Decoding the multimodal signatures of epileptogenic circuit alterations in grey matter heterotopia – ALTEROTOPIA

Grey matter heterotopia are rare neurodevelopmental disorders associated with abnormal cortical function and epilepsy. Affected patients typically have drug-resistant focal epilepsy and require epilepsy surgery evaluation to delineate brain regions containing networks involved in seizure generation. As these epileptogenic networks are heterogeneous and unique to each patient, treatment is very challenging and it is therefore crucial to elucidate the pathophysiological mechanisms involved.
In this project, we will use a comprehensive set of methods and integrate electrophysiological and transcriptomic data from both rodent models and human patients undergoing pre-surgical evaluation. This will allow us to correlate epilepsy-associated electrophysiological properties of anatomically and spatially identified neurons and brain regions with their underlying spatially resolved gene expression changes. Our goal is to delineate key pathophysiological mechanisms underlying epileptogenic circuit alterations in heterotopia, to identify aetiology- or patient-specific alterations that may make epileptogenic networks unique to each patient or preclinical model, and to identify novel biomarkers of epileptogenicity to guide therapy or predict outcome. Overall, this project has the potential to improve our understanding of the pathomechanisms and underlying cellular and molecular determinants of a rare disease affecting neurodevelopment, while providing valuable insights into potential personalized treatment and diagnostic strategies.