Placebo Effects for Stroke Recovery

Overseen By Elly Pichardo, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Spaulding Rehabilitation Hospital

Disqualifiers: Prefrontal lesion, Unstable conditions, Pregnancy, others

Compensation: Varies

Number of Visits: 10

Duration: 2 weeks

56 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment rTMS for stroke recovery?

Research shows that repetitive transcranial magnetic stimulation (rTMS) can help with motor recovery after a stroke, and placebo rTMS has also been found to have a positive effect on post-stroke motor rehabilitation. This suggests that both the actual treatment and the placebo can contribute to recovery, highlighting the importance of the placebo effect in this context. ^{1 2 3 4 5}

Is repetitive transcranial magnetic stimulation (rTMS) safe for humans?

Research shows that repetitive transcranial magnetic stimulation (rTMS) is generally safe and well-tolerated in humans, with some studies specifically evaluating its safety in stroke patients. While some people may experience mild side effects like headaches or scalp discomfort, serious side effects are rare. ^{1 2 3 6 7}

How does the treatment Active rTMS differ from other treatments for stroke recovery?

Active rTMS (repetitive transcranial magnetic stimulation) is unique because it uses magnetic fields to stimulate nerve cells in the brain, which can help improve motor function after a stroke. Unlike traditional treatments, it involves non-invasive brain stimulation and can have significant placebo effects, which may enhance its therapeutic impact. ^{1 3 4 5 8}

What is the purpose of this trial?

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.

Research Team

Felipe Fregni, MD, PhD, MPH

Principal Investigator

Spaulding Rehabilitation Hospital/Harvard Medical School

Eligibility Criteria

This trial is for adults over 18 who've had a stroke at least 6 months ago, resulting in one-sided weakness but still have some arm movement. They should not be severely disabled before the stroke and must understand instructions. People with joint pain, certain brain injuries from their stroke, pregnancy, unstable health conditions or electronic implants near the brain can't join.

Inclusion Criteria

I had a stroke more than 6 months ago.

You had difficulty with daily activities before the stroke.

Your upper arm and hand movement score on the Fugl-Meyer scale is between 11 and 56.

Exclusion Criteria

I had a stroke affecting the front part of my brain, confirmed by EEG.

Pregnancy

I have joint pain that could affect my ability to participate in assessments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized into one of four groups: open placebo, sham rTMS, no intervention, or active rTMS, and undergo 2 weeks of daily intervention visits

2 weeks

10 sessions (in-person)

Follow-up

Participants are monitored for changes in motor function and brain activity after the treatment phase

2 weeks

Treatment Details

Interventions

• Active rTMS
• Open Placebo
• Sham rTMS

Trial Overview The study tests if different types of placebo (openly given as a placebo or disguised) and active repetitive Transcranial Magnetic Stimulation (rTMS), which is a non-invasive brain stimulation technique, affect recovery in chronic stroke patients differently.

Participant Groups

Group I: No Intervention Active Control 1 Intervention

It consists of treatment-as-usual group.

Group II: Active rTMS Active Control 1 Intervention

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.

Group III: Sham rTMS Placebo Group 1 Intervention

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.

Group IV: Open Placebo Placebo Group 1 Intervention

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.

Active rTMS is already approved in United States, European Union for the following indications:

Approved in United States as rTMS for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)
• Smoking Cessation
• Chronic Pain Syndrome

Approved in European Union as rTMS for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)
• Chronic Pain Syndrome
• Generalized Anxiety Disorder (GAD)
• Bipolar Disorder

Who Is Running the Clinical Trial?

Spaulding Rehabilitation Hospital

Lead Sponsor

Trials

143

Recruited

11,200+

Findings from Research

The new real electro-magnetic placebo (REMP) device effectively simulates the scalp sensations of real repetitive transcranial magnetic stimulation (rTMS) while ensuring that it does not produce any biologically active electric fields, making it a more reliable sham for clinical trials.

In tests, naive subjects were more likely to mistake the REMP-attenuated TMS for real rTMS compared to other sham methods, indicating that the REMP device provides a superior placebo experience, which is crucial for accurately assessing the efficacy of rTMS treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real electro-magnetic placebo (REMP) device for sham transcranial magnetic stimulation (TMS). Rossi, S., Ferro, M., Cincotta, M., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) significantly improved motor function in stroke patients within the first month after treatment, particularly in upper limb function, as shown by various motor functional scores assessed over time.

