Background: Potentially curative epilepsy surgery can be offered if a single, discrete epileptoge... more Background: Potentially curative epilepsy surgery can be offered if a single, discrete epileptogenic zone (EZ) can be identified. For individuals in whom there is no clear concordance between clinical localization, scalp EEG, and imaging data, intracranial EEG (icEEG) may be needed to confirm a predefined hypothesis regarding irritative zone (IZ), seizure onset zone (SOZ), and EZ prior to surgery. However, icEEG has limited spatial sampling and may fail to reveal the full extent of epileptogenic network if predefined hypothesis is not correct. Simultaneous icEEG-fMRI has been safely acquired in humans and allows exploration of neuronal activity at the whole-brain level related to interictal epileptiform discharges (IED) captured intracranially.Methods: We report icEEG-fMRI in eight patients with refractory focal epilepsy who had resective surgery and good postsurgical outcome. Surgical resection volume in seizure-free patients post-surgically reflects confirmed identification of the...
Synchronised rhythmic activity of the brain is thought to arise from neuronal network behaviours ... more Synchronised rhythmic activity of the brain is thought to arise from neuronal network behaviours that arise from synaptic signalling between individual cells. This notion has been a basis to explain periodic epileptiform discharges that are driven by interneuronal networks. However, interneuronal spiking not only engages cell-cell GABAergic transmission but also controls the extracellular GABA concentration ([GABA] e ) and thus tonic GABA A receptor conductance ( G tonic ). Furthermore, the firing activity of interneuron populations shows a bell-shaped dependence on G tonic , suggesting an innate susceptibility to self-sustained oscillations. Here, we employ a patch-clamp GABA 'sniffer' and fast two-photon excitation imaging of a GABA sensor to show that periodic epileptiform discharges are preceded by a region-wide, rising wave of extracellular GABA. Neural network simulations based on such observations reveal that it is the volume-transmitted, extrasynaptic actions of GABA targeting multiple off-target cells that drives synchronised interneuronal spiking prompting periodic epileptiform bursts. We validate this hypothesis using simultaneous patch-clamp recordings from multiple nerve cells and selective optogenetic stimulation of fast-spiking interneurons. Our findings thus unveil to a key role of volume-transmitted GABA actions in enabling and pacing regenerative rhythmic activity in brain networks.
Reflex epilepsies have been demonstrated to exploit specific networks that subserve normal physio... more Reflex epilepsies have been demonstrated to exploit specific networks that subserve normal physiological function. It is unclear whether more common forms of epilepsy share this particular feature. By measuring interictal spikes in patients with a range of epilepsies, we show that 2 tasks known to specifically engage the hippocampus and temporal neocortex promoted increased interictal spiking within these regions, whereas a nonhippocampal dependent task did not. This indicates that interictal spike frequency may reflect the processing demands being placed on specific functional–anatomical networks in epilepsy. ANN NEUROL 2019;86:304–309
Current antiseizure therapy is ineffective in approximately one third of people with epilepsy and... more Current antiseizure therapy is ineffective in approximately one third of people with epilepsy and is often associated with substantial side effects. In addition, most current therapeutic paradigms offer treatment, but not cure, and no therapies are able to modify the underlying disease, that is, can prevent or halt the process of epileptogenesis or alleviate the cognitive and psychiatric comorbidities. Preclinical research in the field of epilepsy has been extensive, but unfortunately, not all the animal models being used have been validated for their predictive value. The overall goal of TASK2 of the AES/ILAE Translational Task Force is to organize and coordinate systematic reviews on selected topics regarding animal research in epilepsy. Herein we describe our strategy. In the first part of the paper we provide an overview of the usefulness of systematic reviews and meta-analysis for preclinical research and explain the essentials for their conduct. Then we describe in detail the ...
In current fMRI studies designed to map BOLD changes related to interictal epileptiform discharge... more In current fMRI studies designed to map BOLD changes related to interictal epileptiform discharges (IED), which are recorded on simultaneous EEG, the information contained in the morphology and field extent of the EEG events is exclusively used for their classification. Usually, a BOLD predictor based on IED onset times alone is constructed, effectively treating all events as identical. We used intracranial EEG (icEEG)-fMRI data simultaneously recorded in humans to investigate the effect of including any of the features: amplitude, width (duration), slope of the rising phase, energy (area under the curve), or spatial field extent (number of contacts over which the sharp wave was observed) of the fast wave of the IED (the sharp wave), into the BOLD model, to better understand the neurophysiological origin of sharp wave-related BOLD changes, in the immediate vicinity of the recording contacts. Among the features considered, the width was the only one found to explain a significant amo...
