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Abstract Peroxisomal disorders are rare causes of severe neonatal encephalopathies. Here we report a two-month old infant with refractory neonatal seizures evaluated with first-step metabolic screening in the neonatal intensive care unit. The screening did not indicate the inborn error of metabolism. In a series of electroencephalography (EEG) studies, multifocal epileptic discharges and electroclinic seizures were observed, suggesting epileptic encephalopathy. The analysis of plasma very-long-chain fatty acids indicated a peroxisomal disorder. Then a next-generation DNA sequencing panel of epileptic encephalopathy provided a D-Bifunctional Protein Deficiency (D-BP) with a novel mutant gene. The epilepsy panels with next-generation DNA sequencing, after the primarily metabolic screening for the differential diagnosis of early infantile epileptic encephalopathy, provide guidance for a definitive diagnosis. Next-generation genetic studies are essential in identifying subtypes of peroxisomal disorders because they have similar very-long-chain fatty acid levels and dysmorphic findings. Keywords: D-Bifunctional protein deficiency, epileptic encephalopathy, peroxisomal disorders, Zellweger syndrome, Author(s): Cemile Busra Olculu [1]; Erdem Simsek [1]; Sanem Yilmaz [1]; Ayca Aykut [2]; Asude Durmaz [2]; Hasan Tekgul [1] Introduction A wide variety of inborn errors of metabolism (IEM) [...]

Homocysteine (Hcy), a sulfur-containing nonproteinogenic amino acid, is generated as a metabolic intermediate. Hcy constitutes an important part of the '1-carbon metabolism' during methionine turnover. Elevated levels of Hcy known as hyperhomocysteinemia (HHcy) results from vitamin B deficiency, lack of exercise, smoking, excessive alcohol intake, high-fat and methionine-rich diet, and the underlying genetic defects. These factors directly affect the '1-carbon metabolism (methionine-Hcy-folate)' of a given cell. In fact, the Hcy levels are determined primarily by dietary intake, vitamin status, and the genetic blueprint of the susceptible individual. Although Hcy performs an important role in cellular functions, genetic alterations in any of the key enzymes responsible for the '1-carbon metabolism' could potentially upset the metabolic cycle, thus causing HHcy environment in susceptible people. As such, HHcy relates to several clinical conditions like atherosclerosis, myocardial infarction, stroke, cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and ocular disorders, among others. This article summarizes the findings from our laboratory and public database regarding genetics of HHcy and its effects on ocular disorders, their respective management during dysregulation of the 1-carbon metabolism. Key words: genetic polymorphism, hyperhomocysteinemic eye, oxidative stress, vasculopathy, vision loss. L'homocysteine (Hcy), un acide amine non proteinogenique contenant du soufre, est produite en tant qu'intermediaire metabolique. L'Hcy constitue une importante partie du << metabolisme du 1 carbone >> au cours du << turnover >> de la methionine. La hausse des taux d'Hcy, connue sous le nom d'hyperhomocysteinemie (HHcy), provient d'une carence en vitamine B, d'un manque d'exercice physique, du tabagisme, d'une prise excessive d'alcool, d'un regime alimentaire a teneur elevee en matieres grasses et en methionine, ainsi que de facteurs genetiques sous-jacents. Ces facteurs affectent directement le << metabolisme du 1 carbone (methionine-Hcy-folate) >> d'une cellule donnee. En fait, les taux d'Hcy sont principalement determines par l'apport alimentaire, l'etat vitaminique et le canevas genetique de la personne susceptible. Meme si l'Hcy joue un role important dans le fonctionnement des cellules, les modifications genetiques d'une quelconque enzyme cle responsable du << metabolisme du 1 carbone >> pourraient eventuellement perturber le cycle metabolique, et donc entrainer un environnement d'HHcy chez les personnes susceptibles. De fait, l'HHcy est liee a differents etats cliniques comme l'atherosclerose, l'infarctus du myocarde, l'AVC, les troubles cognitifs, la demence, la maladie de Parkinson, la sclerose en plaques, l'epilepsie et des troubles oculaires, entre autres. Cet article resume les resultats de notre laboratoire et de bases de donnees publiques quant a la genetique de l'HHcy, ainsi que ses effets sur les troubles oculaires, leur prise en charge respective pendant le dereglement du metabolisme du 1 carbone. [Traduit par la Redaction] Mots-cles : polymorphisme genetique, oeil hyperhomocysteinemique, stress oxydatif, vasculopathie, perte de la vision., Introduction Homocysteine (Hcy), more precisely known as a thrombogenic nonproteinogenic amino acid, is a demethylated derivative of methionine that is produced during the '1-carbon metabolism (methionine-Hcy-folate)' cycle (Ray et al. [...]

Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies., Introduction Epileptogenesis is a dynamic process of molecular, cellular, and functional reorganization following precipitating events that leads to brain pathology capable of generating spontaneous seizures (1). Currently used antiepileptic drugs [...]

The relationship of epileptic spikes to seizures has been a matter of debate with researchers reporting higher or lower spike rates before and after seizures. To elucidate a possible role of spikes in ictogenesis (seizure generation) we developed a mathematical framework to investigate the spatiotemporal dynamics of spikes in the epileptic brain. Long-term (5-10 days) intracranial electroencephalograms (iEEGs) from 2 patients with temporal lobe epilepsy who underwent presurgical evaluation for localization of candidate epileptic foci were used in the study. First, spikes were detected using an in-house spike detection algorithm. To characterize the spatiotemporal changes in spikes a novel spatial synchronization measure (SSM) of spikes was developed. Application of SSM to iEEG revealed monotonically increasing long-term preictal synchronization between spike trains at brain sites that included the epileptogenic zone. The presence of preictal synchronization of spikes hours to minutes prior to the onset of seizures indicates a possible predictive value of spike synchronization for seizure occurrence. Furthermore, across seizures and patients, we observed that desynchronization of spikes at critical brain sites mostly occurred in postictal epochs. We characterized these observed changes between preictal and postical spike synchronization by a measure of resetting based on the fraction of pairs that synchronize preictally and desynchronize postictally. On the basis of this resetting measure, we showed that resetting of spike synchronization occurs more commonly at seizures than interictally (p Keywords: Epilepsy, Spikes, Seizures, Spatiotemporal Analysis, Ictogenesis, INTRODUCTION Epilepsy is a widely prevalent neurological disorder affecting around 50 million people worldwide and has been classified as the third most common neurological disorder next to stroke and Alzheimer's. [...]

About 1% of the global population is afflicted with epilepsy and, of all adult epilepsy patients, 60% have focal epilepsy. It has been observed that, during the course of secondarily generalized focal seizures, epileptic activity propagates from focal to other brain sites. This could reflect changes in connectivity mappings. Computer assisted analysis of recorded electrographic activity of the brain (EEG) can allow the characterization and quantification and of brain connectivity patterns during seizures. We developed a method that uses the measure of Generalized Partial Directed Coherence (GPDC) to estimate the effective connections between brain sites, and by the use of surrogate data analysis determines the statistically significant ones. Assuming that the brain functions as a network of directionally interconnected nodes, we then use these derived connections to estimate the inward and outward density of connections for each node over time during seizures. The method was applied to EEG recordings of seizures from three patients with focal temporal lobe epilepsy. In 16 of 19 recorded clinical seizures across these patients, at the start of seizures, a relatively consistent and distinct increase of density of inward connections at focal brain sites was observed, accompanied by an increase of density of outward connections at non-focal brain sites. For some seizures and patients reversal of this pattern was observed as seizures were progressing. Subclinical seizures did not exhibit such a consistent or distinct pattern of connectivity. These findings shed further light on the underlying mechanisms governing seizure spatiotemporal dynamics and could be useful in the elucidation of seizure generation, accurate focus localization and seizure control. Keywords: Network Connectivity, GPDC, Graph Theory, Epilepsy, Seizure Dynamics, INTRODUCTION Epilepsy is one of the most common neurological disorders afflicting approximately 1% of the global population [1]. The disorder is characterized by intermittent abnormal events (seizures) which, if not [...]

