Description	Normalized stroke lesion volume was determined at the one-month time point using structural MRI of the brain.
Time Frame	1 month post-stroke (subacute stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants with stroke who completed this assessment.

Arm/Group Title	Stroke Patients
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.
Measure Participants	35
Mean (Standard Deviation) [cubic mm]	19745 (32285)

5. Primary Outcome

Title	Corticospinal Tract (CST) Lesion
Description	Corticospinal tract (CST) lesion load will be determined at the one-month time point using structural MRI of the brain. The lesion size is expressed as percentage of the entire CST.
Time Frame	1 month post-stroke (subacute stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants with stroke who completed this assessment.

Arm/Group Title	Stroke Patients
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.
Measure Participants	35
Mean (Standard Deviation) [percent of CST]	5.7 (6.77)

6. Secondary Outcome

Title	Motor Function Assessed by Time to Complete the Wolf Motor Function Test (WMFT)
Description	Upper extremity motor ability among participants who had a stroke was evaluated with the Wolf Motor Function Test (WMFT). The test consists of 17 items (6 joint-segment movements, 9 integrative functional movements and 2 strength items). The items are rated on a 6-point functional ability scale (FAS) where 0 is "no attempt is made to use the more affected arm and 5 is a normal appearance of movement execution. The time taken to complete each task will be recorded up to 120 seconds. The mean time to complete all tasks will be used to evaluate motor ability.
Time Frame	1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed this assessment at the indicated study visit.

Arm/Group Title	Stroke Patients
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.
Measure Participants	39
Less affected side - subacute stroke	7.11 (9.49)
More affected side - subacute stroke	36.82 (7.55)
Less affected side - chronic stroke	3.42 (4.86)
More affected side - chronic stroke	18.44 (4.81)

7. Secondary Outcome

Title	Motor Function Assessed by Grip Strength During the Wolf Motor Function Test (WMFT)
Description	During the grip strength assessment of the WMFT, participants grip a dynamometer with as much strength as possible. There are three trials of gripping with a minute rest interval between trials. The mean kilograms of strength exerted during the three trials is calculated.
Time Frame	1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants completing the assessment at the indicated time point.

Arm/Group Title	Stroke Patients
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.
Measure Participants	39
Less affected side - subacute stroke	28.95 (10.88)
More affected side - subacute stroke	15.25 (15.70)
Less affected side - chronic stroke	29.94 (8.06)
More affected side - chronic stroke	17.03 (12.68)

8. Secondary Outcome

Title	Use of Paretic Arm Assessed by the Motor Activity Log (MAL)
Description	In stroke patients, the everyday use of the paretic (the more affected) arm will be measured using the Motor Activity Log (MAL). The MAL is a subjective measure of semi- structured interview to examine a) how much and b) how well the subject uses their more-affected arm outside of the laboratory setting. Total scores range from 0 (no use of the more-affected arm) to 5 (use is as good as before stroke).
Time Frame	1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants with stroke who completed the assessment during the indicated study visit.

Arm/Group Title	Stroke Patients
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.
Measure Participants	35
Amount of use, subacute stroke	2.044 (1.654)
Quality of movement, subacute stroke	1.939 (1.593)
Amount of use, chronic stroke	3.266 (1.625)
Quality of movement, chronic stroke	3.275 (1.597)

9. Secondary Outcome

Title	CST Subpathway Originating in M1 Lesion Load
Description	CST sub M1 lesion volume will be determined at the one- month time point using structural MRI of the brain. The lesion load is expressed as percentage of the entire CST.
Time Frame	1 month post-stroke (subacute stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants with stroke who completed this assessment.

Arm/Group Title	Stroke Patients
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.
Measure Participants	35
Mean (Standard Deviation) [percentage of the entire CST]	5.07 (6.48)

10. Secondary Outcome

Title	Primary Motor Cortex (M1) Activity, Assessed by Functional Magnetic Resonance Imaging (fMRI)
Description	Functional Magnetic Resonance Imaging (fMRI) will be used to determine hand movement related activity in the motor cortex of the brain in all subjects. Blood oxygenation level dependent (BOLD) response during execution of the motor task will be compared to rest. The subacute stroke and chronic stroke time points are compared to single study visit of healthy controls.
Time Frame	1 month post-stroke (subacute stroke) or single study visit for healthy controls, 6 months post-stroke (chronic stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants completing the assessment at the indicated time point.

Arm/Group Title	Stroke Patients	Healthy Controls
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.	Healthy control participants underwent MRI, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS).
Measure Participants	19	31
Ipsilesional - subacute stroke	1.33 (1.10)
Contralesional - subacute stroke	0.14 (0.41)
Contralateral Left - single visit for healthy controls	1.59 (0.75)
Contralateral Right - single visit for healthy controls	1.59 (0.82)
Ipsilateral Left - single visit for healthy controls	0.27 (0.55)
Ipsilateral Right - single visit for healthy controls	0.17 (0.36)
Ipsilesional - chronic stroke	0.68 (0.52)
Contralesional - chronic stroke	0.03 (0.27)

11. Secondary Outcome

Title	Short Interval Cortical Inhibition (SICI) Measured by Repeated Transcranial Magnetic Stimulation (rTMS)
Description	SICI in the contralesional M1 will be measured using paired pulse TMS at an interstimulus interval (ISI) of 2 milliseconds (ms). Cortical stimulation intensity was delivered at 60% and 80% of the motor threshold (MT). SICI is expressed as the ratio between the mean MEP amplitude in response to a single TMS and the mean MEP amplitude in response to a paired pulse TMS. A ratio of 1 means no inhibition, a ratio smaller than 1 means inhibition, and a ratio greater than 1 means facilitation.
Time Frame	1 month post-stroke (subacute stroke) or single study visit for healthy controls, 6 months post-stroke (chronic stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants completing the assessment at the indicated study visit.

