Robotic assessment of sensorimotor and cognitive deficits in patients with temporal lobe epilepsy.

OBJECTIVE: Individuals with temporal lobe epilepsy (TLE) frequently demonstrate impairments in executive function, working memory, and/or declarative memory. It is recommended that screening for cognitive impairment is undertaken in all people newly diagnosed with epilepsy. However, standard neuropsychological assessments are a limited resource and thus not available to all. Our study investigated the use of robotic technology (the Kinarm robot) for cognitive screening. METHODS: 27 participants with TLE (17 left) underwent both a brief neuropsychological screening and a robotic (Kinarm) assessment. The degree of impairments and correlations between standardized scores from both approaches to assessments were analysed across different neurocognitive domains. Performance was compared between people with left and right TLE to look for laterality effects. Finally, the association between the duration of epilepsy and performance was assessed. RESULTS: Across the 6 neurocognitive domains (attention, executive function, language, memory, motor and visuospatial) assessed by our neuropsychological screening, all showed scores that significantly correlated with Kinarm tasks assessing the same cognitive domains except language and memory that were not adequately assessed with Kinarm. Participants with right TLE performed worse on most tasks than those with left TLE, including both visuospatial (typically considered right hemisphere), and verbal memory and language tasks (typically considered left hemisphere). No correlations were found between the duration of epilepsy and either the neuropsychological screening or Kinarm assessment. SIGNIFICANCE: Our findings suggest that Kinarm may be a useful tool in screening for neurocognitive impairment in people with TLE. Further development may facilitate an easier and more rapid screening of cognition in people with epilepsy and distinguishing patterns of cognitive impairment.

Accounting for repeat intervention costs in the economic comparison of laser interstitial thermal therapy and anterior temporal lobectomy for treatment of refractory temporal lobe epilepsy.

OBJECTIVE: Laser interstitial thermal therapy (LITT) is an alternative to anterior temporal lobectomy (ATL) for the treatment of temporal lobe epilepsy that has been found by some to have a lower procedure cost but is generally regarded as less effective and sometimes results in a subsequent procedure. The goal of this study is to incorporate subsequent procedures into the cost and outcome comparison between ATL and LITT. METHODS: This single-center, retrospective cohort study includes 85 patients undergoing ATL or LITT for temporal lobe epilepsy during the period September 2015 to December 2022. Of the 40 patients undergoing LITT, 35 % (N = 14) underwent a subsequent ATL. An economic cost model is derived, and difference in means tests are used to compare the costs, outcomes, and other hospitalization measures. RESULTS: Our model predicts that whenever the percentage of LITT patients undergoing subsequent ATL (35% in our sample) exceeds the percentage by which the LITT procedure alone is less costly than ATL (7.2% using total patient charges), LITT will have higher average patient cost than ATL, and this is indeed the case in our sample. After accounting for subsequent surgeries, the average patient charge in the LITT sample ($103,700) was significantly higher than for the ATL sample ($88,548). A second statistical comparison derived from our model adjusts for the difference in effectiveness by calculating the cost per seizure-free patient outcome, which is $108,226 for ATL, $304,052 for LITT only, and $196,484 for LITT after accounting for the subsequent ATL surgeries. SIGNIFICANCE: After accounting for the costs of subsequent procedures, we found in our cohort that LITT is not only less effective but also results in higher average costs per patient than ATL as a first course of treatment. While cost and effectiveness rates will vary across centers, we also provide a model for calculating cost effectiveness based on individual center data.

Increased Dentate Gyrus Excitability in the Intrahippocampal Kainic Acid Mouse Model for Temporal Lobe Epilepsy.