The epileptic brain typically transits into seizures (ictal states) with preceding (preictal) and following (postictal) states, while it behaves 'normally' between seizures (interictal states). We set to automatically identify these brain states from the electroencephalogram (EEG). The ability to differentiate between epileptic brain states can find many valuable applications in the management of epilepsy. A time-frequency analysis via multivariate matching pursuit (MMP), which efficiently decomposes a multichannel signal into basic waveforms (e.g., Gabor functions), was performed peri-ictally and interictally to long-term intracranial multi-channel EEG recordings from 4 patients with intractable epilepsy. Novel features capturing EEG's complexity, frequency content and energy were estimated from the resulted data. We used these features together with their time lags in a 4-class support vector machine (SVM) classification scheme per patient and tested it under a leave-one-out cross-validation (LOOCV) strategy. Synthetic Minority Oversampling Technique (SMOTE) was also used to treat the highly imbalanced datasets due to considerably longer span of the interictal state compared to the span of the other states. Our analytical scheme achieved high sensitivity in detecting each state in all 4 patients (e.g., 83%, 95%, 100% and 100% for the preictal state per patient respectively). These results suggest potential employment of the devised scheme to a wide range of applications, from seizure prediction and in-time intervention to abolish an upcoming seizure, to accurate and objective monitoring of seizure susceptibility over time, to fast and robust detection of different epileptic brain states hidden in days-long inpatient EEG recordings. Keywords: Multivariate Matching Pursuit, EEG, Brain States, Seizures, Epilepsy, INTRODUCTION Epilepsy is characterized by recurrent seizures and is among the most common disorders of the nervous system, second only to stroke and Alzheimer disease, and affects 1% to 2% [...]

Many clinical cases have been reported where epilepsy profoundly influenced the pathophysiological function of the heart; however, the underlying mechanisms were not elucidated. We use the tremor (TRM) rat as an animal model of epilepsy to investigate the potential mechanisms of myocardial injury. Cardiac functions were assessed by arrhythmia score, heart rate, heart:body mass ratio, and hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular enddiastolic pressure (LVEDP), and maximum rate of left ventricular pressure rise and fall (+dp/[dt.sub.max] and -dp/[dt.sub.max]). Catecholamine level was detectedby HPLC. Apoptotic index was estimated by TUNEL assay. The expressions of Bcl-2, Bax, caspase-3, extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal protein kinases (JNK), and p38 were evaluated by Western blot. The results indicated that there existed cardiac dysfunction and cardiomyocyte apoptosis, accompanied by increasing catecholamine levels in TRM rats. Further investigation revealed that apoptosis was mediated by reducing Bcl-2, upregulating Bax, and activating caspase-3. Additional experiments demonstrated that P-ERK1/2 was decreased, whereas P-JNK and P-p38 were upregulated. Our results suggest that the sympathetic nervous system activation and cardiomyocyte apoptosis are involved in the myocardial injury of TRM rats. The mechanisms of apoptosis might be associated with the activation of the mitochondriainitiated and the mitogen-activated protein kinase pathways. Key words: epilepsy, tremor rat, myocardial injury, cardiomyocyte, apoptosis. Plusieurs cas cliniques ou l'epilepsie influencait profondement les fonctions pathophysiologiques du coeur ont ete rapportes; toutefois, les mecanismes sous-jacents n'ont pas ete elucides. Nous avons utilise le rat << tremor >> (TRM) comme modele animal d'epilepsie afin d'examiner les mecanismes potentiellement responsables du dommage myocardique. Les fonctions cardiaques ont ete evaluees par le score d'arythmie, le rythme cardiaque, le rapport du poids du coeur sur le poids corporel, ainsi que par les parametres hemodynamiques, dont le taux maximum d'elevation et de chute de la pression ventriculaire gauche (+dp/[dt.sub.max] et -dp/[dt.sub.max]). Le niveau de catecholamines a ete detecte par HPLC. L'indice d'apoptose a ete estime par un dosage TUNEL. L'expression de Bcl-2, de Bax, de la capspase-3, des kinases ERK (extracellular signal-regulated kinase), JNK (c-Jun NH2-terminal protein kinase) et p38 a ete evaluee par buvardage Western. Les resultats ont revele une dysfonction cardiaque et la presence d'apoptose chez les cardiomyocytes, accompagnees par un accroissement des niveaux de catecholamines chez les rats TRM. Une recherche plus poussee a revele que la reduction de Bcl-2, l'augmentation de Bax et l'activation de la caspase-3 etaient les mediateurs de l'apoptose. Des experiences additionnelles ont demontre que le niveau de P-ERK1/2 etait diminue alors que ceux de P-JNK et de P-p38 etaient accrus. Nos resultats suggerent que l'activation du systeme nerveux sympathique et l'apoptose des cardiomyocytes sont impliques dans le dommage myocardique chez les rats TRM. Les mecanismes d'apoptose pourraient etre associes a l'activation des voies signaletiques issues des mitochondries et des proteines kinases activees par les mitogenes. [Traduit par la Redaction] Mots-cles: epilepsie, rat << tremor >>, dommage myocardique, cardiomyocyte, apoptose., Introduction Epilepsy is one of the most common neurological disorders. Characterized by recurrent seizures, it affects up to 50 million people worldwide (Carpio and Hauser 2009). Patients with epilepsy have [...]

