Rhythmic intrinsic bursting neurons in human neocortex obtained from pediatric patients with epilepsy.

Neocortical oscillations result from synchronized activity of a synaptically coupled network and can be strongly influenced by the intrinsic firing properties of individual neurons. As such, the intrinsic electroresponsive properties of individual neurons may have important implications for overall network function. Rhythmic intrinsic bursting (rIB) neurons are of particular interest, as they are poised to initiate and/or strongly influence network oscillations. Although neocortical rIB neurons have been recognized in multiple species, the current study is the first to identify and characterize rIB neurons in the human neocortex. Using whole-cell current-clamp recordings, rIB neurons (n = 12) are identified in human neocortical tissue resected from pediatric patients with intractable epilepsy. In contrast to human regular spiking neurons (n = 12), human rIB neurons exhibit rhythmic bursts of action potentials at frequencies of 0.1-4 Hz. These bursts persist after blockade of fast excitatory neurotransmission and voltage-gated calcium channels. However, bursting is eliminated by subsequent application of the persistent sodium current (I(NaP)) blocker, riluzole. In the presence of riluzole (either 10 or 20 µm), human rIB neurons no longer burst, but fire tonically like regular spiking neurons. These data demonstrate that I(NaP) plays a critical role in intrinsic oscillatory activity observed in rIB neurons in the human neocortex. It is hypothesized that aberrant changes in I(NaP) expression and/or function may ultimately contribute to neurological diseases that are linked to abnormal network activity, such as epilepsy.

The electrocortical effects of enflurane: experiment and theory.

BACKGROUND: High concentrations of enflurane will induce a characteristic electroencephalogram pattern consisting of periods of suppression alternating with large short paroxysmal epileptiform discharges (PEDs). In this study, we compared a theoretical computer model of this activity with real local field potential (LFP) data obtained from anesthetized rats. METHODS: After implantation of a high-density 8 x 8 electrode array in the visual cortex, the patterns of LFP and multiunit spike activity were recorded in rats during 0.5, 1.0, 1.5, and 2.0 minimum alveolar anesthetic concentration (MAC) enflurane anesthesia. These recordings were compared with computer simulations from a mean field model of neocortical dynamics. The neuronal effect of increasing enflurane concentration was simulated by prolonging the decay time constant of the inhibitory postsynaptic potential (IPSP). The amplitude of the excitatory postsynaptic potential (EPSP) was modulated, inverse to the neocortical firing rate. RESULTS: In the anesthetized rats, increasing enflurane concentrations consistently caused the appearance of suppression pattern (>1.5 MAC) in the LFP recordings. The mean rate of multiunit spike activity decreased from 2.54/s (0.5 MAC) to 0.19/s (2.0 MAC). At high MAC, the majority of the multiunit action potential events became synchronous with the PED. In the theoretical model, prolongation of the IPSP decay time and activity-dependent EPSP modulation resulted in output that was similar in morphology to that obtained from the experimental data. The propensity for rhythmic seizure-like activity in the model could be determined by analysis of the eigenvalues of the equations. CONCLUSION: It is possible to use a mean field theory of neocortical dynamics to replicate the PED pattern observed in LFPs in rats under enflurane anesthesia. This pattern requires a combination of a moderately increased total area under the IPSP, prolonged IPSP decay time, and also activity-dependent modulation of EPSP amplitude.

Multiscale Aspects of Generation of High-Gamma Activity during Seizures in Human Neocortex.

High-gamma (HG; 80-150 Hz) activity in macroscopic clinical records is considered a marker for critical brain regions involved in seizure initiation; it is correlated with pathological multiunit firing during neocortical seizures in the seizure core, an area identified by correlated multiunit spiking and low frequency seizure activity. However, the effects of the spatiotemporal dynamics of seizure on HG power generation are not well understood. Here, we studied HG generation and propagation, using a three-step, multiscale signal analysis and modeling approach. First, we analyzed concurrent neuronal and microscopic network HG activity in neocortical slices from seven intractable epilepsy patients. We found HG activity in these networks, especially when neurons displayed paroxysmal depolarization shifts and network activity was highly synchronized. Second, we examined HG activity acquired with microelectrode arrays recorded during human seizures (n = 8). We confirmed the presence of synchronized HG power across microelectrode records and the macroscale, both specifically associated with the core region of the seizure. Third, we used volume conduction-based modeling to relate HG activity and network synchrony at different network scales. We showed that local HG oscillations require high levels of synchrony to cross scales, and that this requirement is met at the microscopic scale, but not within macroscopic networks. Instead, we present evidence that HG power at the macroscale may result from harmonics of ongoing seizure activity. Ictal HG power marks the seizure core, but the generating mechanism can differ across spatial scales.

