Non-Invasive Brain Stimulation Techniques Development

Overseen By Carlos A Zarate, M.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: National Institute of Mental Health (NIMH)

Must not be taking: Tricyclics, Antipsychotics, Stimulants, others

Disqualifiers: Pregnancy, Axis I disorders, Seizures, others

Compensation: Varies

Number of Visits: 5

180 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Noninvasive brain stimulation (NIBS) may help diagnose and treat psychiatric and neurological illness. But there is not enough research on how to apply NIBS. This includes how strong to make it, where on the brain to apply it, and for how long. Researchers also want to see what the brain is doing when it receives NIBS. Objective: To increase the effectiveness of NIBS. Eligibility: Healthy native English speakers ages 18-65 Design: Participants will be screened under another protocol with: Medical and psychiatric history Psychiatric evaluation Physical exam Urine tests All participants will start with a 2-hour visit for screening. (see below). They may learn how to do tasks that will be used later. After the screening session, they will be scheduled for an MRI session. The next part of the study is 4 substudies. Each substudy includes up to 4 sessions. A session is usually 2-3 hours but can last up to 8 hours. Participants can join multiple substudies, but only 1 at a time. They can do only 1 session on a given day. Each substudy includes the following: Behavioral tests: Interviews; questionnaires; simple tasks; and tests of memory, attention, and thinking Electromyography: Small sticky electrodes on the skin measure muscle activity. Transcranial magnetic stimulation: A wire coil is held to the scalp. A brief electrical current passes through the coil and affects brain activity. Magnetic resonance imaging (MRI): Participants lie on a table that slides into a machine that takes pictures of the brain. A coil is placed over the head. They will perform simple tasks while in the scanner. They may also get TMS. Electroencephalography: Small electrodes on the scalp record brain waves. Sponsoring Institution: National Institute of M

Will I have to stop taking my current medications?

Yes, you will need to stop taking any medications that affect brain function, such as psychotropic drugs, and any medications that lower the seizure threshold.

What data supports the effectiveness of the treatment Transcranial Magnetic Stimulation (TMS)?

Transcranial Magnetic Stimulation (TMS) is a non-invasive treatment that has shown potential usefulness in treating several neuropsychiatric conditions. It can stimulate the brain without surgery or anesthesia, making it a promising tool for both research and therapy. ^{1 2 3 4 5}

Is transcranial magnetic stimulation (TMS) safe for humans?

Research shows that transcranial magnetic stimulation (TMS) is generally safe and well-tolerated in humans, even when used with deep brain stimulation devices. Some studies have noted that sham TMS, which is a fake version used in trials, can still cause some brain stimulation, but overall, TMS is considered safe. ^{1 3 6 7 8}

How does the non-invasive brain stimulation treatment differ from other treatments for this condition?

This treatment uses transcranial magnetic stimulation (TMS), which is unique because it stimulates the brain non-invasively using magnetic fields, unlike other treatments that may require medication or surgery. The multi-locus TMS (mTMS) system allows for precise targeting of brain areas without moving the coil, making it faster and potentially more effective than traditional TMS methods. ^{3 4 9 10 11}

Research Team

Carlos A Zarate, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility Criteria

Healthy English speakers aged 18-65 can join this trial. It's not for pregnant or breastfeeding women, those with serious medical conditions, hearing loss, metal implants, claustrophobia in MRI machines, drug/alcohol abuse history within a year, or anyone at increased risk of seizures.

Inclusion Criteria

I am a native English speaker.

I am between 18 and 65 years old.

Subjects must be able to give written informed consent prior to participation in this study

Exclusion Criteria

I am not pregnant or breastfeeding.

I haven't had seizures, epilepsy, stroke, brain surgery, or serious head trauma recently.

A current NIMH employee or staff or their immediate family member

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 hours

1 visit (in-person)

Baseline

Participants undergo baseline procedures including MRI and training in behavioral tasks

Varies

Experimental NIBS Sessions

Participants engage in up to 4 sessions per substudy involving NIBS with EEG, EMG, and/or fMRI

1-3 hours per session

Up to 4 visits per substudy

Follow-up

Participants are monitored for safety and effectiveness after NIBS sessions

4 weeks

Treatment Details

Interventions

• Sham TMS
• TMS

Trial Overview The study tests non-invasive brain stimulation (NIBS) techniques like Transcranial Magnetic Stimulation (TMS) and Sham TMS to improve their effectiveness. Participants will undergo behavioral tests, muscle activity measurement, brain imaging (MRI), and brain wave recording (EEG).

Participant Groups

Group I: arm 1 Experimental Treatment 1 Intervention

these are within subject repeated measures studies across a number of conditions

Group II: arm 2 Placebo Group 1 Intervention

these are within subject repeated measures studies across a number of conditions (which can include sham TMS as a placebo)

Who Is Running the Clinical Trial?

National Institute of Mental Health (NIMH)

Lead Sponsor

Trials

3,007

Recruited

2,852,000+

Findings from Research

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]

The new 'sandwich' TMS setup significantly reduces the magnetic field in the sham condition to about one eighth of that in the active stimulation condition, effectively minimizing unwanted stimulation of both the targeted brain area and neighboring regions.

