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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% [...]

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

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

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

Multifunctional Ca2+/ calmodulin-dependant protein kinase II (CaMK) appears to play a large role in the control of neuron excitability in mammalian nervous systems, with a possible role in epilepsy. Studies on the affects of CaMK alpha-subunit null mutations in transgenic mice found that such mutations led to high excitability and and epileptic seizures. Similar mutation of the gamma-subunit had no affects on excitability.

Electrophysiological studies show that the decrease in the amount of gamma-aminobutyric acid (GABA) present in the temporal lobe of humans is because of a decrease in the number of GABA transporters which affects the release of GABA. In the epileptogenic hippocampi, the potassium-stimulated release of GABA increases while the glutamate-induced, calcium-independent release of GABA decreases. However, the number of GABA containing cells and receptors in the neurons of the epileptogenic hippocampi is the same as that in normal neurons. GABA is probably necessary to mediate synaptic transmission and decreases are linked to epileptic seizures.

The 5-hydroxytryptamine-2c (5-HT2c) receptor is vital for the serotonergic control of feeding appetite. Mice with insufficient 5-HT2c receptors are overweight due to a behavioral disorder not a metabolic abnormality. A loss in the 5-HT2c function also results in a diminished seizure threshold and a vigorous advancement of seizure activity. The 5-HT2c receptors link to serotonin, a monoaminergic neurotransmitter involved in the mediation of the tonic inhibition of neuronal network excitability.

High-resolution recordings and fluctuation analysis of miniature inhibitory postsynaptic currents reveal that an increase in functional receptor number in kindled granule cells supports increased GABA(A) receptor-mediated inhibition. This lasts for at least 48 hours after induction. The increased number of receptors does not affect single-channel conductance or kinetics. Increasing the number of functional receptors is an effective way to increase inhibition in mammalian brain.

Adenosine is an inhibitor of neuronal activity in the brain. The local release of adenosine from grafted cells was evaluated as an ex vivo gene therapy approach to suppress synchronous discharges and epileptic seizures. Fibroblasts were engineered to release adenosine by inactivating the adenosine-metabolizing enzymes adenosine kinase and adenosine deaminase. After encapsulation into semipermeable polymers, the cells were grafted into the brain ventricles of electrically kindled rats, a model of partial epilepsy. Grafted rats provided a nearly complete protection from behavioral seizures and a near-complete suppression of afterdischarges in electroencephalogram recordings, whereas the full tonic-clonic convulsions in control rats remained unaltered. Thus, the local release of adenosine resulting in adenosine concentrations [is less than] 25 nM at the site of action is sufficient to suppress seizure activity and, therefore, provides a potential therapeutic principle for the treatment of drug-resistant partial epilepsies.

The regulated expression of type A [Gamma]-aminobutyric acid receptor ([GABA.sub.A]R) subunit genes is postulated to play a role in neuronal maturation, synaptogenesis, and predisposition to neurological disease. Increases in GABA levels and changes in [GABA.sub.A]R subunit gene expression, including decreased [Beta]1 mRNA levels, have been observed in animal models of epilepsy. Persistent exposure to GABA down-regulates [GABA.sub.A]R number in primary cultures of neocortical neurons, but the regulatory mechanisms remain unknown. Here, we report the identification of a TATA-less minimal promoter of 296 bp for the human [GABA.sub.A]R [Beta]1 subunit gene that is neuron specific and autologously down-regulated by GABA. [Beta]1 promoter activity, mRNA levels, and subunit protein are decreased by persistent [GABA.sub.A]R activation. The core promoter, 270 bp, contains an initiator element (Inr) at the major transcriptional start site. Three concatenated copies of the 10-bp Inr and its immediate 3' flanking sequence produce full neural specific activity that is down-regulated by GABA in transiently transfected neocortical neurons. Taking these results together with those of DNase I footprinting, electrophoretic mobility shift analysis, and 2-bp mutagenesis, we conclude that GABA-induced down-regulation of [Beta]1 subunit mRNAs involves the differential binding of a sequence-specific basal transcription factor(s) to the Inr. The results support a transcriptional mechanism for the down-regulation of [Beta]1 subunit [GABA.sub.A]R gene expression and raises the possibility that altered levels of sequence-specific basal transcription factors may contribute to neurological disorders such as epilepsy. transcription | neural specific | epilepsy

