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Temporal lobe epileptics often experience profound interictal (i.e. between seizure) emotional disturbances, such as fear, anxiety, and depression. Although the presence of this interictal emotionality has been well documented, little progress has been made in identifying its precise nature and cause because it is not amenable to experimental analysis in clinical populations. Accordingly, there is much to gain by studying the fundamental nature and neural basis of interictal emotionality using animal models. Kindling is a widely studied animal model of temporal lobe epilepsy in which daily electrical stimulation of certain brain regions results in the gradual progression and intensification of limbic motor seizures. Several investigators have found that partial and short-term kindling produce robust changes in emotional behavior in both cats and rats. Recently, our laboratory has developed a new model to study interictal emotionality using long-term kindling in rats. These long-term kindled rats display profound changes in fearful and defensive behavior which last for at least two months after the final stimulation. We are now beginning to use this model to study the neural mechanisms underlying the development and expression of interictal emotionality.
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PMID:Long-term amygdala kindling in rats as a model for the study of interictal emotionality in temporal lobe epilepsy. 1097 52

Activity-dependent plasticity is a fundamental feature of most CNS synapses and is thought to be a synaptic correlate of memory in rodents. In humans, NMDA receptors have been linked to verbal memory processes, but it is unclear whether NMDA receptor-dependent synaptic plasticity can be recruited for information storage in the human CNS. Here we have for the first time analyzed different forms of synaptic plasticity in human hippocampus. In human subjects who show a morphologically intact hippocampus that is not the primary seizure focus, NMDA receptor-dependent long-term potentiation (LTP) and forskolin-induced long-lasting potentiation are readily induced at the perforant path-dentate gyrus synapse. In this group, long-term potentiation could be partially depotentiated by low-frequency stimulation. Because patients with a hippocampal seizure focus showed a marked reduction in verbal memory performance in previous studies, we asked whether synaptic plasticity is similarly affected by the presence of a hippocampal primary seizure focus. We found that the amount of potentiation induced by high-frequency stimulation or perfusion of forskolin is dramatically reduced in this patient group. In addition, low-frequency stimulation is not effective in inducing synaptic depression. In summary, we show that activity-dependent synaptic plasticity with properties similar to the rodent is available for information storage in the human hippocampus. Because both verbal memory processes and synaptic plasticity are impaired by a hippocampal seizure focus, we suggest that impaired synaptic plasticity may contribute to deficient declarative memory in human temporal lobe epilepsy.
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PMID:Synaptic plasticity in the human dentate gyrus. 1099 55

Electroconvulsive therapy, which is used to treat refractory major depression in humans increases seizure threshold and decreases seizure duration. Moreover, the expression of brain derived neurotrophic factor induced by electroshocks (ECS) might protect hippocampal cells from death in patients suffering from depression. As temporal lobe epilepsy is linked to neuronal damage in the hippocampus, we tested the effect of repeated ECS on subsequent status epilepticus (SE) induced by lithium-pilocarpine and leading to cell death and temporal epilepsy in the rat. Eleven maximal ECS were applied via ear-clips to adult rats. The last one was applied 2 days before the induction of SE by lithium-pilocarpine. The rats were electroencephalographically recorded to study the SE characteristics. The rats treated with ECS before pilocarpine (ECS-pilo) developed partial limbic (score 2) and propagated seizures (score 5) with a longer latency than the rats that underwent SE alone (sham-pilo). Despite this delay in the initiation and propagation of the seizures, the same number of ECS- and sham-pilo rats developed SE with a similar characteristic pattern. The expression of c-Fos protein was down-regulated by repeated ECS in the amygdala and the cortex. In ECS-pilo rats, c-Fos expression was decreased in the piriform and entorhinal cortex and increased in the hilus of the dentate gyrus. Neuronal damage was identical in the forebrain areas of both groups, while it was worsened by ECS treatment in the substantia nigra pars reticulata, entorhinal and perirhinal cortices compared to sham-pilo rats. Finally, while 11 out of the 12 sham-pilo rats developed spontaneous recurrent seizures after a silent period of 40+/-27 days, only two out of the 10 ECS-pilo rats became epileptic, but after a prolonged latency of 106 and 151 days. One ECS-pilo rat developed electrographic infraclinical seizures and seven did not exhibit any seizures. Thus, the extensive neuronal damage occurring in the entorhinal and perirhinal cortices of the ECS-pilo rats seems to prevent the establishment of the hyperexcitable epileptic circuit.
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PMID:Electroshocks delay seizures and subsequent epileptogenesis but do not prevent neuronal damage in the lithium-pilocarpine model of epilepsy. 1099 2

