Resilience through diversity: Lost neuronal heterogeneity in human epilepsy renders networks vulnerable to synchronous transitions

A myriad of pathological changes associated with epilepsy, including the loss of specific cell types, improper ion channel expression, and synaptic sprouting, can all be recast as decreases in cell and circuit heterogeneity. We thus 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. By comparing patch clamp recordings from human layer 5 (L5) cortical neurons from epileptogenic frontal lobe (from patients with epilepsy) to non-epileptogenic temporal lobe (from patients with epilepsy) and non-epileptogenic frontal lobe (obtained during tumor resection), we demonstrate significantly decreased biophysical heterogeneity of excitatory neurons in seizure generating areas (epilepetogenic zone). When implemented computationally, this experimentally observed decrease in heterogeneity renders model neural circuits prone to sudden dynamical transitions into synchronous states with increased firing activity, paralleling ictogenesis. Computational analysis of reduced neural heterogeneity also explains the surprising experimental finding of significantly decreased excitability in the population activation functions (i.e., FI curves) of neurons from epileptogenic tissue. Mathematical analyses based in mean-field theory reveal clear distinctions in the dynamical structure of networks with low and high heterogeneity, including the presence of multi-stability and saddle-node bifurcations only in networks with the lowest heterogeneity. Taken together, this work provides experimental, computational, and mathematical support for the theory that ictogenic dynamics accompany a reduction in biophysical heterogeneity.