TMS for Mild Cognitive Impairment

(NetTMS Trial)

Overseen By Emily Finch, BA

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Duke University

Must not be taking: Seizure threshold, Memory affecting

Disqualifiers: Axis I disorder, Substance abuse, Seizures, Dementia, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 3 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new brain stimulation technique called Network-guided TMS (Transcranial Magnetic Stimulation) to improve memory in people with mild cognitive impairment (MCI), a condition that causes memory problems and other mental difficulties. The researchers aim to determine if this method enhances memory better than a sham version of the treatment. Participants will undergo several sessions of brain stimulation guided by MRI scans. This trial suits English-speaking adults aged 55 to 80 who have been diagnosed with MCI and have no history of major mental health problems or seizures. As an unphased trial, this study offers participants the opportunity to contribute to groundbreaking research that could lead to new treatments for memory improvement.

Will I have to stop taking my current medications?

The trial requires that participants do not use medications known to lower the seizure threshold or affect working memory. If you are taking such medications, you may need to stop them to participate.

What prior data suggests that this neurostimulation approach is safe for individuals with mild cognitive impairment?

Research has shown that transcranial magnetic stimulation (TMS) is generally safe and well-tolerated for people with mild cognitive impairment (MCI). Serious side effects rarely occur. TMS is a non-invasive method, meaning it doesn't involve surgery or entering the body. It uses magnetic fields to stimulate brain cells, which can help improve thinking and memory.

A meta-analysis, which combines results from multiple studies, found that TMS is safe and has few serious side effects. This makes it a promising option for those with MCI. Since TMS is already used for other conditions, like depression, it has a proven safety record in humans.

In summary, TMS for MCI is considered safe with few serious side effects. Participants can feel reassured about its safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about network-guided TMS for mild cognitive impairment because it offers a targeted approach to brain stimulation. Unlike standard treatments that might involve medication or general cognitive therapy, this method uses advanced imaging techniques like MRI to precisely aim the transcranial magnetic stimulation (TMS) at specific brain networks. This precision could potentially enhance cognitive functions more effectively and with fewer side effects. Additionally, the combination of TMS with real-time fMRI allows researchers to directly observe brain activity, providing valuable insights into how the treatment impacts the brain.

What evidence suggests that network-guided TMS is effective for mild cognitive impairment?

Research has shown that network-guided transcranial magnetic stimulation (TMS), which participants in this trial will receive, may help individuals with mild cognitive impairment (MCI). TMS can enhance the brain's ability to change and form new connections, improving memory and thinking skills. Studies have found that people with cognitive impairments often perform better on cognitive tasks after TMS. When TMS targets specific brain areas, it has demonstrated significant improvements compared to placebo treatments. Overall, TMS is considered a safe and effective method to boost thinking abilities in people with MCI. ^{1 3 4 6 7}

Who Is on the Research Team?

Simon W Davis, PhD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

This trial is for English-speaking adults aged 55-80 with mild cognitive impairment (MCI) who can consent to the study and are willing to use birth control if applicable. It's not for those with a history of substance abuse, pregnant or breastfeeding women, people with certain mental disorders, intracranial implants, pacemakers, seizure risks, significant head trauma or neurological conditions like dementia.

Inclusion Criteria

I am between 55 and 80 years old.

You have mild cognitive impairment as diagnosed by a doctor.

Use of effective method of birth control for women of childbearing capacity

Exclusion Criteria

You have a history of alcohol or drug addiction (except for nicotine).

I am not pregnant or breastfeeding.

I have a high risk of seizures due to conditions like epilepsy or serious head injury.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Baseline Assessment

Participants complete neuropsychological tests and provide a saliva sample for APOE genotype determination

1 day

1 visit (in-person)

Initial MRI Scanning

Participants undergo an initial MRI scanning session to collect data for network-based targeting

1 day

1 visit (in-person)

Treatment

Participants undergo combined TMS-fMRI sessions to assess the effects of network-based TMS on memory performance

3 days

3 visits (in-person)

Follow-up

Participants are monitored for changes in neurovascular reactivity, structural connectivity, and episodic memory task performance

3 days

3 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Network-guided TMS

Trial Overview The trial tests a new approach using transcranial magnetic stimulation (TMS), guided by MRI brain connectivity measures. The goal is to see if TMS can improve memory in older adults with MCI compared to fake (sham) treatment.

How Is the Trial Designed?

Group I: Network-guided TMS Experimental Treatment 1 Intervention

The study comprises one arm of five sessions. In Day 1 (\~1.5 hr session), participants fill forms, complete a neuropsychological test battery (NIH Toolbox, NACC UDS, BDI), and provide a saliva sample to be banked for future APOE genotype determination. On Day 2 (\~1 hr session), subjects will perform an initial MRI scanning session. In this session, MRI, RSFA, DWI, and fMRI are collected so they can be used for network-based targeting. In Days 3-5 (each comprising a \~2.5 hr session) a few days later participants will undergo combined TMS-fMRI sessions. In the scanner, participants complete four fMRI runs: 2 runs using either a network-based or standard target location, counterbalanced across participants. Active and Sham TMS trials are intermixed within each run.