Arm/Group Title	Stroke Patients	Healthy Controls
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.	Healthy control participants underwent MRI, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS).
Measure Participants	31	12
Sham Cortex Stimulation 60% MT, Pre - subacute stroke, or healthy control visit	0.92 (0.70)	1.00 (0.56)
Sham Cortex Stimulation 60% MT, Post - subacute stroke, or healthy control visit	0.76 (0.57)	0.73 (0.32)
Sham Cortex Stimulation 80% MT, Pre - subacute stroke, or healthy control visit	0.93 (0.53)	0.73 (0.68)
Sham Cortex Stimulation 80% MT, Post - subacute stroke, or healthy control visit	0.79 (0.36)	0.56 (0.35)
rTMS Cortex Stimulation 60% MT, Pre - subacute stroke, or healthy control visit	0.84 (0.65)	0.98 (0.64)
rTMS Cortex Stimulation 60% MT, Post - subacute stroke, or healthy control visit	0.92 (0.52)	0.99 (0.42)
rTMS Cortex Stimulation (CS) 80% MT, Pre - subacute stroke, or healthy control visit	1.00 (0.55)	0.88 (0.82)
rTMS Cortex Stimulation (CS) 80%, Post - subacute stroke, or healthy control visit	0.84 (0.58)	0.77 (0.52)
Sham Cortex Stimulation 60% MT, Pre - chronic stroke	0.95 (0.68)
Sham Cortex Stimulation 60% MT, Post - chronic stroke	0.89 (0.43)
Sham Cortex Stimulation 80% MT, Pre - chronic stroke	1.12 (0.69)
Sham Cortex Stimulation 80% MT, Post - chronic stroke	0.83 (0.54)
rTMS Cortex Stimulation 60% MT, Pre - chronic stroke	0.92 (0.71)
rTMS Cortex Stimulation 60% MT, Post - chronic stroke	0.89 (0.99)
rTMS Cortex Stimulation (CS) 80% MT, Pre - chronic stroke	0.99 (0.46)
rTMS Cortex Stimulation (CS) 80%, Post - chronic stroke	1.09 (0.46)

12. Secondary Outcome

Title	Peak Velocity During Wrist Extension Movement
Description	Stroke patients are asked to rapidly execute 7 ballistic wrist extension movements following an auditory cue. A 2-dimensional gyrometer is mounted on the dorsum of the hand to measure wrist extension movements. Electromyography (EMG) activity will be recorded on the extensor carpi ulnaris (ECU) muscle, a muscle that supports wrist extension movements.
Time Frame	1 month post-stroke (subacute stroke), 6 months post-stroke (chronic stroke)

Outcome Measure Data

Analysis Population Description

This analysis includes participants with stroke who completed this assessment at the indicated study visit.

Arm/Group Title	Stroke Patients
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.
Measure Participants	35
Less affected side - subacute stroke - rTMS pre	700.54 (248.34)
Less affected side - subacute stroke - rTMS post	686.24 (305.79)
Less affected side - subacute stroke - sham pre	641.29 (280.48)
Less affected side - subacute stroke - sham post	628.23 (264.45)
More affected side - subacute stroke - rTMS pre	389.08 (313.69)
More affected side - subacute stroke - rTMS post	373.75 (294.01)
More affected side - subacute stroke - sham pre	413.10 (317.41)
More affected side - subacute stroke - sham post	398.41 (301.56)
Less affected side - chronic stroke - rTMS pre	659.25 (266.67)
Less affected side - chronic stroke - rTMS post	630.80 (276.10)
Less affected side - chronic stroke - sham pre	670.80 (269.49)
Less affected side - chronic stroke - sham post	653.85 (257.50)
More affected side - chronic stroke - rTMS pre	430.58 (286.32)
More affected side - chronic stroke - rTMS post	415.61 (290.76)
More affected side - chronic stroke - sham pre	444.48 (288.84)
More affected side - chronic stroke - sham post	440.02 (294.17)

Adverse Events

Time Frame	Information on adverse events was collected beginning at the first study visit and continued through the final assessment, up to one year.
Arm/Group Title	Stroke Patients		Healthy Controls
Arm/Group Description	Participants with stroke underwent assessment of their upper extremity and hand motor function, MRI of their brain, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS) at one month and six months post stroke.		Healthy control participants underwent MRI, single pulse transcranial magnetic stimulation (TMS), paired pulse transcranial stimulation (ppTMS), and low frequency repetitive transcranial magnetic stimulation (rTMS).
All Cause Mortality
	Stroke Patients		Healthy Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/31 (0%)
Serious Adverse Events
	Stroke Patients		Healthy Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/31 (0%)
Other (Not Including Serious) Adverse Events
	Stroke Patients		Healthy Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/42 (33.3%)		1/31 (3.2%)
General disorders
Headache	5/42 (11.9%)		1/31 (3.2%)
Musculoskeletal and connective tissue disorders
Soreness in the wrist	1/42 (2.4%)		0/31 (0%)
Psychiatric disorders
Panic attack in MR	1/42 (2.4%)		0/31 (0%)
Skin and subcutaneous tissue disorders
Skin irritation	8/42 (19%)		0/31 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.