Summary
Abnormally enhanced glutamatergic excitation is commonly believed to mark the onset of a focal seizure. This notion, however, is not supported by firm evidence, and it will be challenged ...here. A general reduction of unit firing has been indeed observed in association with low‐voltage fast activity at the onset of seizures recorded during presurgical intracranial monitoring in patients with focal, drug‐resistant epilepsies. Moreover, focal seizures in animal models start with increased γ‐aminobutyric acid (GABA)ergic interneuronal activity that silences principal cells. In vitro studies have shown that synchronous activation of GABAA receptors occurs at seizure onset and causes sizeable elevations in extracellular potassium, thus facilitating neuronal recruitment and seizure progression. A paradoxical involvement of GABAergic networks is required for the initiation of focal seizures characterized by low‐voltage fast activity, which represents the most common seizure‐onset pattern in focal epilepsies.
Loss of myelin and altered oligodendrocyte distribution in the cerebral cortex are commonly observed both in postsurgical tissue derived from different focal epilepsies (such as focal cortical ...dysplasias and tuberous sclerosis) and in animal models of focal epilepsy. Moreover, seizures are a frequent symptom in demyelinating diseases, such as multiple sclerosis, and in animal models of demyelination and oligodendrocyte dysfunction. Finally, the excessive activity reported in demyelinated axons may promote hyperexcitability. We hypothesize that the extracellular potassium rise generated during epileptiform activity may be amplified by the presence of axons without appropriate myelin coating and by alterations in oligodendrocyte function. This process could facilitate the triggering of recurrent spontaneous seizures in areas of altered myelination and could result in further demyelination, thus promoting epileptogenesis.
Summary
Objective
Long‐term recording with intracerebral electrodes is commonly utilized to identify brain areas responsible for seizure generation (epileptogenic zone) and to tailor therapeutic ...surgical resections in patients with focal drug‐resistant epilepsy. This invasive diagnostic procedure generates a wealth of data that contribute to understanding human epilepsy. We analyze intracerebral signals to identify and classify focal ictal patterns.
Methods
We retrospectively analyzed stereo‐electroencephalographic (EEG) data in a cohort of patients either cryptogenic (magnetic resonance imaging negative) or presenting with noncongruent anatomoelectroclinical data. A computer‐assisted method based on EEG signal analysis in frequency and space domains was applied to 467 seizures recorded in 105 patients submitted to stereo‐EEG presurgical monitoring.
Results
Two main focal seizure patterns were identified. P‐type seizures, typical of neocortex, were observed in 73 patients (69.5%), lasted 22 ± 13 seconds (mean +SD), and were characterized by a sharp‐onset/sharp‐offset transient superimposed on low‐voltage fast activity (126 ± 19 Hz). L‐type seizures were observed in 43 patients (40.9%) and consistently involved mesial temporal structures; they lasted longer (93 ± 48 second), started with 116 ± 21 Hz low‐voltage fast activity superimposed on a slow potential shift, and terminated with large‐amplitude, periodic bursting activity. In 23 patients (21.9%), the L‐type seizure was preceded by a P seizure. Spasmlike and unclassifiable EEG seizures were observed in 11.4% of cases.
Significance
The proposed computer‐assisted approach revealed signal information concealed to visual inspection that contributes to identifying two principal seizure patterns typical of the neocortex and of mesial temporal networks.
GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA(A) receptor-mediated ...inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA(A) receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA(A) receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA(A) receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA(A) receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.
Objective
Previous studies of frontal lobe epilepsy (FLE) have documented different impairments of theory of mind (ToM), while the study of frontal lobe (FL) lesion without seizures has produced ...inconsistent results. Given the role played by the FLs in ToM, we evaluated this and other functions in patients with FLE with and without FL lesions. The main objective was to clarify the salience of ToM impairment in the cognitive pattern of FLE and its capacity to discriminate these patients from healthy subjects. The effects of FL lesions on ToM were also explored.
Methods
Seventy‐five adult patients with FLE (40 cases with FL lesions) were compared with 42 healthy controls. The Faux Pas Task (FPT) and other neuropsychological tests were utilized to assess ToM, reasoning, language, memory, praxis, attention, and executive abilities.
Results
The patients obtained lower z scores for the FPT than for other tests. The ToM, Executive, and Verbal factors discriminated patients from healthy subjects. The patients with or without FL lesion showed significant impairments in recognizing and understanding others' epistemic and affective mental states, but adequate capacity to exclude inexistent mental states was retained. In comparison with controls, the patients with FL lesions obtained lower scores for lexical, memory, praxis, attention, and executive functions, whereas those without lesion only showed attention and initiative deficits. Schooling was the major predictor of ToM, whereas the capacity to exclude inexistent mental states was related to seizure onset age and epilepsy duration. Other cognitive functions were related to schooling, age, or FLE laterality.
