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NCT Number: NCT07031687

Effects and Mechanisms of Temporal Interference Brain Stimulation on Memory Function in Preclinical Alzheimer's Disease

The goal of this clinical trial is to learn if personalized, multimodal imaging-guided, EEG-based closed-loop Temporal Interference Brain Stimulation (TIBS) can improve memory function in individuals with preclinical Alzheimer's Disease (AD).

The main questions it aims to answer are:

1. Does personalized TIBS lead to significant changes in functional connectivity strength of hippocampal-cortical networks at the end of the 2-week intervention compared to baseline? 2. What are the short-term (end of 2-week intervention) and medium-to-long-term (4 weeks and 12 weeks post-intervention) effects of personalized TIBS on episodic and working memory, as well as other cognitive domains in preclinical AD? 3. How does personalized TIBS modulate brain activity and connectivity, as measured by EEG power spectra and functional MRI (fMRI) functional connectivity, in preclinical AD? 4. What is the safety profile of personalized TIBS in this population?

Researchers will compare participants receiving active personalized TIBS to participants receiving sham (inactive) stimulation to see if TIBS effectively improves memory function and induces neural plasticity.

Participants will:

1. Undergo initial screening including neuropsychological assessments and blood p-tau217 testing to identify preclinical AD. 2. Receive either active personalized TIBS or sham stimulation daily for 40 minutes, 6 days a week, for 2 weeks. 3. Have individualized TIBS parameters (e.g., target localization, intensity) determined using baseline structural MRI and DTI. 4. Undergo real-time high-density EEG monitoring during daily stimulation sessions to enable closed-loop adjustment of stimulation parameters. 5. Participate in follow-up assessments at the end of the 2-week intervention, and at 4 weeks and 12 weeks post-intervention. 6. Receive multimodal imaging (sMRI, rs-fMRI, task-fMRI, DTI) and blood biomarker assessments at various time points. 7. Receive Aβ-PET and tau-PET scans, along with comprehensive neuropsychological assessments, at the 12-week follow-up. 8. Have their safety continuously monitored throughout the study.

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Key information

Conditions

Alzheimer Disease Brain Diseases Central Nervous System Diseases Dementia Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Tauopathies

Age range

60 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Hainan university, Sanya, Hainan, China

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Individuals recruited from neurology memory clinics or communities.
  • Age between 60 and 80 years old, inclusive; no gender limitation.
  • Right-handed.
  • Cognitive function test results within normal range after age, gender, and education-level adjustment, OR mild cognitive impairment not yet meeting diagnostic criteria for Mild Cognitive Impairment (MCI), OR only subjective cognitive decline.
  • Individuals classified as preclinical AD based on the revised 2024 AD diagnostic and staging criteria (i.e., cognitively normal with positive plasma p-tau217 or positive Aβ PET).
  • Full understanding of the study, voluntary participation, and provision of written informed consent approved by the Ethics Committee.

Exclusion criteria

  • Past or present neurological diseases (e.g., stroke, epilepsy, Parkinson's disease, multiple sclerosis).
  • Psychiatric disorders such as severe depression or severe anxiety.
  • Systemic diseases causing cognitive decline (e.g., severe thyroid dysfunction, severe liver or kidney disease, severe nutritional deficiencies).
  • Currently taking medications that may affect cognitive function (e.g., anticholinergics, benzodiazepines, antipsychotics) that cannot be discontinued or adjusted.
  • Other factors leading to cognitive decline that are not AD-related.
  • Contraindications for MRI scans, such as claustrophobia, implanted metallic devices (e.g., pacemakers, cochlear implants, aneurysm clips), or history of head injury with retained metal fragments.

Treatment and study plan

Active TIBS

Device

Participants receive active TIBS targeted at the bilateral hippocampus. Stimulation parameters include a 5 Hz (Theta band) low-frequency modulation envelope, generated by two high-frequency current pairs (e.g., f1=2000 Hz, f2=2005 Hz). Peak-to-peak current intensity for each pair will be 2 mA (or 1 mA per electrode). Stimulation is delivered daily for 40 minutes, 6 days/week, for a total of 2 weeks. Individualized targeting and initial intensity optimization are guided by baseline sMRI and DTI. Real-time high-density EEG monitoring during each daily session (D2-D11) provides feedback on brain activity

Sham TIBS

Device

Participants receive sham stimulation designed to mimic the sensation of active TIBS without therapeutic output. This involves using a sham coil or a device mode with extremely low current intensity (e.g., 0.1-0.2 mA) or brief ramp-up/ramp-down sensations at the beginning and end of sessions, with no effective current delivery during the main stimulation period. The stimulation position and apparent parameters are identical to the active TIBS group to maintain blinding.

Primary outcomes

  1. Change from Baseline in Functional Connectivity Strength of Hippocampal-Cortical Networks

    Time frame: Baseline, End of 2-week intervention.

