Mechanisms of Open and Hidden Placebo in Stroke Recovery

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).

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.

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.

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.

Subjects will undergo sham repetitive transcranial magnetic stimulation, each session lasting 20 minutes.

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.

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).

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.

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.

Inclusion Criteria: Adults with hemiparesis due to chronic stroke Stroke duration of 6 months or more Fugl-Meyer scale upper extremity motor assessment score of > 11 and ≤ 56 Pre-stroke disability (defined as a score of < 3 on the Modified Rankin Scale) Age 18 or older Exclusion Criteria: Stroke of anterior cerebral artery territory with prefrontal lesion and stroke-related decreased EEG power in the prefrontal cortex Unable to understand instructions TMS contraindications: electronic hardware in close contact to the discharging coil such as cochlear implant, internal pulse generator or medical pump Concurrent unstable medical conditions A score of 24 or higher on the Hamilton Depression Rating Scale (HDRS) Joint or paretic extremity pain likely to interfere with assessments Pregnancy