Studying Network Mechanisms Using Intracranial Stimulation in Epileptic Patients

Patients suffering from focal drug-resistant epilepsy who are explored using intracranial electrodes allow to obtain data of exceptional value for studying brain dynamics in correlation with pathophysiological and cognitive processes. Direct electrical stimulation (DES) of cortical regions and axonal tracts in those patients elicits a number of very specific perceptual or behavioral responses, but also abnormal responses due to specific configurations of epileptic networks. Here, we review how anatomo-functional brain connectivity and epilepsy network mechanisms can be assessed from DES responses measured in patients. After a brief summary of mechanisms of action of brain electrical stimulation, we recall the conceptual framework for interpreting DES results in the context of brain connectivity and review how DES can be used for the characterization of functional networks, the identification of the seizure onset zone, the study of brain plasticity mechanisms, and the anticipation of epileptic seizures. This pool of exceptional data may be underexploited by fundamental research on brain connectivity and leaves much to be learned

Hippocampe et épilepsie : données issues des tissus humains

International audienceSurgical removal of the epileptogenic zone provides an effective therapy for several focal epileptic syndromes. This surgery offers the opportunity to study pathological activity in living human tissue for pharmacoresistant partial epilepsy syndromes including temporal lobe epilepsies with hippocampal sclerosis, cortical dysplasias, epilepsies associated with tumors and developmental malformations. Slices of tissue from patients with these syndromes retain functional neuronal networks and may generate epileptic activities. The properties of cells in this tissue may not be greatly changed, but excitatory synaptic transmission is often enhanced and GABAergic inhibition is preserved. Typically epileptic activity is not generated spontaneously by the neocortex, whether dysplastic or not, but can be induced by convulsants. The initiation of ictal discharges in the neocortex depends on both GABAergic signaling and increased extracellular potassium. In contrast, a spontaneous interictal-like activity is generated by tissues from patients with temporal lobe epilepsies associated with hippocampal sclerosis. This activity is initiated, not in the hippocampus but in the subiculum, an output region, which projects to the entorhinal cortex. Interictal events seem to be triggered by GABAergic cells, which paradoxically excite about 20% of subicular pyramidal cells while simultaneously inhibiting the majority. Interictal discharges thus depend on both GABAergic and glutamatergic signaling. The depolarizing effects of GABA depend on a pathological elevation in levels of chloride in some subicular cells, similar to those of developmentally immature cells. Such defect is caused by a perturbed expression of the cotransporters regulating intracellular chloride concentration, the importer NKCC1 and the extruder KCC2. Blockade of NKCC1 actions by the diuretic bumetanide restores intracellular chloride and thus hyperpolarizing GABAergic actions and consequently suppressing interictal activity.La résection chirurgicale de la zone épileptogène est la procédure thérapeutique de choix de multiples épilepsies focales. Elle permet d’étudier les activités pathologiques dans du tissu humain maintenu en vie in vitro pour divers syndromes épileptiques pharmacorésistantes dont les épilepsies temporales avec sclérose hippocampique, dysplasies corticales, autres malformations développementales ou tumeurs. In vitro, dans des tranches de tissu issues de pièces opératoires, le réseau épileptique est conservé et des activités épileptiques sont produites. À l’échelle neuronale, les propriétés intrinsèques semblent peu modifiées, certaines composantes synaptiques excitatrices glutamatergiques apparaissent renforcées et l’inhibition GABAergique est maintenue. Dans le néocortex, qu’il soit dysplasique ou non, une activité synchrone épileptiforme n’est généralement pas enregistrée spontanément mais doit être induite pharmacologiquement. L’initiation des décharges ictales implique alors la signalisation GABAergique et une augmentation de la concentration extracellulaire en potassium. Au sein de tissus provenant de patients souffrant d’épilepsies mésio-temporales associées à une sclérose hippocampique, une activité épileptiforme est recueillie spontanément. Il s’agit de bouffées interictales générées non pas dans l’hippocampe mais dans le subiculum, sa région de sortie interfacée avec le cortex entorhinal. Cette activité est initiée par la décharge d’interneurones qui excitent paradoxalement par le GABA libéré environ 1/5 des cellules pyramidales, hyperpolarisant les autres. Les décharges sont donc sous-tendues tant par la signalisation GABAergique que glutamatergique. L’origine des réponses dépolarisantes au GABA est une perturbation de l’homéostasie du chlore, secondaire à une modification de l’expression des co-transporteurs régulant sa concentration intracellulaire, NKCC1 et KCC2, évoquant un retour à un phénotype neuronal immature. La restauration d’une concentration normale en chlore en bloquant NKCC1 par le diurétique bumétanide permet ainsi de supprimer les activités interictales

How can I investigate causal brain networks with iEEG?

