Does interictal synchronization influence ictogenesis?

Abstract

The EEG recorded from epileptic patients presents with interictal discharges that are not associated with detectable clinical symptoms but are valuable for diagnostic purposes. Experimental studies have shown that interictal discharges and ictal events (i.e., seizures) are characterized intracellularly by similar (but for duration) neuronal depolarizations leading to sustained action potential firing, thus indicating that they may share similar cellular and pharmacological mechanisms. It has also been proposed that interictal discharges may herald the onset of electrographic seizures, but other studies have demonstrated that interictal events interfere with the occurrence of ictal activity. The relationship between interictal and ictal activity thus remains ambiguous. Here we will review this issue in animal models of limbic seizures that are electrographically close to those seen in TLE patients. In particular we will: (i) focus on the electrophysiological and pharmacological characteristics of, at least, two types of interictal discharge; (ii) propose that they play opposite roles in leading to ictogenesis; and (iii) discuss the possibility that mimicking one of these two types of interictal activity by low frequency repetitive stimulation can control ictogenesis. Finally, we will also review evidence indicating that specific types of interictal discharge may play a role in epileptogenesis. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'.

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

“…Activitydependent changes in excitability, pH, and gap-junction coupling should contribute to the ability of frequent interictal spiking to prevent the occurrence of seizures. In addition, in vitro evidence suggests that a main player in controlling ictogenesis might rest on the ability of recurring interictal spikes to decrease the transient elevations in extracellular potassium that, at least experimentally, appear to be instrumental for ictal discharge onset (Barbarosie et al 2002;Avoli et al 2013a).…”

“…In the first part of this report, we will review the processes that presumably initiate, sustain, and terminate a partial seizure. In the second part, we will analyze the correlation between interictal events and ictal discharges (de Curtis and Avanzini 2001;de Curtis et al 2012;Avoli et al 2013a). …”

Mechanisms of Epileptiform Synchronization in Cortical Neuronal Networks

“…Therefore, CA3-driven interictal events should insure that GABA release during the slow interictal discharge is down-regulated thus controlling the associated elevations in extracellular [K + ]. This hypothesis is further supported by experiments in which parahippocampal structures such as EC, amydala or insular cortex are stimulated at frequencies similar to those of CA3-driven interictal spikes (i.e., at 0.5-1.0 Hz) [21,67]. Clinical studies have indeed shown that low frequency stimulation -delivered through transcranial magnetic or deep-brain electrical procedures -can reduce seizures in epileptic patients not responding to conventional antiepileptic therapy [68][69][70][71].…”

“…For instance, it has been shown that cutting the Schaffer collaterals in brain slices comprising interconnected hippocampus and entorhinal cortex networks during 4AP application, abolishes the propagation of CA3-driven interictal discharges to the entorhinal cortex and discloses slow interictal spikes and seizure-like events in this structure (asterisk and continuous line in (Fig. 5A), respectively) [21,66,67]. At the same time, however, ictal discharge is often preceded (and thus presumably initiated) by a slow interictal spike generated locally (double asterisks in Fig.…”

“…These findings, and in particular the ability of CA3-driven interictal activity to control ictogenesis in parahippocal areas, have been confirmed in rat brain slices in which structures such as perirhinal or insular cortices or the amygdala remained interconnected with the hippocampus proper [21]. The ability of hippocampal outputs to control ictogenesis may also be relevant in TLE, a disorder that is associated to CA3 and CA1 subfield damage [2]; according to this view a decrease in hippocampal output activity secondary to cell damage, should facilitate the generation of ictal discharges in parahippocampal structures [21,66,67].…”