Brain Cooling with TMS for Healthy Subjects

No longer recruiting at 1 trial location

Overseen By Bruce M Luber, Ph.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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how cooling the brain affects its response to a non-invasive procedure called transcranial magnetic stimulation (TMS). Researchers use a cooling cap to gently lower the brain's temperature and then measure changes in brain activity in response to TMS. The study targets right-handed adults aged 18-50 who can abstain from caffeine and tobacco before sessions. Participants will undergo several tests, including MRI and EEG, to monitor changes in brain and muscle activity. As an unphased trial, this study offers participants a unique opportunity to contribute to groundbreaking research on brain function and non-invasive treatments.

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 prior data suggests that this brain cooling technique with TMS is safe for healthy subjects?

Research has shown that transcranial magnetic stimulation (TMS) is generally safe for healthy individuals. TMS uses magnetic fields to activate brain activity and is typically well-tolerated. Expert guidelines emphasize its safety, noting its use in treating depression, which suggests TMS is safe for various purposes.

Some studies have reported mild side effects, such as headaches or slight discomfort at the stimulation site. These effects are usually temporary and resolve on their own. Serious side effects are rare, indicating that the treatment is broadly safe, especially in a controlled clinical setting.

In summary, research supports TMS as a safe procedure for healthy adults, making it a suitable option for studies like this one. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using Transcranial Magnetic Stimulation (TMS) for brain cooling because it represents a novel approach to modulating brain activity. Unlike traditional therapies that might involve medication or invasive procedures, TMS is non-invasive and uses magnetic fields to stimulate nerve cells in the brain. This technique specifically targets the EEG mu rhythm, which could lead to more precise and tailored interventions. If successful, TMS could offer a new way to influence brain function without the side effects typically associated with medication-based treatments.

What evidence suggests that this trial's treatments could be effective?

Research has shown that transcranial magnetic stimulation (TMS) effectively changes brain function. Studies have found that TMS can alter brain activity and help treat conditions like depression. For example, TMS has worked as well as traditional treatments for people whose depression hasn't improved with other therapies. The process uses magnetic fields to stimulate brain cells, changing brain wave patterns. This trial will specifically investigate the effects of TMS triggered to a specific phase of the EEG mu rhythm, aiming to see if altering brain waves with TMS, possibly enhanced by cooling, affects brain and body responses. ^{3 6 7 8 9}

Who Is on the Research Team?

Carlos A Zarate, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Are You a Good Fit for This Trial?

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

Main Study:

Participants must be right-handed

Subjects must be right-handed

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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) 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]

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) 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]

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]

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]

Citations

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Effectiveness of Standard Sequential Bilateral Repetitive ... This randomized noninferiority trial establishes the effectiveness and tolerability of theta burst stimulation compared with standard repetitive transcranial ...

2. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT06631209?draw=2&rank=1

NCT06631209 | Effectiveness of Transcranial Magnetic ... The stimulation will last 40 seconds. The ten TMS sessions will last for one hour between 6-9pm on weekdays. Ideally, there would be a session every weekday ...

3. nature.com nature.com/articles/s41591-023-02764-z

Connectivity-guided intermittent theta burst versus ... MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks.

4. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X22000900

Intermittent theta burst stimulation (iTBS) versus 10 Hz high ... The aim of our study was to compare the efficacy of 10 Hz rTMS and iTBS in treatment-resistant unipolar depression on response rates.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11591941/

Engineering and Technological Advancements in Repetitive ... In 2020, a study confirmed the safety and efficiency of novel H-DC coils for transcranial magnetic stimulation, but they were not significantly ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9094636/

Safety and recommendations for TMS use in healthy subjects ... Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines

7. my.clevelandclinic.org my.clevelandclinic.org/health/treatments/17827-transcranial-magnetic-stimulation-tms

TMS (Transcranial Magnetic Stimulation): What It Is Transcranial magnetic stimulation (TMS) is a noninvasive treatment that involves using a magnetic coil to influence your brain's natural electrical activity.

8. sciencedirect.com sciencedirect.com/science/article/pii/S3050529124000825

A double-blind, randomized, sham-controlled clinical trial ... This randomized, double-blind, sham-controlled clinical trial evaluated the safety, tolerability, and efficacy of applying 10 sessions of iTBS, delivered twice ...

9. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/07/NCT02969707/Prot_SAP_001.pdf

Use of Repetitive Transcranial Magnetic Stimulation (rTMS) ... Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. J Clin Neurophysiol. 2011;28(1):67-. 74. doi ...