Clinical trial NCT06116942: Magnetic Brain Stimulation and Computer-based Motor Training for Rehabilitation After Stroke
Official title: Repetitive Transcranial Magnetic Stimulation for Enhancing Brain Computer Interphase-induced Plasticity in Stroke: a Crossover Design
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Chronic Stroke
Keywords: Transcranial Magnetic Stimulation
Intermittent Theta Burst Stimulation
Brain-Computer Interface
Rehabilitation
EEG
MRI
Molecular changes
Brain plasticity
Stroke
Hemiparesis
Lead sponsor: Max Planck Institute for Human Cognitive and Brain Sciences
Sponsor class: OTHER
Collaborators: name: University of Halle Medical Faculty
First posted: 2023-11-03
Enrollment: 24
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized placebo-controlled cross-over factorial single-blind mono-center trial with 2 arms (active stimulation-placebo stimulation \| placebo stimulation-active stimulation).
Primary purpose: TREATMENT

Brief summary: The goal of the present clinical trial is to explore whether an innovative technology-based approach can help individuals who have had a stroke and can no longer move their hands with ease. Our approach consists of a combination of two technologies: Transcranial Magnetic Stimulation (TMS) and a Brain-Computer Interface (BCI). The former entails the application of magnetic fields over the head to stimulate the brain preparing it for a better ability to produce movement. The latter consists of measuring brain activity to personalize a type of computer-based training that is designed to increase communication between the brain and the muscles.

Detailed description: Aims of the study:

1. to provide preliminary evidence of the effect of rTMS (repetitive Transcranial Magnetic Stimulation) on brain-computer interface (BCI)-mediated plasticity on individuals with hemiparesis after stroke
2. Measure adherence and withdrawal rates of the present protocol for informing a future large-scale randomized controlled trial

The active stimulation (rTMS) consists of an intermittent theta burst (iTBS) protocol whereas the placebo condition encompasses rTMS stimulation delivered with a Sham coil (Sham).

Procedures:

The study will entail 25 sessions. The study is composed of six different types of sessions in a crossover design:

1. Screening session (day 1): Includes the informed consent form signature, enrollment and BCI calibration
2. Before-treatment and after-treatment sessions (day 2, 13, 14 and 25) include the recording of EEG and MRI data, as well as the application of tests and questionnaires for evaluation of motor function
3. Daily visit with blood draw sessions (days 3, 12, 15 and 24): consist of the delivery of active or sham rTMS followed by BCI training preceded and followed by a blood draw.
4. Daily visit sessions without a blood draw (days 4 to 11 and 16 to 23): consist of the delivery of active or sham rTMS followed by BCI training.

After a screening session (day 1), the clinical study begins. The period I of the study begins with a before-treatment session (day 2). Then, the intervention (rTMS or sham followed by BCI training) is delivered during 10 daily visits over a 2-week period excluding weekends (days 3 to 12). Within the daily visits, there are 2 daily visits with blood draws (days 3 and 12) and the rest do not include any blood draws (days 4 to 11). Then, an after-treatment session takes place (day 13).

After period I, a washout period of 4 weeks takes place. No measurements or training are required during this time. In Period II of the study, the session flow is repeated except for the screening session. Therefore, period II includes a before-treatment session (day 14), 10 daily visits (days 15 to 24), with 2 daily visits that include blood draws (days 15 and 24), and an after-treatment session (day 25).

Research questions:

1. Does rTMS promote better motor recovery after BCI training in comparison to sham?
2. Can rTMS propitiate stronger effects on neural physiology after BCI training in comparison with sham?
3. Is there an association between behavioral and physiological changes after the proposed intervention?
4. What is the adherence and withdrawal rate and reason for withdrawal of the proposed study design and procedures?
5. Is there an association between brain structures associated with motor function at baseline and the changes observed after rTMS?
6. Can applying rTMS have a better effect on self-perceived motor performance in daily activities in comparison to Sham?
7. Are serum molecular markers of plasticity and neural turnover modulated by rTMS?

Hypotheses:

1. A higher increase in motor performance will be observed after the rTMS-BCI in comparison with sham-BCI. The motor performance will be assessed as Fugl-Meyer Assessment for upper extremity score as the primary outcome measure; and as the Jebsen Taylor hand function test and BCI accuracy as the secondary outcome measures
2. Higher physiological changes will be observed after rTMS-BCI in comparison with sham-BCI. The electrophysiological changes will be assessed as Motor evoked potentials, as primary outcome measured; and as motor-related cortical potentials, Event-Related Desynchronization and functionalMagnetic Resonance Imaging changes as secondary outcome measures
3. Behavioral and physiological changes will be associated
4. Changes in structural MRI will be associated with behavioral outcome measures after rTMS-BCI and sham-BCI. Structural MRI will be assessed as Fractional Anisotropy changes, as a primary outcome measure; and voxel-based morphometry as a secondary outcome measure
5. Individuals will have a higher perceived improvement in activities of daily living, measured as higher scores in the Upper extremity motor activity log (UE-MAL) and the first and last items of the Stroke impact scale (SIS) questionnaire after rTMS-BCI in comparison with sham-BCI
6. The increase in Brain-Derived Neurotrophic Factor (BDNF) will be higher after rTMS-BCI in comparison with after sham-BCI and an association between BDNF levels and behavioral markers of motor recovery will exist

As an exploratory analysis, the investigators will inspect preliminary evidence of the effects of the stimulation by verifying changes in serological markers of neuronal plasticity and turnover.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of a subcortical stroke at least 6 months before the initiation of the trial and confirmed with magnetic resonance imaging (MRI) or computed tomography
2. Present moderate to severe hemiparesis in an upper limb
3. Language comprehension as well as visual and auditory perception sufficient to engage in Brain Computer Interface training
4. Age from 20 to 80 years old
5. Clear consciousness and stable vital signs
6. Eligible for MRI, EEG, BCI and TMS methods

