Low‐voltage fast seizures in humans begin with increased interneuron firing

Elahian, Bahareh; Lado, Nathan E.; Mankin, Emily A.; Vangala, Sitaram; Misra, Amrit; Moxon, Karen A.; Fried, Itzhak; Sharan, Ashwini; Yeasin, Mohammed; Staba, Richard J.; Bragin, Anatol; Avoli, Massimo; Sperling, Michael R.; Engel, Jerome; Weiss, Shennan A.

doi:10.1002/ana.25325

Cited by 79 publications

(96 citation statements)

References 47 publications

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“…This finding matches well with recent in vivo data obtained from patients with mesial temporal recordings (Elahian et al . ); also here, interneuronal firing increased at seizure onset, along with principal neuronal firing only 10 s into the discharge. At least for this seizure type (spike and wave discharges and peritumoral activity may be an exception), we thus have to conclude that interneurones start the seizure – and not excitatory cells.…”

Section: What Initiates the Spikes: Principal Busters Or Interneurones?supporting

confidence: 52%

Translational perspectives: Interneurones start seizures

Köhling

2019

The Journal of Physiology

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Section: What Initiates the Spikes: Principal Busters Or Interneurones?supporting

confidence: 52%

Translational perspectives: Interneurones start seizures

Köhling

2019

The Journal of Physiology

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“…In chronic epileptic animals, interneurons were preferentially recruited during spontaneous interictal activity in the CA1 region, 43 as well as before and during ictal events. 45 The general conclusion made from these data implies the dominating role of interneuron firing in the onset of both interictal and ictal events, with the delayed pyramidal cell firing as the result of postinhibition rebound excitation. 45 The general conclusion made from these data implies the dominating role of interneuron firing in the onset of both interictal and ictal events, with the delayed pyramidal cell firing as the result of postinhibition rebound excitation.…”

Section: Discussionmentioning

confidence: 80%

Activation of nicotinamide adenine dinucleotide phosphate oxidase is the primary trigger of epileptic seizures in rodent models

Malkov

Ivanov

Latyshkova

et al. 2019

Annals of Neurology

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Objective: Despite decades of epilepsy research, 30% of focal epilepsies remain resistant to antiseizure drugs, with effective drug development impeded by lack of understanding on how seizures are initiated. Here, we report the mechanism of seizure onset relevant to most seizures that are characteristic of focal epilepsies. Methods: Electric and metabolic network parameters were measured using several seizure models in mouse hippocampal slices and acutely induced seizures in rats in vivo to determine metabolic events occurring at seizure onset. Results: We show that seizure onset is associated with a rapid release of H 2 O 2 resulting from N-methyl-D-aspartate (NMDA) receptor-mediated activation of nicotinamide adenine dinucleotide phosphate oxidase (NOX). NOX blockade prevented the fast H 2 O 2 release as well as the direct current shift and seizurelike event induction in slices. Similarly, intracerebroventricular injection of NOX antagonists prevented acutely induced seizures in rats. Interpretation: Our results show that seizures are initiated by NMDA receptor-mediated NOX-induced oxidative stress and can be arrested by NOX inhibition. We introduce a novel use for blood-brain barrier-permeable NOX inhibitor with a significant potential to become the first seizure-specific medication. Thus, targeting NOX may provide a breakthrough treatment for focal epilepsies. ANN NEUROL 2019;85:907-920 A major goal of contemporary epilepsy research is the View this article online at wileyonlinelibrary.com.

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“…) or GABAergic (Elahian et al . ) processes, depending on the seizure morphology. To clarify the role of excitatory and inhibitory neuronal populations in the generation of epileptiform activity, we determined the normalized firing increase of neurons, as well as the contribution of PCs and INS during IISs and seizures and compared these data with those related to SPAs.…”

Section: Resultsmentioning

confidence: 99%

“…) and inhibitory (Elahian et al . ) processes, depending on the morphology of the seizure. We found that the role of excitatory and inhibitory neurons was different in physiological vs .…”

Section: Discussionmentioning

confidence: 99%

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Presence of synchrony‐generating hubs in the human epileptic neocortex

Kandrács

Hofer

Tóth

et al. 2019

The Journal of Physiology

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Key points •Initiation of pathological synchronous events such as epileptic spikes and seizures is linked to the hyperexcitability of the neuronal network in both humans and animals. •In the present study, we show that epileptiform interictal‐like spikes and seizures emerged in human neocortical slices by blocking GABAA receptors, following the disappearance of the spontaneously occurring synchronous population activity. •Large variability of temporally and spatially simple and complex spikes was generated by tissue from epileptic patients, whereas only simple events appeared in samples from non‐epileptic patients. •Physiological population activity was associated with a moderate level of principal cell and interneuron firing, with a slight dominance of excitatory neuronal activity, whereas epileptiform events were mainly initiated by the synchronous and intense discharge of inhibitory cells. •These results help us to understand the role of excitatory and inhibitory neurons in synchrony‐generating mechanisms, in both epileptic and non‐epileptic conditions. Abstract Understanding the role of different neuron types in synchrony generation is crucial for developing new therapies aiming to prevent hypersynchronous events such as epileptic seizures. Paroxysmal activity was linked to hyperexcitability and to bursting behaviour of pyramidal cells in animals. Human data suggested a leading role of either principal cells or interneurons, depending on the seizure morphology. In the present study, we aimed to uncover the role of excitatory and inhibitory processes in synchrony generation by analysing the activity of clustered single neurons during physiological and epileptiform synchronies in human neocortical slices. Spontaneous population activity was detected with a 24‐channel laminar microelectrode in tissue derived from patients with or without preoperative clinical manifestations of epilepsy. This population activity disappeared by blocking GABAA receptors, and several variations of spatially and temporally simple or complex interictal‐like spikes emerged in epileptic tissue, whereas peritumoural slices generated only simple spikes. Around one‐half of the clustered neurons participated with an elevated firing rate in physiological synchronies with a slight dominance of excitatory cells. By contrast, more than 90% of the neurons contributed to interictal‐like spikes and seizures, and an intense and synchronous discharge of inhibitory neurons was associated with the start of these events. Intrinsically bursting principal cells fired later than other neurons. Our data suggest that a balanced excitation and inhibition characterized physiological synchronies, whereas disinhibition‐induced epileptiform events were initiated mainly by non‐synaptically synchronized inhibitory neurons. Our results further highlight the differences between humans and animal models, and between in vivo and (pharmacologically manipulated) in vitro conditions.

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Low‐voltage fast seizures in humans begin with increased interneuron firing

Abstract: Our results suggest that seizure generation and spread during spontaneous mesial-temporal LVF onset events in humans may result from increased inhibitory neuron firing that spawns a subsequent increase in excitatory neuron firing and seizure evolution. Ann Neurol 2018;84:588-600.

Cited by 79 publications

References 47 publications

Translational perspectives: Interneurones start seizures

Translational perspectives: Interneurones start seizures

Activation of nicotinamide adenine dinucleotide phosphate oxidase is the primary trigger of epileptic seizures in rodent models

Presence of synchrony‐generating hubs in the human epileptic neocortex

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