Afterdischarge Threshold Research Articles

The usefulness of olfactory bulb kindling as a model for evaluation of antiepileptics

The present study was undertaken to clarify the behavioral and electroencephalographic characteristics of olfactory bulb (OB) kindling in rats, in comparison with those of amygdala (AMG) kindling. In addition, the usefulness of OB kindling as a model to evaluate antiepileptics was studied. Bipolar electrical stimulation was applied to the OB or AMG every day until generalized seizure was achieved. Antiepileptics (carbamazepine, sodium valproate, zonisamide, clobazam, and topiramate), which are used for complex partial epilepsy or secondary generalized epilepsy in clinical practice, were orally administrated to kindled rats. The afterdischarge (AD) threshold of OB kindling is not different from that of AMG kindling. OB-kindled rats showed more rapid development of the seizure stage and AD duration than AMG-kindled rats; however, fully kindled AD duration did not differ between groups. In AMG kindled rats, AD on day 1 was localized only at the stimulation site, whereas in OB-kindled rats, AD on day 1 was observed at not only the stimulation site (OB) but also in the frontal cortex, hippocampus, and AMG. All five antiepileptics significantly inhibited both the seizure stage and AD duration in OB-kindled rats. In addition, carbamazepine, zonisamide, and topiramate were more effective in suppressing OB-kindled seizures. Zonisamide was not effective at any dose tested in AMG-kindled rats. OB kindling can be used as a new valuable model to evaluate antiepileptic drugs, with the advantage of its rapid development and the efficacy of antiepileptics.

Bumetanide inhibits rapid kindling in neonatal rats

To examine the effects of bumetanide, a selective blocker of Na+-K+-2Cl- cotransporter (NKCC1), on hippocampal excitability and rapid kindling in immature rats. Studies were performed in Wistar rats of three ages: postnatal day 11 (P11, neonatal), P14 (postneonatal), and P21 (preadolescent). Bumetanide (0.2, 0.5, 2.5 mg/kg) was given intraperitoneally 20 min prior to the beginning of the studies. Hippocampal excitability was examined by measuring threshold and duration of afterdischarge, which had been elicited by electrical stimulation of ventral hippocampus. Kindling procedure consisted of 80 electrical stimulations of ventral hippocampus, delivered every 5 min. At P11, bumetanide (0.5 mg/kg) increased the baseline hippocampal afterdischarge threshold and shortened the afterdischarge duration. Bumetanide delayed the occurrence, and reduced the number of full motor seizures during kindling, and prevented the development of kindling-induced enhanced seizure susceptibility in a majority of animals. At P14, bumetanide (0.5 mg/kg) induced no significant antiepileptic effects, although suppression of hippocampal excitability and inhibition of kindling were observed in a subset of animals. At P21, bumetanide (0.2; 2.5 mg/kg) exerted no effects on hippocampal excitability and kindling progression. The obtained results provide further evidence that bumetanide may be beneficial for treating neonatal seizures, and that NKCC1 represents a potential target for antiepileptic interventions in the immature brain.

Edaravone, a free radical scavenger, retards the development of amygdala kindling in rats

This study evaluated the antiepileptogenic effects of edaravone, a newly developed radical scavenger, on the amygdala kindling rats. The afterdischarge duration (ADD), AD threshold (ADT), and seizure severity in animals were measured to study the anticonvulsant effects of edaravone (2 mg/kg or 20 mg/kg i.p. for 7 days) on fully kindled seizures. Furthermore, for the study of antiepileptogenesis effects of the drug (2 mg/kg or 20 mg/kg i.p. for 7 days), not only ADD and seizure severity during kindling but also both the pre- and post-kindling ADT were measured. Edaravone neither induces nor inhibits fully kindled seizures regardless of the dose; however high-dose edaravone (20 mg/kg) retarded kindling development together with shortened ADD and elevated ADT. The present data suggest that high-dose edaravone has an antiepileptogenic drug effect for the prevention of epilepsy. However, other chronic models and clinical trials are needed to confirm the effects of edaravone on the prevention of human epilepsy.

Profile of the new pyrrolidone derivative seletracetam (ucb 44212) in animal models of epilepsy

Seletracetam is a pyrrolidone derivative with a one-log-unit higher affinity for the synaptic vesicle protein 2A (SV2A) than levetiracetam (Keppra®). This study explored its anticonvulsant properties in animal models of epilepsy. Seletracetam reduced both the amplitude and repetitive firing of population spikes induced by a high K+/low Ca2+ concentration fluid (HKLCF) in rat hippocampal slices. The reduction of HKLCF-induced increases in population spike amplitude was particularly pronounced, and occurred at ~10 times lower seletracetam concentrations than previously observed for levetiracetam. These invitro data suggest that desynchronisation of epileptiform activity may contribute significantly to the antiepileptic properties of seletracetam. Seletracetam also showed a potent anti-seizure activity in animal models mimicking partial-onset (kindled animals) and generalized epilepsy (audiogenic seizure susceptible mice and genetic absence epilepsy rats from Strasbourg (GAERS)). In amygdala-kindled rats, seletracetam increased the generalized seizure threshold current and decreased the duration of the after-discharge and the seizure severity observed at the after-discharge threshold current, and generally had a much more potent effect than previously observed for levetiracetam. Seletracetam showed no psychomimetic effects and a very high central nervous system (CNS) tolerability in both kindled and GAERS rats, markedly superior to that of levetiracetam and other antiepileptic drugs. These results suggest that seletracetam may represent an effective and very well tolerated broad-spectrum agent for the symptomatic treatment of epilepsy.

Anticonvulsant and antiepileptic actions of 2‐deoxy‐D‐glucose in epilepsy models

Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Because carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy. Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K(+)](o), 4-aminopyridine, or bicuculline, and in vivo against seizures evoked by 6 Hz stimulation in mice, audiogenic stimulation in Fring's mice, and maximal electroshock and subcutaneous pentylenetetrazol (Metrazol) in rats. Chronic antiepileptic effects of 2DG were evaluated in rats kindled from olfactory bulb or perforant path. 2DG (10mM) reduced interictal epileptiform bursts induced by 7.5mM [K(+)](o), 4-aminopyridine, and bicuculline, and electrographic seizures induced by high [K(+)](o) in CA3 of hippocampus. 2DG reduced seizures evoked by 6 Hz stimulation in mice (effective dose [ED]50 = 79.7 mg/kg) and audiogenic stimulation in Fring's mice (ED50 = 206.4 mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a twofold slowing in progression of kindled seizures at both stimulation sites. 2DG did not protect against maximal electroshock or Metrazol seizures. The glycolytic inhibitor 2DG exerts acute anticonvulsant and chronic antiepileptic actions, and has a novel pattern of effectiveness in preclinical screening models. These results identify metabolic regulation as a potential therapeutic target for seizure suppression and modification of epileptogenesis.

Intraoperative Electrocorticography and Cortical Stimulation in Children

Intraoperative electrocorticography has been used in the surgical management of children with medically refractory epilepsy to localize anatomic areas of focal seizure onset, guide the extent, and completeness of resective epilepsy surgery, aid in functional mapping of cortical anatomy, and predict epilepsy surgical outcome. Evidence to support its utility for these purposes is somewhat controversial, particularly in children where the literature is substantially lacking. Usefulness is often dependent on the underlying pathology, and type of resective surgery. It seems to be valuable in the following circumstances: (1) tailoring the extent of hippocampal resection during temporal lobectomies, (2) guiding resection of cortical brain malformations, low-grade tumors, and other neocortical lesions, especially those involving eloquent cortex, and (3) monitoring for afterdischarges during functional cortical mapping. Most literature on this topic is not purely pediatric, and in most circumstances, is the result of combination of both children and adults cases. Cortical stimulation has been shown to be a useful, reliable and safe technique to assess motor, sensory, and speech function in children. As compared with adults, children manifest the following: (1) they need higher Amperage thresholds to elicit responses. In children younger than 10 years, cortical stimulation identifies language cortex at a lower rate than in children older than 10 years or in adults. (2) They have variability within the same individual in the stimulation threshold depending on the cortical site. This often results in the need to maximize stimulation of currents at each cortical site regardless of adjacent afterdischarge threshold. (3) They demonstrate more difficultly to evoke motor responses particularly with certain pathologies such as retrorolandic low-grade tumors. Often also the effective current intensity decreases after lesion removal. As a consequence of the above, the pulse width used for cortical stimulation in children often varies between 0.14 and 200 ms, the frequency ranges between 20 and 50 Hz, the current intensity between 0.5 and 20 mA, and the train between 3 and 25 seconds. Cortical stimulation can identify cortex with reorganized function secondary to congenital lesions and cerebral plasticity. These lesions include brain tumors, cortical dysplasia resulting in intractable epilepsy, and cavernous angioma causing epilepsy. When compared with other presurgical tests, cortical stimulation was shown to have results consistent with those of functional magnetic resonance imaging and Wada testing. It has the disadvantage of being invasive but the advantage of being highly accurate allowing for surgical tailored resections. Although the evidence for the utility of electrocorticography and cortical stimulation is exclusively level IV evidence, it is unlikely that randomized studies are going to be performed due to practical, ethical, and other reasons. The weight of the uncontrolled data at this stage is such that in children electrocorticography remains to be a useful test in some cases of cortical resection and that cortical stimulation is usually indicated when resection in or near eloquent cortex is needed.

Retarded kindling progression in mice deficient in the extracellular matrix glycoprotein tenascin‐R

We investigated the role of the extracellular matrix glycoprotein tenascin-R (TNR) in formation of a hyperexcitable network in the kindling model of epilepsy. The idea that TNR may be important for this process was suggested by previous studies showing that deficiency in TNR leads to abnormalities in synaptic plasticity, perisomatic GABAergic inhibition and more astrocytes in the hippocampus of adult mice. Constitutively TNR deficient (TNR-/-) mice and their wild-type littermates received repeated electrical stimulation in the amygdala over several days until they developed fully kindled generalized seizures at which time their brains were studied immunohistochemically. In TNR-/- mice, kindling progression was retarded compared with wild-type littermate controls. Morphological analysis of the mice used for the kindling studies revealed that, independently of genotype, numbers of parvalbumin-positive interneurons in the dentate gyrus correlated positively with afterdischarge threshold alterations in kindled mice. The kindling-induced increase in the number of S100 expressing astrocytes in the dentate gyrus was enhanced by TNR deficiency and correlated negatively with the kindling rate. Our data support the view that TNR promotes formation of a hyperexcitable network during kindling and suggest that an increase in S100-expressing astrocytes may contribute to retarded epileptogenesis in TNR-/- mice.

Low-frequency stimulation of the hippocampal CA 3 subfield is anti-epileptogenic and anti-ictogenic in rat amygdaloid kindling model of epilepsy

Neuromodulation with low-frequency stimulation (LFS), of brain structures other than epileptic foci, is effective in inhibiting seizures in animals and patients, whereas selection of targets for LFS requires further investigation. The hippocampal CA 3 subfield is a key site in the circuit of seizure generation and propagation. The present study aimed to illustrate the effects of LFS of the CA 3 region on seizure acquisition and generalization in the rat amygdaloid kindling model of epilepsy. We found that LFS (monophasic square-wave pulses, 1 Hz, 100 μA and 0.1 ms per pulse) of the CA 3 region significantly depressed the duration of epileptiform activity and seizure acquisition by retarding progression from focal to generalized seizures (GS). Moreover, GS duration was significantly shortened and its latency was significantly increased in the LFS group demonstrating an inhibition of the severity of GS and the spread of epileptiform activity. Furthermore, LFS prevented the decline of afterdischarge threshold (ADT) and elevated GS threshold indicating an inhibition of susceptibility to GS. These results suggest that LFS of the hippocampal CA 3 subfield is anti-epileptogenic and anti-ictogenic. Neuromodulation of CA 3 activity using LFS may be an alternative potential approach for temporal lobe epilepsy treatment.

Separating kindling and LTP: Lessons from studies of PKM zeta in developing and adult rats

The kindling model of temporal lobe epilepsy (TLE) and the memory model of long-term potentiation (LTP) may have common underlying mechanisms. This is evident by the demonstration that certain signaling molecules play a key role in both. Recently, a brain specific isoform of protein kinase C (PKMζ) has been shown to play a significant role in both maintaining LTP and memory storage. We were interested in determining if this kinase had a crossover role in kindling-induced epileptogenesis. Using developing and adult rats we examined the role of PKMζ in kindling. In developing (P15) rats we determined the effect of PKMζ on retention of amygdala kindling and kindling rate by intra-amygdala administration of a selective PKMζ antagonist, ZIP (10nmol). In adult rats we examined the effect of PKMζ inhibition, ZIP (10nmol), on after discharge (AD) thresholds and kindling retention using rapid hippocampal kindling. Inhibition of PKMζ by the antagonist ZIP did not affect kindling rate or retention in developing rats. In addition there was also no observed effect on AD thresholds and kindling retention in adult rats. Our results show that, despite the similarities between kindling and LTP in their induction, there is dissociation in the role that PKMζ plays within the two in maintenance. This may be of importance in establishing a separation between the pathophysiological processes involved in sustaining kindling and the physiological mechanisms involved in maintaining LTP and memory storage.

Effects of Antiepileptics on Lateral Geniculate Nucleus–Kindled Seizures in Rats

The present study was undertaken to clarify the characteristics of lateral geniculate nucleus (LGN) kindling in rats, especially the efficacies of antiepileptics, in comparison with those of amygdala (AMG) kindling. Daily electrical stimulation of the LGN led to the development of a generalized convulsion (kangaroo posture and falling back) in all subjects, similar to AMG kindling. The kindling response of the LGN differed from that of the AMG in a number of respects, that is, a high after-discharge (AD) threshold, a large number of stimulations for completion of kindling, and a different pattern of electroencephalogram (EEG) development. On the other hand, the oral administration of sodium valproate, carbamazepine, clobazam, or zonisamide caused dose-dependent inhibitions of both seizure stage and AD duration of LGN-kindled seizures, whereas ethosuximide had no significant effects. In addition, seizure stage was more potently inhibited than AD duration by these antiepileptics, particularly with clobazam. In conclusion, LGN kindling possesses characteristics that are different from AMG kindling. In addition, it was demonstrated that LGN kindling is a useful model, similar to other types of limbic system kindling, for the evaluation of antiepileptics.

Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: An ontogenic study

To examine antiepileptogenic and antiictogenic potential of retigabine (RTG) under conditions of rapid kindling epileptogenesis during different stages of development. The experiments were performed in postnatal day 14 (P14), P21, and P35 male Wistar rats. After stereotaxic implantation of hippocampal stimulating and recording electrodes, the effects of RTG on baseline afterdischarge (AD) properties were studied. Next, the animals underwent rapid kindling (sixty 10 s trains, bipolar 20 Hz square wave pulses delivered every 5 min). The progression of seizures (kindling acquisition), and responses to test stimulations after kindling (retention) were compared between RTG and vehicle-treated rats. Additionally, the effects of RTG on the severity of seizures in previously kindled animals were examined. When administered intraperitoneally in doses that induced only mild, or no motor deficits, RTG significantly dampened brain excitability, evident as the increase of AD threshold and shortening of AD duration. During kindling, RTG delayed the development of focal seizures in P14 rats, and prevented the occurrence of full limbic seizures at all three ages. At P14 and P21, but not at P35, pretreatment with RTG prevented the establishment of kindling-induced enhanced seizure susceptibility. Administration of RTG to kindled animals decreased the severity of seizures induced by test stimulation. The effect was most prominent at P14. RTG exerted both antiepileptogenic and antiictogenic effects under conditions of rapid kindling model. These effects were apparent during postneonatal, early childhood, and adolescent stages of development.

