Noninvasive Temporal Interference Stimulation: Modulating Associative Memory by Targeting Deep-brain Targets

NCT05805215 | Unknown

• 1 other identifier: LX22NPO5107
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Alzheimer's disease and its preclinical stages are characterized by progressive neurodegenerative changes in the hippocampi and default mode network resulting in dysfunctions in episodic memory and its central part the associative memory. Associative memory allows for learning and remembering the relationship between unrelated items. Previous research suggests that non-invasive brain stimulation can influence associative memory but with the caveat of quite a small precision and relatively small effects due to the ability only influence superficial brain areas. Novel Brain stimulation techniques such as temporal interference stimulation (TIS) allow overcoming these caveats by allowing focal non-invasive deep brain stimulation. The main goal of this pilot clinical trial is to modulate associative memory among healthy seniors by influencing the cortico-hippocampal circuits using TIS. Secondly, the goal is to use functional magnetic resonance imaging (fMRI) and EEG to explore the neural correlates of TIS effects on brain networks and find biomarkers that allow predicting better response to brain stimulation.

Conditions

Healthy Aging; Memory Disorders in Old Age; Mild Cognitive Impairment; Alzheimer Disease

Keywords

temporal interference stimulation; associative memory; hippocampus; precuneus; fMRI; EEG

Outcome Measures

Primary Outcomes (2)

• Accuracy in Face-Name association task

  The face-name association task will be composed of blocks of encoding and recall. Each block contained a unique face-name pair. Multiple pairs followed by a delay and a recall period, where participants tried to select the correct name of each face out of five options (i.e., one target name, two foil names that were present in the block but associated with a different face, and two distracting names that were not present during the task). After each name selection, participants were asked to rate their choice confidence (1, not confident at all to 4, extremely confident)

  Measured during stimulation procedure; assessed through study completion, an average of 2 years

• Speed in Face-Name association task

  The face-name association task will be composed of blocks of encoding and recall. Each block contained a unique face-name pair. Multiple pairs followed by a delay and a recall period, where participants tried to select the correct name of each face out of five options (i.e., one target name, two foil names that were present in the block but associated with a different face, and two distracting names that were not present during the task). After each name selection, participants were asked to rate their choice confidence (1, not confident at all to 4, extremely confident)

  Measured during stimulation procedure; assessed through study completion, an average of 2 years

Secondary Outcomes (2)

• changes in resting-state functional connectivity in regions of interest

  Baseline measurement approximately 20 minutes prior stimulation; immediately after stimulation protocol up to 30 minutes

• Transcranial magnetic stimulation evoked activity change over the regions of interest (Precuneus, prefrontal cortex)

  Baseline measurement approximately 30 minutes prior stimulation; immediately after stimulation protocol up to 40 minutes

Study Arms (3)

Active TIS of the hippocampus

EXPERIMENTAL

Participants will undergo Active TIS of the hippocampus as one of the 3 conditions within the trial in randomized order.

Combination Product: Non-invasive Temporal Interference stimulation and Face-name association training task targeting the hippocampus

Active TIS of the precuneus

EXPERIMENTAL

Participants will undergo Active TIS of the precuneus as one of the 3 conditions within the trial in randomized order.

Combination Product: Non-invasive Temporal Interference stimulation and Face-name association training task targeting the Precuneus

High-frequency stimulation

PLACEBO COMPARATOR

High frequency \>1Khz stimulation; Assumption: The intrinsic low-pass filtering of electrical signals by the neural membrane prevents neural electrical activity from following very high-frequency oscillating (e.g., \> 1 kHz) electric fields.

Combination Product: High-frequency stimulation (placebo) with Face-name association training task

Interventions

Non-invasive Temporal Interference stimulation and Face-name association training task targeting the hippocampus COMBINATION_PRODUCT

TIS relies on high frequencies which can penetrate with relatively low loss. High-frequency carriers (\>1 kHz) emitted by two (or more) pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency between the carriers. By controlling field orientation and frequency offset, the hot spot of constructive interference can be precisely targeted. The key aspect of this method is the use of carrier waves at frequencies higher than 1 kHz. Frequencies above this range are regarded as non-stimulating and pass-through tissues with relatively low loss. While these higher frequencies do not stimulate neural tissue, the interference envelope of two phase-shifted frequencies can elicit action potentials because the offset (aka "beat") frequency can be tuned accordingly to \< 100 Hz.

