Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Lévesque, Maxime; Chen, Liyuan; Etter, Guillaume; Shiri, Zahra; Wang, Siyan; Williams, Sylvain

doi:10.1002/ana.25572

Cited by 38 publications

(23 citation statements)

References 49 publications

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“…Such observation is in agreement with a previous study by Assaf and Schiller [67], in which optogenetic activation of PV+ interneurons in the ictal regime had an anti-epileptic effect, but a pro-epileptic effect when they were activated in the inter-ictal regime. More recently, it was discussed that paradoxical effects of PV+ activation shown in [68] could be related to the timing of the neurostimulation [69]. Therefore, our results support that a precise, on-demand (closed-loop) stimulation system is required to deliver stimulation at an optimal timing, and avoid the promotion of epileptiform activity.…”

Section: Discussionsupporting

confidence: 78%

Neural mass modeling of slow-fast dynamics of seizure initiation and abortion

et al. 2020

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Epilepsy is a dynamic and complex neurological disease affecting about 1% of the worldwide population, among which 30% of the patients are drug-resistant. Epilepsy is characterized by recurrent episodes of paroxysmal neural discharges (the so-called seizures), which manifest themselves through a large-amplitude rhythmic activity observed in depth-EEG recordings, in particular in local field potentials (LFPs). The signature characterizing the transition to seizures involves complex oscillatory patterns, which could serve as a marker to prevent seizure initiation by triggering appropriate therapeutic neurostimulation methods. To investigate such protocols, neurophysiological lumped-parameter models at the mesoscopic scale, namely neural mass models, are powerful tools that not only mimic the LFP signals but also give insights on the neural mechanisms related to different stages of seizures. Here, we analyze the multiple time-scale dynamics of a neural mass model and explain the underlying structure of the complex oscillations observed before seizure initiation. We investigate population-specific effects of the stimulation and the dependence of stimulation parameters on synaptic timescales. In particular, we show that intermediate stimulation frequencies (>20 Hz) can abort seizures if the timescale difference is pronounced. Those results have the potential in the design of therapeutic brain stimulation protocols based on the neurophysiological properties of tissue.

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Section: Discussionsupporting

confidence: 78%

Neural mass modeling of slow-fast dynamics of seizure initiation and abortion

et al. 2020

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“…By optogenetically stimulating parvalbumin interneurons in epileptic mice, Lévesque and collaborators found that the seizure rate was reduced, but the seizure probability instead increased, indicating that the enhanced GABA release from parvalbumin interneurons can paradoxically promote seizures. 10 Although we have not evaluated these phenomena in our animals, the GABAergic tone could be expected to increase in trilostane-treated animals, possibly reproducing a situation similar to that characterized by Lévesque and collaborators in their epileptic mice.…”

Section: Discussionmentioning

confidence: 72%

Augmentation of endogenous neurosteroid synthesis alters experimental status epilepticus dynamics

et al. 2020

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Status epilepticus (SE) affects approximately 41 of every 100 000 adults and is difficult to treat. For this reason, up to 20% of cases are reported to involve mortality. 1 Various neurological disorders are associated with SE, including cerebrovascular diseases, trauma, intoxication, and also others, but it is unclear why SE develops only in some patients affected by the previously mentioned central nervous system (CNS) disorders. In addition, SE also develops without a clear reason in some cases. Finally, patients with epilepsy may experience one or more episodes of SE, whereas others

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“…In support of this theory, a loss of inhibitory interneurons was described in the resected tissue of MTLE patients 28 and animal models of MTLE 29 . In addition, all manipulations stimulating GABAergic transmission suppressed seizures in MTLE models 30–33 . On the contrary, some GABAergic interneurons are preserved in human MTLE and rat models 34 or are differently affected in MTLE 29 .…”

Section: Discussionmentioning

confidence: 90%

In vivo γ‐aminobutyric acid increase as a biomarker of the epileptogenic zone: An unbiased metabolomics approach

et al. 2020

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ObjectiveFollowing surgery, focal seizures relapse in 20% to 50% of cases due to the difficulty of delimiting the epileptogenic zone (EZ) by current imaging or electrophysiological techniques. Here, we evaluate an unbiased metabolomics approach based on ex vivo and in vivo nuclear magnetic resonance spectroscopy (MRS) methods to discriminate the EZ in a mouse model of mesiotemporal lobe epilepsy (MTLE).MethodsFour weeks after unilateral injection of kainic acid (KA) into the dorsal hippocampus of mice (KA‐MTLE model), we analyzed hippocampal and cortical samples with high‐resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS). Using advanced multivariate statistics, we identified the metabolites that best discriminate the injected dorsal hippocampus (EZ) and developed an in vivo MEGAPRESS MRS method to focus on the detection of these metabolites in the same mouse model.ResultsMultivariate analysis of HRMAS data provided evidence that γ‐aminobutyric acid (GABA) is largely increased in the EZ of KA‐MTLE mice and is the metabolite that best discriminates the EZ when compared to sham and, more importantly, when compared to adjacent brain regions. These results were confirmed by capillary electrophoresis analysis and were not reversed by a chronic exposition to an antiepileptic drug (carbamazepine). Then, using in vivo noninvasive GABA‐edited MRS, we confirmed that a high GABA increase is specific to the injected hippocampus of KA‐MTLE mice.SignificanceOur strategy using ex vivo MRS‐based untargeted metabolomics to select the most discriminant metabolite(s), followed by in vivo MRS‐based targeted metabolomics, is an unbiased approach to accurately define the EZ in a mouse model of focal epilepsy. Results suggest that GABA is a specific biomarker of the EZ in MTLE.

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Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Cited by 38 publications

References 49 publications

Neural mass modeling of slow-fast dynamics of seizure initiation and abortion

Neural mass modeling of slow-fast dynamics of seizure initiation and abortion

Augmentation of endogenous neurosteroid synthesis alters experimental status epilepticus dynamics

In vivo γ‐aminobutyric acid increase as a biomarker of the epileptogenic zone: An unbiased metabolomics approach

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