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4-Aminopyridine (4AP, 50 μM) induces interictal- and ictal-like discharges in brain slices including parahippocampal areas such as the entorhinal cortex (EC) but the relation between these two types of epileptiform activity remains undifined. Here, by employing field potential recordings in rat EC slices during 4AP application, we found that: (i) interictal events have a wide range of duration (0.4-3.3 s) and interval of occurrence (1.4-84 s); (ii) ictal discharges are either preceded by an isolated "slow" interictal discharge (ISID; duration=1.5 ± 0.1s, interval of occurrence=33.8 ± 1.8 s) or suddenly initiate from a pattern of frequent polispike interictal discharge (FPID; duration=0.8 ± 0.1 s; interval of occurrence=2.7 ± 0.2 s); and (iii) ISID-triggered ictal events have longer duration (116 ± 7.3s) and interval of occurrence (425.8 ± 42.3 s) than those initiating suddenly during FPID (58.3 ± 7.8 s and 202.1 ± 21.8 s, respectively). Glutamatergic receptor antagonists abolished ictal discharges in all experiments, markedly reduced FPIDs but did not influence ISIDs. We also discovered that high-frequency oscillations (HFOs, 80-500 Hz) occur more frequently during ISIDs as compared to FPIDs, and mainly coincide with the onset of ISID-triggered ictal discharges. These findings indicate that interictal events may define ictal onset features resembling those seen in vivo in low-voltage fast activity onset seizures. We propose a similar condition to occur in vivo in temporal lobe epileptic patients and animal models., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) is a promising tool for treating drug-resistant epileptic patients. Currently, the most common approach is fixed-frequency stimulation (periodic pacing) by means of stimulating devices that operate under open-loop control. However, a drawback of this DBS strategy is the impossibility of tailoring a personalized treatment, which also limits the optimization of the stimulating apparatus. Here, we propose a novel DBS methodology based on a closed-loop control strategy, developed by exploiting statistical machine learning techniques, in which stimulation parameters are adapted to the current neural activity thus allowing for seizure suppression that is fine-tuned on the individual scale (adaptive stimulation). By means of field potential recording from adult rat hippocampus-entorhinal cortex (EC) slices treated with the convulsant drug 4-aminopyridine we determined the effectiveness of this approach compared to low-frequency periodic pacing, and found that the closed-loop stimulation strategy: (i) has similar efficacy as low-frequency periodic pacing in suppressing ictal-like events but (ii) is more efficient than periodic pacing in that it requires less electrical pulses. We also provide evidence that the closed-loop stimulation strategy can alternatively be employed to tune the frequency of a periodic pacing strategy. Our findings indicate that the adaptive stimulation strategy may represent a novel, promising approach to DBS for individually-tailored epilepsy treatment., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Temporal lobe epilepsy (TLE) is a chronic epileptic disorder involving the hippocampal formation. Details on the interactions between the hippocampus proper and parahippocampal networks during ictogenesis remain, however, unclear. In addition, recent findings have shown that epileptic limbic networks maintained in vitro are paradoxically less responsive than non-epileptic control (NEC) tissue to application of the convulsant drug 4-aminopyridine (4AP). Field potential recordings allowed us to establish here the effects of 4AP in brain slices obtained from NEC and pilocarpine-treated epileptic rats; these slices included the hippocampus and parahippocampal areas such as entorhinal and perirhinal cortices and the amygdala. First, we found that both types of tissue generate epileptiform discharges with similar electrographic characteristics. Further investigation showed that generation of robust ictal-like discharges in the epileptic rat tissue is (i) favored by decreased hippocampal output (ii) reinforced by EC-subiculum interactions and (iii) predominantly driven by amygdala networks. We propose that a functional switch to alternative synaptic routes may promote network hyperexcitability in the epileptic limbic system.

Deep-brain electrical or transcranial magnetic stimulation may represent a therapeutic tool for controlling seizures in patients presenting with epileptic disorders resistant to antiepileptic drugs. In keeping with this clinical evidence, we have reported that repetitive electrical stimuli delivered at approximately 1 Hz in mouse hippocampus-entorhinal cortex (EC) slices depress the EC ability to generate ictal activity induced by the application of 4-aminopyridine (4AP) or Mg(2+)-free medium (Barbarosie, M., Avoli, M., 1997. CA3-driven hippocampal-entorhinal loop controls rather than sustains in vitro limbic seizures. J. Neurosci. 17, 9308-9314.). Here, we confirmed a similar control mechanism in rat brain slices analyzed with field potential recordings during 4AP (50 microM) treatment. In addition, we used intrinsic optical signal (IOS) recordings to quantify the intensity and spatial characteristics of this inhibitory influence. IOSs reflect the changes in light transmittance throughout the entire extent of the slice, and are thus reliable markers of limbic network epileptiform synchronization. First, we found that in the presence of 4AP, the IOS increases, induced by a train of electrical stimuli (10 Hz for 1 s) or by recurrent, single-shock stimulation delivered at 0.05 Hz in the deep EC layers, are reduced in intensity and area size by low-frequency (1 Hz), repetitive stimulation of the subiculum; these effects were observed in all limbic areas contained in the slice. Second, by testing the effects induced by repetitive subicular stimulation at 0.2-10 Hz, we identified maximal efficacy when repetitive stimuli are delivered at 1 Hz. Finally, we discovered that similar, but slightly less pronounced, inhibitory effects occur when repetitive stimuli at 1 Hz are delivered in the EC, suggesting that the reduction of IOSs seen during repetitive stimulation is pathway dependent as well as activity dependent. Thus, the activation of limbic networks at low frequency reduces the intensity and spatial extent of the IOS changes that accompany ictal synchronization in an in vitro slice preparation. This conclusion supports the view that repetitive stimulation may represent a potential therapeutic tool for controlling seizures in patients with pharmaco-resistant epileptic disorders.