Computational models of epilepsy

PurposeApproximately 30% of epilepsy patients suffer from medically refractory epilepsy, in which seizures can not controlled by the use of anti-epileptic drugs (AEDs). Understanding the mechanisms underlying these forms of drug-resistant epileptic seizures and the development of alternative effective treatment strategies are fundamental challenges for modern epilepsy research. In this context, computational modeling has gained prominence as an important tool for tackling the complexity of the epileptic phenomenon. In this review article, we present a survey of computational models of epilepsy from the point of view that epilepsy is a dynamical brain disease that is primarily characterized by unprovoked spontaneous epileptic seizures.MethodWe introduce key concepts from the mathematical theory of dynamical systems, such as multi-stability and bifurcations, and explain how these concepts aid in our understanding of the brain mechanisms involved in the emergence of epileptic seizures.ResultsWe present a literature survey of the different computational modeling approaches that are used in the study of epilepsy. Special emphasis is placed on highlighting the fine balance between the degree of model simplification and the extent of biological realism that modelers seek in order to address relevant questions. In this context, we discuss three specific examples from published literature, which exemplify different approaches used for developing computational models of epilepsy. We further explore the potential of recently developed optogenetics tools to provide novel avenue for seizure control.ConclusionWe conclude with a discussion on the utility of computational models for the development of new epilepsy treatment protocols.     

Update on the mechanisms and roles of high‐frequency oscillations in seizures and epileptic disorders

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.     

Applications of optogenetic and chemogenetic methods to seizure circuits: Where to go next?

Epilepsy is the quintessential circuit disorder, with seizure activity propagating through anatomically constrained pathways. These pathways, necessary for normal sensory, motor, and cognitive function, are hijacked during seizures. Understanding the network architecture at the level of both local microcircuits and distributed macrocircuits may provide new therapeutic avenues for the treatment of epilepsy. Over the past decade, optogenetic and chemogenetic tools have enabled previously impossible levels of functional circuit mapping in neuroscience. In this review, examples of the application of optogenetics and chemogenetics to epilepsy are raised, the comparative strengths and weaknesses of these approaches are discussed for both preclinical and translational applications, and recent applications of these approaches in other areas of neuroscience are highlighted. These points are raised in an effort to highlight the potential of these methods to address additional unanswered questions in epilepsy.     

“A Light Switch in the #Brain”: Optogenetics on Social Media

Neuroscience communication is increasingly taking place on multidirectional social media platforms, creating new opportunities but also calling for critical ethical considerations. Twitter, one of the most popular social media applications in the world, is a leading platform for the dissemination of all information types, including emerging areas of neuroscience such as optogenetics, a technique aimed at the control of specific neurons. Since its discovery in 2005, optogenetics has been featured in the public eye and discussed extensively on social media, but little is known about how this new technique is portrayed and who the users participating in the conversation are. To address this gap, we conducted content analysis of a sample of 1000 tweets mentioning “optogenetics” over a one-year period between 2014 and 2015. We found that academic researchers are the largest group contributing to the conversation, that the tweets often contain links to third-party websites from news organizations and peer-reviewed journals, and that common thematic motifs include the applications of optogenetics specifically for the control of brain activity and the treatment of disease. We also found that the majority of the tweets are neutral in their tone regarding optogenetics. As Twitter serves as a current and dynamic forum for exchange about advances in neuroscience, the conversation about optogenetics on this engaging platform can inform socially-responsive knowledge dissemination efforts in this area.     

A new technique for controlling the brain: optogenetics and its potential for use in research and the clinic

The recent development of optogenetic techniques has generated considerable excitement in neuroscience research. Optogenetics uses light to control the activity of neurons which have been modified to express light-sensitive proteins. Some proteins, such as channelrhodopsin, are cation channels that produce depolarization of neurons when illuminated. In other cases, neuronal activity can be inhibited through illumination of proteins, such as the chloride pump halorhodopsin, that hyperpolarize neurons. Because these proteins can be selectively expressed in specific cell types and/or in specific locations, optogenetics avoids several of the non-specific effects of electrical or pharmacological brain stimulation. This short review will explain the physiology of this technique, describe the basic and technical aspects of the method, and highlight some of the research as well as the clinical potential of optogenetics.     

