Abstracts

Rationale: Patients with epilepsy suffer from cognitive disabilities, for which interictal epileptic discharges (IEDs) have been identified as potential substrate, at least for memory deficits (1). Thereby, research on IEDs is currently under intense scrutiny (1, 2). Research centered on the primary epileptic focus has led only to a partial understanding of the mechanisms leading to IEDs’ expression, and we still have only a sparse knowledge of the influence of remote regions in the generation of focal IEDs (3). Here, we studied the immediate pre-focal IED period in the epileptic hippocampus as well as in the contralateral hippocampus of the mouse model of unilateral mesial temporal lobe epilepsy, in order to investigate whether network activity might participate in the emergence of IEDs, rather than the epileptic focus alone. Methods: We recorded 8 mice in a head-fixed set-up with one longitudinal intrahippocampal 16-contacts electrode in each hippocampus 4 weeks after kainate injection in the left dorsal hippocampus, as previously described (4, 5). We used a combination of multi-unit activity (MUA), frequency analysis and phase-locking analyses to probe the relation between both hippocampi in the immediate pre-IED period (300 ms before the IED peak). IEDs were defined as sharp dipoles (20-30 Hz) with superimposed high-frequency activity and were never found in the contralateral hippocampus. Results: An average occurrence of 7.15 IEDs/min was identified in the epileptic hippocampus (none in the contralateral hippocampus). Across different frequency bands, we discovered a sequence of activation in both hippocampi before IED. MUA increases significantly in the contralateral hippocampus and is followed by 37 msec by an increase of MUA in the epileptic hippocampus (Friedman test + Dunn’s multiple comparison test p=0.004). Then, ipsilateral MUA is followed by 63 msec by the actual IED (Friedman test + Dunn’s multiple comparison test p<0.0001). Contralateral MUA occurred as bursting activity, yet 85% of MUA bursts were actually not followed by an IED. However, we found that contralateral bursts that occurred before an IED have an increased degree of locking over the theta activity of both hippocampi (test for equal concentration parameters, p<0.0001) and were locked to a slightly different theta phase (parametric Watson-Williams multi-sample test, p<0.0001) than background MUA bursts. Conclusions: IEDs do not occur in a random background. Rather, theta-locked contralateral MUA bursts specifically occur before IED. These bursts could either be a trigger of ipsilateral IEDs, or “failed attempts” to prevent their occurrence. Further studies that manipulate the expression of these bursts will help to decipher their role in the expression of IEDs. Altogether, our work sheds light on the importance of the network in the expression of epileptic activity, and offers new opportunities for potential therapies, if distant areas are proven to participate in the expression of epileptic activities. References 1. Kleen et al. (2013) Neurology. 81, 18-24 2. Holmes and Lenck-Santini (2006) Epilepsy Behav. 8, 504–515 3. Mormann et al. (2007) Brain. 130, 314–333 4. Sheybani et al. (2018) J. Neurosci. 38, 3776–3791 5. Sheybani et al. (2019) eNeuro. 6 Funding: LS is supported by the Swiss National Science Foundation (# 323530-158125)CM is supported by the Swiss National Science Foundation (# 320030-159705), by the National Center of Competence in Research “SYNAPSY,” and by the Center for Biomedical ImagingCQ is supported by the Swiss League Against Epilepsy.