Working memory (WM) relies on a vast network comprising cortical and subcortical structures and its impairment is frequent in normal aging, mild cognitive impairment (MCI) and dementia, often driving fucntional decline. Recent studies have shown that non-invasive brain stimulation (NIBS) methods can modulate neuronal activity, and brain network interactions. A significant body of literature has shown that both striatum and cerebellum are reciprocally connected and implicated in WM performance. However, to date, NIBS studies have mainly focused on cerebellar stimulation with transcranial magnetic stimulation (TMS), often yielding inconclusive or conflicting results. In the investigator hypothesis, sequential and concurrent stimulation of multiple brain regions of the WM subcortical network (i.e. targeting striatum and cerebellum) via transcranial temporal interference stimulation (tTIS) and/or repetitive transcranial magnetic stimulation (rTMS) could enhance WM performance in healthy elderly and/or MCI patients. Moreover, combining different stimulation techniques with multimodal neuroimaging and computational modeling, the investigators expect to acquire better mechanistic understanding through which different NIBS act on the brain and improves cognitive functions.

Executive functions and particularly working memory (WM) play a crucial role in daily life and is frequently impaired in patients with mild cognitive impairment (MCI), constituting one of the driving factors that compromise quality of life and autonomy. WM specifically relies on a vast brain network of cortical and subcortical regions. Among the different subcortical structures implicated in executive functions, both striatum and cerebellum have been linked to WM performance with complementary roles. Striatum is variably affected in the course of different neurodegenerative diseases, while in contrast, the cerebellum has been associated with cognitive resilience and brain reserve, making it a promising target for interventions for cognitive enhancement.

Hence, leveraging the reciprocal striato-cerebellar connections, in this multi-center, randomized, placebo-controlled proof-of-concept trial, the investigators implemented a sequential multifocal plasticity-inducing stimulation of the striatum and the cerebellum to enhance WM in MCI patients.

The investigators will apply an excitatory intermittent theta burst (iTBS) cerebellar TMS to target the left inferior cerebellar hemisphere and transcranial temporal interference stimulation (tTIS) with the same pattern to focally neuromodulate the striatum in MCI patients. In our hypothesis, this combined sequential protocol will synergistically enhance WM performance.

The investigators will analyse not only the resulting behavioral data as the main outcome, but via multimodal neuroimaging (structural and functional magnetic resonance imaging; s/fMRI) and computational modeling methods they will dissect the network mechanisms and patterns of intrinsic connectivity changes underlying the behavioral changes.

Inclusion Criteria:

• For MCI:
• Age > 18 years old;
• Clinical diagnosis of MCI due to possible or probable Lewy Bodies Dementia or amnestic MCI following core clinical and neuropsychological criteria.
• For Healthy Elderlies:
• Age > 60 years old;
• Normal performance on baseline cognitive screening.

Exclusion Criteria:

• presence of dementia as assessed by a cognitive test battery and evaluation of daily activities, any major psychiatric disorder (including major depressive episode);
• history of another neurological disease affecting central nervous system (e.g., tumor, epilepsy, stroke, etc.);
• severe or repeated head injury;
• non-compensated systemic or oncological disease;
• presence of MRI-incompatible metal in the body (e.g., cardiac pacemaker).

Quadruple