Local Generation of Fast Ripples in Epileptic Brain

Abstract

Aperiodic high-frequency oscillations (Ͼ100 Hz) reflect a shortterm synchronization of neuronal electrical activity. It has been shown in the epileptic brain that spontaneous oscillations in the frequency range of 250-600 Hz reflect action potential population bursts of synchronously discharging neuronal clusters. These oscillations occur in the early stages of epileptogenesis in areas adjacent to the brain lesion and may trigger the formation of seizure-generating neuronal networks. We studied the extent of the area generating oscillations in the frequency range of 250-600 Hz [fast ripples (FRs)] in intrahippocampal kainic acid-treated rats with spontaneous seizures, by analyzing voltage versus depth profiles of FRs in hippocampal and parahippocampal areas in freely moving animals and by spatial mapping in hippocampal slice preparations in vitro. The strength of inhibition was compared in areas with and without FRs using a paired-pulse paradigm. The extent of the areas generating FRs did not exceed 1 mm 3 . The areas generating FRs became broader after the application of the GABA A receptor antagonist bicuculline. Paired-pulse fast inhibition at 15-30 msec intervals was similar in areas generating FRs and areas not generating FRs. Our data illustrate that hypothesized clusters of highly interconnected neurons are capable of overcoming interneuron feedback inhibition, resulting in generation of epileptiform bursts, eventually leading to seizure activity.

Mechanisms of physiological and epileptic HFO generation

“…In this scenario, each fast ripple cycle reflects a population spike created by firing from individual neurons but not all neurons contribute to consecutive cycles similarly, hence the emergent character. Such conditions are met very locally so that fast ripples are shown to be confined to small areas of about 1 mm 3 (Bragin et al, 2002a;Crepon et al, 2010;Draguhn et al, 1998;Jiruska et al, 2010a). Thus, HFOs in the form of fast ripples (250-800 Hz) can be brought about locally by both precise and loose firing, which successfully explains the large range of frequencies recorded in situ in epileptic rodents and humans.…”

“…2D). Fast ripples appear to correlate with reduced hippocampal volumes and neuronal loss both in human TLE (Ogren et al, 2009;Staba et al, 2007) and in experimental models (Bragin et al, 2002a;, but can occur in the absence of neuronal death (Jiruska et al, 2010b). Here too, different recruitment delays of several pools of neurons determine a sequential out-of-phase activation resulting in the emergent extracellular fast ripple oscillations.…”

“…The shape and voltage depth profiles of pathological HFOs recorded in the dentate gyrus were similar to the shape and voltage depth profiles of population spikes evoked by perforant path stimulation . On the basis of these and other data it was hypothesized that pathological HFOs reflect spontaneous bursts of population spikes as a result of synchronous discharges of principal cells each of which fires at a lower frequency than the ensemble (Bikson et al, 2003a;Bragin et al, 2002aBragin et al, , 2007Foffani et al, 2007;Ibarz et al, 2010;Jiruska et al, 2010a). Areas generating pathological HFOs are not homogeneously distributed within brain areas and, on the basis of animal studies, a hypothesis was suggested that pathological HFOs are generated by pathologically interconnected neuron clusters or PIN clusters (Bragin et al, 2000(Bragin et al, , 2002a.…”

Generation of physiological and pathological high frequency oscillations: the role of perisomatic inhibition in sharp-wave ripple and interictal spike generation

“…In the case of IIS, the excitatory buildup is much quicker most probably as a result of increased excitability, and increased excitatory synaptic transmission that is only countered by a weakened inhibition. Therefore, PVBCs will receive excitation that drives them into depolarization block (and their already weakened transmission breaks down due to strong short-term depression), resulting in an uncontrolled burst firing in all PCs [22,70]. The similarities between these phenomena suggests that IIS are degenerate forms of SWR and, as concluded previously [4], "epileptic events hijack normal circuitry".…”

Epilepsy: A Review of Selected Clinical Syndromes and Advances in Basic Science

“…Bottom (2): Examples of extracelullarly recorded fast ripples occurring simultaneously in dentate gyrus (top) and entorhinal cortex (bottom) in a rat with chronic kainate-induced epilepsy. Reproduced with permission from Bragin et al (2002). the role of the hippocampus, giving rise to a 'hippocampocentric' perspective (Sloviter, 2005).…”