TMS Impact on Cognitive Sequencing

Overseen By JoAnna Mathena, MS

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Johns Hopkins University

Must not be taking: Anxiolytics, Antidepressants, Neuroleptics, Sedatives

Disqualifiers: Neurological disorder, Stroke, Epilepsy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 hour per session

50 Participants Needed

Trial Summary

What is the purpose of this trial?

Although there is increasing recognition that the cerebellum is involved in cognition as well as motor function, the manner in which the cerebellum contributes to cognition is uncertain. One theory that might account for both motor and cognitive contributions of the cerebellum is that the cerebellum is involved in sequencing of relevant events or stimuli. Previous experiments have suggested that disruption of the cerebellum impairs the prediction of the next event in a sequence. The present experiment will examine the impact of cerebellar stimulation on brain activation during the performance of both sequence-demanding and non-sequence-demanding tasks.

Will I have to stop taking my current medications?

Yes, you will need to stop taking anxiolytic, antidepressant, neuroleptic, or sedative medications to participate in this trial.

What data supports the effectiveness of the treatment TMS Impact on Cognitive Sequencing?

Research shows that repetitive transcranial magnetic stimulation (rTMS) can influence cognitive tasks, such as improving working memory and modulating sequence learning, by targeting specific brain areas like the dorsolateral prefrontal cortex. This suggests that rTMS might be effective in enhancing cognitive sequencing by altering brain activity in targeted regions. ^{1 2 3 4 5}

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

Transcranial magnetic stimulation (TMS) is generally considered safe, but it can cause seizures in rare cases and may have temporary effects on brain function. Most studies suggest that serious problems are unlikely, but further research is needed to fully understand all potential side effects. ^{6 7 8 9 10}

How does the TMS treatment for cognitive sequencing differ from other treatments?

This TMS treatment is unique because it uses non-invasive brain stimulation to specifically target cognitive sequencing tasks, allowing researchers to explore causal brain-behavior relationships and the timing of neural processes, unlike traditional treatments that may not provide such precise control over brain activity. ^{1 3 11 12 13}

Research Team

John E Desmond, Ph.D.

Principal Investigator

Johns Hopkins University

Eligibility Criteria

This trial is for individuals aged 18-50 who can consent, have at least an 8-year education, speak English fluently, and are right-handed. It's not for those with recent drug use, cognitive impairments due to neurological disorders, psychiatric disorders including substance abuse, stroke history, MRI contraindications or visual deficits.

Inclusion Criteria

I am between 18 and 50 years old.

I understand the study and can agree to participate.

You have completed at least 8 years of formal education.

Exclusion Criteria

Uncorrected visual deficits by self-report

Illicit drug use within 30 days of MRI scanning

Contraindications for MRI scanning

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo TMS stimulation during sequence-demanding and non-sequence-demanding tasks, with brain activation measured via fMRI

1 hour per session

Multiple sessions (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• No TMS during non-sequence-demanding task
• No TMS during sequence-demanding task
• TMS during non-sequence-demanding task
• TMS during sequence-demanding task

Trial Overview The study tests the effect of cerebellar stimulation on brain activity during tasks that require sequencing and those that don't. Participants will undergo Transcranial Magnetic Stimulation (TMS) while performing these tasks to see how it affects their brain function.

Participant Groups

Group I: Cerebellar Stimulation Experimental Treatment 4 Interventions

TMS will be administered to the cerebellum on half the trials of a sequence-demanding task, and on half the trials of a non-sequence-demanding task. Task order will be counterbalanced.

Group II: Occipital Stimulation Active Control 4 Interventions

TMS will be administered to an occipital control region on half the trials of a sequence-demanding task, and on half the trials of a non-sequence-demanding task. Task order will be counterbalanced.

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

Repetitive transcranial magnetic stimulation (rTMS) can effectively modulate visuomotor sequence learning, with the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) identified as the most promising targets for stimulation.

The review highlights that low-frequency rTMS over M1 typically weakens performance, while effects on DLPFC are less consistent, emphasizing the need for careful consideration of stimulation protocols and timing in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulating Visuomotor Sequence Learning by Repetitive Transcranial Magnetic Stimulation: What Do We Know So Far? Szücs-Bencze, L., Vékony, T., Pesthy, O., et al.[2023]

Repetitive transcranial magnetic stimulation (rTMS) at 5 Hz applied to the parietal cortex significantly improved reaction times in a working memory task without affecting accuracy, indicating its potential efficacy for enhancing cognitive performance.

The timing of rTMS application is crucial, as improvements were observed only during the retention phase of the task, suggesting that specific stimulation conditions can optimize working memory performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Facilitation of performance in a working memory task with rTMS stimulation of the precuneus: frequency- and time-dependent effects. Luber, B., Kinnunen, LH., Rakitin, BC., et al.[2019]

In a study involving 16 healthy adults, repetitive TMS (rTMS) applied to the dorsolateral prefrontal cortex did not show expected changes in local cortical excitability as measured by TMS-evoked potential (TEP) amplitude, suggesting that traditional metrics may not fully capture the effects of rTMS.

Exploratory analyses revealed that rTMS may induce non-local neural changes and alterations in neural phase and source space, indicating that rTMS could affect brain activity beyond the immediate stimulation area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neural effects of TMS trains on the human prefrontal cortex. Ross, JM., Cline, CC., Sarkar, M., et al.[2023]

Stimulation of the left dorsolateral prefrontal cortex (DLPFC) using slow (1 Hz) repetitive transcranial magnetic stimulation (rTMS) significantly reduced counting bias in random number generation tasks, indicating its role in inhibiting overlearned counting tendencies.