The benefits of rTMS on upper extremity function were observed to last for up to one year, indicating its potential as a long-term therapeutic intervention for motor recovery after stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of repetitive transcranial magnetic stimulation (rTMS) after acute stroke: A one-year longitudinal randomized trial. Guan, YZ., Li, J., Zhang, XW., et al.[2021]

A meta-analysis of 26 placebo-controlled trials involving 381 patients showed that placebo repetitive transcranial magnetic stimulation (rTMS) has a medium and significant effect on improving motor recovery after a stroke, with an effect size of 0.466.

The number of treatment sessions was found to significantly influence the placebo effect size, indicating that more sessions may enhance the perceived benefits of sham rTMS, which also showed sustained motor improvement for at least 3 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo effect of rTMS on post-stroke motor rehabilitation: a meta-analysis. Jin, Y., Pu, T., Guo, Z., et al.[2022]

In a study of 45 patients, the timing of sham rTMS relative to active rTMS significantly influenced pain relief, with placebo analgesia occurring only when sham sessions followed successful active rTMS, indicating a potential conditioned learning effect.

The findings suggest that even modest analgesic effects (around 10%) from active rTMS can enhance placebo responses, implying that the threshold for clinically significant pain relief in trials may need to be reconsidered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

On the importance of placebo timing in rTMS studies for pain relief. André-Obadia, N., Magnin, M., Garcia-Larrea, L.[2022]

Sham transcranial magnetic stimulation (TMS) is commonly used in research to differentiate real effects from side effects, but it has limitations in accurately controlling for placebo and sensory effects.

The authors argue that sham TMS cannot fully serve as a control condition because it does not adequately demonstrate the specificity of TMS effects, suggesting that it should be used alongside other control strategies in TMS studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rethinking the role of sham TMS. Duecker, F., Sack, AT.[2020]

In a meta-analysis of 93 randomized controlled trials involving repetitive transcranial magnetic stimulation (TMS), the overall incidence of adverse events (AEs) was found to be higher in the active TMS group (29.3%) compared to the placebo group (13.6%), indicating a 2.60 times greater risk of experiencing AEs with active treatment.

Despite the higher incidence of AEs, TMS is considered a safe and well-tolerated intervention, with common side effects including headache and dizziness, highlighting the importance of recognizing nocebo effects in both clinical trials and practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Nocebo Phenomena During Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Placebo-Controlled Clinical Trials. Zis, P., Shafique, F., Hadjivassiliou, M., et al.[2022]

In a study involving 15 chronic stroke patients, five sessions of low-frequency repetitive transcranial magnetic stimulation (rTMS) on the unaffected hemisphere significantly improved motor function in the affected hand for up to 2 weeks, compared to a sham treatment.

The study found that this increased rTMS treatment did not lead to any cognitive side effects or increased risk of seizures, indicating it is a safe intervention for enhancing motor recovery in stroke patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Fregni, F., Boggio, PS., Valle, AC., et al.[2022]

The study found that healthy volunteers who believed they received an effective treatment (TENS) showed increased force output and enhanced excitability in the corticospinal system, indicating a placebo effect on motor performance.

Using transcranial magnetic stimulation (TMS), researchers demonstrated that this placebo effect was linked to cognitive factors, as the excitability changes occurred even when all subjects exerted the same force, suggesting a top-down influence on motor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-induced changes in excitatory and inhibitory corticospinal circuits during motor performance. Fiorio, M., Emadi Andani, M., Marotta, A., et al.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

A real electro-magnetic placebo (REMP) device for sham transcranial magnetic stimulation (TMS). [2021]

2. England pubmed.ncbi.nlm.nih.gov

Effectiveness of repetitive transcranial magnetic stimulation (rTMS) after acute stroke: A one-year longitudinal randomized trial. [2021]

3. Italy pubmed.ncbi.nlm.nih.gov

Placebo effect of rTMS on post-stroke motor rehabilitation: a meta-analysis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

On the importance of placebo timing in rTMS studies for pain relief. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Rethinking the role of sham TMS. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Nocebo Phenomena During Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Placebo-Controlled Clinical Trials. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Placebo-induced changes in excitatory and inhibitory corticospinal circuits during motor performance. [2022]