All functions we use in our everyday life depend on a complex interplay between both cortical and subcortical brain areas, communicating in between each others. When a region is affected by either an accident, aging or neurodegenerative diseases, the whole network is disturbed resulting in functional impairments. Hence, it is highly important to find methods allowing to better investigate the role of each brain structure in humans, with the goal of applying this knowledge to improve current rehabilitative and therapeutic solutions.

Noninvasive brain stimulation (NIBS) techniques can help unveiling the functional role of specific brain regions in key behaviors of everyday life, such as motor and cognitive functions. However, current NIBS methods show a major drawback when targeting subcortical areas, the well-known steep depth-focality tradeoff. The higher the distance of the target region from the scalp, the lower the focality as well as the higher the co-activation of no target structures, due to concurrent stimulation of the overlying tissues.
Transcranial Temporal Interference Stimulation (tTIS) is a novel noninvasive deep brain stimulation technique introduced to overcome the depth-focality tradeoff, able to reach deep brain structures in a focal manner. This could provide new insights about the causal role of subcortical regions in humans, which until now was limited to observations from either animals or implanted patients.
First positive results were obtained in mice and phantom modeling, but the translation to humans is still missing. Therefore, the goal of this thesis was to fill this gap, by successfully modulating deep brain regions, leading to behavioral and brain activity changes.
With this purpose, we targeted two main brain regions, the striatum and the hippocampus, known to be key players in non-declarative and declarative memory respectively. Stimulation was delivered in a theta burst pattern, which was previously shown to induce long-term plasticity (LTP)-like effects.

In the first part of the thesis, we investigated the effects of tTIS on striatal and whole brain activity during rest and during a motor learning task in young healthy subjects.
As a next step, behavioral performance of the motor learning task was analysed and a first step towards clinical translation was taken by studying the impact of tTIS in an older cohort compared with a young one.
In a second part of the project, tTIS was applied on the hippocampus in the context of two declarative memory tasks, a spatial navigation task and a face-name association task, to determine the functional role of the hippocampus and the exciting opportunity to neuromodulate its function with respective behavioral and brain activity effects.
This work provides first evidence that tTIS can be used for successful neuromodulation of deep brain structures with good focality in humans. This was proven via both neuroimaging and behavioral data, opening future prospective for the translation of the technique in a rehabilitation setting.