Modern Concepts of Focal Epileptic Networks

Premysl Jiruska*,†,1; Marco de Curtis‡; John G.R. Jefferys§,¶    * Department of Developmental Epileptology, Institute of Physiology, Academy of Sciences of Czech Republic, Prague, Czech Republic
† Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague, Motol University Hospital, Prague, Czech Republic
‡ Department of Epileptology and Experimental Neurophysiology, Fondazione IRCCS, Istituto Neurologico C Besta, Milan, Italy
§ Neuronal Networks Group, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom
¶ Department of Pharmacology, University of Oxford, Oxford, United Kingdom
1 Corresponding author: email address: jiruskapremysl@gmail.com

Early experiments with topical application of convulsants and with local cortical lesions suggested that epileptic activity and seizures can be generated within a highly restricted cortical region, defined as the epileptic focus. Such foci were thought to contain populations of abnormally behaving cells (neurons and glia) that sustain a range of hyperexcitable phenomena including seizures, interictal epileptiform discharges, and pathological network oscillations. This concept was further supported by pioneering recordings and surgical resections from human brain during the early days of epilepsy surgery by Penfield and Jasper (1954). Seizures originating from the epileptic focus were termed focal seizures and the corresponding epilepsy was classified as focal epilepsy (Commission on Classification and Terminology of the International League Against Epilepsy, 1981). Focal seizures can propagate outside the focus to secondarily involve regions that are not functionally altered but are recruited by the epileptiform discharge. When discharge propagation is widespread and also involves subcortical areas, secondary generalization occurs. Altered network dynamics at the focus and local/distant effects of epileptiform activity can disrupt ongoing physiological processes and may result in neurological and cognitive deficits observed in some patients with epilepsy.

Neurobiological research in the field of epilepsy aims to identify specific structural, functional, or genetic abnormalities that can reliably explain how focal epilepsy develops (the study of epileptogenesis) and what are the main mechanisms responsible for seizure initiation (the study of ictogenesis). Advances in experimental and clinical studies brought novel insights into the cellular dynamics and network organization of the epileptic brain that question the concept of the epileptic focus. Specifically, experience from surgical treatment has shown that the concept of a restricted focus is not optimal for planning of epilepsy surgery and could be responsible for failure to achieve seizure freedom in a substantial population of patients who underwent resection. Intracranial recordings demonstrate that the region involved in the generation of seizures and interictal events often includes nonlesional areas and involves spatially distant regions within the same or different lobes. The concept of the epileptic focus was, therefore, redefined and replaced by the identification and the definition of overlapping pathological and pathophysiological zones that generate epileptiform activities: the seizure-onset zone, the irritative zone (the region that generates interictal discharges), the epileptogenic lesion, and the epileptogenic zone, the resection or disconnection of which is necessary and sufficient for seizure freedom (Kahane, Landre, Minotti, Francione, & Ryvlin, 2006; Rosenow & Luders, 2001). The importance of altered network organization in focal epilepsies was stressed by Spencer (2002) and the new classification proposal of epilepsies insists on the concept of the networks when focal epilepsies are discussed (Berg et al., 2010). More recently, the concept of “system epilepsy” was introduced (Avanzini et al., 2012) that suggests that specific networks are prone to generate seizures, possibly only when a part of the network is damaged or functionally altered. The existence of system-specific susceptibility to seizures is also supported by the demonstration that systemic applications of proconvulsive drugs selectively alter specific networks and induce interictal and ictal epileptiform patterns segregated into specific cortical systems (Boido, Jesuthasan, de Curtis, & Uva, 2014; Carriero et al., 2012).

The seeming contradiction between the concepts of epileptic focus and of epileptic networks can be reconciled when time is considered. In hypothetical terms, very localized, focal changes in excitability could in principle develop after an acute injury and the evolution of the acute damage, together with the occurrence of seizure-like discharges, may establish the later development of network changes. Acute recordings in patients with hemorrhagic strokes show that seizure patterns recorded during the acute stage differ from late seizures (Dreier et al., 2012).

The importance of the network concept was substantially bolstered by introduction into epilepsy research of approaches from the fields of complex dynamics of networks and graph theory (Chapter 6; Bullmore & Sporns, 2009; van Diessen, Diederen, Braun, Jansen, & Stam, 2013). This new and rapidly expanding mathematical field has a substantial impact on epilepsy research, and on neuroscience in general. It further demonstrates how important connectivity is for understanding the abnormal behavior generated within epileptic networks and how structural and functional connectivity can shape the epileptic phenomena (Stefan & Lopes da Silva, 2013; Wendling, Chauvel, Biraben, & Bartolomei, 2010). Experimental and clinical findings, together with the advanced use of mathematical and physical approaches in epilepsy research, revealed that epilepsy and seizures are very complex dynamical phenomena and that understanding these processes requires integrating together information from different spatial and temporal domains (Jiruska et al., 2013; Chapter 8). The importance of complexity is well demonstrated by genetic studies. Several genes have been identified within families in which epilepsy occurred across several generations (Lerche et al., 2013). However, people within families sharing the same mutations were identified but some of them did not develop epileptic phenotypes (Lerche et al., 2013). The twentieth century reductionist approach to identify specific genes responsible for diseases proved disappointing in many types of epilepsy, and it is now widely accepted that the epileptic phenotype is the result of complex interactions between genes and cellular networks within the organism, and environmental factors. In addition, development of antiepileptic drugs targeting specific mechanisms implicated in seizure initiation failed to live up to expectations and raised the possibility of much more complex mechanisms being responsible for seizures (Brodie et al., 2011). It is equally necessary to consider multiple factors and complex interactions for understanding how seizures are generated. It is well known that seizure (network) patterns observed in vivo are poorly reproduced in slices, suggesting that wider networks and more complex interactions are required to generate specific patterns of seizures.

On the local (cellular) scale, epileptiform phenomena are the result of the complex interaction between multiple neuronal subtypes. It is well known that behavior of isolated cells may substantially change when the cells are mutually connected; the pattern of connection determines the population behavior. One of the best examples comes from interneurons which, if connected into networks, generate spontaneous oscillations in the gamma band (Whittington, Traub, & Jefferys, 1995). In epilepsy, for a long time it was assumed that epileptic seizures are caused mainly by altered dynamics within the network of epileptic pyramidal neurons; this excitatory theory dominated the field of epilepsy research for decades. Traditionally, epilepsy is described as an imbalance between excitation and inhibition (Westbrook, 1991). Molecular reorganization of pyramidal cells, changes in intrinsic properties increasing neuronal excitability and newly developed pathological communication between pyramidal cells were seen as the main causes of this imbalance. The second factor of this imbalance represented weakened inhibition due to loss of specific interneurons, loss of excitatory drive onto interneurons, etc. (Pavlov, Kaila, Kullmann, & Miles, 2013; Sloviter, 1987; Vreugdenhil, Hack, Draguhn, & Jefferys, 2002). For many years, the shift of the balance between excitation and inhibition toward enhanced excitation dominated the theories on the interictal behavior within the focus and on the mechanisms responsible for initiation of seizures. Contemporary research implicates interneurons in playing more causal roles in seizure initiation and, paradoxically, has shown that intense activity of interneurons may induce complex changes that alter potassium and chloride homeostasis resulting in increased excitability, depolarization, and synchronization of principal cells and a shift brain dynamics toward the seizure (Chapter 7;...