Multipair phase-modulated temporal interference electrical stimulation combined with fMRI.

Temporal Interference Stimulation (TI) is a novel brain stimulation technique that aims to integrate the depth characteristic of conventional deep brain stimulation protocols with the non-invasive nature of transcranial electric stimulation. Recent publications in both mice and humans demonstrate that subcortical areas including hippocampus and striatum can be targeted using TI. However, whereas TI stimulation is set to be focused on a specific region of interest, other off-target areas may still be stimulated, including cortical structures. This is a major concern as off-target stimulation carries the risk of modulating unwanted brain structures and circuits. In the present study, we focused on the prefrontal cortex (PFC) in mice and developed a computational modelling approach to identify the best electrode locations for targeting PFC. Using in-vivo electrophysiological recordings and functional magnetic resonance imaging (fMRI) combined with TI, we confirmed the presence of induced TI fields and hemodynamic responses in the PFC but also identified off-target stimulated sites. To minimize the occurrence of off-target effects, we propose a new configuration with three electrode pairs, one of which has an active phase shift of 180 degrees in relation to the other two TI-inducing pairs. The use of this phase-canceling field allowed us to improve the focality of TI by reducing off-target stimulations without significantly affecting the TI field in the target area. The proposed design effectively addresses one of TI's most critical shortcomings and opens new avenues for applications. ### Competing Interest Statement The authors have declared no competing interest.