The intrahippocampal kainic acid (IHKA) mouse model is an extensively used in vivo model to investigate the pathophysiology of mesial temporal lobe epilepsy (mTLE) and to develop novel therapies for drug-resistant epilepsy. It is characterized by profound hippocampal sclerosis and spontaneously occurring seizures with a major role for the injected damaged hippocampus, but little is known about the excitability of specific subregions. The purpose of this study was to electrophysiologically characterize the excitability of hippocampal subregions in the chronic phase of the induced epilepsy in the IHKA mouse model. We recorded field postsynaptic potentials (fPSPs) after electrical stimulation in the CA1 region and in the dentate gyrus (DG) of hippocampal slices of IHKA and healthy mice using a multielectrode array (MEA). In the DG, a significantly steeper fPSP slope was found, reflecting higher synaptic strength. Population spikes were more prevalent with a larger spatial distribution in the IHKA group, reflecting a higher degree of granule cell output. Only minor differences were found in the CA1 region. These results point to increased neuronal excitability in the DG but not in the CA1 region of the hippocampus of IHKA mice. This method, in which the excitability of hippocampal slices from IHKA mice is investigated using a MEA, can now be further explored as a potential new model to screen for new interventions that can restore DG function and potentially lead to novel therapies for mTLE.

Associations between testing and treatment pathways in lesional temporal or extratemporal epilepsy: A census survey of NAEC center directors.

OBJECTIVE: The evaluation to determine candidacy and treatment for epilepsy surgery in persons with drug-resistant epilepsy (DRE) is not uniform. Many non-invasive and invasive tests are available to ascertain an appropriate treatment strategy. This study examines expert response to clinical vignettes of magnetic resonance imaging (MRI)-positive lesional focal cortical dysplasia in both temporal and extratemporal epilepsy to identify associations in evaluations and treatment choice. METHODS: We analyzed annual report data and a supplemental epilepsy practice survey reported in 2020 from 206 adult and 136 pediatric epilepsy center directors in the United States. Non-invasive and invasive testing and surgical treatment strategies were compiled for the two scenarios. We used chi-square tests to compare testing utilization between the two scenarios. Multivariable logistic regression modeling was performed to assess associations between variables. RESULTS: The supplemental survey response rate was 100% with 342 responses included in the analyses. Differing testing and treatment approaches were noted between the temporal and extratemporal scenarios such as chronic invasive monitoring selected in 60% of the temporal scenario versus 93% of the extratemporal scenario. Open resection was the most common treatment choice; however, overall treatment choices varied significantly (p < .001). Associations between non-invasive testing, invasive testing, and treatment choices were present in both scenarios. For example, in the temporal scenario stereo-electroencephalography (SEEG) was more commonly associated with fluorodeoxyglucose-positron emission tomography (FDG-PET) (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.06-3.29; p = .033), magnetoencephalography (MEG) (OR 2.90; 95% CI 1.60-5.28; p = <.001), high density (HD) EEG (OR 2.80; 95% CI 1.27-6.24; p = .011), functional MRI (fMRI) (OR 2.17; 95% CI 1.19-4.10; p = .014), and Wada (OR 2.16; 95% CI 1.28-3.66; p = .004). In the extratemporal scenario, choosing SEEG was associated with increased odds of neuromodulation over open resection (OR 3.13; 95% CI 1.24-7.89; p = .016). SIGNIFICANCE: In clinical vignettes of temporal and extratemporal lesional DRE, epilepsy center directors displayed varying patterns of non-invasive testing, invasive testing, and treatment choices. Differences in practice underscore the need for comparative trials for the surgical management of DRE.

Disruptions in modular structure and network integration of language-related network predict language performance in temporal lobe epilepsy: Evidence from graph-based analysis.

