Seizure Detection, Prediction, and Forecasting.

SUMMARY: Among the many fears associated with seizures, patients with epilepsy are greatly frustrated and distressed over seizure's apparent unpredictable occurrence. However, increasing evidence have emerged over the years to support that seizure occurrence is not a random phenomenon as previously presumed; it has a cyclic rhythm that oscillates over multiple timescales. The pattern in rises and falls of seizure rate that varies over 24 hours, weeks, months, and years has become a target for the development of innovative devices that intend to detect, predict, and forecast seizures. This article will review the different tools and devices available or that have been previously studied for seizure detection, prediction, and forecasting, as well as the associated challenges and limitations with the utilization of these devices. Although there is strong evidence for rhythmicity in seizure occurrence, very little is known about the mechanism behind this oscillation. This article concludes with early insights into the regulations that may potentially drive this cyclical variability and future directions.

Guidelines for Specialized Epilepsy Centers: Executive Summary of the Report of the National Association of Epilepsy Centers Guideline Panel.

The National Association of Epilepsy Centers first published the guidelines for epilepsy centers in 1990, which were last updated in 2010. Since that update, epilepsy care and the science of guideline development have advanced significantly, including the importance of incorporating a diversity of stakeholder perspectives such as those of patients and their caregivers. Currently, despite extensive published data examining the efficacy of treatments and diagnostic testing for epilepsy, there remain significant gaps in data identifying the essential services needed for a comprehensive epilepsy center and the optimal manner for their delivery. The trustworthy consensus-based statements (TCBS) process produces unbiased, scientifically valid guidelines through a transparent process that incorporates available evidence and expert opinion. A systematic literature search returned 5937 relevant studies from which 197 articles were retained for data extraction. A panel of 41 stakeholders with diverse expertise evaluated this evidence and drafted recommendations following the TCBS process. The panel reached consensus on 52 recommendations covering services provided by specialized epilepsy centers in both the inpatient and outpatient settings in major topic areas including epilepsy monitoring unit care, surgery, neuroimaging, neuropsychology, genetics, and outpatient care. Recommendations were informed by the evidence review and reflect the consensus of a broad panel of expert opinions.

Optimizing Surgical Planning for Epilepsy Patients With Multimodal Neuroimaging and Neurophysiology Integration: A Case Study.

SUMMARY: Current preoperative evaluation of epilepsy can be challenging because of the lack of a comprehensive view of the network's dysfunctions. To demonstrate the utility of our multimodal neurophysiology and neuroimaging integration approach in the presurgical evaluation, we present a proof-of-concept for using this approach in a patient with nonlesional frontal lobe epilepsy who underwent two resective surgeries to achieve seizure control. We conducted a post-hoc investigation using four neuroimaging and neurophysiology modalities: diffusion tensor imaging, resting-state functional MRI, and stereoelectroencephalography at rest and during seizures. We computed region-of-interest-based connectivity for each modality and applied betweenness centrality to identify key network hubs across modalities. Our results revealed that despite seizure semiology and stereoelectroencephalography indicating dysfunction in the right orbitofrontal region, the maximum overlap on the hubs across modalities extended to right temporal areas. Notably, the right middle temporal lobe region served as an overlap hub across diffusion tensor imaging, resting-state functional MRI, and rest stereoelectroencephalography networks and was only included in the resected area in the second surgery, which led to long-term seizure control of this patient. Our findings demonstrated that transmodal hubs could help identify key areas related to epileptogenic network. Therefore, this case presents a promising perspective of using a multimodal approach to improve the presurgical evaluation of patients with epilepsy.

Induction and Quantification of Excitability Changes in Human Cortical Networks.

