Characterizing the treatment gap in the United States among adult patients with a new diagnosis of epilepsy.

OBJECTIVE: Epilepsy is largely a treatable condition with antiseizure medication (ASM). Recent national administrative claims data suggest one third of newly diagnosed adult epilepsy patients remain untreated 3 years after diagnosis. We aimed to quantify and characterize this treatment gap within a large US academic health system leveraging the electronic health record for enriched clinical detail. METHODS: This retrospective cohort study evaluated the proportion of adult patients in the health system from 2012 to 2020 who remained untreated 3 years after initial epilepsy diagnosis. To identify incident epilepsy, we applied validated administrative health data criteria of two encounters for epilepsy/seizures and/or convulsions, and we required no ASM prescription preceding the first encounter. Engagement with the health system at least 2 years before and at least 3 years after diagnosis was required. Among subjects who met administrative data diagnosis criteria, we manually reviewed medical records for a subset of 240 subjects to verify epilepsy diagnosis, confirm treatment status, and elucidate reason for nontreatment. These results were applied to estimate the proportion of the full cohort with untreated epilepsy. RESULTS: Of 831 patients who were automatically classified as having incident epilepsy by inclusion criteria, 80 (10%) remained untreated 3 years after incident epilepsy diagnosis. Manual chart review of incident epilepsy classification revealed only 33% (78/240) had true incident epilepsy. We found untreated patients were more frequently misclassified (p < .001). Using corrected counts, we extrapolated to the full cohort (831) and estimated <1%-3% had true untreated epilepsy. SIGNIFICANCE: We found a substantially lower proportion of patients with newly diagnosed epilepsy remained untreated compared to previous estimates from administrative data analysis. Manual chart review revealed patients were frequently misclassified as having incident epilepsy, particularly patients who were not treated with an ASM. Administrative data analyses utilizing only diagnosis codes may misclassify patients as having incident epilepsy.

A companion to the preclinical common data elements and case report forms for rodent EEG studies. A report of the TASK3 EEG Working Group of the ILAE/AES Joint Translational Task Force.

Electroencephalography (EEG) is commonly used in epilepsy and neuroscience research to study brain activity. The principles of EEG recording such as signal acquisition, digitization, and conditioning share similarities between animal and clinical EEG systems. In contrast, preclinical EEG studies demonstrate more variability and diversity than clinical studies in the types and locations of EEG electrodes, methods of data analysis, and scoring of EEG patterns and associated behaviors. The TASK3 EEG working group of the International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force has developed a set of preclinical common data elements (CDEs) and case report forms (CRFs) for recording, analysis, and scoring of animal EEG studies. This companion document accompanies the first set of proposed preclinical EEG CRFs and is intended to clarify the CDEs included in these worksheets. We provide 7 CRF and accompanying CDE modules for use by the research community, covering video acquisition, electrode information, experimental scheduling, and scoring of EEG activity. For ease of use, all data elements and input ranges are defined in supporting Excel charts (Appendix S1).

Standards for data acquisition and software-based analysis of in vivo electroencephalography recordings from animals. A TASK1-WG5 report of the AES/ILAE Translational Task Force of the ILAE.

Electroencephalography (EEG)-the direct recording of the electrical activity of populations of neurons-is a tremendously important tool for diagnosing, treating, and researching epilepsy. Although standard procedures for recording and analyzing human EEG exist and are broadly accepted, there are no such standards for research in animal models of seizures and epilepsy-recording montages, acquisition systems, and processing algorithms may differ substantially among investigators and laboratories. The lack of standard procedures for acquiring and analyzing EEG from animal models of epilepsy hinders the interpretation of experimental results and reduces the ability of the scientific community to efficiently translate new experimental findings into clinical practice. Accordingly, the intention of this report is twofold: (1) to review current techniques for the collection and software-based analysis of neural field recordings in animal models of epilepsy, and (2) to offer pertinent standards and reporting guidelines for this research. Specifically, we review current techniques for signal acquisition, signal conditioning, signal processing, data storage, and data sharing, and include applicable recommendations to standardize collection and reporting. We close with a discussion of challenges and future opportunities, and include a supplemental report of currently available acquisition systems and analysis tools. This work represents a collaboration on behalf of the American Epilepsy Society/International League Against Epilepsy (AES/ILAE) Translational Task Force (TASK1-Workgroup 5), and is part of a larger effort to harmonize video-EEG interpretation and analysis methods across studies using in vivo and in vitro seizure and epilepsy models.

Lateral and feedforward inhibition suppress asynchronous activity in a large, biophysically-detailed computational model of the striatal network.

Striatal medium spiny neurons (MSNs) receive lateral inhibitory projections from other MSNs and feedforward inhibitory projections from fast-spiking, parvalbumin-containing striatal interneurons (FSIs). The functional roles of these connections are unknown, and difficult to study in an experimental preparation. We therefore investigated the functionality of both lateral (MSN-MSN) and feedforward (FSI-MSN) inhibition using a large-scale computational model of the striatal network. The model consists of 2744 MSNs comprised of 189 compartments each and 121 FSIs comprised of 148 compartments each, with dendrites explicitly represented and almost all known ionic currents included and strictly constrained by biological data as appropriate. Our analysis of the model indicates that both lateral inhibition and feedforward inhibition function at the population level to limit non-ensemble MSN spiking while preserving ensemble MSN spiking. Specifically, lateral inhibition enables large ensembles of MSNs firing synchronously to strongly suppress non-ensemble MSNs over a short time-scale (10-30 ms). Feedforward inhibition enables FSIs to strongly inhibit weakly activated, non-ensemble MSNs while moderately inhibiting activated ensemble MSNs. Importantly, FSIs appear to more effectively inhibit MSNs when FSIs fire asynchronously. Both types of inhibition would increase the signal-to-noise ratio of responding MSN ensembles and contribute to the formation and dissolution of MSN ensembles in the striatal network.

Exposure to cocaine dynamically regulates the intrinsic membrane excitability of nucleus accumbens neurons.

Drug-induced malfunction of nucleus accumbens (NAc) neurons underlies a key pathophysiology of drug addiction. Drug-induced changes in intrinsic membrane excitability of NAc neurons are thought to be critical for producing behavioral alterations. Previous studies demonstrate that, after short-term (2 d) or long-term (21 d) withdrawal from noncontingent cocaine injection, the intrinsic membrane excitability of NAc shell (NAcSh) neurons is decreased, and decreased membrane excitability of NAcSh neurons increases the acute locomotor response to cocaine. However, animals exhibit distinct cellular and behavioral alterations at different stages of cocaine exposure, suggesting that the decreased membrane excitability of NAc neurons may not be a persistent change. Here, we demonstrate that the membrane excitability of NAcSh neurons is differentially regulated depending on whether cocaine is administered contingently or noncontingently. Specifically, the membrane excitability of NAcSh medium spiny neurons (MSNs) was decreased at 2 d after withdrawal from either 5 d intraperitoneal injections (15 mg/kg) or cocaine self-administration (SA). At 21 d of withdrawal, the membrane excitability of NAcSh MSNs, which remained low in intraperitoneally pretreated rats, returned to a normal level in SA-pretreated rats. Furthermore, after a reexposure to cocaine after long-term withdrawal, the membrane excitability of NAcSh MSNs instantly returned to a normal level in intraperitoneally pretreated rats. Conversely, in SA-pretreated rats, the reexposure elevated the membrane excitability of NAcSh MSMs beyond the normal level. These results suggest that the dynamic alterations in membrane excitability of NAcSh MSNs, together with the dynamic changes in synaptic input, contribute differentially to the behavioral consequences of contingent and noncontingent cocaine administration.

Homeostatic synapse-driven membrane plasticity in nucleus accumbens neurons.

Stable brain function relies on homeostatic maintenance of the functional output of individual neurons. In general, neurons function by converting synaptic input to output as action potential firing. To determine homeostatic mechanisms that balance this input-output/synapse-membrane interaction, we focused on nucleus accumbens (NAc) neurons and demonstrated a novel form of synapse-to-membrane homeostatic regulation, homeostatic synapse-driven membrane plasticity (hSMP). Through hSMP, NAc neurons adjusted their membrane excitability to functionally compensate for basal shifts in excitatory synaptic input. Furthermore, hSMP was triggered by synaptic NMDA receptors (NMDARs) and expressed by the modification of SK-type Ca(2+)-activated potassium channels. Moreover, hSMP in NAc neurons was abolished in rats during a short- (2 d) or long- (21 d) term withdrawal from repeated intraperitoneal injections of cocaine (15 mg/kg/d, 5 d). These results suggest that hSMP is a novel form of synapse-to-membrane homeostatic plasticity and dysregulation of hSMP may contribute to cocaine-induced cellular alterations in the NAc.

Effects of dopaminergic modulation on the integrative properties of the ventral striatal medium spiny neuron.

Dopaminergic modulation produces a variety of functional changes in the principal cell of the striatum, the medium spiny neuron (MSN). Using a 189-compartment computational model of a ventral striatal MSN, we simulated whole cell D1- and D2-receptor-mediated modulation of both intrinsic (sodium, calcium, and potassium) and synaptic currents (AMPA and NMDA). Dopamine (DA) modulations in the model were based on a review of published experiments in both ventral and dorsal striatum. To objectively assess the net effects of DA modulation, we combined reported individual channel modulations into either D1- or D2-receptor modulation conditions and studied them separately. Contrary to previous suggestions, we found that D1 modulation had no effect on MSN nonlinearity and could not induce bistability. In agreement with previous suggestions, we found that dopaminergic modulation leads to changes in input filtering and neuronal excitability. Importantly, the changes in neuronal excitability agree with the classical model of basal ganglia function. We also found that DA modulation can alter the integration time window of the MSN. Interestingly, the effects of DA modulation of synaptic properties opposed the effects of DA modulation of intrinsic properties, with the synaptic modulations generally dominating the net effect. We interpret this lack of synergy to suggest that the regulation of whole cell integrative properties is not the primary functional purpose of DA. We suggest that D1 modulation might instead primarily regulate calcium influx to dendritic spines through NMDA and L-type calcium channels, by both direct and indirect mechanisms.

