Shokrollah S. Jahromi

Mechanisms of Morphine Enhancement of Spontaneous Seizure Activity

BACKGROUND:High-dose opioid therapy can precipitate seizures; however, the mechanism of such a dangerous adverse effect remains poorly understood. The aim of our study was to determine whether the neuroexcitatory activity of high-dose morphine is mediated by selective stimulation of opioid receptors. METHODS:Mice hippocampi were resected intact and bathed in low magnesium artificial cerebrospinal fluid to induce spontaneous seizure-like events recorded from CA1 neurons. RESULTS:Application of morphine had a biphasic effect on the recorded spontaneous seizure-like events. In a low concentration (10 &mgr;M), morphine depressed electrographic seizure activity. Higher morphine concentrations (30 and 100 &mgr;M) enhanced seizure activity in an apparent dose-dependent manner. Naloxone, a nonselective opiate antagonist blocked the proconvulsant action of morphine. Selective &mgr; and &kgr; opiate receptor agonists and antagonists enhanced and suppressed the spontaneous seizure activity, respectively. On the contrary, &dgr; opioid receptor ligands did not have an effect. CONCLUSIONS:The proseizure effect of morphine is mediated through selective stimulation of &mgr; and &kgr; opiate receptors but not the activation of the &dgr; receptor system. The observed dose-dependent mechanism of morphine neuroexcitation underscores careful adjustment and individualized opioid dosing in the clinical setting.

The effects of high-frequency oscillations in hippocampal electrical activities on the classification of epileptiform events using artificial neural networks

The existence of hippocampal high-frequency electrical activities (greater than 100 Hz) during the progression of seizure episodes in both human and animal experimental models of epilepsy has been well documented (Bragin A, Engel J, Wilson C L, Fried I and Buzsáki G 1999 Hippocampus 9 137-42; Khosravani H, Pinnegar C R, Mitchell J R, Bardakjian B L, Federico P and Carlen P L 2005 Epilepsia 46 1-10). However, this information has not been studied between successive seizure episodes or utilized in the application of seizure classification. In this study, we examine the dynamical changes of an in vitro low Mg2+ rat hippocampal slice model of epilepsy at different frequency bands using wavelet transforms and artificial neural networks. By dividing the time-frequency spectrum of each seizure-like event (SLE) into frequency bins, we can analyze their burst-to-burst variations within individual SLEs as well as between successive SLE episodes. Wavelet energy and wavelet entropy are estimated for intracellular and extracellular electrical recordings using sufficiently high sampling rates (10 kHz). We demonstrate that the activities of high-frequency oscillations in the 100-400 Hz range increase as the slice approaches SLE onsets and in later episodes of SLEs. Utilizing the time-dependent relationship between different frequency bands, we can achieve frequency-dependent state classification. We demonstrate that activities in the frequency range 100-400 Hz are critical for the accurate classification of the different states of electrographic seizure-like episodes (containing interictal, preictal and ictal states) in brain slices undergoing recurrent spontaneous SLEs. While preictal activities can be classified with an average accuracy of 77.4 +/- 6.7% utilizing the frequency spectrum in the range 0-400 Hz, we can also achieve a similar level of accuracy by using a nonlinear relationship between 100-400 Hz and <4 Hz frequency bands only.

Antiepileptic efficacy of topiramate: assessment in two in vitro seizure models.

The antiepileptic efficacy of topiramate (TPM) has been demonstrated in both whole animal seizure models and clinical trials; however, there is no consensus concerning its mechanism of action. We determined first whether the antiepileptic effect of TPM generalized to in vitro seizure models. Epileptiform discharges, recorded extracellularly, were evoked by repeated tetanic stimulation of Schaffer collaterals and layer III association fibers in entorhinal cortex/hippocampus and piriform cortex slices, respectively. TPM was applied at concentrations of 20 or 100 microM. Whole cell recordings were made from CA1 pyramidal neurons and the effect of TPM was assessed on a variety of intrinsic membrane properties including resting membrane potential, input resistance and postspike potentials. TPM (20 microM) was without effect in entorhinal cortex/hippocampus (N=6); however, 100 microM TPM decreased significantly the Coastline Burst Index from 358.3+/-65.8 to 225. 5+/-77.1 (N=4), the frequency of spontaneous epileptiform discharges to 44.6+/-21.8 (N=5) and the duration of primary afterdischarge (PAD) to 65.9+/-10.1 (N=10) percent of control. In contrast, phenytoin (50 microM, N=7; 100 microM, N=8) reduced PAD to 96.9+/-14. 8 and 86.5+/-17.3 percent of control, respectively. TPM (100 microM) did not reduce significantly the frequency of spontaneous discharges in piriform cortex (85.4+/-12.3 percent of control; N=5). TPM (100 microM) was without significant effect on intrinsic membrane properties in CA1 pyramidal neurons. Likely candidate mechanisms underlying the antiepileptic effect produced by TPM include enhancement of chloride-mediated GABA(A) currents and reduction of kainate and L-type calcium currents.

ELECTRIC CouPLING IN EPILEPTOGENESIS

One of the hallmarks of epileptiform activity is neural synchrony. There are several putative mechanisms for creating neural synchrony in a neural network including the chemical synaptic actions of decreased inhibition or increased excitation, extracellular ionic and volume shifts, and changes in electric coupling. Electric coupling includes ephaptic electrical field effects and direct interneuronal electrotonic (cable-like) coupling via gap junctions. Electric field coupling is governed by cell morphology, propagation velocity of depolarization waves, the rate of change to the transmembrane voltage, and extracellular resistivity. Such an effect can be approximately represented as a capacitative pathway via the extracellular fields. Gap junctional coupling can be represented by low resistive pathways through the adjacent connexins. ExceHeinnemann llent reviews of electrical interactions between neurons have been published.1–3

Benzodiazepine antagonists reduce epileptiform discharges in rat hippocampal slices

Summary: Purpose: The antiepileptic effects of benzodiaze‐pine‐receptor (BZR) agonists have been well documented. Surprisingly, an antiepileptic effect for the BZR antagonist, fluma‐zenil, has also been described, the mechanism of which is unknown. We investigated the effects of nanomolar concentrations of flumazenil and a structurally dissimilar BZR antagonist, propyl‐β‐carboline‐3‐carboxylate (β‐CCP), on normal synaptic responses and epileptiform discharges induced by a variety of methods in the CA1 region of rat hippocampal slices.

The cellular dynamics of spontaneous transition to seizure: More exciting than you think

in all four grades. EEGs for grade 4 records were >2.5 cps, rhythmic and had sharp/spike morphology; grade 3 records were generally less frequent (<2.5) and were either sharp, or rhythmic and nonfocal; grade 2 records were either quasirhythmic, low in frequency (2–2.5 cps) or nonfocal; grade 1 records had frequencies <2 cps. Patients with clinically definite NCSE (e.g. recovery with lorazepam treatment) had grades 4–1. These findings demonstrate that consistent constellations of EEG features can be used to classify NCSE records. These findings need to be prospectively validated, but may characterize NCSE patterns.