PROJECT SUMMARY/ABSTRACT In the most severe cases of epilepsy, where seizures persist despite multiple trials of anti-seizure medications, patients may benefit from surgical removal of seizure-generating brain tissue. Prior to surgery, electrodes are often implanted directly into or onto the patient’s brain and are used to continuously record electrical brain activity over days. Ideally, this enables clinicians to capture seizure activity and determine its point of origin. Then this information is used in combination with the results of brain imaging and other testing to guide removal of brain tissue. While epilepsy surgery may lead to seizure freedom, 70-90% of surgery patients remain on anti-seizure medications and roughly 50% of patients continue to have seizures. The fact that seizures often persist after such a drastic, invasive procedure indicates that current methods for localization of seizure-generating tissue are insufficient. Therefore, the long-term goal of this work is to improve the outcomes of patients undergoing epilepsy surgery by developing more accurate methods to localize seizure-generating tissue. However, in order to achieve accurate, patient-specific seizure localization and successful surgery, there is a critical need to understand how seizures start and spread. Many studies have reported electrophysiological characteristics of seizures, and these vary depending on the spatial scale at which they are measured. Microelectrode arrays provide cellular-level electrophysiological detail, but only within a 4mm x 4mm area on a single gyrus. Standard clinical macroelectrodes provide broader spatial coverage, but they lack the spatial resolution to accurately track seizure dynamics, leading to highly variable estimates of wave sources and directions. Moreover, when measured at these two disparate scales, characteristics of the complex electrical activity that occurs during a seizure can appear contradictory in nature. Therefore, a significant barrier to our understanding of seizures is our inability to bridge the micro and macro spatial scales. To address this, the overall objective of this proposal is to quantify and model seizure dynamics at an intermediate spatial scale with high spatial and temporal resolution. The rationale is that this will unify our understanding of seizure onset and spread across different spatial scales, ultimately improving our ability to localize seizures and surgically treat epilepsy. To attain the overall objective, we will record seizures in patients with refractory epilepsy using high-density subdural grids. Using this data, we will pursue the following specific aims: (1) Quantify mesoscale cortical dynamics of seizure onset and spread. (2) Develop a mesoscale mathematical model of non-uniform seizure wave propagation. Completion of these aims will provide an unprecedented view of seizure dynamics at the millimeter scale, bridging the gap in spatial scales of existing studies. This will have a positi...