Modeling focal epileptic activity in the Wilson-cowan model with depolarization block.

UNLABELLED: Measurements of neuronal signals during human seizure activity and evoked epileptic activity in experimental models suggest that, in these pathological states, the individual nerve cells experience an activity driven depolarization block, i.e. they saturate. We examined the effect of such a saturation in the Wilson-Cowan formalism by adapting the nonlinear activation function; we substituted the commonly applied sigmoid for a Gaussian function. We discuss experimental recordings during a seizure that support this substitution. Next we perform a bifurcation analysis on the Wilson-Cowan model with a Gaussian activation function. The main effect is an additional stable equilibrium with high excitatory and low inhibitory activity. Analysis of coupled local networks then shows that such high activity can stay localized or spread. Specifically, in a spatial continuum we show a wavefront with inhibition leading followed by excitatory activity. We relate our model simulations to observations of spreading activity during seizures. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13408-015-0019-4) contains supplementary material 1.

Corpus callosotomy in multistage epilepsy surgery in the pediatric population.

OBJECT: The object of this study was to evaluate surgical outcome in a select group of patients with medically refractory epilepsy who had undergone corpus callosotomy combined with bilateral subdural electroencephalography (EEG) electrode placement as the initial step in multistage epilepsy surgery. METHODS: A retrospective chart review of 18 children (ages 3.5-18 years) with medically refractory symptomatic generalized or localization-related epilepsy was undertaken. A corpus callosotomy with subdural bihemispheric EEG electrode placement was performed as the initial step in multistage epilepsy surgery. All of the patients had tonic and atonic seizures; 6 patients also experienced complex partial seizures. All of the patients had frequent generalized epileptiform discharges as well as multifocal independent epileptiform discharges on surface EEG monitoring. Most of the patients (94%) had either normal (44%) MR imaging studies of the brain or bihemispheric abnormalities (50%). One patient had a suspected unilateral lesion (prominent sylvian fissure). RESULTS: Of the 18 patients who underwent corpus callosotomy and placement of subdural strips and grids, 12 progressed to further resection based on localizing data obtained during invasive EEG monitoring. The mean patient age was 10.9 years. The duration of invasive monitoring ranged from 3 to 14 days, and the follow-up ranged from 6 to 70 months (mean 35 months). Six (50%) of the 12 patients who had undergone resection had an excellent outcome (Engel Class I or II). There were no permanent neurological deficits or deaths. CONCLUSIONS: The addition of invasive monitoring for patients undergoing corpus callosotomy for medically refractory epilepsy may lead to the localization of surgically amenable seizure foci, targeted resections, and improved seizure outcomes in a select group of patients typically believed to be candidates for palliative surgery alone.

Efficacy of felbamate in the treatment of intractable pediatric epilepsy.

The antiepileptic drug felbamate has demonstrated efficacy against a variety of seizure types in the pediatric population, particularly seizures associated with Lennox-Gastaut syndrome. Postmarketing experience, however, revealed serious idiosyncratic adverse effects not observed during clinical trials, including aplastic anemia and liver failure. As a result, many physicians have been hesitant to prescribe felbamate. This retrospective study evaluated the efficacy of felbamate in a pediatric population with intractable epilepsy. Of 38 patients, 22 had Lennox-Gastaut syndrome (58%); 6 had myoclonic-astatic epilepsy of Doose (16%); 5 had symptomatic generalized epilepsy, not otherwise specified (13%); and 5 had symptomatic localization-related epilepsy (13%). Most patients had multiple seizure types and had been tried on a variety of antiepileptic medications. With felbamate treatment, 6 patients (16%) became seizure free, including 4 of the 6 patients with myoclonic-astatic epilepsy of Doose; 24 patients (63%) had a greater than 50% reduction in seizure frequency. In this population felbamate appeared to be safe, with minimal adverse effects. The study is limited by the small number of patients and by its retrospective nature, but nonetheless adds to the evidence that felbamate is an important antiepileptic drug for medically refractory epilepsy in children and is well tolerated with few adverse effects.

