Project Summary/Abstract One in three patients across neurological and psychiatric disorders are treatment resistant. Neuromodulation could provide these patients with treatment options, but current invasive approaches carry significant risk, while noninvasive approaches have low spatial resolution and cannot stimulate deep brain areas. Transcranial temporal interference stimulation (TIS) is emerging as a novel tool that combines noninvasiveness with favorable focus, high focusing flexibility, and the possibility to stimulate at depth. Successful applications to deep brain targets as well as flexible focusing have been demonstrated in mice. This proposal takes the critical set of next steps so that TIS can be effectively applied to the human brain. In Aim 1, we will realize the key strength of TIS, applying it to deep brain nuclei of non-human primates. In a controlled experiment, we will determine the intensity threshold that produces substantial effects on visual choice behavior, and validate the safety of the stimulation. In Aim 2, we will apply TIS to the motor cortex of humans and use an established method to elicit and measure motor evoked potentials in relation to the phase of the TIS waveform. Using this metric, we will i) validate that effects of TIS are due to the beat pattern and not the carrier, ii) evaluate the effect of the TIS carrier frequency, and iii) devise protocols for transient and sustained neuromodulation. Together, our work provides protocols for effective and safe TIS modulation of the human brain. This development has the potential to provide noninvasive and spatially specific treatment options to the large number of patients with brain disorders that are resistant to, our counter-indicated for, existing forms of treatments.