Brain Cooling with TMS for Healthy Subjects

Recruiting at 1 trial location

Overseen By Carlos A Zarate, M.D.

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: National Institute of Mental Health (NIMH)

Must not be taking: Antidepressants, Anxiolytics, Anticonvulsants, others

Disqualifiers: Psychiatric conditions, Neurologic disorders, Implants, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

63 Participants Needed

Trial Summary

What is the purpose of this trial?

Sub-Study: Phase Triggered Paired Associative Stimulation (PAS) (actively recruiting) Background: -Previous research has shown that the brain s activity changes with changes in brain waves. We can study brain activity with a procedure called transcranial magnetic stimulation (TMS), a form of non-invasive brain stimulation. EEG allows for measuring ongoing brain waves. The goal of this study is to optimize TMS delivery by utilizing EEG-triggered TMS. Objectives: -To see if changes in brain waves change the brain and body s response to TMS. Eligibility: -Healthy, right-handed adults age 18-35. Design: * Participants will be screened under another protocol with medical history and physical exam. They may take a pregnancy test. They will have a magnetic resonance imaging (MRI) scan of the brain. For MRI, participants lie on a table that slides in and out of a metal tube that takes pictures. with: * Participants will have up to 4 outpatient visits lasting 2-3 hours each (4 outpatient visits). The following procedures may occur at a visit: * Magnetic resonance imaging (MRI): Participants lie on a table that slides into a machine that takes pictures of the brain. * Electroencephalography (EEG): Small electrodes on the scalp record brain waves. * Electromyography (EMG): Small sticky electrodes on the skin measure muscle activity. * Transcranial magnetic stimulation (TMS): A wire coil is held to the scalp. A brief electrical current passes through the coil and affects brain activity. Main Study: Influence on Plasticity of Brain Temperature (no longer recruiting) Background: - Brain activity changes with changes in body temperature. Brain activity can be studied with a procedure called transcranial magnetic stimulation (TMS). Researchers want to cool the brain through the scalp using a cooling cap. They want to see if cooling changes the brain and body s response to TMS. Objectives: - To look at the effects of cooling on the brain. Eligibility: - Right-handed adults age 18-50 who can abstain from caffeine and tobacco. Design: * Participants will be screened with medical history and physical exam. They will be asked about alcohol use, smoking, and substance abuse. They may take a pregnancy test. They may have a magnetic resonance imaging (MRI) scan of the brain. For MRI, participants lie on a table that slides in and out of a metal tube that takes pictures. * Participants will have 3 outpatient visits. The following procedures will occur at each visit. * Participants will wear a cooling cap for up to 45 minutes. Cool water will flow through the cap. It will feel like an ice pack in a towel. Their core temperature will be monitored. Their temperature will also be measured under their tongue and on scalp, stomach, forearm, and calf. * Participants will have TMS before and after wearing the cap. A brief electrical current will pass through a wire coil held on their scalp. Electrodes that detect muscle movement will be placed on their hand. They will also have repetitive TMS, which uses repeated magnetic pulses. Their wrist will also receive a shock.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications. The trial excludes participants who are taking medications such as antidepressants, anxiolytics (anti-anxiety drugs), anticonvulsants (anti-seizure drugs), antipsychotics, antiparkinson drugs, hypnotics (sleep aids), stimulants, and antihistamines.

What data supports the effectiveness of this treatment?

Research shows that Theta Burst Stimulation (TBS), a type of Transcranial Magnetic Stimulation (TMS), is effective in treating depression and is more energy- and time-efficient than standard repetitive TMS. Additionally, TBS has been studied for its effects on brain activity and recovery in stroke patients, suggesting its potential benefits in modulating brain function. ^{1 2 3 4 5}

Is brain cooling with TMS safe for healthy humans?

Transcranial Magnetic Stimulation (TMS) and its variations, like Repetitive TMS (rTMS) and Theta Burst Stimulation (TBS), have been studied for safety. Most adverse effects are mild, but there is a small risk of seizures, especially with high-frequency protocols like TBS. Safety guidelines exist to minimize these risks, and TMS is generally considered safe when applied with caution. ^{6 7 8 9 10}

How is the treatment of brain cooling with TMS unique compared to other treatments?

Brain cooling with TMS is unique because it combines transcranial magnetic stimulation (TMS), which uses magnetic pulses to stimulate the brain, with a cooling technique to manage heat generated during the process, potentially enhancing the treatment's effectiveness and duration. ^{11 12 13 14 15}

Research Team

Carlos A Zarate, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility Criteria

This trial is for healthy, right-handed adults aged 18-35 who can lie flat on their back for up to an hour. Participants must not have psychiatric conditions, be pregnant, or have a history of neurological disorders. They should not take certain medications and must abstain from caffeine and tobacco before visits.