How does human brain stimulation result in lasting changes in cortical excitability? Uncertainty on this question hinders the development of personalized brain stimulation therapies. To characterize how cortical excitability is altered by stimulation, we applied repetitive direct electrical stimulation in eight human subjects (male and female) undergoing intracranial monitoring. We evaluated single-pulse corticocortical-evoked potentials (CCEPs) before and after repetitive stimulation across prefrontal (n = 4), temporal (n = 1), and motor (n = 3) cortices. We asked whether a single session of repetitive stimulation was sufficient to induce excitability changes across distributed cortical sites. We found a subset of regions at which 10 Hz prefrontal repetitive stimulation resulted in both potentiation and suppression of excitability that persisted for at least 10 min. We then asked whether these dynamics could be modeled by the prestimulation connectivity profile of each subject. We found that cortical regions (1) anatomically close to the stimulated site and (2) exhibiting high-amplitude CCEPs underwent changes in excitability following repetitive stimulation. We demonstrate high accuracy (72-95%) and discriminability (81-99%) in predicting regions exhibiting changes using individual subjects' prestimulation connectivity profile, and show that adding prestimulation connectivity features significantly improved model performance. The same features predicted regions of modulation following motor and temporal cortices stimulation in an independent dataset. Together, baseline connectivity profile can be used to predict regions susceptible to brain changes and provides a basis for personalizing brain stimulation.SIGNIFICANCE STATEMENT Brain stimulation is increasingly used to treat neuropsychiatric disorders by inducing excitability changes at specific brain regions. However, our understanding of how, when, and where these changes are induced is critically lacking. We inferred plasticity in the human brain after applying electrical stimulation to the brain's surface and measuring changes in excitability. We observed excitability changes in regions anatomically and functionally closer to the stimulation site. Those in responsive regions were accurately predicted using a classifier trained on baseline brain network characteristics. Finally, we showed that the excitability changes can potentially be monitored in real-time. These results begin to fill basic gaps in our understanding of stimulation-induced brain dynamics in humans and offer pathways to optimize stimulation protocols.

Tuning face perception with electrical stimulation of the fusiform gyrus.

The fusiform gyrus (FG) is an important node in the face processing network, but knowledge of its causal role in face perception is currently limited. Recent work demonstrated that high frequency stimulation applied to the FG distorts the perception of faces in human subjects (Parvizi et al. []: J Neurosci 32:14915-14920). However, the timing of this process in the FG relative to stimulus onset and the spatial extent of FG's role in face perception are unknown. Here, we investigate the causal role of the FG in face perception by applying precise, event-related electrical stimulation (ES) to higher order visual areas including the FG in six human subjects undergoing intracranial monitoring for epilepsy. We compared the effects of single brief (100 µs) electrical pulses to the FG and non-face-selective visual areas on the speed and accuracy of detecting distorted faces. Brief ES applied to face-selective sites did not affect accuracy but significantly increased the reaction time (RT) of detecting face distortions. Importantly, RT was altered only when ES was applied 100ms after visual onset and in face-selective but not place-selective sites. Furthermore, ES applied to face-selective areas decreased the amplitude of visual evoked potentials and high gamma power over this time window. Together, these results suggest that ES of face-selective regions within a critical time window induces a delay in face perception. These findings support a temporally and spatially specific causal role of face-selective areas and signify an important link between electrophysiology and behavior in face perception. Hum Brain Mapp 38:2830-2842, 2017. © 2017 Wiley Periodicals, Inc.

iELVis: An open source MATLAB toolbox for localizing and visualizing human intracranial electrode data.

BACKGROUND: Intracranial electrical recordings (iEEG) and brain stimulation (iEBS) are invaluable human neuroscience methodologies. However, the value of such data is often unrealized as many laboratories lack tools for localizing electrodes relative to anatomy. To remedy this, we have developed a MATLAB toolbox for intracranial electrode localization and visualization, iELVis. NEW METHOD: iELVis uses existing tools (BioImage Suite, FSL, and FreeSurfer) for preimplant magnetic resonance imaging (MRI) segmentation, neuroimaging coregistration, and manual identification of electrodes in postimplant neuroimaging. Subsequently, iELVis implements methods for correcting electrode locations for postimplant brain shift with millimeter-scale accuracy and provides interactive visualization on 3D surfaces or in 2D slices with optional functional neuroimaging overlays. iELVis also localizes electrodes relative to FreeSurfer-based atlases and can combine data across subjects via the FreeSurfer average brain. RESULTS: It takes 30-60min of user time and 12-24h of computer time to localize and visualize electrodes from one brain. We demonstrate iELVis's functionality by showing that three methods for mapping primary hand somatosensory cortex (iEEG, iEBS, and functional MRI) provide highly concordant results. COMPARISON WITH EXISTING METHODS: iELVis is the first public software for electrode localization that corrects for brain shift, maps electrodes to an average brain, and supports neuroimaging overlays. Moreover, its interactive visualizations are powerful and its tutorial material is extensive. CONCLUSIONS: iELVis promises to speed the progress and enhance the robustness of intracranial electrode research. The software and extensive tutorial materials are freely available as part of the EpiSurg software project: https://github.com/episurg/episurg.

Evaluation of cortical local field potential diffusion in stereotactic electro-encephalography recordings: A glimpse on white matter signal.

While there is a strong interest in meso-scale field potential recording using intracranial electroencephalography with penetrating depth electrodes (i.e. stereotactic EEG or S-EEG) in humans, the signal recorded in the white matter remains ignored. White matter is generally considered electrically neutral and often included in the reference montage. Moreover, re-referencing electrophysiological data is a critical preprocessing choice that could drastically impact signal content and consequently the results of any given analysis. In the present stereotactic electroencephalography study, we first illustrate empirically the consequences of commonly used references (subdermal, white matter, global average, local montage) on inter-electrode signal correlation. Since most of these reference montages incorporate white matter signal, we next consider the difference between signals recorded in cortical gray matter and white matter. Our results reveal that electrode contacts located in the white matter record a mixture of activity, with part arising from the volume conduction (zero time delay) of activity from nearby gray matter. Furthermore, our analysis shows that white matter signal may be correlated with distant gray matter signal. While residual passive electrical spread from nearby matter may account for this relationship, our results suggest the possibility that this long distance correlation arises from the white matter fiber tracts themselves (i.e. activity from distant gray matter traveling along axonal fibers with time lag larger than zero); yet definitive conclusions about the origin of the white matter signal would require further experimental substantiation. By characterizing the properties of signals recorded in white matter and in gray matter, this study illustrates the importance of including anatomical prior knowledge when analyzing S-EEG data.

The Limited Utility of Multiunit Data in Differentiating Neuronal Population Activity.

To date, single neuron recordings remain the gold standard for monitoring the activity of neuronal populations. Since obtaining single neuron recordings is not always possible, high frequency or 'multiunit activity' (MUA) is often used as a surrogate. Although MUA recordings allow one to monitor the activity of a large number of neurons, they do not allow identification of specific neuronal subtypes, the knowledge of which is often critical for understanding electrophysiological processes. Here, we explored whether prior knowledge of the single unit waveform of specific neuron types is sufficient to permit the use of MUA to monitor and distinguish differential activity of individual neuron types. We used an experimental and modeling approach to determine if components of the MUA can monitor medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) in the mouse dorsal striatum. We demonstrate that when well-isolated spikes are recorded, the MUA at frequencies greater than 100Hz is correlated with single unit spiking, highly dependent on the waveform of each neuron type, and accurately reflects the timing and spectral signature of each neuron. However, in the absence of well-isolated spikes (the norm in most MUA recordings), the MUA did not typically contain sufficient information to permit accurate prediction of the respective population activity of MSNs and FSIs. Thus, even under ideal conditions for the MUA to reliably predict the moment-to-moment activity of specific local neuronal ensembles, knowledge of the spike waveform of the underlying neuronal populations is necessary, but not sufficient.

Corticocortical evoked potentials reveal projectors and integrators in human brain networks.

The cerebral cortex is composed of subregions whose functional specialization is largely determined by their incoming and outgoing connections with each other. In the present study, we asked which cortical regions can exert the greatest influence over other regions and the cortical network as a whole. Previous research on this question has relied on coarse anatomy (mapping large fiber pathways) or functional connectivity (mapping inter-regional statistical dependencies in ongoing activity). Here we combined direct electrical stimulation with recordings from the cortical surface to provide a novel insight into directed, inter-regional influence within the cerebral cortex of awake humans. These networks of directed interaction were reproducible across strength thresholds and across subjects. Directed network properties included (1) a decrease in the reciprocity of connections with distance; (2) major projector nodes (sources of influence) were found in peri-Rolandic cortex and posterior, basal and polar regions of the temporal lobe; and (3) major receiver nodes (receivers of influence) were found in anterolateral frontal, superior parietal, and superior temporal regions. Connectivity maps derived from electrical stimulation and from resting electrocorticography (ECoG) correlations showed similar spatial distributions for the same source node. However, higher-level network topology analysis revealed differences between electrical stimulation and ECoG that were partially related to the reciprocity of connections. Together, these findings inform our understanding of large-scale corticocortical influence as well as the interpretation of functional connectivity networks.

Neurophysiological investigation of spontaneous correlated and anticorrelated fluctuations of the BOLD signal.

Analyses of intrinsic fMRI BOLD signal fluctuations reliably reveal correlated and anticorrelated functional networks in the brain. Because the BOLD signal is an indirect measure of neuronal activity and anticorrelations can be introduced by preprocessing steps, such as global signal regression, the neurophysiological significance of correlated and anticorrelated BOLD fluctuations is a source of debate. Here, we address this question by examining the correspondence between the spatial organization of correlated BOLD fluctuations and correlated fluctuations in electrophysiological high γ power signals recorded directly from the cortical surface of 5 patients. We demonstrate that both positive and negative BOLD correlations have neurophysiological correlates reflected in fluctuations of spontaneous neuronal activity. Although applying global signal regression to BOLD signals results in some BOLD anticorrelations that are not apparent in the ECoG data, it enhances the neuronal-hemodynamic correspondence overall. Together, these findings provide support for the neurophysiological fidelity of BOLD correlations and anticorrelations.

Pathophysiology of epileptic encephalopathies.

The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically of the cortex. We argue that the effects of focal lesions may be magnified through the interaction between cortical and subcortical structures, and that disruption of subcortical arousal centers that regulate cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on electroencephalography (EEG) and as developmental delay or arrest clinically. Finally, prolonged focal epileptic activity during sleep (as occurring in the syndrome of continuous spike-wave in slow sleep, or CSWSS) might interfere with local slow wave activity at the site of the epileptic focus, thereby impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions. Seizures may certainly add to these pathologic processes, but they are likely not necessary for the development of the cognitive pathology. Nevertheless, although seizures may be either a consequence or symptom of the underlying lesion, their effective treatment can improve outcomes as both clinical and experimental studies may suggest. Understanding their substrates may lead to novel, effective treatments for all aspects of the epileptic encephalopathy phenotype.

Interrater reliability to assure valid content in peer review of CME-accredited presentations.

INTRODUCTION: The Accreditation Council for Continuing Medical Education (ACCME) provides guidelines for continuing medical education (CME) materials to mitigate problems in the independence or validity of content in certified activities; however, the process of peer review of materials appears largely unstudied and the reproducibility of peer-review audits for ACCME accreditation and designation of American Medical Association Category 1 Credit(TM) is unknown. METHODS: Categories of presentation defects were constructed from discussions of the CME committee of the American Epilepsy Society: (1) insufficient citation, (2) poor formatting, (3) nonacknowledgment of non-FDA-approved use, (4) misapplied data, (5) 1-sided data, (6) self- or institutional promotion, (7) conflict of interest/commercial bias, (8) other, or (9) no defect. A PowerPoint lecture (n = 29 slides) suitable for presentation to general neurologists was purposefully created with the above defects. A multirater, multilevel kappa statistic was determined from the number and category of defects. RESULTS: Of 14 reviewers, 12 returned completed surveys (86%) identifying a mean +/- standard deviation 1.6 +/- 1.1 defects/slide. The interrater kappa equaled 0.115 (poor reliability) for number of defects/slides. No individual categories achieved kappa > 0.38. DISCUSSION: Interrater reliability on the rating of durable materials used in subspecialty CME was poor. Guidelines for CME appropriate content are too subjective to be applied reliably by raters knowledgeable in their specialty field but relatively untrained in the specifics of CME requirements. The process of peer review of CME materials would be aided by education of physicians on validation of materials appropriate for CME.

