General Anesthetic-induced Seizures Can Be Explained by a Mean-field Model of Cortical Dynamics

GENERAL anesthesia is a state in which cerebral activity is usually profoundly suppressed. It is paradoxical that some general anesthetic agents—drugs whose primary action is to decrease central nervous system activity and that have been widely used to treat seizures—can also provoke cortical seizures when the patient is deeply anesthetized. Traditionally, the explanation for this phenomenon has been sought at a molecular or synaptic level of description, by finding differences between general anesthetic drugs that commonly precipitate seizure activity and those drugs that do not cause seizures. It has been suggested that proconvulsant drugs (such as enflurane) may (1) act to decrease the amplitude of miniature inhibitory postsynaptic currents or (2) elicit greater calcium-induced presynaptic mobilization of excitatory neurotransmitters than anticonvulsant drugs (such as isoflurane or thiopentone). These descriptions are qualitative. Are these observations of true causative mechanisms of seizure genesis, or are they simply observations of epiphenomena? It is not clear exactly how these observations at synaptic and molecular scales would quantitatively result in repetitive synchronous widespread burst firing of cortical neurons—the signature of seizure activity. In this article, we describe a mathematical model of cerebral cortical function (the so-called mean-field model). In our model, we are able to input the known molecular-scale effects of anesthetic drugs and see how they alter the output (a “pseudoencephalogram”) of the computer-simulated “pseudocortex.” We incorporate the values of inhibitory postsynaptic potential (IPSP) amplitude and duration that have been previously published and studied in detail for isoflurane and enflurane, and we compare the output from simulations run on our theoretical mathematical model with various experimental and clinical observations that have been previously reported in the scientific literature. We find that subtle changes in the shape of the IPSP—induced by enflurane—are sufficient to cause the model of the cerebral cortex to undergo a sudden change in behavior from a general anesthetic state (in which neuronal firing is suppressed) into a seizure-like state—manifest as oscillation between neuronal silence and supramaximal neuronal firing. We use the example of enflurane-induced seizures as a dramatic demonstration of the application of mean-field models of cortical dynamics to link molecular and macroscopic descriptions of nervous system phenomena.