A new approach to overcome natural cholesterol interference during simultaneous determination of two stable isotope-enriched cholesterol tracers in human plasma.

We have developed a validated gas chromatography/mass spectrometry (GC/MS) method with two labelled cholesterol tracers, i.e. (2)H(4) ([2H4]-Chol) and (2)H(7) ([2H7]-Chol) enriched moieties, with a new way of calculating the abundance of labelled cholesterol in plasma without natural cholesterol interference. The isotopomers of the analytes could interfere during analysis. Elimination of these interferences can be performed by the blank or mathematical subtraction method. Validation was performed with the two interference elimination methods. For both methods, linearity was obtained in the range 5 x 10(-4) to 10(-2) mM for both labelled cholesterol moieties. In the same range, repeatability and reproducibility were less than 6.5% and 7.5% for [2H4]-Chol and [2H7]-Chol, respectively. Accuracy was about 100% and recoveries always included 100% for the two labelled cholesterols. We demonstrate that measurement of blank plasma is not necessary when using the validated abundance isotope calculation method. This saves time, reagent and samples. This calculation strategy can be extrapolated to comparable tracer approaches.

[Thromboprophylaxis in neurosurgery and head trauma]. / Thromboprophylaxie en neurochirurgie et en neurotraumatologie intracrânienne.

The incidence of deep vein thrombosis (DVT) is between 20 and 35% using contrast venography, with a rate of symptomatic DVT between 2.3 and 6% in neurosurgery without any prophylaxis. The risk of DVT is poorly evaluated in head injured patients but is around 5%. Specific risk factors in neurosurgery are: a motor deficit, a meningioma or malignant tumour, a large tumour, age over 60 years, surgery lasting more than 4 hours, a chemotherapy. The benefit of mechanical methods or low molecular weight heparin (LMWH) for the prevention of DVP in neurosurgery is demonstrated (grade A). Each method decreases the risk by about 50%. A postoperative prophylaxis with a LMWH does not seem to increase the risk of intracranial bleeding (grade C). There is no demonstrated benefit to begin a prophylaxis with LMWH before the intervention. The duration of the prophylaxis is 7 to 10 days but this has not been scientifically determined.

[Thromboprophylaxis in elective spinal surgery and spinal cord injury]. / Thromboprophylaxie en chirurgie rachidienne traumatologique et non traumatologique.

The risk of deep vein thrombosis (DVT) after spinal cord injury is very high. Without prophylaxis the incidence of DVT using venography is 81% and the risk of symptomatic DVT is between 12 and 23%. The risk is much lower in elective spine surgery. After discectomy or laminectomy on less than two spine levels, the risk of DVT is less than 1%. After spinal fusion or extended laminectomy, the risk can be estimated between 0.3 and 2.2%. A prophylaxis is recommended for all patients after spinal cord injury (grade A). The association of a mechanical method and heparin is recommended (grade B). The duration of prophylaxis is 3 months in patients with a motor deficit (grade C). No prophylaxis is recommended after discectomy or limited laminectomy in patients without additional risk factors. Mechanical methods are recommended after spinal fusion or extended laminectomy. For patients with additional risk factors a low molecular weight heparin is recommended.

[Prevention of venous perioperative thromboembolism in ENT and maxillofacial surgery]. / Prévention de la maladie thromboembolique veineuse périopératoire en chirurgie ORL et maxillofaciale.

There are few studies of poor methodological quality on the risk of thromboembolism in head and neck surgery. The incidence of symptomatic deep vein thrombosis is estimated between, 0.1% and 0.6%. The patient's risk factors (cancer, alcoholism, smoking, malnutrition) determine for the assessment of the potential benefit of thromboembolism prophylaxis. No method can be recommended based on the literature. In patients receiving anticoagulant therapy undergoing superficial head and neck surgery or dental extraction, the literature suggest to continue anticoagulation throughout the perioperative period.

Prolactin-releasing peptide (PrRP) promotes awakening and suppresses absence seizures.

