Different mechanisms of ripple-like oscillations in the human epileptic subiculum

Abstract

Objective: Transient high-frequency oscillations (HFOs; 150-600Hz) in local field potentials generated by human hippocampal and parahippocampal areas have been related to both physiological and pathological processes. The cellular basis and effects of normal and abnormal forms of HFOs have been controversial. This lack of agreement is clinically significant, because HFOs may be good markers of epileptogenic areas. Better defining the neuronal correlate of specific HFO frequency bands could improve electroencephalographic analyses made before epilepsy surgery.

Methods: Here, we recorded HFOs in slices of the subiculum prepared from human hippocampal tissue resected for treatment of pharmacoresistant epilepsy. With combined intra- or juxtacellular and extracellular recordings, we examined the cellular correlates of interictal and ictal HFO events.

Results: HFOs occurred spontaneously in extracellular field potentials during interictal discharges (IIDs) and also during pharmacologically induced preictal discharges (PIDs) preceding ictal-like events. Many of these events included frequencies >250Hz and so might be considered pathological, but a significant proportion were spectrally similar to physiological ripples (150-250Hz). We found that IID ripples were associated with rhythmic γ-aminobutyric acidergic and glutamatergic synaptic potentials with moderate neuronal firing. In contrast, PID ripples were associated with depolarizing synaptic inputs frequently reaching the threshold for bursting in most pyramidal cells.

Interpretation: Our data suggest that IID and PID ripple-like oscillations (150-250Hz) in human epileptic hippocampus are associated with 2 distinct population activities that rely on different cellular and synaptic mechanisms. Thus, the ripple band could not help to disambiguate the underlying cellular processes.

Figure 1

A. Extracellular recording from a representative human subicular slice where ictal-like activity was induced by convulsants. Spontaneous interictal (IID) and preictal discharges (PID) could be differentiated by their amplitudes (left plot for data shown in traces; inset shows mean group comparisons). B. Examples of interictal and preictal discharges associated with ripple-like oscillations (IID-ripples and PID-ripples, respectively). Both time-frequency plots and the power spectral densities show a narrow band component around 200 Hz. Note also spectral bleeding of multi-unit activity at >400 Hz C. Power spectrum of all individual events from 83 slices/26 patients. Events are organized by the ripple index, and only those with a well-defined narrow peak at 100-250 Hz were selected. D. Averaged power spectra over all events show similar distributions of frequency components for both IID-ripples and PID-ripples.

Figure 2

A. Raster plots of spike responses from two different cells during IID-ripples and PID-ripples with corresponding peri-event histograms (PSTH, bin size, 10 ms). They demonstrate two different firing dynamics underlying oscillations of the same frequency (~200 Hz). During IID-ripples, firing of Cell 1 is suppressed while that of Cell 2 is unchanged. In contrast, PID-ripples are associated with bursting activity in both cells. Firing probabilities (gray-scale maps and average PSTH at the bottom) show PID-ripples are often associated with bursts, whereas IID-ripples could be associated with either decreased or increased neuronal firing. B. Representative traces show cell spike responses phase-locked to one or more cycles of field oscillations. C. The proportion of firing cells (left) and mean firing rate (right, p<0.0001) are significantly different during IID-ripples and PID-ripples. D. Spike-field coherence shows a major modulation of spikes by the field at 100-250 Hz for both IID-ripples and PID-ripples. Inset shows grouped data on spike-field coherence at 100-250Hz expressed at a log-scale.

Figure 3

A. Membrane potential behaviors of two different cells during IID-ripples and PID-ripples. Potential changes over a range of ±5 mV are shown in color. During IID-ripples, Cell 1 tended to recieve IPSPs, whereas Cell 2 tended to exhibit EPSPs. During PID-ripples both cells recieved EPSPs. The average membrane potential from all cells (color maps and average peri-event traces, bottom) shows a diversity of synaptic activity associated with IID-ripples. In contrast, during PID-ripples membrane potentials mostly reflect depolarization. B. Different examples of simultaneous intracellular and field recordings show IPSP (top) or EPSP (middle and bottom) sequences in intracellular potentials were synchronous with field oscillations. C. The percentage of synaptic events (IPSPs, subthreshold EPSPs, EPSPs leading to burst or no change) shows IPSPs are more expressed during IID-ripples and EPSPs leading to bursts are dominant for PID-ripples. D. Intracellular-field coherence shows that subthreshold membrane potentials and LFPs synchronize below 250 Hz, with significant tuning for IID-ripples at about 200 Hz. Inset shows group data on spike-field coherence at 100-250Hz expressed in log

Figure 4

A. Correlation between mean subthreshold membrane potential for each cell and the proportion of ripple-like oscillations recorded in the local field potential. B. Correlation between mean membrane potential deflections and spectral complexity.