Three-dimensional surface maps link local atrophy and fast ripples in human epileptic hippocampus

Abstract

Objectives: There is compelling evidence that pathological high-frequency oscillations (HFOs), called fast ripples (FR, 150-500Hz), reflect abnormal synchronous neuronal discharges in areas responsible for seizure genesis in patients with mesial temporal lobe epilepsy (MTLE). It is hypothesized that morphological changes associated with hippocampal atrophy (HA) contribute to the generation of FR, yet there is limited evidence that hippocampal FR-generating sites correspond with local areas of atrophy.

Methods: Interictal HFOs were recorded from hippocampal microelectrodes in 10 patients with MTLE. Rates of FR and ripple discharge from each microelectrode were evaluated in relation to local measures of HA obtained using 3-dimensional magnetic resonance imaging (MRI) hippocampal modeling.

Results: Rates of FR discharge were 3 times higher in areas of significant local HA compared with rates in nonatrophic areas. Furthermore, FR occurrence correlated directly with the severity of damage in these local atrophic regions. In contrast, we found no difference in rates of ripple discharge between local atrophic and nonatrophic areas.

Interpretation: The proximity between local HA and microelectrode-recorded FR suggests that morphological changes such as neuron loss and synaptic reorganization may contribute to the generation of FR. Pathological HFOs, such as FR, may provide a reliable surrogate marker of abnormal neuronal excitability in hippocampal areas responsible for the generation of spontaneous seizures in patients with MTLE. Based on these data, it is possible that MRI-based measures of local HA could identify FR-generating regions, and thus provide a noninvasive means to localize epileptogenic regions in hippocampus.

Figure 1

Interictal high frequency oscillations recorded from microelectrodes in the human hippocampus. (A) Coronal post-implant MRI (left) showing depth electrode positioned in left temporal lobe orthogonal to lateral surface of temporal bone. Note that the area of signal dropout is larger than the actual size of the depth electrode. Right, magnification of the distal end of depth electrode showing microelectrode bundle extending beyond the tip (black arrow), and positioned in the head of the hippocampus. (B) Low pass (600Hz) filtered trace of consecutive FR discharges recorded from a different microelectrode positioned in the ipsilateral anterior hippocampus of one patient. To the right of this trace are results of the power spectral density (PSD) analysis using bandpass filtered FR (60–600Hz) recorded on the same microelectrode that shows normalized individual FR power (gray lines) and mean power (thick black line). FR (n=194) recorded from this site had peak power corresponding to frequencies greater than 200Hz (mean peak, 279 Hz) (C) Examples of low pass filtered Ripples recorded from a microelectrode positioned in the contralateral anterior hippocampus of a different patient. Results of PSD analysis (right) indicate Ripples (n=193) recorded on this microelectrode had mean peak power centered on 105 Hz.

Figure 2

3D Hippocampal Surface Modeling. (A) The hippocampus is traced manually in consecutive coronal MRI slices. From the hippocampal tracings, a 3D hippocampal model (B) is constructed. The medial curve (represented in green) threads through the hippocampus longitudinally, connecting hippocampal centers of mass. (C) The distance from the medial curve to the hippocampal surface (radial distance) is measured at each hippocampal surface point and mapped onto the surface model in a color-coded manner. (D) Following electrode localization in 3D space, the distance from each microelectrode tip to the hippocampal surface is measured, and surface points within 5mm of the tip were selected for subsequent analyses. Shown is an example of one microelectrode and corresponding surface area directly above outlined in black. Remote areas outlined in black correspond with other microelectrodes not shown.

Figure 3

Probability or P maps depicting the distribution of statistically significant hippocampal atrophy in MTLE patients. Areas colored white and red indicate regions where patient hippocampi are significantly smaller than control hippocampi (ANOVA p < 0.05). Cooler colors (e.g. green and blue) indicate regions without atrophy relative to control hippocampi (ANOVA p > 0.05). Ipsilateral ("Ipsi", left column) P maps display significant local atrophy in many areas on superior and inferior surfaces. Overall, the distribution of atrophy was statistical significant (p < 0.01). Contralateral ("Contra", right column) P maps show a few isolated areas of atrophy, but when corrected for multiple comparisons, contralateral atrophy was not significant (p = 0.07).

Figure 4

HFO maps depicting rates of FR and Ripple occurrence (events per minute) in hippocampi of ten patients (18 microelectrode recording sites) with MTLE. Maps of sites ipsilateral ("Ipsi") to seizure onset reflect HFO data recorded from 10 microelectrodes, and contralateral ("Contra") maps include HFO data from 8 microelectrodes. Hotter colors (e.g. red and orange) represent higher rates of occurrence, whereas cooler colors (e.g. blue and green) indicate regions where rates of occurrence are lower. (A) Fast Ripple (FR) maps show a greater number of recording sites with high rates of FR occurrence in ipsilateral compared to contralateral hippocampi. In contrast, Ripple maps (B) show more sites with low rates of Ripple occurrence in ipsilateral hippocampi than in contralateral hippocampi. Note that the position of microelectrodes in the contralateral hippocampus overlapped to a greater extent compared to microelectrode placements in the ipsilateral hippocampus.