Phase-amplitude coupling and epileptogenesis in an animal model of mesial temporal lobe epilepsy

Polyrhythmic coupling of oscillatory components in electrophysiological signals results from the interactions between neuronal sub-populations within and between cell assemblies. Since the mechanisms underlying epileptic disorders should affect such interactions, abnormal level of cross-frequency coupling is expected to provide a signal marker of epileptogenesis. We measured phase-amplitude coupling (PAC), a form of cross-frequency coupling between neural oscillations, in a rodent model of mesial temporal lobe epilepsy. Sprague-Dawley rats (n = 4, 250-300 g) were injected with pilocarpine (380 mg/kg, i.p) to induce a status epilepticus (SE) that was stopped after 1 h with diazepam (5 mg/kg, s.c.) and ketamine (50 mg/kg, s.c.). Control animals (n = 6) did not receive any injection or treatment. Three days after SE, all animals were implanted with bipolar electrodes in the hippocampal CA3 subfield, entorhinal cortex, dentate gyrus and subiculum. Continuous video/EEG recordings were performed 24/7 at a sampling rate of 2 kHz, over 15 consecutive days. Pilocarpine-treated animals showed interictal spikes (5.25 (±2.5) per minute) and seizures (n = 32) that appeared 7 (±0.8) days after SE. We found that CA3 was the seizure onset zone in most epileptic animals, with stronger ongoing PAC coupling between seizures than in controls (Kruskal-Wallis test: chi2 (1,36) = 46.3, Bonferroni corrected, p < 0.001). Strong PAC in CA3 occurred between the phase of slow-wave oscillations (<1 Hz) and the amplitude of faster rhythms (50-180 Hz), with the strongest bouts of high-frequency activity occurring preferentially on the ascending phase of the slow wave. We also identified that cross-frequency coupling in CA3 (rho = 0.44, p < 0.001) and subiculum (rho = 0.41, p < 0.001) was positively correlated with the daily number of seizures. Overall, our study demonstrates that cross-frequency coupling may represent a signal marker in epilepsy and suggests that this methodology could be transferred to clinical scalp MEG and EEG recordings.