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The piriform cortex (PC) plays a pivotal role in the onset and propagation of temporal lobe epilepsy (TLE), making it a potential target for therapeutic interventions. This review delves into the anatomy and epileptogenic connections of the PC, highlighting its significance in seizure initiation and resistance to pharmacological treatments. Despite its importance, the PC remains underexplored in surgical approaches for TLE. We examine the specific neuroanatomy of the PC as well as the limitations of current imaging techniques and surgical interventions, emphasizing the need for improved imaging protocols to safely target the PC, especially in minimally invasive procedures. Furthermore, the PC's proximity to vital structures, such as the lenticulostriate arteries, presents challenges that must be addressed in future research. By developing multimodal imaging techniques and refining surgical strategies, the PC could emerge as a crucial node in improving seizure freedom outcomes for TLE patients. [ABSTRACT FROM AUTHOR]

Objective: Epileptogenesis is linked to neuroinflammation. We hypothesized that local heat production caused by neuroinflammation can be visualized non‐invasively in vivo via brain magnetic resonance spectroscopic imaging (MRSI) and MRSI‐thermometry (MRSI‐t) and that there is a relationship in patients with temporal lobe epilepsy (TLE) between MRSI‐t and brain metabolites choline and myo‐inositol and between neuroimaging and cellular and serum biomarkers of inflammation. Methods: Thirty‐six (36) participants, 18 with temporal lobe epilepsy (13 females) and 18 age‐matched healthy controls (nine females), were enrolled prospectively and underwent MRSI/MRSI‐t; TLE participants also provided blood samples. Temperature was measured using creatine as a reference metabolite. Analysis of Functional NeuroImages 3dttest++ tool was used to analyze voxel‐level group differences in temperature, choline, and myo‐inositol. Associations with immune cell subsets, cytokines, and chemokines related to inflammation were quantified using correlation coefficients with significant relationships as noted. Results: Patients with TLE showed elevated temperature, choline, and myo‐inositol in the temporal lobes. Higher brain temperature was associated with higher levels of cytokines and chemokines, including GM‐CSF, TNF, IL‐1β, and IL − 12p70, and lower frequency of immune cells including CD3+ T‐cells, CD4+ T‐cells, CD8+ T‐cells, and classical monocytes. Higher choline was associated with higher levels of the cytokines including LT‐α, IL‐13, and IL‐4, and higher myo‐inositol was associated with a higher frequency of CD4+ T‐cell and CD19+ B‐cell subsets and higher levels of cytokines and chemokines including LT‐α, IL‐13, and CCL3. Significance: This study, for the first time, showed that in temporal lobes of patients with TLE temperature and metabolite changes correlate with cellular and serum biomarkers of inflammation. Our results provide support for further development of MRSI‐t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool. Plain Language Summary: Neuroinflammation is associated with excessive heat production which can be visualized with magnetic resonance spectroscopic imaging and thermometry (MRSI‐t). We prospectively investigated the relationship between MRSI‐t and cellular and serum measures of peripheral inflammation in patients with temporal lobe epilepsy (TLE); we compared the results of MRSI‐t in patients with TLE to healthy controls. We showed a relationship between the temperature elevations in TLE and elevations of various measures of peripheral inflammation. Our results support further development of MRSI‐t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool. [ABSTRACT FROM AUTHOR]

Dendritic Pathology, Spine Loss and Synaptic Reorganization in Human Cortex From Epilepsy Patients Rossini L, De Santis D, Mauceri RR, Tesoriero C, Bentivoglio M, Maderna E, Maiorana A, Deleo F, de Curtis M, Tringali G, Cossu M, Tumminelli G, Bramerio M, Spreafico R, Tassi L, Garbelli R. Brain. 2021;144(1):251-265. doi:10.1093/brain/awaa387 Neuronal dendritic arborizations and dendritic spines are crucial for a normal synaptic transmission and may be critically involved in the pathophysiology of epilepsy. Alterations in dendritic morphology and spine loss mainly in hippocampal neurons have been reported both in epilepsy animal models and in human brain tissues from patients with epilepsy. However, it is still unclear whether these dendritic abnormalities relate to the cause of epilepsy or are generated by seizure recurrence. We investigated fine neuronal structures at the level of dendritic and spine organization using Golgi impregnation, and analyzed synaptic networks with immunohistochemical markers of glutamatergic (vGLUT1) and GABAergic (vGAT) axon terminals in human cerebral cortices derived from epilepsy surgery. Specimens were obtained from 28 patients with different neuropathologically defined etiologies: type Ia and type II focal cortical dysplasia, cryptogenic (no lesion) and temporal lobe epilepsy with hippocampal sclerosis. Autoptic tissues were used for comparison. Three-dimensional reconstructions of Golgi-impregnated neurons revealed severe dendritic reshaping and spine alteration in the core of the type II focal cortical dysplasia. Dysmorphic neurons showed increased dendritic complexity, reduction of dendritic spines, and occasional filopodia-like protrusions emerging from the soma. Surprisingly, the intermingled normal-looking pyramidal neurons also showed severe spine loss and simplified dendritic arborization. No changes were observed outside the dysplasia (perilesional tissue) or in neocortical postsurgical tissue obtained in the other patient groups. Immunoreactivities of vGLUT1 and vGAT showed synaptic reorganization in the core of type II dysplasia characterized by the presence of abnormal perisomatic baskets around dysmorphic neurons, in particular those with filopodia-like protrusions, and changes in vGLUT1/vGAT expression. Ultrastructural data in type II dysplasia highlighted the presence of altered neuropil engulfed by glial processes. Our data indicate that the fine morphological aspect of neurons and dendritic spines are normal in epileptogenic neocortex, with the exception of type II dysplastic lesions. The findings suggest that the mechanisms leading to this severe form of cortical malformation interfere with the normal dendritic arborization and synaptic network organization. The data argue against the concept that long-lasting epilepsy and seizure recurrence per se unavoidably produce a dendritic pathology. [ABSTRACT FROM AUTHOR]

Background: Temporal lobe epilepsy (TLE) is among the most common types of epilepsy and often leads to cognitive, emotional, and psychiatric issues due to the frequent seizures. A notable pathological change related to TLE is hippocampal sclerosis (HS), which is characterized by neuronal loss, gliosis, and an increased neuron fibre density. The mechanisms underlying TLE-HS development remain unclear, but the reactive transcriptomic changes in glial cells and neurons of the hippocampus post-epileptogenesis may provide insights. Methods: To induce TLE, 200 nl of kainic acid (KA) was stereotactically injected into the hippocampal CA1 region of mice, followed by a 7-day postinjection period. Single-cell RNA sequencing (ScRNA-seq), single-nucleus RNA sequencing (SnRNA-seq), and Xenium-based spatial transcriptomics analyses were employed to evaluate the changes in mRNA expression in glial cells and neurons. Results: From the ScRNA-seq and SnRNA-seq data, 31,390 glial cells and 48,221 neuronal nuclei were identified. Analysis of the differentially expressed genes (DEGs) revealed significant transcriptomic alterations in the hippocampal cells of mice with TLE, affecting hundreds to thousands of mRNAs and their signalling pathways. Enrichment analysis indicated notable activation of stress and inflammatory pathways in the TLE hippocampus, while pathways related to axonal development and neural support were suppressed. Xenium analysis demonstrated the expression of all 247 genes across mouse brain sections, revealing the spatial distributions of their expression in 27 cell types. Integrated analysis of the DEGs identified via the three sequencing techniques revealed that Spp1, Trem2, and Cd68 were upregulated in all glial cell types and in the Xenium data; Penk, Sorcs3, and Plekha2 were upregulated in all neuronal cell types and in the Xenium data; and Tle4 and Sipa1l3 were downregulated in all glial cell types and in the Xenium data. Conclusion: In this study, a high-resolution single-cell transcriptomic atlas of the hippocampus in mice with TLE was established, revealing potential intrinsic mechanisms driving TLE-associated inflammatory activation and altered cell interactions. These findings provide valuable insights for further exploration of HS development and epileptogenesis. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate mesial temporal lobe abnormalities in mesial temporal lobe epilepsy (MTLE) patients with hypersynchronous (HYP) and low‐voltage fast rhythms (LVF) onset identified by stereotactic electroencephalography (SEEG) and evaluate their diagnostic and prognostic value. Methods: Fifty‐one MTLE patients were categorized as HYP or LVF by SEEG. High‐resolution MRI volume‐based analysis and 18F‐FDG‐PET standard uptake values of hippocampal and amygdala subfields were quantified and compared with 57 matched controls. Further analyses were conducted to delineate the distinct pathological characteristics differentiating the two groups. Diagnostic and prognostic prediction performance of these biomarkers were assessed using receiver operating characteristic curves. Results: LVF‐onset individuals demonstrated ipsilateral amygdala enlargement (p = 0.048) and contralateral hippocampus hypermetabolism (p = 0.042), pathological results often accompany abnormalities in the temporal lobe cortex, while HYP‐onset subjects had significant atrophy (p < 0.001) and hypometabolism (p = 0.013) in ipsilateral hippocampus and its subfields, as well as amygdala atrophy (p < 0.001), pathological results are highly correlated with hippocampal sclerosis. Severe fimbria atrophy was observed in cases of HYP‐onset MTLE with poor prognosis (AUC = 0.874). Conclusion: Individuals with different seizure‐onset patterns display specific morphological and metabolic abnormalities in the amygdala and hippocampus. Identifying these subfield abnormalities can improve diagnostic and prognostic precision, guiding surgical strategies for MTLE. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy. A major focus of human and animal studies on TLE network has been the limbic circuit. However, there is also evidence suggesting an active role of the basal ganglia in the propagation and control of temporal lobe seizures. Here, we characterize the involvement of the substantia nigra (SN) and somatosensory cortex (SI) during temporal lobe (TL) seizures induced by penicillin injection in the hippocampus (HPC) of two nonhuman primates. The seizure onset and offset patterns were manually classified and spectral power and coherence were calculated. We then compared the 3-second segments recorded in pre-ictal, onset, offset and post-ictal periods based on the seizure onset and offset patterns. Our results demonstrated an involvement of the SN and SI dependent on the seizure onset and offset pattern. We found that low amplitude fast activity (LAF) and high amplitude slow activity (HAS) onset patterns were associated with an increase in activity of the SN while the change in activity was limited to LAF seizures in the SI. However, the increase in HPC/SN coherence was specific to the farther-spreading LAF onset pattern. As for the role of the SN in seizure cessation, we observed that the coherence between the HPC/SN was reduced during burst suppression (BS) compared to other termination phases. Additionally, we found that this coherence returned to normal levels after the seizure ended, with no significant difference in post-ictal periods among the three types of seizure offsets. This study constitutes the first demonstration of TL seizures entraining the SN in the primate brain. Moreover, these findings provide evidence that this entrainment is dependent on the onset and offset pattern and support the hypothesis that the SN might play a role in the maintenance and termination of some specific temporal lobe seizure. [ABSTRACT FROM AUTHOR]

