Resilience through diversity: Loss of neuronal heterogeneity in epileptogenic human tissue impairs network resilience to sudden changes in synchrony

Abstract

A myriad of pathological changes associated with epilepsy can be recast as decreases in cell and circuit heterogeneity. We propose that epileptogenesis can be recontextualized as a process where reduction in cellular heterogeneity renders neural circuits less resilient to transitions into information-poor, over-correlated seizure states. We provide in vitro, in silico, and mathematical support for this hypothesis. Patch clamp recordings from human layer 5 (L5) cortical neurons demonstrate significantly decreased biophysical heterogeneity of excitatory neurons in seizure generating areas (epilepetogenic zone). This decreased heterogeneity renders model neural circuits prone to sudden dynamical transitions into synchronous, hyperactive states (paralleling ictogenesis) while also explaining counter-intuitive differences in population activation functions (i.e., FI curves) between epileptogenic and non-epileptogenic tissue. Mathematical analyses based in mean-field theory reveal clear distinctions in the dynamical structure of networks with low and high heterogeneity, providing the theoretical undergird for how ictogenic dynamics accompany a reduction in biophysical heterogeneity.