OBJECTIVE: Temporal lobe epilepsy (TLE) is a network disorder that alters the total organization of the language-related network. Task-based functional magnetic resonance imaging (fMRI) aimed at functional connectivity is a direct method to investigate how the network is reorganized. However, such studies are scarce and represented mostly by the resting-state analysis of the individual connections between regions. To fill this gap, we used a graph-based analysis, which allows us to cover the total language-related network changes, such as disruptions in an integration/segregation balance, during a language task in TLE. METHODS: We collected task-based fMRI data with sentence completion from 19 healthy controls and 28 people with left TLE. Using graph-based analysis, we estimated how the language-related network segregated into modules and tested whether they differed between groups. We evaluated the total network integration and the integration within modules. To assess intermodular integration, we considered the number and location of connector hubs-regions with high connectivity. RESULTS: The language-related network was differently segregated during language processing in the groups. While healthy controls showed a module consisting of left perisylvian regions, people with TLE exhibited a bilateral module formed by the anterior language-related areas and a module in the left temporal lobe, reflecting hyperconnectivity within the epileptic focus. As a consequence of this reorganization, there was a statistical tendency that the dominance of the intramodular integration over the total network integration was greater in TLE, which predicted language performance. The increase in the number of connector hubs in the right hemisphere, in turn, was compensatory in TLE. SIGNIFICANCE: Our study provides insights into the reorganization of the language-related network in TLE, revealing specific network changes in segregation and integration. It confirms reduced global connectivity and compensation across the healthy hemisphere, commonly observed in epilepsy. These findings advance the understanding of the network-based reorganizational processes underlying language processing in TLE.

Regulation of Keap1-Nrf2 axis in temporal lobe epilepsy-hippocampal sclerosis patients may limit the seizure outcomes.

BACKGROUND: Accumulation of reactive oxygen species (ROS) exacerbates neuronal loss during seizure-induced excitotoxicity. Keap1 (Kelch-like ECH-associated protein1)-nuclear factor erythroid 2-related factor 2 (Nrf2) axis is one of the known active antioxidant response mechanisms. Our study focused on finding the factors influencing Keap1-Nrf2 axis regulation in temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) patients. METHODS: Based on post-surgical follow-up data, patient samples (n = 26) were categorized into class 1 (completely seizure-free) and class 2 (only focal-aware seizures/auras), as suggested by International League Against Epilepsy (ILAE). For molecular analyses, double immunofluorescence assay and Western blot analysis were employed. RESULTS: A significant decrease in expression of Nrf2 (p < 0.005), HO-1; p < 0.02) and NADPH Quinone oxidoreductase1 (NQO1; p < 0.02) was observed in ILAE class 2. Keap1 (p < 0.02) and histone methyltransferases (HMTs) like SetD7 (SET7/9; SET domain-containing 7 histone lysine methyltransferase) (p < 0.009) and enhancer of zeste homolog 2 (EZH2; p < 0.02) and methylated histones viz., H3K4me1 (p < 0.001), H3K9me3 (p < 0.001), and H3K27me3 (p < 0.001) was upregulated in ILAE class 2. Nrf2-interacting proteins viz., p21 (p < 0.001) and heat shock protein 90 (HSP90; p < 0.03) increased in class 1 compared to class 2 patients. CONCLUSION: Upregulation of HMTs and methylated histones can limit phase II antioxidant enzyme expression. Also, HSP90 and p21 that interfere with Keap1-Nrf2 interaction could contribute to a marginal increase in HO-1 and NQO1 expression despite histone methylation and Keap1. Based on our findings, we conclude that TLE-HS patients prone to seizure recurrence were found to have dysfunctional antioxidant response, in part, owing to Keap1-Nrf2 axis. The significance of Keap1-Nrf2 signaling mechanism in generation of phase II antioxidant response. Keap1-Nrf2 controls antioxidant response through regulation of phase II antioxidant enzymes like HO-1 (heme oxygenase-1), NQO1 (NADPH-Quinone Oxidoreductase1), and glutathione S-transferase (GST). Release of Nrf2 from negative regulation by Keap1 causes its translocation into nucleus, forming a complex with cAMP response-element binding protein (CBP) and small Maf proteins (sMaf). This complex subsequently binds antioxidant response element (ARE) and elicits and antioxidant response involving expression of phase II antioxidant enzymes. Reactive oxygen species (ROS) modify Cysteine 151 residue, p62 (sequsetosome-1), and interacts with Nrf2- binding site in Keap 1. p21 and HSP90 prevent Nrf2 interaction with Keap1. At transcriptional level, histone methyltransferases like EZH2 (enhancer of zeste homologue2), and SetD7 (SET7/9; SET domain-containing 7 histone lysine methyltransferase) and corresponding histone targets viz., H3K27me3, H3K9me3, and H3K4me1 influence Nrf2 and Keap1 expression respectively.

Global network alterations of the cognitive phenotypes in pediatric temporal lobe epilepsy.

OBJECTIVE: An emerging literature suggests that the neuropsychological sequelae of pediatric temporal lobe epilepsy (TLE) are characterized by a continuum of cognitive phenotypes that range in type and severity. The goal of the present investigation was to better characterize the neuropsychological networks that underlie these phenotypes. METHODS: The study included 59 patients with TLE who were empirically categorized into three cognitive phenotypes (normal, focal, and generalized impairment). Nine neuropsychological measures representing multiple cognitive domains (i.e., reasoning, language, visouperception, memory, and executive function) were examined by graph theory to characterize the global network properties of the cognitive phenotypes. RESULTS: Across the cognitive phenotype groups (i.e., normal, focal, generalized impaired) the following findings emerged: (1) the adjacency matrices demonstrated different patterns of association between cognitive measures within the neuropsychological network; (2) global measures including global efficiency (GE) and average clustering coefficient (aCC) showed a stepwise increase across the range of impaired pediatric TLE phenotypes; however, modularity (M) demonstrated the opposite pattern. IMPRESSIONS: Cognitive networks in pediatric TLE demonstrate stepwise perturbation in underlying neuropsychological networks. Graph theory offers a novel approach to examine cognitive abnormalities in pediatric TLE that may be applied to other pediatric epilepsies.

Accelerated long-term forgetting in children with temporal lobe epilepsy: A timescale investigation of material specificity and executive skills.

Recently, children with temporal lobe epilepsy (TLE) were found to be at risk of accelerated long-term forgetting (ALF). In this study, we examined the temporal trajectory of ALF, while exploring the relationship between ALF, executive skills, and epilepsy variables. Fifty-one children, (23 with TLE and 28 typically developing) completed a battery of neuropsychological tests of verbal and visual memory, executive skills, and two experimental memory tasks (verbal and visual) involving recall after short (30-min) and extended (1-day and 2-week) delays. Side of seizure focus and hippocampal integrity were considered. On the visual task (Scene Memory), children with TLE performed comparably to typically developing children following a 30-min and 1-day delay, although worse than typically developing children at 2 weeks: ALF was observed in children with right TLE focus. The two groups did not differ on the experimental verbal memory task. Children with TLE also had worse performance than typically developing children on standardized verbal memory test and on tests of executive skills (i.e., verbal generativity, inhibition, working memory, complex attention). Only complex attention was associated with visual ALF. ALF was present for visuo-spatial materials in children with TLE at two weeks, and children with right TLE were most susceptible. A relationship was identified between complex attention and long-term forgetting. The findings extend our understanding of difficulties in long-term memory formation experienced by children with TLE.

Global and local shape features of the hippocampus based on Laplace-Beltrami eigenvalues and eigenfunctions: a potential application in the lateralization of temporal lobe epilepsy.

Using magnetic resonance (MR) images to evaluate changes in the shape of the hippocampus has been an active research topic. This paper presents a new shape analysis approach to quantify and visualize deformations of the hippocampus in epilepsy. The proposed method is based on Laplace-Beltrami (LB) eigenvalues and eigenfunctions as isometric invariant shape features, and thus, the procedure does not require any image registration. In addition to the LB-based shape features, total hippocampal volume and surface area are calculated using manually segmented images. Theses shape and volumetric descriptors are used to distinguish the patients with temporal lobe epilepsy (TLE) (N = 55) from healthy control subjects (N = 12, age = 32.2 ± 9.1, sex (M/F) = 6/6) and patients with right TLE (N = 26, age = 45.1 ± 11.0, sex (M/F) = 9/17) from left TLE (N = 29, age = 45.4 ± 11.9, sex (M/F) = 10/19). Experimental results illustrate the usefulness of the proposed approach for the diagnosis and lateralization of TLE with 93.0% and 86.4% of the cases, respectively. Moreover, the proposed method outperforms the volumetric analysis in terms of both sensitivity (94.9% vs. 88.1%) and specificity (83.3% vs. 50.0%) of the lateralization. The analysis of local hippocampal thickness variations suggests significant deformation in both ipsilateral and contralateral hippocampi of epileptic patients, while there were no differences between right and left hippocampi in controls. It is anticipated that the proposed method could be advantageous in the presurgical evaluation of patients with drug-resistant epilepsy; however, further validation of the method using a larger dataset is required.

