Elsevier

Neurobiology of Disease

Volume 114, June 2018, Pages 111-119
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2018.02.008Get rights and content

Highlights

  • An electrophysiology signal marker of epileptogenicity is proposed.

  • It measures phase-amplitude coupling between slow and fast post-synaptic activity.

  • The strength of such coupling is positively correlated with seizure frequency.

  • This marker is specific of the seizure onset zone.

Abstract

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.

Introduction

Mesial temporal lobe epilepsy (MTLE) is a focal epileptic disorder characterized by recurrent seizures arising from limbic structures such as the hippocampus, the amygdala or entorhinal cortex (Spencer and Spencer, 1994; Salanova et al., 1994; Engel, 1996; Gloor, 1997). Seizures occur following a latent period of several years after an initial brain insult such as status epilepticus (SE), traumatic brain injury, encephalitis or febrile convulsions (Cendes et al., 1993; French et al., 1993). Approximately one-third of MTLE patients are unresponsive to antiepileptic drugs (Jallon, 1997; Wiebe et al., 2001; Engel et al., 2012): MTLE is one of the most refractory forms of focal epilepsy. Surgical resection of the epileptic tissue remains the only therapeutic alternative (Salanova et al., 1994; Wiebe, 2004; Blume and Parrent, 2006; Engel et al., 2012), provided that the seizure onset zones (SOZ) are correctly localized. The identification of the SOZ is challenging, in particular since it is mainly obtained from inter-ictal electrophysiological data. Therefore, the present study emphasizes the possible role of cross-frequency coupling between oscillatory components of neural signal as a signal marker of epilepsy.

Cross-frequency coupling is a phenomenon of inter-dependence between brain rhythms of different frequencies. It has been observed in multiple preparations in rodents and humans, using a variety of electrophysiology techniques, from invasive recordings to scalp magnetoencephalography and source imaging (Canolty and Knight, 2010; Florin and Baillet, 2015; Baillet, 2017). Phase-amplitude coupling (PAC) is a type of cross-frequency coupling where the phase of slow oscillations modulates the amplitude of faster rhythms (Tort et al., 2010). Invasive recordings in rodent models and epileptic patients revealed that PAC was stronger in the seizure onset zones (Amiri et al., 2016; Nariai et al., 2011; Weiss et al., 2013; Ibrahim et al., 2014; Guirgis et al., 2015; Weiss et al., 2016), and during the pre-ictal and ictal phases (Colic et al., 2013; Alvarado-Rojas et al., 2014; Zhang et al., 2017).

We used here the pilocarpine animal model of MTLE (Curia et al., 2008) to investigate the possible association between expressions of PAC and ictogenesis in temporal lobe regions. We measured PAC between the phase of slow oscillations (slow-wave in the delta band: 0.18–4 Hz) and the amplitude of faster rhythms (beta to ripple band: 20–250 Hz) in controls and in pilocarpine-treated rats. Our results indicate a strong association between PAC signal markers (coupling strength and phase) and seizure activity in temporal lobe regions in this rodent model of MTLE.

Section snippets

Animal preparation

The methods for animal preparation have been described in detail previously (Behr et al., 2015, Behr et al., 2017; Lévesque et al., 2011, Lévesque et al., 2012; Salami et al., 2014). All procedures were approved by the Canadian Council on Animal Care and the Institutional Animal Care Committee of McGill University. Every effort was made to minimize the number of animals used and their suffering.

Male Sprague-Dawley rats (250–300 g; Charles-River (St-Constant, QC, Canada)) were let habituate for

Seizures and interictal spikes

Pilocarpine-treated animals showed recurrent spontaneous seizures, on average 7 (±0.8) days after SE. The definition of the seizure onset zone was based on a total of 32 seizures recorded across all animals. As previously reported (Lévesque et al., 2012), CA3 was involved as a seizure onset zone in most cases across all epileptic animals (CA3 = 7, CA3+ = 7, CA3− = 3, widespread = 15, Fig. 2A). We collected a maximum of 7 seizures per day per animal in the epileptic group. The seizures occurred

Discussion

Our study emphasizes multiple aspects of NREM sleep polyrhythmic activity in the seizure onset zone, in the pilocarpine animal model of MTLE: 1) at all recording sites, we confirmed the expression of PAC: the amplitude of fast oscillations above 20 Hz was modulated by the phase of an underlying slow wave below 4 Hz; 2) this coupling was stronger in the CA3 region of epileptic animals compared to controls; 3) PAC strength in CA3 was positively correlated with the number of seizures per day; and

Conflict of interest

None of the authors has any conflict of interest to disclose.

Acknowledgments

The authors thanks Dr. Charles Behr for his help in surgical preparation of the animals used in this study that was supported by the Canadian Institutes of Health Research (CIHR grants 8109 and 74609 to M.A.). S.S. acknowledges the support from McGill University Integrated Program in Neuroscience. S.B. was supported a Discovery Grant from the National Science and Engineering Research Council of Canada (436355-13), the NIH (2R01EB009048-05) and a Platform Support Grant from the Brain Canada

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