Early Appearance and Spread of Fast Ripples in the Hippocampus in a Model of Cortical Traumatic Brain Injury

Abstract

Fast ripples (FRs; activity of >250 Hz) have been considered as a biomarker of epileptic activity in the hippocampus and entorhinal cortex; it is thought that they signal the focus of seizure generation. Similar high-frequency network activity has been produced by changing extracellular medium composition, by using pro-epileptic substances, or by electrical stimulation. Here we study the propagation of these events between different subregions of the male rat hippocampus in a recently introduced experimental model of FRs in entorhinal cortex-hippocampal slices By using a matrix of 4096 microelectrodes, the sites of initiation, propagation pathways, and spatiotemporal characteristics of activity patterns could be studied with unprecedented high resolution. To this end, we developed an analytic tool based on bidimensional current source density estimation, which delimits sinks and sources with a high precision and evaluates their trajectories using the concept of center of mass. With this methodology, we found that FRs can arise almost simultaneously at noncontiguous sites in the CA3-to-CA1 direction, underlying the spatial heterogeneity of epileptogenic foci, while continuous somatodendritic waves of activity develop. An unexpected, yet important propagation route is the propagation of activity from CA3 into the hilus and dentate gyrus. This pathway may cause reverberating activation of both regions, supporting sustained pathological network events and altered information processing in hippocampal networks. Fast ripples (FRs) have been considered as a biomarker of epileptic activity and may signal the focus of seizure generation. In a model of traumatic brain injury in the rat, FRs appear in the hippocampus within a couple of hours after an extrahippocampal, cortical lesion. We analyzed the origin and dynamics of the FRs in the hippocampus using massive electrophysiological recordings, allowing an unprecedented high spatiotemporal resolution. We show that FRs originate in distinct and noncontiguous locations within the CA3 region and uncover, with high precision, the extent and dynamics of their current density. This activity propagates toward CA1 but also backpropagates to the hilus and the dentate gyrus, suggesting activation of defined microcircuits that can sustain recurrent excitation.

Neuronal Glutamatergic Network Electrically Wired with Silent But Activatable Gap Junctions

“…Slice electrophysiology with a microelectrode array of 4096 channels. Slices of 350 mm were prepared as previously described (Ortiz et al, 2018). An hour after incubation of the slices in an air-liquid interface perfusing normal ACSF, the slices were transferred to a high-density CMOS (complementary metal-oxide-semiconductor) technology microelectrode array of 64 Â 64 microelectrodes (BioCam X, 3Brain) and were constantly perfused at 12 ml/min with oxygenated, standard ACSF at 34 6 0.5°C.…”

“…Finally, mefloquine was added to the acidic ACSF with the blockers and the slices were perfused over 45 min before three samples of 5 min each were acquired. A high-K 1 (20 mM) solution was perfused after completing the experiment to record high-voltage activity and check for the viability of the preparation (Ortiz et al, 2018).…”

“…Channels with suprathreshold activity were eliminated when they showed a Gaussian distribution of the amplitudes of the signals, as this distribution reflects noise and not spiking activity; the latter would yield a non-Gaussian distribution. Once channels that do contain spikes were selected, a reflection of the anatomy of the DG and CA3 can be traced by electrophysiological activity (Ortiz et al, 2018). Spikes were detected following these steps: (1) each signal was filtered by a high-pass filter with cutoff frequencies of 400-8000 Hz, which yields multiunit activity; and (2) the threshold (see above) is again computed from these filtered signals within a 5 ms window, each computed with 1 ms displacement.…”

Quantifying and modelling non-local information processing of associative brain regions

“…Both effects notably match what has been described in the literature 33,34 . Fast ripples 35 arise during such a beta band generating stimulus period ( Fig. S8).…”

Recent advances in the noninvasive detection of high-frequency oscillations in the human brain

“…Studies have shown that HFOs recorded using scalp EEG originate from limited cortical regions (Cuello-Oderiz et al 2017;Zelmann et al 2014). Fast ripples may be generated from regions smaller than regions that generate ripples; thus, fast ripples are less likely to be recorded on scalp EEG (Ortiz et al 2018). In the current literature, most studies on the evaluation of HFOs in epilepsy using scalp EEG have been conducted in children, with only a few conducted in adults.…”