How do seizures stop?

Although often overshadowed by factors influencing seizure initiation, seizure termination is a critical step in the return to the interictal state. Understanding the mechanisms contributing to seizure termination could potentially identify novel targets for anticonvulsant drug development and may also highlight the pathophysiological processes contributing to seizure initiation. In this article, we review known physiological mechanisms contributing to seizure termination and discuss additional mechanisms that are likely to be relevant even though specific data are not yet available. This review is organized according to successively increasing "size scales"-from membranes to synapses to networks to circuits. We first discuss mechanisms of seizure termination acting at the shortest distances and affecting the excitable membranes of neurons in the seizure onset zone. Next we consider the contributions of ensembles of neurons and glia interacting at intermediate distances within the region of the seizure onset zone. Lastly, we consider the contribution of brain nuclei, such as the substantia nigra pars reticulata (SNR), that are capable of modulating seizures and exert their influence over the seizure onset zone (and neighboring areas) from a relatively great-in neuroanatomical terms-distance. It is our hope that the attention to the mechanisms contributing to seizure termination will stimulate novel avenues of epilepsy research and will contribute to improved patient care.

Are early myoclonic encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other?

BACKGROUND: Early myoclonic encephalopathy (EME) and the Ohtahara syndrome are currently listed as two separate syndromes in the classification of epilepsies. The most prominent differentiating points are the observations that patients with Ohtahara syndrome experience predominantly tonic seizures; their seizures evolve to infantile spasms and the prognosis is often worse than patients with EME. SUMMARY POINTS: We performed a literature review of published cases. Although syndromes may have distinct courses, the differentiation early on may be impossible as both myoclonus and tonic seizures may coexist. There is also an overlap in the etiologies. Tonic seizures are considered a manifestation of brainstem dysfunction and it is possible that this is more prominent in Ohtahara syndrome. To date, there are 17 autopsy cases (12 presumed to be Ohtahara cases and 5 EME). Evidence of hindbrain pathology was present in all. Tonic seizures or tonic posturing was a feature of all cases. We suggest that the two syndromes may represent a continuum and that the prominence of tonic seizures in the Ohtahara syndrome may be an indication of brainstem dysfunction which may play an important role in the subsequent transition to infantile spasms.

Chronic bilateral stimulation of the anterior thalamus of kainate-treated rats increases seizure frequency.

PURPOSE: Electrical stimulation of the anterior nucleus of the thalamus (ANT) is receiving increased attention as a novel means of controlling intractable epilepsy, and has entered human clinical trial. Animal data supporting the anticonvulsant benefit of ANT stimulation, however, has been obtained from acute chemoconvulsant models of epilepsy rather than models of chronic epilepsy with spontaneous seizures. It is unknown whether ANT stimulation is effective in models of chronic epilepsy. METHODS: Bilateral ANT stimulation was evaluated in rats with chronic epilepsy following acute status epilepticus (SE) produced by systemic kainic acid (KA) administration. The evolution of epilepsy following KA SE and the effects of ANT stimulation were monitored by continuous video-EEG. RESULTS: Following KA SE, most rats have 2-8 seizures per day, and the average seizure rate increases over time, doubling over the course of 14 weeks. Behavioral seizure severity, after the initial development of epilepsy, remains stable. Seizure frequency during ANT stimulation was 2.5 times the baseline seizure frequency. In some cases stimulation triggered seizures were observed. The effects of stimulation were specific to the ANT. Stimulation applied to electrodes placed outside the ANT did not significantly worsen seizure frequency. CONCLUSIONS: ANT stimulation exacerbated seizure frequency in rats with chronic epilepsy following kainate status epilepticus.

