Biomedical subjects

T H Gilbert

Publications and source records attributed to T H Gilbert.

9 recordsLinked to original sources

PubMed2001

Conventional anticonvulsant drugs in the guinea-pig kindling model of partial seizures: effects of acute phenytoin.

This study addressed some of the controversial issues surrounding the anticonvulsant effect of phenytoin, and the predictive validity of the guinea-pig kindling model for the screening of anticonvulsant drugs. Following an intraperitoneal injection of either 50 or 75 mg/kg phenytoin, we analysed plasma concentrations of phenytoin at various time intervals. Behavioural toxicity was assessed at 0.5 h postinjection using quantitative locomotor tests, as well as scores on a sedation/muscle relaxation rating index. The anticonvulsant efficacy of phenytoin was evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD) and behavioural seizure severity at three phases of kindling: non-kindled, kindling acquisition (early and late) and kindled (50+ ADs). ADD and seizure severity were also measured in response to both threshold and suprathreshold kindling stimulation. Plasma levels of phenytoin corresponded to the human therapeutic range at the time of behavioural testing and kindling. Phenytoin did not exert significant adverse effects in guinea-pigs on both the behavioural tests and rating index. Phenytoin increased ADT in non-kindled and kindled guinea-pigs and effectively reduced ADD and seizure severity, indicating that the guinea-pig model correctly predicted phenytoin's anticonvulsant effect. Phenytoin produced reliable anticonvulsant activity in the guinea-pig at threshold stimulation but a somewhat reduced efficacy on seizure severity at suprathreshold stimulation intensities. Kindling in the guinea-pig is a valid model of human partial seizures.

Action Potentials↗

PubMed2001

Conventional anticonvulsant drugs in the guinea-pig kindling model of partial seizures: effects of acute carbamazepine.

This study addressed the anticonvulsant effect of carbamazepine (CBZ) in the guinea-pig kindling model to further test this model for the screening of anticonvulsant drugs. We analysed plasma concentrations of CBZ at various time intervals after intraperitoneal injection of either 10, 25 or 40 mg/kg CBZ. Behavioural toxicity was assessed at 0.5 h postinjection using quantitative locomotor tests, as well as scores on a sedation/muscle relaxation rating index. The anticonvulsant efficacy of CBZ was evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD), and behavioural seizure severity at three phases of kindling: non-kindled, kindling acquisition (early and late) and kindled (50+ ADs). ADD and seizure severity were also measured in response to both threshold and suprathreshold kindling stimulation. Plasma levels of CBZ were within, or higher, than the human therapeutic range at the time of behavioural testing and kindling. CBZ exerted slight effects in guinea-pigs on the sedation rating index but not the behavioural tests. CBZ increased ADT and reduced ADD and seizure severity throughout all phases of kindling, indicating that the guinea-pig model correctly predicts CBZ's anticonvulsant effect. CBZ in the guinea-pig kindling model produced consistent anticonvulsant activity that did not appear to be dependent on stimulation intensity.

Action Potentials↗

PubMed2000

Mossy fiber sprouting is dissociated from kindling of generalized seizures in the guinea-pig.

Controversy surrounds whether aberrant mossy fiber sprouting in the hippocampus is necessary for the establishment of seizure states. We investigated the association between mossy fiber sprouting and kindling in guinea-pigs, using either single-site or alternate-site stimulation. Kindling with single-site amygdaloid stimulation did not induce significant sprouting, despite the development of partial seizures. In contrast, single-site septal and alternating amygdaloid-septal stimulation produced moderate but significant sprouting in about 60% of animals that failed to develop stage 5 generalized seizures. Since the magnitude of sprouting was similar despite striking differences in the intensity of seizures that developed, we conclude that mossy sprouting is not causally associated with seizure development.

Amygdala↗

PubMed2000

Hippocampal kindled seizures impair spatial cognition in the Morris water maze.

We investigated the effects of hippocampally kindled seizures on spatial performance of rats in the Morris water maze (MWM). Seizures were elicited with stimulation of field CA1 of dorsal hippocampus 25-45 min prior to daily testing in the water maze. One group of rats was naive to the MWM (acquisition groups), while another group received pretraining in the MWM (retention groups). These groups were further subdivided into rats that experienced non-convulsive seizures prior to daily testing and rats that experienced fully generalized convulsive seizures prior to daily testing. We found that CA1 seizures significantly disrupted water maze performance during both acquisition and retention, and the effects were similar when either non-convulsive or fully generalized convulsive seizures were evoked. Our findings are consistent with previous reports suggesting that epileptiform activity in the hippocampus acutely impairs performance in tasks sensitive to spatial learning and memory deficits and suggest that both new learning and demonstration of an established place response are susceptible to such disruption.

Animals↗

PubMed1999

Alternate-site kindling in the guinea-pig results in accelerated seizure progression and generalization.

In rats, the concurrent alternate elicitation of epileptiform activity in two forebrain structures can result in both the rapid production of severe seizures and the development of fully generalized seizures in one (dominant) site, while arresting the progress of seizure activity at intermediate stages in the other (suppressed) site. The latter phenomenon is known as kindling antagonism. In this study, we examined alternate-site kindling in the guinea-pig as they fail to express fully generalized (stage 5) convulsions during single-site kindling. We assessed both seizure stage and afterdischarge duration following inter-hemispheric alternate-site kindling stimulation of the amygdala and medial septal areas. Alternating-site kindling of the medial septal and amygdaloid areas bypassed the normal inhibitory mechanisms in some guinea-pigs, enabling them to reach a stage 5 seizure. Furthermore, alternate-site kindled guinea-pigs demonstrated three (absolute, relative, and mutual) types of kindling antagonism. Guinea-pig kindling as a model of human partial epilepsy is discussed.

