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This trial aims to investigate whether placebo in isolation (open and hidden) has a specific neural signature in stroke subjects thus providing a novel mechanism to explain placebo effects that can be used to ultimately enhance stroke rehabilitation therapies.
Placebo effect leads to significant effects on brain excitability and connectivity, ultimately influencing clinical outcomes, including motor learning in stroke. This trial will provide critical mechanistic data to improve the understanding of placebo in stroke clinical trials, as to solve methodological and ethical dilemma in research designs, and to improve its clinical outcomes. It aims to investigate whether placebo in isolation (open and hidden) has a specific neural signature in stroke subjects. For this purpose, the investigators plan to recruit 56 chronic stroke participants, that will be randomized using blocked randomization in a 2:2:2:1 proportion to one of the following groups, respectively: 1) open placebo (OP) alone (16 subjects); 2) sham rTMS alone (16 subjects); 3) no intervention (16 subjects); or 4) active rTMS alone (8 subjects). All four groups will undergo 2 weeks of daily intervention visits (10 sessions).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active rTMS | Active Comparator | The participant will receive a session of low frequency rTMS to the contralesional primary motor cortex. Low frequency rTMS stimulation will be applied according to the following parameter: intensity of 80% MT (intensity could be adjusted if not comfortable to the subject), frequency of 1 Hz, 1200 pulses as a single, continuous train lasting 20 minutes. |
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| Sham rTMS | Sham Comparator | The investigators will place the coil in the same location, usually used for the active stimulation with the same stimulation parameters. However, the investigators will replace the active coil with a sham coil to ensure no stimulation is provided. |
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| Open Placebo | Placebo Comparator | The open placebo will consist of typical prescription medicine bottle of placebo pills with a label clearly marked "placebo pills" "take 2 pills twice daily." The placebo pills are made from Microcrystalline Cellulose. |
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| No Intervention | No Intervention | It consists of treatment-as-usual group. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Active rTMS | Device | Subjects will undergo repetitive transcranial magnetic stimulation, each session lasting 20 minutes. |
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| Measure | Description | Time Frame |
|---|---|---|
| Electroencephalography (EEG): Frontal alpha asymmetry | The FAA score will be calculated by subtracting the natural log-transformed alpha power in the left frontal region (F3, F7, Fp1) from the natural log-transformed power in the right frontal region (F4, F8, Fp2). | Change from 2 weeks to baseline |
| Measure | Description | Time Frame |
|---|---|---|
| Fugl-Meyer motor scale (FM) | The investigators will use this tool for motor function after stroke. It is valid, responsive to change, and widely used for motor function and recovery assessment in stroke patients. Items are scored on a 3-point ordinal scale, being 0 the lowest and 2 the highest value. A higher score means a better outcome. | Change from 2 weeks to baseline |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Felipe Fregni, MD, PhD, MPH | Contact | 6179526156 | fregni.felipe@mgh.harvard.edu | |
| Elly Pichardo, MD | Contact | 6179526154 | epichardo@partners.org |
| Name | Affiliation | Role |
|---|---|---|
| Felipe Fregni, MD, PhD, MPH | Spaulding Rehabilitation Hospital/Harvard Medical School | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Spaulding Hospital Cambridge | Recruiting | Cambridge | Massachusetts | 02138 | United States |
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| ID | Term |
|---|---|
| D020521 | Stroke |
| D010291 | Paresis |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| Sham rTMS | Device | Subjects will undergo sham repetitive transcranial magnetic stimulation, each session lasting 20 minutes. |
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| Open Placebo | Dietary Supplement | The open placebo will consist of an inactive substance pill commonly used in clinical trials and given to the subject in a regular pill dispenser. |
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| Premotor-M1 (PM-M1) connectivity | For the PM-M1 connectivity computation, the investigators will calculate the spectral coherence score, which indicates the functional connectivity in brain activity between two cortical regions and is calculated as a function of frequency. | Change from 2 weeks to baseline |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |