Deep-HiPs: Noninvasive Temporal Interference Stimulation: Modulating Associative Memory by Targeting Deep-brain Targets
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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N/A |
Detailed Description
Alzheimer's disease and its preclinical stages are characterized by progressive neurodegenerative changes in the hippocampi and default mode network [1] resulting in dysfunctions in episodic memory and its central part the associative memory [1,2]. 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 [3,4]. 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 [5-8], 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 [9].
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 [10] or motor striatum [11] 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
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Salami, Alireza, et al. "Elevated hippocampal resting-state connectivity underlies deficient neurocognitive function in aging." Proceedings of the National Academy of Sciences 111.49 (2014): 17654-17659.
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Preston, A. R., and Eichenbaum, H. (2013). Interplay of hippocampus and prefrontal cortex in memory. Curr. Biol. 23, R764-R773. doi: 10.1016/j.cub. 2013.05.041
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Eichenbaum, H. Prefrontal-hippocampal interactions in episodic memory. Nat. Rev. Neurosci. 18, 547-558 (2017).
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Wagner, A. D., et al. Parietal lobe contributions to episodic memory retrieval. Trends Cogn. Sci. 9, 445-453 (2005).
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Koch, Giacomo, et al. "Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease." Neuroimage 169 (2018): 302-311.
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Lang, Stefan, et al. "Theta band high-definition transcranial alternating current stimulation, but not transcranial direct current stimulation, improves associative memory performance." Scientific reports 9.1 (2019): 1-11.
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Wang, Jane X., et al. "Targeted enhancement of cortical-hippocampal brain networks and associative memory." Science 345.6200 (2014): 1054-1057.
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Wang, He, et al. "Cortico-hippocampal brain connectivity-guided repetitive transcranial magnetic stimulation enhances face-cued word-based associative memory in the short term." Frontiers in Human Neuroscience 14 (2020).
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Grossman, Nir, et al. "Noninvasive deep brain stimulation via temporally interfering electric fields." Cell 169.6 (2017): 1029-1041.
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Ma, Ru, et al. "High Gamma and Beta Temporal Interference Stimulation in the Human Motor Cortex Improves Motor Functions." bioRxiv (2021).
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Wessel, Maximilian Jonas, et al. "Evidence for temporal interference (TI) stimulation effects on motor striatum." Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation 14.6 (2021): 1684.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: 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. |
Combination Product: Non-invasive Temporal Interference stimulation and Face-name association training task
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.
|
Experimental: 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. |
Combination Product: Non-invasive Temporal Interference stimulation and Face-name association training task
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.
|
Placebo Comparator: 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. |
Combination Product: Non-invasive Temporal Interference stimulation and Face-name association training task
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.
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Outcome Measures
Primary Outcome Measures
- Face-Name association task [During stimulation]
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)
Secondary Outcome Measures
- resting-state fMRI [Baseline measurement prior stimulation; after each stimulation condition]
resting-state fMRI: the analysis will be primarily focused on nodes within the Default mode Network and between network connectivity
- TMS-EEG [Baseline measurement prior stimulation; after each stimulation condition]
Transcranial magnetic stimulation (TMS) evoked potentials; Investigation of local cortical circuits and networks activated following stimulation
Eligibility Criteria
Criteria
Inclusion Criteria:
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Intact cognition
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with the ability to comprehend the experimental task
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right-handed
Exclusion Criteria:
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left-handed
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severe internal disease, cancer
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brain tumour, intracranial surgery, psychiatric disorder
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severe neurological brain disease; i.e.: epilepsy, stroke etc.
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the presence of a pacemaker/defibrillator, metal incompatible with magnetic resonance in the body
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incapacitating musculoskeletal disorders
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cognitive impairment based on screening tests
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severe impairment of vision
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | CEITEC Masaryk university | Brno | Czechia | 62500 |
Sponsors and Collaborators
- Masaryk University
- St. Anne's University Hospital Brno, Czech Republic
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- LX22NPO5107