Epilepsy, a neurological disorder characterized by excessive neuronal activity and synchronized electrical discharges, ranks among the most prevalent global neurological conditions. Despite common use, antiepileptic drugs often result in adverse effects and lack effectiveness in controlling seizures in temporal lobe epilepsy (TLE) patients. Recent research explored the potential of occidentalin-1202, a peptide inspired by Polybia occidentalis venom, in safeguarding Wistar rats from chemically induced seizures. The present study evaluated the new analog from occidentalin-1202 named NOR-1202 using acute and chronic pilocarpine-induced models and an acute kainic acid (KA) male mice model. NOR-1202 was administered through the intracerebroventricular (i.c.v.), subcutaneous, or intraperitoneal routes, with stereotaxic procedures for the i.c.v. injection. In the acute pilocarpine-induced model, NOR-1202 (i.c.v.) protected against generalized seizures and mortality but lacked systemic antiepileptic activity. In the KA model, it did not prevent generalized seizures but improved survival. In the chronic TLE model, NOR-1202′s ED50 did not differ significantly from the epileptic or healthy groups regarding time spent in spontaneous recurrent seizures during the five-day treatment. However, the NOR-1202 group exhibited more seizures than the healthy group on the second day of treatment. In summary, NOR-1202 exhibits antiepileptic effects against chemoconvulsant-induced seizures, but no effect was observed when administered systemically. [ABSTRACT FROM AUTHOR]

Although several adult rat models of medial temporal lobe epilepsy (mTLE) have been described in detail, our knowledge of mTLE epileptogenesis in infant rats is limited. Here, we present a novel infant rat model of mTLE (InfRPil‐mTLE) based on a repetitive, triphasic injection regimen consisting of low‐dose pilocarpine administrations (180 mg/kg. i.p.) on days 9, 11, and 15 post partum (pp). The model had a survival rate of >80% and exhibited characteristic spontaneous recurrent electrographic seizures (SRES) in both the hippocampus and cortex that persisted into adulthood. Using implantable video‐EEG radiotelemetry, we quantified a complex set of seizure parameters that demonstrated the induction of chronic electroencephalographic seizure activity in our InfRPil‐mTLE model, which predominated during the dark cycle. We further analyzed selected candidate genes potentially relevant to epileptogenesis using a RT‐qPCR approach. Several candidates, such as the low‐voltage‐activated Ca2+ channel Cav3.2 and the auxiliary subunits β1 and β2, which were previously reported to be upregulated in the hippocampus of the adult pilocarpine mTLE model, were found to be downregulated (together with Cav2.1, Cav2.3, M1, and M3) in the hippocampus and cortex of our InfRPil‐mTLE model. From a translational point of view, our model could serve as a blueprint for childhood epileptic disorders and further contribute to antiepileptic drug research and development in the future. [ABSTRACT FROM AUTHOR]

Epilepsy is known to cause alterations in neural networks. However, many details of these changes remain poorly understood. The objective of this study was to investigate changes in the properties of hippocampal CA1 pyramidal neurons and their synaptic inputs in a rat lithium–pilocarpine model of epilepsy. In the chronic phase of the model, we found a marked loss of pyramidal neurons in the CA1 area. However, the membrane properties of the neurons remained essentially unaltered. The results of the electrophysiological and morphological studies indicate that the direct pathway from the entorhinal cortex to CA1 neurons is reinforced in epileptic animals, whereas the inputs to them from CA3 are either unaltered or even diminished. In particular, the dendritic spine density in the str. lacunosum moleculare, where the direct pathway from the entorhinal cortex terminates, was found to be 2.5 times higher in epileptic rats than in control rats. Furthermore, the summation of responses upon stimulation of the temporoammonic pathway was enhanced by approximately twofold in epileptic rats. This enhancement is believed to be a significant contributing factor to the heightened epileptic activity observed in the entorhinal cortex of epileptic rats using an ex vivo 4-aminopyridine model. [ABSTRACT FROM AUTHOR]

In animal models of epilepsy, cranial surgery is often required to implant electrodes for electroencephalography (EEG) recording. However, electrode implants can lead to the activation of glial cells and interfere with physiological neuronal activity. In this study, we evaluated the impact of epidural electrode implants in the pilocarpine mouse model of temporal lobe epilepsy. Brain neuroinflammation was assessed 1 and 3 weeks after surgery by cytokines quantification, immunohistochemistry, and western blotting. Moreover, we investigated the effect of pilocarpine, administered two weeks after surgery, on mice mortality rate. The reported results indicate that implanted mice suffer from neuroinflammation, characterized by an early release of pro-inflammatory cytokines, microglia activation, and subsequent astrogliosis, which persists after three weeks. Notably, mice subjected to electrode implants displayed a higher mortality rate following pilocarpine injection 2 weeks after the surgery. Moreover, the analysis of EEGs recorded from implanted mice revealed a high number of single spikes, indicating a possible increased susceptibility to seizures. In conclusion, epidural electrode implant in mice promotes neuroinflammation that could lower the seizure thresholds to pilocarpine and increase the death rate. An improved protocol considering the persistent neuroinflammation induced by electrode implants will address refinement and reduction, two of the 3Rs principles for the ethical use of animals in scientific research. [ABSTRACT FROM AUTHOR]

An epilepsy diagnosis reduces a patient's quality of life tremendously, and it is a fate shared by over 50 million people worldwide. Temporal lobe epilepsy (TLE) is largely considered a nongenetic or acquired form of epilepsy that develops in consequence of neuronal trauma by injury, malformations, inflammation, or a prolonged (febrile) seizure. Although extensive research has been conducted to understand the process of epileptogenesis, a therapeutic approach to stop its manifestation or to reliably cure the disease has yet to be developed. In this review, we briefly summarize the current literature predominately based on data from excitotoxic rodent models on the cellular events proposed to drive epileptogenesis and thoroughly discuss the major molecular pathways involved, with a focus on neurogenesis-related processes and transcription factors. Furthermore, recent investigations emphasized the role of the genetic background for the acquisition of epilepsy, including variants of neurodevelopmental genes. Mutations in associated transcription factors may have the potential to innately increase the vulnerability of the hippocampus to develop epilepsy following an injury—an emerging perspective on the epileptogenic process in acquired forms of epilepsy. [ABSTRACT FROM AUTHOR]

Reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) is a commonly used tool for gene expression analysis. The selection of stably expressed reference genes is required for accurate normalization. The aim of this study was to identify the optimal reference genes for RT-qPCR normalization in various brain regions of rats at different stages of the lithium–pilocarpine model of acquired epilepsy. We tested the expression stability of nine housekeeping genes commonly used as reference genes in brain research: Actb, Gapdh, B2m, Rpl13a, Sdha, Ppia, Hprt1, Pgk1, and Ywhaz. Based on four standard algorithms (geNorm, NormFinder, BestKeeper, and comparative delta-Ct), we found that after pilocarpine-induced status epilepticus, the stability of the tested reference genes varied significantly between brain regions and depended on time after epileptogenesis induction (3 and 7 days in the latent phase, and 2 months in the chronic phase of the model). Pgk1 and Ywhaz were the most stable, while Actb, Sdha, and B2m demonstrated the lowest stability in the analyzed brain areas. We revealed time- and region-specific changes in the mRNA expression of the housekeeping genes B2m, Actb, Sdha, Rpl13a, Gapdh, Hprt1, and Sdha. These changes were more pronounced in the hippocampal region during the latent phase of the model and are thought to be related to epileptogenesis. Thus, RT-qPCR analysis of mRNA expression in acquired epilepsy models requires careful selection of reference genes depending on the brain region and time of analysis. For the time course study of epileptogenesis in the rat lithium–pilocarpine model, we recommend the use of the Pgk1 and Ywhaz genes. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the clinical application of 18F-FDG PET radiomics features for temporal lobe epilepsy and to create PET radiomics-based machine learning models for differentiating temporal lobe epilepsy (TLE) patients from healthy controls. Methods: A total of 347 subjects who underwent 18F-FDG PET scans from March 2014 to January 2020 (234 TLE patients: 25.50 ± 8.89 years, 141 male patients and 93 female patients; and 113 controls: 27.59 ± 6.94 years, 48 male individuals and 65 female individuals) were allocated to the training (n = 248) and test (n = 99) sets. All 3D PET images were registered to theMontreal Neurological Institute template. PyRadiomics was used to extract radiomics features from the temporal regions segmented according to the Automated Anatomical Labeling (AAL) atlas. The least absolute shrinkage and selection operator (LASSO) and Boruta algorithms were applied to select the radiomics features significantly associated with TLE. Eleven machine-learning algorithms were used to establish models and to select the best model in the training set. Results: The final radiomics features (n = 7) used for model training were selected through the combinations of the LASSO and the Boruta algorithms with cross-validation. All data were randomly divided into a training set (n = 248) and a testing set (n = 99). Among 11 machine-learning algorithms, the logistic regression (AUC 0.984, F1-Score 0.959)model performed the best in the training set. Then, we deployed the corresponding online website version (https://wane199.shinyapps.io/TLE_Classification/), showing the details of the LR model for convenience. The AUCs of the tuned logistic regression model in the training and test sets were 0.981 and 0.957, respectively. Furthermore, the calibration curves demonstrated satisfactory alignment (visually assessed) for identifying the TLE patients. Conclusion: The radiomics model from temporal regions can be a potential method for distinguishing TLE. Machine learning-based diagnosis of TLE from preoperative FDG PET images could serve as a useful preoperative diagnostic tool. [ABSTRACT FROM AUTHOR]

Although granule cell dispersion (GCD) in the hippocampus is known to be an important feature associated with epileptic seizures in temporal lobe epilepsy (TLE), the endogenous molecules that regulate GCD are largely unknown. In the present study, we have examined whether there is any change in AEG-1 expression in the hippocampus of a kainic acid (KA)-induced mouse model of TLE. In addition, we have investigated whether the modulation of astrocyte elevated gene-1 (AEG-1) expression in the dentate gyrus (DG) by intracranial injection of adeno-associated virus 1 (AAV1) influences pathological phenotypes such as GCD formation and seizure susceptibility in a KA-treated mouse. We have identified that the protein expression of AEG-1 is upregulated in the DG of a KA-induced mouse model of TLE. We further demonstrated that AEG-1 upregulation by AAV1 delivery in the DG-induced anticonvulsant activities such as the delay of seizure onset and inhibition of spontaneous recurrent seizures (SRS) through GCD suppression in the mouse model of TLE, while the inhibition of AEG-1 expression increased susceptibility to seizures. The present observations suggest that AEG-1 is a potent regulator of GCD formation and seizure development associated with TLE, and the significant induction of AEG-1 in the DG may have therapeutic potential against epilepsy. [ABSTRACT FROM AUTHOR]

Background: Epilepsy stands as an intricate disorder of the central nervous system, subject to the influence of diverse risk factors and a significant genetic predisposition. Within the pathogenesis of temporal lobe epilepsy (TLE), the apoptosis of neurons and glial cells in the brain assumes pivotal importance. The identification of differentially expressed apoptosis-related genes (DEARGs) emerges as a critical imperative, providing essential guidance for informed treatment decisions. Methods: We obtained datasets related to epilepsy, specifically GSE168375 and GSE186334. Utilizing differential expression analysis, we identified a set of 249 genes exhibiting significant variations. Subsequently, through an intersection with apoptosis-related genes, we pinpointed 16 genes designated as differentially expressed apoptosis-related genes (DEARGs). These DEARGs underwent a comprehensive array of analyses, including enrichment analyses, biomarker selection, disease classification modeling, immune infiltration analysis, prediction of miRNA and transcription factors, and molecular docking analysis. Results: In the epilepsy datasets examined, we successfully identified 16 differentially expressed apoptosis-related genes (DEARGs). Subsequent validation in the external dataset GSE140393 revealed the diagnostic potential of five biomarkers (CD38, FAIM2, IL1B, PAWR, S100A8) with remarkable accuracy, exhibiting an impressive area under curve (AUC) (The overall AUC of the model constructed by the five key genes was 0.916, and the validation set was 0.722). Furthermore, a statistically significant variance (p < 0.05) was observed in T cell CD4 naive and eosinophil cells across different diagnostic groups. Exploring interaction networks uncovered intricate connections, including gene-miRNA interactions (164 interactions involving 148 miRNAs), gene-transcription factor (TF) interactions (22 interactions with 20 TFs), and gene-drug small molecule interactions (15 interactions involving 15 drugs). Notably, IL1B and S100A8 demonstrated interactions with specific drugs. Conclusion: In the realm of TLE, we have successfully pinpointed noteworthy differentially expressed apoptosis-related genes (DEARGs), including CD38, FAIM2, IL1B, PAWR, and S100A8. A comprehensive understanding of the implications associated with these identified genes not only opens avenues for advancing our comprehension of the underlying pathophysiology but also bears considerable potential in guiding the development of innovative diagnostic methodologies and therapeutic interventions for the effective management of epilepsy in the future. [ABSTRACT FROM AUTHOR]

Objective: Cognitive deficit is common in patients with temporal lobe epilepsy (TLE). Here, we aimed to investigate the modular architecture of functional networks associated with distinct cognitive states in TLE patients together with the role of the thalamus in modular networks. Methods: Resting‐state functional magnetic resonance imaging scans were acquired from 53 TLE patients and 37 matched healthy controls. All patients received the Montreal Cognitive Assessment test and accordingly were divided into TLE patients with normal cognition (TLE‐CN, n = 35) and TLE patients with cognitive impairment (TLE‐CI, n = 18) groups. The modular properties of functional networks were calculated and compared including global modularity Q, modular segregation index, intramodular connections, and intermodular connections. Thalamic subdivisions corresponding to the modular networks were generated by applying a 'winner‐take‐all' strategy before analyzing the modular properties (participation coefficient and within‐module degree z‐score) of each thalamic subdivision to assess the contribution of the thalamus to modular functional networks. Relationships between network properties and cognitive performance were then further explored. Results: Both TLE‐CN and TLE‐CI patients showed lower global modularity, as well as lower modular segregation index values for the ventral attention network and the default mode network. However, different patterns of intramodular and intermodular connections existed for different cognitive states. In addition, both TLE‐CN and TLE‐CI patients exhibited anomalous modular properties of functional thalamic subdivisions, with TLE‐CI patients presenting a broader range of abnormalities. Cognitive performance in TLE‐CI patients was not related to the modular properties of functional network but rather to the modular properties of functional thalamic subdivisions. Conclusions: The thalamus plays a prominent role in modular networks and potentially represents a key neural mechanism underlying cognitive impairment in TLE. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy. Levetiracetam (LEV) is an antiepileptic drug whose mechanism of action at the genetic level has not been fully described. Therefore, the aim of the present work was to evaluate the relevant gene expression changes in the dentate gyrus (DG) of LEV-treated rats with pilocarpine-induced TLE. Whole-transcriptome microarrays were used to obtain the differential genetic profiles of control (CTRL), epileptic (EPI), and EPI rats treated for one week with LEV (EPI + LEV). Quantitative RT–qPCR was used to evaluate the RNA levels of the genes of interest. According to the results of the EPI vs. CTRL analysis, 685 genes were differentially expressed, 355 of which were underexpressed and 330 of which were overexpressed. According to the analysis of the EPI + LEV vs. EPI groups, 675 genes were differentially expressed, 477 of which were downregulated and 198 of which were upregulated. A total of 94 genes whose expression was altered by epilepsy and modified by LEV were identified. The RT–qPCR confirmed that LEV treatment reversed the increased expression of Hgf mRNA and decreased the expression of the Efcab1, Adam8, Slc24a1, and Serpinb1a genes in the DG. These results indicate that LEV could be involved in nonclassical mechanisms involved in Ca2+ homeostasis and the regulation of the mTOR pathway through Efcab1, Hgf, SLC24a1, Adam8, and Serpinb1a, contributing to reduced hyperexcitability in TLE patients. [ABSTRACT FROM AUTHOR]

