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A key question in epilepsy is the organization and size of the neuronal networks necessary for generating seizures. Hypotheses include: a single focal neuronal network drives seizure discharges across the brain, which may or may not be identical with the circuits that generate interictal spikes; or multiple neuronal networks link together in re-entrant loops or other long-range networks. It remains unclear whether any of these hypotheses apply to spontaneous seizures in freely moving animals. We used the tetanus toxin chronic model of epilepsy to test the different predictions made by each hypothesis about the propagation and interaction of epileptic discharges during seizures. Seizures could start in either the injected or noninjected dorsal hippocampus, suggesting that seizures have multifocal onsets in the tetanus toxin model. During seizures, individual bursts propagated in either direction, both between the right and left dorsal hippocampi, and between CA3 and the dentate gyrus in the same hippocampus. These findings argue against one site "driving" seizures or seizures propagating around a limbic loop. Specifically, the side leading each burst switched a median of three times during the first 20 s of a seizure. Analysis of bursts during seizures suggested that the network at each recording site acted like a neuronal oscillator. Coupling of population spikes in right and left CA3 increased during the early part of seizures, but the cross-correlation of their whole-discharge waveforms changed little over the same period. Furthermore, the polarity of the phase difference between population spikes did not follow the phase difference for complete discharges. We concluded that the neuronal aggregate necessary for seizures in our animals comprises multiple spatially distributed neuronal networks and that the increased synchrony of the output (population spike firing) of these networks during the early part of seizures may contribute to seizure generation.

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The dentate gyrus is thought to be a key area in containing the spread of seizure discharges in temporal lobe epilepsy. We investigated whether it actively contributes to the transition to seizure in vivo using the tetanus toxin chronic experimental epilepsy. Brief epileptic discharges lasted <2 s in freely moving animals and were clearly distinguishable from spontaneous seizures that lasted tens of seconds. This suggested that the changes underpinning the transition to seizure started within the first few seconds of seizure onset. During this period, we found that the amplitude of dentate gyrus population spikes depressed initially, but from 1.1 s after seizure onset, they potentiated. The amplitude and number of CA3 population spikes paralleled the pattern found in the dentate gyrus. We used hippocampal slices to study dentate filtering in more detail. The perforant pathway was stimulated repetitively at the frequency of field postsynaptic potentials found during epileptic discharges in vivo. The amplitude of dentate gyrus population spikes decreased to a steady state in naïve hippocampal slices. In hippocampal slices prepared from rats previously injected with tetanus toxin, population spike amplitude decreased transiently and then potentiated. We found that the biphasic profile and rate of potentiation of dentate population spikes in vivo can be reproduced in naïve hippocampal slices by blocking GABA(B) receptors. We conclude that the filtering properties of the dentate gyrus are altered in the tetanus toxin model of epilepsy and propose how this contributes to the transition to seizure in our animals.

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Cortical maps express experience-dependent plasticity. However, the underlying cellular mechanisms remain unclear. We have recently shown that sensory deprivation results in large changes of the short-term dynamics of excitatory synapses at the junction of deprived and spared somatosensory (barrel) cortex, which may contribute to map reorganization. A key issue is whether the alterations in short-term synaptic dynamics are driven by a loss of sensory input or by competition between deprived and spared inputs. Here, we report that short-term dynamics of horizontal pathways in the middle of uniformly deprived cortex change only modestly. Vertical intracortical pathways were unaffected by deprivation. Our results suggest that uniform loss of sensory activity has a limited effect on short-term synaptic dynamics. We concluded that competition between sensory inputs is necessary to produce large-scale changes in synaptic dynamics after sensory deprivation.

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Unilateral intrahippocampal injection of tetanus toxin results in a chronic syndrome of intermittent epileptic seizures. During some of these seizures, rats develop a stereotypic, pathological motor behavior that indicates secondary generalization of epileptic activity. We report that secondary generalization was preceded by a 9-16 Hz oscillation of field potentials which was synchronized between the right and left dorsal hippocampi. The oscillation was associated with increased synchrony of population spike firing in right and left CA1 subregions which form the major output of the hippocampi. Cutting the ventral commissure abolished synchrony across the hippocampi and reduced the probability that the 9-16 Hz activity would be followed by secondary generalization. We concluded that a bilaterally synchronous 9-16 Hz hippocampal oscillation played a role in the secondary generalization of focal seizures in this chronic model of limbic epilepsy.

