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

Trial Summary

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 data supports the effectiveness of this treatment?

Research suggests that intermittent theta burst stimulation (iTBS) can influence brain activity and has shown promise in treating depression and improving motor function in conditions like multiple sclerosis. However, its effects on healthy individuals are less clear, with some studies indicating no significant difference between iTBS and sham treatments in terms of brain excitability. ^{1 2 3 4 5}

Is transcranial magnetic stimulation (TMS) safe for healthy volunteers?

Research shows that theta burst stimulation (TBS), a type of transcranial magnetic stimulation, is generally safe for humans, with most side effects being mild and occurring in about 5% of people. However, there is a small risk of seizures, so it should be used with caution. ^{6 7 8 9 10}

How is transcranial magnetic stimulation different from other treatments?

Transcranial magnetic stimulation (TMS) is unique because it uses magnetic fields to stimulate nerve cells in the brain, which is different from traditional treatments that often involve medication. This non-invasive method can be used for various conditions, including depression and motor function recovery, by influencing brain activity without the need for drugs. ^{2 5 7 11 12}

What is the purpose of this trial?

Background: People with substance use disorder (SUD) often have changes in brain function that can make it difficult to control drug-seeking behavior. These changes may heighten the urge to use drugs or lessen the desire to seek nondrug-related rewards. Researchers want to know how a technique called transcranial magnetic stimulation (TMS) may cause changes in brain activity that may help people with SUD. Objective: To test TMS in healthy volunteers. Eligibility: Healthy people aged 18 to 45 years who are right-handed. Design: Participants can volunteer for up to 5 different experiments. Each experiment requires 2 to 8 clinic visits. Each visit will last 3 to 7 hours. Some visits will include TMS. A coil will be placed on the participant s head. A brief electrical current will pass through the coil to create a magnetic field. Participants may feel a tapping or pulling sensation on the skin under the coil. They may feel a twitch in their face, neck, arm, or leg muscles. Participants may be asked to tense certain muscles during TMS. Some visits will include functional magnetic resonance imaging (fMRI) scans. Participants will lie on a bed that slides into a large tube. They will perform tasks on a computer inside the tube. The fMRI will show which parts of the brain are used during each task. Participants will perform tasks on a computer. Some tasks may be done at a desk as well as during TMS and fMRI. Participants may look at images, listen to sounds, smell odors, or taste flavored liquids. Their vital signs may be monitored and their eye movements may be tracked during tasks.

Research Team

Thorsten Kahnt, Ph.D.

Principal Investigator

National Institute on Drug Abuse (NIDA)

Eligibility Criteria

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

Right-handed

In good general health based on the assessment of the MAI

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

Unable to undergo MRI or TMS due to certain metallic or magnetic devices or implants in the body, claustrophobia, or other reasons

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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]

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]

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 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]

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]

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 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]

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]

References

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

Corticospinal integrity and motor impairment predict outcomes after excitatory repetitive transcranial magnetic stimulation: a preliminary study. [2016]

2. 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]

3. France pubmed.ncbi.nlm.nih.gov

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5-day repeated sessions study. [2022]

4. Netherlands 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. [2021]

5. Estonia 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. [2020]

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

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

7. Ireland pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. [2022]

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

Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy. [2022]

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

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

10. Netherlands 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. [2018]

11. 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]

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

Intermittent theta burst stimulation over ipsilesional primary motor cortex of subacute ischemic stroke patients: a pilot study. [2022]