Temporal Interference Stimulation Treatment in Patients With Cognitive Impairment

Official title

A Randomized, Sham-Controlled Trial of Temporal Interference Stimulation Treatment in Patients With Cognitive Impairment

Overview

This study aims to evaluate the efficacy and safety of temporal interference stimulation (TIS), a non-invasive neuromodulation technique, in improving cognitive function in patients with cognitive impairment. TIS uses two high-frequency currents applied transcranially, which intersect within the brain to generate a low-frequency modulation field. This technique selectively modulates deep brain regions while minimizing the stimulation of superficial cortical layers. Participants will undergo individualized MRI-based modeling to determine the optimal electrode placement and stimulation parameters. The intervention consists of 10 stimulation sessions over a period of 14 days, using either active TIS or sham stimulation. Cognitive assessments, EEG recordings, and functional MRI scans will be conducted at baseline; 5 days after intervention initiation; at the end of the 10-day intervention; and during follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention to evaluate both immediate and long-term effects on cognitive performance and neural activity. The study aims to determine whether TIS can serve as a feasible and effective neuromodulation strategy for individuals with cognitive impairment.

Interventions

• Device Temporal Interference Stimulation
  Temporal interference stimulation will be delivered using two high-frequency alternating currents at 2000 Hz and 2100 Hz, generating a low-frequency envelope. Stimulation will be delivered in a theta-burst-like pattern with 2 seconds on and 8 seconds off. Frontal and temporal targets will be stimulated sequentially. In the sham-controlled group, participants will receive active stimulation during Days 6-10 following 5 days of sham stimulation. In the active stimulation groups, participants will
• Device Sham Temporal Interference Stimulation
  Sham stimulation will use two identical high-frequency currents of 2000 Hz and 2000 Hz, producing no frequency difference and no modulation envelope. The stimulation timing, electrode placement, and procedures will be consistent with active stimulation to maintain blinding. In the sham-controlled group, sham stimulation will be administered during Days 1-5 before switching to active stimulation.
• Behavioral Targeted Cognitive Training
  Participants will complete structured cognitive training tasks designed to engage specific cognitive processes associated with the study objectives.
• Behavioral General Cognitive Training
  Participants will complete general cognitive training tasks involving multiple cognitive domains without specifically emphasizing the primary targeted cognitive process.

Primary outcome measures

• Changes from Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]

Secondary outcome measures (12)

• Cross-frequency Neural Oscillations [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Change from baseline in resting-state frontal-temporal EEG functional connectivity strength [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from Baseline in Frontal and Temporal Gray Matter Density (sMRI) [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from Baseline in Cortical Thickness (sMRI) [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from baseline in ALFF [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from baseline in ReHo [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from baseline in resting-state functional connectivity [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from baseline in FA [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from baseline in MD [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from baseline in AD [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from baseline in RD [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]
• Changes from Baseline in Mini-Mental State Examination (MMSE) Score [Time frame: Baseline; 5 days after intervention initiation; end of the 10-day intervention; and follow-up assessments at 4 weeks, 8 weeks, and 12 weeks post-intervention.]

Eligibility criteria

Inclusion criteria

• meets the criteria for probable AD and MCI due to AD as defined by the 2024 National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines;
• Positive amyloid biomarker (amyloid PET or CSF tTau/Aβ 42);
• Positive tau biomarker (tau-PET or CSF pTau181);
• AD-related standard treatments (acetyl cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists) taken at a stable dose for at least 12 weeks prior to baseline.
• meets the criteria for probable bvFTD as defined by the revised diagnostic criteria for the behavioural variant of frontotemporal dementia (2011), or PPA as defined by the Classification of primary progressive aphasia and its variants (2011);
• Optional genetic confirmation of FTD-related pathogenic mutations (if available).
• Aged between 45 and 85 years, inclusive; no gender limitation.
• Right-handed.
• Education level ≥ 3 years.
• Mini-Mental State Examination (MMSE) score ≥ 11.
• Clinical Dementia Rating (CDR) score of 1 or 2.
• with a reliable caregiver
• Able to cooperate with cognitive assessments and cognitive training procedures.
• Full understanding of the study, voluntary participation, and provision of written informed consent approved by the Ethics Committee.

Exclusion criteria

• Diagnosis of other types of dementia or major neurological disorders (e.g., stroke, epilepsy, Lewy body dementia, vascular dementia, Parkinson's disease dementia, Huntington's disease).
• Major psychiatric disorders such as severe depression or anxiety.
• Severe systemic or organ dysfunction (e.g., heart failure III-IV, liver cirrhosis, renal failure).
• Use of medications that significantly affect cognition (e.g., anticholinergics, sedatives), unless approved by the physician.
• Presence of metal implants incompatible with MRI or TIS (e.g., pacemakers, deep brain stimulators).
• Skull defects or cranial abnormalities.
• Inability to tolerate EEG or head stabilization.
• Severe visual or hearing impairment preventing task performance.
• History of alcohol or drug abuse.
• Participation in another clinical trial within the past 3 months.
• Current or recent treatment with anti-amyloid monoclonal antibodies (e.g., lecanemab, donanemab).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Tianjin Huanhu Hospital — Tianjin

Publications

• Li LM, Violante IR, Leech R, Ross E, Hampshire A, Opitz A, Rothwell JC, Carmichael DW, Sharp DJ. Brain state and polarity dependent modulation of brain networks by transcranial direct current stimulation. Hum Brain Mapp. 2019 Feb 15;40(3):904-915. doi: 10.1002/hbm.24420. Epub 2018 Oct 30. PMID 30378206
• Wessel MJ, Beanato E, Popa T, Windel F, Vassiliadis P, Menoud P, Beliaeva V, Violante IR, Abderrahmane H, Dzialecka P, Park CH, Maceira-Elvira P, Morishita T, Cassara AM, Steiner M, Grossman N, Neufeld E, Hummel FC. Noninvasive theta-burst stimulation of the human striatum enhances striatal activity and motor skill learning. Nat Neurosci. 2023 Nov;26(11):2005-2016. doi: 10.1038/s41593-023-01457-7. PMID 37857774
• 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
• 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
• 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

Identifiers

NCT: NCT07643363 · TJHH-CI-TIS-2025-12

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