Exclusion Criteria:

1. Drug abuse or recent changes in medications that may alter the central nervous system when the measurements begin or during the measurements (e.g., benzodiazepines, serotoninergic and dopaminergic agents)
2. History of seizure
3. Bone, joint and muscle diseases
4. Peripheral neuropathy or other neurological or psychiatric diseases (including, tinnitus, migraine, or mood disorders with the exception of minimal, mild, and moderate depression, reflected as a Beck depression scale score lower than 29).
5. Strong cognitive deficits (including speech, attention, hearing, vision, sensation or intelligence deficits) reflected as a Montreal Cognitive Assessment (MoCA) score lower or equal to 24
6. Lesions in the upper extremities
7. Bone, joint and muscle diseases
8. Severe spasticity (higher than 3) or pain in the upper limb and affecting wrist extension
9. Contraindications of undergoing TMS examinations: history of seizures, history of epilepsy, unclear unconsciousness, migraines or metals on the head
10. Contraindications for MRI: metals in the body, metallic prosthetics or claustrophobia
11. Participation in other interventional trials using BCI or rTMS within less than 6 months ago
12. Participation in another interventional clinical trial
13. Suspected lack of compliance
14. Pregnant or nursing women

Primary outcomes:
measure: Motor-evoked potential (MEP) parameters
timeFrame: Measured two times per day, at the days: 3-12 and 15-24. The first measurement is performed immediately before the rTMS-BCI intervention and the second immediately after the rTMS-BCI intervention.
measure: Fugl-Meyer upper extremity assessment of sensorimotor function
timeFrame: Measured one time at day, at the days: 2, 13, 14, and 25.
measure: Event-related desynchronization (ERD)
timeFrame: Measured one time per day, at the days: 2, 13, 14, and 25.
Secondary outcomes:
measure: Brain-Computer Interface accuracy
timeFrame: Measured one time per day, at days 3-12 and days 15-24.
measure: Task-related functional Magnetic Resonance Imaging (t-fMRI)
timeFrame: Measured one time per day, at the days 2, 13, 14, and 25.
measure: Jebsen-Taylor Hand Function Test
timeFrame: Measured one time per day, at the days 2, 13, 14, and 25.
measure: Diffusion-based tractography
timeFrame: Measured one time per day, at the days 2, 13, 14, and 25.
measure: Movement-related cortical potential amplitude
timeFrame: Measured one time per day, at the days 2, 13, 14, and 25.
measure: Resting-state functional Magnetic Resonance Imaging (rs-fMRI)
timeFrame: Measured one time per day, at the days 2, 13, 14, and 25.
measure: Voxel-based morphometry
timeFrame: Measured one time per day, at the days 2, 13, 14, and 25.
measure: Brain-derived neurotrophic factor (BDNF) in serum
timeFrame: Measured twice per day, at the days 3, 12, 15 and 24. The first measure occurs before the intervention and the second measure after the intervention.
Other outcomes:
measure: Adherence
timeFrame: Through study completion, for 25 days.
measure: Upper extremity motor activity log (UE-MAL)
timeFrame: Measured one time per day, at days 2, 13, 14, and 25.
measure: Withdrawal rate
timeFrame: Through study completion, for 25 days.
measure: Last item of the stroke impact scale (SIS)
timeFrame: Measured once per day, at days 2, 13, 14, and 25.
measure: Micro fractional anisotropy (micro-FA)
timeFrame: Measured once per day, at days 2, 13, 14, and 25.
measure: Glial fibrillary acidic protein (GFAP)
timeFrame: Measured twice per day, at the days 3, 12, 15 and 24. The first measure occurs before the intervention and the second measure after the intervention.
measure: Neurofilaments (light chain)
timeFrame: Measured twice per day, at the days 3, 12, 15 and 24. The first measure occurs before the intervention and the second measure after the intervention.
measure: Beta-synuclein
timeFrame: Measured twice per day, at the days 3, 12, 15 and 24. The first measure occurs before the intervention and the second measure after the intervention.
Locations:
city: Leipzig
country: Germany
facility: Max Planck Institute for Human Cognitive and Brain Sciences
state: Saxony
Study officials:
affiliation: Charité Universitätmedizin Berlin and Max Planck Institute for Human Cognitive and Brain Sciences
name: Aimee Flores-Sandoval, MsC
role: STUDY_CHAIR
affiliation: Max Planck Institute for Human Cognitive and Brain Sciences
name: Arno Villringer, MD PhD
role: STUDY_DIRECTOR
affiliation: Max Planck Institute for Human Cognitive and Brain Sciences and Halle University
name: Bernhard Sehm, PD. med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Max Planck Institute for Human Cognitive and Brain Sciences
name: Vadim Nikulin, PhD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tang Z, Han K, Wang R, Zhang Y, Zhang H. Excitatory Repetitive Transcranial Magnetic Stimulation Over the Ipsilesional Hemisphere for Upper Limb Motor Function After Stroke: A Systematic Review and Meta-Analysis. Front Neurol. 2022 Jun 20;13:918597. doi: 10.3389/fneur.2022.918597. eCollection 2022.
citation: Peng Y, Wang J, Liu Z, Zhong L, Wen X, Wang P, Gong X, Liu H. The Application of Brain-Computer Interface in Upper Limb Dysfunction After Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Hum Neurosci. 2022 Mar 29;16:798883. doi: 10.3389/fnhum.2022.798883. eCollection 2022.