Decision-making in temporal lobe epilepsy surgery based on invasive stereo-electroencephalography (sEEG).

In medical refractory temporal lobe epilepsy (TLE), the epileptogenic zone can be difficult to identify and therefore difficult to treat, especially in the absence of clear MRI pathologies and specific results from presurgical evaluation. Invasive monitoring with stereo-electroencephalography (sEEG) is a tool for a better determination of the epileptogenic zone. Here, we investigate the impact of sEEG on decision-making in temporal lobe epilepsy surgery. We reviewed patients with TLE who underwent further investigation with sEEG in our epilepsy unit. We examined specifically how sEEG findings influenced our decision regarding indication for a surgical procedure and resection volume. From 2013 to 2017, we performed 152 temporal resections in epilepsy patients. Twenty-one of these patients were designated for further preoperative investigation with sEEG due to incongruent findings in presurgical evaluation. Six patients were implanted bitemporally. In five cases, the hypothesis for the epileptogenic zone and localization had to be changed due to sEEG findings and resulted in a different tailored resection than intended. In three cases, sEEG findings led to the cancelation of the originally intended temporal resection as the epileptogenic zone was not definable or bilateral. In another three cases, the prognosis for reduction of seizures postoperatively had to be reduced due to the sEEG findings. However, the resection was performed after interdisciplinary discussion and informed consent of the patient. The examination by sEEG led to a change of plan for further treatment in 13 patients (61.9%) suffering TLE in total. Invasive monitoring with sEEG electrodes had a strong impact on decision-making for further treatment in patients suffering from temporal lobe epilepsy with incongruent findings in presurgical examination designated for epilepsy surgery. This applies to resection volumes as well as to prediction of seizure outcome.

PET imaging of metabolic changes after neural stem cells and GABA progenitor cells transplantation in a rat model of temporal lobe epilepsy.

PURPOSE: Stem cell transplantation is promising for temporal lobe epilepsy (TLE) treatment. This study aimed to use PET imaging for the investigation of dynamic metabolic changes after transplantation of human neural stem cells (NSCs) and human GABA progenitor cells (GPCs) in a rat model of TLE. METHODS: 18F-FDG PET imaging, video-electroencephalography (EEG), whole-cell patch-clamp recordings and immunostaining were performed after transplantation of NSCs and GPCs. RESULTS: PET imaging demonstrated that glucose metabolism was gradually improved in the NSCs group, but decreased in GPCs and the control. Video-EEG manifested that seizures were suppressed after NSCs or GPCs transplantation; whole-cell patch-clamp confirmed increased inhibitory response of GPC-derived cells; immunostaining studies verified that the transplanted NSCs and GPCs could survive, migrate and differentiate into mature neuronal subtypes. CONCLUSION: 18F-FDG PET imaging could be a distinguishing approach for evaluation of dynamic glycolytic metabolic changes after transplantation of NSCs and GPCs in TLE. Whole-cell patch-clamp provides evidence for functional maturation and integration of transplanted stem cells within host circuits.

High-Throughput Data of Circular RNA Profiles in Human Temporal Cortex Tissue Reveals Novel Insights into Temporal Lobe Epilepsy.

