Temporal Interference Stimulation Treatment in Patients With Cognitive Impairment (TIS)
A Randomized, Sham-Controlled Trial of Temporal Interference Stimulation Treatment in Patients With Cognitive Impairment
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.
Studieöversikt
Status
Studietyp
Inskrivning (Beräknad)
Fas
- Inte tillämpbar
Kontakter och platser
Studiekontakt
- Namn: Mou Zhehui
- Telefonnummer: +86 18959257015
- E-post: muzhehui@gmail.com
Studieorter
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Tianjin Municipality
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Tianjin, Tianjin Municipality, Kina
- Rekrytering
- Tianjin Huanhu Hospital
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Kontakt:
- Li Pan, Director
- Telefonnummer: +86 13114881943
- E-post: doc_panpan@163.com
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Deltagandekriterier
Urvalskriterier
Åldrar som är berättigade till studier
- Vuxen
- Äldre vuxen
Tar emot friska volontärer
Beskrivning
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).
Studieplan
Hur är studien utformad?
Designdetaljer
- Primärt syfte: Behandling
- Tilldelning: Randomiserad
- Interventionsmodell: Parallellt uppdrag
- Maskning: Fyrdubbla
Vapen och interventioner
Deltagargrupp / Arm |
Intervention / Behandling |
|---|---|
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Sham Comparator: Sham TIS + Active TIS + Targeted Cognitive Training
Participants will receive sham temporal interference stimulation during the first 5 days, followed by active temporal interference stimulation during the next 5 days.
Targeted cognitive training will be administered during the intervention period.
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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 receive active stimulation throughout the entire 10-day intervention period. Two sessions will be administered per day, with each session lasting 40 minutes.
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.
Participants will complete structured cognitive training tasks designed to engage specific cognitive processes associated with the study objectives.
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Experimentell: Active TIS + Active TIS + Targeted Cognitive Training
Participants will receive active temporal interference stimulation during the first 5 days and the next 5 days.
Targeted cognitive training will be administered during the intervention period.
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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 receive active stimulation throughout the entire 10-day intervention period. Two sessions will be administered per day, with each session lasting 40 minutes.
Participants will complete structured cognitive training tasks designed to engage specific cognitive processes associated with the study objectives.
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Aktiv komparator: Active TIS + Active TIS + General Cognitive Training
Participants will receive active temporal interference stimulation during the first 5 days and the next 5 days.
General cognitive training will be administered during the intervention period.
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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 receive active stimulation throughout the entire 10-day intervention period. Two sessions will be administered per day, with each session lasting 40 minutes.
Participants will complete general cognitive training tasks involving multiple cognitive domains without specifically emphasizing the primary targeted cognitive process.
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Vad mäter studien?
Primära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
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Changes from Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
Tidsram: 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.
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Measures global cognitive function. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is a clinician-administered scale commonly used to assess cognitive performance in individuals with cognitive impairment and dementia. Full Scale Name: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Typical Total Score Range: 0 to 70. Higher Scores Mean: Greater cognitive impairment (worse cognitive performance). |
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.
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Sekundära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
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Cross-frequency Neural Oscillations
Tidsram: 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.
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Electrophysiological indices of cross-frequency neural interactions will be quantified using electroencephalography (EEG).
Measures will include phase-amplitude coupling (PAC) between low-frequency and high-frequency bands (e.g., theta-gamma and alpha-gamma coupling), cross-frequency coherence, and power modulation across frequency bands.
These metrics reflect the integrity of neural communication and network coordination within cognition-related brain systems.
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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.
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Change from baseline in resting-state frontal-temporal EEG functional connectivity strength
Tidsram: 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.
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After EEG preprocessing, frequency-band decomposition, and functional connectivity analysis, functional connectivity strength within frontal regions, within temporal regions, and between frontal and temporal regions will be calculated.
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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.
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Changes from Baseline in Frontal and Temporal Gray Matter Density (sMRI)
Tidsram: 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.
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Evaluation of changes in gray matter density or volume within frontal and temporal brain regions, quantified using structural Magnetic Resonance Imaging (sMRI).
This measure assesses the structural integrity and potential neuroplastic changes, including cortical thinning or gray matter increase, in brain regions critically involved in executive function, language processing, and memory-related cognitive processes.
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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.
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Changes from Baseline in Cortical Thickness (sMRI)
Tidsram: 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.
