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Seizures beget seizures is a longstanding theory that proposed that seizure activity can impact the structural and functional properties of the brain circuits in ways that contribute to epilepsy progression and the future occurrence of seizures. Originally proposed by Gowers, this theory continues to be quoted in the pathophysiology of epilepsy. We critically review the existing data and observations on the consequences of recurrent seizures on brain networks and highlight a range of factors that speak for and against the theory. The existing literature demonstrates clearly that ictal activity, especially if recurrent, induces molecular, structural, and functional changes including cell loss, connectivity reorganization, changes in neuronal behavior, and metabolic alterations. These changes have the potential to modify the seizure threshold, contribute to disease progression, and recruit wider areas of the epileptic network into epileptic activity. Repeated seizure activity may, thus, act as a pathological positive‐feedback mechanism that increases seizure likelihood. On the other hand, the time course of self‐limited epilepsies and the presence of seizure remission in two thirds of epilepsy cases and various chronic epilepsy models oppose the theory. Experimental work showed that seizures could induce neural changes that increase the seizure threshold and decrease the risk of a subsequent seizure. Due to the complex nature of epilepsies, it is wrong to consider only seizures as the key factor responsible for disease progression. Epilepsy worsening can be attributed to the various forms of interictal epileptiform activity or underlying disease mechanisms. Although seizure activity can negatively impact brain structure and function, the "seizures beget seizures" theory should not be used dogmatically but with extreme caution. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disorder, with one third of patients not responding to currently available antiepileptic drugs. The proportion of pharmacoresistant epilepsies has remained unchanged for many decades. To cure epilepsy and control seizures requires a paradigm shift in the development of new approaches to epilepsy diagnosis and treatment. Contemporary medicine has benefited from the exponential growth of computational modeling, and the application of network dynamics theory to understanding and treating human brain disorders. In epilepsy, the introduction of these approaches has led to personalized epileptic network modeling that can explore the patient's seizure genesis and predict the functional impact of resection on its individual network's propensity to seize. The application of the dynamic systems approach to neurostimulation therapy of epilepsy allows designing stimulation strategies that consider the patient's seizure dynamics and long‐term fluctuations in the stability of their epileptic networks. In this article, we review, in a nontechnical fashion suitable for a broad neuroscientific audience, recent progress in personalized dynamic brain network modeling that is shaping the future approach to the diagnosis and treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Summary: In vitro brain tissue preparations allow the convenient and affordable study of brain networks and have allowed us to garner molecular, cellular, and electrophysiologic insights into brain function with a detail not achievable in vivo. Preparations from both rodent and human postsurgical tissue have been utilized to generate in vitro electrical activity similar to electrographic activity seen in patients with epilepsy. A great deal of knowledge about how brain networks generate various forms of epileptiform activity has been gained, but due to the multiple in vitro models and manipulations used, there is a need for a standardization across studies. Here, we describe epileptiform patterns generated using in vitro brain preparations, focusing on issues and best practices pertaining to recording, reporting, and interpretation of the electrophysiologic patterns observed. We also discuss criteria for defining in vitro seizure‐like patterns (i.e., ictal) and interictal discharges. Unifying terminologies and definitions are proposed. We suggest a set of best practices for reporting in vitro studies to favor both efficient across‐lab comparisons and translation to in vivo models and human studies. [ABSTRACT FROM AUTHOR]

In vitro preparations are a powerful tool to explore the mechanisms and processes underlying epileptogenesis and ictogenesis. In this review, we critically review the numerous in vitro methodologies utilized in epilepsy research. We provide support for the inclusion of detailed descriptions of techniques, including often ignored parameters with unpredictable yet significant effects on study reproducibility and outcomes. In addition, we explore how recent developments in brain slice preparation relate to their use as models of epileptic activity. [ABSTRACT FROM AUTHOR]