Significance
Impaired understanding of real mental states is a specific, salient, and discriminating cognitive aspect of FLE. Poor education is a risk factor for ToM deficit, whereas the clinical variables and FL lesions have no impact. These results suggest that impaired ToM may be a marker of FLE neurobehavioral phenotype.
Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense ...experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.
The identification of the epileptogenic zone (EZ) boundaries is crucial for effective focal epilepsy surgery. We verify the value of a neurophysiological biomarker of focal ictogenesis, characterized ...by a low‐voltage fast‐activity ictal pattern (chirp) recorded with intracerebral electrodes during invasive presurgical monitoring (stereoelectroencephalography SEEG). The frequency content of SEEG signals was retrospectively analyzed with semiautomatic software in 176 consecutive patients with focal epilepsies that either were cryptogenic or presented with discordant anatomoelectroclinical findings. Fast activity seizure patterns with the spectrographic features of chirps were confirmed by computer‐assisted analysis in 95.4% of patients who presented with heterogeneous etiologies and diverse lobar location of the EZ. Statistical analysis demonstrated (1) correlation between seizure outcome and concordance of sublobar regions included in the EZ defined by visual analysis and chirp‐generating regions, (2) high concordance in contact‐by contact analysis of 68 patients with Engel class Ia outcome, and (3) that discordance between chirp location and the visually outlined EZ correlated with worse seizure outcome. Seizure outcome analysis confirms the fast activity chirp pattern is a reproducible biomarker of the EZ in a heterogeneous group of patients undergoing SEEG.
Summary
Purpose
Dravet syndrome (DS) is caused by dominant mutations of the SCN1A gene, encoding the NaV1.1 sodium channel α subunit. Gene targeted mouse models of DS mutations replicate patients' ...phenotype and show reduced γ‐aminobutyric acid (GABA)ergic inhibition. However, little is known on the properties of network hyperexcitability and on properties of seizure generation in these models. In fact, seizures have been studied thus far with surface electroencephalography (EEG), which did not show if specific brain regions are particularly involved. We have investigated hyperexcitability and epileptiform activities generated in neuronal networks of a mouse model of DS.
Methods
We have studied heterozygous NaV1.1 knock‐out mice performing field potential recordings in combined hippocampal/cortical slices in vitro and video/depth electrode intracerebral recordings in vivo during hyperthermia‐induced seizures.
Key Findings
In slices, we have disclosed specific signs of hyperexcitability of hippocampal circuits in both the pre‐epileptic and epileptic periods, and a specific epileptiform activity was generated in the hippocampus upon application of the convulsant 4‐aminopyridine in the epileptic period. During in vivo hyperthermia‐induced seizures, we have observed selective hippocampal activity in early preictal phases and pronounced hippocampal activity in the ictal phase.
Significance
We have identified specific epileptiform activities and signs of network hyperexcitability, and disclosed the important role of the hippocampus in seizure generation in this model. These activities may be potentially used as targets for screenings of antiepileptic approaches.
Summary
In vivo electrophysiological recordings are widely used in neuroscience research, and video‐electroencephalography (vEEG) has become a mainstay of preclinical neuroscience research, including ...studies of epilepsy and cognition. Studies utilizing vEEG typically involve comparison of measurements obtained from different experimental groups, or from the same experimental group at different times, in which one set of measurements serves as “control” and the others as “test” of the variables of interest. Thus, controls provide mainly a reference measurement for the experimental test. Control rodents represent an undiagnosed population, and cannot be assumed to be “normal” in the sense of being “healthy.” Certain physiological EEG patterns seen in humans are also seen in control rodents. However, interpretation of rodent vEEG studies relies on documented differences in frequency, morphology, type, location, behavioral state dependence, reactivity, and functional or structural correlates of specific EEG patterns and features between control and test groups. This paper will focus on the vEEG of standard laboratory rodent strains with the aim of developing a small set of practical guidelines that can assist researchers in the design, reporting, and interpretation of future vEEG studies. To this end, we will: (1) discuss advantages and pitfalls of common vEEG techniques in rodents and propose a set of recommended practices and (2) present EEG patterns and associated behaviors recorded from adult rats of a variety of strains. We will describe the defining features of selected vEEG patterns (brain‐generated or artifactual) and note similarities to vEEG patterns seen in adult humans. We will note similarities to normal variants or pathological human EEG patterns and defer their interpretation to a future report focusing on rodent seizure patterns.
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