Preeminence of extrahippocampal structures in the generation of mesial temporal seizures: evidence from human depth electrode recordings

PURPOSE: To examine the intralimbic localization and morphology of mesial temporal seizure onsets and to correlate the findings with patterns of initial seizure spread and the presence or absence of clinical manifestations. METHODS: Eighteen patients with temporal lobe epilepsy were investigated with intracranial depth electrodes implanted in the amygdala (AM), anterior hippocampus (HP), and parahippocampal gyrus (PH). Focal and regional ictal-onset morphologies were classified as rhythmic limbic spiking <2 Hz (RLS), spike-and-wave activity >2 Hz (S/W), rhythmic polyspike activity >13 Hz (RPS), and rhythmic sharp activity <13 Hz (RS). RESULTS: Onset morphologies in 389 total seizures (260 regional + 129 focal) were 50% RPS, 35% RS, 11% RLS, and 4% S/W. Focal AM or HP onsets (30% and 58% of focal onsets, respectively) were more likely to show RLS, whereas RPS was more common in regional onsets. Most patients showed two or more different morphologies and focal onsets at more than one ipsilateral limbic site. Seizure propagation and clinical manifestations were significantly more common with AM or PH onsets (both 67% clinical seizures): only 23% of focal HP onsets resulted in clinical seizures. CONCLUSIONS: (a) There is substantial inter- and intrapatient variability in the morphology and localization of mesial temporal seizure onsets, which suggests that the epileptogenic temporolimbic system may be conceptualized as a dynamic network containing a multiplicity of potential ictal generators; (b) Seizures beginning in the AM or PH are more likely to propagate and give rise to clinical manifestations than are focal-onset HP seizures, which suggests that inhibitory circuits within the HP may function to prevent seizure spread.     

Seizure suppression by adenosine-releasing cells is independent of seizure frequency

PURPOSE: Intraventricular cellular delivery of adenosine was recently shown to be transiently efficient in the suppression of seizure activity in the rat kindling model of epilepsy. We tested whether the suppression of seizures by adenosine-releasing grafts was independent of seizure frequency. METHODS: Adenosine-releasing cells were encapsulated and grafted into the lateral brain ventricle of rats kindled in the hippocampus. During 4 weeks after grafting, electric test stimulations were delivered at a frequency of either once a week or 3 times per week. Seizure activity was evaluated by visual scoring of seizure severity and by the recording of EEGs. RESULTS: Adenosine released from encapsulated cells exerted potent antiepileptic activity for >/=2 weeks. One week after grafting, treated rats displayed a complete protection from clonic seizures, and a protection from focal seizures was observed in the majority of animals. Seizure suppression was accompanied by a reduction of afterdischarges in EEG recordings. The protective efficacy of the grafted cells was the same irrespective of whether electrical test stimulations were delivered 1 or 3 times per week. Rats receiving control grafts continued to display full clonic convulsions. CONCLUSIONS: This study demonstrated that the frequency of test stimulations did not influence the seizure-suppressive potential of adenosine-releasing grafts. Thus the local delivery of adenosine is likely to be effective in seizure control over a threefold range of seizure-discharge frequency.     

Amygdaloid kindling in glutamate transporter (GLAST) knockout mice

PURPOSE: Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system. We previously reported abnormal glutamate release during seizures after kindling. GLAST and GLT-1 are astrocytic glutamate transporters, highly concentrated in the cerebellum and the telencephalon, respectively. We have investigated whether stages of amygdala kindling in knockout (KO) mice deficient in GLAST are the same as those of wild mice. METHODS: Electrodes were implanted into the basolateral amygdala, bilaterally, in C57BL/6J mice and GLAST KO mice under anesthesia. Once-daily stimulation was applied on one side through these electrodes, and bilateral EEG recordings were obtained. RESULTS: The behavioral manifestations of kindling in mice were (a) arrest of behavior, (b) head nodding, (c) forelimb clonus, (d) bilateral forelimb clonus with rearing, (e) tonic generalized convulsion with elevation of tail and falling with generalized tonic convulsion (GTC). Results of kindling: (a) Mutant mice kindled more slowly than wild-type mice (more stimulations were required to reach each stage in mutants); (b) after kindling was completed, additional stimulations induced shorter afterdischarges (ADs) in mutants than in wild-type mice; (c) Interictal epileptic spikes were more frequent in the mutants than in the wild-type mice, both in the stimulated amygdala and in the contralateral amygdala. CONCLUSIONS: GLAST KO mice, which are missing one type of astrocytic glutamate transporter, demonstrate kindling of an epileptic focus. However, the kindling is significantly slower in the GLAST mutant than in wild-type mice. These findings suggest that glutamate transport by the astrocytic GLAST transporter may have a role in normal epileptogenesis.     

