Diaphragm relaxation causes seizure-related apnoeas in chronic and acute seizure models in rats.

Ictal central apnoea is a feature of focal temporal seizures. It is implicated as a risk factor for sudden unexpected death in epilepsy (SUDEP). Here we study seizure-related apnoeas in two different models of experimental seizures, one chronic and one acute, in adult genetically-unmodified rats, to determine mechanisms of seizure-related apnoeas.

Mouse model of focal cortical dysplasia type II generates a wide spectrum of high-frequency activities.

High-frequency oscillations (HFOs) represent an electrographic biomarker of endogenous epileptogenicity and seizure-generating tissue that proved clinically useful in presurgical planning and delineating the resection area. In the neocortex, the clinical observations on HFOs are not sufficiently supported by experimental studies stemming from a lack of realistic neocortical epilepsy models that could provide an explanation of the pathophysiological substrates of neocortical HFOs. In this study, we explored pathological epileptiform network phenomena, particularly HFOs, in a highly realistic murine model of neocortical epilepsy due to focal cortical dysplasia (FCD) type II.

Carotid body stimulation as a potential intervention in sudden death in epilepsy.

Objective: To investigate carotid body (CB) mechanisms related to sudden death during seizure. Ictal activation of oxygen-conserving reflexes (OCRs) can trigger fatal cardiorespiratory collapse in seizing rats, which presents like human sudden unexpected death in epilepsy (SUDEP). The CB is strongly implicated in OCR pathways; we hypothesize that modulating CB activity will provide insight into these mechanisms of death.

Acute and chronic cardiorespiratory consequences of focal intrahippocampal administration of seizure-inducing agents. Implications for SUDEP.

The risk factors for SUDEP are undoubtedly heterogenous but the main factor is the frequency of generalized tonic-clonic seizures with apnoea and/or cardiac abnormalities likely precipitating the lethal event. By its very nature modelling SUDEP experimentally is challenging, yet insights into the nature of the lethal event and precipitating factors are vital in order to understand and prevent fatalities. Acute animal models, which induce status epilepticus (SE), can be used to help understand pathophysiological processes during and following seizures, which sometimes lead to death.

Long-term seizure dynamics are determined by the nature of seizures and the mutual interactions between them.

The seemingly random and unpredictable nature of seizures is a major debilitating factor for people with epilepsy. An increasing body of evidence demonstrates that the epileptic brain exhibits long-term fluctuations in seizure susceptibility, and seizure emergence seems to be a consequence of processes operating over multiple temporal scales. A deeper insight into the mechanisms responsible for long-term seizure fluctuations may provide important information for understanding the complex nature of seizure genesis.

Ictal activation of oxygen-conserving reflexes as a mechanism for sudden death in epilepsy.

Objective: To test the hypothesis that death with physiological parallels to human cases of sudden unexpected death in epilepsy (SUDEP) can be induced in seizing rats by ictal activation of oxygen-conserving reflexes (OCRs).

Methods: Urethane-anesthetized female Long-Evans rats were implanted with electrodes for electrocardiography (ECG), electrocorticography (ECoG), and respiratory thermocouple; venous and arterial cannulas; and a laryngoscope guide and cannula or nasal cannula for activation of the laryngeal chemoreflex (LCR) or mammalian diving reflex (MDR), respectively. Kainic acid injection, either systemic or into the ventral hippocampus, induced prolonged acute seizures.

Mechanisms and prevention of acid reflux induced laryngospasm in seizing rats.

Objective: Recent animal work and limited clinical data have suggested that laryngospasm may be involved in the cardiorespiratory collapse seen in sudden unexpected death in epilepsy (SUDEP). In previous work, we demonstrated in an animal model of seizures that laryngospasm and sudden death were always preceded by acid reflux into the esophagus. Here, we expand on that work by testing several techniques to prevent the acid reflux or the subsequent laryngospasm.

Controversies on the network theory of epilepsy: Debates held during the ICTALS 2019 conference.

Debates on six controversial topics on the network theory of epilepsy were held during two debate sessions, as part of the International Conference for Technology and Analysis of Seizures, 2019 (ICTALS 2019) convened at the University of Exeter, UK, September 2-5 2019. The debate topics were (1) From pathologic to physiologic: is the epileptic network part of an existing large-scale brain network? (2) Are micro scale recordings pertinent for defining the epileptic network? (3) From seconds to years: do we need all temporal scales to define an epileptic network? (4) Is it necessary to fully define the epileptic network to control it? (5) Is controlling seizures sufficient to control the epileptic network? (6) Does the epileptic network want to be controlled? This article, written by the organizing committee for the debate sessions and the debaters, summarizes the arguments presented during the debates on these six topics.

Cardiac effects of repeated focal seizures in rats induced by intrahippocampal tetanus toxin: Bradyarrhythmias, tachycardias, and prolonged interictal QT interval.

Objective: To determine electrical changes in the heart in a chronic, nonstatus model of epilepsy.

Methods: Electrocorticography (ECoG) and electrocardiography (ECG) of nine animals (five made epileptic by intrahippocampal injection of tetanus neurotoxin (TeNT) and four controls), are monitored continuously by radiotelemetry for up to 7 weeks.

Results: Epileptic animals develop a median of 168 seizures, with postictal tachycardias reaching a mean of 487 beats/min and lasting a mean of 661 seconds.

