rTMS for Stroke-Related Fatigue

Overseen By Korey Little, BS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: VA Office of Research and Development

Disqualifiers: Seizures, Multiple sclerosis, Depression, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4-6 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This experimental trial is investigating the use of magnetic stimulation of the brain as a possible treatment for people with post-stroke fatigue. Fatigue is a common condition after a stroke and can negatively impact an individual's ability to perform desired social and physical activities. Magnetic stimulation of the brain has been shown to improve signs and symptoms of related psychological (e.g., depression) conditions. Participants in this trial will receive a type of magnetic stimulation called repetitive magnetic stimulation, or rTMS. The investigators will measure feelings of fatigue, and other clinical characteristics related to mood and cognition, before and after participants receive rTMS.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have comorbid psychological conditions like depression or anxiety, you may not be eligible to participate.

What data supports the effectiveness of the treatment High frequency repetitive transcranial magnetic stimulation (rTMS) for stroke-related fatigue?

Research shows that repetitive transcranial magnetic stimulation (rTMS) can help with recovery after a stroke by promoting changes in the brain that improve function. It has also been found effective for treating post-stroke depression, which suggests it might help with stroke-related fatigue as well. ^{1 2 3 4 5}

Is rTMS safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) has been studied for safety in various conditions, including depression and stroke. Research shows that rTMS is generally safe, with some studies specifically evaluating its safety in stroke patients and others in people with depression. Common side effects are mild and may include headaches or scalp discomfort. ^{4 6 7 8 9}

How does the treatment rTMS for stroke-related fatigue differ from other treatments?

rTMS (repetitive transcranial magnetic stimulation) is unique because it is a non-invasive treatment that uses magnetic fields to stimulate nerve cells in the brain, promoting neuroplasticity (the brain's ability to reorganize itself) and potentially aiding recovery after a stroke. Unlike other treatments, it does not involve medication or surgery, and it can be targeted to specific brain areas to improve function. ^{3 5 10 11 12}

Research Team

John H Kindred

Principal Investigator

Ralph H. Johnson VA Medical Center, Charleston, SC

Eligibility Criteria

This trial is for individuals aged 35-80 who have experienced a stroke at least 6 months ago and are dealing with fatigue. They must be able to walk 10 meters without help. People with metal in their head, history of seizures, multiple strokes across both brain hemispheres, other neurological or severe psychological conditions, or those who are pregnant cannot participate.

Inclusion Criteria

I often feel very tired.

It has been over 6 months since my stroke.

I can walk 10 meters by myself.

Exclusion Criteria

Pregnancy

I have had a stroke in my cerebellum or brainstem.

You have had a stroke in the areas of the brain where stimulation will be done.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive high-frequency repetitive transcranial magnetic stimulation (rTMS) or sham rTMS for approximately 40 minutes per session

4-6 weeks

Follow-up

Participants are monitored for changes in fatigue severity and impact, mood, and cognition after treatment

3 months

Treatment Details

Interventions

• High frequency repetitive transcranial magnetic stimulation
• Sham repetitive transcranial magnetic stimulation

Trial Overview The study tests high frequency repetitive transcranial magnetic stimulation (rTMS) against a sham procedure to see if it reduces post-stroke fatigue. Participants will receive rTMS and their levels of fatigue, mood, and cognitive function will be assessed before and after treatment.

Participant Groups

Group I: Real M1 High Frequency rTMS Experimental Treatment 1 Intervention

Participants will be randomly assigned to receive high-frequency repetitive transcranial magnetic stimulation (rTMS) to the top of their head for approximately 40 minutes.

Group II: Real LDLPFC High Frequency rTMS Experimental Treatment 1 Intervention

Participants will be randomly assigned to receive high-frequency repetitive transcranial magnetic stimulation (rTMS) to the left frontal part of their head for approximately 40 minutes.

Group III: Sham rTMS Placebo Group 1 Intervention

Participants will be randomly assigned to receive sham/placebo repetitive transcranial magnetic stimulation (rTMS) to the their head for approximately 40 minutes. This is a control condition.

High frequency repetitive transcranial magnetic stimulation is already approved in Canada, United States, European Union for the following indications:

Approved in Canada as rTMS for:

• Post-stroke depression
• Post-stroke fatigue

Approved in United States as rTMS for:

• Treatment-resistant depression
• Post-stroke depression
• Post-stroke fatigue

Approved in European Union as rTMS for:

• Treatment-resistant depression
• Post-stroke depression

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Ralph H. Johnson VA Medical Center

Collaborator

Trials

21

Recruited

5,700+

Findings from Research

In a study comparing transcranial magnetic stimulation (TMS) and peripheral electrical stimulation in patients with central nervous system lesions and healthy controls, prolonged recovery times of motor evoked potential (MEP) amplitudes indicated that central fatigue is primarily a cortical phenomenon rather than a result of muscle or spinal issues.

The findings suggest that measuring MEP recovery times is an effective and objective method for assessing central fatigue and distinguishing between individuals with CNS lesions and healthy individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central fatigue assessed by transcranial magnetic stimulation. Liepert, J., Kotterba, S., Tegenthoff, M., et al.[2019]

In a pilot study involving 6 patients with post-stroke depression, an accelerated rTMS protocol significantly reduced depression scores (HAMD) from an average of 15.5 to 4.17, with effects lasting up to 3 months after treatment.

The study found that the accelerated rTMS treatment was safe, with no significant adverse events reported, suggesting it could be a viable alternative or adjunctive therapy for post-stroke depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel TMS for Stroke and Depression (NoTSAD): Accelerated Repetitive Transcranial Magnetic Stimulation as a Safe and Effective Treatment for Post-stroke Depression. Frey, J., Najib, U., Lilly, C., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) shows promise in enhancing recovery from post-stroke deficits by promoting neuroplasticity, with effects depending on the stimulation site and frequency.