Animals↗

PubMed1996

Kindling of hippocampal field CA1 impairs spatial learning and retention in the Morris water maze.

We used two procedures to assess the spatial learning and memory of rats in the Morris water maze task subsequent to kindling of hippocampal field CA1: (1) seizures were kindled with stimulation of CA1 prior to training in the water maze (acquisition); and (2) maze training was imposed until performance stabilized, seizures were kindled with stimulation of CA1, and then performance in the maze was reassessed (retention). In both conditions, behavioral testing occurred 24 h after the last kindled seizure. When the effects of CA1 kindling on acquisition were tested, we found that kindling of generalized seizures with stimulation of field CA1 (kindling), but not kindling of non-convulsive or partial seizures (partial kindling), produced deficits in the water maze. When the effects of CA1 kindling on retention were tested, however, we found that kindling of either partial or generalized seizures produced deficits in the water maze. The results suggest that the processing of spatial information is vulnerable to the long-lasting changes in neural excitability associated with kindling.

Animals↗

PubMed1995

Further characterization of kindling antagonism.

Alternating stimulation of two sites in the forebrain culminates in typical kindling of generalized seizures from one site (dominant), whereas the other site (suppressed) supports only nongeneralized seizures for as long as stimulation of the dominant site continues, a phenomenon referred to as kindling antagonism. With the termination of stimulation of the dominant site, however, seizures provoked from the suppressed site eventually generalize, a progression thought to reflect the resumption of kindling from a previous point of arrest. To further assess the nature of kindling antagonism, we established antagonism between the amygdala and the septal area and subsequently evaluated the development of seizures provoked by stimulation of sites distal to the dominant site (always the amygdala). In Experiment 1, a 30-d stimulation-free period imposed after the establishment of antagonism failed to result in immediate generalization of seizures provoked from the suppressed site (septal area) in seven of eight rats. Although these results suggest that antagonism reflects an actual arrest of kindling rather than a transient inhibition of seizures, they are not entirely unambiguous: Rats exposed to the prolonged stimulation-free period required only half the number of septal stimulations for the expression of a generalized seizure as compared to rats receiving septal stimulation immediately after the establishment of antagonism. The latter finding is suggestive of a transient component of antagonism. In Experiment 2, development of generalized seizures from the previously naive right amygdala was virtually identical in rats previously kindled from the left amygdala and in rats expressing antagonism between the septal area and left amygdala. Development of generalized seizures from the right amygdala was faster than from the left amygdala in both groups of rats, however, suggesting that the expression of seizures provoked from the suppressed site after the establishment of antagonism does not involve a general impairment or enhancement of transfer. Experiment 3 revealed that radio-frequency lesions of the dominant site (amygdala) after the establishment of antagonism did not alter the subsequent development of generalized seizures from the suppressed site (septal area). This suggests that the expression of generalized seizures from the suppressed site after the establishment of kindling antagonism is not dictated by the functional state of the dominant site.

Animals↗

PubMed1993

Kindling antagonism: mapping of susceptible sites.

Previous research has shown that concurrent alternating stimulation of paired limbic sites culminates in kindling of generalized seizures from 1 (dominant) site, whereas the other (suppressed) site supports only focal or partial seizures. This phenomenon has been referred to as kindling antagonism, and it has been proposed that antagonism reflects an arrest of kindling, which is therefore viewed as a non-continuous stepwise process. We have attempted to replicate these important observations in adult rats stimulated in various combinations of forebrain sites. Kindling antagonism was displayed by rats stimulated in the amygdala and the septal area, in the bilateral amygdala, the septal area and the splenium of the corpus callosum, and the amygdala and the cingulate cortex. We also found that antagonism between the amygdala and septal area as well as electrographic and behavioral correlates of alternating stimulation were sensitive to the hemispheric relation of the electrodes and to the order in which the sites received initial stimulations. That is, rats that carried ipsilateral amygdaloid and septal electrodes were less likely to display antagonism when the amygdala was the first site stimulated. On the other hand, we failed to obtain antagonism from rats stimulated in other limbic pairs (e.g. entorhinal cortex and septal areas.

Amygdala↗

PubMed1989

Meningiomas: MR and histopathologic features.

The magnetic resonance (MR) appearances of 40 biopsy-proved meningiomas were blindly evaluated and correlated with their predominant histologic pattern--fibroblastic, transitional, syncytial, angioblastic, or mixed. T1-weighted images were not particularly useful in discriminating pathologic subtype, because most tumors were isointense with or hypointense to cortex regardless of histologic type. Signal intensity and features on T2-weighted images strongly correlated with histopathologic findings in over 75% of cases, however. Meningiomas markedly hypointense to cortex on T2-weighted images (seven of 40 cases) were composed predominantly of fibroblastic or transitional elements, while markedly hyperintense meningiomas (14 of 40 cases) demonstrated predominance of syncytial or angioblastic elements. Consideration of secondary features visible at MR imaging (degree of edema, cyst formation, presence of calcium aggregates) led to a more specific histologic prediction in over half of the remaining isointense tumors. The varied MR appearance of meningiomas has a clear histologic basis, and crude prediction of pathologic subtype is possible in over three-fourths of cases.

Brain Neoplasms↗