Optogenetics in neuroscience: what we gain from studies in mammals

Optogenetics is a newly-introduced technology in the life sciences and is gaining increasing attention.It refers to the combination of optical technologies and genetic methods to control the activity of specific cell groups in living tissue,during which high-resolution spatial and temporal manipulation of cells is achieved.Optogenetics has been applied to numerous regions,including cerebral cortex,hippocampus,ventral tegmental area,nucleus accumbens,striatum,spinal cord,and retina,and has revealed new directions of research in neuroscience and the treatment of related diseases.Since optogenetic tools are controllable at high spatial and temporal resolution,we discuss its applications in these regions in detail and the recent understanding of higher brain functions,such as reward-seeking,learning and memory,and sleep.Further,the possibilities of improved utility of this newly-emerging technology are discussed.We intend to provide a paradigm of the latest advances in neuroscience using optogenetics.     

Aging Models of Acute Seizures and Epilepsy

Aged animals have been used by researchers to better understand the differences between the young and the aged brain and how these differences may provide insight into the mechanisms of acute seizures and epilepsy in the elderly. To date, there have been relatively few studies dedicated to the modeling of acute seizures and epilepsy in aged, healthy animals. Inherent challenges to this area of research include the costs associated with the purchase and maintenance of older animals and, at times, the unexpected and potentially confounding comorbidities associated with aging. However, recent studies using a variety of in vivo and in vitro models of acute seizures and epilepsy in mice and rats have built upon early investigations in the field, all of which has provided an expanded vision of seizure generation and epileptogenesis in the aged brain. Results of these studies could potentially translate to new and tailored interventional approaches that limit or prevent the development of epilepsy in the elderly.     

Basic Science

The hormone melatonin has been reported to exhibit antiepileptic properties in clinical trials. However, recent animal studies have demonstrated that melatonin can have opposite effects on brain function, depending on the dose and timing of melatonin administration. In other words, although high pharmacologic doses are able to decrease brain excitability and suppress seizures, smaller doses of melatonin (administered at night when melatonin levels in the brain are highest), similar in amount to what is produced by the brain, can actually increase the excitability of neurons, making them more susceptible to seizure activity. In this study, we used an animal model of epilepsy to study the effects of melatonin on seizure development. We made two important observations: (a) seizures induced by the drug pilocarpine occurred with a shorter latency at night (when brain melatonin levels are highest) than during the day, and (b) when small doses of drug that block melatonin receptors are injected directly into the hippocampus, an area of the brain important for the development and spread of seizures, then seizures during the night were delayed. Furthermore, this effect was reversed by a drug that blocks the activity of GABA, the major inhibitory neurotransmitter in the brain, suggesting that melatonin may decrease GABA-receptor function in the hippocampus. Although we did not study the effects of melatonin directly, our data suggest that endogenous melatonin may enhance brain excitability and contribute to the development of epileptic seizures. This process may be involved with certain forms of nocturnal epilepsy and may raise a caution for persons with epilepsy who take melatonin. Epilepsia 2005;46(4).     

Review: Molecular characteristics of long‐term epilepsy‐associated tumours (LEATs) and mechanisms for tumour‐related epilepsy (TRE)

Brain tumours are the second most common cause of seizures identified in epilepsy surgical series. While any tumour involving the brain has the potential to cause seizures, specific subtypes are more frequently associated with epilepsy. Tumour‐related epilepsy (TRE) has a profound impact on patients with brain tumours and these seizures are often refractory to anti‐epileptic treatments, resulting in long‐term disability and patient morbidity. Despite the drastic impact of epilepsy‐associated tumours on patients, they have not traditionally enjoyed as much attention as more malignant neoplasms. However, recently a number of developments have been achieved towards further understanding of the molecular and developmental backgrounds of specific epilepsy‐associated tumours. In addition, the past decade has seen an expansion in the literature on the pathophysiology of TRE. In this review, we aim to summarize the mechanisms by which tumours may cause seizures and detail recent data regarding the pathogenesis of specific developmental epilepsy‐associated tumours.     

The role of inflammation in epilepsy

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis.     