BACKGROUND/AIMS: Circular RNAs (circRNAs) are a class of long noncoding RNAs with a closed loop structure that regulate gene expression as microRNA sponges. CircRNAs are more enriched in brain tissue, but knowledge of the role of circRNAs in temporal lobe epilepsy (TLE) has remained limited. This study is the first to identify the global expression profiles and characteristics of circRNAs in human temporal cortex tissue from TLE patients. METHODS: Temporal cortices were collected from 17 TLE patients and 17 non-TLE patients. Total RNA was isolated, and high-throughput sequencing was used to profile the transcriptome of dysregulated circRNAs. Quantitative PCR was performed for the validation of changed circRNAs. RESULTS: In total, 78983 circRNAs, including 15.29% known and 84.71% novel circRNAs, were detected in this study. Intriguingly, 442 circRNAs were differentially expressed between the TLE and non-TLE groups (fold change≥2.0 and FDR≤0.05). Of these circRNAs, 188 were up-regulated, and 254 were down-regulated in the TLE patient group. Eight circRNAs were validated by real-time PCR. Remarkably, circ-EFCAB2 was intensely up-regulated, while circ-DROSHA expression was significantly lower in the TLE group than in the non-TLE group (P<0.05). Bioinformatic analysis revealed that circ-EFCAB2 binds to miR-485-5p to increase the expression level of the ion channel CLCN6, while circ-DROSHA interacts with miR-1252-5p to decrease the expression level of ATP1A2. CONCLUSIONS: The dysregulations of circRNAs may reflect the pathogenesis of TLE and circ-EFCAB2 and circ-DROSHA might be potential therapeutic targets and biomarkers in TLE patients.

Investigation of microstructural abnormalities in white and gray matter around hippocampus with diffusion tensor imaging (DTI) in temporal lobe epilepsy (TLE).

OBJECTIVE: The objective of this study was to apply diffusion tensor imaging (DTI) to investigate microstructural abnormalities in temporal lobe epilepsy (TLE) with and without hippocampal sclerosis (HS). MATERIALS: Totally, 19 patients with TLE with HS and 23 patients with TLE without HS were included. Fiber tracking fibers focused on the parahippocampal cingulum (PHC), cingulate gyrus (CG), and fornix (FORX). Fractional anisotropy (FA) and mean diffusivity (MD) values were obtained, and hippocampal volumes were measured. RESULTS: Compared with the contralateral side, for the HS group, FA values of ipsilateral CG and FORX were significantly decreased, and MD value of ipsilateral hippocampus was significantly higher, with significantly declined ipsilateral hippocampal volume. For the MRI-Neg group, FA values of ipsilateral CG, FORX, and hippocampus were significantly decreased, while MD values of ipsilateral FORX and hippocampus were significantly higher. Moreover, for the MRI-Neg group, the FA value of contralateral PHC was significantly decreased. Fractional anisotropy values of ipsilateral CG for both groups were significantly decreased, and FA value of ipsilateral FORX for the HS group was significantly decreased. Furthermore, MD value of ipsilateral hippocampus for the HS group was significantly higher, and FA value of ipsilateral hippocampus for the MRI-Neg group was significantly decreased. In addition, ipsilateral hippocampal volumes for both groups were significantly decreased. Fractional anisotropy value of ipsilateral CG and FORX had a correlation with the seizure frequency. CONCLUSION: Diffusion tensor imaging can detect microstructural abnormalities in brain from patients with TLE, which might be hard to find with routine Magnetic Resonance Imaging (MRI) sequence.

Role of BDNF Val66Met functional polymorphism in temporal lobe epilepsy.

Various studies suggested that brain-derived neurotrophic factor (BDNF) gene polymorphisms contributed to the development of many neurological disorders. However, whether BDNF Val66Met polymorphism is associated with epilepsy remains controversial. In our study, we tried to investigate the effects of this functional polymorphism on the occurrence of temporal lobe epilepsy (TLE) and its clinical phenotypes. Case-control studies were employed to study the association between BDNF Val66Met polymorphism and TLE, as well as its clinical phenotypes, and magnetic resonance imaging examinations and voxel-based morphometry analyses were carried out for further study. Our results showed that the frequency of Met allele was found to be lower in the TLE patients compared with the control subjects (43.9% vs. 48.6%, P = 0.012, OR = 1.21, 95% CI = 1.04-1.41), and the frequency of Met66 allele carriers in the TLE with hippocampal sclerosis was significantly lower than those non-carriers (20.5% vs. 29.1%, P = 0.040). However, we failed to find the difference between different genotypes and hippocampal asymmetry. Our findings suggested that BDNF Val66Met polymorphism might be correlated with epileptogenesis, and Met66 allele might play a protective role against the occurrence of TLE.