This innovative design allows researchers to conduct TMS studies with a reliable sham condition, ensuring that subjects cannot distinguish between active and sham stimulation based on external cues, thus improving the overall quality of TMS research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation--a sandwich coil design for a better sham. Sommer, J., Jansen, A., Dräger, B., et al.[2021]

Different sham transcranial magnetic stimulation (TMS) techniques can produce varying levels of cortical stimulation, with some sham conditions inducing significant brain activity, which could affect trial outcomes.

The study found that a two-wing 45-degree tilt sham condition resulted in only 24% lower voltage than active TMS, indicating that not all sham methods are equally effective in mimicking a true placebo, highlighting the importance of selecting appropriate sham techniques in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Lisanby, SH., Gutman, D., Luber, B., et al.[2022]

The eSham system is a new portable sham TMS technology designed to mimic the scalp sensations of real TMS, addressing a major limitation in TMS research related to traditional sham techniques.

Preliminary results from a study with 9 healthy adults showed that the eSham system produced similar sensory experiences and tolerability ratings compared to real TMS, suggesting it could be a valid option for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and evaluation of a portable sham transcranial magnetic stimulation system. Borckardt, JJ., Walker, J., Branham, RK., et al.[2021]

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that offers advantages over other methods like vagus nerve stimulation and deep brain stimulation, which require surgery or anesthesia.

TMS has shown promise in various areas, including as a therapeutic tool for neuropsychiatric conditions, a research instrument in neuroscience, and a potential method to enhance cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms and the current state of transcranial magnetic stimulation. George, MS., Nahas, Z., Kozol, FA., 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]

Transcranial magnetic stimulation (TMS) is safe to use with implanted deep brain stimulation (DBS) devices at low to moderate intensities, as no movement or temperature increase was observed during stimulation at 0.2 Hz with 100% intensity for 1 hour.

However, caution is advised when using high-intensity TMS (over 50%) near looped DBS leads, as it can exceed the safety limit for charge density, potentially leading to electrical tissue injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of transcranial magnetic stimulation with deep brain stimulation instruments. Shimojima, Y., Morita, H., Nishikawa, N., et al.[2010]

In a study involving 33 patients undergoing rTMS treatment, the sham condition used was effective as most participants could not distinguish between real and sham stimulation, indicating its suitability for clinical trials.

Both groups, those receiving real stimulation and those receiving sham, showed a high willingness to recommend rTMS to others, suggesting that the treatment is perceived positively regardless of the actual stimulation received.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sham or real--post hoc estimation of stimulation condition in a randomized transcranial magnetic stimulation trial. Herwig, U., Cardenas-Morales, L., Connemann, BJ., et al.[2015]

The study introduces a novel electronic targeting method for transcranial magnetic stimulation (TMS) using a set of overlapping coils, allowing for faster and more precise stimulation of specific brain areas without the need for physical coil movement.

With just two coils, the device can adjust the stimulation location along a 30-mm line in the cortex, demonstrating a significant advancement in TMS technology that could enhance research and therapeutic applications in brain stimulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-locus transcranial magnetic stimulation-theory and implementation. Koponen, LM., Nieminen, JO., Ilmoniemi, RJ.[2019]

Transcranial magnetic stimulation (TMS) was successfully used in a 2-year-old boy with EBV encephalitis, leading to improvements in mutism, ataxia, and other neurological deficits after treatment.

The case suggests that TMS can normalize decreased brain cortex activity, indicating its potential as a therapeutic tool for various neurological conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation. A case report and review of the literature. Anninos, P., Kotini, A., Tamiolakis, D., et al.[2006]

The newly developed multi-locus transcranial magnetic stimulation (mTMS) system allows for precise electronic control of the stimulation location and orientation within a targeted cortical area, enhancing the ability to stimulate specific brain regions.

In a proof-of-concept experiment with a healthy volunteer, the mTMS system successfully demonstrated that varying the position of the induced electric field resulted in consistent changes in motor evoked potentials, confirming its efficacy in targeted brain stimulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-locus transcranial magnetic stimulation system for electronically targeted brain stimulation. Nieminen, JO., Sinisalo, H., Souza, VH., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Rethinking the role of sham TMS. [2020]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation--a sandwich coil design for a better sham. [2021]

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

Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. [2022]

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

Development and evaluation of a portable sham transcranial magnetic stimulation system. [2021]

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

Mechanisms and the current state of transcranial magnetic stimulation. [2019]

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. England pubmed.ncbi.nlm.nih.gov

The safety of transcranial magnetic stimulation with deep brain stimulation instruments. [2010]

8. Ireland pubmed.ncbi.nlm.nih.gov

Sham or real--post hoc estimation of stimulation condition in a randomized transcranial magnetic stimulation trial. [2015]

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

Multi-locus transcranial magnetic stimulation-theory and implementation. [2019]

10. Italy pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation. A case report and review of the literature. [2006]

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

Multi-locus transcranial magnetic stimulation system for electronically targeted brain stimulation. [2022]