Applying low-frequency rTMS (around 1 Hz) to the unaffected hemisphere can help restore inhibition, while high-frequency rTMS (5 Hz or more) to the affected hemisphere can reactivate hypoactive brain regions, suggesting a tailored approach to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stroke recovery can be enhanced by using repetitive transcranial magnetic stimulation (rTMS). Lefaucheur, JP.[2016]

The study involving 33 patients with multiple sclerosis (MS) found that deep brain H-coil repetitive transcranial magnetic stimulation (rTMS) is safe and well tolerated, with no serious adverse events reported.

Patients experienced a significant reduction in fatigue, as measured by the Fatigue Severity Scale, with a median decrease of 1.0 point that was maintained during follow-up, suggesting potential efficacy for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and preliminary efficacy of deep transcranial magnetic stimulation in MS-related fatigue. Gaede, G., Tiede, M., Lorenz, I., et al.[2022]

In a preliminary study involving 15 patients with moderate to severe motor dysfunction after stroke, the combination of neuromuscular electrical stimulation (NMES) and repetitive transcranial magnetic stimulation (rTMS) led to significant improvements in motor function as measured by various tests.

The treatment was applied twice daily for two weeks, and the results indicate that this combined approach could be beneficial for enhancing recovery in patients with motor impairments following a stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NMES with rTMS for moderate to severe dysfunction after stroke. Koyama, S., Tanabe, S., Warashina, H., et al.[2022]

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) significantly reduces depression in stroke patients, with a large effect size (SMD of -1.01) based on a meta-analysis of 17 randomized controlled trials involving over 1,000 participants.

While HF-rTMS is effective, it is associated with a higher incidence of headaches compared to control treatments, indicating a need for further safety evaluations in larger multicenter studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of High-Frequency Repetitive Transcranial Magnetic Stimulation for Poststroke Depression: A Systematic Review and Meta-analysis. Liu, C., Wang, M., Liang, X., et al.[2020]

In a study involving 18 subjects with major depression, repetitive transcranial magnetic stimulation (rTMS) for up to 4 weeks was found to be generally safe, with no significant mean deficits in neuropsychologic function or auditory thresholds.

However, two patients experienced mild high-frequency hearing loss, indicating that while rTMS is safe for most, individual responses may vary and warrant further investigation into long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychologic functioning, electroencephalogram, and auditory threshold in depressed patients. Loo, C., Sachdev, P., Elsayed, H., et al.[2019]

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]

Suprathreshold rTMS over the left primary sensorimotor cortex significantly increased brain activity in the stimulated area and supplementary motor area (SMA) in most subjects, indicating effective neuronal activation.

Subthreshold rTMS did not activate the primary sensorimotor cortex but still modulated activity in remote areas like the SMA and lateral premotor cortex, suggesting it influences corticocortical connections without inducing motor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subthreshold high-frequency TMS of human primary motor cortex modulates interconnected frontal motor areas as detected by interleaved fMRI-TMS. Bestmann, S., Baudewig, J., Siebner, HR., et al.[2019]

In a study of 62 subacute stroke patients, high-frequency rTMS (10 Hz) applied over 10 days significantly improved upper limb motor function, as measured by the Fugl-Meyer Assessment, particularly in patients with intact corticospinal tract integrity and specific BDNF genotypes.

The results indicate that individual patient characteristics, especially CST integrity and BDNF genotype, should guide the use of rTMS for optimizing motor recovery in stroke rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors influencing the response to high-frequency repetitive transcranial magnetic stimulation in patients with subacute stroke. Chang, WH., Uhm, KE., Shin, YI., et al.[2023]

In a study involving poststroke patients, high-frequency rTMS applied to the primary motor cortex significantly reduced F-wave persistence and F/M Amp.Ratio, indicating a decrease in spinal excitability related to spasticity.

The results suggest that rTMS may enhance inhibitory effects on the corticospinal tract, providing a potential therapeutic mechanism for managing increased spasticity in poststroke patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

F-wave suppression induced by suprathreshold high-frequency repetitive trascranial magnetic stimulation in poststroke patients with increased spasticity. Wupuer, S., Yamamoto, T., Katayama, Y., et al.[2022]

References

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

Central fatigue assessed by transcranial magnetic stimulation. [2019]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Novel TMS for Stroke and Depression (NoTSAD): Accelerated Repetitive Transcranial Magnetic Stimulation as a Safe and Effective Treatment for Post-stroke Depression. [2021]

3. France pubmed.ncbi.nlm.nih.gov

Stroke recovery can be enhanced by using repetitive transcranial magnetic stimulation (rTMS). [2016]

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

Safety and preliminary efficacy of deep transcranial magnetic stimulation in MS-related fatigue. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

NMES with rTMS for moderate to severe dysfunction after stroke. [2022]

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

Efficacy and Safety of High-Frequency Repetitive Transcranial Magnetic Stimulation for Poststroke Depression: A Systematic Review and Meta-analysis. [2020]

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

Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychologic functioning, electroencephalogram, and auditory threshold in depressed patients. [2019]

8. 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]

9. 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]

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

Subthreshold high-frequency TMS of human primary motor cortex modulates interconnected frontal motor areas as detected by interleaved fMRI-TMS. [2019]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Factors influencing the response to high-frequency repetitive transcranial magnetic stimulation in patients with subacute stroke. [2023]

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

F-wave suppression induced by suprathreshold high-frequency repetitive trascranial magnetic stimulation in poststroke patients with increased spasticity. [2022]