Effectiveness of Transcranial Magnetic Stimulation in Subacute Stroke Patients With Severe Upper Limb Paresis

Study Overview
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Brief Summary
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There has been A-level evidence for the effectiveness of inhibitory rTMS of the contralesional M1 hand region in stroke patients in the acute stage. However, it has been reported to be ineffective in the chronic stage. In addition, it has been reported that the patient group benefiting from rTMS is mostly those with moderate to mild motor impairment. In contrast, a recent randomized controlled study has reported that ipsilesional excitatory rTMS or contra-lesional inhibitory rTMS may also have positive effects in stroke patients with severe upper limb motor impairment. The aim of this study is to investigate the effect of inhibitory repetitive transcranial magnetic stimulation applied to the contralesional primary motor cortex, by using the rTMS parameters specified in the current recommendation guide, on motor function, activities of daily living, and quality of life in subacute stroke patients with severe upper limb motor impairment.

Detailed Description
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The level of stroke-related upper limb motor impairment varies widely among individuals, from mild to severe. Because of this heterogeneity, rehabilitation interventions are tailored individually. In recent years, many studies have been published on the effectiveness of add-on non-invasive neuromodulation methods such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation in the treatment of stroke-related upper limb motor impairment. There has been A-level evidence for the effectiveness of inhibitory rTMS of the contralesional M1 hand region in stroke patients in the acute stage. However, it has been reported to be ineffective in the chronic stage. In addition, it has been reported that the patient group benefiting from rTMS is mostly those with moderate to mild motor impairment. It has been reported that contra-lesional hemisphere inactivation impairs paretic upper extremity performance in severely infarcted animals. In humans, contra-lesional hemisphere inactivation has been reported to slow down the reaction time. In contrast, a recent randomized controlled study has reported that ipsilesional excitatory rTMS or contralesional inhibitory rTMS may have positive effects in stroke patients with severe upper limb motor impairment. However, the literature on rTMS in post-stroke rehabilitation is highly heterogeneous in terms of frequency, session duration, location, patient characteristics, and outcome scales, and this ambiguity makes it difficult to adapt rTMS to the clinical practice. In this regard, future studies are needed to determine whether rTMS provides an additional benefit to traditional/task-specific rehabilitation approaches in stroke patients with severe upper limb paresis. The aim of this study is to investigate the effect of inhibitory repetitive transcranial magnetic stimulation applied to the contralesional primary motor cortex, by using the rTMS parameters specified in the current recommendation guide, on motor function, activities of daily living, and quality of life in subacute stroke patients with severe upper limb motor impairment.

Official Title
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Effectiveness of Add-on Inhibitory Repetitive Transcranial Magnetic Stimulation Over the Contralesional Primary Motor Cortex in Subacute Stroke Patients With Severe Upper Limb Motor Impairment

Conditions
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Stroke Rehabilitation

Intervention / Treatment
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* Device: Repetitive transcranial magnetic stimulation
* Device: Sham Repetitive transcranial magnetic stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of subcortical ischemic stroke affecting the middle cerebral artery territory, which has been confirmed by imaging methods Having a stroke for the first time Presence of subacute stroke (< 6 months) Mini-mental test score ≥ 24 Severe upper limb motor impairment (The Fugl-Meyer Assessment Scale - Upper Extremity motor impairment score ≤ 19/60, excluding reflex assessments) Lack of motor evoked potential (MEP) recording from the first dorsal interosseous muscle of the paretic extremity with single-pulse transcranial magnetic stimulation of the ipsilesional primary motor cortex (hand region) Exclusion Criteria: To have a clinical condition (metallic implant, cardiac pace, pregnancy, breastfeeding, claustrophobia, epilepsy, head trauma, cranial operation history) that will constitute a contraindication to transcranial magnetic stimulation History of psychiatric illness such as major depression/personality disorder History of convulsion or epilepsy or taking medication for epilepsy Cognitive impairment Pregnancy or breastfeeding Alcohol or drug addiction Previously treated with transcranial magnetic stimulation Moderate or mild upper extremity motor impairment (The Fugl-Meyer Assessment Scale - Upper Extremity score > 19/60, excluding reflex assessments) Presence of neglect

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active stimulation group<br>Fifteen sessions of inhibitory repetitive transcranial magnetic stimulation (rTMS) treatment at 1 Hz frequency will be applied to the contralesional primary motor cortex (hand region). The application will be performed with Neurosoft-Neuro MS / D device. 120% of the resting motor threshold will be used in the stimulation. One session of stimulation will last for a total of 30 minutes and a total of 1800 pulses in the form of 1 Hz stimulation. | Device: Repetitive transcranial magnetic stimulation<br>* Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive intervention that uses magnetic fields to stimulate nerve cells to improve the symptoms of a variety of disorders, including stroke-related motor impairment.<br>* Other names: Neuro Soft;|
| Sham Comparator: Sham stimulation group<br>Fifteen sessions of sham repetitive transcranial magnetic stimulation (rTMS) treatment will be applied to the contralesional primary motor cortex (hand region). The application will be performed with Neurosoft-Neuro MS / D device. The probe of the device will be held in an upright position and stimulation will be performed at the 10% of the resting motor threshold. | Device: Sham Repetitive transcranial magnetic stimulation<br>* Sham Repetitive transcranial magnetic stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the Fugl-Meyer Assessment for Upper Extremity | The Fugl-Meyer Assessment for upper extremity (FMA-UE) is a widely used scale for motor recovery of the upper limb after stroke. FMA-UE comprises four domains (shoulder-arm, wrist, hand, and coordination-speed) developed to measure the severity of motor impairment from synergy to isolated voluntary movement. Scoring is based on direct observation of performance. Each item is scored on a three-point ordinal scale between 0 and 2 (0=cannot perform; 1=partially performs; 2=performs fully) according to performance. The score for an individual range between 0 and 66. The higher the score, the lower the motor impairment. | (1) Baseline, (2) At the end of the last session of the intervention (immediately after the 15th session, each session is 1 day), and (3) 4 weeks after the last session of the intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the Modified Barthel Index for Activities of Daily Living | The Modified Barthel Index assesses the activity of daily living based on performance. It comprises 10 domains, including nutrition, dressing, self-care, toilet use, bladder care, bowel care, transfer, mobility, climbing stairs, and bathing. Scoring is performed over 100 points. The level of independence is determined by the level of the patient's need for physical or verbal help. High scores mean that the level of independence is higher. The patient is allowed to use assistive devices. | (1) Baseline, (2) At the end of the last session of the intervention (immediately after the 15th session, each session is 1 day), and (3) 4 weeks after the last session of the intervention) | 
| Change from baseline in the Stroke-Specific Quality of Life Scale | The stroke-Specific Quality of Life Scale assesses the quality of life in stroke patients. It consists of 12 domains and 49 items: mobility, energy, upper extremity function, work/productivity, mood, self-care, social role, family role, vision, language, thinking, and personality. Each item is evaluated on a 5-point Likert scale. The total score ranges from 49 to 245. Higher scores show a better quality of life. | (1) Baseline, (2) At the end of the last session of the intervention (immediately after the 15th session, each session is 1 day), and (3) 4 weeks after the last session of the intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, Upper limb impairment, Repetitive transcranial magnetic stimulation