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

NCT ID: NCT05805215

Last Updated: 2023-10-19

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Clinical Phase

NA

Total Enrollment

30 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-01-30

Study Completion Date

2025-12-12

Brief Summary

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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.

Detailed Description

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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. Encoding of associative information occurs in the distributed brain networks involving the inferior frontal cortex, fusiform cortex, medial temporal lobe, premotor and posterior parietal cortex including the precuneus. Previous studies have shown that by targeting specific nodes within the cortico-hippocampal circuits via the tools of non-invasive brain stimulation the associative memory (AM) performance can be manipulated, however, only relatively surface areas of this circuit were accessible by current non-invasive stimulation techniques. Novel modalities of non-invasive transcranial electrical stimulation such as temporal interference stimulation (TIS) holds a promise to stimulate deeper brain structures without compromising the focality.

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. The latest studies showed positive behavioral effects of TIS applied over the primary motor cortex or motor striatum in healthy young adults. To date, no studies have investigated the effect of TIS on AM.

The specific objectives include: 1) Implement a novel temporal interference stimulation (TIS) technique in a proof-of-concept study targeting deep structures of the cortico-hippocampal circuit, which were until this date unattainable reliably by non-invasive stimulation techniques, with the aim to modulate associative memory in healthy seniors. 2) Explore neural underpinnings of TIS effects and find biomarkers associated with better temporal interference stimulation outcomes and with optimal candidates' selection by using EEG/fMRI techniques

Conditions

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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

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
Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Caregivers
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.

Study Groups

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Active TIS of the hippocampus

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

Group Type EXPERIMENTAL

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

Intervention Type 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

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

Group Type EXPERIMENTAL

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

Intervention Type 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.

High-frequency stimulation

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.

Group Type PLACEBO_COMPARATOR

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

Intervention Type COMBINATION_PRODUCT

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

Interventions

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

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.

Intervention Type COMBINATION_PRODUCT

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

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.

Intervention Type COMBINATION_PRODUCT

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

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

Intervention Type COMBINATION_PRODUCT

Eligibility Criteria

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Inclusion Criteria

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

Exclusion Criteria

* 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
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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St. Anne's University Hospital Brno, Czech Republic

OTHER

Sponsor Role collaborator

Masaryk University

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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CEITEC Masaryk university

Brno, , Czechia

Site Status

Countries

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Czechia

Facility Contacts

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Patrik Simko, PhD.

Role: primary

+420 54949 7643

Monika Pupikova, PhD.

Role: backup

+420 54949 8313

References

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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.

Reference Type BACKGROUND
PMID: 25422457 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24028960 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 28655882 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 16054861 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 29277405 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 31189985 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25170153 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 33192388 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 28575667 (View on PubMed)

Related Links

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Other Identifiers

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LX22NPO5107

Identifier Type: -

Identifier Source: org_study_id

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