Prolactin releasing peptide (PrRP) is a recently identified neuropeptide that stimulates prolactin release from pituitary cells. The presence of its receptor outside the hypothalamic-pituitary axis suggests that it may have other functions. We present here evidence that PrRP can modulate the activity of the reticular thalamic nucleus, a brain region with prominent PrRP receptor expression that is critical for sleep regulation and the formation of non-convulsive absence seizures. Intracerebroventricular injection of PrRP (1-10 nmol) into sleeping animals significantly suppresses sleep oscillations and promotes rapid and prolonged awakening. Higher concentrations of PrRP (10-100 nmol) similarly suppress spike wave discharges seen during absence seizures in genetic absence epilepsy rats from Strasbourg, an animal model for this disorder. In concordance with these findings, PrRP suppressed evoked oscillatory burst activity in reticular thalamic slices in vitro. These results indicate that PrRP modulates reticular thalamic function and that activation of its receptor provides a new target for therapies directed at sleep disorders and absence seizures.

Differential sensitivity to inverse agonists of GABA(A)/benzodiazepine receptors in rats with genetic absence-epilepsy.

A strain of Wistar rats, genetic absence epilepsy rats from Strasbourg (GAERS), was selected and inbred over 40 generations for occurrence of spontaneous spike-wave discharges characteristic of absence seizures, simultaneously with a strain of non-epileptic rats (NER). GAERS demonstrate an excessive sensitivity to antagonists of the GABA(A) receptor. The sensitivity to convulsions induced by various inverse agonists of the GABA(A)/benzodiazepine receptor was compared in GAERS and NERs. The beta-carbolines FG 7142 and DMCM, and the imidazobenzodiazepines RO 19-4603 and the alpha 5-selective RY 024 were several times more convulsant in GAERS than in NERs. The largest differences were found with the non-selective RO 19-4603- and FG 7142. The proconvulsant imidazobenzodiazepine RO 15-4513, binding also to diazepam-insensitive receptors, had low efficacy. The high affinity binding of GABA(A)/BZD receptors with (3H) RO 15-1788 in the brain of naive rats and after administration of FG 7142 did not differ in GAERS and NERs. The data indicate that the hypersensitivity of GAERS to various inverse agonists of the GABA(A)/benzodiazepine receptor involves cortical GABA(A) receptors and is not related to differential activity of a subunit-selective receptor.

Medium-voltage 5-9-Hz oscillations give rise to spike-and-wave discharges in a genetic model of absence epilepsy: in vivo dual extracellular recording of thalamic relay and reticular neurons.

In humans with absence epilepsy, spike-and-wave discharges develop in the thalamocortical system during quiet immobile wakefulness or drowsiness. The present study examined the initial stage of the spontaneous development of spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg. Bilateral electrocorticograms were recorded in epileptic and non-epileptic rats under freely moving and undrugged conditions and under neuroleptanalgesia. Short-lasting episodes of medium-voltage 5-9-Hz (mean=6-Hz) oscillations usually emerged spontaneously from a desynchronized electrocorticogram and in bilateral synchrony in both rat strains. These oscillations were distinguishable from sleep spindles regarding their internal frequency, duration, morphology, and moment of occurrence. Spontaneous spike-and-wave discharges developed from such synchronized medium-voltage oscillations, the spike-and-wave complex occurring at the same frequency as the 5-9-Hz wave. Because the thalamus is thought to play a significant role in the generation of spike-and-wave discharges, dual extracellular recording and juxtacellular labelling of relay and reticular neurons were conducted to study the thalamic cellular mechanisms associated with the generation of spike-and-wave discharges. During medium-voltage 5-9-Hz oscillations, discharges of relay and reticular cells had identical patterns in epileptic and non-epileptic rats, consisting of occasional single action potentials and/or bursts (interburst frequency of up to 6-8 Hz) in relay cells, and of rhythmic bursts (up to 12-15 Hz) in reticular neurons, these discharging in the burst mode almost always before relay neurons. The discharge frequency of reticular bursts decelerated to 6 Hz by the beginning of the spike-and-wave discharges. During these, relay and reticular neurons usually fired in synchrony a single action potential or a high-frequency burst of two or three action potentials and a high-frequency burst, respectively, about 12 ms before the spike component of the spike-and-wave complexes. The frequency of these corresponded to the maximal frequency of the thalamocortical burst discharges associated with 5-9-Hz oscillations. The patterns of relay and reticular phasic cellular firings associated with spike-and-wave discharges had temporal characteristics similar to those associated with medium-voltage 5-9-Hz oscillations, suggesting that these normal and epileptic oscillations are underlain by similar thalamic cellular mechanisms. In conclusion, medium-voltage 5-9-Hz oscillations in the thalamocortical loop give rise to spike-and-wave discharges. Such oscillations are not themselves sufficient to initiate spike-and-wave discharges, meaning that genetic factors render thalamocortical networks prone to generate epileptic electrical activity, possibly by decreasing the excitability threshold in reticular cells. While these GABAergic neurons play a key role in the synchronization of glutamatergic relay neurons during seizures, relay cells may participate significantly in the regulation of the recurrence of the spike-and-wave complex. Furthermore, it is very likely that synchronization of relay and reticular cellular discharges during absence seizures is generated in part by corticothalamic inputs.

