Human seizures self-terminate across spatial scales via a critical transition

Abstract

Why seizures spontaneously terminate remains an unanswered fundamental question of epileptology. Here we present evidence that seizures self-terminate via a discontinuous critical transition or bifurcation. We show that human brain electrical activity at various spatial scales exhibits common dynamical signatures of an impending critical transition-slowing, increased correlation, and flickering-in the approach to seizure termination. In contrast, prolonged seizures (status epilepticus) repeatedly approach, but do not cross, the critical transition. To support these results, we implement a computational model that demonstrates that alternative stable attractors, representing the ictal and postictal states, emulate the observed dynamics. These results suggest that self-terminating seizures end through a common dynamical mechanism. This description constrains the specific biophysical mechanisms underlying seizure termination, suggests a dynamical understanding of status epilepticus, and demonstrates an accessible system for studying critical transitions in nature.critical slowing down | epilepsy | electrocorticogram | local field potential A lthough extensive observations and research have elucidated some mechanism of seizure initiation and maintenance, how seizures spontaneously terminate remains one of the most important, but still unanswered, questions in epileptology (1). Some of the potential mechanisms of seizure termination (2) include glutamate depletion (3), dynamic changes in ion concentrations (4-6), persistent activation of a hyperpolarization-activated cation conductance (7), changing synaptic effectiveness (5, 8), modulatory effects from subcortical structures and the cerebellum (9), and reduced pH (10). Together, these studies suggest distinct pathways to seizure termination through specific biophysical mechanisms.We propose here a dynamical understanding of seizure termination that encompasses and constrains these and other hypothesized biophysical mechanisms. Specifically, we propose that focal seizures with secondary generalization terminate in a manner consistent with crossing a critical transition or bifurcation in which the system traverses a critical threshold and shifts suddenly to an alternative, attracting dynamical regime (11). Such regime shifts between alternative stable states have been described in many real-world systems (12-14) and exhibit a repertoire of early warning indicators (15-17). The seizing brain provides a unique living system for studying the signatures of an impending critical transition as well as one in which interventions can have profound practical import.We characterize the features of seizure termination in both multiscale in vivo data from patients with epilepsy and a computational model of cortical field activity. We show that population electrical activity-observed at macroscopic spatial scales-exhibits numerous signatures of an impending critical transition, whereas spatially localized recordings of neural spiking activity possess different dynamics. These insi...

Pathophysiology of status epilepticus

“…Status epilepticus can be considered as repetitive approaching and then retreating from the critical transition. This results in a decrease in the frequency of mean power and an increase in autocorrelation followed by the converse [23]. Such variation may explain the cyclical nature of the EEG and clinical manifestations of status epilepticus that have been described [24].…”

“…Indeed, effective treatment of status epilepticus seems to promote spatial synchronization prior to status epilepticus termination. This has led to a further examination of seizure dynamics prior to seizure termination, which found increased spatial and temporal synchronization, slowing of the frequency of mean power and flickering (fluctuations between ictal and post-ictal EEG variance values, measured over small, 50 ms, intervals) [23]. These observations have led to the concept that there is a critical transition from an ictal to a post-ictal state (Fig.…”

Initiation, Propagation, and Termination of Partial (Focal) Seizures

“…Large amplitude activity synchronized in time and in space represented by large amplitude bursts typically develops at the end of a partial seizure, strongly suggesting that synchroniza-tion of excitation may be involved in seizure termination (Topolnik et al 2003;Jiruska et al 2013). Resynchronization of intracranial signals during the late seizure phase was shown in human partial seizures (Wendling et al 2003;Schindler et al 2007b), suggesting that networks are fragmented at seizure onset and merge during seizure progression, to form a single dominant component before seizure termination (Kramer et al 2012).…”

Predicting the onset of period-doubling bifurcations in noisy cardiac systems

“…early warning signals | period-doubling bifurcations | cardiac arrhythmias | dynamical systems T he development of early warning signals to predict the onset of transitions in complex systems is relevant in diverse contexts (1), including climate change (2,3), ecology (4,5), population dynamics (6)(7)(8), physiology (9,10), and finance (11). Anticipating the onset of these transitions remains challenging.…”