Evaluation of machine learning algorithms for treatment outcome prediction in patients with epilepsy based on structural connectome data.

The objective of this study is to evaluate machine learning algorithms aimed at predicting surgical treatment outcomes in groups of patients with temporal lobe epilepsy (TLE) using only the structural brain connectome. Specifically, the brain connectome is reconstructed using white matter fiber tracts from presurgical diffusion tensor imaging. To achieve our objective, a two-stage connectome-based prediction framework is developed that gradually selects a small number of abnormal network connections that contribute to the surgical treatment outcome, and in each stage a linear kernel operation is used to further improve the accuracy of the learned classifier. Using a 10-fold cross validation strategy, the first stage in the connectome-based framework is able to separate patients with TLE from normal controls with 80% accuracy, and second stage in the connectome-based framework is able to correctly predict the surgical treatment outcome of patients with TLE with 70% accuracy. Compared to existing state-of-the-art methods that use VBM data, the proposed two-stage connectome-based prediction framework is a suitable alternative with comparable prediction performance. Our results additionally show that machine learning algorithms that exclusively use structural connectome data can predict treatment outcomes in epilepsy with similar accuracy compared with "expert-based" clinical decision. In summary, using the unprecedented information provided in the brain connectome, machine learning algorithms may uncover pathological changes in brain network organization and improve outcome forecasting in the context of epilepsy.

Functional connectivity homogeneity correlates with duration of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is often associated with progressive changes to seizures, memory, and mood during its clinical course. However, the cerebral changes related to this progression are not well understood. Because the changes may be related to changes in brain networks, we used functional connectivity MRI (fcMRI) to determine whether brain network parameters relate to the duration of TLE. Graph theory-based analysis of the sites of reported regions of TLE abnormality was performed on resting-state fMRI data in 48 subjects: 24 controls, 13 patients with left TLE, and 11 patients with right TLE. Various network parameters were analyzed including betweenness centrality (BC), clustering coefficient (CC), path length (PL), small-world index (SWI), global efficiency (GE), connectivity strength (CS), and connectivity diversity (CD). These were compared for patients with TLE as a group, compared to controls, and for patients with left and right TLE separately. The association of changes in network parameters with epilepsy duration was also evaluated. We found that CC, CS, and CD decreased in subjects with TLE compared to control subjects. Analyzed according to epilepsy duration, patients with TLE showed a progressive reduction in CD. In conclusion, we found that several network parameters decreased in patients with TLE compared to controls, which suggested reduced connectivity in TLE. Reduction in CD associated with epilepsy duration suggests a homogenization of connections over time in TLE, indicating a reduction of the normal repertoire of stronger and weaker connections to other brain regions.

Decreased expression of Gab2 in patients with temporal lobe epilepsy and pilocarpine-induced rat model.

Growth factor receptor bound protein-2 associated binding protein-2 (Gab2) is widely expressed in the central nervous system, and participates in multiple signaling pathways. Recent studies showed that Gab2 was involved in the pathogenesis of Alzheimer's disease (AD). Gab2 reduces tau phosphorylation levels and is associated with cellular apoptosis and differentiation. However, whether Gab2 was also involved in the pathogenesis of epilepsy, remains unknown. This study aimed to investigate the expression pattern of Gab2 protein in brains with temporal lobe epilepsy (TLE) and in pilocarpine-induced rat model of TLE. Western blot, immunohistochemistry, and immunofluorescence were used to assess the location and the expression level of Gab2 in the neocortex of the temporal lobe in patients with TLE and in rat model of epilepsy. Results showed that Gab2 protein was expressed mainly in the membranes and cytoplasm of neurons in the cortex and hippocampus. Gab2 protein expression was remarkably reduced in temporal neocortex of TLE patients. In hippocampus and adjacent cortex in rat epilepsy model, Gab2 expression was decreased at different time points after kindling compared with the controls, and the lowest level of Gab2 expression occurred at 1 week. Thus, significant reductions of Gab2 protein in both TLE patients and epilepsy rats suggest that Gab2 may play an important role in the pathogenesis of TLE.