Seizures in the developing brain.

PURPOSE: Development and sex hormones are important determinants of seizure susceptibility. Seizures develop in the immature brain more readily than in the mature brain. Male children experience a higher incidence of epilepsy or unprovoked seizures than do female children. Sex-specific differences in the development of seizure-suppressing neuronal networks may account, at least in part, for this increased age- and sex-related susceptibility to seizures. The control of seizures can be influenced by the substantia nigra pars reticulata (SNR) in an age- and sex-specific manner. In the adult male rat SNR, two topographically discrete regions (SNRanterior and SNRposterior) mediate distinct effects on seizures, by using divergent output networks in response to localized infusions of gamma-aminobutyric acid (GABA)A agents, such as muscimol. The GABAA-sensitive "anticonvulsant" region is located in the SNRanterior, whereas the GABAA-sensitive "proconvulsant region is in the SNRposterior. In immature postnatal day (PN)15-21 male rats, the SNR is not topographically segregated, and GABAAergic drug infusions produce similar effects when applied in the SNRanterior or SNRposterior. Only a GABAA-sensitive proconvulsant network is evident. By contrast, female SNR does not contain any region that mediates muscimol-related proconvulsant effects. As with the adult, immature female rats do not develop a proconvulsant SNR region at any age. METHODS: We measured the effects of SNR muscimol infusions on seizures in male rats castrated at birth to better understand the effects of testosterone on the formation of age- and sex-specific features of the SNR. RESULTS: Neonatal castration permanently alters the maturation of the muscimol-sensitive SNR effect on seizures. The SNR of neonatally castrated rats develops functionally like the "female" SNR. The "proconvulsant" SNR region does not develop in the absence of testosterone in the immediate postnatal period. The "male" type of SNR effects can be induced in neonatally castrated rats by restoration of testosterone levels or in female rats by artificially increasing testosterone levels. Dihydrotestosterone and estrogen, produced by the reduction and aromatization of testosterone, respectively, are the direct mediators of testosterone actions. At PN0, only beta estrogen receptors are equally expressed in the SNRs of males and females and may be responsible for testosterone-mediated effects in both sexes. CONCLUSIONS: The phenotype of SNR GABAergic neurons, as characterized by GABAA-receptor subunit composition, by muscimol-induced electrophysiologic responses, and by connectivity of output networks each may be altered by the presence of testosterone. Higher KCC2 messenger RNA (mRNA) expression in female PN15 SNR neurons compared with males may be responsible for sex-related differences in muscimol-induced electrophysiologic responses. In summary, a growing body of compelling evidence identifying sex-related differences in the SNR implicates postnatal testosterone as a critical factor in the development of pro- or anticonvulsant circuits. The recognition of sex- and age-related features in the SNR holds the promise that these findings can be translated into the development of specific and effective treatments for seizure disorders.

The effect of electrical stimulation of the subthalamic nucleus on seizures is frequency dependent.

PURPOSE: Animal studies and anecdotal human case reports have indicated that the subthalamic nucleus (STN) may be a site of anticonvulsant action. METHODS: We tested the hypothesis that continuous electrical stimulation of the STN inhibits seizures acutely. We determined the effects of three stimulation frequencies, 130 Hz, 260 Hz, and 800 Hz, on generalized clonic and tonic-clonic flurothyl seizures. Adult male rats were implanted with concentric bipolar stimulating electrodes in the STN bilaterally. After recovery, rats underwent flurothyl seizures to compare the effects of each stimulation frequency on seizure threshold. Rats were tested 4 times, twice in the stimulated condition, and twice in the unstimulated condition. The order of trials was random, except that stimulation trials alternated with control trials. Flurothyl seizure thresholds under each stimulation condition were compared with control values from the same animal. RESULTS: Bilateral stimulation of the STN at 130 Hz produced a significant increase in the seizure threshold for clonic flurothyl seizures, whereas stimulation at 260 Hz did not appear to have any effect on seizures. STN stimulation at 800 Hz significantly lowered seizure threshold for tonic-clonic seizures. CONCLUSIONS: We conclude that electrical stimulation of the STN can be anticonvulsant, but the effects appear to depend on the stimulation frequency and the type of seizure.