There remains a need for new drug targets for treatment-resistant temporal lobe epilepsy. The ATP-gated P2X7 receptor coordinates neuroinflammatory responses to tissue injury. Previous studies in mice reported that the P2X7 receptor antagonist JNJ-47965567 suppressed spontaneous seizures in the intraamygdala kainic acid model of epilepsy and reduced attendant gliosis in the hippocampus. The drug-resistance profile of this model is not fully characterised, however, and newer P2X7 receptor antagonists with superior pharmacokinetic profiles have recently entered clinical trials. Using telemetrybased continuous EEG recordings in mice, we demonstrate that spontaneous recurrent seizures in the intraamygdala kainic acid model are refractory to the common anti-seizure medicine levetiracetam. In contrast, once-daily dosing of JNJ-54175446 (30 mg/kg, intraperitoneal) resulted in a significant reduction in spontaneous recurrent seizures which lasted several days after the end of drug administration. Using a combination of immunohistochemistry and ex vivo radiotracer assay, we find that JNJ-54175446-treated mice at the end of recordings display a reduction in astrogliosis and altered microglia process morphology within the ipsilateral CA3 subfield of the hippocampus, but no difference in P2X7 receptor surface expression. The present study extends the characterisation of the drug-resistance profile of the intraamygdala kainic acid model in mice and provides further evidence that targeting the P2X7 receptor may have therapeutic applications in the treatment of temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

Objective: Several studies have attributed epileptic activities in temporal lobe epilepsy (TLE) to the hippocampus; however, the participation of nonhippocampal neuronal networks in the development of TLE is often neglected. Here, we sought to understand how these nonhippocampal networks are involved in the pathology that is associated with TLE disease. Methods: A kainic acid (KA) model of temporal lobe epilepsy was induced by injecting KA into dorsal hippocampus of C57BL/6J mice. Network activation after spontaneous seizure was assessed using c‐Fos expression. Protocols to induce seizure using visual or auditory stimulation were developed, and seizure onset zone (SOZ) and frequency of epileptic spikes were evaluated using electrophysiology. The hippocampus was removed to assess seizure recurrence in the absence of hippocampus. Results: Our results showed that cortical and hippocampal epileptic networks are activated during spontaneous seizures. Perturbation of these networks using visual or auditory stimulation readily precipitates seizures in TLE mice; the frequency of the light‐induced or noise‐induced seizures depends on the induction modality adopted during the induction period. Localization of SOZ revealed the existence of cortical and hippocampal SOZ in light‐induced and noise‐induced seizures, and the development of local and remote epileptic spikes in TLE occurs during the early stage of the disease. Importantly, we further discovered that removal of the hippocampi does not stop seizure activities in TLE mice, revealing that seizures in TLE mice can occur independent of the hippocampus. Significance: This study has shown that the network pathology that evolves in TLE is not localized to the hippocampus; rather, remote brain areas are also recruited. The occurrence of light‐induced or noise‐induced seizures and epileptic discharges in epileptic mice is a consequence of the activation of nonhippocampal brain areas. This work therefore demonstrates the fundamental role of nonhippocampal epileptic networks in generating epileptic activities with or without the hippocampus in TLE disease. [ABSTRACT FROM AUTHOR]

The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the transition to seizure is complex, potentially leading to imprecise delineation of epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing and others suggesting reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principle applies in limbic structures. We analysed simultaneous electrocorticography (ECoG) and neuronal recordings of 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, which at times co-existed within seizures. Overall, 156 single units were isolated, subclassified by cell-type and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (P < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition, with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (P = 0.014). This study provides evidence for entrained high-gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, reduced neuronal firing suggested preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or indicates a 'seizure-responsive' state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help to refine the surgical treatment of mesial temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

CA3 Principal Cell Activation Triggers Hypersynchronous-Onset Seizures in a Mouse Model of Mesial Temporal Lobe Epilepsy Wang S, Lévesque M, Fisher TAJ, Kennedy TE, Avoli M. J Neurophysiol. 2023;130(4):1041-1052. doi:10.1152/jn.00244.2023 Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy, and it is characterized by seizures that are often refractory to medications. Seizures in MTLE have two main patterns of onset that have been termed hypersynchronous (HYP) and low-voltage fast (LVF) and are believed to mainly depend on the activity of excitatory principal cells and inhibitory interneurons, respectively. In this study, we investigated whether unilateral open-loop optogenetic activation of CaMKII-positive principal cells in the hippocampus CA3 region favors the generation of spontaneous HYP seizures in kainic acid-treated (KA) CaMKII-ChR2 mice. Optogenetic activation of CA3 principal cells (1 Hz, 180 s ON, 220 s OFF) was implemented for 15 days after KA-induced status epilepticus. We found that both LVF and HYP seizures occurred in nonstimulated CaMKII-ChR2 (n = 6) and stimulated CaMKII-Cre (n = 5) mice. In contrast, optogenetic activation of principal cells in CaMKII-ChR2 mice (n = 5) triggered only HYP seizures that were characterized by high fast ripple (250–500 Hz) rates during the pre-ictal and ictal periods. These results provide firm evidence that in MTLE spontaneous seizures with different onset patterns depend on distinct neuronal network mechanisms of generation. They also demonstrate that HYP seizures occurring in vivo along with their associated fast ripples depend on the activity of principal cells in the CA3 region. NEW & NOTEWORTHY Previous evidence suggested that different seizure onset patterns rely on the activity of distinct neuronal populations. In this study, we show for the first time that in vivo optogenetic stimulation of CaMKII principal cells in kainic acid-treated mice triggers hypersynchronous-onset seizures that are associated with fast ripples. Our findings indicate that in patients with predominant HYP-onset seizures, anticonvulsant treatments should be aimed at limiting the firing of principal neurons in the seizure onset zone. [ABSTRACT FROM AUTHOR]

Background: Epilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of patients and growing evidence indicates that oxidative stress contributes to the development of such epilepsies. Activation of the Nrf2 pathway, which is involved in cellular defense, offers a potential strategy for reducing oxidative stress and epilepsy treatment. Dimethyl fumarate (DMF), an Nrf2 activator, exhibits antioxidant and anti-inflammatory effects and is used to treat multiple sclerosis. Methods: The expression of Nrf2 and its related genes in vehicle or DMF treated rats were determined via RT-PCR and Western blot analysis. Neuronal cell death was evaluated by immunohistochemical staining. The effects of DMF in preventing the onset of epilepsy and modifying the disease were investigated in the kainic acid-induced status epilepticus model of temporal lobe epilepsy in rats. The open field, elevated plus maze and T-Maze spontaneous alteration tests were used for behavioral assessments. Results: We demonstrate that administration of DMF following status epilepticus increased Nrf2 activity, attenuated status epilepticus-induced neuronal cell death, and decreased seizure frequency and the total number of seizures compared to vehicle-treated animals. Moreover, DMF treatment reversed epilepsy-induced behavioral deficits in the treated rats. Moreover, DMF treatment even when initiated well after the diagnosis of epilepsy, reduced symptomatic seizures long after the drug was eliminated from the body. Conclusions: Taken together, these findings suggest that DMF, through the activation of Nrf2, has the potential to serve as a therapeutic target for preventing epileptogenesis and modifying epilepsy. [ABSTRACT FROM AUTHOR]

