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

Обзор

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.

Вмешательства

• Устройство 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.
• Устройство 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.

Первичные конечные точки

• Change from Baseline in Functional Connectivity Strength of Hippocampal-Cortical Networks [Срок оценки: Baseline, End of 2-week intervention.]

Вторичные конечные точки (12)

• Changes from Baseline in Hippocampal Gray Matter Density (sMRI) [Срок оценки: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention]
• Changes from Baseline in Cortical Thickness (sMRI) [Срок оценки: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention]
• Changes from Baseline in Resting-State Functional Connectivity (fMRI) [Срок оценки: Baseline, 4 weeks post-intervention, 12 weeks post-intervention]
• Changes from Baseline in White Matter Integrity (DTI) [Срок оценки: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention]
• Changes from Baseline in AD Molecular Pathologies and Blood Biomarkers [Срок оценки: Baseline, 12 weeks post-intervention]
• Changes from Baseline in Auditory Verbal Learning Test-H (AVLT-H) Score [Срок оценки: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention]
• Changes from Baseline in n-back Task Performance Score [Срок оценки: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention]
• Changes from Baseline in Mini-Mental State Examination (MMSE) Score [Срок оценки: 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 [Срок оценки: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention]
• Changes from Baseline in Verbal Fluency Test Score [Срок оценки: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention]
• Changes from Baseline in Boston Naming Test (BNT) Score [Срок оценки: 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 [Срок оценки: Baseline, End of 2-week intervention, 4 weeks post-intervention, 12 weeks post-intervention]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

Китай · 2 центра

• Hainan university — Sanya
• Xuanwu Hospital of Capital Medical University — Пекин

Публикации

• 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
• 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
• 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
• 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. PMID 37857775
• 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
• 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
• 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
• 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 J PMID 38934362

Идентификаторы

NCT: NCT07031687 · TIBS_hanying_0605

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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