Dietary cholesterol is secreted in intestinally derived chylomicrons during several subsequent postprandial phases in healthy humans.

BACKGROUND: The process of intestinal absorption and chylomicron resecretion of dietary cholesterol in humans is poorly understood. OBJECTIVE: The present study aimed to test the hypothesis that dietary cholesterol ingested during a given meal is resecreted into chylomicrons (and plasma) during several subsequent postprandial periods. DESIGN: Seven healthy subjects ingested 3 comparable mixed test meals (at 0, 8, and 24 h) containing a given amount of fat (49 g) and cholesterol (157 mg); blood samples were taken 3 and 6 h after each test meal and 48 and 72 h after the beginning of the experiment. Heptadeuterated dietary cholesterol was present in the first test meal only, enabling its specific determination with use of gas chromatography-mass spectrometry. Chylomicrons, LDL, and HDL were isolated and lipids were quantified. RESULTS: In apolipoprotein B-48-containing chylomicrons, deuterated cholesterol concentrations were moderate after the first meal (1.3 x 10(-4) mmol/L), reached a maximum after the second meal (2.4 x 10(-4) mmol/L), and were still elevated after the third meal (1.7 x 10(-4) mmol/L). In plasma, LDL and HDL cholesterol enrichment in deuterated cholesterol was lower than in chylomicrons and plateaued after 24--48 h. Estimates of newly secreted exogenous deuterated cholesterol in chylomicrons indicate that 30.7%, 55.2%, and 14.1% of the total was secreted after the first, second, and third meals, respectively. CONCLUSION: Ingested dietary cholesterol is secreted by the small intestine in chylomicrons into the circulation during > or =3 subsequent postprandial periods in healthy humans. This likely results from a complex multistep intestinal processing of cholesterol with dietary fat as a driving force.

Specific alteration in the expression of glial fibrillary acidic protein, glutamate dehydrogenase, and glutamine synthetase in rats with genetic absence epilepsy.

Astrocytes play a predominant role in energy metabolism and in the catabolism of gamma-aminobutyric acid (GABA) and glutamate, neurotransmitters critically involved in epileptic processes. We show specific astrocytic alterations in the genetic absence epilepsy rats from Strasbourg (GAERS). Spontaneous absence seizures appear in this strain in the cortex and thalamus after the age of 1 month. In these brain structures, we demonstrate increased GFAP expression in both adult and young GAERS, suggesting that reactive astrocytes are already present before the onset of seizures. Glutamate dehydrogenase (GDH) and glutamine synthetase (GS), which are localized mainly in astrocytes and involved in glutamate catabolism, are shown to be differentially altered. GDH expression was increased in the thalamus of both young and adult GAERS and in the cortex of young GAERS. GS expression was slightly decreased in the thalamus of young GAERS. These astrocytic modifications are not adaptive responses to seizures, as the modifications appear before the development of absence seizures. Thus, astrocytes might be involved in the neuronal processes giving rise to epileptic seizures in this strain.

Sleep and epilepsy: A key role for nitric oxide?