Inclusion Criteria

I am between 18 and 50 years old.

I am between 18 and 35 years old.

Main Study:

Exclusion Criteria

I do not have clinically diagnosed hearing loss.

I am not on medication that increases my risk of seizures.

Participants with claustrophobia severe enough to prevent MRI scanning are excluded

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Main Study Treatment

Participants undergo cooling and TMS procedures to study the effects of cooling on brain plasticity

3 visits

3 visits (in-person)

Sub-study Treatment

Participants undergo EEG phase-triggered paired associative stimulation (PAS) to optimize TMS delivery

3-4 visits

3-4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Transcranial Magnetic Stimulation (TMS)

Trial Overview The study tests how brain waves influence the body's response to Transcranial Magnetic Stimulation (TMS). It involves MRI scans to image the brain, EEG to record brain waves, EMG for muscle activity measurement, and TMS where a coil affects brain activity with electrical currents.

Participant Groups

Group I: EEG phase-triggered PAS Experimental Treatment 1 Intervention

TMS triggered to a specific phase of the EEG mu rhythm

Transcranial Magnetic Stimulation (TMS) is already approved in United States, European Union for the following indications:

Approved in United States as Transcranial Magnetic Stimulation (TMS) for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)
• Migraine Headache Symptoms

Approved in European Union as Transcranial Magnetic Stimulation (TMS) for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)

Who Is Running the Clinical Trial?

National Institute of Mental Health (NIMH)

Lead Sponsor

Trials

3,007

Recruited

2,852,000+

Findings from Research

In a study involving 300 patients with treatment-resistant depression, accelerated bilateral theta burst stimulation (TBS) was found to be effective and safe, with a treatment response rate of 43.7% and a remission rate of 28.2%.

The study revealed no significant differences in efficacy between different TBS intensities or when compared to traditional unilateral 10 Hz rTMS, indicating that the accelerated TBS does not provide faster antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial. Chen, L., Thomas, EHX., Kaewpijit, P., et al.[2022]

In a study involving nine healthy right-handed subjects, continuous theta burst stimulation (cTBS) inhibited motor-evoked potential (MEP) amplitudes, while intermittent theta burst stimulation (iTBS) facilitated them, but neither showed significantly stronger effects compared to conventional rTMS protocols.

The study found that the type of pulse waveform and current direction did not significantly influence the effects of TBS, indicating that TBS's efficacy is consistent across different configurations, which helps clarify the mechanisms of transcranial magnetic stimulation on the motor cortex.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative assessment of best conventional with best theta burst repetitive transcranial magnetic stimulation protocols on human motor cortex excitability. Zafar, N., Paulus, W., Sommer, M.[2008]

Repeated applications of Theta Burst stimulation (TBS) in rats showed complex effects on neuronal activity markers, with some markers increasing while others decreased, indicating that the response to TBS is not simply accumulative.

Specifically, while the expression of the vesicular glutamate transporter (VGLUT1) increased with stimulation, markers for inhibitory activity like GAD67 and calcium-binding proteins decreased, suggesting a nuanced interaction between excitatory and inhibitory neuronal responses to repeated TBS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-dependence of changes in cortical protein expression induced with repeated transcranial magnetic theta-burst stimulation in the rat. Volz, LJ., Benali, A., Mix, A., et al.[2016]

Theta burst stimulation (TBS) is as effective and safe as standard repetitive transcranial magnetic stimulation (rTMS) for treating depression, based on a meta-analysis of nine randomized controlled trials involving 1124 patients.

The study found no significant differences in response rates or adverse events between TBS and rTMS, suggesting that TBS could be a viable alternative due to its shorter treatment sessions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Theta Burst vs Repetitive Transcranial Magnetic Stimulation for the Treatment of Depression: A Meta-Analysis of Randomized Controlled Trials. Liu, C., Li, L., Li, B., et al.[2023]

In a study involving 20 chronic ischemic stroke patients, both continuous theta burst stimulation (cTBS) and low frequency repetitive transcranial magnetic stimulation (rTMS) combined with physical therapy showed significant improvements in motor function and daily living activities after 10 treatment sessions.

While both real cTBS and rTMS were effective, only rTMS significantly reduced spasticity in multiple muscle groups, indicating that while these interventions help with functional recovery, their impact on spasticity may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Sham Controlled Continuous Theta Burst Stimulation and Low Frequency Repetitive Transcranial Magnetic Stimulation on Upper Extremity Spasticity and Functional Recovery in Chronic Ischemic Stroke Patients. Kuzu, Ö., Adiguzel, E., Kesikburun, S., et al.[2021]

In a study of 165 pediatric participants aged 6 to 18, theta-burst TMS (TBS) demonstrated a similar safety profile to single- and paired-pulse TMS (sp/ppTMS), with no severe adverse effects reported.

