Mechanisms of Open and Hidden Placebo in Stroke Recovery

Overview

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.

Detailed description

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).

Interventions

• Device Active rTMS
  Subjects will undergo repetitive transcranial magnetic stimulation, each session lasting 20 minutes.
• Device Sham rTMS
  Subjects will undergo sham repetitive transcranial magnetic stimulation, each session lasting 20 minutes.
• Dietary supplement Open Placebo
  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.

Primary outcome measures

• Electroencephalography (EEG): Frontal alpha asymmetry [Time frame: Change from 2 weeks to baseline]

Secondary outcome measures (2)

• Fugl-Meyer motor scale (FM) [Time frame: Change from 2 weeks to baseline]
• Premotor-M1 (PM-M1) connectivity [Time frame: Change from 2 weeks to baseline]

Eligibility criteria

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

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

Triple blind

Primary purpose

Other

Study locations

United States · 1 center

• Spaulding Hospital Cambridge — Cambridge

Publications

• Ortega-Marquez J, Camargo L, Gianlorenco AC, Sosa W, Black-Schaffer R, Wang QM, Fregni F. Mechanisms of open and hidden placebo in stroke recovery: targeting neuroplasticity insights of the placebo effect - study protocol for a controlled, parallel, randomised clinical trial. BMJ Open. 2026 Jul 22;16(7):e113119. doi: 10.1136/bmjopen-2025-113119. PMID 42486522

Identifiers

NCT: NCT05832567 · 2023P000884

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