The transition to status epilepticus: how the brain meets the demands of perpetual seizure activity.

The pathophysiology leading to the development of status epilepticus (SE) remains a topic of significant scientific interest and clinical relevance. The use of multiple experimental and computational models has shown that SE relies on a complex interaction between mechanisms that operate at both a cellular and network level. In this narrative review, we will summarise the current knowledge on the factors that play a key role in allowing SE to develop and persist.

The role of interictal discharges in ictogenesis - A dynamical perspective.

Interictal epileptiform discharge (IED) is a traditional hallmark of epileptic tissue that is generated by the synchronous activity of a population of neurons. Interictal epileptiform discharges represent a heterogeneous group of pathological activities that differ in shape, duration, spatiotemporal distribution, underlying cellular and network mechanisms, and their relationship to seizure genesis. The exact role of IEDs in epilepsy is still not well understood, and there remains a persistent dichotomy about the impact on IEDs on seizures.

Brainstem activity, apnea, and death during seizures induced by intrahippocampal kainic acid in anaesthetized rats.

Objective: To investigate how prolonged seizure activity affects cardiorespiratory function and activity of pre-Bötzinger complex, leading to sudden death.

Methods: Urethane-anesthetized female Long-Evans rats were implanted with nasal thermocouple; venous and arterial cannulae; and electrodes for electrocardiography (ECG) and hippocampal, cortical, and brainstem recording. Kainic acid injection into the ventral hippocampus induced status epilepticus.

A Method of Flexible Micro-Wire Electrode Insertion in Rodent for Chronic Neural Recording and a Device for Electrode Insertion.

Reliable chronic neural recording from focal deep brain structures is impeded by insertion injury and foreign body response, the magnitude of which is correlated with the mechanical mismatch between the electrode and tissue. Thin and flexible electrodes cause less glial scarring and record longer than stiff electrodes. However, the insertion of flexible microelectrodes in brain has been a challenge.

Loss of neuronal network resilience precedes seizures and determines the ictogenic nature of interictal synaptic perturbations.

The mechanism of seizure emergence and the role of brief interictal epileptiform discharges (IEDs) in seizure generation are two of the most important unresolved issues in modern epilepsy research. We found that the transition to seizure is not a sudden phenomenon, but is instead a slow process that is characterized by the progressive loss of neuronal network resilience. From a dynamical perspective, the slow transition is governed by the principles of critical slowing, a robust natural phenomenon that is observable in systems characterized by transitions between dynamical regimes.

Acid reflux induced laryngospasm as a potential mechanism of sudden death in epilepsy.

Objective: Recent research suggests that obstructive laryngospasm and consequent respiratory arrest may be a mechanism in sudden unexpected death in epilepsy. We sought to test a new hypothesis that this laryngospasm is caused by seizures driving reflux of stomach acid into the larynx, rather than spontaneous pathological activity in the recurrent laryngeal nerve.

Approach: We used an acute kainic acid model under urethane anesthesia to observe seizure activity in Long-Evans rats.

Chemogenetic Recruitment of Specific Interneurons Suppresses Seizure Activity.

Current anti-epileptic medications that boost synaptic inhibition are effective in reducing several types of epileptic seizure activity. Nevertheless, these drugs can generate significant side-effects and even paradoxical responses due to the broad nature of their action. Recently developed chemogenetic techniques provide the opportunity to pharmacologically recruit endogenous inhibitory mechanisms in a selective and circuit-specific manner.

A New Approach of Modified Submerged Patch Clamp Recording Reveals Interneuronal Dynamics during Epileptiform Oscillations.

Simultaneous epileptiform LFPs and single-cell activity can be recorded in the membrane chamber.Interneuron firing can be linked to epileptiform high frequency activity.Fast ripples, unique to chronic epilepsy, can be modeled in tissue from TeNT-treated rats.

Cavity Resonator Wireless Power Transfer System for Freely Moving Animal Experiments.

Objective: The goal of this paper is to create a large wireless powering arena for powering small devices implanted in freely behaving rodents.

Methods: We design a cavity resonator based wireless power transfer (WPT) system and utilize our previously developed optimal impedance matching methodology to achieve effective WPT performance for operating sophisticated implantable devices, made with miniature receive coils (<8 mm in diameter), within a large volume (dimensions: 60.96 cm × 60.

Specific cytoarchitectureal changes in hippocampal subareas in daDREAM mice.

Background: Transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a Ca(2+)-binding protein that regulates Ca(2+) homeostasis through gene regulation and protein-protein interactions. It has been shown that a dominant active form (daDREAM) is implicated in learning-related synaptic plasticity such as LTP and LTD in the hippocampus. Neuronal spines are reported to play important roles in plasticity and memory.

Models of drug-induced epileptiform synchronization in vitro.

Models of epileptiform activity in vitro have many advantages for recording and experimental manipulation. Neural tissues can be maintained in vitro for hours, and in neuronal or organotypic slice cultures for several weeks. A variety of drugs and other agents increase activity in these in vitro conditions, in many cases resulting in epileptiform activity, thus providing a direct model of symptomatic seizures.

Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus.

Adenosine inhibits excitatory neurons widely in the brain through adenosine A1 receptor, but activation of adenosine A2A receptor (A2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2A R expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons.