Transcranial Magnetic Stimulation for Healthy Volunteers

Overseen By Thorsten Kahnt, Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: National Institute on Drug Abuse (NIDA)

Must not be taking: Psychotropics, Anticonvulsants

Disqualifiers: Neurological disorders, Psychiatric disorders, Seizure risk, others

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

Compensation: Varies

Number of Visits: 2

600 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a technique called transcranial magnetic stimulation (TMS) to observe changes in brain activity in healthy individuals. The goal is to determine whether TMS can enhance brain function, potentially aiding in the treatment of substance use disorder (SUD) in the future. Healthy, right-handed individuals aged 18 to 45 are suitable candidates for this study. Participants will attend several clinic visits, where they may experience TMS, including continuous Theta Burst Stimulation (cTBS), intermittent Theta Burst Stimulation (iTBS), or sham Theta Burst Stimulation (sham TBS), and engage in tasks while researchers monitor brain activity. As an Early Phase 1 trial, this research aims to understand how TMS works in people, offering participants a chance to contribute to groundbreaking science.

Will I have to stop taking my current medications?

The trial requires that you have not used any investigational drugs or medications with psychotropic or anti/pro-convulsive effects in the past two weeks, and no daily use for more than one week within the past three months. If you are currently taking such medications, you may need to stop before participating.

What prior data suggests that transcranial magnetic stimulation (TMS) is safe for healthy volunteers?

Previous studies have shown that continuous Theta Burst Stimulation (cTBS) is generally well-tolerated. Most participants experienced only mild headaches, easily treated with common pain relievers like acetaminophen. Although rare, there have been reports of seizures.

Research has also shown that intermittent Theta Burst Stimulation (iTBS) is safe and well-tolerated, with no major side effects like seizures reported. The most common side effects were mild, such as headaches and fatigue.

Both treatments use magnetic fields to stimulate the brain, which can cause brief sensations like tapping on the skin or muscle twitches. Overall, both cTBS and iTBS have been shown to be safe for most people, with only minor side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores innovative uses of transcranial magnetic stimulation (TMS) techniques in healthy volunteers. Unlike traditional TMS methods, this study examines continuous Theta Burst Stimulation (cTBS) and intermittent Theta Burst Stimulation (iTBS), which are thought to influence brain activity more effectively and rapidly. These techniques may offer insights into brain function and potentially pave the way for new treatments with faster results and fewer side effects compared to conventional TMS. By including a sham TBS group, the trial aims to better understand the specific impact of these novel stimulation patterns.

What evidence suggests that transcranial magnetic stimulation could be effective for substance use disorder?

This trial will explore the effects of different types of transcranial magnetic stimulation (TMS) on healthy volunteers. Studies have shown that TMS can alter brain activity in ways that might aid in treating substance use disorder. Participants may receive continuous Theta Burst Stimulation (cTBS), which research indicates may alleviate symptoms like hearing voices and is generally safe, though certain cTBS methods may not always be effective. Alternatively, participants may receive intermittent Theta Burst Stimulation (iTBS), which has been found to enhance brain activity and improve movement, showing promise in treating depression by facilitating brain adaptation. These findings suggest that TMS, specifically through cTBS and iTBS, could potentially help manage conditions related to changes in brain activity. ^{6 7 8 9 10}

Who Is on the Research Team?

Thorsten Kahnt, Ph.D.

Principal Investigator

National Institute on Drug Abuse (NIDA)

Are You a Good Fit for This Trial?

This trial is for healthy, right-handed individuals aged 18 to 45. Participants will engage in up to five experiments involving transcranial magnetic stimulation (TMS) and functional MRI scans while performing various tasks.

Inclusion Criteria

Willingness to comply with all study procedures and availability for the duration of the study. Consent signature will be documentation of meeting this criterion

In good general health based on the assessment of the MAI

Right-handed

Exclusion Criteria

Recent history (within past 12 months) of learning disability, major DSM-5 psychiatric disorder including major affective disorder, ADHD, obsessive-compulsive disorder, schizophrenia, PTSD, SUD (excluding Tobacco Use Disorder). This will be determined at the discretion of the MAI

Any other condition that in the judgment of the investigators is incompatible with participation

I have smoked daily for at least a month in the past year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Experimentation

Participants undergo up to 5 different experiments involving TMS and fMRI, with tasks performed on a computer.

Varies per experiment (2 to 8 visits, each lasting 3 to 7 hours)

2 to 8 visits per experiment

Follow-up

Participants are monitored for task performance and cognitive function modulation after each intervention

After each intervention

What Are the Treatments Tested in This Trial?

Interventions

• continuous Theta Burst Stimulation (cTBS)
• intermittent Theta Burst Stimulation (iTBS)
• sham Theta Burst Stimulation (sham TBS)

Trial Overview The study tests intermittent and continuous Theta Burst Stimulation (iTBS/cTBS), plus a sham version, using TMS on healthy volunteers. The goal is to understand how TMS affects brain activity related to learning and decision-making.

How Is the Trial Designed?

Group I: Experiment 5 Experimental Treatment 2 Interventions

Healthy volunteers in experiment 5

Group II: Experiment 4 Experimental Treatment 1 Intervention

Healthy volunteers in experiment 4

Group III: Experiment 3 Experimental Treatment 2 Interventions

Healthy volunteers in experiment 3

Group IV: Experiment 2 Experimental Treatment 3 Interventions

Healthy volunteers in experiment 2

Group V: Experiment 1 Experimental Treatment 3 Interventions

Healthy volunteers in experiment 1

Who Is Running the Clinical Trial?

National Institute on Drug Abuse (NIDA)

Lead Sponsor

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

Intermittent theta-burst stimulation (iTBS) significantly improves hand function in stroke patients, particularly in those with higher baseline motor function and the presence of motor-evoked potentials (MEPs).

The study of 72 stroke patients showed that those with MEPs and better grip strength (Group A) had the greatest improvement in motor function, suggesting that iTBS effectiveness can be predicted by these factors, allowing for more tailored neurostimulation strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corticospinal integrity and motor impairment predict outcomes after excitatory repetitive transcranial magnetic stimulation: a preliminary study. Lai, CJ., Wang, CP., Tsai, PY., et al.[2016]

In a randomized, double-blind trial involving 56 patients, intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex showed a significant reduction in negative symptoms for patients with depression, but not for those with schizophrenia.

The treatment was generally safe and well-tolerated, with serious adverse events occurring only in the sham group, indicating that iTBS may be a promising intervention for depressive symptoms in certain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dorsomedial prefrontal theta burst stimulation to treat anhedonia, avolition, and blunted affect in schizophrenia or depression - a randomized controlled trial. Bodén, R., Bengtsson, J., Thörnblom, E., et al.[2021]

Continuous theta burst stimulation (cTBS) effectively inhibits synaptic transmission in the primary motor cortex for up to 1 hour, demonstrating its potential as a novel neuromodulation technique.

cTBS applied to the left motor cortex increases local GABA levels, indicating enhanced GABAergic activity, while not significantly affecting glutamate/glutamine levels, suggesting a specific mechanism of action for this stimulation technique.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy. Stagg, CJ., Wylezinska, M., Matthews, PM., et al.[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]

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]

In a study of 27 participants, a prolonged intermittent theta burst stimulation (piTBS) protocol using 1,800 pulses showed limited effectiveness for major depressive disorder, with only 18.2% of participants achieving a response and 9.1% reaching remission.

Safety and tolerability were concerns, as 18.5% of participants experienced issues, suggesting that while piTBS is a promising approach, further research is needed to optimize its parameters and improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. Richard, M., Noiseux, C., Desbeaumes Jodoin, V., et al.[2022]

In a study involving 29 patients with major depression, continuous theta-burst transcranial magnetic stimulation (cTBS) did not show a significant overall improvement compared to sham treatment, indicating modest efficacy.