PURPOSE: It has been suggested that nitric oxide (NO) is involved in sleep mechanisms and in the pathophysiology of epilepsy. Data are, however, controversial because it is not clear whether NO facilitates sleep or waking, or whether it exerts pro-or antiepileptic influences. METHODS: The question was considered through NO voltammetric measurements and electroencephalographic recordings performed in GAERS rats (Genetic Absence Epilepsy Rat from Strasbourg): an experimental model of "petit-mal" human disease. Regulatory processes of sleep and epilepsy were studied after administration of a NO synthase inhibitor [l-arginine-p-nitroanilide (l-ANA) 100 mg/kg i.p.], a NO donor (SIN-1 100 ng/2 microl i.c.v.), and the antiepileptic drugs used in clinic [valproate (VPA 200 mg/kg i.p.) and ethosuximide (ESM 100 mg/kg i.p.)]. RESULTS: In GAERS rats, spontaneous circadian organizations of spike-wave discharges and paradoxical sleep (PS) occur in an opposite way; spontaneous NO concentrations are higher during seizures than during wakefulness, slow-wave sleep, and PS, respectively. l-ANA induces a disappearance of NO peak, an epileptic induction, and a loss of PS while SIN-1 induces opposite effects. Antiepileptic effects of VPA and ESM are associated with a PS increase and a significant release of NO. CONCLUSIONS: These results indicate that NO could be, in GAERS rats, a central piece in the reciprocal inhibitory mechanisms regulating the induction of PS and spike-wave discharges. NO could prevent absence epilepsy and act as an antiepileptic substance in facilitating PS. Antiepileptic efficiency of VPA and ESM may work through their ability to release NO. A track for a new treatment of petit-mal disease in children can be envisioned.

Increased expression of mRNA encoding ferritin heavy chain in brain structures of a rat model of absence epilepsy.

Differential mRNA display was carried out to find genes that are differentially regulated in the brain of a rat strain with absence epilepsy, the genetic absence epilepsy rats from Strasbourg (GAERS). Among the 32 differentially displayed cDNA fragments actually cloned and sequenced, one shows 100% identity with the rat heavy chain ferritin (H-ferritin) mRNA. Northern blot analysis confirmed the up-regulation of the H-ferritin mRNA. Using dot blotting, a 40% increase in expression was reported in the subcortical forebrain of the adult GAERS, while cortex, brain stem, and cerebellum appeared unmodified. This change was not observed in the brain of 25-day-old rats, an age at which the epileptic phenotype is not present. By in situ hybridization, the enhanced expression was localized in the hippocampus. The increase in mRNA encoding H-ferritin was not immunodetected at the protein level by Western blotting. These results are not apparently related to the neural substrate of SWD or to the distribution of local increase in glucose metabolism previously described in the GAERS. It is hypothesized that the up-regulation of the H-ferritin mRNA is part of a mechanism protecting the hippocampus, a seizure-prone area, against a possible overactivation during absence seizures.

Selective susceptibility to inhibitors of GABA synthesis and antagonists of GABA(A) receptor in rats with genetic absence epilepsy.

Thalamocortical spike-and-wave discharges characterize the nonconvulsive absence seizures that occur spontaneously in genetic absence epilepsy rats from Strasbourg (GAERS), a selected strain of Wistar rats. GABA is crucial in the generation of absence seizures. The susceptibility to convulsions induced by threshold doses of various GABA receptor antagonists and inhibitors of GABA synthesis, kainic acid and strychnine, was compared in GAERS and in nonepileptic rats from a selected control strain (NE). The brain structures involved in the drug-elicited convulsive seizures were mapped by c-Fos immunohistochemistry. Injection of various antagonists of the GABA(A) receptor, bicuculline and picrotoxin, and inverse agonists of the benzodiazepine site (FG 7142 and DMCM) induced myoclonic spike-and-wave discharges followed by clonic or tonic-clonic seizures with high paroxysmal activity on the cortical EEG. The incidence of the convulsions was dose-dependent and was higher in GAERS than in NE rats. Mapping of c-Fos expression showed that the frontoparietal cortex was constantly involved in the convulsive seizures elicited by a threshold convulsant dose, whereas limbic participation was variable. In contrast, GAERS were less susceptible than NE rats to the tonic-clonic convulsions induced by the inhibitors of glutamate decarboxylase, isoniazide and 3-mercaptopropionic acid. The GABA(B) receptor antagonist CGP 56999 and kainic acid induced a similar incidence of seizures in GAERS and NE rats and predominantly activated the hippocampus. No difference in the tonic seizures elicited by strychnine could be evidenced between the strains. These results suggest that an abnormal cortical GABAergic activity may underlie absence seizures in GAERS.

Epileptiform activity induced by 4-aminopyridine in entorhinal cortex hippocampal slices of rats with a genetically determined absence epilepsy (GAERS).

