TMS Network Activity Modeling for Healthy Subjects

Overseen By Tommi Raij, MD, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Massachusetts General Hospital

Must not be taking: Neurological, Psychiatric

Disqualifiers: Epilepsy, Pregnancy, Substance abuse, others

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

Compensation: Varies

Number of Visits: 5

80 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial excludes participants who are on medications that influence brain function, so you may need to stop taking such medications to participate.

What data supports the effectiveness of the treatment Paired associative stimulation (PAS) and Single-pulse TMS (spTMS)?

Research shows that transcranial magnetic stimulation (TMS) can change brain activity and behavior, but its effects vary across different brain regions and individuals. This suggests that TMS, including its use in paired associative stimulation (PAS), may be effective in modulating brain networks, although individual responses can differ. ^{1 2 3 4 5}

Is transcranial magnetic stimulation (TMS) generally safe for humans?

TMS is generally considered safe, but it can cause seizures in some individuals. The exact rate of seizures and other adverse events is not well known, but they are considered rare. ^{1 3 6 7 8}

How does the treatment Paired associative stimulation (PAS) and Single-pulse TMS (spTMS) differ from other treatments?

Paired associative stimulation (PAS) and Single-pulse TMS (spTMS) are unique because they use magnetic fields to stimulate specific brain areas, potentially altering brain network activity and connectivity. This approach is different from traditional treatments that might rely on medication or other forms of therapy, as it directly targets brain function and connectivity, which could lead to more personalized treatment strategies. ^{1 3 9 10 11}

What is the purpose of this trial?

This is a study of normal brain physiology in healthy human volunteers. The study aims to understand the physiology of connectivity between brain regions. To reach this aim, it delivers single-pulse transcranial magnetic stimulation (spTMS) to one or two brain areas at a time while electroencephalography (EEG) is measured. When only one brain area is stimulated (uni-focal TMS), the goal is to record how many milliseconds it takes for the activity to spread from the stimulated area to other brain regions (conduction delay). When two brain areas are stimulated (bi-focal TMS), the TMS pulses are separated by a short millisecond-level time interval ("asynchrony") in a so-called paired associative stimulation (PAS) design. The central hypothesis is that PAS may increase or decrease connectivity between the stimulated areas depending on the asynchrony value. All techniques in the study are non-invasive and considered safe.

Research Team

Aapo Nummenmaa, PhD

Principal Investigator

Mass General Brigham

Eligibility Criteria

This trial is for healthy individuals with normal hearing and vision (corrected if necessary) who can understand and consent to participate. It's not suitable for those with metal in their body, heart devices, neurological or psychiatric conditions affecting brain function, developmental disorders, seizure history, substance abuse issues, pregnancy or breastfeeding.

Inclusion Criteria

My hearing and vision, with aids if necessary, are normal.

I understand the study and can give my consent.

Healthy

Exclusion Criteria

Implanted pumps

History of developmental disorders (e.g., dyslexia)

Prisoners

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

MRI Scanning

Participants undergo MRI scans including T1-weighted, T2-weighted, diffusion MRI, and resting-state fMRI

1 day

1 visit (in-person)

Uni-focal TMS Session

Participants receive uni-focal TMS to various cortical targets while EEG is recorded to determine inter-regional conduction delays

1 day

1 visit (in-person)

Bi-focal TMS Sessions

Participants undergo bi-focal TMS (PAS) sessions with different asynchronies to assess connectivity changes

3 weeks

3 visits (in-person), each session at least one week apart

Follow-up

Participants are monitored for safety and effectiveness after the TMS sessions

4 weeks

Treatment Details

Interventions

• Paired associative stimulation (PAS)
• Single-pulse TMS (spTMS)

Trial Overview The study tests how the brain's network activity responds to non-invasive stimulation using transcranial magnetic stimulation (TMS). It measures connectivity between brain regions by delivering single-pulse TMS while recording EEG data. The effects of varying time intervals between pulses on different areas are also explored.

