ABSTRACT The goal of this project is to significantly advance the field of acute and semichronic epilepsy monitoring using novel, high-resolution electrocorticography (ECoG) record/stimulate grids (4096/256 channels, respectively) and stereoelectroencephalography (sEEG) depth electrodes (120/8 micro/macro) with full wireless data and power transfer. This project builds on our previous success in conducting the first-ever human trials for acute mapping of eloquent brain tissue with multi-thousand channel microelectrode grids. The proposed system encompasses multiple transformative technological approaches, including: (1) leveraging advanced thin-film microfabrication on 8” diameter substrates, thus permitting long integrated connectorization from thousands of channels; (2) exploiting a newly developed platinum nanorod (PtNR) microelectrode technology with excellent low impedance, high charge-injection-capacity (4.4mC/cm2), stability, and biocompatibility; and (3) using a thin (~10μm) parylene C substrate that is compliant to brain movements, conformal to brain curvature, and transparent, permitting easier visualization of brain anatomy during the acute mapping. Further, (4) the grids developed for this project are modular and can be trimmed to fit different sizes of craniotomies, and (5) this system offers a new generation of minimally invasive sEEG electrodes with easily reconfigurable microcontact distribution in different regions of the brain Our proposed system also (6) employs state-of-the-art acquisition electronics with a miniaturized 1024ch neural interface system-on-chip and radio transmission of data and power, enabling fully wireless monitoring that eliminates wire externalization, and (7) deploys multi-screen and multi- window visualization of the whole repertoire of electrophysiological activity, with the option to display and interpret signals in standard fashion. Our goal is to demonstrate in the semichronic clinical setting a high-definition display of traditional and emerging clinical biomarkers for epilepsy monitoring and treatment. To achieve this goal, we will pursue in Aim 1 regulatory input from the FDA and scale our grids under good quality laboratory practices (GLP), and perform benchtop testing and hardware and software development under a quality management system. In Aim 2, we will perform semichronic animal testing under GLP to demonstrate safety, tolerability, and efficacy of the new epilepsy-monitoring system. In Aim 3, we will will perform pre-clinical and human intraoperative recordings with appropriate IRB authorization. We will pursue FDA clearance for semichronic implants in Aim 4, and transition Aim 5 to semichronic epilepsy monitoring in patients with intractable epilepsy. The methods employed in device and system development, surgical approaches, electrophysiology, and data analysis will not only advance functional and epilepsy monitoring but will also have significant implications for numerous applications in neuromodulation/therapeutic stimulation, minimally destructive brain-machine interfaces, and spinal cord stimulation.

NARRATIVE Epilepsy is now believed to result from aberrant activity of multiple neural “nodes” that together create a self- reinforcing network phenomenon. Standard clinical electrodes used in the diagnosis and treatment of drug- resistant epilepsy do not offer sufficiently fine resolution for microscale interrogation of the epileptogenic networks. This project aims to deliver a fully wireless multi-thousand channel electrode system with large-scale but precise cortical coverage, which will advance our understanding and treatment of epilepsy through analysis of neural activity at an unprecedented resolution, as demonstrated in acute human studies, semichronic animal safety and efficacy tests, and a small clinical trial.