iTBS for Healthy Individuals

(STEP-MC Trial)

Overseen By Dewi Clark, MHSc

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Centre for Addiction and Mental Health

Must not be taking: Psychotropic medications

Disqualifiers: Age, DSM-5 diagnosis, Neurological conditions, others

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

Compensation: Varies

Number of Visits: 5

Duration: 2 weeks

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

If you are currently using any psychotropic medications (like anti-depressants or anti-convulsants), you will need to stop taking them to participate in this trial.

What data supports the effectiveness of the treatment Compressed iTBS, Intermittent Theta-Burst Stimulation, iTBS, Compressed iTBS, iTBS-c, Sham iTBS, Sham Intermittent Theta Burst Stimulation, Sham iTBS, Spaced iTBS, Intermittent Theta-Burst Stimulation, iTBS, Spaced iTBS, Compressed iTBS?

Research shows that Intermittent Theta-Burst Stimulation (iTBS) is effective for treatment-resistant depression, as it is a faster alternative to traditional methods and has been approved by the U.S. Food and Drug Administration. Additionally, iTBS has been shown to influence motor function recovery, suggesting its potential benefits in other areas. ^{1 2 3 4 5}

Is iTBS safe for healthy individuals?

Research shows that intermittent theta burst stimulation (iTBS) is generally safe, 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. ^{2 5 6 7 8}

How is the treatment Compressed iTBS different from other treatments for healthy individuals?

Compressed iTBS is a unique form of brain stimulation that can be delivered in just over 3 minutes, making it much quicker than traditional methods. It targets specific brain areas to influence brain activity and has been shown to help with conditions like depression and stress, although its use in healthy individuals is still being explored. ^{2 5 9 10 11}

What is the purpose of this trial?

The goal of this clinical trial is to explore the effects of non-invasive brain stimulation protocols using intermittent theta-burst stimulation (iTBS) on brain plasticity in healthy, right-handed individuals aged 18 to 50 years. Brain plasticity is the brain's ability to change through growth or reorganization. iTBS is a form of transcranial magnetic stimulation (TMS), where magnetic pulses are applied to the scalp using a coil. These pulses pass through the scalp, and can alter brain activity in the area underneath the coil. Based on previous research conducted in animals and humans, researchers believe that iTBS can strengthen the connections between cells in the brain, leading to improved brain plasticity. This trial will compare the effects of the compressed iTBS (iTBS-c) protocol, which is commonly used to treat depression, and the spaced iTBS (iTBS-s) protocol. Researchers want to find out which protocol is better able to produce changes in brain plasticity. Sham iTBS (iTBS-sh) will be used as a control to make the results of the study more reliable. Participants will complete 5 study visits within the span of 3 months, including: * Screening assessments to determine eligibility (Visit 1); * Calibration iTBS session (Visit 2) to assess tolerability of brain stimulation; * Three experimental iTBS sessions (iTBS-s, iTBS-c, and iTBS-sh) in a randomized order (Visits 3-5), each separated by at least 72 hours. During each session, the study team will stimulate the motor cortex and record the muscle activity of your hand to measure changes in brain plasticity.

Eligibility Criteria

This trial is for healthy, right-handed individuals aged 18 to 50 who are interested in contributing to research on brain plasticity. Participants should be able to attend five study visits over three months.

Inclusion Criteria

I am willing and able to give my consent for treatment.

Right handedness, assessed using the Edinburgh Handedness Inventory (EHI)

Sufficiently proficient in English to complete the required study assessments, as per investigator judgement

Exclusion Criteria

I am either 17 years old or younger, or older than 51.

Contraindications to transcranial magnetic stimulation (TMS), as per investigator judgment

Lifetime history of any Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnosis, assessed using the Structured Clinical Interview for DSM-5 (SCID-5), except simple phobias

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Calibration

Calibration iTBS session to assess tolerability of brain stimulation

1 week

1 visit (in-person)

Treatment

Participants undergo three experimental iTBS sessions (iTBS-s, iTBS-c, and iTBS-sh) in a randomized order, each separated by at least 72 hours. The study team stimulates the motor cortex and records muscle activity to measure changes in brain plasticity.

2 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Compressed iTBS
• Sham iTBS
• Spaced iTBS

Trial Overview The trial tests the effects of different iTBS protocols on brain plasticity. It compares spaced iTBS (iTBS-s), compressed iTBS (iTBS-c), and sham iTBS (iTBS-sh) using non-invasive magnetic pulses applied to the motor cortex.

Participant Groups

Group I: Spaced iTBS Experimental Treatment 1 Intervention

After completing Visits 1-2 (Screening and Calibration), participants will undergo the iTBS-s condition in a randomized order during Visits 3 to 5. iTBS-s is the experimental study intervention.

Group II: Compressed iTBS Active Control 1 Intervention

After completing Visits 1-2 (Screening and Calibration), participants will undergo the iTBS-c condition in a randomized order during Visits 3 to 5. iTBS-c is the active comparator.