However, patients who were either medication-free or had unchanged medication status experienced a greater reduction in depression scores with active cTBS, suggesting it may be beneficial for those not responding to traditional pharmacological treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: a double-blind sham-controlled study. Chistyakov, AV., Kreinin, B., Marmor, S., et al.[2018]

In a study involving 20 healthy participants over five days, daily intermittent theta burst stimulation (iTBS) did not show any significant cumulative increase in cortical excitability compared to sham stimulation, suggesting that repeated sessions may not enhance therapeutic effects as previously believed.

The results indicate high variability in individual responses to both active and sham iTBS, with no consistent pattern of improvement, which raises questions about the effectiveness of iTBS in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5-day repeated sessions study. Perellón-Alfonso, R., Kralik, M., Pileckyte, I., et al.[2022]

In a study involving 36 multiple sclerosis patients, intermittent theta burst stimulation (iTBS) significantly improved manual dexterity, as shown by faster completion times in the nine-hole peg test and increased performance in the Box and Block Test.

However, iTBS did not have a significant impact on hand motor imagery abilities, indicating that while it can enhance physical tasks, it may not affect cognitive aspects of motor function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Intermittent Theta Burst Stimulation on Manual Dexterity and Motor Imagery in Patients with Multiple Sclerosis: A Quasi-Experimental Controlled Study. Azin, M., Zangiabadi, N., Iranmanesh, F., et al.[2020]

In a study involving 12 subacute stroke patients, prolonged transcranial magnetic stimulation (iTBS1200) was found to be safe and well-tolerated, with no significant adverse effects reported.

Patients receiving iTBS1200 showed measurable improvements in stroke severity and upper extremity function shortly after treatment and at 60 days post-stroke, suggesting potential benefits that warrant further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent theta burst stimulation over ipsilesional primary motor cortex of subacute ischemic stroke patients: a pilot study. Hsu, YF., Huang, YZ., Lin, YY., et al.[2022]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6344075/

Effects of continuous theta-burst stimulation of the primary ... From the 18 healthy right-handed volunteers, only 16 (mean age ± SD, SD: 23.8 ± 2.3 years; 6 men) were included in the analysis, due to insufficient data about ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1935861X15008967

Efficacy and Time Course of Theta Burst Stimulation in ... ITBS applied for 190 s significantly increases cortical excitability up to 60 min with a mean maximum potentiation of 35.54 ± 3.32%.

3. nature.com nature.com/articles/s41598-024-81399-7

Continuous theta burst stimulation at 30 hz does not ... This study aimed to investigate the efficacy of a 30 Hz continuous TBS (cTBS) protocol. Participants (n = 20) underwent an experimental session ...

4. frontiersin.org frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2024.1446849/full

The efficacy and safety of continuous theta burst ... Preliminary findings have suggested that cTBS therapy may yield positive results in improving auditory hallucination and minimizing adverse ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT07033780

NCT07033780 | Theta-Burst Stimulation to Treat Depression This study explores iTBS for depression, comparing iTBS-c and iTBS-s protocols to improve brain plasticity and depression symptoms.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8617062/

A Systematic Review of the Safety and Tolerability of Theta ... The cTBS protocol was tolerated with no serious adverse events. Adverse events included a mild headache that was relieved with one dose of acetaminophen. Two ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3260517/

Safety of Theta Burst Transcranial Magnetic Stimulation The most serious acute risk is a seizure occurring at the time of treatment. Less serious, but more frequent side effects of rTMS include headache and neck pain ...

8. frontiersin.org frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2015.00029/full

Safety and tolerability of theta burst stimulation vs. single ... To our knowledge, only one serious adverse event (AE), seizure, was reported in a healthy adult male during continuous TBS performed at 100% of ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0149291820302794

Safety Considerations for Cerebellar Theta Burst Stimulation No serious adverse events have been reported for cerebellar TBS. There is no substantial evidence of a tolerable maximal-efficacy stimulation dose in humans.

10. clinicaltherapeutics.com clinicaltherapeutics.com/article/S0149-2918(20)30279-4/pdf

Safety Considerations for Cerebellar Theta Burst Stimulation TBS uses fewer pulses at lower intensities, which is tolerable, but also higher frequencies, which increase the risk of adverse effects, particularly seizures.