Epilepsy affects approximately 50 million people worldwide, and 20-30% of these cases are refract... more Epilepsy affects approximately 50 million people worldwide, and 20-30% of these cases are refractory to antiepileptic drugs. Many patients with intractable epilepsy can benefit from surgical resection of the tissue generating the seizures; however, difficulty in precisely localising seizure foci has limited the number of patients undergoing surgery as well as potentially lowered its effectiveness. Here we demonstrate a novel imaging method for monitoring rapid changes in cerebral tissue impedance occurring during interictal and ictal activity, and show that it can reveal the propagation of pathological activity in the cortex. Cortical impedance was recorded simultaneously to ECoG using a 30-contact electrode mat placed on the exposed cortex of anaesthetised rats, in which interictal spikes (IISs) and seizures were induced by cortical injection of 4-aminopyridine (4-AP), picrotoxin or penicillin. We characterised the tissue impedance responses during IISs and seizures, and imaged the...
Seizure activity has been proposed to result in the generation of reactive oxygen species (ROS), ... more Seizure activity has been proposed to result in the generation of reactive oxygen species (ROS), which then contribute to seizure-induced neuronal damage and eventually cell death. Although the mechanisms of seizure-induced ROS generation are unclear, mitochondria and cellular calcium overload have been proposed to have a crucial role. We aim to determine the sources of seizure-induced ROS and their contribution to seizure-induced cell death. Using live cell imaging techniques in glioneuronal cultures, we show that prolonged seizure-like activity increases ROS production in an NMDA receptor-dependent manner. Unexpectedly, however, mitochondria did not contribute to ROS production during seizure-like activity. ROS were generated primarily by NADPH oxidase and later by xanthine oxidase (XO) activity in a calcium-independent manner. This calcium-independent neuronal ROS production was accompanied by an increase in intracellular [Na(+)] through NMDA receptor activation. Inhibition of NA...
The mechanisms underlying neuronal death following excessive activity such as occurs during prolo... more The mechanisms underlying neuronal death following excessive activity such as occurs during prolonged seizures are unclear, but mitochondrial dysfunction has been hypothesized to play a role. Here, we tested this with fluorescence imaging techniques in rat glio-neuronal neocortical co-cultures using low magnesium to induce seizure-like activity. Glutamate activation of NMDA receptors resulted in calcium oscillations in neurons and a sustained depolarization of the mitochondrial membrane potential, which was cyclosporine A sensitive indicating mitochondrial permeability transition pore opening and dependent on glutamate release and NMDA receptor activation, as it was not observed after depleting vesicular glutamate with vacuolar-type H+ ATPase concanamycin A or blocking NMDA receptors with APV. Neuronal ATP levels in soma and dendrites decreased significantly during prolonged seizures and correlated with the frequency of the oscillatory calcium signal, indicative of activity-dependen...
SummaryCerebral cavernous malformations (CCMs) are well‐defined, mostly singular lesions present ... more SummaryCerebral cavernous malformations (CCMs) are well‐defined, mostly singular lesions present in 0.4–0.9% of the population. Epileptic seizures are the most frequent symptom in patients with CCMs and have a great impact on social function and quality of life. However, patients with CCM‐related epilepsy (CRE) who undergo surgical resection achieve postoperative seizure freedom in only about 75% of cases. This is frequently because insufficient efforts are made to adequately define and resect the epileptogenic zone. The Surgical Task Force of the Commission on Therapeutics of the International League Against Epilepsy (ILAE) and invited experts reviewed the pertinent literature on CRE. Definitions of definitive and probable CRE are suggested, and recommendations regarding the diagnostic evaluation and etiology‐specific management of patients with CRE are made. Prospective trials are needed to determine when and how surgery should be done and to define the relations of the hemosideri...
This narrative review is intended to introduce clinicians treating epilepsy and researchers famil... more This narrative review is intended to introduce clinicians treating epilepsy and researchers familiar with mammalian models of epilepsy to experimentally tractable, non-mammalian research models used in epilepsy research, ranging from unicellular eukaryotes to more complex multicellular organisms. The review focuses on four model organisms: the social amoeba Dictyostelium discoideum, the roundworm Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the zebrafish Danio rerio. We consider recent discoveries made with each model organism and discuss the importance of these advances for the understanding and treatment of epilepsy in humans. The relative ease with which mutations in genes of interest can be produced and studied quickly and cheaply in these organisms, together with their anatomical and physiological simplicity in comparison to mammalian species, are major advantages when researchers are trying to unravel complex disease mechanisms. The short generation times ...
