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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how different parts of the brain connect and communicate in healthy individuals. Researchers use safe, non-invasive techniques like single-pulse transcranial magnetic stimulation (spTMS) to measure signal travel between brain regions. The study may also use paired associative stimulation (PAS) to determine if small timing changes can alter these connections. Healthy individuals with normal vision and hearing who can give informed consent are suitable candidates for this trial. As an unphased study, this research provides a unique opportunity to contribute to the scientific understanding of brain connectivity.

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 prior data suggests that these techniques are safe for healthy participants?

Previous studies have shown that single-pulse transcranial magnetic stimulation (spTMS) is very safe. Most side effects, such as headaches, occur only occasionally and are mild. Serious side effects, like seizures, are very rare and can be avoided with careful use.

Research also shows that paired associative stimulation (PAS) is generally safe. Some studies mention possible minor side effects, but these are uncommon. One study found that PAS did not cause any heart-related issues during a one-hour follow-up.

Overall, both spTMS and PAS are non-invasive and well-tolerated. Existing research should reassure participants about the safety of these treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how transcranial magnetic stimulation (TMS) can influence brain network activity in healthy individuals. Unlike traditional methods that focus on single areas of the brain, this trial uses a technique called paired associative stimulation (PAS) to deliver TMS to two different brain sites simultaneously, with varying timing. This approach aims to better understand how different regions of the brain communicate and adapt, potentially leading to more precise and effective uses of TMS in the future. Additionally, by incorporating advanced brain imaging and EEG monitoring, the trial seeks to uncover the underlying mechanisms of TMS, paving the way for breakthroughs in treating neurological and psychiatric conditions.

What evidence suggests that this study's techniques are effective for understanding brain connectivity?

Research has shown that paired associative stimulation (PAS), one of the methods studied in this trial, can alter brain connections. Studies have found that it boosts brain activity by pairing stimulations to specific areas, enhancing activity in certain regions and aiding tasks that require coordination. In contrast, single-pulse transcranial magnetic stimulation (spTMS), another method under investigation, is known for its safety and can temporarily affect brain activity. It has been used to slow responses in certain brain areas, demonstrating its impact on brain function. Both methods are non-invasive, meaning they do not require surgery, making them safe options for brain studies. ^{1 5 6 7 8}

Who Is on the Research Team?

Aapo Nummenmaa, PhD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11130975/

The Effectiveness of Paired Associative Stimulation on ... Seven studies evaluated the outcome on upper limb and one on lower limb motor recovery. Although several studies omit crucial methodological ...

2. eneuro.org eneuro.org/content/7/2/ENEURO.0396-19.2020

Paired Associative Stimulation Fails to Induce Plasticity in ... Paired associative stimulation (PAS) has been explored in humans as a noninvasive tool to drive plasticity and promote recovery after ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12110737/

A Methodological Evaluation of Four Different Paired ... PAS-25 with 225 pairings significantly increased corticospinal excitability in responders, and the pairwise comparisons identified significant ...

4. nature.com nature.com/articles/s41598-019-40474-0

Increasing the frequency of peripheral component in paired ... Optimal peripheral nerve stimulation intensity for paired associative stimulation with high-frequency peripheral component in healthy subjects.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0149763424004020

Investigating the effects of cortico-cortical paired ... The study found an increase in CSE and a decrease in short interval intracortical inhibition (SICI) measured at rest after the ccPAS intervention, suggesting ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6718871/

A Systematic Review of Paired Associative Stimulation (PAS ... PAS results in a rapid change in corticomotor excitability (CME) of the corticospinal pathway to the target muscle. This change in CME is ...

7. frontiersin.org frontiersin.org/journals/rehabilitation-sciences/articles/10.3389/fresc.2023.1200958/full

The effect of paired associative stimulation with a high- ... This study revealed that high PAS is safe and does not show any cardiovascular effects over a 60-min follow-up. An increase in the HF band ...

8. mdpi.com mdpi.com/2076-3425/13/3/475

Effects of Paired Associative Stimulation on Cortical ... Paired associative stimulation (PAS) increases and decreases cortical excitability in primary motor cortex (M1) neurons, depending on the spike ...