Brain-Oscillation-Synchronized Stimulation to Enhance Motor Recovery in Early Subacute Stroke

Study Overview
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Brief Summary
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We will investigate the therapeutic efficacy of EEG-synchronized noninvasive repetitive transcranial magnetic stimulation (rTMS) in the early subacute phase after ischemic stroke to improve upper limb motor rehabilitation. We hypothesize that synchronization of rTMS with the phase of the ongoing sensorimotor oscillation indicating high corticospinal excitability leads to significantly stronger improvement of paretic upper limb motor function than the same rTMS protocol non-synchronized to the ongoing sensorimotor oscillation or sham stimulation.

Detailed Description
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High-frequency rTMS will be applied to the ipsilesional motor cortex in 400 bursts of 100 Hz triplets with a mean inter-burst interval of 3 s (20 min treatment duration, 1,200 pulses per day) for 5 consecutive workdays (6,000 pulses total) at a stimulus intensity of 80% of resting motor threshold, in one of three conditions/arms, followed by 40 min task-specific hand/arm-physiotherapy.

Official Title
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Brain-Oscillation-Synchronized Stimulation to Enhance Motor Recovery in Early Subacute Stroke

Conditions
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Ischemic Stroke, Acute

Intervention / Treatment
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* Device: Bossdevice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects meeting all of the following criteria will be considered for admission to the trial: Age ≥ 18 years at the time of signing the informed consent. Cerebral ischemia identified by brain imaging (cerebral MRI or CT) occurred 1-14 days ago. Subject understands and voluntarily signs an informed consent document prior to any study related assessments/procedures. Stroke has resulted in a new arm-/hand motor deficit with ≤ 50 points in the FMA-UE. Presence of motor evoked potentials (MEPs) in the paretic hand. MEPs has to be obtained in the resting muscle o If no MEPs can be obtained, MEP search procedure can be repeated later up to 14 days after stroke onset. ● μ-oscillation (8-12 Hz) is recordable by EEG in the ipsilesional sensorimotor cortex with a sufficient signal-to-noise ratio of at least 3 dB ● Subject is able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: Subjects presenting with any of the following criteria will not be included in the trial: Hemorrhagic stroke (this refers to primary intracerebral hemorrhage only; hemorrhagic transformation of ischemic infarcts is not an exclusion criterion) Estimated life expectancy < 12 months Presence of intracranial ferromagnetic metal (extracranial stents ≥10 cm away from the TMS coil are acceptable) in accordance with current safety guidelines [18] Intraocular metal, cochlear implants If TMS might interact with sensors of active implants (e.g., intra-cardiac defibrillators). If a cranial bone gap affects currents induced by TMS (such as after craniotomy). History of seizures or epilepsy. Treatment intervention can't be started within 14 days after onset of stroke. Women during pregnancy and lactation. Participation in other studies if they are MDR or AMG studies or there is otherwise a high risk of insurance law issues intervening between two studies. In case of uncertainty, competing insurances must be contacted prior to participation persistent addiction disorder (except for nicotine dependence) CNS malignoma If there is any concern by the investigator regarding the safe participation of the subject in the study or for any other reason the investigator considers the subject inappropriate for participation in the study. The ability to consent for patients who are unable to speak will be assessed on the basis of the NIHS-Score by an independent physician (details see chapter 21 and appendix).

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Multicenter randomized controlled double-blind three-arm parallel-group exploratory clinical trial Medical Device Regulation (MDR) clinical trail
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Personalized stimulation<br>Each 100 Hz triplet is triggered when a real-time analyzed EEG-defined state of high corticospinal excitability is detected (i.e., the negative peak of the ongoing sensorimotor  10 Hz μ-oscillation). | Device: Bossdevice<br>* The bossdevice is a real-time digital signal processor consisting of hardware and software algorithms. It is designed to read-in a real-time raw data stream from a bio-signal amplifier (electroencephalography, EEG), to continuously analyze this data and to detect patterns based on oscillations in different frequencies. When such a specific bio-signal pattern is detected, the device indicates this through a standard output port. This enables a connected device to know with millisecond accuracy when a specific biosignal pattern occurs.<br>|
| No Intervention: Non-personalized stimulation<br>The identical rTMS protocol as in Arm 1, but 100 Hz triplets are not synchronized to the ongoing sensorimotor μ-oscillation. | |
| No Intervention: Sham stimulation<br>The same protocol as in arm 1 synchronized to the EEG-defined high excitability state, but with ineffective rTMS, using the sham side of an active/placebo TMS coil designed for double-blind clinical trials. Conditions/arm 2 and 3 are control conditions. Arm 2 controls for the specific effect of Condition/arm 1 to synchronize stimulation to the ongoing μ-oscillation. Arm 3 tests if auditory or somatosensory inputs (which are identical in the real and sham stimulation conditions) synchronized with the ongoing μ-oscillation are relevant for the effects of Arm 1. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor performance after the intervention | Primary efficacy endpoint is the motor performance after the intervention, as assessed by the Fugl-Meyer assessment (FMA-UE, range 0-66, 0 = no motor function, 66 = normal motor function) of the upper extremity (FMA-UE). The upper-extremity (UE) portion of the Fugl-Meyer assessment is the most frequently used scale to quantify post-stroke motor recovery of the upper extremity. The FMA-UE was used as an endpoint in most of the recent high-frequency rTMS trials in early subacute stroke patients. | After the last treatment session (5 days after first treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor performance after 3 months | Motor performance 3 months after the intervention, as assessed by the FMA-UE | 3 months after the intervention | 
| grip strength | Relative grip strength measured with a vigorimeter (measured in kg). | At screening and after 3 months after treatment | 
| Assessment to measure quality of life | Stroke-Specific Quality-of-Life Scale (SS-QOL) | At screening and after 3 months after treatment | 
| modified Rankin Scale Score | Rankin Scale Score (range 0-6, 0 = no disability, 6 =death) | At screening and after 3 months after treatment | 
| Barthel Index | Barthel Index (ordinary scale ordinal scale 0-100, 0 = fully dependent, 100 =independent in feeding, walking and grooming) | At screening and after 3 months after treatment | 
| inpatient/npatient rehabilitation | Number of days as an inpatient (in days) Number of days in inpatient rehabilitation (in days) | At screening and after 3 months after treatment |