Objective: Temporal lobe epilepsy (TLE) is the most common cause of drug-resistant epilepsy and can be treated surgically to control seizures. In this study, we analyzed the relevant research literature in the field of temporal lobe epilepsy (TLE) treatment to understand the background, hotspots, and trends in TLE treatment research. Methods: We discussed the trend, frontier, and hotspot of scientific output in TLE treatment research in the world in the last 20 years by searching the core collection of the Web of Science database. Excel and CiteSpace software were used to analyze the basic data of the literature. Result: We identified a total of 2,051 publications on TLE treatment from 75 countries between 2003 and 2023. We found that the publication rate was generally increasing. The United States was the most publishing country; among the research institutions on TLE treatment, the University of California system published the most relevant literature and collaborated the most with other institutions. The co-citation of literature, keyword co-occurrence, and its clustering analysis showed that the early studies focused on open surgical treatment, mainly by lobectomy. In recent years, the attention given to stereotactic, microsurgery, and other surgical techniques has gradually increased, and the burst analysis indicated that new research hotspots may appear in the future in the areas of improved surgical procedures and mechanism research. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is associated with widespread brain alterations. Using quantitative susceptibility mapping (QSM) alongside transverse relaxation rate (R2*), we investigated regional brain susceptibility changes in 36 patients with left‐sided (LTLE) or right‐sided TLE (RTLE) secondary to hippocampal sclerosis, and 27 healthy controls (HC). We compared three susceptibility calculation methods to ensure image quality. Correlations of susceptibility and R2* with age of epilepsy onset, frequency of focal‐to‐bilateral tonic–clonic seizures (FBTCS), and neuropsychological test scores were examined. Weak‐harmonic QSM (WH‐QSM) successfully reduced noise and removed residual background field artefacts. Significant susceptibility increases were identified in the left putamen in the RTLE group compared to the LTLE group, the right putamen and right thalamus in the RTLE group compared to HC, and a significant susceptibility decrease in the left hippocampus in LTLE versus HC. LTLE patients who underwent epilepsy surgery showed significantly lower left‐versus‐right hippocampal susceptibility. Significant R2* changes were found between TLE and HC groups in the amygdala, putamen, thalamus, and in the hippocampus. Specifically, decreased R2* was found in the left and right hippocampus in LTLE and RTLE, respectively, compared to HC. Susceptibility and R2* were significantly correlated with cognitive test scores in the hippocampus, globus pallidus, and thalamus. FBTCS frequency correlated positively with ipsilateral thalamic and contralateral putamen susceptibility and with R2* in bilateral globi pallidi. Age of onset was correlated with susceptibility in the hippocampus and putamen, and with R2* in the caudate. Susceptibility and R2* changes observed in TLE groups suggest selective loss of low‐myelinated neurons alongside iron redistribution in the hippocampi, predominantly ipsilaterally, indicating QSM's sensitivity to local pathology. Increased susceptibility and R2* in the thalamus and putamen suggest increased iron content and reflect disease severity. [ABSTRACT FROM AUTHOR]

A significant proportion of temporal lobe epilepsy (TLE) patients experience drug-resistant seizures associated with mesial temporal sclerosis, in which there is extensive cell loss in the hippocampal CA1 and CA3 subfields, with a relative sparing of dentate gyrus granule cells and CA2 pyramidal neurons (PNs). A role for CA2 in seizure generation was suggested based on findings of a reduction in CA2 synaptic inhibition (Williamson and Spencer, 1994) and the presence of interictal-like spike activity in CA2 in resected hippocampal tissue from TLE patients (Wittner et al., 2009). We recently found that in the pilocarpine-induced status epilepticus (PILO-SE) mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al., 2022). In the present study, we explored the cellular basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches in PILO-SE male and female mice. We report a widespread decrease in the density of pro-cholecystokinin-immunopositive (CCK1) interneurons and a functional impairment of CCK1 interneuron-mediated inhibition of CA2 PNs. We also found a disruption in the perisomatic perineuronal net in the CA2 stratum pyramidale. Such pathologic alterations may contribute to an enhanced excitation of CA2 PNs and CA2-dependent seizure activity in the PILO-SE mouse model. [ABSTRACT FROM AUTHOR]

Neuroinflammation represents a dynamic process of defense and protection against the harmful action of infectious agents or other detrimental stimuli in the central nervous system (CNS). However, the uncontrolled regulation of this physiological process is strongly associated with serious dysfunctional neuronal issues linked to the progression of CNS disorders. Moreover, it has been widely demonstrated that neuroinflammation is linked to epilepsy, one of the most prevalent and serious brain disorders worldwide. Indeed, NLRP3, one of the most well-studied inflammasomes, is involved in the generation of epileptic seizures, events that characterize this pathological condition. In this context, several pieces of evidence have shown that the NLRP3 inflammasome plays a central role in the pathophysiology of mesial temporal lobe epilepsy (mTLE). Based on an extensive review of the literature on the role of NLRP3-dependent inflammation in epilepsy, in this review we discuss our current understanding of the connection between NLRP3 inflammasome activation and progressive neurodegeneration in epilepsy. The goal of the review is to cover as many of the various known epilepsy models as possible, providing a broad overview of the current literature. Lastly, we also propose some of the present therapeutic strategies targeting NLRP3, aiming to provide potential insights for future studies. [ABSTRACT FROM AUTHOR]

Objective: More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild‐to‐moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of γ‐aminobutyric acid transporter‐1, and to test its seizure suppression effects in a rat model of chronic MTLE. Methods: We first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100 mg/kg/day of E2730 subcutaneously for 1 week. Blood sampling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid‐induced status epilepticus, and 9 weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video‐electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures. Results: Plasma levels following continuous infusion of E2730 showed a clear dose‐related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48 h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose‐dependent manner, with 65% of rats becoming seizure‐free at the highest dose tested. Mean seizure class did not differ between the treatment groups. Significance: This study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose‐dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials. [ABSTRACT FROM AUTHOR]

Focal epilepsy is characterized by repeated spontaneous seizures that originate from cortical epileptogenic zone networks (EZN). Analysis of intracerebral recordings showed that subcortical structures, and in particular the thalamus, play an important role in seizure dynamics as well, supporting their structural alterations reported in the neuroimaging literature. Nonetheless, between‐patient differences in EZN localization (e.g., temporal vs. non‐temporal lobe epilepsy) as well as extension (i.e., number of epileptogenic regions) might impact the magnitude as well as spatial distribution of subcortical structural changes. Here we used 7 Tesla MRI T1 data to provide an unprecedented description of subcortical morphological (volume, tissue deformation, and shape) and longitudinal relaxation (T1) changes in focal epilepsy patients and evaluate the impact of the EZN and other patient‐specific clinical features. Our results showed variable levels of atrophy across thalamic nuclei that appeared most prominent in the temporal lobe epilepsy group and the side ipsilateral to the EZN, while shortening of T1 was especially observed for the lateral thalamus. Multivariate analyses across thalamic nuclei and basal ganglia showed that volume acted as the dominant discriminator between patients and controls, while (posterolateral) thalamic T1 measures looked promising to further differentiate patients based on EZN localization. In particular, the observed differences in T1 changes between thalamic nuclei indicated differential involvement based on EZN localization. Finally, EZN extension was found to best explain the observed variability between patients. To conclude, this work revealed multi‐scale subcortical alterations in focal epilepsy as well as their dependence on several clinical characteristics. [ABSTRACT FROM AUTHOR]

Although the piriform cortex (PC) has been previously implicated as a critical node for seizure generation and propagation, the underlying neural mechanism has remained unclear. Here, we found increased excitability in PC neurons during amygdala kindling acquisition. Optogenetic or chemogenetic activation of PC pyramidal neurons promoted kindling progression, whereas inhibition of these neurons retarded seizure activities induced by electrical kindling in the amygdala. Furthermore, chemogenetic inhibition of PC pyramidal neurons alleviated the severity of kainic acid‐induced acute seizures. These results demonstrate that PC pyramidal neurons bidirectionally modulate seizures in temporal lobe epilepsy, providing evidence for the efficacy of PC pyramidal neurons as a potential therapeutic target for epileptogenesis. Key points: While the piriform cortex (PC) is an important olfactory centre critically involved in olfactory processing and plays a crucial role in epilepsy due to its close connection with the limbic system, how the PC regulates epileptogenesis is largely unknown.In this study, we evaluated the neuronal activity and the role of pyramidal neurons in the PC in the mouse amygdala kindling model of epilepsy.PC pyramidal neurons are hyperexcited during epileptogenesis.Optogenetic and chemogenetic activation of PC pyramidal neurons significantly promoted seizures in the amygdala kindling model, whereas selective inhibition of these neurons produced an anti‐epileptic effect for both electrical kindling and kainic acid‐induced acute seizures.The results of the present study indicate that PC pyramidal neurons bidirectionally modulate seizure activity. [ABSTRACT FROM AUTHOR]