Every second, our brains take feedback from the world and provide us with a sense of consciousness: awareness of what we are doing and what we have just done. How [...]

Galanin receptors type 1 (GalR1) and/or type 2 (GalR2) represent unique pharmacological targets for treatment of seizures and epilepsy. Previous studies have shown that the endogenous peptide ligand galanin exerts powerful anticonvulsant effect through activation of these two G protein-coupled receptors, which are highly expressed in the temporal lobe of rodent brain. Here we report the characterization of a putative GalR2-positive allosteric modulator CYM2503. CYM2503 potentiated the galanin-stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the [sup.125]I galanin--binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator. In the rat Li-pilocarpine status epilepticus model, CYM2503, injected intraperitoneally, increased the latency to first electrographic seizure and the latency to first stage 3 behavioral seizure, decreased the latency to the establishment of status epilepticus, and dramatically decreased the mortality. In a Li-pilocarpine seizure model in mice, CYM2503 increased the latency to first electrographic seizure and decreased the total time in seizure. CYM2503 also attenuated electroshock-induced seizures in mice. Thus, CYM2503 provides a starting point for the development of anticonvulsant therapy using the galanin R2 receptor as target. galanin | seizure | G protein-coupled receptor | status epilepticus doi/ 10.1073/pnas.1008986107

The optogenetic approach to gain control over neuronal excitability both in vitro and in vivo has emerged as a fascinating scientific tool to explore neuronal networks, but it also opens possibilities for developing novel treatment strategies for neurologic conditions. We have explored whether such an optogenetic approach using the light-driven halorhodopsin chloride pump from Natronomonas pharaonis (NpHR), modified for mammalian CNS expression to hyperpolarize central neurons, may inhibit excessive hyperexcitability and epileptiform activity. We show that a lentiviral vector containing the NpHR gene under the calcium/calmodulin-dependent protein kinase II[alpha] promoter transduces principal cells of the hippocampus and cortex and hyperpolarizes these cells, preventing generation of action potentials and epileptiform activity during optical stimulation. This study proves a principle, that selective hyperpolarization of principal cortical neurons by NpHR is sufficient to curtail paroxysmal activity in transduced neurons and can inhibit stimulation train-induced bursting in hippocampal organotypic slice cultures, which represents a model tissue of pharmacoresistant epilepsy. This study demonstrates that the optogenetic approach may prove useful for controlling epileptiform activity and opens a future perspective to develop it into a strategy to treat epilepsy. epilepsy | hippocampus | NpHR | paroxysmal depolarizing shift (PDS) | stimulation train-induced bursting (STIB)