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Many representations of sensory stimuli in the neocortex are arranged as topographic maps. These cortical maps are not fixed, but show experience-dependent plasticity. For instance, sensory deprivation causes the cortical area representing the deprived sensory input to shrink, and neighbouring spared representations to enlarge, in somatosensory, auditory or visual cortex. In adolescent and adult animals, changes in cortical maps are most noticeable in the supragranular layers at the junction of deprived and spared cortex. However, the cellular mechanisms of this experience-dependent plasticity are unclear. Long-term potentiation and depression have been implicated, but have not been proven to be necessary or sufficient for cortical map reorganization. Short-term synaptic dynamics have not been considered. We developed a brain slice preparation involving rat whisker barrel cortex in vitro. Here we report that sensory deprivation alters short-term synaptic dynamics in both vertical and horizontal excitatory pathways within the supragranular cortex. Moreover, modifications of horizontal pathways amplify changes in the vertical inputs. Our findings help to explain the functional cortical reorganization that follows persistent changes of sensory experience.

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Anatomical advances have led to a reappraisal of the organization of hippocampal circuitry. However, it is not clear whether the functional connectivity is fully determined by the anatomical connectivity or whether it is significantly modified by feed-forward inhibition and modulatory inputs. Therefore, we have mapped CA1 responses evoked by stimulation of ipsilateral and contralateral CA3 in vivo. Population spike amplitude and threshold were plotted to produce response maps. All CA3 subregions projected diffusely to ipsilateral CA1. However, a pattern of maximal response emerged. Caudal CA3 stimulation evoked the maximal responses septally, while rostral CA3 responses were maximal temporally. The ipsilateral CA3 response maps were compared with those produced by stimulation at the homotopic point in the contralateral CA3. The CA1 areas of maximal functional connectivity were the same implying that there is convergence of the input to CA1 from homotopic CA3 sites in the two hippocampi. Although a response in CA1 was evoked widely, our results suggest that the functional connectivity is ordered, within and between the dorsal hippocampi, and that it is consistent with the recent anatomical data. The present findings allow more precise study of the propagation of normal and abnormal neuronal activity, within and between the dorsal hippocampi. Information on the site and speed of propagation of neuronal activity would be necessary for the development of a physiologically realistic model of hippocampal computation.

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Carbamazepine (CBZ) is a widely used antiepileptic drug (AED). Recently, a chewable tablet (Tegretol chewtabs) has been formulated. This open substitution study was designed to compare the two formulations with respect to efficacy and tolerability in patients with intractable epilepsy. Thirty patients (24 males, 6 females, mean age 46 years, range 28-83) were studied. Duration of epilepsy was 21-68 years (median 34 years). Four patients were taking CBZ monotherapy, 17, 6 and 3 patients were respectively taking CBZ plus 1, 2 and 3 additional AEDs. Upon entry to study, patients were switched to an equivalent dose of chewtabs and subsequently evaluated at 2, 4, 8 and 12 weeks. Two patients did not complete the study. On entry, the mean 14 day seizure rate was 2.5. On chewtabs mean 14 day rates were 2.4, 2.2, 2.4 and 2.7 after 2, 4, 8 and 12 weeks of treatment respectively. On entry the mean steady state trough serum CBZ concentration was 35 mumols/l compared to 32, 31, 32 and 34 mumols/l after 2, 4, 8 and 12 weeks respectively. Nineteen patients were classified showing good or excellent tolerability, 7 satisfactory and 2 fair. In conclusion, chewtabs were essentially equivalent to the conventional formulation in efficacy and tolerability. After 12 weeks treatment, 19 patients preferred the chewable formulation.

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To study the absorption of levodopa and interaction with the extracerebral dopamine antagonist domperidone, 15 patients with idiopathic Parkinson's disease were given levodopa 500 mg p.o., alone, and with domperidone pre-treatment. Domperidone pretreatment (10, 20, 40 mg, p.o., i.v. or i.m.) caused a mean 12% increase in peak plasma levodopa concentration, which occurred a mean of 10 min earlier than when levodopa was given alone. Parkinsonian disability scores were improved and peak clinical response occurred 16 min earlier with domperidone than without. Domperidone slightly increases the immediate bioavailability (over 4 h) and anti-parkinsonian response to a given dose of levodopa.

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