High-frequency oscillations ( HFOs) are a type of brain activity that is recorded from brain regions capable of generating seizures. Because of the close association of HFOs with epileptogenic tissue and ictogenesis, understanding their cellular and network mechanisms could provide valuable information about the organization of epileptogenic networks and how seizures emerge from the abnormal activity of these networks. In this review, we summarize the most recent advances in the field of HFOs and provide a critical evaluation of new observations within the context of already established knowledge. Recent improvements in recording technology and the introduction of optogenetics into epilepsy research have intensified experimental work on HFOs. Using advanced computer models, new cellular substrates of epileptic HFOs were identified and the role of specific neuronal subtypes in HFO genesis was determined. Traditionally, the pathogenesis of HFOs was explored mainly in patients with temporal lobe epilepsy and in animal models mimicking this condition. HFOs have also been reported to occur in other epileptic disorders and models such as neocortical epilepsy, genetically determined epilepsies, and infantile spasms, which further support the significance of HFOs in the pathophysiology of epilepsy. It is increasingly recognized that HFOs are generated by multiple mechanisms at both the cellular and network levels. Future studies on HFOs combining novel high-resolution in vivo imaging techniques and precise control of neuronal behavior using optogenetics or chemogenetics will provide evidence about the causal role of HFOs in seizures and epileptogenesis. Detailed understanding of the pathophysiology of HFOs will propel better HFO classification and increase their information yield for clinical and diagnostic purposes. [ABSTRACT FROM AUTHOR]

Objectives High-frequency oscillations ( HFOs) represent a novel electrophysiologic marker of endogenous epileptogenicity. Clinically, this propensity can be utilized to more accurately delineate the resection margin before epilepsy surgery. Currently, prospective application of HFOs is limited because of a lack of an exact quantitative measure to reliably identify HFO-generating areas necessary to include in the resection. Here, we evaluated the potential of a patient-individualized approach of identifying high-rate HFO regions to plan the neocortical resection. Methods Fifteen patients with neocortical seizure-onset zones ( SOZs) underwent intracranial electroencephalographic monitoring. To identify interictal HFOs, we applied an automated, hypersensitive HFO-detection algorithm followed by post hoc processing steps to reject false detections. The spatial relationship between HFO distribution and the SOZ was evaluated. To address high interpatient variability in HFO properties, we evaluated the high-rate HFO region, an unbiased statistical parameter, in each patient. The relationship between resection of the high-rate HFO region and postoperative outcome was examined. Results Grouped data demonstrated that the rate of ripple (60-200 Hz) and fast ripple (200-500 Hz) was increased in the SOZ (both p < 0.01). Intrapatient analysis of the HFO distribution localized the SOZ in 11 patients. High-rate HFO regions were determined in all patients by an individually adjusted threshold. Resection of high-rate HFO regions was significantly associated with a seizure-free outcome (p < 0.01). The extent/ratio of SOZ or spiking region resection did not differ between seizure-free and seizure-persistent groups. Significance Intrapatient analysis of high-rate HFOs provides more detailed description of HFO-generating areas and can mark the areas of clinically significant epileptogenicity-a crucial component of the neocortical epileptic network that should be removed to achieve a good outcome. Validating and adopting an unbiased quantitative HFO parameter has the potential to propel wider and prospective utilization of HFOs in the surgical treatment of neocortical epilepsy and to improve its outcome. [ABSTRACT FROM AUTHOR]

Epilepsy has been historically seen as a functional brain disorder associated with excessive synchronization of large neuronal populations leading to a hypersynchronous state. Recent evidence showed that epileptiform phenomena, particularly seizures, result from complex interactions between neuronal networks characterized by heterogeneity of neuronal firing and dynamical evolution of synchronization. Desynchronization is often observed preceding seizures or during their early stages; in contrast, high levels of synchronization observed towards the end of seizures may facilitate termination. In this review we discuss cellular and network mechanisms responsible for such complex changes in synchronization. Recent work has identified cell-type-specific inhibitory and excitatory interactions, the dichotomy between neuronal firing and the non-local measurement of local field potentials distant to that firing, and the reflection of the neuronal dark matter problem in non-firing neurons active in seizures. These recent advances have challenged long-established views and are leading to a more rigorous and realistic understanding of the pathophysiology of epilepsy. [ABSTRACT FROM AUTHOR]

