Macroscale and microcircuit dissociation of focal and generalized human epilepsies

Yifei Weng,Boris C Bernhardt,Guangming Lu,Lorenzo Caciagli,B T Thomas Yeo,Andrea Bernasconi,Neda Bernasconi,Qiang Xu,Zhiqiang Zhang,Raúl Rodríguez-Cruces,Reinder Vos De Wael,Sara Larivière,Jessica Royer

doi:10.1038/s42003-020-0958-5

Abstract

Thalamo-cortical pathology plays key roles in both generalized and focal epilepsies, but there is little work directly comparing these syndromes at the level of whole-brain mechanisms. Using multimodal imaging, connectomics, and computational simulations, we examined thalamo-cortical and cortico-cortical signatures and underlying microcircuits in 96 genetic generalized (GE) and 107 temporal lobe epilepsy (TLE) patients, along with 65 healthy controls. Structural and functional network profiling highlighted extensive atrophy, microstructural disruptions and decreased thalamo-cortical connectivity in TLE, while GE showed only subtle structural anomalies paralleled by enhanced thalamo-cortical connectivity. Connectome-informed biophysical simulations indicated modest increases in subcortical drive contributing to cortical dynamics in GE, while TLE presented with reduced subcortical drive and imbalanced excitation–inhibition within limbic and somatomotor microcircuits. Multiple sensitivity analyses supported robustness. Our multiscale analyses differentiate human focal and generalized epilepsy at the systems-level, showing paradoxically more severe microcircuit and macroscale imbalances in the former.

Highlights

Thalamo-cortical pathology plays key roles in both generalized and focal epilepsies, but there is little work directly comparing these syndromes at the level of whole-brain mechanisms
Biophysical simulations complemented these findings and indicated marked reductions of subcortical drive together with increases in recurrent excitation–inhibition in temporal lobe epilepsy (TLE), in limbic and frontocentral networks, while GE presented with increased subcortical drive but no changes in recurrent cortical excitation–inhibition
Findings indicated more marked anomalies in TLE relative to controls and GE, suggesting that the archetypal “focal” epilepsy is paradoxically associated with more severe whole-brain anomalies than an epilepsy syndrome electro-clinically defined by generalized seizures

Summary

Introduction

Thalamo-cortical pathology plays key roles in both generalized and focal epilepsies, but there is little work directly comparing these syndromes at the level of whole-brain mechanisms. A recent study in healthy individuals has shown that these models can make robust simulations of functional connectivity from structural connectivity, and that the model can be used to infer regional-specific microcircuit parameters, such as recurrent excitation–inhibition and external subcortical drive[22] Applying these models to epilepsy will provide a complementary and mechanistic perspective on the role of the thalamo-cortical system on cortico-cortical dynamics. To foreshadow our results, we observed more marked imaging anomalies in TLE relative to controls and GE, suggesting that this “focal” epilepsy is paradoxically associated with more severe whole-brain anomalies than an epilepsy syndrome defined by generalized seizures Biophysical simulations complemented these findings and indicated marked reductions of subcortical drive together with increases in recurrent excitation–inhibition in TLE, in limbic and frontocentral networks, while GE presented with increased subcortical drive but no changes in recurrent cortical excitation–inhibition.

Methods

Results

Conclusion