Network-guided TMS is already approved in United States, European Union for the following indications:

Approved in United States as rTMS for:

• Resistant depression
• Obsessive-compulsive disorder
• Migraine

Approved in European Union as rTMS for:

• Depression
• Anxiety disorders

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

Transcranial magnetic stimulation (TMS) can effectively differentiate between patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively normal older adults by measuring cortical excitability and plasticity, with 2728 participants analyzed across 61 studies.

The study found that patients with AD had higher cortical excitability and lower inhibition compared to cognitively normal individuals, with no reported seizure events from TMS, indicating its safety as a diagnostic tool.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cortical excitability and plasticity in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis of transcranial magnetic stimulation studies. Chou, YH., Sundman, M., Ton That, V., et al.[2022]

In a study involving 11 patients with mild-to-moderate Alzheimer's disease, chronic treatment with rivastigmine increased the amplitude of motor evoked potentials (MEP) after a single stimulus, indicating some improvement in cortical excitability.

However, rivastigmine did not affect short-term synaptic plasticity or the normal facilitation of MEP during repetitive transcranial magnetic stimulation (rTMS), suggesting that the limited clinical benefits of cholinesterase inhibitors in Alzheimer's may not be due to enhanced cortical plasticity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic treatment with rivastigmine in patients with Alzheimer's disease: a study on primary motor cortex excitability tested by 5 Hz-repetitive transcranial magnetic stimulation. Trebbastoni, A., Gilio, F., D'Antonio, F., et al.[2015]

In a study of 40 patients with amnestic mild cognitive impairment (aMCI), it was found that they exhibited lower cortical excitability and altered synaptic plasticity compared to healthy controls, as measured by 5 Hz repetitive transcranial magnetic stimulation (5 Hz-rTMS).

The study revealed that specific TMS parameters, such as the resting motor threshold and the ratio of the first to the tenth motor-evoked potential, correlated with the time it took for patients to convert to Alzheimer's disease, suggesting these measures could serve as early neurophysiological markers for disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered Cortical Synaptic Plasticity in Response to 5-Hz Repetitive Transcranial Magnetic Stimulation as a New Electrophysiological Finding in Amnestic Mild Cognitive Impairment Converting to Alzheimer's Disease: Results from a 4-year Prospective Cohort Study. Trebbastoni, A., Pichiorri, F., D'Antonio, F., et al.[2023]

Neuro-navigated rTMS applied to the left angular gyrus significantly improved cognitive performance in patients with amnestic mild cognitive impairment and Alzheimer's disease, indicating its potential as a therapeutic intervention.

The study found that changes in brain network connectivity, particularly in higher-order cognitive networks, could predict individual responses to rTMS treatment, suggesting a personalized approach to therapy based on baseline brain dynamics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional network connectivity patterns predicting the efficacy of repetitive transcranial magnetic stimulation in the spectrum of Alzheimer's disease. Chen, H., Li, M., Qin, Z., et al.[2023]

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]

This study introduces a novel network-based model for optimizing TMS (transcranial magnetic stimulation) treatment by targeting disease-specific brain networks, which could enhance treatment outcomes for conditions like depression and schizophrenia.

The model was validated using empirical data from two depression cohorts and one schizophrenia cohort, suggesting that individualized coil placement based on the patient's specific brain network abnormalities may lead to improved therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the pathological network: Feasibility of network-based optimization of transcranial magnetic stimulation coil placement for treatment of psychiatric disorders. Cao, Z., Xiao, X., Zhao, Y., et al.[2023]

This study demonstrates the feasibility of using individual resting-state fMRI to identify optimal TMS targets for Alzheimer's disease, focusing on the default mode and fronto-parietal networks, which are crucially affected in AD.

The individualized fMRI-guided TMS targeting approach showed significant differences in target localization compared to traditional methods, suggesting that personalized targeting could enhance the effectiveness of TMS treatments in Alzheimer's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional Imaging to Guide Network-Based TMS Treatments: Toward a Tailored Medicine Approach in Alzheimer's Disease. Bagattini, C., Brignani, D., Bonnì, S., et al.[2021]

Citations

1. 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 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04549155

Network-guided TMS in Early Alzheimer's Disease ... Transcranial magnetic stimulation (TMS) is a promising non-invasive therapeutic approach that has been shown to increase brain plasticity and enhance cognitive ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12192757/

Network-targeted transcranial magnetic stimulation (TMS) for ... Greater precision and personalization of TMS offer the promise of achieving better outcomes for individuals with MCI or mild AD dementia. 1. Introduction.

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

Efficacy and Safety of Transcranial Magnetic Stimulation on ... The reviewed studies provide favorable evidence of improved cognition with TMS across all groups with cognitive impairment. TMS was safe and ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2818365

Effectiveness of Personalized Hippocampal ... Personalized hippocampal network–targeted stimulation demonstrated a significant improvement in cognition and functional performances compared with the sham ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04549155

Network-guided TMS in Early Alzheimer's Disease Transcranial magnetic stimulation (TMS) is a promising non-invasive therapeutic approach that has been shown to increase brain plasticity and enhance cognitive ...

7. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2837379

Long-Term Therapy With Transcranial Magnetic ... Objective To evaluate the efficacy, safety, and adherence of transcranial magnetic stimulation (TMS) plus language therapy in participants with ...