Transcranial Magnetic Stimulation for Mild Cognitive Impairment

(TMS-AD Trial)

Overseen By Emily Finch, BA

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Duke University

Must not be taking: Seizure threshold, Working memory

Disqualifiers: Axis I disorders, Substance abuse, Implants, Seizure risk, Neurological disorder, 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: 4

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how transcranial magnetic stimulation (TMS), a type of brain stimulation, can boost memory in people with mild cognitive impairment (MCI) and healthy older adults. Researchers aim to determine if targeting specific brain areas with TMS can improve working memory, which is crucial for tasks like remembering where keys are placed. Participants will receive different forms of TMS, including a real and a sham (fake) version, to compare effects. This trial suits English-speaking individuals willing to provide consent and who do not have certain neurological disorders or a history of seizures. As an unphased trial, it offers a unique opportunity to contribute to groundbreaking research on memory enhancement.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications known to lower the seizure threshold or affect working memory.

What prior data suggests that transcranial magnetic stimulation is safe for mild cognitive impairment?

Research has shown that Transcranial Magnetic Stimulation (TMS) is generally safe and well-tolerated. Studies have found that using TMS for mild cognitive impairment (MCI) rarely causes serious side effects. Most people experience only mild issues, such as headaches or scalp discomfort, which usually resolve quickly. Other research supports that TMS can safely enhance thinking and memory in people with MCI. Overall, TMS appears to be a promising option with a good safety record for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about transcranial magnetic stimulation (TMS) for mild cognitive impairment because it offers a non-invasive way to influence brain activity directly. While current treatments often focus on medication or cognitive therapies to manage symptoms, TMS targets the brain's alpha oscillations through magnetic pulses, which could potentially improve memory performance more effectively. This trial is unique because it explores different TMS approaches: rhythmic stimulation that may entrain brain rhythms, randomized pulses to disrupt and potentially enhance brain activity, and a sham comparator to ensure the effects are genuine. By manipulating brain waves, TMS could offer a novel, dynamic way to tackle cognitive decline, sparking hope for faster and more targeted improvements.

What evidence suggests that transcranial magnetic stimulation is effective for mild cognitive impairment?

Research has shown that transcranial magnetic stimulation (TMS) can improve thinking and memory in people with mild cognitive impairment (MCI). Studies have found that repeated TMS can boost memory in individuals with MCI. In this trial, participants will be assigned to different TMS conditions: one group will receive rhythmic (ordered) alpha-frequency TMS, another will receive arrhythmic (randomized) TMS, and a third group will receive sham stimulation. Previous studies have demonstrated that those who received TMS performed better on cognitive tests than those who did not. Another study discovered that using high-frequency TMS on different parts of the brain over a longer period led to noticeable improvements in thinking skills. Overall, TMS is considered a safe and promising method to enhance memory and thinking in people with MCI. ^{2 4 5 6 7}

Who Is on the Research Team?

Andy Liu, MD

Principal Investigator

Duke University

Simon W Davis, PhD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

This trial is for English-speaking adults who are experiencing mild cognitive impairment or general cognitive decline. Participants must be willing to provide consent. It aims to help those noticing memory challenges associated with aging.

Inclusion Criteria

Willing to provide consent

English Speaking

Exclusion Criteria

Intracranial implants (e.g. aneurysms clips, shunts, stimulators, cochlear implants, or electrodes), cardiac pacemakers, or vagus Nerve stimulation device

Current history of substance abuse or dependence (excluding nicotine)

I do not have any major neurological disorders.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Neuroimaging

Initial neuroimaging session to collect baseline data on functional network connectivity and vascular density

2 days

2 visits (in-person)

TMS-EEG

Application of closed-loop TMS to the prefrontal cortex and measurement of EEG-based connectivity and working memory task performance

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after TMS intervention

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Transcranial Magnetic Stimulation

Trial Overview The study tests a technique called closed-loop transcranial magnetic stimulation (TMS), targeting the Prefrontal Cortex, to improve working memory in older adults and those with mild cognitive impairment by modulating brain networks.

