Clinically indicated electrical stimulation strategies to treat patients with medically refractory epilepsy.

Focal epilepsies represent approximately half of all diagnoses, and more than one-third of these patients are refractory to pharmacologic treatment. Although resection can result in seizure freedom, many patients do not meet surgical criteria, as seizures may be multifocal in origin or have a focus in an eloquent region of the brain. For these individuals, several U.S. Food and Drug Administration (FDA)-approved electrical stimulation paradigms serve as alternative options, including vagus nerve stimulation, responsive neurostimulation, and stimulation of the anterior nucleus of the thalamus. All of these are safe, flexible, and lead to progressive seizure control over time when used as an adjunctive therapy to antiepileptic drugs. Focal epilepsies frequently involve significant comorbidities such as cognitive decline. Similar to antiepilepsy medications and surgical resection, current stimulation targets and parameters have yet to address cognitive impairments directly, with patients reporting persistent comorbidities associated with focal epilepsy despite a significant reduction in the number of their seizures. Although low-frequency theta oscillations of the septohippocampal network are critical for modulating cellular activity and, in turn, cognitive processing, the coordination of neural excitability is also imperative for preventing seizures. In this review, we summarize current FDA-approved electrical stimulation paradigms and propose that theta oscillations of the medial septal nucleus represent a novel neuromodulation target for concurrent seizure reduction and cognitive improvement in epilepsy. Ultimately, further advancements in clinical neurostimulation strategies will allow for the efficient treatment of both seizures and comorbidities, thereby improving overall quality of life for patients with epilepsy

Advances toward precision therapeutics for developmental and epileptic encephalopathies

Developmental and epileptic encephalopathies are childhood syndromes of severe epilepsy associated with cognitive and behavioral disorders. Of note, epileptic seizures represent only a part, although substantial, of the clinical spectrum. Whether the epileptiform activity per se accounts for developmental and intellectual disabilities is still unclear. In a few cases, seizures can be alleviated by antiseizure medication (ASM). However, the major comorbid features associated remain unsolved, including psychiatric disorders such as autism-like and attention deficit hyperactivity disorder-like behavior. Not surprisingly, the number of genes known to be involved is continuously growing, and genetically engineered rodent models are valuable tools for investigating the impact of gene mutations on local and distributed brain circuits. Despite the inconsistencies and problems arising in the generation and validation of the different preclinical models, those are unique and precious tools to identify new molecular targets, and essential to provide prospects for effective therapeutics

Oscillations and neuronal synchronization in epilepsy: an approach based on oscillation theory and statistical mechanics.

openIn questo lavoro si propone di studiare i processi di sincronizzazione neuronale dal punto di vista dei sistemi dinamici, in particolare, della teoria delle oscillazioni. Si può dimostrare che esistono oscillazioni macroscopiche nel sistema talamocorticale dei topi epilettici. Questo fatto permette di modellare gli attacchi epilettici come processi di sincronizzazione di uno o due oscillatori auto-sostenuti, i cui parametri vengono ricavati dalle funzioni di risposta di fase ottenute sperimentalmente. Si osservano anche le cosiddette lingue di Arnold e i plateau di sincronizzazione, caratteristici della risposta di fase dei processi con un ciclo limite. Inoltre, utilizzando metodi della fisica statistica e la teoria di informazione, si ricava un rapporto fra la sincronizzazione e la quantità di informazione contenuta nelle rette funzionali del cervello. Si osserva che questa quantità di informazione è massima a livelli intermedi di sincronizzazione, in stati normali di veglia, e molto più bassa durante gli attacchi epiletticiIn this work we propose to study the neuronal synchronization processes from the point of view of the dynamical systems, in particular of the oscillations theory. It can be demonstrated that there are macroscopic oscillations in the thalamocortical network in epileptic rats. So we are able to model the epileptic seizures as synchronization processes of one or two self-sustained oscillator, whose parameters are extracted from the phase response functions obtained experimentally. We observe also the Arnold tongues and the synchronization plateau that are typical pf the phase response processes with a limit cycle. Moreover, using statistical physics and information theory methods, we obtain a relation between synchronization and quantity of information contained in the brain functional lines. This quantity of information has a peak at intermediate synchronization levels, as in conscious awareness states, and it is lower during epileptic seizures

