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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for fatigue commonly experienced after a stroke. It uses magnetic pulses to stimulate the brain, potentially alleviating tiredness and improving mood and cognitive skills. Participants will receive either real magnetic stimulation (high-frequency repetitive transcranial magnetic stimulation) to different areas of the head or a placebo treatment with no actual stimulation. This trial may suit individuals who had a stroke over six months ago, feel fatigued, and can walk at least 10 meters unassisted. As an unphased trial, this study provides a unique opportunity to contribute to innovative research that could lead to new treatment options for post-stroke fatigue.

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 prior data suggests that this magnetic stimulation technique is safe for treating post-stroke fatigue?

Research has shown that high-frequency rTMS (repetitive transcranial magnetic stimulation) is generally safe for treating various conditions. Studies have found it can help with issues like depression and chronic fatigue without major safety concerns. For instance, research on individuals with chronic fatigue syndrome found that rTMS was safe and practical when applied to the front part of the brain.

Other studies have explored rTMS in stroke recovery and found it effective for improving movement and cognitive skills. These studies did not report serious side effects, suggesting that rTMS is well-tolerated. Some individuals might experience mild side effects like headaches or scalp discomfort, but these are usually temporary and not severe.

Overall, previous studies have demonstrated that high-frequency rTMS is a promising and safe option for various conditions, including those related to stroke. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about high-frequency repetitive transcranial magnetic stimulation (rTMS) for stroke-related fatigue because it offers a non-invasive approach that directly targets brain activity. Unlike traditional treatments for fatigue, such as medication or physical therapy, rTMS uses magnetic fields to stimulate specific brain areas, potentially improving energy levels and reducing fatigue more efficiently. The real M1 and LDLPFC high-frequency rTMS treatments focus on different brain regions, which could lead to personalized treatment options based on an individual’s specific needs. This technique is promising because it may offer quicker relief from fatigue symptoms compared to conventional methods.

What evidence suggests that rTMS might be an effective treatment for post-stroke fatigue?

Research has shown that repetitive transcranial magnetic stimulation (rTMS) can alleviate various symptoms after a stroke. Studies have found that rTMS improves movement, often impaired by a stroke, and aids in recovering cognitive skills. In this trial, participants will receive either real high-frequency rTMS or sham rTMS, assigned randomly. Evidence indicates that rTMS can balance brain activity, potentially reducing fatigue. This balance might explain why some individuals feel less fatigued after rTMS treatment. Overall, these findings suggest that rTMS could help ease fatigue in stroke survivors. ^{3 5 6 7 8}

Who Is on the Research Team?

John H Kindred

Principal Investigator

Ralph H. Johnson VA Medical Center, Charleston, SC

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

Citations

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Neural effective connectivity explains subjective fatigue in stroke We suggest that the balance in inter-hemispheric inhibitory effects between primary motor regions can explain subjective post-stroke fatigue.

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Impact of Repetitive Transcranial Magnetic Stimulation on ... The aim of the present study was to investigate the impact of low-frequency rTMS on post-stroke dysmnesia, the impact of BDNF Val66Met SNP in patients with ...

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Effects of Repetitive Transcranial Magnetic Stimulation on ... rTMS has a positive effect on motor recovery in patients with stroke, especially for those with subcortical stroke.