Background: Potentially curative epilepsy surgery can be offered if a single, discrete epileptoge... more Background: Potentially curative epilepsy surgery can be offered if a single, discrete epileptogenic zone (EZ) can be identified. For individuals in whom there is no clear concordance between clinical localization, scalp EEG, and imaging data, intracranial EEG (icEEG) may be needed to confirm a predefined hypothesis regarding irritative zone (IZ), seizure onset zone (SOZ), and EZ prior to surgery. However, icEEG has limited spatial sampling and may fail to reveal the full extent of epileptogenic network if predefined hypothesis is not correct. Simultaneous icEEG-fMRI has been safely acquired in humans and allows exploration of neuronal activity at the whole-brain level related to interictal epileptiform discharges (IED) captured intracranially.Methods: We report icEEG-fMRI in eight patients with refractory focal epilepsy who had resective surgery and good postsurgical outcome. Surgical resection volume in seizure-free patients post-surgically reflects confirmed identification of the...
Synchronised rhythmic activity of the brain is thought to arise from neuronal network behaviours ... more Synchronised rhythmic activity of the brain is thought to arise from neuronal network behaviours that arise from synaptic signalling between individual cells. This notion has been a basis to explain periodic epileptiform discharges that are driven by interneuronal networks. However, interneuronal spiking not only engages cell-cell GABAergic transmission but also controls the extracellular GABA concentration ([GABA] e ) and thus tonic GABA A receptor conductance ( G tonic ). Furthermore, the firing activity of interneuron populations shows a bell-shaped dependence on G tonic , suggesting an innate susceptibility to self-sustained oscillations. Here, we employ a patch-clamp GABA 'sniffer' and fast two-photon excitation imaging of a GABA sensor to show that periodic epileptiform discharges are preceded by a region-wide, rising wave of extracellular GABA. Neural network simulations based on such observations reveal that it is the volume-transmitted, extrasynaptic actions of GABA targeting multiple off-target cells that drives synchronised interneuronal spiking prompting periodic epileptiform bursts. We validate this hypothesis using simultaneous patch-clamp recordings from multiple nerve cells and selective optogenetic stimulation of fast-spiking interneurons. Our findings thus unveil to a key role of volume-transmitted GABA actions in enabling and pacing regenerative rhythmic activity in brain networks.
Reflex epilepsies have been demonstrated to exploit specific networks that subserve normal physio... more Reflex epilepsies have been demonstrated to exploit specific networks that subserve normal physiological function. It is unclear whether more common forms of epilepsy share this particular feature. By measuring interictal spikes in patients with a range of epilepsies, we show that 2 tasks known to specifically engage the hippocampus and temporal neocortex promoted increased interictal spiking within these regions, whereas a nonhippocampal dependent task did not. This indicates that interictal spike frequency may reflect the processing demands being placed on specific functional–anatomical networks in epilepsy. ANN NEUROL 2019;86:304–309
Current antiseizure therapy is ineffective in approximately one third of people with epilepsy and... more Current antiseizure therapy is ineffective in approximately one third of people with epilepsy and is often associated with substantial side effects. In addition, most current therapeutic paradigms offer treatment, but not cure, and no therapies are able to modify the underlying disease, that is, can prevent or halt the process of epileptogenesis or alleviate the cognitive and psychiatric comorbidities. Preclinical research in the field of epilepsy has been extensive, but unfortunately, not all the animal models being used have been validated for their predictive value. The overall goal of TASK2 of the AES/ILAE Translational Task Force is to organize and coordinate systematic reviews on selected topics regarding animal research in epilepsy. Herein we describe our strategy. In the first part of the paper we provide an overview of the usefulness of systematic reviews and meta-analysis for preclinical research and explain the essentials for their conduct. Then we describe in detail the ...
In current fMRI studies designed to map BOLD changes related to interictal epileptiform discharge... more In current fMRI studies designed to map BOLD changes related to interictal epileptiform discharges (IED), which are recorded on simultaneous EEG, the information contained in the morphology and field extent of the EEG events is exclusively used for their classification. Usually, a BOLD predictor based on IED onset times alone is constructed, effectively treating all events as identical. We used intracranial EEG (icEEG)-fMRI data simultaneously recorded in humans to investigate the effect of including any of the features: amplitude, width (duration), slope of the rising phase, energy (area under the curve), or spatial field extent (number of contacts over which the sharp wave was observed) of the fast wave of the IED (the sharp wave), into the BOLD model, to better understand the neurophysiological origin of sharp wave-related BOLD changes, in the immediate vicinity of the recording contacts. Among the features considered, the width was the only one found to explain a significant amo...
