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

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.

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

Eligibility Criteria:
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