Patterned stimulation (intermittent theta-burst) generating temporal interference in the striatum; see Wessel et al., 2023, Nat Neurosci. for details

Sham stimulation : ramp-up [5 s] immediately followed by ramp-down [5 s] of high-frequency currents (see Vassiliadis et al., 2023, Nat Hum Behav for more details)

tTIS is an innovative non-invasive brain stimulation approach, in which two or more independent stimulation channels deliver high-frequency currents in the kHz range (oscillating at f1 and f1 + Δf). These high-frequency currents are assumed to be too high to effectively modulate neuronal activity. Still, by applying a small shift in frequency, they result in a modulated electric field with the envelope oscillating at the low-frequency Δf (target frequency) where the two currents overlap. The peak of the modulated envelope amplitude can be steered towards specific areas located deep in the brain, by tuning the positions of the electrodes and the current ratio across stimulation channels. Here, we applied tTIS via surface electrodes applying a low-intensity (2mA baseline to peak), sub-threshold protocol following the safety guidelines for low-intensity transcranial electric stimulation in humans.

The primary outcome of the study is a laboratory-developed computerized motor task. It is not a standardized clinical scale, but a custom-designed measure specifically created to assess motor learning (e.g., Maceira-Elvira et al. 2022). The task consists of pressing, as quickly and accurately as possible, four buttons corresponding to the fingers labeled from 2 to 5 (2 for the index and 5 for the pinky finger). According to an explicit sequence displayed on a computer screen, the participants learn the sequence. The task performance is evaluated as how fast (sequence, consisting 9 elements/button key presses) and accurate (% of correct sequence) participants perform, within a block of 90 seconds, and their changes over time (during training and following training).

Diffusion-weighted and resting-state MRI are performed at baseline, and they allow to evaluate inter-individual anatomical factors associated to the primary outcome. While specific hypotheses exist, particularly regarding cortico-subcortical interactions (i.e., involving striatum), the analyses are exploratory in nature, given complexity of connectivity measures. Functional connectivity will be evaluated using correlation-based methods and graph metrics; structural connectivity will be assessed through diffusion tractography (with graph metrics as well).