While many human imaging methodologies probe the structural and functional connectivity of the brain, techniques to investigate cortical networks in a causal and directional manner are critical but limited. The use of iEEG enables several approaches to directly characterize brain regions that are functionally connected and in some cases also establish directionality of these connections. In this chapter we focus on the basis, method and application of the cortico-cortical evoked potential (CCEP), whereby electrical pulses applied to one set of intracranial electrodes yields an electrically-induced brain response at local and remote regions. In this chapter, CCEPs are first contextualized within common brain connectivity methods used to define cortical networks and how CCEP adds unique information. Second, the practical and analytical considerations when using CCEP are discussed. Third, we review the neurophysiology underlying CCEPs and the applications of CCEPs including exploring functional and pathological brain networks and probing brain plasticity. Finally, we end with a discussion of limitations, caveats, and directions to improve CCEP utilization in the future.Comment: Forthcoming chapter in "Intracranial EEG for Cognitive Neuroscience

Tracking slow modulations in synaptic gain using dynamic causal modelling : validation in epilepsy

In thiswork we propose a proof of principle that dynamic causal modelling can identify plausible mechanisms at the synaptic level underlying brain state changes over a timescale of seconds. As a benchmark example for validation we used intracranial electroencephalographic signals in a human subject. These data were used to infer the (effective connectivity) architecture of synaptic connections among neural populations assumed to generate seizure activity. Dynamic causal modelling allowed us to quantify empirical changes in spectral activity in terms of a trajectory in parameter space -identifying key synaptic parameters or connections that cause observed signals. Using recordings from three seizures in one patient, we considered a network of two sources (within and just outside the putative ictal zone). Bayesian model selection was used to identify the intrinsic (within-source) and extrinsic (between-source) connectivity. Having established the underlying architecture, we were able to track the evolution of key connectivity parameters (e.g., inhibitory connections to superficial pyramidal cells) and test specific hypotheses about the synaptic mechanisms involved in ictogenesis. Our key finding was that intrinsic synaptic changes were sufficient to explain seizure onset, where these changes showed dissociable time courses over several seconds. Crucially, these changes spoke to an increase in the sensitivity of principal cells to intrinsic inhibitory afferents and a transient loss of excitatory-inhibitory balance

: Seizure onset zone imaging

International audienceStereo-electroencephalography is used to localize the seizure onset zone and connected neuronal networks in surgical candidates suffering from intractable focal epilepsy. The concept of an epileptogenicity index has been proposed recently to represent the likelihood of various regions being part of the seizure onset zone. It quantifies low-voltage fast activity, the electrophysiological signature of seizure onset usually assessed visually by neurologists. Here, we revisit epileptogenicity in light of neuroimaging tools such as those provided in statistical parametric mapping software. Our goal is to propose a robust approach, allowing easy exploration of patients' brains in time and space. The procedure is based upon statistical parametric mapping, which is an established framework for comparing multi-dimensional image data that allows one to correct for inherent multiple comparisons. Statistics can also be performed at the group level, between seizures in the same patient or between patients suffering from the same type of epilepsy using normalization of brains to a common anatomic atlas. Results are obtained from three case studies (insular reflex epilepsy, cryptogenic frontal epilepsy and lesional occipital epilepsy) where tailored resection was performed, and from a group of 10 patients suffering from mesial temporal lobe epilepsy. They illustrate the basics of the technique and demonstrate its very good reproducibility and specificity. Most importantly, the proposed approach to the quantification of the seizure onset zone allows one to summarize complex signals in terms of a time-series of statistical parametric maps that can support clinical decisions. Quantitative neuroimaging of stereo-electroencephalographic features of seizures might thus help to provide better pre-surgical assessment of patients undergoing resective surgery

On the Dynamics of Epileptic Spikes and Focus Localization in Temporal Lobe Epilepsy

abstract: Interictal spikes, together with seizures, have been recognized as the two hallmarks of epilepsy, a brain disorder that 1% of the world's population suffers from. Even though the presence of spikes in brain's electromagnetic activity has diagnostic value, their dynamics are still elusive. It was an objective of this dissertation to formulate a mathematical framework within which the dynamics of interictal spikes could be thoroughly investigated. A new epileptic spike detection algorithm was developed by employing data adaptive morphological filters. The performance of the spike detection algorithm was favorably compared with others in the literature. A novel spike spatial synchronization measure was developed and tested on coupled spiking neuron models. Application of this measure to individual epileptic spikes in EEG from patients with temporal lobe epilepsy revealed long-term trends of increase in synchronization between pairs of brain sites before seizures and desynchronization after seizures, in the same patient as well as across patients, thus supporting the hypothesis that seizures may occur to break (reset) the abnormal spike synchronization in the brain network. Furthermore, based on these results, a separate spatial analysis of spike rates was conducted that shed light onto conflicting results in the literature about variability of spike rate before and after seizure. The ability to automatically classify seizures into clinical and subclinical was a result of the above findings. A novel method for epileptogenic focus localization from interictal periods based on spike occurrences was also devised, combining concepts from graph theory, like eigenvector centrality, and the developed spike synchronization measure, and tested very favorably against the utilized gold rule in clinical practice for focus localization from seizures onset. Finally, in another application of resetting of brain dynamics at seizures, it was shown that it is possible to differentiate with a high accuracy between patients with epileptic seizures (ES) and patients with psychogenic nonepileptic seizures (PNES). The above studies of spike dynamics have elucidated many unknown aspects of ictogenesis and it is expected to significantly contribute to further understanding of the basic mechanisms that lead to seizures, the diagnosis and treatment of epilepsy.Dissertation/ThesisPh.D. Electrical Engineering 201