Members of the SLC4 bicarbonate transporter family are involved in solute transport and pH homeostasis. Here we report that disrupting the Sic4a10 gene, which encodes the [Na.sup.+]-coupled [Cl.sup.-]-HC[O.sub.3]- exchanger Slc4al0 (NCBE), drastically reduces brain ventricle volume and protects against fatal epileptic seizures in mice. In choroid plexus epithelial cells, Slc4al0 localizes to the basolateral membrane. These cells displayed a diminished recovery from an acid load in KO mice. Slc4al0 also was expressed in neurons. Within the hippocampus, the Slc4al0 protein was abundant in CA3 pyramidal cells. In the CA3 area, propionate-induced intracellular acidification and attenuation of 4-aminopyridine-induced network activity were prolonged in KO mice. Our data indicate that Slc4a10 is involved in the control of neuronal pH and excitability and may contribute to the secretion of cerebrospinal fluid. Hence, Slc4a10 is a promising pharmacological target for the therapy of epilepsy or elevated intracranial pressure. cerebrospinal fluid | epilepsy | ion transport | knockout mouse | pH regulation

Endogenous CO, a product of heme oxygenase activity, has vasodilator and cytoprotective effects in the cerebral circulation of newborn pigs. CO-releasing molecule (CORM)-A1 (sodium boranocarbonate) is a novel, watersoluble, CO-releasing compound. We addressed the hypotheses that CORM-A1 1) can deliver CO to the brain and exert effects of CO on the cerebral microvasculature and 2) is cerebroprotective. Acute and delayed effects of topically and systemically administered CORM-A 1 on cerebrovascular and systemic circulatory parameters were determined in anesthetized newborn pigs with implanted closed cranial windows. Topical application of CORM-A1 ([10.sup.-7] - [10.sup.-5] M) to the brain produced concentration-dependent CO release and pial arteriolar dilation. Systemically administered CORM-A1 (2 mg/kg ip or iv) caused pial arteriolar dilation and increased cortical cerebrospinal fluid CO concentration. Systemic CORM-A1 did not have acute or delayed effects on blood pressure, heart rate, or blood gases. Potential cerebroprotective vascular effects of CORM-A1 (2 mg/kg ip, 30 min before seizures) were tested 2 days after bicuculline-induced epileptic seizures (late postictal period). In control piglets, seizures reduced postictal cerebrovascular responsiveness to selective physiologically relevant vasodilators (bradykinin, hemin, and isoproterenol) indicative of cerebrovascular injury. In contrast, in CORM-Al-pretreated animals, no loss of postictal cerebrovascular reactivity was observed. We conclude that systemically administered CORM-A1 delivers CO to the brain, elicits the vasodilator and cytoprotective effects of CO in the cerebral circulation, and protects the neonatal brain from cerebrovascular injury caused by epileptic seizures. cerebral circulation; newborn pig; heme oxygenase; vasoprotection; epilepsy; postictal state; bicuculline

Gap junctions have been postulated to exist between the axons of excitatory cortical neurons based on electrophysiological, modeling, and dye-coupling data. Here, we provide ultrastructural evidence for axoaxonic gap junctions in dentate granule cells. Using combined confocal laser scanning microscopy, thin-section transmission electron microscopy, and grid-mapped freeze-fracture replica immunogold labeling, 10 close appositions revealing axoaxonic gap junctions ([approximately equal to] 30-70 nm in diameter) were found between pairs of mossy fiber axons ([approximately equal to] 100-200 nm in diameter) in the stratum lucidum of the CA3b field of the rat ventral hippocampus, and one axonal gap junction ([approximately equal to] 100 connexons) was found on a mossy fiber axon in the CA3c field of the rat dorsal hippocampus. Immunogold labeling with two sizes of gold beads revealed that connexin36 was present in that axonal gap junction. These ultrastructural data support computer modeling and in vitro electrophysiological data suggesting that axoaxonic gap junctions play an important role in the generation of very fast (>70 Hz) network oscillations and in the hypersynchronous electrical activity of epilepsy. axoaxonic | connexin | electrical synapse | epilepsy | synchronization