Computational Modeling of Seizure Dynamics Using Coupled Neuronal Networks: Factors Shaping Epileptiform Activity

International audienceEpileptic seizure dynamics span multiple scales in space and time. Understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. Mathematical models have been developed to reproduce seizure dynamics across scales ranging from the single neuron to the neural population. In this study, we develop a network model of spiking neurons and systematically investigate the conditions, under which the network displays the emergent dynamic behaviors known from the Epileptor, which is a well-investigated abstract model of epileptic neural activity. This approach allows us to study the biophysical parameters and variables leading to epileptiform discharges at cellular and network levels. Our network model is composed of two neuronal populations, characterized by fast excitatory bursting neurons and regular spiking inhibitory neurons, embedded in a common extracellular environment represented by a slow variable. By systematically analyzing the parameter landscape offered by the simulation framework, we reproduce typical sequences of neural activity observed during status epilepticus. We find that exogenous fluctuations from extracellular environment and electro-tonic couplings play a major role in the progression of the seizure, which supports previous studies and further validates our model. We also investigate the influence of chemical synaptic coupling in the generation of spontaneous seizure-like events. Our results argue towards a temporal shift of typical spike waves with fast discharges as synaptic strengths are varied. We demonstrate that spike waves, including interictal spikes, are generated primarily by inhibitory neurons, whereas fast discharges during the wave part are due to excitatory neurons. Simulated traces are compared with in vivo experimental data from rodents at different stages of the disorder. We draw the conclusion that slow variations of global excitability, due to exogenous fluctuations from extracellular environment, and gap junction communication push the system into paroxysmal regimes. We discuss potential mechanisms underlying such machinery and the relevance of our approach, supporting previous detailed modeling studies and reflecting on the limitations of our methodology

Advances in understanding basic mechanisms of epilepsy and seizures

AbstractSixty years ago the clinical neurophysiology of epilepsy had progressed to the stage that it posed questions that could be addressed by major advances in cellular electrophysiology made around the that time. However, it took about 25–30 years to build up serious momentum in understanding the mechanisms of epileptic discharges. Over the past 2–3 decades developments in pharmacology and molecular biology have substantially increased the depth and complexity of our insights into the nervous system in general and the epileptic brain in particular. One of the biggest advances in our understanding of the brain is in its plasticity in the adult – that is its ability to modify its structure and function. The current state of play is that for most chronic epileptic foci it is possible to identify multiple differences from normal brain tissue in both the structure and function of neurons, neuronal networks and glia. This review will chart some of this progress to give an idea of the pace of advances over the decades

Epileptogenesis in rodents leads to neural system dysfunction and loss of associative memory measured by auditory event related potentials.

Epilepsy is a common and disabling neurological condition affecting 1-2% of the world’s population. Individuals suffering from epilepsy are prone to cognitive dysfunctions with detrimental effects in neural processing and memory resulting in decreases in quality of life. An evaluation of inherent neural processes is valuable information to diagnose and clinically assess cognitive function, which could significantly improve the treatment possibilities and thereby the quality of life for epilepsy patients. An evaluation of cognitive functions during epileptogenesis was performed by experiments using auditory event related potentials (ERP) in rats before and after induction of status epilepticus (SE) using the Lithium-Pilocarpine model (LP) of epilepsy. The aim of this study was to assess changes in neural system function during epileptogenesis by evaluating inherent responses to auditory stimuli in three ERP tasks at different time periods: before SE (control state), one week-, one month- and two months- after SE (epileptic state). 1. Habituation- (a.) evaluate the ability to habituate to repeated auditory stimuli using the N70 peak response, (b.) examine the time-frequency response through inter-trial coherence (ITC) and event-related spectral perturbation (ERSP); 2. Chirp- evaluate the auditory steady state responses through ITC; and, 3. Mismatch-Negativity (MMN)- evaluate associative memory through ERP responses to regular or odd tones. Habituation tasks showed increased N70 peak magnitude during epileptogenesis from 1-week, 1-month, and 2-months after SE using repeated measures analysis of variance (rANOVA) with significant differences before and after SE (p\u3c0.05, 1-week, 2-months). ITC showed significant differences between groups during habituation from 0.5-20 Hz and ERSP from 60-100 Hz and 0.5-15 Hz, with baseline corrected ERSP revealing differences from 1-30 Hz. The habituation results indicate a diminished ability to properly habituate to repeated stimuli with abnormal neuronal firing in the epileptic state compared to the non-epileptic control state linking a possible mechanism with imbalances in neuronal inhibition and excitation during epileptogenesis. Chirp response ITC showed increased synchronous activity in high gamma band (\u3e40 Hz) during epileptogenesis indicating the neuronal response in epileptic groups are phase locked to the chirp stimuli at a higher incidence than controls. Epileptic MMN ERP responses for odd and regular tones exhibited a decrease in the response curves from 250-350ms post-stimulus indicating a loss of ability to distinguish tones and difficulties with their associative memory during epileptogenesis.Our results indicate that a proper EEG-based analysis of auditory ERPs are useful in evaluating neural systems during epileptogenesis showing clear imbalances in excitatory: inhibitory function, as well as an indication that associative memory is detrimentally affected. The ERP methods employed may help in the diagnosis of the epileptic patients with cognitive disabilities as their epilepsy progresses, as it is simple, non-invasive and cost effective