How Is the Trial Designed?

Group I: TMS-Randomized Experimental Treatment 1 Intervention

Three different closed-loop conditions will be tested, each triggered by the presence of a sustained period of alpha-band power. In the first condition, arrhythmic TMS trains with a stochastic (randomized) inter-pulse interval, will be used to disrupt cortical alpha oscillations and thus be expected to enhance memory performance.

Group II: TMS-Ordered Experimental Treatment 1 Intervention

Three different closed-loop conditions will be tested, each triggered by the presence of a sustained period of alpha-band power. In the second condition, rhythmic (ordered) alpha-frequency TMS trains, with the expectation that this alpha stimulation will further entrain a synchronization during the task and thereby worsen memory performance.

Group III: TMS-Sham Placebo Group 1 Intervention

Three different closed-loop conditions will be tested, each triggered by the presence of a sustained period of alpha-band power. In a third condition, sham stimulation will be delivered at the same randomized inter-pulse interval, but with no TMS delivered to the brain.

Transcranial Magnetic Stimulation is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder
• Obsessive Compulsive Disorder

Approved in Canada as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder

Approved in European Union as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

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]

In a study involving 40 patients with Parkinson's disease and mild cognitive impairment, combining repetitive transcranial magnetic stimulation (rTMS) with virtual reality (VR) training led to significantly greater improvements in cognitive functions, particularly in memory and executive function, compared to rTMS alone.

The rTMS-VR group showed enhanced cognitive benefits immediately after treatment and maintained improvements in delayed memory scores at a 3-month follow-up, suggesting that this combined approach could be an effective strategy for cognitive rehabilitation in Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integration of Virtual Reality into Transcranial Magnetic Stimulation Improves Cognitive Function in Patients with Parkinson's Disease with Cognitive Impairment: A Proof-of-Concept Study. Cheng, TC., Huang, SF., Wu, SY., et al.[2022]

In a study of 21 patients with amnestic mild cognitive impairment (aMCI), repetitive transcranial magnetic stimulation (rTMS) significantly improved cognitive performance and altered functional connectivity within the default mode network (DMN) compared to a sham treatment.

The changes in DMN connectivity, particularly a decrease in connectivity, were linked to cognitive improvements, suggesting that baseline DMN activity could predict how well patients respond to rTMS therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation Induced Hypoconnectivity Within the Default Mode Network Yields Cognitive Improvements in Amnestic Mild Cognitive Impairment: A Randomized Controlled Study. Cui, H., Ren, R., Lin, G., et al.[2020]

Repetitive Transcranial Magnetic Stimulation (rTMS) targeting the left parietal cortex significantly improved memory performance in a patient with amnestic Mild Cognitive Impairment (aMCI).

The memory improvement was not only immediate but also sustained, remaining significant 24 weeks after the stimulation began, suggesting a lasting effect of rTMS on cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain stimulation improves associative memory in an individual with amnestic mild cognitive impairment. Cotelli, M., Calabria, M., Manenti, R., et al.[2016]

Repetitive magnetic stimulation (rTMS) is a non-invasive and painless technique that can effectively activate specific areas of the brain, making it useful for studying language, memory, and visual perception.

rTMS shows potential therapeutic benefits for conditions like movement disorders and depression, but there are safety considerations regarding its potential to induce seizures, which are addressed in the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Repetitive transcranial magnetic stimulation. Possibilities, limits and safety aspects]. Brandt, SA., Ploner, CJ., Meyer, BU.[2019]

Repetitive transcranial magnetic stimulation (rTMS) has gained popularity for its ability to modulate brain activity, but safety considerations are crucial, especially with the recent updates to safety guidelines published in 2021.

