Brain Stimulation for Mild Cognitive Impairment

Overseen By Minsu Zhang

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Texas at Austin

Must not be taking: Benzodiazepines, Anticonvulsants, Antipsychotics, others

Disqualifiers: Epilepsy, Schizophrenia, Substance use, 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: Unknown

Duration: 8 weeks

180 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether non-invasive brain stimulation can improve cognitive functions in people with mild cognitive impairment (MCI) or in healthy older adults. Participants will engage in a cognitive video game while researchers monitor their brain activity and provide targeted brain stimulation based on engagement levels. The study aims to determine if this closed-loop brain stimulation approach is more effective than other methods. Ideal candidates are adults aged 60 to 90 with an MCI diagnosis or those without cognitive issues who can easily follow instructions. As an unphased trial, participants have the opportunity to contribute to groundbreaking research that could enhance cognitive health strategies.

Will I have to stop taking my current medications?

If you are currently taking medications that affect the mind or enhance cognition, like certain anxiety or memory drugs, you will need to stop taking them to join this trial.

What prior data suggests that this brain stimulation technique is safe for enhancing cognitive control abilities?

Research has shown that transcranial magnetic stimulation (TMS) is generally safe and well-tolerated for improving thinking skills in people with mild cognitive impairment (MCI). One study found that TMS, used in both closed-loop and open-loop theta burst stimulation (TBS), rarely causes serious side effects, allowing most people to undergo it without major issues.

For open-loop TBS, there's more good news. The FDA has already approved this method for treating depression, indicating a strong safety record. Studies have found it to be safe and tolerable, with people usually experiencing only mild discomfort, such as a tingling sensation on the scalp.

Overall, both closed-loop and open-loop TBS appear to be safe options for those considering participation in brain stimulation trials for cognitive improvement. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about closed-loop brain stimulation for mild cognitive impairment because it offers a more targeted approach than current treatments like medications or open-loop brain stimulation. Unlike these standard treatments, closed-loop stimulation can adjust in real-time based on the brain's activity, potentially leading to more precise and effective outcomes. This personalized intervention could improve cognitive functions more efficiently, offering hope for better management of mild cognitive impairment.

What evidence suggests that this trial's treatments could be effective for mild cognitive impairment?

Research shows that theta burst stimulation (TBS), a type of non-invasive brain treatment, may enhance thinking and memory skills. Studies have found that intermittent TBS can boost these skills in people with mild cognitive impairment (MCI) and early Alzheimer's disease. In this trial, participants will receive either Closed-Loop TBS, which adjusts the treatment based on brain activity, or Open-Loop TBS, which uses a set pattern. Both methods aim to improve cognitive control, crucial for memory and attention. Early results suggest these techniques could benefit those experiencing cognitive decline. ^{1 4 6 7 8}

Who Is on the Research Team?

José del R. Millán, PhD

Principal Investigator

University of Texas at Austin

Robin Hilsabeck, PhD, ABPP

Principal Investigator

University of Texas at Austin

Are You a Good Fit for This Trial?

This trial is for healthy adults aged 18-35 and older adults aged 60-90 with mild cognitive impairment (MCI) who have at least an elementary school education, normal or corrected vision, and good general health. Participants must score at least 23 on the Montreal Cognitive Assessment. Those with EEG/TMS acquisition issues, MRI contraindications, neurological/psychiatric diseases, or using certain psychotropic/cognitive enhancing medications cannot join.

Inclusion Criteria

I am 60-90 years old with mild memory problems, in good health, and can see well with glasses if needed.

I am 18-35, healthy, with good vision (or corrected) and understand middle school level instructions.

I am between 60-90, healthy, with good vision and at least elementary education. My mental function test score is 23 or higher.

Exclusion Criteria

Factors hindering MRI acquisition (e.g., implants, metallic tattoos, etc.)

I am currently taking medication to improve my memory or attention.

I don't have skin issues that would interfere with EEG or TMS procedures.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive theta burst stimulation (TBS) while playing a cognitive video game, with brain-computer interface (BCI) monitoring and triggering TBS based on engagement.

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with cognitive assessments conducted up to 8 weeks post-intervention.