Little is known about the differential long-term outcome from surgical and nonsurgical therapy in patients with chronic epilepsy. In the present study, 161 surgically or nonsurgically treated patients with drug-resistant temporal lobe epilepsy (TLE) were re-evaluated according to a detailed clinical, neuropsychological, and psychosocial protocol with a mean follow-up interval of 58 months. Freedom from seizures was achieved in 64% of the surgical group; yet 23% of the nonsurgical patients became seizure-free as a result of modifications in drug therapy. Generally, socioeconomic development was poorer in nonsurgical than in surgical patients. Freedom from seizures, employment, and the absence of depression were significant determinants of better quality of life. As for neuropsychological outcome, verbal memory impairment was common after left-sided temporal resection; however, there was no evidence of a marked progression of cognitive impairment after the first postoperative year. In nonsurgical patients, too, cognitive capacities were surprisingly stable over time, although persisting seizures and good baseline performance predicted a poorer neuropsychological outcome.
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PMID:[Temporal lobe epilepsy: longitudinal clinical, neuropsychological and psychosocial follow-up of surgically and conservatively managed patients]. 1099 13

Long-term potentiation and depression of glutamatergic synaptic responses are accompanied by an increased firing probability of neurons in response to a given excitatory input. This property, named excitatory postsynaptic potential/spike potentiation, has also been described in epileptic tissue and has pro-epileptic consequences. In this study, we show that excitatory postsynaptic potential/spike potentiation can be reversed in the kainic acid lesioned rat hippocampus, a chronic model of temporal lobe epilepsy. Simultaneous in vitro extracellular recordings in stratum radiatum and stratum pyramidale were performed in the CA1 area of the kainic acid lesioned rat hippocampal slices. Fifteen minutes, application of the K(+) channel blocker tetraethylammonium resulted in excitatory postsynaptic potential/spike potentiation (measured 90min after the start of the washout period) which could be reversed by subsequent low-frequency or tetanic stimuli. Excitatory postsynaptic potential/spike potentiation and its subsequent reversal by an electrical conditioning stimulus were found to have a N-methyl-D-aspartate receptor-independent component. Tetraethylammonium treatment also resulted in excitatory postsynaptic potential/spike potentiation of pharmacologically isolated N-methyl-D-aspartate receptor-mediated responses which could be reversed by subsequent low-frequency or tetanic stimuli. We conclude that excitatory postsynaptic potential/spike potentiation can be reversed in epileptic tissue, even in the absence of synaptic plasticity. These results suggest the presence of endogenous regulatory mechanisms which are able to decrease cell excitability.
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PMID:Changes in neuronal excitability and synaptic function in a chronic model of temporal lobe epilepsy. 1131 84

To elucidate the gating mechanism of the epileptic dentate gyrus on seizure-like input, we investigated dentate gyrus field potentials and granule cell excitatory postsynaptic potentials (EPSPs) following high-frequency stimulation (10-100 Hz) of the lateral perforant path in an experimental model of temporal lobe epilepsy (i.e., kindled rats). Although control slices showed steady EPSP depression at frequencies greater than 20 Hz, slices taken from animals 48 h after the last seizure presented pronounced EPSP facilitation at 50 and 100 Hz, followed by steady depression. However, 28 days after kindling, the EPSP facilitation was no longer detectable. Using the specific N-methyl-D-aspartate (NMDA) and RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproponic acid (AMPA) receptor antagonists 2-amino-5-phosphonovaleric acid and SYM 2206, we examined the time course of alterations in glutamate receptor-dependent synaptic currents that parallel transient EPSP facilitation. Forty-eight hours after kindling, the fractional AMPA and NMDA receptor-mediated excitatory postsynaptic current (EPSC) components shifted dramatically in favor of the NMDA receptor-mediated response. Four weeks after kindling, however, AMPA and NMDA receptor-mediated EPSCs reverted to control-like values. Although the granule cells of the dentate gyrus contain mRNA-encoding kainate receptors, neither single nor repetitive perforant path stimuli evoked kainate receptor-mediated EPSCs in control or in kindled rats. The enhanced excitability of the kindled dentate gyrus 48 h after the last seizure, as well as the breakdown of its gating function, appear to result from transiently enhanced NMDA receptor activation that provides significantly slower EPSC kinetics than those observed in control slices and in slices from kindled animals with a 28-day seizure-free interval. Therefore, NMDA receptors seem to play a critical role in the acute throughput of seizure activity and in the induction of the kindled state but not in the persistence of enhanced seizure susceptibility.
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PMID:Kindling induces transient NMDA receptor-mediated facilitation of high-frequency input in the rat dentate gyrus. 1135 34