Hippocampal kindling in rats with absence epilepsy resembles amygdaloid kindling

WAG/Rij and GAERS rats show delays or resistance to secondary generalization of limbic seizures during amygdaloid kindling. In this study, we aimed to evaluate the kindling from a different limbic site, hippocampus, and to compare its effects on spike-and-wave discharges (SWDs) with that of amygdaloid kindling. Recording electrodes were implanted epidurally and a stimulation/recording electrode was implanted into the ventral hippocampus in the WAG/Rij, GAERS and Wistar rats. Animals received kindling stimulation twice daily at their afterdischarge thresholds until they reached stage 5 seizures, or the maximum number of stimulations (50) had been delivered. The EEG was recorded to analyze SWDs and afterdischarge durations. All Wistar rats reached stage 5 by the 34th stimulation. 4 of 8 WAG/Rij rats and 3 of 6 GAERS rats displayed stage 4/5 seizures (kindling-prone rats); the rest stayed at stage 2 seizures (kindling-resistant rats) even after 50th stimulations. The cumulative duration and number of SWDs decreased in the post-stimulation period after the first stage 2 seizures, whereas these parameters increased after the first stage 3 seizures in the kindling-prone WAG/Rij and GAERS. The peak frequency of SWDs and its harmonics decreased significantly only in the GAERS group after stage 4 seizures. Hippocampal kindling resembles amygdaloid kindling in showing a delay of or resistance to secondary seizure generalization, which supported the interaction of thalamo-cortical and limbic circuitry in GAERS and WAG/Rij.

The antiepileptic activity of Vitex agnus castus extract on amygdala kindled seizures in male rats

The antiepileptic activity of hydrophilic extract of Vitex agnus castus fruit (Vitex) was evaluated by the kindling model of epilepsy. Intact male rats (250-300 g) were stereotaxically implanted with a tripolar and two monopolar electrodes in amygdala and dura, respectively. The afterdischarge (AD) threshold was determined in each animal and stimulated daily until fully kindled. The animals were administered different doses (60, 120 or 180 mg/kg) of Vitex or 0.1 ml of hydro alcoholic solvent intra-peritoneally (i.p.) and kindling parameters including AD threshold, seizure stages (SS), afterdischarge duration (ADD), stage 4 latency (S4L) and stage 5 duration (S5D) were recorded 30 min post-injection. The obtained data showed that even low dose (60 mg/kg) of Vitex could significantly increase the AD threshold and decrease the ADD and S5D (P<0.05). These changes were more significant with higher doses (120 or 180 mg/kg) for ADD (P<0.01) and S5D (P<0.001). Vitex at the dose of 120 mg/kg, induced significant increment in S4L (P<0.05). This effect was more prominent at the dose of 180 mg/kg (P<0.001). The latter dose could significantly reduce seizure stage (P<0.01) and most of the animals did not show S5. These results indicate that Vitex can reduce or prevent epileptic activity as demonstrated by reduction of ADD and S5D (length of convulsion) in a dose dependent manner. In conclusion, Vitex at appropriate dose can probably reduce or control epileptic activities.

Controlled pulse delivery of electrical stimulation differentially reduces epileptiform activity in Mg 2+-free-treated hippocampal slices

Electrical stimulation for applications in epilepsy has been attempted in multiple brain re4gions using high- or low-frequency stimulation protocols. Data suggest that specific frequencies may have more benefit at controlling seizure activity. To this end, investigators have tested low-frequency stimulation (LFS) protocols (0.1 to 25Hz) in both animal models and in human epileptic patients and reported reduced epileptiform synchronization, afterdischarge thresholds, and seizure activity in general. Collectively, these studies imply that LFS may have benefit in reducing epileptiform activity, however, the effectiveness of various electrical parameters still needs to be determined in specific targets. This study aimed to systematically control the total number of stimulation pulses when using primarily LFS protocols (0.5, 0.75, 1, 2, 5, 10, and 25Hz) delivered for the suppression of seizure-like activity in the hippocampal brain slice using a Mg 2+-free model of epilepsy. Fifty Hz was also tested as a reference higher frequency protocol. Regulating the total number of pulses also controlled the amount of electrical work delivered. Of the LFS protocols tested, 0.5Hz, and 1Hz were optimal and significantly ( p < 0.05) reduced several measures of epileptiform activity. However, the higher frequency protocol, 50Hz was similarly effective at significantly ( p < 0.05) suppressing several aspects of epileptiform activity (but not for reduction of population-spike amplitude). The data show that these protocols, which had a controlled number of pulses differentially reduced epileptiform activity in our model where increasing the frequency of stimulation did not result in increased attenuation.