Epilepsy surgery outcomes: quality of life and seizure control.

A consecutive, retrospective analysis of seizure control and quality of life was performed among 83 pediatric patients undergoing epilepsy surgery at Children's Hospital of Wisconsin. Seizure outcomes were generally favorable, with 68.7% class I outcomes; class II, 12%; and class III, 19.3%. Seizure freedom was highest among temporal lobectomies (84.2%) and hemispherectomies (76.2%). Outcomes among hemispherectomies were substantially superior to those of multilobar resections. Cortical dysplasia was associated with lower seizure freedom, at 57.5%. Among age groups, seizure-free outcomes in infants were lowest, at 50%. The lower infant seizure-free rate was likely attributable to frequency of multilobar resections and type of pathology (cortical dysplasia). Quality-of-life measures generally paralleled seizure outcomes. These results indicate that epilepsy surgery in children with intractable epilepsy can result in significant improvements in seizure control, quality of life, and development. Anticipated type of surgery, presumed location of epileptogenic site, absence of a defined lesion on magnetic resonance imaging scan of the brain, and patient's age should not prevent surgical evaluations of children with intractable epilepsy.

Neuronal bursting properties in focal and parafocal regions in pediatric neocortical epilepsy stratified by histology.

To test the hypothesis that focal and parafocal neocortical tissue from pediatric patients with intractable epilepsy exhibits cellular and synaptic differences, the authors characterized the propensity of these neurons to generate (a) voltage-dependent bursting and (b) synaptically driven paroxysmal depolarization shifts. Neocortical slices were prepared from tissue resected from patients with intractable epilepsy. Multiunit network activity and simultaneous whole-cell patch recordings were made from neurons from three patient groups: (1) those with normal histology; (2) those with mild and severe cortical dysplasia; and (3) those with abnormal pathology but without cortical dysplasia. Seizure-like activity was characterized by population bursting with concomitant bursting in intracellularly recorded cortical neurons (n = 59). The authors found significantly more N-methyl-D-aspartic acid-driven voltage-dependent bursting neurons in focal versus parafocal tissue in patients with severe cortical dysplasia (P < 0.01). Occurrence of paroxysmal depolarization shifts and burst amplitude and burst duration were significantly related to tissue type: focal or parafocal (P < 0.05). The authors show that functional differences between focal and parafocal tissue in patients with severe cortical dysplasia exist. There are functional differences between patient groups with different histology, and bursting properties can be significantly associated with the distinction between focal and parafocal tissue.

Role of persistent sodium current in bursting activity of mouse neocortical networks in vitro.

Most types of electrographic epileptiform activity can be characterized by isolated or repetitive bursts in brain electrical activity. This observation is our motivation to determine mechanisms that underlie bursting behavior of neuronal networks. Here we show that the persistent sodium (Na(P)) current in mouse neocortical slices is associated with cellular bursting and our data suggest that these cells are capable of driving networks into a bursting state. This conclusion is supported by the following observations. 1) Both low concentrations of tetrodotoxin (TTX) and riluzole reduce and eventually stop network bursting while they simultaneously abolish intrinsic bursting properties and sensitivity levels to electrical stimulation in individual intrinsically bursting cells. 2) The sensitivity levels of regular spiking neurons are not significantly affected by riluzole or TTX at the termination of network bursting. 3) Propagation of cellular bursting in a neuronal network depended on excitatory connectivity and disappeared on bath application of CNQX (20 microM) + CPP (10 microM). 4) Voltage-clamp measurements show that riluzole (20 microM) and very low concentrations of TTX (50 nM) attenuate Na(P) currents in the neural membrane within a 1-min interval after bath application of the drug. 5) Recordings of synaptic activity demonstrate that riluzole at this concentration does not affect synaptic properties. 6) Simulations with a neocortical network model including different types of pyramidal cells, inhibitory interneurons, neurons with and without Na(P) currents, and recurrent excitation confirm the essence of our experimental observations that Na(P) conductance can be a critical factor sustaining slow population bursting.