Introduction: Goals

Summary: Epilepsy is characterized by recurrent seizures. Many epilepsies with focal seizures as well as convulsive generalized seizures respond satisfactorily to antiepileptic drugs (AEDs) that reduce repetitive firing (e.g., phenytoin, carbamazepine, and valproate) or that augment GABA_A-mediated inhibition (e.g., phenobarbital and benzodiazepines). A number of drugs presently under development, such as NMDA receptor antagonists, loreclezole, losigamone, meth-ysticine, and dextromethorphan, are promising in acute animal models of otherwise drug-resistant convulsant activity. As a result of recent studies in both experimental models and surgically resected human epileptic brain, the prospects for development of AEDs have significantly improved. Several new AEDs recently have reached the commercial market or are in experimental or clinical trials. A comparative presentation of the standing of the new AEDs with respect to their efficacy and side effects is necessary, but still very difficult. Because initial experience with new AEDs is restricted to populations with severe drug-resistant epilepsy, the crucial question whether potential new AEDs can alter prognosis is not yet definitively answered. There is a clear need to compare the effects of standard AEDs and new AEDs in naive patients and over longer follow-up periods. Moreover, because of the strong desire to develop antiepileptic therapy that directly treats the primary etiology of a given epileptic syndrome , or modifies the neurobiological processes that cause recurrent seizures, better experimental epilepsy models for chronic epilepsy and further clinical studies are necessary to increase the knowledge on the pathophysiology of distinct epileptic syndromes. In this respect, studies on the differences between responders and nonresponders to a given AED treatment are extremely valuable.     

GABA-ergic cell therapy for epilepsy: Advances,limitations and challenges

Diminution in the number of gamma-amino butyric acid positive (GABA-ergic) interneurons and their axon terminals, and/or alterations in functional inhibition are conspicuous brain alterations believed to contribute to the persistence of seizures in acquired epilepsies such as temporal lobe epilepsy. This has steered a perception that replacement of lost GABA-ergic interneurons would improve inhibitory synaptic neurotransmission in the epileptic brain region and thereby reduce the occurrence of seizures. Indeed, studies using animal prototypes have reported that grafting of GABA-ergic progenitors derived from multiple sources into epileptic regions can reduce seizures. This review deliberates recent advances, limitations and challenges concerning the development of GABA-ergic cell therapy for epilepsy. The efficacy and limitations of grafts of primary GABA-ergic progenitors from the embryonic lateral ganglionic eminence and medial ganglionic eminence (MGE), neural stem/progenitor cells expanded from MGE, and MGE-like progenitors generated from human pluripotent stem cells for alleviating seizures and co-morbidities of epilepsy are conferred. Additional studies required for possible clinical application of GABA-ergic cell therapy for epilepsy are also summarized.     

The methylation hypothesis: do epigenetic chromatin modifications play a role in epileptogenesis?

Any structural brain lesion can provoke epilepsy, although onset and progression of seizures as well as response to antiepileptic drug (AED) treatment remain difficult to predict in each patient. Tremendous work has focused on the development of new AED compounds with the intention to treat seizures. However, these efforts have not yet discovered a "magic bullet" that cures epilepsy in every patient or modifies disease progression. With the "methylation hypothesis" we propose that epigenetic mechanisms play a pivotal role in epileptogenesis in patients with structural lesions. "Epigenetics" is defined as information that is heritable during cell division other than the DNA sequence itself, that is, DNA methylation or histone tail modifications, which can produce lasting alterations in chromatin structure and gene expression. They are increasingly recognized as fundamental regulatory processes in central nervous system development, synaptic plasticity, and memory, and also play a role in neurologic disorders such as schizophrenia and spinal muscular atrophy. The methylation hypothesis suggests that seizures by themselves can induce epigenetic chromatin modifications, thereby aggravating the epileptogenic condition. The impact of the methylation hypothesis for new-onset epilepsy will be discussed. Unravelling of epigenetic pathomechanisms will also open new strategies to identify molecular targets for pharmacologic treatment in epilepsies.     

Effects of seizures on developmental processes in the immature brain

Infants and children are at a high risk for seizures compared with adults. Although most seizures in children are benign and result in no long-term consequences, increasing experimental animal data strongly suggest that frequent or prolonged seizures in the developing brain result in long-lasting sequelae. Such seizures may intervene with developmental programmes and lead to inadequate construction of cortical networks rather than induction of neuronal cell loss. As a consequence, the deleterious actions of seizures are strongly age dependent: seizures have different effects on immature or migrating neurons endowed with few synapses and more developed neurons that express hundreds of functional synapses. This differential effect is even more important in human beings and subhuman primates who have an extended brain development period. Seizures also beget seizures during maturation and result in a replay of development programmes, which suggests that epileptogenesis recapitulates ontogenesis. Therefore, to understand seizures and their consequences in the developing brain, it is essential to determine how neuronal activity modulates the main steps of cortical formation. In this Review, we present basic developmental principles obtained from animal studies and examine the long-lasting consequences of epilepsy.     

