TMS Tolerability for Healthy Subjects

Overseen By Isabelle Taylor, MA

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Florida State University

Must not be taking: Tricyclics, Clozapine, NSAIDs, Opioids

Disqualifiers: Seizure disorder, Schizophrenia, Pregnancy, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3-36 months

20 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial requires you to stop any medications that significantly lower the seizure threshold or impact sensory and tolerability measures. This includes tricyclic antidepressants, clozapine, topical anesthetics, botulinum toxin injections, ketamine, NSAIDs, opioids, and anticonvulsants used in pain management.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications that significantly lower the seizure threshold or impact sensory and tolerability measures. This includes certain antidepressants, pain medications, and substances like ketamine and opioids.

What data supports the idea that TMS Tolerability for Healthy Subjects is an effective treatment?

The available research shows that TMS, or Transcranial Magnetic Stimulation, can change brain activity in healthy subjects, which suggests it might be effective for treating certain conditions. For example, one study found that TMS can alter sensory functions, while another showed it can stimulate specific brain areas related to muscle control. Although these studies focus on healthy subjects, they provide important information that could help in understanding how TMS might work as a treatment for conditions like depression or stroke. However, more research is needed to fully understand its effectiveness compared to other treatments. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment TMS, Transcranial Magnetic Stimulation, Repetitive Transcranial Magnetic Stimulation (rTMS)?

Research shows that rTMS can change brain activity and has been explored as a treatment for conditions like stroke, Parkinson's disease, and depression, with some small studies showing positive results. ^{1 2 3 4 5}

What safety data exists for TMS treatment?

Safety data for TMS, including rTMS, indicates that while it is generally safe, there are some risks. Mild adverse effects like headaches and nausea have been noted, and seizures, though extremely rare, are the most serious potential adverse effect. Guidelines have been developed to minimize risks, including recommended limits on stimulation parameters and monitoring protocols. Safety has been evaluated in various populations, including healthy adults and pediatric groups, with most adverse events occurring when guidelines are exceeded or in patients with conditions that lower the seizure threshold. ^{6 7 8 9 10}

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

Transcranial magnetic stimulation (TMS) is generally considered safe for healthy individuals, with mild side effects like headaches and nausea being the most common. Seizures are a rare but serious risk, often occurring when guidelines are not followed or in individuals taking certain medications. Safety guidelines have been developed to minimize these risks. ^{6 7 8 9 10}

Is TMS a promising treatment for healthy subjects?

Yes, TMS is a promising treatment because it can safely and noninvasively stimulate the brain, helping to study and potentially improve brain functions. It has shown promise in treating conditions like depression and is being explored for other uses like stroke and Alzheimer's disease. ^{1 6 11 12 13}

How is TMS treatment different from other treatments for brain conditions?

TMS (Transcranial Magnetic Stimulation) is unique because it uses magnetic fields to noninvasively stimulate specific areas of the brain, unlike medications that work chemically. It can directly modulate brain activity, offering a way to study and potentially treat conditions like depression by normalizing brain activity patterns. ^{1 6 11 12 13}

What is the purpose of this trial?

The primary objective is to characterize the tolerability of TMS by scalp location (over parietal, motor, modified Beam F3 prefrontal, THREE-D prefrontal, orbitofrontal, and medial prefrontal) and stimulation parameters (single pulse, 10 Hz, theta burst). The secondary objective is to evaluate the knee as a surrogate location to safely trial tolerability of novel TMS parameters.

Eligibility Criteria

This trial is for healthy individuals who are interested in participating in a study to assess the comfort level of TMS (Transcranial Magnetic Stimulation) when applied to different areas of the scalp and with varying stimulation settings.

Inclusion Criteria

I can understand and follow the study's procedures for its duration.

I have or haven't had TMS therapy before.