Objectives. Social cognition (SC) is a multifaceted concept involving mental processes to understand, store, and apply information regarding social relationships. Brain lesions in key areas can impair critical components of SC, but seizures and epileptiform discharges could also be associated with deficits in SC. To verify this hypothesis, this study evaluated SC in persons with generalized or focal epilepsy without detectable brain lesion. Materials and Methods. Forty-eight adult persons with idiopathic generalized epilepsy (IGE) or temporal lobe epilepsy without brain lesion (cryptoTLE) and 24 healthy controls were evaluated by means of the Faux Pas Test (FPT), Social Situation Test (SST), Moral/Conventional Distinction Test (MCDT), and Empathy Questionnaire (EQ) which assess theory of mind (ToM), recognition of social behaviors and moral and conventional rules, and empathy. Clinical work-up included information on age at seizure onset, epilepsy duration, seizure symptoms and frequency, demographic characteristics, and the presence of comorbidities. Results. Compared to controls, persons with IGE or cryptoTLE were impaired in the understanding of existent faux pas on the FPT. On the SST, persons with cryptoTLE also showed significant deficits, whereas the IGE persons only were less accurate in recognizing normative behaviors. In cryptoTLE persons, the capacity to recognize cognitive and affective mental states correlated with seizure frequency and age, whereas, in IGE persons, the SST and MCDT scores correlated with schooling and age, respectively. Conclusions. CryptoTLE can cause extensive deficits in ToM and recognition of social situations, whereas IGE is only associated with deficits in fewer domains. Dysfunction of temporolimbic areas could be related to seizure frequency and associated with more severe SC impairment in cryptoTLE. Older age and poor education may be associated with SC deficits in focal or generalized epilepsy. [ABSTRACT FROM AUTHOR]

Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1-BDNF system; (5) astrocytic Na+/K+/ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosinemetabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells. [ABSTRACT FROM AUTHOR]

Aims: Mesial temporal lobe epilepsy without hippocampal sclerosis (no‐HS MTLE) refers to those MTLE patients who have neither magnetic resonance imaging (MRI) lesions nor definite pathological evidence of hippocampal sclerosis. They usually have resistance to antiepileptic drugs, difficulties in precise seizure location and poor surgical outcomes. Adenosine is a neuroprotective neuromodulator that acts as a seizure terminator in the brain. The role of adenosine in no‐HS MTLE is still unclear. Further research to explore the aetiology and pathogenesis of no‐HS MTLE may help to find new therapeutic targets. Methods: In surgically resected hippocampal specimens, we examined the maladaptive changes of the adenosine system of patients with no‐HS MTLE. In order to better understand the dysregulation of the adenosine pathway in no‐HS MTLE, we developed a rat model based on the induction of focal cortical lesions through a prenatal freeze injury. Results: We first examined the adenosine system in no‐HS MTLE patients who lack hippocampal neuronal loss and found ectopic expression of the astrocytic adenosine metabolising enzyme adenosine kinase (ADK) in hippocampal pyramidal neurons, as well as downregulation of neuronal A1 receptors (A1Rs) in the hippocampus. In the no‐HS MTLE model rats, the transition of ADK from neuronal expression to an adult pattern of glial expression in the hippocampus was significantly delayed. Conclusions: Ectopic expression of neuronal ADK might be a pathological hallmark of no‐HS MTLE. Maladaptive changes in adenosine metabolism might be a novel target for therapeutic intervention in no‐HS MTLE. [ABSTRACT FROM AUTHOR]

Objective: In the management of epilepsy, there is an ongoing quest to discover new biomarkers to improve the diagnostic process, the monitoring of disease progression, and the evaluation of treatment responsiveness. In this regard, biochemical traceability in biofluids is notably absent in contrast to other diseases. In the present preclinical study, we investigated the potential of neurofilament light chain (NfL) as a possible diagnostic and response fluid biomarker for epilepsy. Methods: We gained insights into NfL levels during the various phases of the intrahippocampal kainic acid mouse model of temporal lobe epilepsy—namely, the status epilepticus (SE) and the chronic phase with spontaneous seizures. To this end, NfL levels were determined directly in the cerebral interstitial fluid (ISF) with cerebral open flow microperfusion as sampling technique, as well as in cerebrospinal fluid (CSF) and plasma. Lastly, we assessed whether NfL levels diminished upon curtailing SE with diazepam and ketamine. Results: NfL levels are higher during SE in both cerebral ISF and plasma in kainic acid‐treated mice compared to sham‐injected mice. Additionally, ISF and plasma NfL levels are lower in mice treated with diazepam and ketamine to stop SE compared with the vehicle‐treated mice. In the chronic phase with spontaneous seizures, higher NfL levels could only be detected in ISF and CSF samples, and not in plasma. No correlations could be found between NfL levels and seizure burden, nor with immunohistological markers for neurodegeneration/inflammation. Significance: Our findings demonstrate the translational potential of NfL as a blood‐based fluid biomarker for SE. This is less evident for chronic epilepsy, as in this case higher NfL levels could only be detected in ISF and CSF, and not in plasma, acknowledging the invasive nature of CSF sampling in chronic epilepsy follow‐up. [ABSTRACT FROM AUTHOR]

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The gap-junction-coupled astroglial network plays a central role in the regulation of neuronal activity and synchronisation, but its involvement in the pathogenesis of neuronal diseases is not yet understood. Here, we present the current state of knowledge about the impact of impaired glial coupling in the development and progression of epilepsy and discuss whether astrocytes represent alternative therapeutic targets. We focus mainly on temporal lobe epilepsy (TLE), which is the most common form of epilepsy in adults and is characterised by high therapy resistance. Functional data from TLE patients and corresponding experimental models point to a complete loss of astrocytic coupling, but preservation of the gap junction forming proteins connexin43 and connexin30 in hippocampal sclerosis. Several studies further indicate that astrocyte uncoupling is a causal event in the initiation of TLE, as it occurs very early in epileptogenesis, clearly preceding dysfunctional changes in neurons. However, more research is needed to fully understand the role of gap junction channels in epilepsy and to develop safe and effective therapeutic strategies targeting astrocytes. [ABSTRACT FROM AUTHOR]

In the last 30 years, over 20 new anti-seizure medicines (ASMs) have been introduced into the market for the treatment of epilepsy using well-established preclinical seizure and epilepsy models. Despite this success, approximately 20–30% of patients with epilepsy have drug-resistant epilepsy (DRE). The current approach to ASM discovery for DRE relies largely on drug testing in various preclinical model systems that display varying degrees of ASM drug resistance. In recent years, attempts have been made to include more etiologically relevant models in the preclinical evaluation of a new investigational drug. Such models have played an important role in advancing a greater understanding of DRE at a mechanistic level and for hypothesis testing as new experimental evidence becomes available. This review provides a critical discussion of the pharmacology of models of adult focal epilepsy that allow for the selection of ASM responders and nonresponders and those models that display a pharmacoresistance per se to two or more ASMs. In addition, the pharmacology of animal models of major genetic epilepsies is discussed. Importantly, in addition to testing chemical compounds, several of the models discussed here can be used to evaluate other potential therapies for epilepsy such as neurostimulation, dietary treatments, gene therapy, or cell transplantation. This review also discusses the challenges associated with identifying novel therapies in the absence of a greater understanding of the mechanisms that contribute to DRE. Finally, this review discusses the lessons learned from the profile of the recently approved highly efficacious and broad-spectrum ASM cenobamate. [ABSTRACT FROM AUTHOR]

