Theta-Burst-Stimulation in Early Rehabilitation of Stroke

Study Overview
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Brief Summary
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The present prospective, randomized, controlled, double-blinded trial investigates the effects of intermittent theta-burst stimulation (iTBS) during the early rehabilitation after stroke. Patients with hemipresis will receive either sham or real iTBS over their affected hemispheres before occupational therapy for 8 days. Motor recovery is assessed one day after the intervention phase and three months after enrollment.

Detailed Description
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To date, rehabilitation of stroke with hemiparesis mainly includes physiotherapy and occupational therapy. Yet, the majority of patients retain movement impairment relevant for activities of daily living. One explanation for this deficit is the insufficient recovery of connectivity between brain regions after stroke. It is possible to modulate this process by repetitive transcranial magnetic stimulation (rTMS) using the protocol of intermittent theta-burst stimulation (iTBS). Previous data indicate that modulation of the motor cortex with iTBS enhances the effects of subsequent motor training. The present study aims at investigating whether daily repetitive transcranial magnetic stimulation over 8 days combined with subsequent physiotherapy leads to better motor recovery, compared with physiotherapy after sham stimulation. In the first weeks and after three months, motor function, degree of disability and quality of life are examined in order to evaluate the effects of iTBS in the rehabilitation of stroke patients. Amendment (approved by the Ethics-Committee of the Medical Faculty of the University of Cologne, 20/12/2016): Specification of exclusion criteria. Amendment (approved by the Ethics-Committee of the Medical Faculty of the University of Cologne, 15/11/2018): Change of inclusion and exclusion criteria.

Official Title
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Theta-Burst-Stimulation in Der frühen Rehabilitation Von Schlaganfallpatienten

Conditions
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Stroke

Intervention / Treatment
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* Device: Magstim Super Rapid2 System, intermittent theta-burst-stimulation (iTBS) protocol
* Device: Magstim Super Rapid2 System, sham-stimulation (in iTBS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: written consent age: 40-90 years ischemic stroke hemiparesis with impaired hand motor function Exclusion Criteria: Subjects who are legally detained in an official institute (§20 MPG) Participation in clinical trial within the last 12 weeks Electronic implants or ferromagnetic Implants located in the head, neck or thorax (e.g. clips, intracranial shunt, artificial heart valve, pacemaker) Medication pump (e.g. insulin pump) Metal splinters in eye or head Pregnancy / breastfeeding Severe Neurodegenerative disease Severe Neuroinflammatory disease History of seizures / epilepsy Physical addiction to alcohol, medication, or drugs (excluded: nicotine) Insufficient compliance Present or past malignant tumor involving the central nervous system Severe Psychiatric disease Clinically manifest bilateral hemiparesis or infarcts in the primary motor cortex or along the tractus corticospinalis in the hemisphere ipsilateral to the hemiparesis Pre-existing cerebral infarctions with hemiparesis or pre-existing cerebral infarctions in the primary motor cortex or along the tractus corticospinalis, excluding microangiopathic changes (e.g. clinically asymptomatic lacunae <1cm) Known brain lesion (surgical, traumatic) Evidence for enhanced cerebral pressure Severe cardial dysfunction life expectancy < 12 months NIHSS Score > 20 Blood glucose imbalances resistant to treatment (<50 mg/dl or >300 mg/dl) Elevated blood pressure resistant to treatment (RR > 185/110mmHg) Systemic Thrombolysis using r-tPA or thrombectomy within the last 24 hours before enrollment in study Medication with benzodiazepines, high-potency antipsychotics or tricyclic antidepressants before hospitalization or long-term during hospitalization

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 90 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Real-rTMS<br>Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex in the lesioned hemisphere using the intermittent theta-burst-stimulation protocol (iTBS; application of 3 pulses with a frequency of 50 Hz, in a theta-rhythm of 5 Hz for 2 seconds, repeated every 10 seconds, duration of one session: about 3,5 minutes) before physiotherapy for 8 days | Device: Magstim Super Rapid2 System, intermittent theta-burst-stimulation (iTBS) protocol<br>* iTBS applied over ipsilesional M1<br>|
| Sham Comparator: Sham-rTMS<br>Repetitive transcranial magnetic stimulation (rTMS) in sham position (tilted coil over parieto-occipital vertex) before physiotherapy for 8 days | Device: Magstim Super Rapid2 System, sham-stimulation (in iTBS)<br>* iTBS applied with tilted coil over parieto-occipital vertex<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative grip force | grip force as measured with vigorimeter | 3 months after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative grip force | grip force as measured with vigorimeter | after 8 days of intervention, and 3 months after enrollment | 
| Motor function | Action Research Arm Test, ARAT | after 8 days of intervention, and 3 months after enrollment | 
| Motor function | Fugl-Meyer Motor Scale of the upper extremity, FM | after 8 days of intervention, and 3 months after enrollment | 
| Stroke severity | National Instituts of Health Stroke Scale, NIHSS | after 8 days of intervention, and 3 months after enrollment | 
| Degree of disability | modified Rankin Scale, mRS | after 8 days of intervention, and 3 months after enrollment | 
| Motorcortex excitability | Motor evoked potential induced by stimulation of the affected motor cortex, MEP | after 8 days of intervention, and 3 months after enrollment | 
| Motorcortex excitability | Resting motor threshold as measured by stimulation of the affected motor cortex, RMT | after 8 days of intervention, and 3 months after enrollment | 
| Quality of life | EuroQol 5D questionnaire, EQ-5D | after 8 days of intervention, and 3 months after enrollment | 
| Activities of daily living at admission and discharge in external rehabilitation facility | Barthel-Index (BI) scores as documented by external rehabilitation facility | 3 months after enrollment | 
| Days of rehabilitation after intervention phase | Days of rehabilitation after intervention phase as documented by external rehabilitation facility | 3 months after enrollment |