    Quantified by resting-state fMRI (rs-fMRI) functional connectivity strength within and between key memory-related networks (e.g., default mode network, hippocampal-cortical network) at the end of the 2-week intervention. Specific metrics will include ALFF, ReHo, FCS, and ACF.

Secondary outcomes

  1. Changes from Baseline in Hippocampal Gray Matter Density (sMRI)

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Evaluation of changes in hippocampal gray matter density or volume, quantified using structural Magnetic Resonance Imaging (sMRI). This measure assesses the structural integrity and potential atrophy or increase in gray matter in a key brain region associated with memory.

  2. Changes from Baseline in Cortical Thickness (sMRI)

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Evaluation of changes in cortical thickness across various brain regions, quantified using structural Magnetic Resonance Imaging (sMRI). This measure assesses the integrity and potential thinning or thickening of the cerebral cortex.

  3. Changes from Baseline in Resting-State Functional Connectivity (fMRI)

    Time frame: Baseline, 4 weeks post-intervention, 12 weeks post-intervention

    Evaluation of changes in resting-state functional connectivity using functional Magnetic Resonance Imaging (fMRI). This assesses the temporal correlations between spontaneous fluctuations in BOLD signals across different brain regions, reflecting synchronized neural activity. Specific brain networks (e.g., Default Mode Network, Salience Network) or seed-based connectivity will be analyzed.

  4. Changes from Baseline in White Matter Integrity (DTI)

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Evaluation of changes in white matter integrity, assessed using Diffusion Tensor Imaging (DTI). Key metrics to be analyzed include Fractional Anisotropy (FA), Mean Diffusivity (MD), Axial Diffusivity (AD), and Radial Diffusivity (RD), reflecting the directionality and magnitude of water diffusion in white matter tracts.

  5. Changes from Baseline in AD Molecular Pathologies and Blood Biomarkers

    Time frame: Baseline, 12 weeks post-intervention

    Evaluation of brain amyloid-beta (Aβ) deposition via Aβ-PET imaging, brain tau pathology via tau-PET imaging, and dynamic changes in plasma biomarkers (e.g., p-tau217, Aβ42/40 ratio, NfL, GFAP, α-synuclein, BDNF).

  6. Changes from Baseline in Auditory Verbal Learning Test-H (AVLT-H) Score

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Measures episodic memory. The Auditory Verbal Learning Test - Delayed Recall (AVLT-H) score typically represents the number of words recalled after a delay.

    Full Scale Name: Auditory Verbal Learning Test-H Minimum Value: 0 Maximum Value: Delayed Recall--12; Recognition--24 Higher Scores Mean: Better memory.

  7. Changes from Baseline in n-back Task Performance Score

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Measures working memory. Performance on the n-back task is typically measured by accuracy (percentage of correct responses) or the highest 'n' level achieved.

    Full Scale Name: n-back Task Performance Minimum Value: 0% accuracy or lowest 'n' level Maximum Value: 100% accuracy or highest 'n' level tested Higher Scores Mean: Better working memory.

  8. Changes from Baseline in Mini-Mental State Examination (MMSE) Score

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Measures global cognitive function. Full Scale Name: Mini-Mental State Examination (MMSE) Minimum Value: 0 Maximum Value: 30 Higher Scores Mean: A better global cognitive function.

  9. Changes from Baseline in Montreal Cognitive Assessment - Basic (MoCA-B) Score

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Measures global cognitive function. Full Scale Name: Montreal Cognitive Assessment - Basic (MoCA-B) Minimum Value: 0 Maximum Value: 30 Higher Scores Mean: A better global cognitive function.

  10. Changes from Baseline in Verbal Fluency Test Score

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Measures language function. The score represents the number of words generated. Full Scale Name: Verbal Fluency Test Minimum Value: 0 Maximum Value: None Higher Scores Mean: A better verbal fluency.

  11. Changes from Baseline in Boston Naming Test (BNT) Score

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Measures language function. The score represents the number of words generated. Full Scale Name: Boston Naming Test Minimum Value: 0 Maximum Value: 30 Higher Scores Mean: A better naming ability.

  12. Changes from Baseline in Shape trails test A&B (STT-A&B) Score

    Time frame: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention

    Measures visual scanning and motor speed. The score is the time taken to complete the task.

    Full Scale Name: Shape trails test Minimum Value: 0 Maximum Value: None Higher Scores Mean: Slower completion time

  13. Incidence and Severity of Adverse Events (AEs)

    Time frame: through study completion, an average of 14 weeks

    Monitoring and reporting of all adverse events and serious adverse events related to the intervention, including their frequency, severity, and relationship to the study intervention

Study contacts

Contact information is provided by the study sponsor or research team.

Ying Han, PhD

CONTACT

[email protected]

+86 13621011941

Sponsors and collaborators

Lead sponsor

Xuanwu Hospital, Beijing

Other

Registry information

Important dates

Study start
2025
Primary completion
2028
Study completion
2029
First posted
Jun 22, 2025
Registry last updated
Aug 15, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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