8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Closed-Loop Brain Stimulation

Trial Overview The study tests if theta burst stimulation (TBS), a non-invasive brain stimulation technique, can improve cognitive functions in people with MCI. It compares sham (fake) TBS to two types: closed-loop TBS triggered by specific brain signals during a video game task and open-loop TBS that's not contingent on brain activity.

How Is the Trial Designed?

Group I: Closed-Loop TBS Active Control 1 Intervention

Group II: Sham TBS Active Control 1 Intervention

Group III: Open-Loop TBS Active Control 1 Intervention

Closed-Loop Brain Stimulation is already approved in United States, European Union for the following indications:

Approved in United States as Transcranial Magnetic Stimulation (TMS) for:

• Resistant Depression
• Obsessive Compulsive Disorder
• Migraine

Approved in European Union as Transcranial Magnetic Stimulation (TMS) for:

• Resistant Depression
• Obsessive Compulsive Disorder

Who Is Running the Clinical Trial?

University of Texas at Austin

Lead Sponsor

Trials

387

Recruited

86,100+

Published Research Related to This Trial

In a study of 35 patients with Parkinson's disease and mild cognitive impairment, those receiving intermittent theta burst stimulation (iTBS) showed significant improvements in cognitive function compared to a sham treatment, both immediately after the intervention and at a 3-month follow-up.

The effectiveness of iTBS was correlated with baseline brain activity in the basal ganglia, suggesting that certain brain characteristics may predict better responses to this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Theta Burst Magnetic Stimulation Improves Parkinson's-Related Cognitive Impairment: A Randomised Controlled Study. He, W., Wang, JC., Tsai, PY.[2022]

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 involving 34 patients with mild cognitive impairment (MCI), those receiving 20 days of anodal transcranial direct current stimulation (tDCS) showed significant improvements in cognitive functions, including episodic verbal memory and overall cognitive function, compared to a sham group.

The results suggest that anodal tDCS may enhance cognitive symptoms in MCI patients, indicating its potential as a therapeutic tool, although further research is needed to clarify the underlying mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects on cognition of 20-day anodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex in patients affected by mild cognitive impairment: a case-control study. Fileccia, E., Di Stasi, V., Poda, R., et al.[2020]

Anodal transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex significantly improved cognitive tasks related to processing speed, selective attention, and planning in five older adults with mild cognitive impairment (MCI).

The study suggests that combining tDCS with cognitive stimulation programs may enhance cognitive performance in individuals with MCI, but further research is needed to explore long-term effects and practical applications in daily life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effects of Transcranial Direct Current Stimulation on the Cognitive Functions in Older Adults with Mild Cognitive Impairment: A Pilot Study. Cruz Gonzalez, P., Fong, KNK., Brown, T.[2022]

Theta burst stimulation (TBS) shows promise in improving associative memory and enhancing functional connectivity in the hippocampus and other brain regions in individuals with mild cognitive impairment (MCI).

This study suggests that TBS can effectively target the hippocampus using functional MRI and diffusion-weighted MRI, although the findings are preliminary and based on a small sample size.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diffusion MRI-guided theta burst stimulation enhances memory and functional connectivity along the inferior longitudinal fasciculus in mild cognitive impairment. Chen, YC., Ton That, V., Ugonna, C., et al.[2022]

Theta burst stimulation (TBS) is a promising technique for altering brain excitability, with a review of studies showing that adverse events were mostly mild and occurred in only 5% of subjects, indicating a generally safe profile.

Despite its safety, TBS carries a theoretical higher risk of seizures compared to other stimulation methods, necessitating cautious application and further research into its dosing parameters to better understand seizure risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. Oberman, L., Edwards, D., Eldaief, M., et al.[2022]

The study identified key brain regions, including the dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus (IFG), as effective targets for non-invasive brain stimulation (NIBS) in treating mild cognitive impairment (MCI) based on a meta-analysis and resting state functional connectivity analysis of 45 MCI patients.

