mTLE Patients Research Articles

Circulating cell-free DNA methylation mirrors alterations in cerebral patterns in epilepsy

BackgroundDNA methylation profiling of circulating cell-free DNA (cfDNA) has rapidly become a promising strategy for biomarker identification and development. The cell-type-specific nature of DNA methylation patterns and the direct relationship between cfDNA and apoptosis can potentially be used non-invasively to predict local alterations. In addition, direct detection of altered DNA methylation patterns performs well as a biomarker. In a previous study, we demonstrated marked DNA methylation alterations in brain tissue from patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE–HS).ResultsWe performed DNA methylation profiling in cfDNA isolated from the serum of MTLE patients and healthy controls using BeadChip arrays followed by systematic bioinformatic analysis including deconvolution analysis and integration with DNase accessibility data sets. Differential cfDNA methylation analysis showed an overrepresentation of gene ontology terms and transcription factors related to central nervous system function and regulation. Deconvolution analysis of the DNA methylation data sets ruled out the possibility that the observed differences were due to changes in the proportional contribution of cortical neurons in cfDNA. Moreover, we found no overrepresentation of neuron- or glia-specific patterns in the described cfDNA methylation patterns. However, the MTLE–HS cfDNA methylation patterns featured a significant overrepresentation of the epileptic DNA methylation alterations previously observed in the hippocampus.ConclusionsOur results support the use of cfDNA methylation profiling as a rational approach to seeking non-invasive and reproducible epilepsy biomarkers.

Synthetic relaxometry combined with MUSE DWI and 3D-pCASL improves detection of hippocampal sclerosis

PurposeTo investigate the diagnostic value of synthetic MRI combined MUSE DWI and 3D-pCASL in hippocampal sclerosis (HS). MethodA total of 30 HS patients participated in the study. At the same time, 51 healthy volunteers were collected as the control group. All patients and healthy volunteers underwent epilepsy MR scanning protocol (including oblique coronal MAGiC, MUSE DWI, and axial 3D-pCASL) at 3.0 T MR scanner.The independent samples T test and Mann-Whitney U test were used to compare the differences of the apparent dispersion coefficient(ADC), cerebral blood flow(CBF) and quantitative parameters, including T1 relaxation time (T1), T2 relaxation time (T2), and proton density (PD) values, in the hippocampus of the affected side of HS and the contralateral and control groups, respectively. The diagnostic performance was evaluated using binary logistic regression analysis and area under the receiver operating characteristic (ROC) curves (AUC). ResultsSignificant statistical differences in T1, T2, CBF, and ADC values were observed between the affected hippocampus of HS patients and contralateral and control hippocampus (all P < 0.005). The T2 has higher discrimination abilities compared with other univariable parameters, with the AUC of 0.899. The combined T2, ADC and CBF model had the best diagnostic performance of HS in MTLE patients with AUC, sensitivity and specificity of 0.946, 86.67 %, 93.33 %, respectively. ConclusionsRelaxometry parameters derived from synthetic MRI contributed to diagnosis of HS. The proposed approach combining T2, ADC and CBF showed a strong diagnostic capability.

Altered Resting State Networks Before and After Temporal Lobe Epilepsy Surgery.

To explore the resting state networks (RSNs) alterations in patients with unilateral mesial temporal lobe epilepsy (mTLE) before and after successful surgery. Resting-state functional MRI and T1-weighted structural MRI were obtained in 37 mTLE patients who achieved seizure freedom after anterior temporal lobectomy. Patients were scanned before surgery and at two years after surgery. Twenty-eight age- and sex-matched healthy controls were scanned once. Functional connectivity (FC) changes within and between ten common RSNs before and after surgery, and FC changes between hippocampus and RSNs were explored. Before surgery, decreased FC was found within visual network and basal ganglia network, while after surgery, FC within basal ganglia network further decreased but FC within sensorimotor network and dorsal attention network increased. Before surgery, between-network FC related to basal ganglia network, visual network and dorsal attention network decreased, while between-network FC related to default mode network increased. After surgery, between-network FC related to visual network and dorsal attention network significantly increased. In addition, before surgery, ipsilateral hippocampus showed decreased FC with visual network, basal ganglia network, sensorimotor network, default mode network and frontoparietal network, while contralateral rostral hippocampus showed increased FC with salience network. After surgery, no obvious FC changes were found between contralateral hippocampus and these RSNs. MTLE patients showed significant RSNs alterations before and after surgery. Basal ganglia network showed progressive decline in functional connectivity. Successful surgery may lead to RSNs reorganization. These results provide preliminary evidence for postoperative functional remodeling at whole-brain-network level.

