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

Overview

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

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.

Interventions

• Device Bossdevice
  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 wh

Primary outcome measures

• Motor performance after the intervention [Time frame: After the last treatment session (5 days after first treatment)]

Secondary outcome measures (6)

• Motor performance after 3 months [Time frame: 3 months after the intervention]
• grip strength [Time frame: At screening and after 3 months after treatment]
• Assessment to measure quality of life [Time frame: At screening and after 3 months after treatment]
• modified Rankin Scale Score [Time frame: At screening and after 3 months after treatment]
• Barthel Index [Time frame: At screening and after 3 months after treatment]
• inpatient/npatient rehabilitation [Time frame: At screening and after 3 months after treatment]

Eligibility criteria

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Germany · 4 centers

• Universitätsklinikum Frankfurt, Zentrum der Neurologie und Neurochirurgie — Frankfurt a.M.
• Uniklinik Köln, Klinik und Poliklinik für Neurologie — Cologne
• Universitätsklinikum Münster, Klinik für Allgemeine Neurologie — Münster
• Universitätsklinikum Tübingen, Klinik für Neurologie — Tübingen

Publications

• Lieb A, Zrenner B, Zrenner C, Kozak G, Martus P, Grefkes C, Ziemann U. Brain-oscillation-synchronized stimulation to enhance motor recovery in early subacute stroke: a randomized controlled double-blind three- arm parallel-group exploratory trial comparing personalized, non- personalized and sham repetitive transcranial magnetic stimulation (Acronym: BOSS-STROKE). BMC Neurol. 2023 May 25;23(1):204 PMID 37231390

Identifiers

NCT: NCT05600374 · BOSS-STROKE · CIV-22-01-038788 · 01KG2125

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