Structurally Reorganizing Motor Cortex in Stroke Patients Through Hebbian-type Stimulation

Study Overview
=================
Brief Summary
-----------------
Stroke is a leading cause of morbidity in the United States but identification of treatment strategies to improve outcome is limited by the incomplete understanding of the mechanisms of recovery. Motor cortex (M1) reorganization 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 Specific Aim 1, investigators will determine if repeated exposure to training combined with Hebbian-type M1 stimulation enhances functional M1 reorganization in lesioned M1 of stroke patients. In Specific Aim 2, investigators will determine if repeated exposure to training combined with Hebbian-type M1 stimulation enhances structural cortical reorganization in lesioned M1 of stroke patients and to explore whether these structural changes are related to the training induced functional cortical reorganization. The overall goal of this project is to determine the effect of Hebbian- type stimulation on both, functional and structural brain reorganization, thereby obtaining indirect evidence for the neuronal substrate underlying training related improvement and maintenance of motor function in stroke patients. This knowledge may have a substantial positive impact on treatment for stroke patients that may significantly improve recovery and could move the field of neuro-rehabilitation forward.

Detailed Description
-----------------
Stroke is a leading cause of morbidity in the United States but identification of treatment strategies to improve outcome is limited by the incomplete understanding of the mechanisms of recovery. Motor cortex (M1) reorganization 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. Non-invasive cortical stimulation can enhance the beneficial effects of motor training on performance and functional plasticity of motor cortex. Among the different approaches used in these studies, Hebbian-type M1 stimulation is particularly intriguing, as it seems to be more effective when compared to random M1 stimulation. There is emerging evidence that motor training or cortical stimulation related improvement of function are associated with increases in the grey matter of targeted brain areas. While there is therefore some evidence supporting structural reorganization in human M1 in response to motor learning and cortical stimulation, the mechanisms underlying these changes and their relationship to functional plasticity are not known. A better understanding of the sequences of events is critical to development of optimal therapeutic interventions to improve recovery following stroke. In Specific Aim 1, investigators will determine if repeated exposure to training combined with Hebbian-type M1 stimulation enhances functional M1 reorganization in lesioned M1 of stroke patients. In Specific Aim 2, investigators will determine if repeated exposure to training combined with Hebbian-type M1 stimulation enhances structural cortical reorganization in lesioned M1 of stroke patients and to explore whether these structural changes are related to the training induced functional cortical reorganization. The overall goal of this project is to determine the effect of Hebbian- type stimulation on both, functional and structural brain reorganization, thereby obtaining indirect evidence for the neuronal substrate underlying training related improvement and maintenance of motor function in stroke patients. This knowledge may have a substantial positive impact on treatment for stroke patients that may significantly improve recovery and could move the field of neuro-rehabilitation forward.

Official Title
-----------------
Structurally Reorganizing Motor Cortex in Stroke Patients Through Hebbian-type Stimulation

Conditions
-----------------
Stroke

Intervention / Treatment
-----------------
* Device: Repetitive Transcranial Magnetic Stimulation (rTMS)
* Device: Sham stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18-85 Single cerebral ischemic infarction > 6 month affecting the primary motor output system of the hand at a cortical (M1) level as defined by MRI of the brain At the time of cerebral infarct a motor deficit of hand of MRC of <4- of wrist and finger extension/flexion movement Good 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 No other neurological disorder No intake of CNS active drugs Ability to give informed consent Ability to meet criteria of inclusion experiment No major cognitive impairment No contraindication to TMS or MRI