Exclusion Criteria

Contraindication for scalp sensitivity and tolerability testing (e.g., sunburn, active headache, history of frequent and severe headaches)

Contraindication for participants with metal in both knees, unless knee testing skipped at the investigators' discretion

Active substance use disorder in last 3 months or any current substance use that puts the participant at increased risk or significant impairment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Characterization of the tolerability of TMS by scalp location and stimulation parameters

3-36 months

Multiple visits for TMS sessions and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• TMS

Trial Overview The study aims to determine how tolerable TMS is at various scalp locations using different parameters like single pulse, rapid bursts, and repetitive stimulations. It also looks into using the knee as an alternative site for testing new TMS protocols.

Participant Groups

Group I: Single Arm Experimental Treatment 1 Intervention

This will be a single arm study with measurements of scalp location and TMS stimulation parameters.

TMS is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Transcranial Magnetic Stimulation for:

• Depression
• Anxiety disorders
• Post-traumatic stress disorder (PTSD)
• Obsessive-compulsive disorder (OCD)

Approved in European Union as Transcranial Magnetic Stimulation for:

• Depression
• Anxiety disorders
• Post-traumatic stress disorder (PTSD)
• Obsessive-compulsive disorder (OCD)

Approved in Canada as Transcranial Magnetic Stimulation for:

• Depression
• Anxiety disorders
• Post-traumatic stress disorder (PTSD)
• Obsessive-compulsive disorder (OCD)

Who Is Running the Clinical Trial?

Florida State University

Lead Sponsor

Trials

234

Recruited

41,100+

Findings from Research

Low-frequency repetitive transcranial magnetic stimulation (rTMS) significantly increased current perception thresholds, indicating a global anesthetic effect on sensory functions in healthy subjects.

rTMS also decreased the amplitude of somatosensory evoked potentials, suggesting reduced excitability in the primary sensory cortex, which may have implications for treating chronic pain conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in sensory functions after low-frequency repetitive transcranial magnetic stimulation over the motor cortex. Kodama, M., Aono, K., Masakado, Y.[2011]

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]

Stimulation of the 'hot spot' for the abductor pollicis brevis (APB) resulted in significantly lower motor thresholds compared to a standard scalp position and movement thresholds, indicating that coil positioning is crucial for accurate TMS measurements.

The study found no significant differences in motor-evoked potential amplitudes when adjusting stimulation intensity based on different threshold methods, suggesting that the method of determining thresholds may not affect the resulting muscle response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of coil position and electrophysiological monitoring on determination of motor thresholds to transcranial magnetic stimulation. Conforto, AB., Z'Graggen, WJ., Kohl, AS., et al.[2008]

Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive brain stimulation technique that can enhance brain excitability and potentially improve conditions like stroke, Parkinson's disease, and depression, as discussed in a 2010 symposium with insights from both animal studies and small clinical trials.

While there is significant interest and some signs of therapeutic success with rTMS, the current models explaining its effects may need refinement to fully understand the underlying mechanisms and outcomes observed in various studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain stimulation and brain repair--rTMS: from animal experiment to clinical trials--what do we know? Platz, T., Rothwell, JC.[2013]

A new algorithm was developed to accurately locate the dorsolateral prefrontal cortex (DLPFC) and primary motor cortex (M1) for transcranial magnetic stimulation (TMS) using individual MRI data, improving targeting reliability across different investigators.

The study demonstrated good inter-rater reliability in determining the coordinates of these brain regions, with variations influenced by factors like gender and age, which can enhance the standardization of TMS procedures in therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definition of DLPFC and M1 according to anatomical landmarks for navigated brain stimulation: inter-rater reliability, accuracy, and influence of gender and age. Mylius, V., Ayache, SS., Ahdab, R., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) is a powerful tool that can effectively treat clinical depression and potentially other brain disorders, but it carries risks, including the potential to induce seizures, as evidenced by 7 known cases by 1996.

A workshop established safety guidelines for rTMS, emphasizing the importance of monitoring, ethical considerations, and the expertise required for its administration to minimize risks and enhance therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Wassermann, EM.[2022]

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]

In a study involving 429 pediatric patients undergoing transcranial magnetic stimulation (TMS) for motor and language mapping, most adverse events were benign, with seizures occurring in 5.8% of sessions but not conclusively linked to TMS.