Latent, Early or Late Human Herpes Virus-6B Expression in Adult Mesial Temporal Lobe Epilepsy: Association of Virus Life Cycle with Inflammatory Cytokines in Brain Tissue and Cerebral Spinal Fluid

Background: Human herpes virus-6B (HHV-6B) was suggested as an important etiologic factor of mesial temporal lobe epilepsy, while the mechanism is still unknown. Here, we aimed to analyze antigens representing latent, early and late HHV-6B infection and the association with inflammatory cytokines in brain tissue and cerebral spinal fluid (CSF) from MTLE patients with HHV-6B-positivity. Methods: Nested polymerase chain reaction (nPCR), real-time PCR, immunohistochemistry (IHC) and suspension bead array for cytokines were performed. Results: Nested polymerase chain reaction (nPCR) in brain tissue revealed HHV-6B DNA in 19 of 49 MTLE patients (39%) and 1 of 19 controls (5%) (P < 0.001), but not in CSF. ICH showed HHV-6B early antigen (P41) positivity in 3 patients (6%), late antigen (gp116/54/64) positivity in 5 patients (10%), latent antigen (U94) positivity in 8 patients (16%), and multiple antigen (early and late or/and latent) positivity in 9 patients (18%). None of these HHV-6B related proteins were found positive in control brain tissue. PCR revealed significant up-regulation of IL-1a, IL-2 and IL-7 mRNA levels in the brain tissue from MTLE patients expressing early antigens compared to those expressing late, latent, multiple antigens, negative antigens and the controls. Suspension bead array of the CSF confirmed significant up-regulation of IL-1a and IL-7 protein expression from MTLE patients expressing early antigens compared to the other groups. Conclusions: Our finding suggests HHV-6B is a common etiologic agent of MTLE. Different virus life cycle may play an important modifying role in inflammatory biology that warrants further investigation. Though virus DNA is difficult detected in CSF, up-regulation of IL-1a and IL-7 in CSF indicates the two cytokines may be taken as indirect biomarker of HHV-6B infection.

Association of intraoperative end-tidal carbon dioxide level with ablation volume during magnetic resonance-guided laser interstitial thermal therapy for mesial temporal lobe epilepsy.

Maximal safe ablation of target structures during magnetic resonance-guided laser interstitial thermal therapy (MRgLiTT) is critical to achieving good seizure outcome in patients with mesial temporal lobe epilepsy (mTLE). The authors sought to determine whether intraoperative physiological variables are associated with ablation volume during MRgLiTT. Patients with mTLE who underwent MRgLiTT at our institution from 2014 to 2019 were retrospectively analyzed. Ablation volume was determined with volumetric analysis of intraoperative postablation MR images. Physiological parameters (systolic blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure [MAP], end-tidal carbon dioxide [ETCO2]) measured 40 minutes prior to ablation were analyzed. Univariate and multivariate regression analyses were performed to determine independent predictors of ablation volume. Forty-four patients met the inclusion criteria. The median (interquartile range) ablation volume was 4.27 (2.92-5.89) cm3, and median ablation energy was 7216 (6402-8784) J. The median MAP, SBP, DBP, and ETCO2 values measured during the 40-minute period leading up to ablation were 72.8 (66.2-81.5) mm Hg, 104.4 (96.4-114.4) mm Hg, 62.4 (54.1-69.8) mm Hg, and 34.1 (32.0-36.2) mm Hg, respectively. In univariate analysis, only total laser energy (r = 0.464, p = 0.003) and 40-minute average ETCO2 (r = -0.388, p = 0.012) were significantly associated with ablation volume. In multivariate analysis, only ETCO2 ≤ 33 mm Hg (p = 0.001) was significantly associated with ablation volume. Total ablation energy and ETCO2, but not blood pressure, may significantly affect ablation volume in mTLE patients undergoing MRgLiTT. Mild hypocapnia was associated with increased extent of ablation. Intraoperative monitoring and modulation of ETCO2 may help improve extent of ablation, prediction of ablation volume, and potentially seizure outcome.

