High-Frequency Network Activity, Global Increase in Neuronal Activity, and Synchrony Expansion Precede Epileptic SeizuresIn Vitro

Abstract

How seizures start is a major question in epilepsy research. Preictal EEG changes occur in both human patients and animal models, but their underlying mechanisms and relationship with seizure initiation remain unknown. Here we demonstrate the existence, in the hippocampal CA1 region, of a preictal state characterized by the progressive and global increase in neuronal activity associated with a widespread buildup of low-amplitude high-frequency activity (HFA) (Ͼ100 Hz) and reduction in system complexity. HFA is generated by the firing of neurons, mainly pyramidal cells, at much lower frequencies. Individual cycles of HFA are generated by the near-synchronous (within ϳ5 ms) firing of small numbers of pyramidal cells. The presence of HFA in the low-calcium model implicates nonsynaptic synchronization; the presence of very similar HFA in the high-potassium model shows that it does not depend on an absence of synaptic transmission. Immediately before seizure onset, CA1 is in a state of high sensitivity in which weak depolarizing or synchronizing perturbations can trigger seizures. Transition to seizure is characterized by a rapid expansion and fusion of the neuronal populations responsible for HFA, associated with a progressive slowing of HFA, leading to a single, massive, hypersynchronous cluster generating the high-amplitude low-frequency activity of the seizure.

Mechanisms of physiological and epileptic HFO generation

“…Many of them rely on blocking GABA A receptor mediated inhibition with drugs such as picrotoxin, bicuculline or penicillin (Dingledine and Gjerstad, 1979;Schwartzkroin and Prince, 1978). Convulsant treatments which do not block inhibition include 4-aminopyridine (Avoli et al, 1996;D'Antuono et al, 2002;Rutecki et al, 1987), elevated K + (Jiruska et al, 2010a;Rutecki et al, 1985;Traub and Dingledine, 1990) and low Mg 2+ (Anderson et al, 1986;Derchansky et al, 2008). Another acute and realistic model in vivo is brain trauma, which leads to electrographic seizures in the majority of animals (Topolnik et al, 2003).…”

“…Reducing extracellular Ca 2+ close to zero results in a seizure-like activity lasting tens of seconds despite the absence of chemical synaptic transmission (Jefferys and Haas, 1982;Jiruska et al, 2010a). In this situation the prolonged bursts are primarily synchronized on a slow time scale by transient increases in extracellular K + (Bikson et al, 2003b;Yaari et al, 1983) and on a faster time scale by ephaptic or field effect interactions (Frohlich and McCormick, 2010;Jefferys, 1995).…”

“…However, the possibility remains that pHFOs have a causal role in, for instance, ictogenesis, which would have conceptual importance and could have an impact in developing improved treatments. The progressive expansion of the spatial extent of HFO clusters before low-Ca 2+ seizure like events (Jiruska et al, 2010a) suggests that a causal role is conceivable.…”

“…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.…”

“…A study of CA3 in elevated extracellular K + argues for a role for intrinsic burst firing characteristic of CA3 pyramidal cells (Dzhala and Staley, 2004). Seizure-like events, or "field bursts", in the lowCa 2+ model start with HFOs extending into the fast ripple band, which represent the collective activity of multiple clusters of neurons firing at lower frequencies (Bikson et al, 2003a;Jiruska et al, 2010a) (see Section 5.3 below). A common theme from all these studies in vitro is that HFOs arise when neuronal networks are hyperexcitable, but they can do so through several distinct mechanisms.…”