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

Trial Summary

What is the purpose of this trial?

The proposed research will use closed-loop transcranial magnetic stimulation (TMS) based on individualized brain networks to establish parameters that can reliably control brain states. This will be tested in healthy aging and mild cognitive impairment (MCI) cohorts. The investigators will study network activation and neural oscillatory mechanisms underlying the network that regulates working memory and then target this network using closed-loop TMS to the Prefrontal Cortex. Investigators will measure the impact of TMS on working memory performance and task-based neural activity. The project will use brain stimulation and network modeling techniques to enhance working memory in healthy older adults and MCI and will demonstrate the value of closed-loop, network-guided TMS for future clinical applications.

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 data supports the effectiveness of the treatment Transcranial Magnetic Stimulation for Mild Cognitive Impairment?

Research shows that repetitive Transcranial Magnetic Stimulation (rTMS) can improve cognitive function in people with mild cognitive impairment (MCI). Studies have found that rTMS can enhance memory performance and cognitive abilities, with some improvements lasting for weeks after treatment. ^{1 2 3 4 5}

Is transcranial magnetic stimulation (TMS) safe for humans?

Transcranial magnetic stimulation (TMS) is generally considered safe, with guidelines established to minimize risks. Some mild side effects like headaches and nausea have been reported, and there is a rare risk of seizures, but serious adverse effects are uncommon. ^{6 7 8 9 10}

How does the treatment Transcranial Magnetic Stimulation differ from other treatments for mild cognitive impairment?

Transcranial Magnetic Stimulation (rTMS) is unique because it uses magnetic fields to stimulate specific areas of the brain, potentially enhancing cognitive function in patients with mild cognitive impairment. Unlike traditional drug treatments, rTMS is non-invasive and can improve brain activity and memory performance by targeting cognitive-related brain areas. ^{1 2 4 5 11}

Research Team

Simon W Davis, PhD

Principal Investigator

Duke University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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) 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]

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]

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]

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) 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]

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 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]

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 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]

References

1. Netherlands 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. [2022]

2. Netherlands 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. [2020]

3. England 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. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Brain stimulation improves associative memory in an individual with amnestic mild cognitive impairment. [2016]

5. Ireland pubmed.ncbi.nlm.nih.gov

Effect of transcranial magnetic stimulation as an enhancer of cognitive stimulation sessions on mild cognitive impairment: Preliminary results. [2021]

6. England 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. [2023]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. [2023]

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

Side effects of repetitive transcranial magnetic stimulation. [2005]

9. Germany pubmed.ncbi.nlm.nih.gov

[Repetitive transcranial magnetic stimulation. Possibilities, limits and safety aspects]. [2019]

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

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

11. India 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. [2021]