rTMS + CCFES Therapy for Severe Stroke

(rTMS+CCFES Trial)

Overseen by Ela Plow, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: The Cleveland Clinic

Must not be taking: Anticonvulsants, Antidepressants

Disqualifiers: Metal implant, Seizures, Alcohol abuse, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new therapy for stroke patients with severe arm and hand movement issues. It combines brain stimulation with muscle electrical stimulation to improve recovery. The goal is to see if this combination works better than other treatments.

Will I have to stop taking my current medications?

The trial requires that you stop taking anticonvulsants or antidepressants that are not safe to use with TMS (a type of brain stimulation).

What data supports the effectiveness of this treatment for severe stroke?

Research suggests that repetitive transcranial magnetic stimulation (rTMS) can help improve motor function after a stroke by balancing brain activity between the damaged and undamaged sides. Studies show that targeting the contralesional hemisphere with rTMS may enhance recovery by reducing overactivity that can hinder progress. ^{1 2 3 4 5}

Is rTMS therapy generally safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) is generally considered safe, with guidelines established to minimize risks. Common side effects include temporary headaches and local pain, while more serious effects like seizures are rare. Safety guidelines have been updated over the years to ensure safe use in various conditions, including stroke. ^{6 7 8 9 10}

What makes the rTMS + CCFES treatment unique for severe stroke?

The rTMS + CCFES treatment is unique because it combines repetitive transcranial magnetic stimulation (rTMS), which uses magnetic fields to stimulate nerve cells in the brain, with contralaterally controlled functional electrical stimulation (CCFES), which uses electrical impulses to stimulate muscles on the opposite side of the body. This combination aims to improve motor function by enhancing brain plasticity and muscle activation, offering a novel approach compared to traditional stroke therapies. ^{1 3 4 5 11}

Research Team

Ela Plow, PhD

Principal Investigator

Lerner Research Institute; Cleveland Clinic Foundation

Eligibility Criteria

This trial is for adults aged 18-90 who had a severe stroke at least 6 months ago, resulting in significant upper limb weakness. They must be able to follow commands and have no recent history of seizures or substance abuse. People with metal head implants, pacemakers, or those on certain medications cannot join.

Inclusion Criteria

I can move my shoulder and elbow enough to place my hand on my lap for exercises.

It has been over 6 months since I had a stroke.

I finished occupational therapy over 2 months ago and am not currently in therapy.

Exclusion Criteria

You have a metal implant in your head.

Cardiac pacemaker or other programmable implant

You had problems with alcohol or drugs within the last 10 years.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 12 weeks of treatment with CCFES and rTMS, including 10 sessions per week of self-administered exercises and 2 sessions per week of lab-based task practice

12 weeks

10 sessions per week (home-based), 2 sessions per week (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at 24 and 36 weeks

24 weeks

Assessments at 24 and 36 weeks

Treatment Details

Interventions

• Contralaterally Controlled Functional Electrical Stimulation (Behavioural Intervention)
• Conventional rTMS approach (Procedure)
• New rTMS approach (Procedure)
• Sham rTMS approach (Procedure)

Trial Overview The study tests if a new rTMS approach targeting the undamaged brain hemisphere combined with CCFES therapy improves arm function in severe stroke patients more than conventional rTMS or sham treatments.

Participant Groups

Group I: CCFES + rTMS facilitating iM1 Active Control 2 Interventions

This rTMS paradigm is the "Conventional Approach".Facilitation of M1 will be achieved using 5Hz rTMS. After rTMS, the participant will participate in one hour of CCFES-mediated functional task practice. The therapist will instruct and guide the participants in practicing functional tasks with their paretic hand with the assistance of CCFES. Tasks will involve using the paretic hand to pick up, manipulate, and release objects commonly used in daily life. Early sessions will focus on simpler tasks, such as practicing opening the hand adequately to acquire an object.

Group II: CCFES + rTMS facilitating cHMC Active Control 2 Interventions

This rTMS paradigm is the "New Approach". Facilitation of the intact hemisphere target (cHMC) will be achieved using 5Hz rTMS. After rTMS, the participant will participate in one hour of CCFES-mediated functional task practice. The therapist will instruct and guide the participants in practicing functional tasks with their paretic hand with the assistance of CCFES. Tasks will involve using the paretic hand to pick up, manipulate, and release objects commonly used in daily life. Early sessions will focus on simpler tasks, such as practicing opening the hand adequately to acquire an object.