Several models that develop epileptiform discharges and epilepsy have been associated with a decrease in the activity of calmodulin-dependent kinase II. However, none of these studies has demonstrated a causal relationship between a decrease in calcium/calmodulin kinase II activity and the development of seizure activity. The present study was conducted to determine the effect of directly reducing calcium/calmodulin-dependent kinase activity on the development of epileptiform discharges in hippocampal neurons in culture. Complimentary oligonucleotides specific for the subunit of the calcium/calmodulin kinase were used to decrease the expression of the enzyme. Reduction in kinase expression was confirmed by Western analysis, immunocytochemistry, and exogenous substrate phosphorylation. Increased neuronal excitability and frank epileptiform discharges were observed after a significant reduction in calmodulin kinase II expression. The epileptiform activity was a synchronous event and was not caused by random neuronal firing. Furthermore, the magnitude of decreased kinase expression correlated with the increased neuronal excitability. The data suggest that decreased calmodulin kinase II activity may play a role in epileptogenesis and the long-term plasticity changes associated with the development of pathological seizure activity and epilepsy.

Kainic acid (KA)-induced status epilepticus in adult rats leads to delayed, selective death of pyramidal neurons in the hippocampal CA1 and CA3. Death is preceded by down-regulation of glutamate receptor 2 (GluR2) mRNA and protein [the subunit that limits [Ca.sup.2+] permeability of [Alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] in CA1 and CA3, as indicated by in situ hybridization, immunolabeling, and quantitative Western blotting. GluR1 mRNA and protein are unchanged or slightly increased before cell death. These changes could lead to formation of GluR2-lacking, [Ca.sup.2+]-permeable AMPA receptors and increased toxicity of endogenous glutamate. GluR2 immunolabeling is unchanged in granule cells of the dentate gyrus, which are resistant to seizure-induced death. Thus, formation of [Ca.sup.2+]-permeable AMPA receptors may be a critical mediator of delayed neurodegeneration after status epilepticus. epilepsy | seizures | [Alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors | neurodegeneration | kainate

Epileptic seizures are associated with increases in hippocampal excitability, but the mechanisms that render the hippocampus hyperexcitable chronically (in epilepsy) or acutely (in status epilepticus) are poorly understood. Recent evidence suggests that substance P (SP), a peptide that has been implicated in cardiovascular function, inflammatory responses, and nociception, also contributes to hippocampal excitability and status epilepticus, in part by enhancing glutamate release. Here we report that mice with disruption of the preprotachykinin A gene, which encodes SP and neurokinin A, are resistant to kainate excitoxicity. The mice show a reduction in the duration and severity of seizures induced by kainate or pentylenetetrazole, and both necrosis and apoptosis of hippocampal neurons are prevented. Although kainate induced the expression of bax and caspase 3 in the hippocampus of wild-type mice, these critical intracellular mediators of cell death pathways were not altered by kainate injection in the mutant mice. These results indicate that the reduction of seizure activity and the neuroprotection observed in preprotachykinin A null mice are caused by the extinction of a SP/neurokinin A-mediated signaling pathway that is activated by seizures. They suggest that these neurokinins are critical to the control of hippocampal excitability, hippocampal seizures, and hippocampal vulnerability.

Neuronal rhythmic activities within thalamocortical circuits range from partially synchronous oscillations during normal sleep to hypersynchrony associated with absence epilepsy. It has been proposed that recurrent inhibition within the thalamic reticular nucleus serves to reduce synchrony and thus prevents seizures. Inhibition and synchrony in slices from mice devoid of the [Gamma]-aminobutyric acid type-A ([GABA.sub.A]) receptor [Β.sub.3] subunit were examined, because in rodent thalamus, [Β.sub.3] is largely restricted to reticular nucleus. In [Β.sub.3] knockout mice, [GABA.sub.A]-mediated inhibition was nearly abolished in reticular nucleus, but was unaffected in relay cells. In addition, oscillatory synchrony was dramatically intensified. Thus, recurrent inhibitory connections within reticular nucleus act as 'desynchronizers.', Inhibitory circuits arising in the reticular thalamic nucleus (RTN) play important roles in various oscillatory activities related to sleep and some epilepsies (1-5). The major projections of inhibitory neurons in [...]

Studies conducted on the role of the neurotransmitter gamma-amino butyric acid (GABA) show that the amount of GABA in the hippocampus affected by epilepsy is less than in the normal hippocampus. The number of neurons which contain GABA and GABA receptors are unaffected in the affected temporal lobe but the number of GABA transporters are less. In the epileptic hippocampus, the release of GABA is mainly vesicular and the non-vesicular release decreases compared to a normal hippocampus. Inhibition of GABA activity causes epileptic seizures.

IT WAS A KIND OF MINI-EPIDEMIC, AN unnerving reminder that the information age can have frightening unintended consequences. On a Tuesday evening last December, emergency rooms around Japan were deluged [...]