Neural Networks in Human Epilepsy: Evidence of and Implications for Treatment

Abstract

A considerable amount of compelling evidence exists, predominantly from animal models and experimental paradigms, for the existence of specific cortical and subcortical networks in the genesis and expression of partial- and generalized-onset seizures (1–13). My goal is to present the concept of human epilepsy as a disorder of large neural networks and to support through several lines of reasoning how applicable the observations from experimental models are to localization-related seizures in the human disorder. I do not attempt to define specifically every possible operational human network or even all the limits or components of those that I do address, but I hope to show in a compelling way that the evidence we already have is not consistent with any other explanation. This is a new way of understanding, diagnosing, and potentially treating the various forms of human epilepsy. In this context, I consider a network to be a functionally and anatomically connected, bilaterally represented, set of cortical and subcortical brain structures and regions in which activity in any one part affects activity in all the others. The essential operational component of this definition is the observation that vulnerability to seizure activity in any one part of the network is influenced by activity everywhere else in the network, and that the network as a whole is responsible for the clinical and electrographic phenomena that we associate with human seizures. Implicit in this idea is that the seizures may entrain this large neural network from any given part, such that it becomes irrelevant to discuss the "onset" of seizures in any specific part of the network. In other words, the electrical hyperexcitability associated with seizure activity reverberates within the neural structures of the network, which operate together and inextricably to culminate in the eventual expression of seizures. A singular concept is the distinction between the anatomic structures involved in seizure propagation, and those belonging to the neural network that underlies a specific patient's epilepsy. The network structures are connected functionally and structurally; they are essential to the development of the seizure and thus the existence and maintenance of the epileptic disorder. Independently, seizures propagate in a variably extensive way that might involve any region or neural structure with anatomic connections to the primary seizure network; seizures can propagate to many more regions than those that are involved in the network. Important corollaries that derive from these ideas are that interruption of the network, in a structural sense, or modification of network activity by electrical, biochemical, or metabolic influences in any part of the network will alter seizure expression or its occurrence. The corollaries have the greatest implications for treatment, as we will see later. Based on extensive experience with a great number and diversity of human epilepsy patients with intractable seizures, I describe and support the evidence for three specific large human epilepsy networks. Many others are likely, but the data are not so extensive. The first is the network associated with the most common human intractable epilepsy, and the one about which we have the most information: the medial temporal/limbic network. The medial temporal/limbic network is bilateral, cortical, and subcortical, and includes the hippocampi, the amygdalae, the entorhinal cortices, lateral temporal neocortices, and extratemporal components of the medial thalamus and the inferior frontal lobes. The other two networks are less commonly identified, even in their component parts: the medial occipital/lateral temporal network and the superior parietal/medial frontal network. Two additional networks, for which evidence is highly suggestive, but which I do not discuss in detail, include the bifrontal/pontine/subthalamic network and the parietal/medial temporal network. The lines of evidence that support the existence and importance of these networks in the genesis of human epilepsy are clinical observations, intracranial EEG, functional neuroimaging, anatomic observations, and the response of seizures to specific invasive treatments. Intracranial EEG is the most significant of the observations that support the network hypothesis. Because the entire network participates in the expression of the seizure activity and can be entrained from any of its various parts, initial electrical events (at "seizure onset") may vary in their specific location of expression and occurrence within the network. The initial area of apparent seizure involvement is not really an onset area, because "onset" could be expressed any place in the network, and might even vary from seizure to seizure in a given patient. This locational variability may produce different morphologies of "seizure onset" when EEG recording is performed in only one part of the network (14–19). 1-4 are examples of several se