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

NCT07031687 | Recruiting

• 1 other identifier: TIBS_hanying_0605
• Study Type: interventional
• Target: 1,200
• Locations: 1 country
• Sites: 2

Brief Summary

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

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Changes from Baseline in Hippocampal Gray Matter Density (sMRI)

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

• Changes from Baseline in Cortical Thickness (sMRI)

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

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

  Baseline, 4 weeks post-intervention, 12 weeks post-intervention

• Changes from Baseline in White Matter Integrity (DTI)

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

• Changes from Baseline in AD Molecular Pathologies and Blood Biomarkers

  Baseline, 12 weeks post-intervention

Study Arms (2)

Personalized Closed-Loop Temporal Interference Brain Stimulation

EXPERIMENTAL

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

Sham Temporal Interference Brain Stimulation

SHAM COMPARATOR

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

Interventions

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

Personalized Closed-Loop Temporal Interference Brain Stimulation

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.

Sham Temporal Interference Brain Stimulation

Eligibility Criteria

• Age: 60 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Xuanwu Hospital, Beijing: lead

Study Sites (2)

Hainan university

Sanya, Hainan, China

RECRUITING

Xuanwu Hospital of Capital Medical University

Beijing, China

RECRUITING

Related Publications (8)

• 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.

  PMID: 37919158 BACKGROUND

• 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.

  PMID: 37098612 BACKGROUND

• 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.

  PMID: 39392880 BACKGROUND

• 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. Erratum In: Nat Neurosci. 2023 Dec;26(12):2252. doi: 10.1038/s41593-023-01517-y.

  PMID: 37857775 BACKGROUND

• 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.

  PMID: 38811696 BACKGROUND

• 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.

  PMID: 39475597 BACKGROUND

• 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.

  PMID: 28575667 BACKGROUND

• 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.

  PMID: 38934362 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Ying Han, PhD

  Xuanwu Hospital of Capital Medical University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ying Han, PhD

CONTACT

+86 13621011941; hanying@xwh.ccmu.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 6, 2025
• First Posted: June 22, 2025
• Study Start: July 1, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029
• Last Updated: August 15, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

CN (2)