Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy

Behr, Charles; Lévesque, Maxime; Ragsdale, David S.; Avoli, Massimo

doi:10.1016/j.eplepsyres.2015.05.006

Cited by 43 publications

(28 citation statements)

References 51 publications

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“…In addition, we found that interictal spikes occurred more regularly in PV-ChR2 compared to PV-Cre animals, suggesting that temporal coordination of hippocampal interneuronal activity through chronic optogenetic stimulation may lead to neuronal plasticity that makes interictal spiking more regular. 42 The stimulation of PV-positive interneurons through optogenetics could therefore inhibit excessive excitatory network activity in the CA3 region of the hippocampus, which is often the first region to show epileptiform activity during the latent period. 41 We have also discovered that optogenetics significantly modulates HFOs, because lower rates of interictal spikes with fast ripples were observed in PV-ChR2 animals when compared with PV-Cre mice.…”

Section: Discussionmentioning

confidence: 99%

“…Isolated fast ripples also occurred at significantly low rates in the PV-ChR2 group, similar to what was previously shown in the CA3 region of epileptic animals treated with the antiepileptic drug lacosamide. 42 The stimulation of PV-positive interneurons through optogenetics could therefore inhibit excessive excitatory network activity in the CA3 region of the hippocampus, which is often the first region to show epileptiform activity during the latent period. 43 Fast ripples are believed to reflect the synchronous firing of principal (glutamatergic) neurons in the epileptic hippocampus.…”

Section: Discussionmentioning

confidence: 99%

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Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Lévesque

Chen

Etter

et al. 2019

Annals of Neurology

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Objective: To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500Hz) occurring after pilocarpine-induced status epilepticus (SE)-a proven model of mesial temporal lobe epilepsy (MTLE)-in transgenic mice expressing or not expressing ChR2. Methods: PV-ChR2 (n = 6) and PV-Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450nm, 25mW, 20-millisecond pulses delivered at 8Hz for 30 seconds every 2 minutes) of CA3 PV-positive interneurons was implemented for 14 continuous days in both groups. Results: Rates of seizures (p < 0.01), interictal spikes (p < 0.001), and interictal spikes with fast ripples (250-500Hz) (p < 0.001) were lower in PV-ChR2 than in PV-Cre mice. Ripples (80-200Hz) occurring outside of interictal spikes had higher rates in the PV-ChR2 group (p < 0.01), whereas isolated fast ripples had lower rates (p < 0.01). However, seizure probability was higher during optogenetic stimulation in PV-ChR2 compared to PV-Cre animals (p < 0.05). Interpretation: Our findings show that the unilateral activation of CA3 PV-positive interneurons exerts anti-ictogenic effects associated with decreased rates of interictal spikes and fast ripples in this MTLE model. However, PV-positive interneuron stimulation can paradoxically trigger seizures in epileptic animals, supporting the notion that γ-aminobutyric acid type A signaling can also initiate ictogenesis. ANN NEUROL 2019;86:714-728 View this article online at wileyonlinelibrary.com.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Lévesque

Chen

Etter

et al. 2019

Annals of Neurology

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“…In vivo, pilocarpine‐treated animals treated with levetiracetam show decreased interictal spike rates in temporal lobe regions compared to pilocarpine‐treated animals that are not treated with anti‐epileptic drugs (Lévesque et al ., ), which replicates previous findings obtained in epileptic patients with this anti‐epileptic drug (Stodieck et al ., ). In addition, lacosamide, a potent anti‐ictogenic drug in the pilocarpine animal model, was capable of decreasing interictal spike rates in temporal lobe regions of pilocarpine‐treated rats (Behr et al ., ). In epileptic patients, however, lacosamide induced no effect or only a non‐significant decrease in interictal spiking activity (Giorgi et al ., ; Li et al ., ).…”