Group III: Sham iTBS Placebo Group 1 Intervention

After completing Visits 1-2 (Screening and Calibration), participants will undergo the iTBS-sh condition in a randomized order during Visits 3 to 5. iTBS-sh is the sham comparator.

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Findings from Research

In a study of 71 participants with Major Depressive Disorder who had limited response to high-frequency left-sided stimulation, subthreshold intensity intermittent theta-burst stimulation priming (iTBS-P) led to a greater reduction in depressive symptoms compared to suprathreshold intensity stimulation.

The results suggest that iTBS-P may work through homeostatic plasticity mechanisms, indicating that lower intensity stimulation could be more effective for clinical improvement in depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subthreshold stimulation intensity is associated with greater clinical efficacy of intermittent theta-burst stimulation priming for Major Depressive Disorder. Lee, JC., Corlier, J., Wilson, AC., et al.[2021]

Intermittent theta burst stimulation (iTBS) is as effective as standard high-frequency (10 Hz) rTMS for treating treatment-resistant depression, showing non-inferiority in improving depression scores over 4-6 weeks in a study with 414 participants.

Both iTBS and 10 Hz rTMS had similar safety profiles and dropout rates, with headaches being the most common side effect, indicating that iTBS can be a viable alternative that allows for more patients to be treated in a shorter time without losing effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Blumberger, DM., Vila-Rodriguez, F., Thorpe, KE., et al.[2022]

In a study of 22 participants with treatment-resistant depression, the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, which uses high-dose intermittent theta-burst stimulation (iTBS) guided by functional connectivity MRI, showed a remarkable remission rate of 90.5%.

The treatment was well tolerated with no negative cognitive side effects reported, suggesting that SAINT could be a safe and effective option for patients who have not responded to traditional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Cole, EJ., Stimpson, KH., Bentzley, BS., et al.[2020]

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 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]

Intermittent theta-burst stimulation (iTBS) may enhance cognitive function compared to control conditions, but results vary widely across studies due to methodological differences and small sample sizes (often less than 30 participants).

The meta-analysis highlights the need for standardization in iTBS application, as factors like stimulation location significantly affect outcomes, while the type of cognitive task does not contribute to variability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of the efficacy of intermittent theta burst stimulation (iTBS) on cognitive enhancement. Pabst, A., Proksch, S., Médé, B., 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 of 26 patients with bipolar depression, active intermittent theta burst stimulation (iTBS) showed a high response rate of 72% and a remission rate of 42%, indicating its potential efficacy in treating this condition.

No adverse events were reported, demonstrating that iTBS is safe and well-tolerated, but further research with larger sample sizes is needed to confirm its superiority over sham treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Twice-daily neuronavigated intermittent theta burst stimulation for bipolar depression: A Randomized Sham-Controlled Pilot Study. Bulteau, S., Beynel, L., Marendaz, C., et al.[2020]

Intermittent theta-burst stimulation (iTBS) and high-frequency rTMS (HF-rTMS) show similar efficacy in treating treatment-resistant depression (TRD), with response rates of 48.0% for iTBS and 45.5% for HF-rTMS based on two high-quality randomized controlled trials involving 474 participants.

Both iTBS and HF-rTMS have comparable safety profiles, with similar rates of discontinuation and adverse events, such as headaches, indicating that iTBS is a safe alternative to HF-rTMS for patients with TRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. Lan, XJ., Yang, XH., Qin, ZJ., et al.[2023]

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]

In a study involving 34 healthy female participants, the effectiveness of intermittent theta burst stimulation (iTBS) on reducing stress was linked to the resting-state functional connectivity (rsFC) between the left dorsolateral prefrontal cortex (DLPFC) and the caudal anterior cingulate cortex (ACC).

Participants with a stronger negative correlation in rsFC experienced a greater reduction in stress sensitivity after active iTBS, suggesting that individual brain connectivity patterns could help tailor and improve the treatment's effectiveness for stress-related disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Individual resting-state frontocingular functional connectivity predicts the intermittent theta burst stimulation response to stress in healthy female volunteers. de Wandel, L., Pulopulos, MM., Labanauskas, V., et al.[2021]

References

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

Subthreshold stimulation intensity is associated with greater clinical efficacy of intermittent theta-burst stimulation priming for Major Depressive Disorder. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. [2022]

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

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. [2020]

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

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

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

A systematic review and meta-analysis of the efficacy of intermittent theta burst stimulation (iTBS) on cognitive enhancement. [2022]

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

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

8. France pubmed.ncbi.nlm.nih.gov

Twice-daily neuronavigated intermittent theta burst stimulation for bipolar depression: A Randomized Sham-Controlled Pilot Study. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. [2023]

10. 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]

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

Individual resting-state frontocingular functional connectivity predicts the intermittent theta burst stimulation response to stress in healthy female volunteers. [2021]