The overall rate of adverse effects was 10.5% for TBS and 12.4% for sp/ppTMS, with most effects rated as minimal or mild, indicating that TBS is a safe option for further investigation in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects. Hong, YH., Wu, SW., Pedapati, EV., et al.[2020]

Theta burst stimulation (TBS) is a promising technique for altering brain excitability, with a review of studies showing that adverse events were mostly mild and occurred in only 5% of subjects, indicating a generally safe profile.

Despite its safety, TBS carries a theoretical higher risk of seizures compared to other stimulation methods, necessitating cautious application and further research into its dosing parameters to better understand seizure risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. Oberman, L., Edwards, D., Eldaief, M., et al.[2022]

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]

Repetitive transcranial magnetic stimulation (rTMS) is a powerful tool that can effectively treat clinical depression and potentially other brain disorders, but it carries risks, including the potential to induce seizures, as evidenced by 7 known cases by 1996.

A workshop established safety guidelines for rTMS, emphasizing the importance of monitoring, ethical considerations, and the expertise required for its administration to minimize risks and enhance therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Wassermann, EM.[2022]

Theta burst stimulation (TBS) protocols, including continuous (cTBS) and intermittent (iTBS), appear to be safe for healthy individuals, with no seizures or serious side effects reported during the study involving 24 participants.

The most notable side effect was the occurrence of vagal reactions, and while some changes in brain activity were observed, there was no significant impact on mood or cognitive performance, indicating that further research is needed to fully understand the effects of TBS on the prefrontal cortex.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Theta burst stimulation of the prefrontal cortex: safety and impact on cognition, mood, and resting electroencephalogram. Grossheinrich, N., Rau, A., Pogarell, O., et al.[2009]

A new pre-chilled heat sink was developed to manage heat during transcranial magnetic stimulation (TMS), allowing for longer operational durations of the stimulation coils.

This innovation extended the operational time of TMS coils by 5.8 to 19.3 minutes compared to standard methods, enabling researchers to collect more data in a single session.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accessory to dissipate heat from transcranial magnetic stimulation coils. Belyk, M., Murphy, BK., Beal, DS.[2020]

Local scalp cooling significantly reduced scalp temperature by an average of 12.5°C and led to a decrease in corticomotor excitability, as measured by motor evoked potentials (MEPs), in healthy male adults (n=12).

The study provides the first neurophysiological evidence that changes in scalp temperature can have lasting effects on corticomotor excitability, with no impact on MEP latency, indicating a specific effect of cooling rather than discomfort from the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lasting depression in corticomotor excitability associated with local scalp cooling. Tremblay, F., Remaud, A., Mekonnen, A., et al.[2015]

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 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) is a non-invasive method that stimulates the brain's cortex, showing promise for both research and treatment of neuropsychiatric disorders, supported by extensive safety data from prior studies.

The article reviews the technical aspects of TMS, including its safety profile and potential adverse effects, emphasizing the importance of understanding these factors to optimize its applications in neuroscience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Transcranial magnetic stimulation]. Tormos, JM., Catalá, MD., Pascual-Leone, A.[2009]

References

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

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial. [2022]

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

Comparative assessment of best conventional with best theta burst repetitive transcranial magnetic stimulation protocols on human motor cortex excitability. [2008]

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

Dose-dependence of changes in cortical protein expression induced with repeated transcranial magnetic theta-burst stimulation in the rat. [2016]

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

Efficacy and Safety of Theta Burst vs Repetitive Transcranial Magnetic Stimulation for the Treatment of Depression: A Meta-Analysis of Randomized Controlled Trials. [2023]

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

The Effect of Sham Controlled Continuous Theta Burst Stimulation and Low Frequency Repetitive Transcranial Magnetic Stimulation on Upper Extremity Spasticity and Functional Recovery in Chronic Ischemic Stroke Patients. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects. [2020]

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

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. [2022]

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

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

9. Ireland pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. [2022]

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

Theta burst stimulation of the prefrontal cortex: safety and impact on cognition, mood, and resting electroencephalogram. [2009]

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

Accessory to dissipate heat from transcranial magnetic stimulation coils. [2020]

12. Ireland pubmed.ncbi.nlm.nih.gov

Lasting depression in corticomotor excitability associated with local scalp cooling. [2015]

13. Italy pubmed.ncbi.nlm.nih.gov

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

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

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

15. Spain pubmed.ncbi.nlm.nih.gov

[Transcranial magnetic stimulation]. [2009]