Reduced Metabotropic Glutamate Receptor Type 5 Availability in the Epileptogenic Hippocampus: An in vitro Study.

Abnormalities in the expression of metabotropic glutamate receptor type 5 (mGluR5) have been observed in the hippocampus of patients with drug-resistant mesial Temporal Lobe Epilepsy (mTLE). Ex-vivo studies in mTLE hippocampal surgical specimens have shown increased mGluR5 immunoreactivity, while in vivo whole brain imaging using positron emission tomography (PET) demonstrated reduced hippocampal mGluR5 availability. To further understand mGluR5 abnormalities in mTLE, we performed a saturation autoradiography study with [3H]ABP688 (a negative mGluR5 allosteric modulator). We aimed to evaluate receptor density (Bmax) and dissociation constants (KD) in hippocampal mTLE surgical specimens and in non-epilepsy hippocampi from necropsy controls. mTLE specimens showed a 43.4% reduction in receptor density compared to control hippocampi, which was independent of age, sex and KD (multiple linear regression analysis). There was no significant difference in KD between the groups, which suggests that the decreased mGluR5 availability found in vivo with PET cannot be attributed to reduced affinity between ligand and binding site. The present study supports that changes within the epileptogenic tissue include mGluR5 internalization or conformational changes that reduce [3H]ABP688 binding, as previously suggested in mTLE patients studied in vivo.

ID:16352 Differences Between Left and Right Temporal Lobe Epilepsy Using Resting-State Network fMRI and SEEG Connectivity

The most common type of surgical epilepsy is mesial temporal lobe epilepsy (mTLE). Due to rapid contralateral spread, lateralization of mTLE is challenging. Abnormalities have been found in resting-state networks of mTLE patients.1 It is unclear if non-directed/directed connectivity between resting-state networks and mesial temporal lobe structures can aid in lateralization of mTLE patients. Also, it is unknown if directional hippocampal connectivity using fMRI resembles directional connections using stereo-electroencephalography (SEEG).

Interictal dynamic network transitions in mesial temporal lobe epilepsy.

To reveal the possible routine of brain network dynamic alterations in patients with mesial temporal lobe epilepsy (mTLE) and to establish a predicted model of seizure recurrence during interictal periods. Seventy-nine unilateral mTLE patients with hippocampal sclerosis and 97 healthy controls from two centers were retrospectively enrolled. Dynamic brain configuration analyses were performed with resting-state functional magnetic resonance imaging (MRI) data to quantify the functional stability over time and the dynamic interactions between brain regions. Relationships between seizure frequency and ipsilateral hippocampal module allegiance were evaluated using a machine learning predictive model. Compared to the healthy controls, patients with mTLE displayed an overall higher dynamic network, switching mainly in the epileptogenic regions (false discovery rate [FDR] correctedp-FDR < .05). Moreover, the dynamic network configuration in mTLE was characterized by decreased recruitment (intra-network communication), and increased integration (inter-network communication) among hippocampal systems and large-scale higher-order brain networks (p-FDR < .05). We further found that the dynamic interactions between the hippocampal system and the default-mode network (DMN) or control networks exhibited an opposite distribution pattern (p-FDR < .05). Strikingly, we showed that there was a robust association between predicted seizure frequency based on the ipsilateral hippocampal-DMN dynamics model and actual seizure frequency (p-perm < .001). These findings suggest that the interictal brain of mTLE is characterized by dynamical shifts toward unstable state. Our study provides novel insights into the brain dynamic network alterations and supports the potential use of DMN dynamic parameters as candidate neuroimaging markers in monitoring the seizure frequency clinically during interictal periods.

