Abstract Nonivasive stimulation of the brain in health and disease is an important goal of the Brain Initiative. Current methods include Transcranial Magnetic Stimulation (TMS), Transcranial Electric Stimulation (TES) and Transcranial Focused Ultrasound Stimulation (TFUS). The mechanisms of the perturbation effects are not well understood. We hypothesize that Transcranial Radio Frequency Stimulation (TRFS; 900 MHz to few GHz), when using appropriate frequency, power and stimulation regimes, can offer a safe experimental and clinical tool that can combine advantages of the existing noninvasive perturbation methods with potentially fewer side effects. We propose to examine the membrane, single unit, circuit, and circuit modification mechanism of TRFS. We designed a set of experiments to examine non-thermal, electric field-induced effects of RF stimulation in behaving rodents, with the goal of establishing safe margins of stimulation patterns and RF power for effective driving of neuronal activity at the single neuron and circuit levels, using state-of-the-art optical and large-scale electrophysiological and electronic techniques combined with modeling of RF effects. The first goal is to establish safe parameters of homogeneous RF fields, which can effectively entrain cortical and subcortical neurons with no or negligible thermal effects even after long-term exposure. Second, exclude any potential non-thermal artifacts (such as cochlear-mediated or 'metal-in-the-brain' effects) and other periphery-mediated effects. The third important milestone is to identify the membrane channels involved in the RF-induced field effects. Finally, we will examine the spatially focused effects of RF stimulation by using directionally acting antenna(s). The feasibility of the project is supported by extensive preliminary findings. Our data and know- how will be made available to qualified researchers. TRFS will facilitate discovery science and its future human application is expected to become invaluable in the treatment of multiple psychiatric and neurological conditions. ! !

Narrative We suggest that Transcranial Radio Frequency Stimulation (TRFS; 900 MHz to few GHz), when using appropriate frequency, power and stimulation regimes, can offer a safe experimental and clinical tool that can combine advantages of the existing noninvasive perturbation methods with potentially fewer side effects. We propose to examine the membrane, single unit, circuit, and circuit modification mechanism of TRFS. !