Fourth Conference on Epileptogenesis, May 23–26, 2007, Pisa, Italy

Fourth Conference on Epileptogenesis, May 23–26, 2007, Pisa, Italy

Neuromodulation du système nerveux central dans le traitement des épilepsies II – mécanismes d’action et perspectives

Review of available evidence of the mechanisms of action underlying the anticonvulsant effect of current applied to various CNS structures. Studies were conducted from observations of patients with drug-resistant seizures and treated with neuromodulation. Seizures originated from various cortical areas with secondary generalization or were initially generalized without a focal origin, either clinically or on EEG or SEEG. Intracranial recordings and SEEG were performed using subdural grids or depth electrodes implanted either for recordings or therapeutic deep brain stimulation (DBS). In a group of mesial temporal lobe epilepsy patients investigated with subdural or SEEG electrodes, the epileptogenic focus area was stimulated for 15 days before anterior temporal lobectomy. The surgical specimen was examined using standard and electronic microscopy and autoradiography in order to identify several neurotransmitter receptors. They also were compared to other surgical specimens from epileptic patients who had intracerebral recordings but without stimulation (epileptic controls) and to autopsy specimens from subjects with no history of epilepsy (nonepileptic controls). High-frequency (HF) stimulation increases the after-discharge threshold of the stimulated site and alters the cycles of potentials evoked by a test stimulation using a paradigm of coupled stimulations. HF stimulation also decreases local cerebral blood flow in the stimulated area as demonstrated on SPECT. Parahippocampal cortex HF stimulation significantly increases the GABAergic benzodiazepine receptor density in the stimulated area. In addition, centromedianum (CM) thalamic nucleus HF stimulation suppresses thalamic and cortical spike-waves, as well as secondary synchronous discharges visible on EEG. Conversely, low-frequency (3-Hz) bilateral CM stimulation induces a typical absence clinically and on EEG. High-frequency stimulation is responsible for an inhibition of local and propagated epileptogenesis. Low-frequency stimulation may trigger or enhance epileptogenesis when applied on epileptogenic regions.

Altered Synaptic Dynamics and Hippocampal Excitability but Normal Long-Term Plasticity in Mice Lacking Hyperpolarizing GABAA Receptor-Mediated Inhibition in CA1 Pyramidal Neurons

GABA(A) receptor (GABA-AR)-mediated inhibition is critical for proper operation of neuronal networks. Synaptic inhibition either shifts the membrane potential farther away from the action potential firing threshold (hyperpolarizing inhibition) or via increase in the membrane conductance shunts the excitatory currents. However, the relative importance of these different forms of inhibition on the hippocampal function is unclear. To study the functional consequences of the absence of hyperpolarizing inhibition, we have used KCC2-deficient mice (KCC2hy/null) maintaining only 15-20% of the neuron-specific K-Cl-cotransporter. Gramicidin-perforated patch-clamp recordings in hippocampal CA1 pyramidal cells revealed that the reversal potential of the GABA-AR-mediated postsynaptic currents (E(GABA-A)) was approximately 20 mV more positive in KCC2hy/null mice than in wild-type (WT) animals. The basic glutamatergic transmission appeared unaltered in the KCC2hy/null mice, yet they displayed lowered threshold for stimulation-induced synchronous afterdischarges in the CA1 area. Also fatigue of field excitatory postsynaptic potentials/excitatory postsynaptic currents in response to repetitious stimulation was smaller in KCC2hy/null mice, indicating altered synaptic dynamics. Interestingly, this effect was present also under blockade of GABA-ARs and was dependent on the extracellular K+ concentration. Moreover, there were no differences in the levels of either long-term potentiation or long-term depression between the genotypes. The local hippocampal CA1 network can in several aspects maintain its functional viability even in the absence of hyperpolarizing inhibition in pyramidal cells. Our results underscore the central role of shunting type of inhibition in controlling the neuronal excitation/inhibition balance. Moreover, our data demonstrate a novel, unexpected role for the KCC2, namely the modulation of properties of glutamatergic transmission during repetitious afferent activity.