Role of TNF-alpha receptors in mice intoxicated with the parkinsonian toxin MPTP

Local application of GABA-potentiating agents can prevent or reduce the development and maintenance of behavioral seizures induced by limbic kindling in rats. Microinjection and lesion studies suggest that the transition zone between anterior and posterior piriform cortex (PC), termed here central PC, is a potential target for transplantation of GABA-producing cells. In the present study, we transplanted conditionally immortalized mouse cortical neurons, engineered with the GABA-synthesizing enzyme GAD(65), to the central PC of rats. Suspensions of 1.5 x 10(5) cells in 1 microl were transplanted bilaterally. Control animals received transplantation of beta-galactosidase (beta-gal)-expressing cells. All rats were subsequently kindled through a chronically implanted electrode placed in the basolateral amygdala. The pre- and postkindling threshold currents for eliciting behavioral seizures were determined before and after kindling. We found the prekindling partial seizure threshold to be significantly increased by about 200% in the rats that received the GABA-producing cells compared to rats receiving beta-gal-producing transplants. After kindling, the seizure threshold tended to be higher by 100% in rats that received GABA-producing cells, although the difference from controls was not statistically significant. GABA-producing transplants had no significant effect on the rate of amygdala kindling, but the latency to the first generalized seizure during kindling was significantly increased in animals receiving GABA-producing cells. The transplanted cells showed long-term GAD(65) expression as verified immunohistologically after termination of the experiments. The findings substantiate and extend previous findings that the central PC is part of the anatomical substrate that facilitates propagation from partial to generalized seizures. The data demonstrate that genetically engineered cells have the potential to raise seizure thresholds when transplanted to the central PC.     

Decision-making and addiction (part II): myopia for the future or hypersensitivity to reward?

On a decision-making instrument known as the "gambling task" (GT), a subgroup of substance dependent individuals (SDI) opted for choices that yield high immediate gains in spite of higher future losses. This resembles the behavior of patients with ventromedial (VM) prefrontal cortex lesions. In this study, we addressed the possibility that hypersensitivity to reward may account for the "myopia" for the future in this subgroup of SDI. We used a variant version of the GT, in which the good decks yielded high immediate punishment but higher delayed reward. The bad decks yielded low immediate punishment and lower delayed reward. We measured the skin conductance response (SCR) of subjects after receiving reward (reward SCR) and during their pondering from which deck to choose (anticipatory SCR). A subgroup of SDI who was not impaired on the original GT performed normally on the variant GT. The subgroup of SDI who was impaired on the original GT showed two levels of performance on the variant GT. One subgroup (36% of the sample) performed poorly on the variant GT, and showed similar behavioral and physiological impairments to VM patients. The other subgroup of SDI (64% of the sample) performed normally on the variant task, but had abnormally large physiological responses to reward, i.e. large SCR after receiving reward (reward SCR) and large SCR in anticipation of outcomes that yield large reward. Thus, the combined cognitive and physiological approach of assessing decision-making characterizes three sub-populations of SDI. One sub-population is without impairments that can be detected by any measure of the GT paradigm. Another sub-population is similar to VM patients in that they are insensitive to the future, both positive and negative. A third sub-population is hypersensitive to reward, so that the presence or the prospect of receiving, reward dominates their behavior.     

2,3,7,8-Tetrachlorodibenzo-p-dioxin treatment induces c-Fos expression in the forebrain of the Long-Evans rat

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic environmental pollutants. In the present study, we examined c-Fos expression in the central nervous system (CNS) after administration of a lethal dose of TCDD to the adult Long-Evans rat to clarify if the CNS participates in TCDD-induced intoxication. A single dose of TCDD (dissolved in olive oil, 50 microg/kg) or olive oil alone was administered to the rats by gavage. Animals were allowed to survive for 1 day to 5 weeks. Three days after the administration, a significantly large number of Fos-immunopositive cells were found in the hypothalamus (i.e. dorsomedial hypothalamic nucleus, paraventricular hypothalamic nucleus, medial preoptic nucleus), central amygdaloid nucleus and bed nucleus of the stria terminalis. These results suggest that some TCDD toxicity may be induced by its direct action on the CNS.     

Experience facilitates vomeronasal and olfactory influence on Fos expression in medial preoptic area during pheromone exposure or mating in male hamsters

Chemosensory stimuli are essential for mating in male hamsters but either main olfactory or vomeronasal input is sufficient in sexually experienced males. Activation in central chemosensory pathways and medial preoptic area, after stimulation with female chemosignals or after mating, was estimated by counting neurons expressing Fos protein in experienced and naive males, with or without vomeronasal organ lesions. Regions counted included main and accessory olfactory bulbs, corticomedial amygdala, bed nucleus stria terminalis and medial preoptic area. Chemosensory stimulation was more effective in activating medial preoptic area in experienced than in naive males. In experienced males with vomeronasal organs removed, main olfactory input was as effective in activating medial preoptic area as was the combination of main and accessory input available to intact animals. As previously reported, the main olfactory input remaining after vomeronasal lesions in naive males was poorly effective in activating medial preoptic area, and these animals had impaired mating behavior. The change in access of chemosensory input to medial preoptic area after experience suggests that an experience-dependent synaptic modulation in this pathway, perhaps in the amygdala, may underlie some changes in mating behavior with experience.     