Active TIS of the hippocampus

Non-invasive Temporal Interference stimulation and Face-name association training task targeting the Precuneus COMBINATION_PRODUCT

TIS relies on high frequencies which can penetrate with relatively low loss. High-frequency carriers (\>1 kHz) emitted by two (or more) pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency between the carriers. By controlling field orientation and frequency offset, the hot spot of constructive interference can be precisely targeted. The key aspect of this method is the use of carrier waves at frequencies higher than 1 kHz. Frequencies above this range are regarded as non-stimulating and pass-through tissues with relatively low loss. While these higher frequencies do not stimulate neural tissue, the interference envelope of two phase-shifted frequencies can elicit action potentials because the offset (aka "beat") frequency can be tuned accordingly to \< 100 Hz.

Active TIS of the precuneus

High-frequency stimulation (placebo) with Face-name association training task COMBINATION_PRODUCT

High-frequency (\>1 kHz) stimulation; Standardly used as a carrier frequency; Effects are expected to he high-pass filtered by neurons

High-frequency stimulation

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Intact cognition
• with the ability to comprehend the experimental task
• right-handed

You may not qualify if:

• left-handed
• severe internal disease, cancer
• brain tumour, intracranial surgery, psychiatric disorder
• severe neurological brain disease; i.e.: epilepsy, stroke etc.
• the presence of a pacemaker/defibrillator, metal incompatible with magnetic resonance in the body
• incapacitating musculoskeletal disorders
• cognitive impairment based on screening tests
• severe impairment of vision

Sponsors & Collaborators

• Masaryk University: lead
• St. Anne's University Hospital Brno, Czech Republic: collaborator

Study Sites (1)

CEITEC Masaryk university

Brno, 62500, Czechia

Location

Related Publications (9)

• Salami A, Pudas S, Nyberg L. Elevated hippocampal resting-state connectivity underlies deficient neurocognitive function in aging. Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17654-9. doi: 10.1073/pnas.1410233111. Epub 2014 Nov 24.

  PMID: 25422457 BACKGROUND

• Preston AR, Eichenbaum H. Interplay of hippocampus and prefrontal cortex in memory. Curr Biol. 2013 Sep 9;23(17):R764-73. doi: 10.1016/j.cub.2013.05.041.

  PMID: 24028960 BACKGROUND

• Eichenbaum H. Prefrontal-hippocampal interactions in episodic memory. Nat Rev Neurosci. 2017 Sep;18(9):547-558. doi: 10.1038/nrn.2017.74. Epub 2017 Jun 29.

  PMID: 28655882 BACKGROUND

• Wagner AD, Shannon BJ, Kahn I, Buckner RL. Parietal lobe contributions to episodic memory retrieval. Trends Cogn Sci. 2005 Sep;9(9):445-53. doi: 10.1016/j.tics.2005.07.001.

  PMID: 16054861 BACKGROUND

• Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, Ponzo V, Picazio S, Di Lorenzo F, Serra L, Motta C, Maiella M, Marra C, Cercignani M, Martorana A, Caltagirone C, Bozzali M. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage. 2018 Apr 1;169:302-311. doi: 10.1016/j.neuroimage.2017.12.048. Epub 2017 Dec 19.

  PMID: 29277405 BACKGROUND

• Lang S, Gan LS, Alrazi T, Monchi O. Theta band high definition transcranial alternating current stimulation, but not transcranial direct current stimulation, improves associative memory performance. Sci Rep. 2019 Jun 12;9(1):8562. doi: 10.1038/s41598-019-44680-8.

  PMID: 31189985 BACKGROUND

• Wang JX, Rogers LM, Gross EZ, Ryals AJ, Dokucu ME, Brandstatt KL, Hermiller MS, Voss JL. Targeted enhancement of cortical-hippocampal brain networks and associative memory. Science. 2014 Aug 29;345(6200):1054-7. doi: 10.1126/science.1252900.

  PMID: 25170153 BACKGROUND

• Wang H, Jin J, Cui D, Wang X, Li Y, Liu Z, Yin T. Cortico-Hippocampal Brain Connectivity-Guided Repetitive Transcranial Magnetic Stimulation Enhances Face-Cued Word-Based Associative Memory in the Short Term. Front Hum Neurosci. 2020 Oct 30;14:541791. doi: 10.3389/fnhum.2020.541791. eCollection 2020.

  PMID: 33192388 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

Related Links

• Related Info

MeSH Terms

Conditions

Cognitive Dysfunction; Alzheimer Disease

Condition Hierarchy (Ancestors)

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

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: The study participant and researcher applying brain stimulation will be blinded to the stimulation condition. high-frequency stimulation (\>1Khz) will be used as a control condition.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will undergo 3 types of TIS in randomized order: 1. targeting the hippocampus 2. targeting the precuneus 3. control condition with high-frequency stimulation

Study Record Dates

• First Submitted: March 28, 2023
• First Posted: April 7, 2023
• Study Start: January 30, 2024
• Primary Completion: November 1, 2025
• Study Completion: December 12, 2025
• Last Updated: October 19, 2023

Record last verified: 2023-10

Locations

CZ (1)