TMS was safely performed in patients with cranial metal, and useful mapping results were achieved in nearly all cases, indicating that TMS is a safe option for functional mapping in pediatric patients with epilepsy or brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Image-guided TMS is safe in a predominately pediatric clinical population. Braden, AA., Weatherspoon, SE., Boardman, T., et al.[2022]

Mild adverse effects (MAEs) from transcranial magnetic stimulation (TMS) occur in about 5% of sessions, with most symptoms like headache and nausea reported after the sessions, particularly during initial treatments.

The study found no significant links between participant characteristics (age and gender) or TMS parameters (frequency and intensity) and the occurrence of MAEs, suggesting that initial participant anxiety may play a role in these reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation. Maizey, L., Allen, CP., Dervinis, M., et al.[2022]

Transcranial magnetic stimulation (TMS) has a strong safety record, with seizures being an extremely rare adverse effect, particularly in patients receiving repetitive TMS (rTMS) under certain conditions.

The updated guidelines provide comprehensive safety recommendations for TMS applications, including risk assessments for new stimulation paradigms and precautions for use in patients with implanted devices or in neuroimaging settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Rossi, S., Hallett, M., Rossini, PM., et al.[2022]

In a study involving 15 healthy participants, both 600 and 1200 pulses of 5-Hz rTMS significantly increased motor cortex excitability immediately and 30 minutes after stimulation, indicating its efficacy in enhancing cortical activity.

However, there was no significant difference in the effects of the two pulse conditions, suggesting a potential ceiling effect where increasing the number of pulses beyond a certain point does not further enhance cortical excitability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of different pulse numbers of transcranial magnetic stimulation on motor cortex excitability: Single-blind, randomized cross-over design. Tang, ZM., Xuan, CY., Li, X., et al.[2020]

High frequency rTMS at 25 Hz significantly decreased motor thresholds and reduced the duration of the silent period in the motor cortex of 16 healthy young adult males, indicating increased cortical excitability.

The effects of rTMS lasted for at least 30 minutes after treatment, suggesting potential for therapeutic applications in enhancing brain plasticity, although the effects returned to baseline within 2 hours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of motor cortical excitability following rapid-rate transcranial magnetic stimulation. Khedr, EM., Rothwell, JC., Ahmed, MA., et al.[2008]

Transcranial magnetic stimulation (TMS) is a safe and noninvasive technique that can disrupt brain function to study the prefrontal cortex's role in cognitive functions like working memory and language.

Repetitive TMS has been effectively used to treat medication-resistant depression by stimulating the left dorsolateral prefrontal cortex, and research is ongoing to explore its potential for other conditions like stroke and Alzheimer's disease, although most applications are not yet FDA-approved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation: Neurophysiological and clinical applications. Burke, MJ., Fried, PJ., Pascual-Leone, A.[2020]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Changes in sensory functions after low-frequency repetitive transcranial magnetic stimulation over the motor cortex. [2011]

2. 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]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Impact of coil position and electrophysiological monitoring on determination of motor thresholds to transcranial magnetic stimulation. [2008]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Brain stimulation and brain repair--rTMS: from animal experiment to clinical trials--what do we know? [2013]

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

Definition of DLPFC and M1 according to anatomical landmarks for navigated brain stimulation: inter-rater reliability, accuracy, and influence of gender and age. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. [2022]

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. Netherlands pubmed.ncbi.nlm.nih.gov

Image-guided TMS is safe in a predominately pediatric clinical population. [2022]

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

Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Effect of different pulse numbers of transcranial magnetic stimulation on motor cortex excitability: Single-blind, randomized cross-over design. [2020]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Modulation of motor cortical excitability following rapid-rate transcranial magnetic stimulation. [2008]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation: Neurophysiological and clinical applications. [2020]