LOCAL SYNAPTIC NETWORK INTERACTIONS IN THE DENTATE GYRUS OF A CORTICAL CONTUSION MODEL OF POSTTRAUMATIC EPILEPSY

Posttraumatic epilepsy is a common consequence of brain trauma. However, little is known about how long-term changes in local excitatory and inhibitory synaptic networks contribute to epilepsy after closed-head brain injury. This study adapted a widely used model of experimental brain injury as a mouse model of posttraumatic epilepsy. Behavioral seizure activity and alterations in synaptic circuitry in the dentate gyrus were examined in mice after experimental cortical contusion brain injury. Spontaneous behavioral seizures were observed in 20% of mice after moderate injury and 36-40% of mice weeks after severe injury. In the dentate gyrus, most mice displayed regionally localized mossy fiber reorganization ipsilateral to the injury that was absent in control mice or sections contralateral to the injury. Extracellular field and whole-cell patch clamp recordings were performed in acute brain slice preparations of the dentate gyrus. Dentate granule cells displayed spontaneous and evoked activity that was consistent with network synchronization and the formation of recurrent excitatory network only in slices that had posttraumatic mossy fiber sprouting. The excitability of surviving hilar GABAergic interneurons, which provide important feedback inhibition to granule cells, was examined at similar time points. Cell-attached and whole-cell voltage-clamp recordings revealed increased spontaneous and glutamate photostimulation-evoked excitatory input to hilar GABA neurons ipsilateral to the injury, versus control and contralateral slices. Despite increased excitatory synaptic input to interneurons, whole-cell voltage-clamp recordings revealed a reduction in inhibitory synaptic input to granule cells. These findings suggest that there are alterations in excitatory and inhibitory circuits in mice with posttraumatic mossy fiber sprouting and seizures after cortical contusion head injury

Hippocampus dependent and independent theta-networks of working memory maintenance

Working memory is the ability to briefly maintain and manipulate information beyond its transient availability to our senses. This process of short-term stimulus retention has often been proposed to be anatomically distinct from long-term forms of memory. Although it’s been well established that the medial temporal lobe (MTL) is critical to long-term declarative memory, recent evidence has suggested that MTL regions, such as the hippocampus, may also be involved in the working memory maintenance of configural visual relationships. I investigate this possibility in a series of experiments using Magnetoencephalography to record the cortical oscillatory activity within the theta frequency band of patients with bilateral hippocampal sclerosis and normal controls. The results demonstrate that working memory maintenance of configural-relational information is supported by a theta synchronous network coupling frontal, temporal and occipital visual areas, and furthermore that this theta synchrony is critically dependent on the integrity of the hippocampus. Alternate forms of working memory maintenance, that do not require the relational binding of visual configurations, engage dissociable theta synchronous networks functioning independently of the hippocampus. In closing, I will explore the interactions between long-term and short-term forms of memory and demonstrate that through these interactions, memory performance can effectively be improved