Novel diagnostic stimulation to quantify cortical excitability and guide epilepsy therapy

PROJECT SUMMARY/ABSTRACT Focal epilepsy is a network disease marked by focal areas of cortical hyperexcitability and interconnected brain regions that affect excitability. For many patients, it is challenging to accurately localize brain regions involved in seizure initiation and to determine nodes of the seizure network that affect excitability on an individual basis. We hypothesize that seizure-related brain tissue is chronically compromised and exhibits aberrant, interictal, hyperexcitability that can be interrogated dynamically using stimulation. We propose using novel stimulation- based biomarkers to develop reliable and precise estimates of seizure onset locations and related network nodes. Whereas stimulation-based biomarkers have typically utilized single pulses of electrical stimulation to map connectivity, we propose two diagnostic stimulation biomarkers which utilize multiple stimulation pulses, novel waveforms and time-varying amplitude envelopes to interrogate adaptation and inhibitory feedback. Leveraging high-channel count stimulation, we suggest a method to rapidly map modulatory network connections which could serve as implanted device targets. We utilize simultaneous single unit recordings to underpin our proposed invasive EEG biomarkers of hyperexcitability. Our aims are to: 1) Develop stimulation-based biomarkers of the seizure onset zone, 2) Identify patient- specific, modulatory network connections, and 3) Determine whether there are interictal single neuron signatures of hyperexcitability. To do this, we will use a newly developed external stimulator will allow for automated, efficient stimulation of 128-256 channels in epilepsy patients implanted with temporary invasive electrodes. Simultaneous recordings from microelectrodes will allow us to correlate single and multiunit activity with EEG activity recorded from macroelectrodes. We will examine these results within the novel mathematical framework of fractional dynamics that can link the timescales of responses to excitability. Grant outcomes will include a rapid protocol using stimulation-based interictal biomarkers to localize the seizure onset zone and identify relevant network nodes. Microelectrode recordings will provide a single/multiunit scale understanding of EEG excitability dynamics. This proposal explores the largely uncharted territory of stimulation-based biomarkers beyond single pulse electrical stimulation to improve treatment for drug-resistant epilepsy.