Differential composition of GABAA receptor (GABAAR) subunits underlies the variability of fast inhibitory synaptic transmission; alteration of specific GABAAR subunits in localized brain regions may contribute to abnormal brain states such as absence epilepsy. We combined immunocytochemistry and high-resolution ImmunoGold electron microscopy to study cellular and subcellular localization of [GABA.sub.A]R [alpha]l, [alpha]3, and [beta]2/[beta]3 subunits in ventral posterior nucleus (VP) and reticular nucleus (RTN) of control rats and WAG/Rij rats, a genetic model of absence epilepsy. In control rats, [alpha]1 subunits were prominent at inhibitory synapses in VP and much less prominent in RTN; in contrast, the [alpha]3 subunit was highly evident at inhibitory synapses in RTN. [beta]2/[beta]3 subunits were evenly distributed at inhibitory synapses in both VP and RTN. ImmunoGold particles representing all subunits were concentrated at postsynaptic densities with no extrasynaptic localization. Calculated mean number of particles for al subunit per postsynaptic density in nonepileptic VP was 6.1 [+ or -] 3.7, for a3 subunit in RTN it was 6.6 [+ or -] 3.4, and for [beta]2/[beta]3 subunits in VP and RTN the mean numbers were 3.7 [+ or -] 1.3 and 3.5 [+ or -] 1.2, respectively. In WAG/Rij rats, there was a specific loss of [alpha]3 subunit immunoreactivity at inhibitory synapses in RTN, without reduction in [alpha]3 subunit mRNA or significant change in immunostaining for other markers of RTN cell identity such as GABA or parvalbumin, [alpha]3 immunostaining in cortex was unchanged. Subtle, localized changes in GABAAR expression acting at highly specific points in the interconnected thalamocortical network lie at the heart of idiopathic generalized epilepsy. absence epilepsy | inhibition | quantitative electron microscopy

In clinical applications where structural asymmetries between homologous shapes have been correlated with pathology, the questions of definition and quantification of 'asymmetry' arise naturally. When not only the degree but the position of deformity is thought relevant, asymmetry localization must also be addressed. Asymmetries between paired shapes have already been formulated in terms of (nonrigid) diffeomorphisms between the shapes. For the infinity of such maps possible for a given pair, we define optimality as the minimization of deviation from isometry under the constraint of piecewise deformation homogeneity. We propose a novel variational formulation for segmenting asymmetric regions from surface pairs based on the minimization of a functional of both the deformation map and the segmentation boundary, which defines the regions within which the homogeneity constraint is to be enforced. The functional minimization is achieved via a quasi-simultaneous evolution of the map and the segmenting curve, conducted on and between two-dimensional surface parametric domains. We present examples using both synthetic data and pairs of left and right hippocampal structures and demonstrate the relevance of the extracted features through a clinical epilepsy classification analysis. Index Terms--Author, please supply your own keywords or send a blank e-mail to keywords@ieee.org to receive a list of suggested keywords.

