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

Study Overview
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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

Official Title
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Noninvasive Temporal Interference Stimulation: An Approach for Modulating Associative Memory by Targeting Deep-brain Targets

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

Intervention / Treatment
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* Combination Product: Non-invasive Temporal Interference stimulation and Face-name association training task targeting the hippocampus
* Combination Product: Non-invasive Temporal Interference stimulation and Face-name association training task targeting the Precuneus
* Combination Product: High-frequency stimulation (placebo) with Face-name association training task


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants will undergo 3 types of TIS in randomized order: targeting the hippocampus targeting the precuneus control condition with high-frequency stimulation
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active TIS of the hippocampus<br>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<br>* 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.<br>|
| Experimental: Active TIS of the precuneus<br>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<br>* 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.<br>|
| Placebo Comparator: High-frequency stimulation<br>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<br>* High-frequency (>1 kHz) stimulation; Standardly used as a carrier frequency; Effects are expected to he high-pass filtered by neurons<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in resting-state functional connectivity in regions of interest | resting-state fMRI: the analysis will be primarily focused on alterations within nodes in the Default mode Network and between network connectivity; Secondary focus on task-positive networks, namely: Central executive network and Dorsal attentional network | 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) | Transcranial magnetic stimulation (TMS) evoked potentials; Investigation of local cortical circuits and networks activated following stimulation | Baseline measurement approximately 30 minutes prior stimulation; immediately after stimulation protocol up to 40 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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temporal interference stimulation, associative memory, hippocampus, precuneus, fMRI, EEG