Developmental aspects of the basal ganglia and therapeutic perspectives.

Development and sex hormones play an important role in the expression of seizures. Sex-specific differences in the development of seizure suppressing neuronal networks may account, at least in part, for age- and sex related susceptibility to seizures. The substantia nigra pars reticulata is a site involved in the control of seizures. In adult male rats, there are two distinct GABAA sensitive regions within the substantia nigra pars reticulata, which mediate opposite effects in flurothyl seizures. Muscimol infused into the anterior region is anticonvulsant while similar infusions into the posterior region are proconvulsant. These two regions differ morphologically, and utilize different efferent networks. In contrast, in postnatal day 15 male rats, there is no such differentiation and muscimol infusions have only proconvulsant effects. The hallmark of the female substantia nigra pars reticulata is the fact that muscimol- mediated proconvulsant effects cannot be demonstrated in any region at any age. The sex-related difference in nigral seizure control may be related to the lack of testosterone in females. Accordingly, neonatal castration of males results in the loss of the proconvulsant region. The male type of the substantia nigra pars reticulata effects can be induced by exogenous testosterone administration in neonatally castrated male or in female rats. The phenotype of nigral GABAergic neurons, as characterized by GABAA receptor subunit composition, muscimol-induced electrophysiological responses, and connectivity of output networks may each be altered by the presence of testosterone. Better understanding of the influence of the endocrine system on brain development and neuronal activity may provide new insight into the treatment of age- and sex-dependent seizure disorders.

Seizure-induced hippocampal damage in the mature and immature brain.

Neurologists caring for patients who have experienced a first seizure or who are at increased risk of seizures are concerned with two questions. First, at what point do seizures lesion the brain and create the conditions for unprovoked, recurrent seizures, i.e. epilepsy. And second, seizure-induced changes can be prevented pharmacologically following an initial prolonged seizure, or prophylactically in individuals deemed at high risk of epilepsy? The number, duration and severity of seizures each influence the likelihood that an individual will experience chronic seizure-induced brain damage. However, the thresholds for deleterious seizure-induced sequelae are not well understood. Will repeated brief seizures produce similar changes as a single prolonged seizure? Do permanent alterations of neuronal function result from a single brief seizure? How long can neurons resist damage caused by prolonged seizures? These are all questions of immediate clinical significance. The anatomical, synaptic and functional consequences of seizures have been most extensively studied in the hippocampus, an epileptogenic structure that plays a central role in the generation of temporal lobe seizures. In this review, we will discuss the spectrum of known hippocampal alterations in epilepsy and highlight mechanisms through which neuronal and synaptic changes accrue. In addition to discussing the effects of prolonged seizures on the hippocampus, we will also review current data regarding the effects of repeated brief seizures as well as the effect of a single brief seizure. We will also discuss the relevance of development and gender on the manifestations of seizure-induced damage, in order to begin to stratify the risk of seizure sequelae to different human populations depending on age, and - to a lesser extent - on gender. The decision whether to treat, and how to treat seizures, results from an understanding of the immediate and long-term risks to the patient of either recurrent seizures, or of seizure-induced brain damage. Paradigmatic to this type of decision is the assessment of febrile seizures, a common occurrence in childhood. Current clinical and laboratory data indicate that simple febrile seizures do not result in long-term brain injury. However, novel laboratory findings indicate that even "benign" febrile seizures may produce subtle long-term changes in neuronal behavior - such as altered synaptic function. The improved understanding of the mechanism producing these long term effects is a necessary first step in the development of neuroprotective treatments that can be applied either in the acute setting at the time of an initial prolonged seizure, or prophylactically in individuals most likely to high risk of developing epilepsy.