Kyle E. Thomson

Human neocortical electrical activity recorded on nonpenetrating microwire arrays: applicability for neuroprostheses.

OBJECT The goal of this study was to determine whether a nonpenetrating, high-density microwire array could provide sufficient information to serve as the interface for decoding motor cortical signals. METHODS Arrays of nonpenetrating microwires were implanted over the human motor cortex in 2 patients. The patients performed directed stereotypical reaching movements in 2 directions. The resulting data were used to determine whether the reach direction could be distinguished through a frequency power analysis. RESULTS Correlation analysis revealed decreasing signal correlation with distance. The gamma-band power during motor planning allowed binary classification of gross directionality in the reaching movements. The degree of power change was correlated to the underlying gyral pattern. CONCLUSIONS The nonpenetrating microwire platform showed good potential for allowing differentiated signals to be recorded with high spatial fidelity without cortical penetration.

A Simple Quantitative Method for Analyzing Electrographic Status Epilepticus in Rats

Electrographic status epilepticus (ESE) is a medical emergency consisting of repetitive seizures and may result in death or severe brain damage. Epilepsy can develop following ESE. The properties of ESE (e.g., duration and intensity) are variable, as are the effects of putative therapeutic treatments. Therefore a straightforward method to quantify different components of ESE would be beneficial for both researchers and clinicians. A frequency range close to the gamma band was selected for extraction of seizure-related activity from the EEG. This filtering strategy reduced motion artifacts and other noise sources in the electrophysiological recordings, thus increasing the signal-to-noise ratio of the EEG spike activity. EEG spiking was quantified using an energy operator and modeled by an eighth-order polynomial. In a benzodiazepine-resistant rat model of pilocarpine-induced ESE, the efficacy of various pharmaceutical agents at suppressing ESE was analyzed with this and other methods on data collected for < or =24 h after ESE induction. This approach allows for the objective, quantitative, and rapid assessment of the effects of both short- and long-lasting pharmacological manipulations on ESE and other forms of prolonged repetitive electrical activity.

Classification of spoken words using surface local field potentials

Cortical surface potentials recorded by electrocorticography (ECoG) have enabled robust motor classification algorithms in large part because of the close proximity of the electrodes to the cortical surface. However, standard clinical ECoG electrodes are large in both diameter and spacing relative to the underlying cortical column architecture in which groups of neurons process similar types of stimuli. The potential for surface micro-electrodes closely spaced together to provide even higher fidelity in recording surface field potentials has been a topic of recent interest in the neural prosthetic community. This study describes the classification of spoken words from surface local field potentials (LFPs) recorded using grids of subdural, nonpenetrating high impedance micro-electrodes. Data recorded from these micro-ECoG electrodes supported accurate and rapid classification. Furthermore, electrodes spaced millimeters apart demonstrated varying classification characteristics, suggesting that cortical surface LFPs may be recorded with high temporal and spatial resolution to enable even more robust algorithms for motor classification.

Hippocampal TNFα signaling contributes to seizure generation in an infection-induced mouse model of limbic epilepsy

Abstract Central nervous system infection can induce epilepsy that is often refractory to established antiseizure drugs. Previous studies in the Theiler’s murine encephalomyelitis virus (TMEV)-induced mouse model of limbic epilepsy have demonstrated the importance of inflammation, especially that mediated by tumor necrosis factor-α (TNFα), in the development of acute seizures. TNFα modulates glutamate receptor trafficking via TNF receptor 1 (TNFR1) to cause increased excitatory synaptic transmission. Therefore, we hypothesized that an increase in TNFα signaling after TMEV infection might contribute to acute seizures. We found a significant increase in both mRNA and protein levels of TNFα and the protein expression ratio of TNF receptors (TNFR1:TNFR2) in the hippocampus, a brain region most likely involved in seizure initiation, after TMEV infection, which suggests that TNFα signaling, predominantly through TNFR1, may contribute to limbic hyperexcitability. An increase in hippocampal cell-surface glutamate receptor expression was also observed during acute seizures. Although pharmacological inhibition of TNFR1-mediated signaling had no effect on acute seizures, several lines of genetically modified animals deficient in either TNFα or TNFRs had robust changes in seizure incidence and severity after TMEV infection. TNFR2–/– mice were highly susceptible to developing acute seizures, suggesting that TNFR2-mediated signaling may provide beneficial effects during the acute seizure period. Taken together, the present results suggest that inflammation in the hippocampus, caused predominantly by TNFα signaling, contributes to hyperexcitability and acute seizures after TMEV infection. Pharmacotherapies designed to suppress TNFR1-mediated or augment TNFR2-mediated effects of TNFα may provide antiseizure and disease-modifying effects after central nervous system infection.

The impact of nonadherence to antiseizure drugs on seizure outcomes in an animal model of epilepsy

Nonadherence to prescribed dosing regimens is a significant problem in the treatment of pediatric and adult chronic epilepsy, and can result in severe consequences to patient outcomes. In this first‐of‐kind preclinical study, the impact of nonadherence on seizure control was studied by simulating human patterns of nonadherence in an animal epilepsy model.

Repeated low-dose kainate administration in C57BL/6J mice produces temporal lobe epilepsy pathology but infrequent spontaneous seizures.

More efficient or translationally relevant approaches are needed to model acquired temporal lobe epilepsy (TLE) in genetically tractable mice. The high costs associated with breeding and maintaining transgenic, knock-in, or knock-out lines place a high value on the efficiency of induction and animal survivability. Herein, we describe our approaches to model acquired epilepsy in C57BL/6J mice using repeated, low-dose kainate (KA) administration paradigms. Four paradigms (i.p.) were tested for their ability to induce status epilepticus (SE), temporal lobe pathology, and the development of epilepsy. All four paradigms reliably induce behavioral and/or electrographic SE without mortality over a 7d period. Two of the four paradigms investigated produce features indicative of TLE pathology, including hippocampal cell death, widespread astrogliosis, and astrocyte expression of mGluR5, a feature commonly reported in TLE models. Three of the investigated paradigms were able to produce aberrant electrographic features, such as interictal spiking in cortex. However, only one paradigm, previously published by others, produces spontaneous recurrent seizures over an eight week period. Presentation of spontaneous seizures is rare (N=2/14), with epilepsy preferentially developing in animals having a high number of seizures during SE. Overall, repeated, low-dose KA administration improves the efficiency and pathological relevance of a systemic KA insult, but does not produce a robust epilepsy phenotype under the experimental paradigms described herein.

Development and pharmacologic characterization of the rat 6 Hz model of partial seizures

The mouse 6 Hz model of psychomotor seizures is a well‐established and commonly used preclinical model for antiseizure drug (ASD) discovery. Despite its widespread use both in the identification and differentiation of novel ASDs in mice, a corresponding assay in rats has not been developed. We established a method for 6 Hz seizure induction in rats, with seizure behaviors similar to those observed in mice including head nod, jaw clonus, and forelimb clonus.