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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.
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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.
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Changes from baseline in ALFF
Tidsram: 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.
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Resting-state fMRI will be used to quantify changes in the amplitude of low-frequency fluctuations (ALFF) within frontal and temporal brain regions following intervention.
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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.
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Changes from baseline in ReHo
Tidsram: 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.
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Resting-state fMRI data will be analyzed to evaluate changes in regional homogeneity (ReHo), reflecting local synchronization of spontaneous neural activity within frontal and temporal regions.
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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.
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Changes from baseline in resting-state functional connectivity
Tidsram: 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.
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Evaluation of changes in resting-state functional connectivity between frontal and temporal brain regions using fMRI, reflecting synchronized neural activity within memory and attention-related networks.
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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.
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Changes from baseline in FA
Tidsram: 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.
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Evaluation of changes in fractional anisotropy (FA) in white matter tracts using diffusion tensor imaging (DTI), reflecting directional water diffusion and white matter integrity.
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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.
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Changes from baseline in MD
Tidsram: 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.
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Evaluation of changes in mean diffusivity (MD) in white matter tracts using DTI, reflecting overall magnitude of water diffusion.
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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.
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Changes from baseline in AD
Tidsram: 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.
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Evaluation of changes in axial diffusivity (AD) in white matter tracts using DTI, reflecting diffusion along the principal axis of fibers.
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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.
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Changes from baseline in RD
Tidsram: 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.
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Evaluation of changes in radial diffusivity (RD) in white matter tracts using DTI, reflecting diffusion perpendicular to fiber orientation and potential demyelination.
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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.
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Changes from Baseline in Mini-Mental State Examination (MMSE) Score
Tidsram: 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.
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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.
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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.
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Changes from Baseline in Montreal Cognitive Assessment - Basic (MoCA-B) Score
Tidsram: 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.
|
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.
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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.
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Changes from Baseline in Clinical Dementia Rating (CDR) Score
Tidsram: 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.
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Measures global cognitive and functional status using the Clinical Dementia Rating (CDR) scale, which assesses cognitive performance and daily functioning across multiple domains, including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The CDR provides a global rating of dementia severity based on structured interviews with the participant and an informant, reflecting overall cognitive impairment and functional impact. |
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.
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Changes from Baseline in Zarit Caregiver Burden Interview (ZBI) Score
Tidsram: 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.
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Assesses perceived caregiver burden. The Zarit Caregiver Burden Interview (ZBI) is a widely used, caregiver-reported questionnaire designed to evaluate the level of burden experienced by individuals providing care to persons with cognitive impairment or other chronic conditions. The scale assesses emotional, physical, social, and financial aspects of caregiver strain. Total Score Range: 0 to 88. Higher Scores Mean: Greater caregiver burden. Change in ZBI score from baseline to each assessment time point will be analyzed. |
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.
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Changes from Baseline in AD Molecular Pathologies and Blood Biomarkers
Tidsram: 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.
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Plasma concentrations of Alzheimer's disease-related biomarkers-including the Aβ42/40 ratio, phosphorylated tau-217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)-will be quantified using validated immunoassay platforms.
These biomarkers reflect amyloid pathology, tau phosphorylation, axonal injury, and astroglial activation, respectively.
Changes from baseline will be assessed to evaluate peripheral biochemical responses to the intervention.
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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.
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Incidence and Severity of Adverse Events (AEs)
Tidsram: Through study completion, an average of 14 weeks
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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
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Through study completion, an average of 14 weeks
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Samarbetspartners och utredare
Sponsor
Samarbetspartners
Publikationer och användbara länkar
Allmänna publikationer
- 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.
- 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. Epub 2023 Oct 19.
- 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.
- 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.
- 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.
Studieavstämningsdatum
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Studiestart (Beräknad)
Primärt slutförande (Beräknad)
Avslutad studie (Beräknad)
Studieregistreringsdatum
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Först inskickad som uppfyllde QC-kriterierna
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- Hjärnsjukdomar
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- Demens
- Tauopatier
- Neurodegenerativa sjukdomar
- TDP-43 Proteinopatier
- Proteostasbrister
- Frontotemporal Lobar Degeneration
- Närings- och metabola sjukdomar
- Alzheimers sjukdom
- Frontotemporal demens
Andra studie-ID-nummer
- TJHH-CI-TIS-2025-12
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