Patients with absence epilepsy frequently develop convulsions later in life. We were therefore interested whether tissue from rats with a genetic absence epilepsy is more prone to seizure generation than normal animals. We compared the epileptiform activities induced by 4-aminopyridine (4-AP) induced in hippocampal-entorhinal cortex slices from genetic absence epilepsy rats of Strasbourg (GAERS, age 6 months) in which absence seizures have been present for about 4 months and from control non epileptic rats (NE). 4-AP induced short recurrent discharges in area CA1 of rat hippocampus, seizure-like events and interictal discharges in the entorhinal cortex. The various epileptiform discharges did not differ between the two strains in amplitude, duration and frequency. However, the latency for induction of different epileptiform activities by 50 microM 4-AP was significantly shorter in GAERS (about 16 min) than in NE rats (about 25 min). We also analysed differences in evoked field potentials (fp) in hippocampal area CA1 before, during and after application of 4-AP. Before application of 4-AP, responses to stimulation of Schaffer collateral were smaller in GAERS than in NE rats. Paired pulse potentiation was significantly larger in GAERS than in NE rats. 4-AP in the bath augmented the size of the evoked field potentials and this increase was larger in GAERS than in NE rats. Our findings show a greater excitability of hippocampal area CA1 in GAERS rats and a greater ability to develop 4-AP-induced epileptiform activity in combined hippocampal-enthorhinal cortex slices in GAERS than in NE rats.

Susceptibility to focal and generalized seizures in Wistar rats with genetic absence-like epilepsy.

The susceptibility to develop cortically induced focal and generalized seizures was examined in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), an inbred strain of Wistar rats with absence epilepsy. A GABA-withdrawal syndrome induced after suppression of a 2-h intracortical GABA infusion was used as a model of focal epileptogenesis: localized cortical discharges appear at the infusion site within 1 h. GAERS were more prone to develop a GABA-withdrawal syndrome than non-epileptic inbred controls and non-selected Wistar rats. After a transient suppression of absence seizures following GABA infusion in GAERS, generalized spike-and-wave discharges and focal spikes were recorded simultaneously in the cortex. GAERS also showed a higher incidence of systemic pentylenetetrazol-induced convulsions at the dose of 25 mg/kg. Higher doses had similar convulsant effects in all groups. In conclusion, the results confirm a genetic susceptibility in GAERS and/or resistance in inbred non-epileptic rats to focal and generalized seizures involving the cortex. Rats with absence epilepsy appear to be more prone to seizures elicited by cortical GABA deficiency.

Repetitive electroconvulsive seizures induce activity of c-Jun N-terminal kinase and compartment-specific desensitization of c-Jun phosphorylation in the rat brain.

Electroconvulsive seizures (ECS) are used for therapy of pharmacoresistent depression and are supposed to induce long-lasting neuronal alterations in morphology and gene expression. In this study, we have investigated the phosphorylation of the transcription factor protein c-Jun at its serine 73 residue by immunohistochemistry and the activity of the c-Jun N-terminal kinase 1 (JNK1) by immunocomplex assay following repetitive ECS in adult rats. In untreated controls, nuclear c-Jun immunoreactivity, but not N-terminal phosphorylation, was present in a variety of neuronal populations including the hippocampus, the temporobasal cortex and the amygdalar complex. Daily ECS for 1, 5 or 10 days (1x, 5x or 10x ECS) did not alter the expression of c-Jun but caused a substantial N-terminal phosphorylation of c-Jun (phospho-c-Jun). Nuclear phospho-c-Jun immunoreactivity was maximal within 15 min following ECS, and became absent after 30 min. The highest levels of phospho-c-Jun labeling were found after 1x ECS in the amygdalar complex, the dorsomedial hypothalamus and the piriform cortex. The inducibility of c-Jun N-terminal phosphorylation was preserved in the medial amygdala and piriform cortex, but significantly declined in the basal amygdala and medial hypothalamus with progressive ECS stimulation. One single ECS 3 or 5 days following 10x ECS yielded a pattern of phospho-c-Jun as seen following 10x ECS; thus, a lag of 5 days was not sufficient to provoke the initial level of N-terminal phosphorylation of c-Jun. In the rostral hippocampus, c-Jun was not phosphorylated at any investigated time inspite of its high constitutive expression. In some contrast with this compartment-specific phosphorylation of c-Jun, immunocomplex assays revealed that the JNK1 activity was strongly enhanced in both amygdala and hippocampus. Our findings demonstrate that rapid JNK activation and phosphorylation of c-Jun as stand-by transcription factor characterize the beginning of neuroplastic changes, e.g., following ECS, a classic treatment of mental disorders. The N-terminal phosphorylation is compartment specific and can habituate following repetitive stimulation suggesting that the differential activation of the JNK/c-Jun axis is part of the neuronal strategy to integrate transynaptic excitation.