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The discovery that electroencephalography (EEG) contains useful information at frequencies above the traditional 80Hz limit has had a profound impact on our understanding of brain function. In epilepsy, high-frequency oscillations (HFOs, >80Hz) have proven particularly important and useful. This literature review describes the morphology, clinical meaning, and pathophysiology of epileptic HFOs. To record HFOs, the intracranial EEG needs to be sampled at least at 2,000Hz. The oscillatory events can be visualized by applying a high-pass filter and increasing the time and amplitude scales, or EEG time-frequency maps can show the amount of high-frequency activity. HFOs appear excellent markers for the epileptogenic zone. In patients with focal epilepsy who can benefit from surgery, invasive EEG is often required to identify the epileptic cortex, but current information is sometimes inadequate. Removal of brain tissue generating HFOs has been related to better postsurgical outcome than removing the seizure onset zone, indicating that HFOs may mark cortex that needs to be removed to achieve seizure control. The pathophysiology of epileptic HFOs is challenging, probably involving populations of neurons firing asynchronously. They differ from physiological HFOs in not being paced by rhythmic inhibitory activity and in their possible origin from population spikes. Their link to the epileptogenic zone argues that their study will teach us much about the pathophysiology of epileptogenesis and ictogenesis. HFOs show promise for improving surgical outcome and accelerating intracranial EEG investigations. Their potential needs to be assessed by future research. Ann Neurol 2012;71:169-178 [ABSTRACT FROM AUTHOR]

Brain stimulation is currently used as an experimental treatment for patients with medically refractory epilepsy. However, the results of such stimulation are still less than optimal. A major factor is the lack of understanding of the mechanisms of applied stimuli. Herein we review evidence on the effects of stimulation in models of epileptic seizures. We show that the effects of stimulation during epileptic seizures can differ from those observed under normal conditions. Several studies suggest a potentially greater beneficial therapeutic effect of strong depolarizing and overactivating stimulations than hyperpolarizing ones in the treatment of seizures. The potential relevance of these results to other therapeutic stimulation protocols is discussed. [ABSTRACT FROM AUTHOR]

Synchronization of neuronal activity in the visual cortex at low (30–70 Hz) and high gamma band frequencies (> 70 Hz) has been associated with distinct visual processes, but mechanisms underlying high-frequency gamma oscillations remain unknown. In rat visual cortex slices, kainate and carbachol induce high-frequency gamma oscillations (fast-γ; peak frequency ∼ 80 Hz at 37°C) that can coexist with low-frequency gamma oscillations (slow-γ; peak frequency ∼ 50 Hz at 37°C) in the same column. Current-source density analysis showed that fast-γ was associated with rhythmic current sink-source sequences in layer III and slow-γ with rhythmic current sink-source sequences in layer V. Fast-γ and slow-γ were not phase-locked. Slow-γ power fluctuations were unrelated to fast-γ power fluctuations, but were modulated by the phase of theta (3–8 Hz) oscillations generated in the deep layers. Fast-γ was spatially less coherent than slow-γ. Fast-γ and slow-γ were dependent on γ-aminobutyric acid (GABA)A receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and gap-junctions, their frequencies were reduced by thiopental and were weakly dependent on cycle amplitude. Fast-γ and slow-γ power were differentially modulated by thiopental and adenosine A1 receptor blockade, and their frequencies were differentially modulated by N-methyl-d-aspartate (NMDA) receptors, GluK1 subunit-containing receptors and persistent sodium currents. Our data indicate that fast-γ and slow-γ both depend on and are paced by recurrent inhibition, but have distinct pharmacological modulation profiles. The independent co-existence of fast-γ and slow-γ allows parallel processing of distinct aspects of vision and visual perception. The visual cortex slice provides a novel in vitro model to study cortical high-frequency gamma oscillations. [ABSTRACT FROM AUTHOR]