Implementation of dual simultaneous microelectrode recording systems during deep brain stimulation surgery for Parkinson's disease: technical note.

OBJECTIVE: Microelectrode recording during deep brain stimulation surgery improves the likelihood of successful target localization and enables the electrophysiological characterization of human neural structures. Many clinical recording systems do not support the ability to capture research-quality recordings. Established clinical centers already using such equipment may be prevented from acquiring human intracranial data because of the need to completely change recording systems to obtain research-quality recordings. This technical note describes the novel design and implementation of a recording system that significantly improves research capabilities without disrupting the existing clinical setup. METHODS: This design introduces a second recording system (including pre-amplifier, differential amplifier, analog-to-digital converter, and computer with analysis software) that divides the microelectrode signal into two independent streams. RESULTS: This design preserves the existing intraoperative recording setup, but significantly improves research-level recording, data storage, and analysis capabilities. CONCLUSION: We provide the first description of such a system using components that are all commercially available and relatively inexpensive. This approach presents an appealing alternative to the purchase of an entirely new system for surgical teams that already perform intraoperative recordings to assist in stereotactic target localization, yet wish to expand their neurophysiological recording capabilities.

Conventional MRI is inadequate to delineate the relationship between the red nucleus and subthalamic nucleus in Parkinson's disease.

BACKGROUND: An understanding of the relationships between the anterior commissure-posterior commissure line (AC-PC), the subthalamic nucleus (STN), and red nucleus (RN) is imperative if these structures are to be used for targeting in deep brain stimulation. Currently, these relationships are incompletely understood and difficult to assess using conventional MRI. We examined the location and relationships of the STN and the RN to the AC-PC line and to each other in order to provide a greater understanding of their utility when targeting the STN, and the consistency of these anatomic relationships when examined using conventional MRI. METHODS: A total of 52 STN and RN in 26 patients with Parkinson's disease were evaluated on T2-weighted MR images. The anterior and posterior commissures and the border coordinates of the STN and RN were derived using frame coordinates. The distances from the midcommissural point (mcp) to the centers of the STN and RN, the diameters for each nucleus, and the distances between the nuclei were calculated in the x-, y-, and z-axes. RESULTS: The mean AC-PC length was 26.1 +/- 1.3 mm. The distance from the mcp to the center of the STN was 10 +/- 0.7 mm in the x-axis, 0.2 +/- 0.7 mm in the y-axis, and 3.3 +/- 0.9 mm in the z-axis. The distance from the mcp to the center of the RN was 4.7 +/- 0.6 mm in the x-axis, -5.9 +/- 1.0 mm in the y-axis, and 6.1 +/- 1.3 mm in the z-axis. The distance between the STN and RN was 2.3 +/- 0.7 mm in the x-axis, 2.1 +/- 1.0 mm in the y-axis, and -0.2 +/- 1.3 mm in the z-axis. CONCLUSIONS: Although recent studies imply that the RN can be used as a relatively consistent marker for the position of the STN, the present data suggest otherwise. These data indicate that a single targeting method may be inadequate given the resolution of conventional MRI, and that it is imperative to use multiple anatomical measurements when targeting the STN for deep brain stimulation in Parkinson's disease.

NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computational model of the nucleus accumbens medium spiny projection neuron.

We describe a computational model of the principal cell in the nucleus accumbens (NAcb), the medium spiny projection (MSP) neuron. The model neuron, constructed in NEURON, includes all of the known ionic currents in these cells and receives synaptic input from simulated spike trains via NMDA, AMPA, and GABAA receptors. After tuning the model by adjusting maximal current conductances in each compartment, the model cell closely matched whole-cell recordings from an adult rat NAcb slice preparation. Synaptic inputs in the range of 1000-1300 Hz are required to maintain an "up" state in the model. Cell firing in the model required concurrent depolarization of several dendritic branches, which responded independently to afferent input. Depolarization from action potentials traveled to the tips of the dendritic branches and increased Ca2+ influx through voltage-gated Ca2+ channels. As NMDA/AMPA current ratios were increased, the membrane showed an increase in hysteresis of "up" and "down" state dwell times, but intrinsic bistability was not observed. The number of oscillatory inputs required to entrain the model cell was determined to be approximately 20% of the "up" state inputs. Altering the NMDA/AMPA ratio had a profound effect on processing of afferent input, including the ability to entrain to oscillations in afferent input in the theta range (4-12 Hz). These results suggest that afferent information integration by the NAcb MSP cell may be compromised by pathology in which the NMDA current is altered or modulated, as has been proposed in both schizophrenia and addiction.