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.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Device: Active TIBS; Device: Sham TIBS

• Study Type: Interventional
• Enrollment (Estimated): 1200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ying Han, PhD; Phone Number: +86 13621011941; Email: hanying@xwh.ccmu.edu.cn

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Xuanwu Hospital of Capital Medical University
    • Contact: Ying Han, PhD; Phone Number: +86 13621011941; Email: hanying@xwh.ccmu.edu.cn
  • Hainan
    • Sanya, Hainan, China
      • Recruiting
      • Hainan university
      • Contact: Hao Wang, PhD; Phone Number: +86 18512810570; Email: haowang@hainanu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Personalized Closed-Loop Temporal Interference Brain Stimulation; Participants in this arm will 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 will be delivered daily for 40 minutes, 6 days/week, for a total of 2 weeks. Individualized targeting and initial intensity optimization will be guided by baseline sMRI and DTI. Real-time high-density EEG monitoring during each daily session (D2-D11) will provide feedback on brain activity (e.g., EEG power spectra, functional connectivity features) to enable closed-loop optimization of transcranial stimulation intensity and phase parameters.	Device: Active TIBS; 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 Comparator: Sham Temporal Interference Brain Stimulation; Participants in this arm will receive sham stimulation designed to mimic the sensation of active TIBS without therapeutic output. This will involve 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 will be identical to the active TIBS group to maintain blinding.	Device: Sham TIBS; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Functional Connectivity Strength of Hippocampal-Cortical Networks	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.	Baseline, End of 2-week intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes from Baseline in Hippocampal Gray Matter Density (sMRI)	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.	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in Cortical Thickness (sMRI)	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.	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in Resting-State Functional Connectivity (fMRI)	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.	Baseline, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in White Matter Integrity (DTI)	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.	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in AD Molecular Pathologies and Blood Biomarkers	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).	Baseline, 12 weeks post-intervention
Changes from Baseline in Auditory Verbal Learning Test-H (AVLT-H) Score	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.	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in n-back Task Performance Score	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.	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in Mini-Mental State Examination (MMSE) Score	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.	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in Montreal Cognitive Assessment - Basic (MoCA-B) Score	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.	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in Verbal Fluency Test Score	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.	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in Boston Naming Test (BNT) Score	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.	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Changes from Baseline in Shape trails test A&B (STT-A&B) Score	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	Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention
Incidence and Severity of Adverse Events (AEs)	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	through study completion, an average of 14 weeks

Collaborators and Investigators

• Sponsor: Xuanwu Hospital, Beijing
• Investigators: Principal Investigator: Ying Han, PhD, Xuanwu Hospital of Capital Medical University

Publications and helpful links

General Publications

• Grossman N, Bono D, Dedic N, Kodandaramaiah SB, Rudenko A, Suk HJ, Cassara AM, Neufeld E, Kuster N, Tsai LH, Pascual-Leone A, Boyden ES. Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields. Cell. 2017 Jun 1;169(6):1029-1041.e16. doi: 10.1016/j.cell.2017.05.024.
• Chen Q, Chen F, Long C, Zhu Y, Jiang Y, Zhu Z, Lu J, Zhang X, Nedelska Z, Hort J, Zhang B. Spatial navigation is associated with subcortical alterations and progression risk in subjective cognitive decline. Alzheimers Res Ther. 2023 Apr 25;15(1):86. doi: 10.1186/s13195-023-01233-6.
• Vassiliadis P, Beanato E, Popa T, Windel F, Morishita T, Neufeld E, Duque J, Derosiere G, Wessel MJ, Hummel FC. Non-invasive stimulation of the human striatum disrupts reinforcement learning of motor skills. Nat Hum Behav. 2024 Aug;8(8):1581-1598. doi: 10.1038/s41562-024-01901-z. Epub 2024 May 29.
• Violante IR, Alania K, Cassara AM, Neufeld E, Acerbo E, Carron R, Williamson A, Kurtin DL, Rhodes E, Hampshire A, Kuster N, Boyden ES, Pascual-Leone A, Grossman N. Non-invasive temporal interference electrical stimulation of the human hippocampus. Nat Neurosci. 2023 Nov;26(11):1994-2004. doi: 10.1038/s41593-023-01456-8. Epub 2023 Oct 19.
• Lv X, Cheng Z, Wang Q, Gao F, Dai L, Du C, Liu C, Xie Q, Shen Y, Shi J; China Aging and Neurodegenerative Initiative (CANDI) Consortium. High burdens of phosphorylated tau protein and distinct precuneus atrophy in sporadic early-onset Alzheimer's disease. Sci Bull (Beijing). 2023 Nov 30;68(22):2817-2826. doi: 10.1016/j.scib.2023.10.019. Epub 2023 Oct 27.
• Zhao K, Wang D, Wang D, Chen P, Wei Y, Tu L, Chen Y, Tang Y, Yao H, Zhou B, Lu J, Wang P, Liao Z, Chen Y, Han Y, Zhang X, Liu Y. Macroscale connectome topographical structure reveals the biomechanisms of brain dysfunction in Alzheimer's disease. Sci Adv. 2024 Oct 11;10(41):eado8837. doi: 10.1126/sciadv.ado8837. Epub 2024 Oct 11.
• Beanato E, Moon HJ, Windel F, Vassiliadis P, Wessel MJ, Popa T, Pauline M, Neufeld E, De Falco E, Gauthier B, Steiner M, Blanke O, Hummel FC. Noninvasive modulation of the hippocampal-entorhinal complex during spatial navigation in humans. Sci Adv. 2024 Nov;10(44):eado4103. doi: 10.1126/sciadv.ado4103. Epub 2024 Oct 30.
• Jack CR Jr, Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, Hansson O, Ho C, Jagust W, McDade E, Molinuevo JL, Okonkwo OC, Pani L, Rafii MS, Scheltens P, Siemers E, Snyder HM, Sperling R, Teunissen CE, Carrillo MC. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024 Aug;20(8):5143-5169. doi: 10.1002/alz.13859. Epub 2024 Jun 27.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: June 6, 2025
• First Submitted That Met QC Criteria: June 12, 2025
• First Posted (Actual): June 22, 2025

Study Record Updates

• Last Update Posted (Estimated): August 15, 2025
• Last Update Submitted That Met QC Criteria: August 13, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: TIBS_hanying_0605

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No