Dynamic Mechanisms of Neocortical Focal Seizure Onset

Recent experimental and clinical studies have provided diverse insight into the mechanisms of human focal seizure initiation and propagation. Often these findings exist at different scales of observation, and are not reconciled into a common understanding. Here we develop a new, multiscale mathematical model of cortical electric activity with realistic mesoscopic connectivity. Relating the model dynamics to experimental and clinical findings leads us to propose three classes of dynamical mechanisms for the onset of focal seizures in a unified framework. These three classes are: (i) globally induced focal seizures; (ii) globally supported focal seizures; (iii) locally induced focal seizures. Using model simulations we illustrate these onset mechanisms and show how the three classes can be distinguished. Specifically, we find that although all focal seizures typically appear to arise from localised tissue, the mechanisms of onset could be due to either localised processes or processes on a larger spatial scale. We conclude that although focal seizures might have different patient-specific aetiologies and electrographic signatures, our model suggests that dynamically they can still be classified in a clinically useful way. Additionally, this novel classification according to the dynamical mechanisms is able to resolve some of the previously conflicting experimental and clinical findings.Author Summary: According to the WHO fact sheet, epilepsy is a neurological disorder affecting about 50 million people worldwide. Even today 30% of epilepsy patients do not respond well to drug therapies. Neocortical focal epilepsy is a particular type of epilepsy in which drug treatments fail and surgical success rate is low. Hence, research is essential to improve the treatment of this type of epilepsy. Recent advances in brain recording methods have led to new observations regarding the nature of neocortical focal epilepsy. However, some of the observations appear to be contradictory. Here, we develop a computational modelling framework that can explain the different observations as different aspects of possible mechanisms that can all lead to seizure onset. Specifically, we classify three main conditions under which focal seizure onset can happen. This classification is clinically important, as our model predicts different treatment strategies for each class. We conclude that focal seizures are diverse, not only in their electrographic appearance and aetiology, but also in their onset mechanism. Combined multiscale recordings as well as stimulation studies are required to elucidate the onset mechanism in each patient. Our work provides the first classification of possible onset mechanism.