Magnetic Brain Stimulation and Computer-based Motor Training for Rehabilitation After Stroke

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.

• Brain-Computer Interface accuracy [Срок оценки: Measured one time per day, at days 3-12 and days 15-24.]
• Task-related functional Magnetic Resonance Imaging (t-fMRI) [Срок оценки: Measured one time per day, at the days 2, 13, 14, and 25.]
• Jebsen-Taylor Hand Function Test [Срок оценки: Measured one time per day, at the days 2, 13, 14, and 25.]
• Diffusion-based tractography [Срок оценки: Measured one time per day, at the days 2, 13, 14, and 25.]
• Movement-related cortical potential amplitude [Срок оценки: Measured one time per day, at the days 2, 13, 14, and 25.]
• Resting-state functional Magnetic Resonance Imaging (rs-fMRI) [Срок оценки: Measured one time per day, at the days 2, 13, 14, and 25.]
• Voxel-based morphometry [Срок оценки: Measured one time per day, at the days 2, 13, 14, and 25.]
• Brain-derived neurotrophic factor (BDNF) in serum [Срок оценки: 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.]