Emergent Dynamics of Fast Ripples in the Epileptic Hippocampus

Abstract

Fast ripples are a type of transient high-frequency oscillations recorded from the epileptogenic regions of the hippocampus and the temporal cortex of epileptic humans and rodents. These events presumably reflect hypersynchronous bursting of pyramidal cells. However, the oscillatory spectral content of fast ripples varies from 250 to 800 Hz, well above the maximal firing frequency of most hippocampal pyramidal neurons. How such high-frequency oscillations are generated is therefore unclear. Here, we combine computational simulations of fast ripples with multisite and juxtacellular recordings in vivo to examine the underlying mechanisms in the hippocampus of epileptic rats. We show that populations of bursting cells firing individually at 100 -400 Hz can create fast ripples according to two main firing regimes: (1) in-phase synchronous firing resulting in "pure" fast ripples characterized by single spectral peaks that reflect single-cell behavior and (2) out-of-phase firing that results in "emergent" fast ripples. Using simulations, we found that fast ripples generated under these two different regimes can be quantitatively separated by their spectral characteristics, and we took advantage of this separability to examine their dynamics in vivo. We found that in-phase firing can reach frequencies up to 300 Hz in the CA1 and up to 400 Hz in the dentate gyrus. The organization of out-of-phase firing is determined by firing delays between cells discharging at low frequencies. The two firing regimes compete dynamically, alternating randomly from one fast ripple event to the next, and they reflect the functional dynamic organization of the different regions of the hippocampus.

Mechanisms of physiological and epileptic HFO generation

“…Juxtacellular recordings revealed bursts of action potentials aligned with individual fast ripple cycles (Ibarz et al, 2010) and with large population spikes (Bragin et al, 2011). However, a poor correlation between the firing frequency of individual cells and the dominant spectral peak in the local EEG confirms that fast ripples emerge as a network phenomenon and that single cells rarely fire faster than 400 Hz.…”

“…Analysis of voltage depth profiles of pathological HFOs in the kainic acid model showed that the maximum of their amplitude and the location of their sinkssources (Ibarz et al, 2010) were in the cellular layers of the dentate gyrus or of CA1 area of hippocampus. Discharges of identified granular (Bragin et al, 2011) and pyramidal cells are phase locked with troughs of locally recorded pathological HFOs.…”

“…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.…”

“…Intriguingly, single pyramidal cells from these slices were found to fire similarly but less precisely than cells recorded from slices prepared from a normal animal, suggesting that less precise bursting correlate in this case with faster and more disorganized HFO power spectra . It was later shown that populations of bursting cells firing individually at 100-400 Hz can create fast ripples according to two main firing regimes: (1) in-phase synchronous firing resulting in fast ripples characterized by single spectral peaks that reflect single-cell behavior and (2) out-of-phase firing that results in emergent fast ripples at a broader frequency band (Ibarz et al, 2010) (see also Bikson et al, 2003a;Jiruska et al, 2010a). 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.…”

“…However, a poor correlation between the firing frequency of individual cells and the dominant spectral peak in the local EEG confirms that fast ripples emerge as a network phenomenon and that single cells rarely fire faster than 400 Hz. This leads to the out-ofphase cluster hypothesis that suggest that independent pools of cells fire in concert but outof-phase with each other thus contributing to the higher frequency of fast ripples (Bikson et al, 2003a;D'Antuono et al, 2005;Foffani et al, 2007;Ibarz et al, 2010;Jiruska et al, 2010a).…”