Haemodynamic correlates of interictal and ictal epileptic discharges and ictal semiology using simultaneous scalp video-EEG-fMRI and intracranial EEG-fMRI

Interictal and ictal epileptic discharges are produced by focal and widespread dysfunctional neuronal networks. Identification and characterization of epileptic discharges underlie the diagnosis and the choice of treatment for epilepsy patients. A better knowledge of the generation, propagation and localisation of epileptic discharges, and their interaction with the physiological and pathological brain networks can be very helpful in planning epilepsy surgery and minimizing the risk of damaging the physiological brain networks. This work describes a number of methodological developments and novel applications investigating the epileptic networks in humans using EEG-fMRI. First, I implemented synchronized video recording inside the MRI-scanner during simultaneous EEG-fMRI studies, which did not deteriorate the imaging and EEG data quality. Secondly, I used video recordings to identify physiological activities to be modelled as confounds in the functional imaging data analysis for interictal activity, thus increasing the sensitivity of video-EEG-fMRI. Thirdly, I applied this modelling approach to investigate seizure related functional networks in patients with focal epilepsy. Video recordings allowed partitioning seizures into phases separating the ictal onset related functional networks from propagation related networks. Localisation of the ictal onset related networks may be useful in the planning for epilepsy surgery in a selected group of patients, as demonstrated by their comparison with intracranial-EEG recordings. Further, I investigated haemodynamic changes during preictal period which suggested recruitment of an inhibitory followed by an excitatory network prior to the ictal onset on scalp EEG. In the next step, I used simultaneous intracranial-EEG-fMRI in patients undergoing invasive evaluation, demonstrating that local and remote networks associated with very focal interictal discharges recorded on intracranial-EEG may predict the surgical outcome. Finally, I investigated the interaction of epileptic discharges with the working memory, using scalp video-EEG-fMRI, showing that the presence of epileptic activity may alter the working memory related networks. Methodological constraints, clinical applications and future perspectives are discussed

Epilepsije u dječjoj dobi uzrokovane hipoksično-ishemičnom encefalopatijom

Hypoxic-ischemic encephalopathy is a condition associated with low uteroplacental blood flow that results in perinatal asphyxia. As a consequence of neonatal oxygen deprivation, perinatal asphyxia at the time of delivery is more common than in utero. Hypoxic-ischemic encephalopathy leads to several unfavorable neurodevelopmental outcomes. Epilepsy, cerebral palsy, mental retardation, visual and hearing problems are some of them. Epilepsy in children with perinatal asphyxia and hypoxic-ischemic encephalopathy is at the primary focus in this graduate thesis paper. Neonatal seizures are seizures that occur during neonatal period – first 28 days of the life of a full-term infant. Fifty percent of neonatal seizures are subtle and characterized by orolingual movements, automatisms, progression and purposeless movements. Most of the newborn seizures usually last 10 seconds to 1-2 minutes. Seizures are mostly repetitive with a median of a few minutes between each seizure. Many different epilepsy types are seen in children some of which being Ohtahara syndrome, West syndrome, and Lennox-Gastaut syndrome. Electroencephalography is the gold standard for diagnosis of neonatal epileptic seizures. 85% of electrographic seizures are usually silent. First line antiepileptic drugs of choice are phenobarbital and phenytoin.Hipoksično-ishemična encefalopatija je stanje koje nastaje kao posljedica slabog uteroplacentalnog krvotoka koji rezultira perinatalnom asfiksijom. Pojavljuje se kao posljedica niske saturacije kisikom u novorođenčeta u vrijeme poroda. Hipoksičnoishemična encefalopatija dovodi do nekoliko nepovoljnih neurorazvojnih ishoda kao što su epilepsija, cerebralna paraliza, mentalna retardacija, problemi s vidom i sluhom. Epilepsija i epileptički napadaji uzrokovani perinatalnom asfiksijom i hipokičnoishemičnom encefalopatijom su glavna tema ovoga diplomskoga rada. Epileptički napadaji koji se javljaju tijekom neonatalnog razdoblja, prvih 28 dana života prematurnog i terminskog djeteta. Pedeset posto neonatalnih napadaja su suptilni napadaji za koje su karakteristični orolingvalni pokreti sisanja, gutanja, slinjenja; pokreti poput veslanja i plivanja, multifokalni klonički grčevi. Većina cerebralnih napadaja obično traje 10 sekundi do 1-2 minute. Različite vrste epilepsija mogu se prezentirati u dječjoj dobi kao na primjer Ohtahara sindrom, Westov sindrom i Lennox-Gastautov sindrom. Elektroencefalografija je zlatni standard za dijagnozu cerebralnih epileptičkih napadaja. 85% elektrografskih napadaja obično je tiho to jest nisu klinički prepoznati. Prva linija antiepileptičkih lijekova po izboru su fenobarbital i fenitoin