Participant Groups

Group I: Healthy participants Experimental Treatment 2 Interventions

All participants participate in five core sessions. Session 1 consists of MRI scans (T1-weighted, T2-weighted, diffusion MRI, resting-state fMRI). Thereafter, there are four TMS-EEG sessions. Session 2 delivers uni-focal spTMS to various cortical targets while EEG is recorded to determine inter-regional conduction delays. Thereafter, Sessions 3 - 5 deliver bi-focal TMS (PAS), each session using a different asynchrony (shorter, equal to, or longer than the conduction delay). The three PAS sessions are at least one week apart. Each of the PAS sessions have three segments: (a) TMS-EEG-behavioral recordings before PAS, (b) the PAS modulation, and (c) TMS-EEG-behavioral recordings after PAS. In addition to these core sessions, some participants may be invited for additional sessions for parameter optimization and for assessing test-retest repeatability.

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Findings from Research

This study mapped the optimal stimulation areas for the thenar and anterior tibial muscles in the primary motor cortex using navigated transcranial magnetic stimulation (TMS) in 59 healthy right-handed subjects, providing important normative data for future clinical assessments.

The research revealed significant variability in optimal stimulation sites, particularly in the anteroposterior direction, which is crucial for understanding how brain plasticity affects functional cortical areas in clinical populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Group-level variations in motor representation areas of thenar and anterior tibial muscles: Navigated Transcranial Magnetic Stimulation Study. Niskanen, E., Julkunen, P., Säisänen, L., et al.[2021]

Transcranial magnetic stimulation (TMS) is safe to use with implanted deep brain stimulation (DBS) devices at low to moderate intensities, as no movement or temperature increase was observed during stimulation at 0.2 Hz with 100% intensity for 1 hour.

However, caution is advised when using high-intensity TMS (over 50%) near looped DBS leads, as it can exceed the safety limit for charge density, potentially leading to electrical tissue injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of transcranial magnetic stimulation with deep brain stimulation instruments. Shimojima, Y., Morita, H., Nishikawa, N., et al.[2010]

Transcranial magnetic stimulation (TMS) has a very low seizure risk, with only 0.08 seizures reported per 1,000 sessions, and less than 0.02 seizures per 1,000 sessions when guidelines are followed for individuals without known risk factors.

The study found that exceeding safety guidelines increases the risk of seizures, and seizures are more likely to occur during the first few TMS sessions, suggesting that TMS is generally safe when administered properly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Seizures from transcranial magnetic stimulation 2012-2016: Results of a survey of active laboratories and clinics. Lerner, AJ., Wassermann, EM., Tamir, DI.[2021]

Stereotactic transcranial magnetic stimulation (TMS) was successfully used in two patients to map motor functions in the brain before surgery, showing it is a well-tolerated and noninvasive technique.

The TMS results closely matched those obtained from direct electrical cortical stimulation during surgery, with over 75% of TMS responses occurring within 1 cm of the stimulation site, indicating its accuracy for presurgical planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic transcranial magnetic stimulation: correlation with direct electrical cortical stimulation. Krings, T., Buchbinder, BR., Butler, WE., et al.[2019]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Spread of activity following TMS is related to intrinsic resting connectivity to the salience network: A concurrent TMS-fMRI study. [2019]

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

The physiological effects of noninvasive brain stimulation fundamentally differ across the human cortex. [2020]

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

Modeling motor connectivity using TMS/PET and structural equation modeling. [2022]

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

Individual Activation Patterns After the Stimulation of Different Motor Areas: A Transcranial Magnetic Stimulation-Electroencephalography Study. [2020]

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

Group-level variations in motor representation areas of thenar and anterior tibial muscles: Navigated Transcranial Magnetic Stimulation Study. [2021]

6. England pubmed.ncbi.nlm.nih.gov

The safety of transcranial magnetic stimulation with deep brain stimulation instruments. [2010]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Seizures from transcranial magnetic stimulation 2012-2016: Results of a survey of active laboratories and clinics. [2021]

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

Stereotactic transcranial magnetic stimulation: correlation with direct electrical cortical stimulation. [2019]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Modeling motor-evoked potentials from neural field simulations of transcranial magnetic stimulation. [2021]

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

An integrated framework for targeting functional networks via transcranial magnetic stimulation. [2021]

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

Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex. [2007]