Commentary: 2016 Epilepsia Basic Science Prize

Electrical stimulation applied directly to the brain to control seizures is a technology with a long history. Neurostimulation has been applied to key nodes of presumed epileptogenic circuits (as with stimulation of the anterior nucleus of the thalamus, a node in the limbic circuit of Papez), and directly to the brain regions thought to give rise to seizures (as with responsive neurostimulation). In both cases, large clinical trials have shown efficacy, but in both cases the benefit for the large majority of individuals is incremental and not curative. Although the technology holds out the promise of restraining seizures and modulating ictal circuits without tissue ablation, the success rate of direct brain neurostimulation in controlling seizures at present is much lower than that of ablative surgery; and neurostimulation is reserved for cases where ablative surgery is not feasible or would produce unacceptable deficits. The current generation of neurostimulation devices, then, has succeeded in delivering worthwhile and consistent benefit. Realizing the fullest potential of neurostimulation, however, requires additional advances and insights. Deep brain electrical stimulation (DBS) was developed as a nonlesional treatment for Parkinson disease (PD) that was initially thought to be equivalent to a “reversible lesion. ” However, current hypotheses on the mechanism of DBS now focus instead on the effects of stimulation on the activity pattern in the network of interconnected nuclei comprising the extrapyramidal motor system. Application of neurostimulation to control seizures has been even more challenging. Compared to PD, where common pathology and circuits are shared between individuals, the localization and pathology of epileptogenic brain tissue vary enormously. Optimal targets for controlling seizures must be investigated and identified for each individual, and often are incompletely known. Epilepsy may also be—at least in part —a “network disease,” where seizures can arise from a distributed network of interconnected neurons. How then, should neurostimulation for epilepsy be tailored to individuals? Where should stimulation be applied; and what stimulation parameters should be used for optimal seizure control? Answering these questions may require reconceptualizing the mechanism of action of stimulation by examining dynamics and interactions of biologic oscillators. As a result of network interactions, stimulation applied at a precise moment in the oscillatory cycle can disrupt synchronized oscillators, or conversely, stimulation at critical frequencies can entrain unsynchronized oscillators (see the seminal work of AT Winfree, for example). The selection for the 2016 Epilepsia Basic Science Prize, “Should stimulation parameters be individualized to stop seizures: Evidence in support of this approach” by Sobayo and Mogul, is a valuable step in the development of the next generation of neurostimulation devices. Sobayo and Mogul provide both a specific, testable algorithm for optimization of stimulation parameters; and perhaps even more importantly, they offer a proof-of-concept that modifying seizure network dynamics using multisite stimulation tuned to the individual’s unique network may be more effective than current methods. Sobayo and Mogul hypothesized that seizure-stopping electrical stimulation would be more effective if the spatial and temporal pattern of stimulation replicated the spatial and temporal pattern of activity in the epileptic network at seizure termination. They began by making multisite recordings of spontaneous and evoked seizures from rats rendered epileptic following lithium-pilocarpine status epilepticus. Recording electrodes were placed bilaterally in the hippocampi and in the left anteromedial nucleus of the thalamus. The investigators showed that as spontaneous or evoked seizures ended, the electroencephalography (EEG) activity across the recording sites became synchronized at a reproducible, characteristic frequency unique to each rat. Indeed, the dynamics—that is, the spatial and temporal pattern of activity—of seizure discharges near termination were similar for spontaneous and evoked seizures, indicating that network dynamics, not mode of seizure onset, dominated seizure termination. The investigators then applied electrical stimulation at the “target” frequency determined from seizure recordings. Multisite stimulation at the Wiley Periodicals, Inc. © 2017 International League Against Epilepsy