Goodman, R. R. | bioRxiv Science

bioRxiv2021

Human interictal epileptiform discharges are traveling waves reflecting ictal self-organization

Interictal epileptiform discharges (IEDs), also known as interictal spikes, are large intermittent electrophysiological events observed between seizures in patients with epilepsy. Though they occur far more often than seizures, IEDs are less studied, and their relationship to seizures remains unclear. To better understand this relationship, we examined multi-day recordings of microelectrode arrays implanted in human epilepsy patients, allowing us to precisely observe the spatiotemporal propagation of IEDs, spontaneous seizures, and how they relate. These recordings showed that the majority of IEDs are traveling waves, traversing the same path as ictal discharges during seizures, and with a fixed direction relative to seizure propagation. Moreover, the majority of IEDs, like ictal discharges, were bidirectional, with one predominant and a second, less frequent antipodal direction. These results reveal a fundamental spatiotemporal similarity between IEDs and ictal discharges. These results also imply that most IEDs arise in brain tissue outside the site of seizure onset and propagate toward it, indicating that the propagation of IEDs provides useful information for localizing the seizure focus.

neuroscience↗

bioRxiv2020

Neuronal firing and waveform alterations through ictal recruitment in humans

AO_SCPLOWBSTRACTC_SCPLOWClinical analyses of neuronal activity during seizures, invariably using extracellular recordings, is greatly hindered by various phenomena that are well established in animal studies: changes in local ionic concentration, changes in ionic conductance, and intense, hypersynchronous firing. The first two alter the action potential waveform, whereas the third increases the "noise"; all three factors confound attempts to detect and classify single neurons (units). To address these analytical difficulties, we developed a novel template-matching based spike sorting method, which enabled identification of 1,239 single units in 27 patients with intractable focal epilepsy, that were tracked throughout multiple seizures. These new analyses showed continued neuronal firing through the ictal transition, which was defined as a transient period of intense tonic firing consistent with previous descriptions of the ictal wavefront. After the ictal transition, neurons displayed increased spike duration (p < 0.001) and reduced spike amplitude (p < 0.001), in keeping with prior animal studies; units in non-recruited territories, by contrast, showed more stable waveforms. All units returned to their pre-ictal waveforms after seizure termination. Waveshape changes were stereotyped across seizures within patients. Our analyses of single neuron firing patterns, at the ictal wavefront, showed widespread intense activation, and commonly involving marked waveshape alteration. We conclude that the distinction between tissue that has been recruited to the seizure versus non-recruited territories is evident at the level of single neurons, and that increased waveform duration and decreased waveform amplitude are hallmarks of seizure invasion that could be used as defining characteristics of local recruitment. SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWAnimal studies consistently show marked changes in action potential waveform during epileptic discharges, but acquiring similar evidence in humans has proved difficult. Assessing neuronal involvement in ictal events is pivotal to understanding seizure dynamics and in defining clinical localization of epileptic pathology. Using a novel method to track neuronal firing, we analyzed microelectrode array recordings of spontaneously occurring human seizures, and here report two dichotomous activity patterns. In cortex that is recruited to the seizure, neuronal firing rates increase and waveforms become longer in duration and shorter in amplitude, while penumbral tissue shows stable action potentials, in keeping with the "dual territory" model of seizure dynamics.

neuroscience↗

bioRxiv2019

A theoretical model for focal seizure initiation, propagation, termination, and progression

We developed a neural network model that can account for the major elements common to human focal seizures. These include the tonic-clonic transition, slow advance of clinical semiology and corresponding seizure territory expansion, widespread EEG synchronization, and slowing of the ictal rhythm as the seizure approaches termination. These were reproduced by incorporating usage-dependent exhaustion of inhibition in an adaptive neural network that receives global feedback inhibition in addition to local recurrent projections. Our model proposes mechanisms that may underline common EEG seizure onset patterns and status epilepticus and postulates a role for synaptic plasticity in emergence of epileptic foci. Complex patterns of seizure activity and bi-stable seizure evolution end-points arise when stochastic noise is included. With the rapid advancement of clinical and experimental tools, we believe that this can provide a roadmap and potentially a testbed for future explorations of seizure mechanisms and clinical therapies.

neuroscience↗