Contributions of fMRI towards our understanding of the response to psychosocial stress in epilepsy and psychogenic nonepileptic seizures.

There are multiple definitions of stress. For this review, as a reference point, we will use the concept of acute emotional/psychosocial stress ("stress"). The presence of acute stress has been reported to have a significant effect on seizure control, with several studies showing patients with seizure disorders being able to predict with reasonable accuracy seizure occurrence within the following hours or days. However, neuroimaging investigations of the pathophysiological mechanisms underlying stress reactivity (e.g., hypothalamic-pituitary-adrenal (HPA) axis activation) in humans, in general, and in patients with seizure disorders, in particular, are scarce. The reasons for this are multiple and likely include difficulty with designing appropriate probes that test various aspects of stress response, obtaining approval for studies that induce stress in patients who are prone to having stress-induced seizures, difficulties with assessing the physiological response to stress inside the scanner (e.g., heart rate, respiratory rate, oxygenation, cortisol levels, and galvanic skin responses), participant identification, and choice of epilepsy syndrome for investigation. With the recent explosion of neuroimaging literature focusing on correlating stress of various types and levels with cortical activations in healthy and diseased populations, it is incumbent upon us to examine the available neuroimaging data in patients with seizure disorders in order to identify the existing gaps and the needs/directions for future investigations. This approach is consistent with the goals of several of the 2014 Benchmarks for Epilepsy Research for the National Institute of Neurological Disorders and Stroke and the American Epilepsy Society.

Circulating miRNAs as Novel Clinical Biomarkers in Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) represents the most common form of refractory focal epilepsy. The identification of innovative clinical biomarkers capable of categorizing patients with TLE, allowing for improved treatment and outcomes, still represents an unmet need. Circulating microRNAs (c-miRNAs) are short non-coding RNAs detectable in body fluids, which play crucial roles in the regulation of gene expression. Their characteristics, including extracellular stability, detectability through non-invasive methods, and responsiveness to pathological changes and/or therapeutic interventions, make them promising candidate biomarkers in various disease settings. Recent research has investigated c-miRNAs in various bodily fluids, including serum, plasma, and cerebrospinal fluid, of TLE patients. Despite some discrepancies in methodologies, cohort composition, and normalization strategies, a common dysregulated signature of c-miRNAs has emerged across different studies, providing the basis for using c-miRNAs as novel biomarkers for TLE patient management.

Repeat testing enhances long-term verbal memory in children with epilepsy.

To (i) determine whether accelerated long-term forgetting (ALF) can be found using standardized verbal memory test materials in children with genetic generalized epilepsy (GGE) and temporal lobe epilepsy (TLE), and (ii) to establish whether ALF is impacted by executive skills and repeat testing over long delays. One hundred and twenty-three children aged 8 to 16, (28 with GGE, 23 with TLE, and 72 typically developing; TD) completed a battery of standardized tests assessing executive functioning and memory for two stories. Stories were recalled immediately and after a 30-min delay. To examine whether repeat testing impacts long-term forgetting, one story was tested via free recall at 1-day and 2-weeks, and the other at 2-weeks only. Recognition was then tested for both stories at 2-weeks. Children with epilepsy recalled fewer story details, both immediately and after 30-min relative to TD children. Compared to TD children, the GGE group, but not the TLE group, showed ALF, having significantly poorer recall of the story tested only at the longest delay. Poor executive skills were significantly correlated with ALF for children with epilepsy. Standard story memory materials can detect ALF in children with epilepsy when administered over long delays. Our findings suggest that (i) ALF is related to poor executive skills in children with epilepsy, and (ii) repeated testing may ameliorate ALF in some children.