The guidelines emphasize the importance of screening for risks, monitoring for adverse events, and specific safety measures when using rTMS, particularly in patients with conditions like stroke and traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. Kim, WS., Paik, NJ.[2023]

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]

In a study involving 22 patients with mild cognitive impairment (MCI), repetitive Transcranial Magnetic Stimulation (rTMS) was found to significantly enhance the effects of Cognitive Stimulation (CS) as measured by the Montreal Cognitive Assessment (MoCA).

The study consisted of 30 sessions over 10 weeks, and while the active group showed significant improvements, the sham group did not, indicating that rTMS may be a beneficial tool for cognitive enhancement in MCI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of transcranial magnetic stimulation as an enhancer of cognitive stimulation sessions on mild cognitive impairment: Preliminary results. Gy, RR., Jv, RL., J, RG., et al.[2021]

In a double-blind, sham-controlled trial involving 24 patients with amnestic mild cognitive impairment (aMCI), high-frequency repetitive transcranial magnetic stimulation (rTMS) significantly improved cognitive function as measured by the Montreal Cognitive Assessment after 4 weeks of treatment.

The rTMS treatment also led to notable changes in brain activity, specifically increasing the amplitude of low-frequency fluctuations in key cognitive areas, suggesting that rTMS may enhance cognitive function by altering brain activity patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroimaging mechanisms of high-frequency repetitive transcranial magnetic stimulation for treatment of amnestic mild cognitive impairment: a double-blind randomized sham-controlled trial. Yuan, LQ., Zeng, Q., Wang, D., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) can effectively improve cognitive function and behavioral symptoms in dementia patients, as demonstrated in a case where a patient showed significant improvement after switching from 1 Hz to 10 Hz rTMS.

While rTMS is generally beneficial, it can lead to adverse reactions such as seizures; however, adjusting the treatment parameters (like reducing the frequency) can help mitigate these risks and continue to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The repetitive transcranial magnetic stimulation in Alzheimer's disease patients with behavioral and psychological symptoms of dementia: a case report. Yang, Z., Zhou, Y.[2023]

Repetitive transcranial magnetic stimulation (rTMS) significantly improved cognitive function in older patients with mild to moderate Alzheimer's disease, based on a meta-analysis of seven randomized controlled trials involving 194 participants.

rTMS is considered a safe and well-tolerated alternative intervention for cognitive impairment, showing a moderate effect size in enhancing cognition compared to sham treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of repetitive transcranial magnetic stimulation on improvement of cognition in elderly patients with cognitive impairment: a systematic review and meta-analysis. Cheng, CPW., Wong, CSM., Lee, KK., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10573645/

Repetitive Transcranial Magnetic Stimulation (rTMS) in Mild ... The results of the reviewed studies suggested that rTMS in MCI patients is safe and effective for enhancing cognitive functions, thus making it a potential ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34764859/

Effects of Repetitive Transcranial Magnetic Stimulation in ... This study shows that rTMS can improve cognitive function in patients with MCI, especially when applied at high frequency, multi-site, and for a prolonged ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1876201825004010

A Meta-Analysis of Randomized Sham-Controlled Trials Efficacy and safety of transcranial magnetic stimulation on cognition in mild cognitive impairment, Alzheimer's disease, Alzheimer's disease ...

4. frontiersin.org frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2024.1436448/full

The effects of repetitive transcranial magnetic and ... This meta-analysis suggests that rTMS and tDCS are safe and efficient tools to improve memory functions in patients with MCI, while rTMS had a larger effect ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05730296

Transcranial Magnetic Stimulation in Patients With Mild ... In this study the research group has demonstrated that after 10 sessions of active TMS (two thousand pulses at 10 Hz, 5-s train duration, and 25-seconds ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11306417/

Efficacy and Safety of Transcranial Magnetic Stimulation on ... TMS was safe and well tolerated with infrequent serious adverse events. Keywords: cognition, dementia, meta-analysis, MCI, mild cognitive ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2213158225000890

Network-targeted transcranial magnetic stimulation (TMS) ... Transcranial magnetic stimulation (TMS) is a promising non-pharmacological intervention for treatment of mild cognitive impairment (MCI) and early Alzheimer's ...