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

Trial Summary

What is the purpose of this trial?

The goal of this clinical study is to investigate the effectiveness of non-invasive stimulation to enhance cognitive control abilities in cognitively healthy adults and older adults diagnosed with mild cognitive disorder (MCI). The main questions it aims to answer are: * whether it is possible to restore various cognitive functions in older adults diagnosed with MCI by delivering theta burst stimulation (TBS), a form of transcranial magnetic stimulation, and * whether closed-loop TBS is able to induce therapeutic benefits that outperform open-loop TBS. Participants play a cognitive video game while a brain-computer interface (BCI) analyzes their electroencephalogram (EEG) signals and decodes the presence or absence of the contingent negative variation (CNV) potential, a marker of cognitive control. The BCI triggers TBS when its outputs indicate that the participant is not engaged properly in the video game. Researchers will compare the effects of sham, closed-loop, and open-loop TBS using the outcome metrics described below to see how much cognitive restorations is achievable with each stimulation modality.

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 data supports the effectiveness of the treatment Closed-Loop Brain Stimulation, Non-Invasive Brain Stimulation, Transcranial Magnetic Stimulation (TMS), Theta Burst Stimulation (TBS), Brain-Computer Interface (BCI) Driven Stimulation for mild cognitive impairment?

Research shows that theta burst stimulation (TBS), a type of non-invasive brain stimulation, can improve memory and brain connectivity in people with mild cognitive impairment (MCI). Another study found that TBS improved cognitive function in patients with Parkinson's disease who also had MCI, suggesting it may have broader benefits for cognitive health. ^{1 2 3 4 5}

Is brain stimulation safe for humans?

Brain stimulation techniques like transcranial magnetic stimulation (TMS) and theta burst stimulation (TBS) are generally considered safe, with most adverse events being mild and occurring in a small percentage of people. However, there is a potential risk of seizures, especially with TBS, so it should be used with caution. ^{5 6 7 8 9}

How is Closed-Loop Brain Stimulation different from other treatments for mild cognitive impairment?

Closed-Loop Brain Stimulation is unique because it combines non-invasive techniques like Transcranial Magnetic Stimulation (TMS) and Brain-Computer Interface (BCI) to potentially enhance cognitive function by targeting specific brain areas, unlike traditional treatments that may not be as precise. ^{3 4 10 11 12}

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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) 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]

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]

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]

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]

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]

References

1. United States 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. [2022]

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

Theta Burst Magnetic Stimulation Improves Parkinson's-Related Cognitive Impairment: A Randomised Controlled Study. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Is non-invasive brain stimulation effective for cognitive enhancement in Alzheimer's disease? An updated meta-analysis. [2023]

4. Switzerland 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. [2022]

5. Netherlands 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. [2022]

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

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta-burst transcranial magnetic stimulation in children. [2012]

8. 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]

9. Switzerland 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. [2020]

10. Italy 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. [2020]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical utility and tolerability of transcranial direct current stimulation in mild cognitive impairment. [2022]

12. 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]