Additionally, the temporoparietal junction and other areas like the bilateral orbital prefrontal gyrus and inferior temporal gyrus were recommended as potential stimulation sites, providing new insights for optimizing NIBS treatment strategies for MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Perspective for Non-invasive Brain Stimulation Site Selection in Mild Cognitive Impairment: Based on Meta- and Functional Connectivity Analyses. Liu, J., Zhang, B., Wilson, G., et al.[2022]

Repetitive Transcranial Magnetic Stimulation (rTMS) and Transcranial Direct Current Stimulation (tDCS) have been shown to significantly enhance cognitive function in patients with Alzheimer's disease (AD), with rTMS also providing beneficial long-term effects.

The study recommends using high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) as a probably effective treatment for AD, while anodal tDCS over the same area is considered possibly effective, based on a meta-analysis of 32 studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is non-invasive brain stimulation effective for cognitive enhancement in Alzheimer's disease? An updated meta-analysis. Šimko, P., Kent, JA., Rektorova, I.[2023]

In a study involving 11 patients with Mild Cognitive Impairment (MCI), transcranial direct current stimulation (tDCS) was found to be safe and well-tolerated, with no significant adverse effects reported during the treatment.

tDCS significantly improved memory recall in patients, with benefits observed immediately after treatment and persisting for at least one month, suggesting its potential as a therapeutic strategy for cognitive deficits in MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical utility and tolerability of transcranial direct current stimulation in mild cognitive impairment. Murugaraja, V., Shivakumar, V., Sivakumar, PT., et al.[2022]

Theta-burst stimulation (TBS) was found to be safe for children, with no serious adverse events reported among 40 participants aged under 18, including those with Tourette syndrome and typically developing children.

Only 11.6% of participants experienced mild, self-limited side effects, such as finger twitching and headaches, indicating that TBS is well tolerated in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta-burst transcranial magnetic stimulation in children. Wu, SW., Shahana, N., Huddleston, DA., et al.[2012]

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]

In a study of 165 pediatric participants aged 6 to 18, theta-burst TMS (TBS) demonstrated a similar safety profile to single- and paired-pulse TMS (sp/ppTMS), with no severe adverse effects reported.

The overall rate of adverse effects was 10.5% for TBS and 12.4% for sp/ppTMS, with most effects rated as minimal or mild, indicating that TBS is a safe option for further investigation in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects. Hong, YH., Wu, SW., Pedapati, EV., et al.[2020]

Citations

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Effects of intermittent theta-burst stimulation on cognition ... These findings suggest that iTBS can produce delayed cognitive enhancement in individuals with amnestic MCI and very mild AD, while the impact ...

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

Efficacy and Safety of Transcranial Magnetic Stimulation on ... We aim to analyze the efficacy and safety of TMS on cognition in mild cognitive impairment (MCI), Alzheimer disease (AD), AD-related dementias, and nondementia ...

3. jneuroengrehab.biomedcentral.com jneuroengrehab.biomedcentral.com/articles/10.1186/s12984-025-01566-3

Efficacy of non-invasive brain stimulation interventions on ... This umbrella review indicates that NIBS techniques, particularly rTMS and tDCS, can significantly improve cognitive functions such as global cognition, ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S3050529125000042

Neurocognitive effects of theta burst stimulation for ... Results suggested that TBS for TRD may produce neurocognitive enhancement across specific neurocognitive domains including executive functioning, attention, ...

5. academic.oup.com academic.oup.com/brain/article/147/12/4003/7889082

emerging field of non-invasive brain stimulation in Alzheimer's ... Non-invasive brain stimulation is increasingly emerging as a therapeutic approach to ameliorate performance in patients with cognitive impairment.

6. sciencedirect.com sciencedirect.com/science/article/pii/S0022395623005666

Efficacy and safety of non-invasive brain stimulation on ... We conducted a meta-analysis to investigate the cognitive improvement and safety of NIBS on schizophrenia-related cognitive impairment.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04866979

Applying Non-invasive Brain Stimulation in Alzheimer's ... The goal is to evaluate the clinical efficacy TBS in patients diagnosed with mild cognitive decline (MCI) and AD, verifying if TBS in conjunction with cognitive ...

8. eneuro.org eneuro.org/content/7/1/ENEURO.0235-19.2019

Transcranial Magnetic Stimulation in Alzheimer's Disease Transcranial magnetic stimulation (TMS) has emerged as a promising possibility, but evidence regarding long-term efficacy and mechanism of action is limited.