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hebbian-type Stimulation<br>Participants will be randomized to receive motor training with Hebbian-type stimulation. | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Training sessions for 5 days in a row<br>|
| Sham Comparator: Sham Stimulation<br>Participants will be randomized to receive sham stimulation. | Device: Sham stimulation<br>* Sham stimulation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Motor Cortex (M1) Excitability Derived From Stimulus Response Curve | Motor evoked potential (MEP) amplitudes were measured prior to treatment (baseline), one week after the treatment (post-training 1), and 4 weeks after treatment (post-training 2).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). Long-lasting increases in MEP amplitude indicate increases in motor cortex excitability and are associated with motor learning. | Baseline, Post-Training 1 (1 Week), Post-Training 2 (4 Weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Time to Completion for Jebsen Hand Function Test (JTT) | The JTT provides a standardized and objective evaluation of fine and gross motor hand function using simulated activities of daily living assessing the speed of performance. Total score is the sum of time taken for each sub-test, which were normalized to standard scores (also expressed in seconds).Total scores range from +1 to -1 where -1 indicates best function. | Baseline, Post-Training (1 Week), Post-Training (4 Weeks) | 
| Mean Peak Acceleration of Wrist Extension Movements | Mean peak acceleration was measured at baseline, one week after the treatment (post-training 1), and four weeks after the treatment (post-training 2). 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. | Baseline, Post-Training (1 Week), Post-Training (4 Weeks) | 
| Mean Reaction Time of Wrist Extension Movements | Subjects will be asked to perform 7 auditory-cued ballistic wrist extensions before and after motor training. Electromyographic (EMG) activity recorded during the ballistic wrist extensions will be used to measure reaction time. Reaction time is the length of time between the auditory cue and the onset of the movement-related EMG burst of the extensor carpi ulnaris muscle. A longer time indicated longer time to reaction. | Baseline, Post-Training (1 Week), Post-Training (4 Weeks) | 
| Mean Motor Activity Log (MAL) Score: Amount Subtest | Individuals are asked to rate amount of movement during 30 daily functional tasks. Items are scored on a 0 to 6-point ordinal scale as follows: 0 = The weaker arm was not used at all for that activity (never) 1 = Occasionally used weaker arm, but only very rarely (very rarely) 2= Sometimes used weaker arm, but did the activity most of the time with stronger arm (rarely) 3 = Used weaker arm about half as much as before the stroke (half pre-stroke) 4 = Used weaker arm almost as much as before the stroke (3/4 pre-stroke) 5 = The ability to use the weaker arm for that activity was as good as before the stroke (normal) Total scores range from 0 to 140; 0 indicating the least movement 140 indicating the most movement. The scores were converted into percentage scores where higher percent score indicate more movement and lower percent score less movement. | Baseline, Post-Training (1 Week), Post-Training (4 Weeks) | 
| Mean Motor Activity Log (MAL): How Well Subtest | Individuals are asked to rate quality of movement during 30 daily functional tasks. Items are scored on a 6-point ordinal scale as follows: 0=The weaker arm was not used at all for that activity (never); 1=The weaker arm was moved during that activity, but was not helpful (very poor); 2=The weaker arm was of some use during the activity, but needed help from the stronger arm or moved very slowly or with difficulty (poor); 3=The weaker arm was used for the purpose indicated, but movements were slow or were made with only some effort (fair); 4=The movements made by the weaker arm were almost normal, but were not quite as fast or accurate as normal (almost normal); 5=The ability to use the weaker arm for that activity was as good as before the stroke (normal) Total scores range from 0 to 140; 0 indicating the least movement and 140 indicating the most movement. | Baseline, Post-Training (1 Week), Post-Training (4 Weeks) | 
| Mean Wolf Motor Function Test (WMFT) Total Time | The Wolf Motor Function Test (WMFT) is a quantitative index of upper extremity motor ability examinable through the use of timed and functional tasks. There are 15 timed tasks included with a time cap of 120 seconds. The max amount of time to completion is 1800 seconds if all tasks are failed. The time in seconds were summed across all the tasks to obtain the total duration. Values in the table represent the time taken in seconds to successfully complete all 15 tasks). | Baseline, Post-Training (1 Week), Post-Training (4 Weeks) | 
| Mean Wolf Motor Function Test Functional Ability (WMFT-FS) Scale Score | The WMFT is a 17 item scale that quantifies upper extremity (UE) motor ability through timed and functional tasks. The items are rated on a 6-point scale.Total scores can range from 17 to 102. Lower scores indicate debilitating mobility (such as no or limited functionality), while higher score indicate greater mobility (such as slow movement and normal movement). | Baseline, Post-Training (1 Week), Post-Training (4 Weeks) | 
| Mean Wolf Motor Function Test (WMFT) Grip Strength | Participants attempt to grip the dynamometer with greatest grip strength possible. The test should be conducted 3 times with a 1-minute rest between trials. The mean of grip strength exerted (kg) on 3 trials is then calculated. | Baseline, Post-Training (1 Week), Post-Training (4 Weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stroke, Neurology, Neurophysiology, Transcranial Magnetic Stimulation (TMS), Physical Medicine and Rehabilitation