Spatial and temporal relationships between C-Fos expression and kindling of audiogenic seizures in Wistar rats.

In a strain of Wistar rats selected in our laboratory, audiogenic seizures (AS), characterized by a wild running phase followed by a tonic seizure, can be elicited by exposure to sound. In these animals repeated daily stimulations induce permanent changes which reflect the extension of seizure activity from the brainstem to the forebrain. C-Fos immunoreactivity was used to further characterize the sound-susceptibility of the strain and to specify the spatiotemporal relationships between c-Fos expression and development of AS kindling. AS susceptible rats appeared to be more sensitive to a subthreshold sound as compared to controls. Sound-evoked wild running induced a similar pattern of c-Fos as a full AS in naive rats, confirming the epileptic nature of this early component. AS-induced c-Fos labeling in the auditory pathways of the brainstem extended to the forebrain with repetition of AS and marked increases in c-Fos expression sequentially occurred in the amygdala and perirhinal cortex, followed by the frontoparietal cortex, the piriform cortex, and finally the hippocampus and entorhinal cortex. These results show that the kindled AS preferentially propagate from the brainstem, through the amygdala and the perirhinal cortex, to the motor cortex, with the piriform cortex and hippocampus as secondary targets. No more c-Fos expression was detected 24 h after an AS. A down-regulation of cortical c-Fos induction was observed 1 and 2 days after daily exposure to kindled AS, with full recovery of c-Fos expression after a 5-day seizure-free period. This suggests a regulatory function of c-Fos expression in development of kindling.

Expression of mRNA encoding alpha1E and alpha1G subunit in the brain of a rat model of absence epilepsy.

Low voltage-activated calcium channels are thought to play a key role in the generation of spike and waves discharges characteristic of absence epilepsy. Therefore, the expression level of mRNA encoding calcium channel alpha1E and alpha1G subunits was measured in the brain of genetic absence epilepsy rats from Strasbourg (GAERS). Using quantitative RT-PCR and in situ hybridization, no difference was found in alpha1G mRNA expression between GAERS and control animals, while a decreased expression of alpha1E was seen in the cerebellum and the brain stem of the GAERS. This phenomenon was not observed in young animals when the epileptic phenotype is not expressed.

Method for simultaneous measurements of traces of heptadeuterated cholesterol and cholesterol by gas chromatography-mass spectrometry: application in humans.

An assay was developed to quantify deuterated cholesterol (used as a tracer) and cholesterol using gas chromatography-mass spectrometry. Ergosterol and epicoprostanol were used as internal standards. Deuterated cholesterol was quantified by comparing its peak area to that of epicoprostanol and cholesterol to ergosterol. The mean absolute recovery in spiked serum was 99.96%; the precision was in the range 0.16-10.9% and accuracy 90.4-100%; the limit of detection in plasma was 3x10(-5) mmol l(-1). Using two internal standards, the method described herein seems particularly suitable for application in humans i.e., measuring traces of deuterated cholesterol (range: 0-6.26 x 10(-4) mmol l(-1)) along with natural cholesterol (range: 0.065-4.42 mmol l(-1)) in human plasma and lipid fractions postprandially.

Decreased seizure threshold and more rapid rate of kindling in rats with cortical malformation induced by prenatal treatment with methylazoxymethanol.

In humans, cortical malformations are highly epileptogenic. In rats, prenatal treatment with methylazoxymethanol (MAM) cause a diffuse cortical malformation that is yet not associated with seizures. We performed rapid hippocampal kindling in MAM and control rats. We show that MAM rats present (i) a lower initial afterdischarge threshold; (ii) a more rapid progression to generalized seizures. We conclude that MAM rats may serve as models for human epileptogenic cortical malformations.