In contrast, fast (10 Hz) rTMS over the left DLPFC exaggerated counting bias, demonstrating that the effects of rTMS on cognitive processing are frequency-dependent and highlighting the specific functional importance of the left DLPFC in managing sequential responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suppressing versus releasing a habit: frequency-dependent effects of prefrontal transcranial magnetic stimulation. Knoch, D., Brugger, P., Regard, M.[2006]

Recent advances in paired-pulse, dual-site transcranial magnetic stimulation (TMS) allow researchers to causally investigate interactions between brain areas, particularly in the human motor system, enhancing our understanding of goal-directed behavior.

The dual-site TMS protocol can transiently improve synaptic efficiency in interconnected brain regions, offering potential for targeted manipulation of neural pathways to enhance cognitive-motor functions and inform treatments for neurological and psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measuring and Manipulating Functionally Specific Neural Pathways in the Human Motor System with Transcranial Magnetic Stimulation. Goldenkoff, ER., Mashni, A., Michon, KJ., et al.[2020]

In a meta-analysis of 93 randomized controlled trials involving repetitive transcranial magnetic stimulation (TMS), the overall incidence of adverse events (AEs) was found to be higher in the active TMS group (29.3%) compared to the placebo group (13.6%), indicating a 2.60 times greater risk of experiencing AEs with active treatment.

Despite the higher incidence of AEs, TMS is considered a safe and well-tolerated intervention, with common side effects including headache and dizziness, highlighting the importance of recognizing nocebo effects in both clinical trials and practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Nocebo Phenomena During Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Placebo-Controlled Clinical Trials. Zis, P., Shafique, F., Hadjivassiliou, M., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) has not been thoroughly studied for side effects, with the main known risk being the acute production of seizures.

While tissue damage from rTMS is unlikely, there are concerns about potential cognitive effects and the possibility of long-term changes in brain function that have not yet been fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of repetitive transcranial magnetic stimulation. Wassermann, EM.[2005]

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]

Transcranial magnetic stimulation (TMS) is generally safe and does not cause persistent changes in cognitive function or EEG, although transient effects may occur during treatment.

While TMS does not typically induce seizures, there is a potential risk for individuals with heightened susceptibility, indicating that further research is needed to fully understand any unwanted effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of transcranial magnetic stimulation reconsidered: evidence regarding cognitive and other cerebral effects. Bridgers, SL.[2007]

Transcranial magnetic stimulation (TMS) is a safe and effective method for establishing causal relationships between brain regions and behavior, allowing researchers to understand how specific areas of the brain contribute to tasks like reading.

TMS offers advantages over traditional lesion studies, such as better precision and the ability to use participants as their own controls, although it does have limitations like potential interference from auditory and sensory stimuli.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation for investigating causal brain-behavioral relationships and their time course. Sliwinska, MW., Vitello, S., Devlin, JT.[2022]

Transcranial magnetic stimulation (TMS) is a valuable non-invasive tool for studying brain function and behavior, particularly in visual perception and cognition, and offers unique advantages over traditional neuropsychological lesion studies.

Despite its usefulness, TMS has limitations, particularly regarding the understanding of its physiological effects, which can lead to ambiguous interpretations of results; combining TMS with functional neuroimaging may help address some of these issues, but challenges remain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining transcranial magnetic stimulation and functional imaging in cognitive brain research: possibilities and limitations. Sack, AT., Linden, DE.[2019]

Sham transcranial magnetic stimulation (TMS) can actually improve reaction times in visual target detection tasks when applied at specific time intervals (150-250 ms before the target), indicating that the non-neural effects of TMS can influence performance.

The positioning of the TMS coil also matters; placing it on the same side as the target (ipsilateral) enhances reaction times compared to placing it on the opposite side (contralateral), highlighting the need for careful control conditions in TMS studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-stimulus sham TMS facilitates target detection. Duecker, F., Sack, AT.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Modulating Visuomotor Sequence Learning by Repetitive Transcranial Magnetic Stimulation: What Do We Know So Far? [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Facilitation of performance in a working memory task with rTMS stimulation of the precuneus: frequency- and time-dependent effects. [2019]

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

Neural effects of TMS trains on the human prefrontal cortex. [2023]

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

Suppressing versus releasing a habit: frequency-dependent effects of prefrontal transcranial magnetic stimulation. [2006]

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

Measuring and Manipulating Functionally Specific Neural Pathways in the Human Motor System with Transcranial Magnetic Stimulation. [2020]

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

Safety, Tolerability, and Nocebo Phenomena During Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Placebo-Controlled Clinical Trials. [2022]

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

Side effects of repetitive transcranial magnetic stimulation. [2005]

8. 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]

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

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

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

The safety of transcranial magnetic stimulation reconsidered: evidence regarding cognitive and other cerebral effects. [2007]

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

Transcranial magnetic stimulation for investigating causal brain-behavioral relationships and their time course. [2022]

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

Combining transcranial magnetic stimulation and functional imaging in cognitive brain research: possibilities and limitations. [2019]

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

Pre-stimulus sham TMS facilitates target detection. [2022]