Group III: CCFES + Sham rTMS Placebo Group 2 Interventions

This rTMS paradigm is the "Sham Approach". Immediately after sham rTMS, the participant will participate in one hour of CCFES-mediated functional task practice. The therapist will instruct and guide the participants in practicing functional tasks with their paretic hand with the assistance of CCFES. Tasks will involve using the paretic hand to pick up, manipulate, and release objects commonly used in daily life. Early sessions will focus on simpler tasks, such as practicing opening the hand adequately to acquire an object.

Who Is Running the Clinical Trial?

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

David Peter

The Cleveland Clinic

Chief Medical Officer

MD, board-certified in Hospice and Palliative Medicine

Tomislav Mihaljevic

The Cleveland Clinic

Chief Executive Officer since 2018

MD from University of Zagreb School of Medicine

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Dr. Diana W. Bianchi

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Chief Executive Officer since 2016

MD from Stanford University

Dr. Alison Cernich

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Chief Medical Officer since 2020

PhD in Clinical Psychology from University of Maryland

Findings from Research

In a study involving 8 chronic stroke patients and 8 healthy subjects, navigated low-frequency rTMS significantly increased excitability in the non-stimulated motor cortex of stroke patients, leading to improved motor function, particularly in tasks like finger tapping and pinch force.

The effects of rTMS were more pronounced in stroke patients compared to healthy controls, suggesting that this intervention may effectively enhance motor responses in individuals with residual motor deficits after a stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced motor function and its neurophysiological correlates after navigated low-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex in stroke. Bashir, S., Vernet, M., Najib, U., et al.[2018]

After a stroke, the contralesional hemisphere can become hyperexcitable, which may hinder recovery; however, some patients show beneficial contralesional activity, suggesting its complex role in motor recovery.

Therapies like brain-computer interface (BCI) and transcranial magnetic stimulation (TMS) can target either hemisphere to enhance recovery, with TMS showing promise in improving outcomes by either exciting the ipsilesional cortex or inhibiting the contralesional cortex.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of the Contralesional vs. Ipsilesional Hemisphere in Stroke Recovery. Dodd, KC., Nair, VA., Prabhakaran, V.[2020]

In a case study of two stroke patients, 6-Hz primed low-frequency rTMS applied to the contralesional primary motor area successfully disrupted cortical activation, suggesting a potential mechanism for enhancing motor function by disinhibiting the ipsilesional motor area.

While one subject showed positive changes in intracortical inhibition and facilitation, the other did not exhibit behavioral improvements, highlighting the importance of combining rTMS with behavioral training to maximize recovery outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

6-Hz primed low-frequency rTMS to contralesional M1 in two cases with middle cerebral artery stroke. Carey, JR., Anderson, DC., Gillick, BT., et al.[2021]

The study found that contralesional repetitive transcranial magnetic stimulation (rTMS) was safe and well-tolerated in 10 chronic stroke patients, with no adverse effects like seizures or worsening motor function, indicating its potential as a noninvasive treatment option.

There was a positive relationship between the integrity of transcallosal motor fibers and motor improvement after rTMS, suggesting that rTMS may enhance neuroplasticity in the brain, which could be useful for rehabilitation in severe chronic stroke patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effects of contralesional rTMS in severe stroke: safety, cortical excitability, and relationship with transcallosal motor fibers. Demirtas-Tatlidede, A., Alonso-Alonso, M., Shetty, RP., et al.[2018]

A systematic review of 19 trials with 588 participants found that repetitive transcranial magnetic stimulation (rTMS) did not significantly improve functional recovery or motor function in stroke patients compared to sham therapy.

While rTMS was generally safe with few mild side effects reported, the current evidence does not support its routine use for stroke treatment, indicating a need for further research to establish effective protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation for improving function after stroke. Hao, Z., Wang, D., Zeng, Y., et al.[2023]

Repetitive transcranial magnetic stimulation (rTMS) has gained popularity for its ability to modulate brain activity, but safety considerations are crucial, especially with the recent updates to safety guidelines published in 2021.