Optogenetic stimulation: Understanding memory and treating deficits

Technology allowing genetically targeted cells to be modulated by light has revolutionized neuroscience in the past decade, and given rise to the field of optogenetic stimulation. For this, non‐native, light activated proteins (e.g., channelrhodopsin) are expressed in a specific cell phenotype (e.g., glutamatergic neurons) in a subset of central nervous system nuclei, and short pulses of light of a narrow wavelength (e.g., blue, 473 nm) are used to modulate cell activity. Cell activity can be increased or decreased depending on which light activated protein is used. We review how the greater precision provided by optogenetics has transformed the study of neural circuits, in terms of cognition and behavior, with a focus on learning and memory. We also explain how optogenetic modulation is facilitating a better understanding of the mechanistic underpinnings of some neurological and psychiatric conditions. Based on this research, we suggest that optogenetics may provide tools to improve memory in neurological conditions, particularly diencephalic amnesia and Alzheimer's disease.     

Recent advances in epilepsy

We have reviewed some of the important studies published within the last 18 months that have advanced our understanding of the epilepsies, their aetiology and treatment. Clinical studies have revealed new insights into old themes including seizure prediction, mortality in epilepsy, febrile seizures and the pathophysiology of focal cortical dysplasias. The rapid advances in genetics and particularly whole exome sequencing have had an impact on our understanding of epileptic encephalopathies, and the aetiology of hippocampal sclerosis. Experimental research techniques such as viral vector gene delivery, optogenetics and cell based transplantation techniques have set the framework for novel approaches to the treatment of pharmacoresistant epilepsy. These few examples are indicative of the great strides that have recently been made in epilepsy research.     

Epilepsy after head injury

PURPOSE OF REVIEW: The purpose of this short review is to provide an update on the epidemiology of posttraumatic epilepsy, associated risk factors, data from prevention studies, and recent breakthroughs in experimental research. RECENT FINDINGS: There is increasing evidence that neuroimaging findings, stratification by neurosurgical procedures performed, and genomic information (e.g. apolipoprotein E and haptoglobin genotypes) may provide useful predictors of the individual risk of developing posttraumatic epilepsy. While antiepileptic drug prophylaxis can be effective in protecting against acute (provoked) seizures occurring within 7 days after injury, no antiepileptic drug treatment has been found to protect against the development of posttraumatic epilepsy and therefore long-term anticonvulsant prophylaxis is not recommended. Glucocorticoid administration early after head injury also has not been found to reduce the risk of posttraumatic epilepsy. At the basic research level, there have been advances in the understanding of pathophysiological changes in posttraumatic excitatory and inhibitory synapses, and the critical period for epileptogenesis after head injury has been better defined. Finally, the development of a novel animal model, which mimicks more closely human posttraumatic epilepsy, may facilitate efforts to characterize relevant epileptogenic mechanisms and to identify clinically effective antiepileptogenic treatments. SUMMARY: Despite the continuing lack of clinically effective agents for posttraumatic epilepsy prophylaxis, recent advances in basic and clinical research offer new hope for success in the development of new strategies for prevention and treatment.     

Brain complex network analysis by means of resting state fMRI and graph analysis: Will it be helpful in clinical epilepsy?

Functional magnetic resonance imaging (fMRI) has just completed 20 years of existence. It currently serves as a research tool in a broad range of human brain studies in normal and pathological conditions, as is the case of epilepsy. To date, most fMRI studies aimed at characterizing brain activity in response to various active paradigms. More recently, a number of strategies have been used to characterize the low-frequency oscillations of the ongoing fMRI signals when individuals are at rest. These datasets have been largely analyzed in the context of functional connectivity, which inspects the covariance of fMRI signals from different areas of the brain. In addition, resting state fMRI is progressively being used to evaluate complex network features of the brain. These strategies have been applied to a number of different problems in neuroscience, which include diseases such as Alzheimer's, schizophrenia, and epilepsy. Hence, we herein aimed at introducing the subject of complex network and how to use it for the analysis of fMRI data. This appears to be a promising strategy to be used in clinical epilepsy. Therefore, we also review the recent literature that has applied these ideas to the analysis of fMRI data in patients with epilepsy.This article is part of a Special Issue entitled “NEWroscience 2013”.