Our objective was to evaluate the brain regions showing increased and decreased metabolism in patients at the time of generalized bursts of epileptic discharges in order to understand their mechanism of generation and effect on brain function. By recording the electroencephalogram during the functional MRI, changes in the blood oxygenation level-dependent signal were obtained in response to epileptic discharges observed in the electroencephalogram of 15 patients with idiopathic generalized epilepsy. A group analysis was performed to determine the regions of positive (activation) and negative (deactivation) blood oxygenation level-dependent responses that were common to the patients. Activations were found bilaterally and symmetrically in the thalamus, mesial midfrontal region, insulae, and midline and bilateral cerebellum and on the borders of the lateral ventricles. Deactivations were bilateral and symmetrical in the anterior frontal and parietal regions and in the posterior cingulate gyri and were seen in the left posterior temporal region. Activations in thalamus and midfrontal regions confirm known involvement of these regions in the generation or spread of generalized epileptic discharges. Involvement of the insulae in generalized discharges had not previously been described. Cerebellar activation is not believed to reflect the generation of discharges. Deactivations in frontal and parietal regions remarkably followed the pattern of the default state of brain function. Thalamocortical activation and suspension of the default state may combine to cause the actual state of reduced responsiveness observed in patients during spike-and-wave discharges. This brief lapse of responsiveness may therefore not result only from the epileptic discharge but also from its effect on normal brain function. absence | epilepsy | thalamus

The extended postictal state is characterized by neurological problems in patients. Inadequate blood supply to the brain and impaired cerebral autoregulation may contribute to seizure-induced neuronal damage. Recent evidence in newborn pigs indicates that activation of the antioxidative enzyme heine oxygenase (HO) at the onset of seizures is necessary for increased cerebral blood flow during the ictal episode and for normal cerebral vascular functioning during the immediate postictal period. We hypothesized that seizures cause prolonged postictal cerebral vascular dysfunction that can be accentuated by HO inhibition and rescued by HO overexpression. Cerebral vascular responses to endothelium-dependent (hypercapnia, bradykinin) and -independent (isoproterenol, sodium nitroprusside) stimuli were assessed 48 h after bicuculline-induced seizures in: 1) saline-control newborn piglets, 2) HO-inhibited animals (HO was inhibited by tin protoporphyrin, SnPP, 3 mg/kg iv), and 3) HO-overexpressing piglets (HO-1 was upregulated by cobalt protoporphyrin, CoPP, 50 mg/kg ip). Extended alterations of HO expression in cerebral microvessels were confirmed by measuring CO production and inducible HO (HO-1) and constitutive HO (HO-2) proteins. Our data provide evidence that seizures cause a severe, sustained, postictal cerebral vascular dysfunction as reflected by impaired vascular reactivity to physiologically relevant dilators. During the delayed postictal state, vascular reactivity to all dilator stimuli was reduced in saline control and, to a greater extent, in HO-inhibited animals. In CoPP-treated piglets, no reduction in postictal cerebral vascular reactivity was observed. These findings may indicate that CoPP prevents postictal cerebral vascular dysfunction by upregulating HO-1, a finding that might have implications for preventing postictal neurological complications. cerebral circulation; epilepsy; postictal state; heme oxygenase; cobalt protoporphyrin

Two doctors review the cellular and molecular causes of epilepsy. Topics include absence epilepsy, epilepsy associated with ion-channel mutations, mesial temporal-lobe epilepsy, cortical malformations, and the role of glial cells. Epilepsy is the most common neurological disease, affecting 3% of the world's population at some time in their lives.

Objectives: To investigate the use of whole brain voxel based morphometry (VBM) and stereological analysis to study brain morphology in patients with medically intractable temporal lobe epilepsy; and to determine [...]

In this paper, we apply a new time-frequency spectral estimation method for multichannel data to epileptiform electroencephalography (EEG). The method is based on the smooth localized complex exponentials (SLEX) functions which are time-frequency localized versions of the Fourier functions and, hence, are ideal for analyzing nonstationary signals whose spectral properties evolve over time. The SLEX functions are simultaneously orthogonal and localized in time and frequency because they are obtained by applying a projection operator rather than a window or taper. In this paper, we present the Auto-SLEX method which is a statistical method that 1) computes the periodogram using the SLEX transform, 2) automatically segments the signal into approximately stationary segments using an objective criterion that is based on log energy, and 3) automatically selects the optimal bandwidth of the spectral smoothing window. The method is applied to the intracranial EEG from a patient with temporal lobe epilepsy. This analysis reveals a reduction in average duration of stationarity in preseizure epochs of data compared to baseline. These changes begin up to hours prior to electrical seizure onset in this patient. Index Terms--Electroencephalography, spectral analysis, stochastic processes, time-frequency analysis.