Background: Epilepsy is one of the most common neurologic diseases, and around 30% of all epilepsies, particularly the temporal lobe epilepsy (TLE), are highly refractory to current pharmacological treatments. Abnormal synchronic neuronal activity, brain glucose metabolism alterations, neurodegeneration and neuroinflammation are features of epilepsy. Further, neuroinflammation has been shown to contribute to dysregulation of neuronal excitability and the progression of epileptogenesis. Flufenamic acid (FLU), a non-steroidal anti-inflammatory drug, is also characterized by its wide properties as a dose-dependent ion channel modulator. In this context, in vitro studies have shown that it abolishes seizure-like events in neocortical slices stimulated with a gamma-aminobutyric acid A (GABAA) receptor blocker. However, little is known about its effects in animal models. Thus, our goal was to assess the efficacy and safety of a relatively high dose of FLU in the lithium-pilocarpine rat model of status epilepticus (SE). This animal model reproduces many behavioral and neurobiological features of TLE such as short-term brain hypometabolism, severe hippocampal neurodegeneration and inflammation reflected by a marked reactive astrogliosis. Methods: FLU (100 mg/kg, i.p.) was administered to adult male rats, 150 min before SE induced by pilocarpine. Three days after the SE, brain glucose metabolism was assessed by 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG) positron emission tomography (PET). Markers of hippocampal integrity, neurodegeneration and reactive astrogliosis were also evaluated. Results: FLU neither prevented the occurrence of the SE nor affected brain glucose hypometabolism as assessed by [ 18F]FDG PET. Regarding the neurohistochemical studies, FLU neither prevented neuronal damage nor hippocampal reactive astrogliosis. On the contrary, FLU increased the mortality rate and negatively affected body weight in the rats that survived the SE. Conclusions: Our results do not support an acute anticonvulsant effect of a single dose of FLU. Besides, FLU did not show short-term neuroprotective or anti-inflammatory effects in the rat lithium-pilocarpine model of SE. Moreover, at the dose administered, FLU resulted in deleterious effects. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological condition that causes unprovoked, recurrent seizures and memory impairment is a common side effect of epileptic treatment. The present study was conceptualized to evaluate the protective effect of the nootropic herbal drink MulminaTM against memory impairment induced by Gabapentin in a pentylenetetrazole-induced epileptic mouse model. The antiepileptic and memory impairment activity were found to be significantly (p<0.05) higher in the gabapentin group, whereas the combination of gabapentin + MulminaTM significantly (p<0.05) increased antiepileptic and decreased the memory impairment activity. Furthermore, Mulmina, alone exhibited synergistic antiepileptic and memory enhancement activity. Thus, combining herbal drugs/nootropics with anti-epileptic drugs provides synergistic activity while lowering the dose of synthetic drugs, which may cause more adverse effects in the human body. The results of this study show that gabapentin has memory impairment potential and that it can be corrected by co-administration of MulminaTM. However, future research is warranted to assess the underlying molecular mechanism of memory enhancing activity of MulminaTM against gabapentin induced memory impairment. [ABSTRACT FROM AUTHOR]

Introduction: Temporal lobe epilepsy (TLE) is the most prevalent form of drug-resistant epilepsy with concurrent cognitive impairment. Prevention, earlier diagnosis, and personalized management of cognitive deficits in TLE require more understanding of underlying structural and functional brain Ialterations. No study has evaluated the performance of TLE patients in different cognitive domains based on their structural brain lesions. Methods: In this study, 69 refractory TLE patients underwent magnetic resonance imaging (MRI) epilepsy protocol and several neuropsychological tests, consisting of the Wechsler adult intelligence scale-revised, Rey-Osterrieth complex figure test, verbal fluency test, digit span test, spatial span test, Wechsler memory scale-III, design fluency test, Rey visual design learning test, auditory-verbal learning test, and trail making test. MRI findings were classified into the following groups: Focal cortical dysplasia, gliosis, atrophy, mesial temporal sclerosis (MTS), tumor, vascular malformation, and other lesions or normal. Results of neuropsychological tests were compared between MRI groups using a generalized linear model with gamma distribution and log link. Results: Patients with MTS showed better performance in general intellectual functioning, working memory, attentional span, and auditory-verbal learning compared to patients with non-MTS MRI lesions. Atrophy and focal cortical dysplasia had the largest differences from MTS. Conclusion: Cognitive performance of refractory TLE patients varies concerning structural brain alterations. Further neuroimaging studies of TLE lead to prevention and more accurate management of cognitive decline in clinical settings. [ABSTRACT FROM AUTHOR]

Animal models of human brain disorders permit researchers to explore disease mechanisms and to test potential therapies. However, therapeutic molecules derived from animal models often translate poorly to the clinic. Although human data may be more relevant, experiments on patients are constrained, and living tissue is unavailable for many disorders. Here, we compare work on animal models and on human tissue for three epileptic syndromes where human tissue is excised therapeutically: (1) acquired temporal lobe epilepsies, (2) inherited epilepsies associated with cortical malformations, and (3) peritumoral epilepsies. Animal models rest on assumed equivalencies between human brains and brains of mice, the most frequently used model animal. We ask how differences between mouse and human brains could influence models. General principles and compromises in model construction and validation are examined for a range of neurological diseases. Models may be judged on how well they predict novel therapeutic molecules or new mechanisms. The efficacy and safety of new molecules are evaluated in clinical trials. We judge new mechanisms by comparing data from work on animal models with data from work on patient tissue. In conclusion, we stress the need to cross‐verify findings from animal models and from living human tissue to avoid the assumption that mechanisms are identical. [ABSTRACT FROM AUTHOR]

Objective: To test the feasibility and reliability of intracranial electrophysiological recordings in an acute status epilepticus model on laboratory swine. Method: Intrahippocampal injection of kainic acid (KA) was performed on 17 male Bama pigs (Sus scrofa domestica) weighing between 25 and 35 kg. Two stereoelectroencephalography (SEEG) electrodes with a total of 16 channels were implanted bilaterally along the sensorimotor cortex to the hippocampus. Brain electrical activity was recorded 2 h daily for 9-28 days. Three KA dosages were tested to evaluate the quantities capable of evoking status epilepticus. Local field potentials (LFPs) were recorded and compared before and after the KA injection. We quantified the epileptic patterns, including the interictal spikes, seizures, and high-frequency oscillations (HFOs), up to 4 weeks after the KA injection. Test-retest reliability using intraclass correlation coefficients (ICCs) were performed on interictal HFO rates to evaluate the recording stability of this model. Results: The KA dosage test suggested that a 10 µl (1.0 µg/µl) intrahippocampal injection could successfully evoke status epilepticus lasting from 4 to 12 h. At this dosage, eight pigs (50% of total) had prolonged epileptic events (tonicchronic seizures + interictal spikes n = 5, interictal spikes alone n = 3) in the later 4 weeks of the video-SEEG recording period. Four pigs (25% of total) had no epileptic activities, and another four (25%) had lost the cap or did not complete the experiments. Animals that showed epileptiform events were grouped as E + (n = 8) and the four animals showing no signs of epileptic events were grouped as E-(n = 4). A total of 46 electrophysiological seizures were captured in the 4-week post-KA period from 4 E + animals, with the earliest onset on day 9. The seizure durations ranged from 12 to 45 s. A significant increase of hippocampal HFOs rate (num/min) was observed in the E+ group during the post-KA period (weeks 1, 2,4, p < 0.05) compared to the baseline. But the E-showed no change or a decrease (in week 2, p = 0.43) compared to their baseline rate. The between-group comparison showed much higher HFO rates in E + vs. E - (F = 35, p < 0.01). The high ICC value [ICC (1, k) = 0.81, p < 0.05] quantified from the HFO rate suggested that this model had a stable measurement of HFOs during the four-week post-KA periods. Significance: This study measured intracranial electrophysiological activity in a swine model of KA-induced mesial temporal lobe epilepsy (mTLE). Using the clinical SEEG electrode, we distinguished abnormal EEG patterns in the swine brain. The high test-retest reliability of HFO rates in the post-KA period suggests the utility of this model for studying mechanisms of epileptogenesis. The use of swine may provide satisfactory translational value for clinical epilepsy research. [ABSTRACT FROM AUTHOR]

Thalidomide (TAL) has shown potential therapeutic effects in neurological diseases like epilepsy. Both clinical and preclinical studies show that TAL may act as an antiepileptic drug and as a possible treatment against disease development. However, the evidence for these effects is limited. Therefore, the antiepileptogenic and anti-inflammatory effects of TAL were evaluated herein. Sprague Dawley male rats were randomly allocated to one of five groups (n = 18 per group): control (C); status epilepticus (SE); SE-TAL (25 mg/kg); SE-TAL (50 mg/kg); and SE-topiramate (TOP; 60mg/kg). The lithium-pilocarpine model was used, and one day after SE induction the rats received pharmacological treatment for one week. The brain was obtained, and the hippocampus was micro-dissected 8, 18, and 28 days after SE. TNF-α, IL-6, and IL-1β concentrations were quantified. TOP and TAL (50 mg/kg) increased the latency to the first of many spontaneous recurrent seizures (SRS) and decreased SRS frequency, as well as decreasing TNF-α and IL-1β concentrations in the hippocampus. In conclusion, the results showed that both TAL (50 mg/kg) and TOP have anti-ictogenic and antiepileptogenic effects, possibly by decreasing neuroinflammation. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) is a physiological barrier maintaining a specialized brain micromilieu that is necessary for proper neuronal function. Endothelial tight junctions and specific transcellular/efflux transport systems provide a protective barrier against toxins, pathogens, and immune cells. The barrier function is critically supported by other cell types of the neurovascular unit, including pericytes, astrocytes, microglia, and interneurons. The dysfunctionality of the BBB is a hallmark of neurological diseases, such as ischemia, brain tumors, neurodegenerative diseases, infections, and autoimmune neuroinflammatory disorders. Moreover, BBB dysfunction is critically involved in epilepsy, a brain disorder characterized by spontaneously occurring seizures because of abnormally synchronized neuronal activity. While resistance to antiseizure drugs that aim to reduce neuronal hyperexcitability remains a clinical challenge, drugs targeting the neurovasculature in epilepsy patients have not been explored. The use of novel imaging techniques permits early detection of BBB leakage in epilepsy; however, the detailed mechanistic understanding of causes and consequences of BBB compromise remains unknown. Here, we discuss the current knowledge of BBB involvement in temporal lobe epilepsy with the emphasis on the neurovasculature as a therapeutic target. [ABSTRACT FROM AUTHOR]

