Abstracts

Rationale: Previous EEG studies found increased gamma event connectivity (GEC) outside the seizure onset zone (SOZ) in surgical patients who were not seizure free (Shamas et al. 2021). We hypothesized strong GEC could represent an increase in interneuron synchrony that controls hyperexcitability in seizure-generating brain regions. To evaluate this hypothesis, we studied putative interneuron and pyramidal cell firing in relation to GEC in patients with epilepsy.

Methods: Ten patients who were candidates for epilepsy surgery underwent diagnostic invasive EEG tests with hybrid intracranial macro- and micro-electrodes. We examined 185 microelectrodes, excluding those containing noise, that were positioned in hippocampus and entorhinal cortex. Interictal wide bandwidth recording were 71.5 ± 36.9 minutes in duration and sampled at 27 kHz. Neuronal action potentials were detected, neuronal spike trains sorted into 313 single units, and classified as interneurons (n=61) and pyramidal cells (n=252). On these same microelectrodes the continuous EEG was filtered in the gamma band (30-70 Hz) and individual high amplitude gamma events were detected. We performed phase analysis between gamma events and unit firing, and quantified rate and synchrony of unit firing during high- and low-amplitude gamma events in the SOZ and outside the SOZ (NSOZ).


Results: Most pyramidal cells (93.6%) preferentially fired at 180 degrees or the trough of the gamma event, whereas 51% of interneurons had a preferred phase at 180 degrees. In the SOZ, interneurons, but not pyramidal cells, had higher firing rates at the preferred phase versus other phases of the gamma event. Interneuron, but not pyramidal cell, synchrony of firing correlated with the strength of GEC, especially when GEC was strong (r = 0.464, p = 0.038). During high-amplitude gamma events, principal cell firing was lower in the SOZ than NSOZ (P = 0.021, Cohen’s d = 0.248), but during low-amplitude gamma, there was no difference in principal cell firing. Conversely, during low-amplitude gamma, interneuron firing was higher in the SOZ than NSOZ (P = 0.005, Cohen’s d = 1.135).


Conclusions: The single unit correlates during high-amplitude gamma events, especially with interneurons, indicate GEC includes gamma oscillatory activity. During interictal periods in brain areas capable of generating seizures, strong GEC corresponds with strong interneuron synchrony that coordinates pyramidal cell firing and regulates excitability. However, during periods when GEC weakens, interneuron firing increases, but synchrony decreases, which is less effective in controlling pyramidal cell firing. These latter periods could represent conditions when strong afferent inputs drive pyramidal cells and interneurons into abnormal patterns that generate epileptiform activity.


Funding: This study was supported by the NIH grant NS106957 (RS) , 033310 (JE) and Christina Louise George Trust.