Synaptic plasticity in the pathway from the medial geniculate body to the lateral amygdala is induced by seizure repetition

Repeated induction of generalized audiogenic seizures (AGS) (AGS kindling) induces expansion of the seizure network and evokes additional convulsive behaviors. The medial geniculate body (MGB) and amygdala are implicated in the network expansion induced by AGS kindling, although these sites are not required for AGS before kindling. A recent study indicated that amygdala neuronal responses are greatly increased by AGS kindling. The present study examined the effects of AGS kindling on the thalamo-amygdala pathway in genetically epilepsy-prone rats (GEPR-9s) by examining the neuronal responses in lateral amygdala (LAMG) to electrical stimulation in MGB in vivo. AGS kindling in GEPR-9s involved 14 AGS in response to twice daily acoustic stimulation. Sham-kindled normals received the mean stimulation parameters presented to kindled animals. Spontaneous LAMG extracellular action potentials (APs) and APs evoked by electrical stimuli in the MGB were examined in ketamine-anesthetized rats. The mean spontaneous LAMG firing in kindled GEPR-9s was significantly elevated as compared to non-kindled GEPRs, sham-kindled and non-kindled normals. LAMG firing evoked by MGB stimuli in kindled GEPR-9s was significantly elevated, and a significant mean threshold reduction was also observed in kindled GEPR-9s, as compared to other animal groups. These changes may be due to enhanced glutamate receptor-mediated excitation and/or compromised GABA receptor-mediated inhibition in AMG, as previously reported in electrical kindling in the amygdala. These findings indicate that AGS kindling increases the efficacy of the thalamo-amygdala pathway in GEPR-9s, suggesting that synaptic plasticity in this portion of the expanded neuronal network is an important pathophysiological mechanism subserving AGS kindling.     

Complex partial status epilepticus induced by a microinjection of kainic acid into unilateral amygdala in dogs and its brain damage

OBJECTIVE: In order to investigate kainic acid (KA)-induced amygdaloid seizure and seizure-induced brain damage in dogs, and to compare these findings with that in other species, a KA-induced seizure model in dogs was produced. MATERIAL AND METHODS: Normal beagle dogs were used. A Teflon cannula for KA injection was inserted into the left amygdala, and cortical or depth electrodes were positioned. One week after surgery, 1.5 microg of KA was microinjected into the left amygdala. EEGs and the behavior of the animals were monitored for 2 months after KA injection. In addition, neuron-specific enolase levels in the cerebrospinal fluid (CSF-NSE) were measured intermittently. At 2 months after the injection, histopathological studies were performed. RESULTS: KA-treated dogs showed limbic seizures that started from the left amygdala within 30 min after injection. The seizures developed into complex partial status epilepticus (CPSE), and started independently from the bilateral amygdala during the CPSE. The CPSE lasted for 1-3 days, and the animals showed no spontaneous seizures during the 2-month observation period. A significant increase in CSF-NSE was observed immediately after CPSE. Histopathologically, extensive necrosis, which formed large cavity lesions, was observed around the bilateral amygdala. SUMMARY: A microinjection of KA into unilateral amygdala in dogs induced CPSE. The seizures elicited independently from bilateral amygdala, and bilateral limbic structures suffered extensive injury. In addition, CSF-NSE was demonstrated as a useful marker of acute neuronal damage.     

Effect of transient hippocampal inhibition on amygdaloid kindled seizures and amygdaloid kindling rate

In this study the effect of transient inhibition of the CA1 region of the dorsal hippocampus by lidocaine on amygdala kindling rate and amygdaloid kindled seizures was investigated. In experiment 1, rats were divided into four groups. In group 1, animals were implanted only with a tripolar electrode into the amygdala but in groups 2-4, two guide cannulae were also implanted into the CA1 regions of the dorsal hippocampi. Animals were stimulated daily to be kindled. In groups 3 and 4, saline or 2% lidocaine (1 microl/2 min) was also injected respectively into the hippocampus, 5 min before each stimulation. Results obtained showed that amygdala kindling rate and the number of stimulations to receive from stage 4 to stage 5 seizure were significantly increased in group 4. In experiment 2, lidocaine (1% and 2%) was infused (1 microl/2 min) into the hippocampus of amygdala kindled rats bilaterally and animals were stimulated at 5, 15 and 30 min after drug injection. Twenty four h before lidocaine injection, saline was also infused (1 microl/2 min) into the hippocampus as control. Obtained results showed that afterdischarge duration was reduced 5 min after lidocaine (1% and 2%) injection. Stage 5 seizure duration was also decreased 5 and 15 min after 2% lidocaine. Thus, it may be suggested that in amygdala kindling, activation of the hippocampal CA1 region has a role in seizure acquisition and seizure severity so that inhibition of this region results in decreasing of seizure severity and retards amygdala kindling rate.