Lowvoltage fast (LVF) and hypersynchronous (HYP) patterns are the seizure-onset patterns most frequently observed in intracranial EEG recordings from mesial temporal lobe epilepsy (MTLE) patients. Both patterns also occur in models of MTLE in vivo and in vitro, and these studies have highlighted the predominant involvement of distinct neuronal network/neurotransmitter receptor signaling in each of them. First, LVF-onset seizures in epileptic rodents can originate from several limbic structures, frequently spread, and are associated with high-frequency oscillations in the ripple band (80-200 Hz), whereas HYP onset seizures initiate in the hippocampus and tend to remain focal with predominant fast ripples (250-500 Hz). Second, in vitro intracellular recordings from principal cells in limbic areas indicate that pharmacologically induced seizure-like discharges with LVF onset are initiated by a synchronous inhibitory event or by a hyperpolarizing inhibitory postsynaptic potential barrage; in contrast, HYP onset is associated with a progressive impairment of inhibition and concomitant unrestrained enhancement of excitation. Finally, in vitro optogenetic experiments show that, under comparable experimental conditions (i.e., 4-aminopyridine application), the initiation of LVFor HYP-onset seizures depends on the preponderant involvement of interneuronal or principal cell networks, respectively. Overall, these data may provide insight to delineate better therapeutic targets in the treatment of patients presenting with MTLE and, perhaps, with other epileptic disorders as well. [ABSTRACT FROM AUTHOR]

Automatic detection of epileptic seizures is important in epilepsy control and treatment, and specific feature extraction assists in accurate detection. We developed a feature extraction method for seizure detection based on multi-site synchronous changes and an edge detection algorithm. We investigated five chronic temporal lobe epilepsy rats with 8- and 12-channel detection sites in the hippocampus and limbic system. Multi-site synchronous changes were selected as a specific feature and implemented as a seizure detection method. For preprocessing, we used magnitude-squared coherence maps and Canny edge detection algorithm to find the frequency band with the most significant change in synchronization and the important channel pairs. In detection, we used the maximal cross-correlation coefficient as an indicator of synchronization and the correlation coefficient curves' average value and standard deviation as two detection features. The method achieved high performance, with an average 96.60% detection rate, 2.63/h false alarm rate, and 1.25 s detection delay. The experimental results show that synchronization is an appropriate feature for seizure detection. The magnitude-squared coherence map can assist in selecting a specific frequency band and channel pairs to enhance the detection result. We found that individuals have a specific frequency band that reflects the most significant synchronization changes, and our method can individually adjust parameters and has good detection performance. [ABSTRACT FROM AUTHOR]

Low-frequency electrical stimulation is used to treat some drug-resistant forms of epilepsy. Despite the effectiveness of the method in suppressing seizures, there is a considerable risk of side effects. An optogenetic approach allows the targeting of specific populations of neurons, which can increase the effectiveness and safety of low-frequency stimulation. In our study, we tested the efficacy of the suppression of ictal activity in entorhinal cortex slices in a 4-aminopyridine model with three variants of low-frequency light stimulation (LFLS): (1) activation of excitatory and inhibitory neurons (on Thy1-ChR2-YFP mice), (2) activation of inhibitory interneurons only (on PV-Cre mice after virus injection with channelrhodopsin2 gene), and (3) hyperpolarization of excitatory neurons (on Wistar rats after virus injection with archaerhodopsin gene). Only in the first variant did simultaneous LFLS of excitatory and inhibitory neurons replace ictal activity with interictal activity. We suggest that LFLS caused changes in the concentration gradients of K+ and Na+ cations across the neuron membrane, which activated Na-K pumping. According to the mathematical modeling, the increase in Na-K pump activity in neurons induced by LFLS led to an antiepileptic effect. Thus, a less specific and generalized optogenetic effect on entorhinal cortex neurons was more effective in suppressing ictal activity in the 4-aminopyridine model. [ABSTRACT FROM AUTHOR]

Growing studies indicate that vigilance states and circadian rhythms can influence seizure occurrence in patients with epilepsy and rodent models of epilepsy. Electrical kindling, referred to brief, repeated stimulations of a limbic structure, is a commonly used model of temporal lobe epilepsy. Kindling via the classic protocol lasting a few weeks does not generally induce spontaneous recurrent seizures (SRS), but extended kindling that applies over the course of a few months has shown to induce SRS in several animal species. Kindling-induced SRS in monkeys and cats were observed mainly during resting wakefulness or sleep, but the behavioral activities associated with SRS in rodent models of extended kindling remain unknown. We aimed to add information in this area using a mouse model of extended hippocampal kindling. Middle-aged C57 black mice experienced ≥80 hippocampal stimulations (delivered twice daily) and then underwent continuous 24 h electroencephalography (EEG)-video monitoring for SRS detection. SRS were recognized by EEG discharges and associated motor seizures. The five stages of the modified Racine scale for mice were used to score motor seizure severities. Seizure-preceding behaviors were assessed in a 3 min period prior to seizure onset and categorized as active and inactive. Three main observations emerged from the present analysis. (1) SRS were found to predominantly manifest as generalized (stage 3-5) motor seizures in association with tail erection or Straub tail. (2) SRS occurrences were not significantly altered by the light on/off cycle. (3) Generalized (stage 3-5) motor seizures were mainly preceded by inactive behaviors such as immobility, standing still, or apparent sleep without evident volitional movement. Considering deeper subcortical structures implicated in genesis of tail erection in other seizure models, we postulate that genesis of generalized motor seizures in extended kindled mice may involve deeper subcortical structures. Our present data together with previous findings from post-status epilepticus models support the notion that ambient cage behaviors are strong influencing factors of SRS occurrence in rodent models of temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: Sleep disorders are common comorbidities in patients with temporal lobe epilepsy (TLE), but the underlying mechanisms remain poorly understood. Since the lateral hypothalamic (LH) and the perifornical orexinergic (ORX) and melanin-concentrating hormone (MCH) neurons are known to play opposing roles in the regulation of sleep and arousal, dysregulation of ORX and MCH neurons might contribute to the disturbance of sleep-wakefulness following epileptic seizures. Methods: To test this hypothesis, rats were treated with lithium chloride and pilocarpine to induce status epilepticus (SE). Electroencephalogram (EEG) and electromyograph (EMG) were recorded for analysis of sleep-wake states before and 24 h after SE. Double-labeling immunohistochemistry of c-Fos and ORX or MCH was performed on brain sections from the epileptic and control rats. In addition, anterograde and retrograde tracers in combination with c-Fos immunohistochemistry were used to analyze the possible activation of the amygdala to ORX neural pathways following seizures. Results: It was found that epileptic rats displayed prolonged wake phase and decreased non-rapid eye movement (NREM) and rapid eye movement (REM) phase compared to the control rats. Prominent neuronal activation was observed in the amygdala and the hypothalamus following seizures. Interestingly, in the LH and the perifornical nucleus, ORX but not MCH neurons were significantly activated (c-Fos+). Neural tracing showed that seizure-activated (c-Fos+) ORX neurons were closely contacted by axon terminals originating from neurons in the medial amygdala. Discussion: These findings suggest that the spread of epileptic activity from amygdala to the hypothalamus causes selective activation of the wake-promoting ORX neurons but not sleep-promoting MCH neurons, which might contribute to the disturbance of sleep-wakefulness in TLE. [ABSTRACT FROM AUTHOR]

Under physiological conditions, neuronal network synchronization leads to different oscillatory EEG patterns that are associated with specific behavioral and cognitive functions. Excessive synchronization can, however, lead to focal or generalized epileptiform activities. It is indeed well established that in both epileptic patients and animal models, focal epileptiform EEG patterns are characterized by interictal and ictal (seizure) discharges. Over the last three decades, employing in vitro and in vivo recording techniques, several experimental studies have firmly identified a paradoxical role of GABAA signaling in generating interictal discharges, and in initiating—and perhaps sustaining—focal seizures. Here, we will review these experiments and we will extend our appraisal to evidence suggesting that GABAA signaling may also contribute to epileptogenesis, i.e., the development of plastic changes in brain excitability that leads to the chronic epileptic condition. Overall, we anticipate that this information should provide the rationale for developing new specific pharmacological treatments for patients presenting with focal epileptic disorders such as mesial temporal lobe epilepsy (MTLE). [ABSTRACT FROM AUTHOR]