PMC

Flow diagram of the dysfunctional mechanisms leading to LVF and HYP seizure onset. Experimental evidence taken into account for providing the mechanisms involved in LVF seizure onset was provided in the following studies: , , , , , , , , and . Data identifying the mechanisms leading to HYP seizure onset originate from the following studies: , Derchanski et al. 2006, , and .

Analysis of high-frequency oscillations (HFOs) occurring before and during LVF and HYP seizures in pilocarpine-treated epileptic rats. A: left, recordings from the CA3 region of a pilocarpine-treated rat during an LVF seizure. The signal is shown in the wideband, ripple (80–200 Hz) and fast ripple (250–500 Hz) frequency range. Note the occurrence of a ripple (boxed dotted portion of the trace) with no co-occurrence of a fast ripple. Right, recording from CA3 during an HYP seizure in a pilocarpine-treated animal. Note in this case the occurrence of a fast ripple (boxed dotted portion of the trace). B: temporal distribution of HFOs recorded during 18 LVF seizures in pilocarpine-treated animals. Note that ripples predominate over fast ripples, especially after seizure onset. C: temporal distribution of HFOs recorded during 21 HYP seizures in pilocarpine-treated animals. Note the high occurrence of fast ripples compared with ripples. Rates of ripples and fast ripples were compared using nonparametric Wilcoxon signed-rank tests followed by Bonferroni-Holm corrections for multiple comparisons (*P < 0.05). Data were obtained during the experiments published by Lévesque et al. (2012)

Optogenetic activation of interneurons or principal cells leads to LVF or HYP ictal discharges, respectively. A: a, LVF-onset ictal discharges occurring spontaneously during bath application of 4-aminopyridine (top) and during parvalbumin-positive interneuron light stimulation (bottom); one event under each condition is further expanded to reveal the onset pattern. Stimuli were 1 s long and delivered at 0.2 Hz for 30 s. Note that, in both spontaneous and stimulated events, the ictal discharge is preceded by one or two negative-going interictal field potentials (arrows). b, Plots of the average rate of ripples and fast ripples occurring during spontaneous (top) and optogenetically stimulated (bottom) ictal discharges (n = 10 events were used for both plots). Note that ripple rates are significantly higher than fast ripple rates at the onset of both LVF discharges (*P < 0.01). B: a, spontaneous LVF ictal discharges occurring during bath application of 4-aminopyridine are shown in the top while those induced by optogenetic stimulation of calcium/calmodulin-dependent protein kinase II-positive principal cells are shown on the bottom; light pulses were 20 ms long and were delivered at 2 Hz for 30 s; note that this procedure triggers ictal discharges preceded by repeated spiking (arrows), a pattern that is characteristic of HYP-onset events. b, Plots of the average rate of ripples and fast ripples occurring during spontaneous (top) and optogenetically stimulated (bottom) ictal discharges; note that the stimulated HYP events are characterized by higher fast ripple rates at onset. Ten events were used for both plots (*P < 0.01). Data were obtained from the experiments published by , ).

Electrographic features of low-voltage fast (LVF) and hypersynchronous (HYP) seizure onsets in humans (A) as well as in in vivo (B) and in vitro (C) experimental models. Traces shown in A were obtained from hippocampal recordings performed during presurgical intracranial monitoring with depth macroelectrodes in a patient with a focal cortical dysplasia of the temporal lobe (trace on left) and in a patient with malformation (i.e., altered rotation) of the hippocampus that was associated with hippocampal sclerosis verified on magnetic resonance and histological examinations (trace on right). The asterisk in the LVF sample identifies the single, “sentinel” spike that can occur at onset, whereas asterisks in the HYP sample highlight the initial series of large-amplitude spikes at ∼1 Hz; note in this case that spikes at a similar frequency (arrowheads) reappear during the initial part of the seizure. Traces in B were recorded from the CA3 area of the hippocampus in a pilocarpine-treated epileptic rat; note that both types of seizure onsets could be recorded from the same animal; asterisks identify specific EEG events as described for the recordings shown in A. Traces in C were obtained from experiments performed with rat brain slices maintained in vitro and bathed in medium containing 4-aminopyridine; the LVF seizure-like onset shown on the left was recorded from the medial entorhinal cortex, whereas the HYP seizure on the right was obtained from the perirhinal cortex; these in vitro recordings were performed with DC amplifiers, and thus seizure-like discharges are associated with robust negative-going shifts. Traces shown in A were kindly provided by Dr. Stefano Francione and Dr. Laura Tassi of the Claudio Munari Epilepsy Surgery Center (Milan, Italy).

Field, extracellular K⁺ concentration ([K⁺]_o), and intracellular recordings obtained in vitro during LVF-onset seizure-like dischargers. A: simultaneous field (Field) and intracellular (−68 mV) recordings obtained from the entorhinal cortex of a rat brain slice during bath application of 4-aminopyridine; in this and the following panels the dotted lines indicate the resting membrane potential of the neuron recorded intracellularly. Traces shown in the inset were obtained from a different neuron during active depolarization with intracellular current from a resting membrane potential at approximately −62 mV. B: field and [K⁺]_o activities recorded during application of 4-aminopyridine from the deep layers of the rat entorhinal cortex; the dotted line indicates the [K⁺]_o base level. C: simultaneous field and intracellular (−65 mV) recordings obtained from a principal cell in the entorhinal cortex during the perfusion of 50 μM bicuculline for 3 min in the in vitro isolated guinea pig brain. The spectrogram on the top illustrates the fast activity at around 20 Hz at the onset of the seizure-like event. The fast activity occurring at the onset of the seizure-like discharge is expanded in the inset where the principal cell was depolarized by intracellular injection of steady current. D: field and intracellular recordings of the response induced by lateral olfactory tract stimulation in an entorhinal cortex neuron with a resting membrane potential of −60 mV. Note that the brief inhibitory postsynaptic potentials (IPSPs) that correlate to the fast activity oscillations have reversal potentials similar to what is seen with the lateral olfactory tract-evoked IPSP. E: simultaneous field and intracellular recordings from a principal cell in the perirhinal cortex of a rat brain slice during bath application of 4-aminopyridine; note that ictal discharge onset is characterized by preictal spiking acceleration as well as that both interictal (arrow) and “preictal” discharges consist of depolarizations with action potential bursts followed by a hyperpolarizing potential that progressively decreases in amplitude (arrowheads) and coincides with more intense action potential bursting. F: simultaneous field and [K⁺]_o recordings obtained in the deep layers of the perirhinal cortex during 4-aminopyridine application. Note the progressive increases in [K⁺]_o that accompany the preictal spikes up to ictal discharge initiation that coincide with values larger than 6.3 mM. Data were obtained during experiments that have been published by , ), , , , and ), , and .