Epilepsy affects approximately 50 million people worldwide, and 20-30% of these cases are refract... more Epilepsy affects approximately 50 million people worldwide, and 20-30% of these cases are refractory to antiepileptic drugs. Many patients with intractable epilepsy can benefit from surgical resection of the tissue generating the seizures; however, difficulty in precisely localising seizure foci has limited the number of patients undergoing surgery as well as potentially lowered its effectiveness. Here we demonstrate a novel imaging method for monitoring rapid changes in cerebral tissue impedance occurring during interictal and ictal activity, and show that it can reveal the propagation of pathological activity in the cortex. Cortical impedance was recorded simultaneously to ECoG using a 30-contact electrode mat placed on the exposed cortex of anaesthetised rats, in which interictal spikes (IISs) and seizures were induced by cortical injection of 4-aminopyridine (4-AP), picrotoxin or penicillin. We characterised the tissue impedance responses during IISs and seizures, and imaged the...
Seizure activity has been proposed to result in the generation of reactive oxygen species (ROS), ... more Seizure activity has been proposed to result in the generation of reactive oxygen species (ROS), which then contribute to seizure-induced neuronal damage and eventually cell death. Although the mechanisms of seizure-induced ROS generation are unclear, mitochondria and cellular calcium overload have been proposed to have a crucial role. We aim to determine the sources of seizure-induced ROS and their contribution to seizure-induced cell death. Using live cell imaging techniques in glioneuronal cultures, we show that prolonged seizure-like activity increases ROS production in an NMDA receptor-dependent manner. Unexpectedly, however, mitochondria did not contribute to ROS production during seizure-like activity. ROS were generated primarily by NADPH oxidase and later by xanthine oxidase (XO) activity in a calcium-independent manner. This calcium-independent neuronal ROS production was accompanied by an increase in intracellular [Na(+)] through NMDA receptor activation. Inhibition of NA...
The mechanisms underlying neuronal death following excessive activity such as occurs during prolo... more The mechanisms underlying neuronal death following excessive activity such as occurs during prolonged seizures are unclear, but mitochondrial dysfunction has been hypothesized to play a role. Here, we tested this with fluorescence imaging techniques in rat glio-neuronal neocortical co-cultures using low magnesium to induce seizure-like activity. Glutamate activation of NMDA receptors resulted in calcium oscillations in neurons and a sustained depolarization of the mitochondrial membrane potential, which was cyclosporine A sensitive indicating mitochondrial permeability transition pore opening and dependent on glutamate release and NMDA receptor activation, as it was not observed after depleting vesicular glutamate with vacuolar-type H+ ATPase concanamycin A or blocking NMDA receptors with APV. Neuronal ATP levels in soma and dendrites decreased significantly during prolonged seizures and correlated with the frequency of the oscillatory calcium signal, indicative of activity-dependen...
SummaryCerebral cavernous malformations (CCMs) are well‐defined, mostly singular lesions present ... more SummaryCerebral cavernous malformations (CCMs) are well‐defined, mostly singular lesions present in 0.4–0.9% of the population. Epileptic seizures are the most frequent symptom in patients with CCMs and have a great impact on social function and quality of life. However, patients with CCM‐related epilepsy (CRE) who undergo surgical resection achieve postoperative seizure freedom in only about 75% of cases. This is frequently because insufficient efforts are made to adequately define and resect the epileptogenic zone. The Surgical Task Force of the Commission on Therapeutics of the International League Against Epilepsy (ILAE) and invited experts reviewed the pertinent literature on CRE. Definitions of definitive and probable CRE are suggested, and recommendations regarding the diagnostic evaluation and etiology‐specific management of patients with CRE are made. Prospective trials are needed to determine when and how surgery should be done and to define the relations of the hemosideri...
This narrative review is intended to introduce clinicians treating epilepsy and researchers famil... more This narrative review is intended to introduce clinicians treating epilepsy and researchers familiar with mammalian models of epilepsy to experimentally tractable, non-mammalian research models used in epilepsy research, ranging from unicellular eukaryotes to more complex multicellular organisms. The review focuses on four model organisms: the social amoeba Dictyostelium discoideum, the roundworm Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the zebrafish Danio rerio. We consider recent discoveries made with each model organism and discuss the importance of these advances for the understanding and treatment of epilepsy in humans. The relative ease with which mutations in genes of interest can be produced and studied quickly and cheaply in these organisms, together with their anatomical and physiological simplicity in comparison to mammalian species, are major advantages when researchers are trying to unravel complex disease mechanisms. The short generation times ...
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