Human periventricular nodular heterotopia shows several interictal epileptic patterns and hyperexcitability of neuronal firing

Abstract

Periventricular nodular heterotopia (PNH) is a malformation of cortical development that frequently causes drug-resistant epilepsy. The epileptogenicity of ectopic neurons in PNH as well as their role in generating interictal and ictal activity is still a matter of debate. We report the first in vivo microelectrode recording of heterotopic neurons in humans. Highly consistent interictal patterns (IPs) were identified within the nodules: (1) Periodic Discharges PLUS Fast activity (PD+F), (2) Sporadic discharges PLUS Fast activity (SD+F), and (3) epileptic spikes (ES). Neuronal firing rates were significantly modulated during all IPs, suggesting that multiple IPs were generated by the same local neuronal populations. Furthermore, firing rates closely followed IP morphologies. Among the different IPs, the SD+F pattern was found only in the three nodules that were actively involved in seizure generation but was never observed in the nodule that did not take part in ictal discharges. On the contrary, PD+F and ES were identified in all nodules. Units that were modulated during the IPs were also found to participate in seizures, increasing their firing rate at seizure onset and maintaining an elevated rate during the seizures. Together, nodules in PNH are highly epileptogenic and show several IPs that provide promising pathognomonic signatures of PNH. Furthermore, our results show that PNH nodules may well initiate seizures.

Keywords: epilepsy; human; in vivo; interictal; microelectrode; periventricular nodular heterotopia; seizure.

Figure 1

Electrode implantation into the PNH nodules and interictal LFP patterns. (A, D, G, J) Brain MRI showing the electrode trajectories, exploring the four analyzed nodules (A, Patient 1, Nodule 1; D and G, Patient 2, Nodules 2 and 3; J, Patient 3, Nodule 4). (B, E, H, K) Schematic representation of the macro–microelectrodes (M1–M4: macroelectrode contacts; μ1–μ8: microelectrodes). All the geometrical features of the electrodes are expressed in millimeters. Macroelectrode recordings (C, F, I, L) are shown in a bipolar montage. Three LFP patterns were recorded: periodic discharge plus fast activity (PD+F), sporadic discharges plus fast activity (SD+F), and epileptic spikes (ES). These patterns were apparent on microelectrodes (LFP μ1 and μ2) and to a smaller degree also on macroelectrodes (M1–M2). LFP patterns were associated with MUA recorded on the microelectrodes.

Figure 2

Local field potentials (LFP) and time–frequency spectra of the interictal patterns. Each row represents one nodule, with every panel/column an interictal pattern, indicated by the panel title. The amplitude of the LFP is scaled per nodule and displayed on the far-right y-axis of every row. The average time–frequency representations (60 Hz−200 Hz) are expressed in percentage change from the baseline period, indicated by the color bar in every panel. Insets show the average power spectra during the peak activity of every pattern, indicated by a horizontal bar above the x-axis. The dotted lines in the inset show peak frequency and % power increased versus baseline. Note that due to the fact that these values are averaged over a time segment, the percentage change is lower than indicated in the time–frequency plots.

Figure 3

Statistical analysis of firing rate responses during the IPs. Each row represents the firing responses of one unit, shown with a firing rate histogram centered on the onset of IP, above the respective raster plot. The yellow color indicates significant increases and the blue color decreases compared with the average firing rate during baseline (indicated in the x-axis). Two units are shown for every nodule (three patients). Panel titles indicate an interictal pattern. Note that each unit (row) shows significant modulation in every pattern. Inset shows 100 examples of action potential spikes, overlaid with their average spike waveform in white.

Figure 4

Unit firing behavior during seizures. Two representative seizures originating from Nodule 1 (A) to Nodule 4 (C), respectively. The ictal activity from two adjacent contacts of the macroelectrode (M1–M2, M2–M3, bipolar montage) is reported together with that obtained from two different microelectrodes (μ1 and μ2). The microelectrode activity is then shown as LFP and MUA activity. TRaster plot, time-locked to seizure onset, for Nodule 1 (B) and Nodule 4 (D). In the raster plot, different shades of gray denote different units. Each line of the raster plot shows the unit's behavior during a seizure. The first line in the raster plot corresponds to the seizure shown above. Note that the units are the same as those analyzed for IEDs, here showing that they are also recruited during seizures.