Recent studies suggest that childhood sexual abuse (CSA) elicits a cascade of neurohumoral events that affect brain development and is also a risk factor for the later development of substance abuse. We hypothesize that the cerebellar vermis may be a key region linking these observations. The vermis has a protracted ontogeny and a high density of glucocorticoid receptors, rendering it highly susceptible to early stress. The vermis modulates dopamine turnover in the accumbens and receives direct dopamine input through fibers with dopamine transporters. To test this hypothesis, steady-state functional magnetic resonance imaging (fMRI) (T2 relaxometry) was performed to assess resting blood flow in the vermis of 24 young adults (18-22 years) selected by screening from a large community sample. Eight subjects had a history of repeated CSA but were unmedicated and not under psychiatric care. Sixteen subjects were age-matched controls who had no personal or family history of Axis I psychiatric disorders. All subjects were screened to exclude known abnormalities affecting brain development, and any history of drug or alcohol abuse. CSA subjects had higher T2 relaxation time (T2-RT) than controls in the vermis but not in cerebral or cerebellar hemispheres. Vermal T2-RT correlated strongly with Limbic System Checklist (LSCL-33) ratings of temporal lobe epilepsy (TLE)-like symptomatology. From 537 prescreened young adults we found that their frequency of substance use was associated with a monotonic increase in LSCL-33 ratings and depression scores. Together these findings suggest that early trauma may interfere with the development of the vermis, and produce neuropsychiatric symptoms associated with drug use.
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PMID:Abnormal T2 relaxation time in the cerebellar vermis of adults sexually abused in childhood: potential role of the vermis in stress-enhanced risk for drug abuse. 1175 Jul 81

Metabotropic glutamate receptors (mGluRs) control excitatory neurotransmission as inhibitory autoreceptors at many synapses throughout the CNS. Since pharmacological activation of mGluRs potently depresses excitatory transmission, anticonvulsive effects were found in a number of experimental epilepsies. However, although native rodent mGluRs and heterologously expressed human mGluRs have so far been investigated in great detail, our knowledge about native human mGluRs in situ is limited. Here we used acute human hippocampal slices prepared from hippocampi surgically removed for the treatment of temporal lobe epilepsy in order to investigate the modulation of glutamatergic transmission by human mGluRs at the perforant path-granule cell synapse. The broad spectrum mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) profoundly and reversibly reduced field EPSPs (fEPSPs) with an EC(50) of 30+/-7.4 microM. Paired-pulse depression of fEPSPs was converted into strong facilitation. The inhibition of fEPSPs by ACPD was mimicked by the specific group II mGluR agonist (2S, 2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), while the specific group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) was ineffective. The effect of ACPD was blocked by group II antagonist (2S,3S,4S)-2methyl-2-(carboxycyclopropyl)glycine (MCCG) but was not changed by coapplication of the specific group III antagonist (S)2 amino2methyl4phosphonobutanoic acid (MAP4). ACPD reduced pharmacologically isolated intracellular EPSPs in granule cells to the same extent as fEPSPs, whereas a specific group III agonist had no effect on EPSPs. Whole-cell recordings from morphologically identified granule cells revealed that DCG-IV significantly reduced the frequency of miniature EPSCs (mEPSCs) in granule cells while the mean amplitude of mEPSCs was not affected. We conclude that in human dentate gyrus mGluR2/3 can almost completely depress glutamate release by a presynaptic mechanism which acts downstream of presynaptic voltage gated calcium-entry and most likely involves a direct modulation of the release machinery.
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PMID:Presynaptic group II metabotropic glutamate receptors reduce stimulated and spontaneous transmitter release in human dentate gyrus. 1189 8

Vincent van Gogh (1853-1890) had an eccentric personality and unstable moods, suffered from recurrent psychotic episodes during the last 2 years of his extraordinary life, and committed suicide at the age of 37. Despite limited evidence, well over 150 physicians have ventured a perplexing variety of diagnoses of his illness. Henri Gastaut, in a study of the artist's life and medical history published in 1956, identified van Gogh's major illness during the last 2 years of his life as temporal lobe epilepsy precipitated by the use of absinthe in the presence of an early limbic lesion. In essence, Gastaut confirmed the diagnosis originally made by the French physicians who had treated van Gogh. However, van Gogh had earlier suffered two distinct episodes of reactive depression, and there are clearly bipolar aspects to his history. Both episodes of depression were followed by sustained periods of increasingly high energy and enthusiasm, first as an evangelist and then as an artist. The highlights of van Gogh's life and letters are reviewed and discussed in an effort toward better understanding of the complexity of his illness.
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PMID:The illness of Vincent van Gogh. 1192 86

In this study, we investigated three female patients given a diagnosis of temporal lobe epilepsy preceded by depression. It is notable that all the patients complained of abnormal sensations, either in the throat or oral. The depression in the three patients showed no improvement with antidepressants, but carbamazepine was effective for both epileptic seizures and depression. EEG should be performed on patients who develop antidepressant treatment-refractory depression accompanied by hypochondriacal complaints.
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PMID:Depressive disorders preceding temporal lobe epilepsy. 1204 3


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