Multi-scale modelling of the epileptic brain: advantages of computational therapy exploration

Abstract

Epilepsy is a complex disease spanning across multiple scales, from ion channels in neurons to neuronal circuits across the entire brain. Over the past decades, computational models have been used to describe the pathophysiological activity of the epileptic brain from different aspects. Traditionally, each computational model can aid in optimizing therapeutic interventions, therefore, providing a particular view to design strategies for treating epilepsy. As a result, most studies are concerned with generating specific models of the epileptic brain that can help us understand the certain machinery of the pathological state. Those specific models vary in complexity and biological accuracy, with system-level models often lacking biological details. Here, we review various types of computational models of epilepsy and discuss their potential for different therapeutic approaches and scenarios, including drug discovery, surgical strategies, brain stimulation, and seizure prediction. We propose that we need to consider an integrated approach with a unified modelling framework across multiple scales to understand the epileptic brain. Our proposal is based on the recent increase in computational power, which has opened up the possibility of unifying those specific epileptic models into simulations with an unprecedented level of detail. A multi-scale epilepsy model can bridge the gap between biologically detailed models, used to address molecular and cellular questions, and brain-wide models based on abstract models which can account for complex neurological and behavioral observations. With these efforts, we move toward the next generation of epileptic brain models capable of connecting cellular features, such as ion channel properties, with standard clinical measures such as seizure severity.

SCN1A Channels a Wide Range of Epileptic Phenotypes: Report of Novel and Known Variants with Variable Presentations

“…The selection of proper approaches requires characterization and understanding of pathogenic mechanisms. As a complex disease, epilepsy extends to multiple levels of pathophysiology including inherent genetic alterations in the neurotransmission machinery components or acquired lesions linked to drug or other substance toxicity, strokes or infectious diseases and traumas/injuries [ 3 ]. Channelopathies, synaptopathies and interneuronopathies, as well as epigenetic dysregulation, neurodegeneration and mitochondrial deficiencies, are some of the genetic causes of epilepsy.…”