Mossy cells are bi-directionally connected through a positive feedback loop to granule cells, the principal cells of the dentate gyrus. This recurrent circuit is strategically placed between the entorhinal cortex and the hippocampal CA3 region. In spite of their potentially pro-convulsive arrangement with granule cells, mossy cells have not been seriously considered to promote seizures, because mossy cells, allegedly one of the most vulnerable cell types in the entire mammalian brain, have long been `known' to die en masse in epilepsy. However, new data suggest that rumors of the rapid demise of the mossy cells might have been greatly exaggerated.

Abstract The objective was to assess the changes in cortical excitability after sleep deprivation in normal subjects. Sleep deprivation activates EEG epileptiform activity in an unknown way. Transcranial magnetic stimulation [...]

Byline: N. V. Pasikova (1), V. G. Marchenko (1), N. S. Kositsyn (1) Keywords: isolated neocortical areas; pyramidal neurons; synchronization Abstract: Studies in long-term isolated areas of the rat neocortex were performed to investigate the dynamics of the numbers and areas of nerve cell bodies in layer V and to compare these data with the degree of synchronization of epileptic discharges evoked by application of penicillin. Decreases in the number of pyramidal neurons with body areas of 200--350 um.sup.2 in isolated strips after maintenance for 30 and 90 days led to decreases in the degree of synchronization of epileptiform potentials. Large pyramidal neurons are known to have long horizontal axon collaterals, spreading into layers V and VI of the neocortex. It is suggested that the neural networks formed by large pyramidal neurons by means of their long horizontal collaterals mediate the process of intracortical synchronization. Author Affiliation: (1) Russian Academy of Sciences, Institute of Higher Nervous Activity and Neurophysiology, 5A Butlerov Street, 117865, Moscow, Russia Article History: Registration Date: 08/10/2004

Epileptic seizures are discussed relative to their neurophysiological cellular, thalamocortical, cortical and hippocampal network bases. Every aspect of neuronal and glial function, including genes, synapses and networks, has a modulatory influence, at least. Epileptic syndromes and their causes are varied, but the cellular mechanisms of generation of seizure seem to be in only two categories, rhythmic or tonic runaway excitation or the synchronized, rhythmic interactions of excitatory, inhibitory neurons and membrane conductances.

Chronically epileptic (induced by a single systemic injection of lithium and pilocarpine about 30 days before the experiment began) male rats were trained within a radial maze while they were administered either GABA-pentin (Neurontin), or prednisolone or given no treatment. There was no significant improvement in learning or memory between the groups. Numbers of trials per day were positively correlated with the time required to display the overt stereotyped forelimb clonus after the single pilocarpine injection. The numbers of correct trials completed during the first few days of acquisition were significantly greater for the rats that had received weak (1 [Mu]T) complex, pulsed magnetic fields over the right hemisphere during the first 24 hr. after seizure induction than for those who received the same field over the left hemisphere or that had been exposed to reference conditions. Implications of the enhanced sensitivity of limbic neurons to subtle electromagnetic interaction during electrical lability are discussed.

The relationship between acute indispensable amino acid deficiency (IAA) induced by amino acid imbalanced diets and vulnerability to chemically induced seizures was investigated in a model using rats with experimentally-induced epilepsy. During IAA, rats showed an increase in activity in the anterior piriform cortex (APC), a region of the brain that is prone to seizures. Amino acid-deficient animals showed increased susceptibility to seizures compared to controls, suggesting that IAA deficiency is associated with activation of APC.