High-Resolution Multimodal Profiling of Human Epileptic Brain Activity via Explanted Depth Electrodes

Understanding neurological disorders necessitates systems-level approaches that integrate multimodal data, but progress has been hindered by limited sample availability, and the absence of combined electrophysiological and molecular data from live patients. Here, we demonstrate that intracranial stereoelectroencephalography (SEEG) electrodes used for identifying the seizure focus in epilepsy patients enable the integration of RNA sequencing, genomic variants and epigenome maps with in vivo recordings and brain imaging. Specifically, we report a method, MoPEDE (Multimodal Profiling of Epileptic Brain Activity via Explanted Depth Electrodes) that recovers extensive protein-coding transcripts, DNA methylation and mutation profiles from explanted SEEG electrodes matched with electrophysiological and radiological data allowing for high-resolution reconstructions of brain structure and function in human patients. Our study shows that epilepsies of different aetiologies have distinct molecular landscapes and identify transcripts correlating with neurophysiological signals, including immediate early genes, inflammation markers, and axon guidance molecules. Additionally, we identify DNA methylation profiles indicative of transcriptionally permissive or restrictive chromatin states. While gene expression gradients corresponded with the assigned epileptogenicity index, we found outlier molecular fingerprints in some electrodes, potentially indicating seizure generation or propagation zones not detected during electroclinical assessments. These findings validate that RNA profiles, genetic variation and genome-wide epigenetic data from explanted SEEG electrodes offer high-resolution surrogate molecular landscapes of brain activity. Our transformative MoPEDE approach has the potential to enhance diagnostic decisions and deepen our understanding of epileptogenic network processes in the human brain.