Cortical language localization in left, dominant hemisphere

The localization of cortical sites essential for language was assessed by stimulation mapping in the left, dominant hemispheres of 117 patients. Sites were related to language when stimulation at a current below the threshold for afterdischarge evoked repeated statistically significant errors in object naming. The language center was highly localized in many patients to form several mosaics of 1 to 2 sq cm, usually one in the frontal and one or more in the temporoparietal lobe. The area of individual mosaics, and the total area related to language was usually much smaller than the traditional Broca-Wernicke areas. There was substantial individual variability in the exact location of language function, some of which correlated with the patient's sex and verbal intelligence. These features were present for patients as young as 4 years and as old as 80 years, and for those with lesions acquired in early life or adulthood. These findings indicate a need for revision of the classical model of language localization. The combination of discrete localization in individual patients but substantial individual variability between patients also has major clinical implications for cortical resections of the dominant hemisphere, for it means that language cannot be reliably localized on anatomic criteria alone. A maximal resection with minimal risk of postoperative aphasia requires individual localization of language with a technique like stimulation mapping.

Conditioning of interictal behaviours, but not ictal behaviours, seizures or afterdischarge threshold, by kindling of the amygdala in rats

Rats received 45 pairings of kindling or sham stimulation in distinctive contexts before a conditioned place preference/aversion test, to determine whether the stimulation and seizures were rewarding or punishing. After more pairings, rats received kindling stimulation in each context (switch test). Ictal measures in this test included afterdischarge duration, clonus duration, latency to clonus, class of convulsion and falls. After more pairings, afterdischarge threshold was measured in each context. On every fourth day of pairings, the rats' behaviour in the prestimulation interval was recorded, to measure conditioned anticipatory defensive behaviour. We partially replicated the finding of Barnes et al. (2001, Behav. Neurosci., 115, 1065-1072) that conditioned anticipatory responses and conditioned place aversion are associated with the kindling environment. However, there were no conditioned effects on any ictal measures, including afterdischarge threshold. Our results fail to support the hypothesis that conditioning is a universal mechanism for kindling.

Multiple roles of midline dorsal thalamic nuclei in induction and spread of limbic seizures

Studies have suggested that the medial dorsal nucleus of the thalamus plays a role in the behavioral expression of limbic seizures, but it is unclear whether this region is a key component for the primary seizure circuitry or a path for seizure spread from one region to another. This study was undertaken to determine the potential role of this region in limbic seizure activity. Adult male rats received kindling stimulation either under urethane anesthesia or while awake. Glutamate or its agonists or the GABA antagonist bicuculline or agonist muscimol were infused into the medial dorsal nucleus. In another series, kindling acquisition was compared among three thalamic sites as well as with the amygdala and hippocampus Drugs that enhanced excitatory drive or blocked GABA resulted in significant prolongation of electrographic seizure activity compared to saline infused controls. Enhanced GABA activity resulted in a significant reduction of seizure duration. Infusion of the compounds lateral to the medial dorsal nucleus did not affect seizure duration. In the kindling studies the medial dorsal region is the only thalamic nucleus from which hippocampal seizures can be induced, but with an elevated afterdischarge threshold compared to the two limbic sites. However, the seizures generalized more rapidly from the medial dorsal region. This study demonstrates that the medial dorsal nucleus and other dorsal midline nuclei have a significant role in the primary seizure circuits of limbic seizures as well as in spread of seizure activity to other regions.