The guidelines emphasize the importance of screening for risks, monitoring for adverse events, and specific safety measures when using rTMS, particularly in patients with conditions like stroke and traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. Kim, WS., Paik, NJ.[2023]

High-frequency rTMS (20 and 25 Hz) applied to the motor cortex of chronic stroke patients may increase the risk of seizures, as indicated by EMG bursts and muscle excitation observed during the study.

Despite the safety concerns, the study found no significant increase in motor cortex excitability or improvement in hand strength after rTMS, suggesting that the stimulation parameters used may not be effective for rehabilitation in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety study of high-frequency transcranial magnetic stimulation in patients with chronic stroke. Lomarev, MP., Kim, DY., Richardson, SP., et al.[2016]

A patient with treatment-resistant depression (TRD) showed unexpected improvement after experiencing a seizure during repetitive transcranial magnetic stimulation (rTMS), suggesting a potential link between seizure activity and therapeutic effects in TRD.

While rTMS is generally safe, known adverse events include headaches and seizures; this case highlights an unusual outcome where a seizure may have contributed to the patient's improvement, warranting further investigation into the mechanisms of rTMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-Resistant Depression Entering Remission Following a Seizure during the Course of Repetitive Transcranial Magnetic Stimulation. Kim, JW., Bae, KY., Kim, SW., et al.[2020]

Repetitive transcranial magnetic stimulation (rTMS) has not been thoroughly studied for side effects, with the main known risk being the acute production of seizures.

While tissue damage from rTMS is unlikely, there are concerns about potential cognitive effects and the possibility of long-term changes in brain function that have not yet been fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of repetitive transcranial magnetic stimulation. Wassermann, EM.[2005]

Repetitive transcranial magnetic stimulation (rTMS) was found to be safe for a patient with an implanted subdural cortical electrode, showing no serious adverse effects during treatment.

Ex-vivo experiments indicated that rTMS caused only a slight increase in coil temperature and no displacement of the electrodes, suggesting that rTMS can be safely applied in clinical settings for patients with such implants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of repetitive transcranial magnetic stimulation in patients with implanted cortical electrodes. An ex-vivo study and report of a case. Phielipp, NM., Saha, U., Sankar, T., et al.[2019]

In a study involving 18 healthy subjects, real low-frequency (1 Hz) rTMS applied to the right primary motor cortex significantly increased regional cerebral blood flow in the left motor cortex during right hand movement, indicating enhanced brain activity, although this did not translate to improved motor performance.

The same rTMS effects were observed in two stroke patients, suggesting that low-frequency rTMS may promote beneficial brain connectivity and plasticity, highlighting its potential as a therapeutic tool in stroke rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neural substrates of low-frequency repetitive transcranial magnetic stimulation during movement in healthy subjects and acute stroke patients. A PET study. Conchou, F., Loubinoux, I., Castel-Lacanal, E., et al.[2021]

References

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

Enhanced motor function and its neurophysiological correlates after navigated low-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex in stroke. [2018]

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

Role of the Contralesional vs. Ipsilesional Hemisphere in Stroke Recovery. [2020]

3. Ireland pubmed.ncbi.nlm.nih.gov

6-Hz primed low-frequency rTMS to contralesional M1 in two cases with middle cerebral artery stroke. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Long-term effects of contralesional rTMS in severe stroke: safety, cortical excitability, and relationship with transcallosal motor fibers. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation for improving function after stroke. [2023]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Safety study of high-frequency transcranial magnetic stimulation in patients with chronic stroke. [2016]

8. Korea (South) pubmed.ncbi.nlm.nih.gov

Treatment-Resistant Depression Entering Remission Following a Seizure during the Course of Repetitive Transcranial Magnetic Stimulation. [2020]

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

Side effects of repetitive transcranial magnetic stimulation. [2005]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Safety of repetitive transcranial magnetic stimulation in patients with implanted cortical electrodes. An ex-vivo study and report of a case. [2019]

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

Neural substrates of low-frequency repetitive transcranial magnetic stimulation during movement in healthy subjects and acute stroke patients. A PET study. [2021]