Project Summary Minimally invasive neural modulation at sub-millimeter spatial resolution remains a critical yet unmet biomedical need. Researchers have explored a broad spectrum of electromagnetic wave and developed wireless neuromodulation methods. Due to its long wavelength, transcranial magnetic stimulation does not provide sufficient spatial resolution to target a functional unit such as a single ocular dominance column in the visual cortex or a diseased peripheral nerve. On the other hand, photons, with their short wavelength, offer micrometer-scale spatial precision but can barely penetrate couple hundred micrometers into the tissue, not to mention the human skull. Microwave (MW), with frequencies between 300 MHz and 300 GHz, fills the gap between optical wave and magnetic wave, yet, has rarely been explored for neuromodulation. We propose a minimally invasive neuromodulation device by taking advantage of a microwave split ring resonator (SRR) design. The SRR has a perimeter of approximately one half of MW wavelength, thus acting as a resonant antenna. It couples the microwave wirelessly and concentrates the microwave at the gap, producing a localized electrical field of ~100 μm in space. Our scientific premise is based on the nonthermal neural inhibitory effect of microwave and the resonance effect of the SRR. The SRR produces concentrated microwave and allows for neuromodulation beyond the microwave diffraction limit, reaching ~100 μm spatial precision. In the proposed work, we will design and fabricate an implantable SRR with titanium for its superior biocompatibility. We will then validate the SRR’s potential in neural inhibition using primary neurons in vitro and a mouse epilepsy model in vivo. By accomplishing the proposed studies, we will have developed a biocompatible and implantable neuromodulation device. The centimeter-scale penetration depth provided by microwave and the sub-millimeter spatial precision provided by SRR promises broad biomedical applications. For central nervous system, our technology allows minimally invasive transcranial modulation of neural activities inside brain and for clinical treatment of epilepsy. A multi-disciplinary team with complementary expertise is assembled to implement the proposed activities.