Section: Modulation Of Interictal Oscillations By Anticonvulsantsmentioning

confidence: 97%

“…Indeed, a decrease in anti‐epileptic medication in epileptic patients is associated with an increase in seizures, HFO rates and duration (Zijlmans et al ., ). These findings resemble what was reported in pilocarpine‐treated animals as a long‐term administration of levetiracetam or lacosamide significantly decreases the occurrence of ripples and fast ripples (Behr et al ., ; Lévesque et al ., ). This supports the hypothesis that HFOs, like seizures, are sensitive to anti‐epileptic drugs and are presumably better biomarkers of the underlying pathological network activity than interictal spikes (Worrell & Gotman, ).…”

Section: Modulation Of Interictal Oscillations By Anticonvulsantsmentioning

confidence: 99%

Interictal oscillations and focal epileptic disorders

Lévesque

Salami

Shiri

et al. 2017

Eur J of Neuroscience

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Neuronal network oscillations represent a main feature of the brain activity recorded in the EEG under normal and pathological conditions such as epilepsy. Specific oscillations occur between seizures in patients and in animal models of focal epilepsy, and thus, they are termed interictal. According to their shape and intrinsic signal frequency, interictal oscillations are classified as spikes and high-frequency oscillations (HFOs). Interictal spikes are recorded in the 'wideband' EEG signal and consist of large-amplitude events that usually last less than 1 s; HFOs, in contrast, are extracted by amplifying the appropriately filtered EEG signal and are usually categorized as ripples (80-200 Hz) and fast ripples (250-500 Hz). Interictal spikes and HFOs are used in clinical practice to localize the seizure onset zone in focal epileptic disorders, which is fundamental for performing successful surgical interventions in epileptic patients not responding to anti-epileptic drug therapy. Both types of interictal oscillations have been widely studied in animal models of focal epilepsy to identify the mechanisms underlying their generation as well as to establish their role in ictogenesis and epileptogenesis. In this review, we will address the cellular mechanisms underlying the generation of interictal spikes and HFOs in animal models of epileptiform synchronization and of focal epilepsy. Moreover, we will highlight in vitro and in vivo evidence indicating that these interictal oscillations mirror specific, dynamic changes in neuronal network excitability causing seizure generation (i.e. ictogenesis) and leading to a chronic epileptic condition (i.e. epileptogenesis).

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“…For instance, in the pilocarpine model, seizures and HFO rates decreased following the application of levetiracetam 64 or lacosamide. 65 The response to antiepileptic drugs has the potential to be used as a diagnostic test to differentiate between pathological HFOs and physiological ones.…”

Section: Hfos In Epileptogenesismentioning

confidence: 99%

Update on the mechanisms and roles of high‐frequency oscillations in seizures and epileptic disorders

et al. 2017

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Objective High-frequency oscillations (HFOs) are a type of brain activity that is recorded from brain regions capable of generating seizures. Due to the close association of HFOs with epileptogenic tissue and ictogenesis, understanding their cellular and network mechanisms could provide valuable information about the organization of epileptogenic networks and how seizures emerge from the abnormal activity of these networks. Methods In this review we summarize the most recent advances in the field of HFOs and provide a critical evaluation of new observations within the context of already established knowledge. Results Recent improvements in recording technology and the introduction of optogenetics into epilepsy research has intensified experimental work on HFOs. Using advanced computer models, new cellular substrates of epileptic HFOs were identified and the role of specific neuronal subtypes in HFO genesis determined. Traditionally, the pathogenesis of HFOs was explored mainly in patients with temporal lobe epilepsy and in animal models mimicking this condition. HFOs have also been reported to occur in other epileptic disorders and models such as neocortical epilepsy, genetically-determined epilepsies and infantile spasms, which further support the significance of HFOs in the pathophysiology of epilepsy. Significance It is increasingly recognized that HFOs are generated by multiple mechanisms at both cellular and network level. Future studies on HFOs combining novel high-resolution in vivo imaging techniques and precise control of neuronal behavior using optogenetics or chemogenetics will provide evidence about the causal role of HFOs in seizures and epileptogenesis. Detailed understanding of the pathophysiology of HFOs will propel better HFO classification and increase their information yield for clinical and diagnostic purposes.

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Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy

Cited by 43 publications

References 51 publications

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Interictal oscillations and focal epileptic disorders

Update on the mechanisms and roles of high‐frequency oscillations in seizures and epileptic disorders

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