High-resolution multimodal profiling of human epileptic brain activity via explanted depth electrodes.

The availability and integration of electrophysiological and molecular data from the living brain is critical in understanding and diagnosing complex human disease. Intracranial stereo electroencephalography (SEEG) electrodes used for identifying the seizure focus in patients with epilepsy could enable the integration of such multimodal data. Here, we report multimodal profiling of epileptic brain activity via explanted depth electrodes (MoPEDE), a method that recovers extensive protein-coding transcripts, including cell type markers, DNA methylation, and short variant profiles from explanted SEEG electrodes matched with electrophysiological and radiological data allowing for high-resolution reconstructions of brain structure and function. We found gene expression gradients that corresponded with the neurophysiology-assigned epileptogenicity index but also outlier molecular fingerprints in some electrodes, potentially indicating seizure generation or propagation zones not detected during electroclinical assessments. Additionally, we identified DNA methylation profiles indicative of transcriptionally permissive or restrictive chromatin states and SEEG-adherent differentially expressed and methylated genes not previously associated with epilepsy. Together, these findings validate that RNA profiles and genome-wide epigenetic data from explanted SEEG electrodes offer high-resolution surrogate molecular landscapes of brain activity. The MoPEDE approach has the potential to enhance diagnostic decisions and deepen our understanding of epileptogenic network processes in the human brain.