Metabolic phenotyping of hand automatisms in mesial temporal lobe epilepsy

PurposeHand automatisms (HA) are common clinical manifestations in mesial temporal lobe epilepsy. However, the location of the symptomatogenic zone (EZ) in HA as well as the networks involved, are still unclear. To have a better understanding of HA underlying mechanisms, we analyzed images from interictal [18F] fluorodeoxyglucose-positron emission tomography (FDG-PET) in patients with mesial temporal lobe epilepsy (mTLE).MethodsWe retrospectively recruited 79 mTLE patients and 18 healthy people that substituted the control group for the analysis. All patients underwent anterior temporal lobectomy and were seizure-free. Based on the semiology of the HA occurrence, the patients were divided into three subgroups: patients with unilateral HA (Uni-HA), with bilateral HA (Bil-HA) and without HA (None-HA). We performed the intergroup comparison analysis of the interictal FDG-PET images and compared the functional connectivity within metabolic communities.ResultsOur analysis showed that the metabolic patterns varied among the different groups. The Uni-HA subgroup had significant differences in the extratemporal lobe brain areas, mostly in the ipsilateral supplementary motor area (SMA) and middle cingulate cortex (MCC) when compared to the healthy control group. The Bil-HA subgroup demonstrated that the bilateral SMA and MCC areas were differentially affected, whereas in the None-HA subgroup the differences were evident in limited brain areas. The metabolic network involving HA showed a constrained network embedding the SMA and MCC brain regions. Furthermore, the increased metabolic synchronization between SMA and MCC was significantly correlated with HA.ConclusionThe metabolic pattern of HA was most conspicuous in SMA and MCC brain regions. Increased metabolic synchronization within SMA and MCC was considered as the major EZ of HA.

Cortical remodeling before and after successful temporal lobe epilepsy surgery.

To explore dynamic alterations of cortical thickness before and after successful anterior temporal lobectomy (ATL) in patients with unilateral mesial temporal lobe epilepsy (mTLE). High-resolution T1-weighted MRI was obtained in 28 mTLE patients who achieved seizure freedom for at least 24months after ATL and 29 healthy controls. Patients were scanned at five timepoints, including before surgery, 3, 6, 12 and 24months after surgery. Preoperative cortical thickness of mTLE patients were compared with healthy controls. Dynamic alterations of cortical thickness before and after surgery were compared among five scans using linear mixed models. Patients with mTLE showed cortical thinning pre-surgically in ipsilateral entorhinal cortex, parahippocampal gyrus, inferior parietal cortex, lateral occipital cortex; contralateral pericalcarine cortex (PCC); and bilateral caudal middle frontal gyrus (cMFG), paracentral lobule, precentral gyrus (PCG), superior parietal cortex. Cortical thickening was observed in contralateral rostral anterior cingulate cortex (rACC). Patients showed postsurgical cortical thinning in ipsilateral temporal lobe, fusiform gyrus, caudal anterior cingulate cortex, lingual gyrus, and insula. Ipsilateral cMFG, PCC, and contralateral PCG showed significant cortical thickening after surgery. In addition, contralateral rACC showed cortical thickening at 3 months follow-up, however, with obvious cortical thinning at 24months follow-up. Mesial temporal lobe epilepsy patients showed widespread cortical thinning before and after anterior temporal lobectomy. Progressive cortical thinning mainly existed in neighboring regions of resection. Postoperative cortical thickening may indicate cortical remodeling after successful surgery.

Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology.

Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis.

336 Connectivity Between Resting-State Networks and Mesial Temporal Regions May Distinguish Between Right and Left Mesial Temporal Lobe Epilepsy

INTRODUCTION: Mesial temporal lobe epilepsy (mTLE) is the most common surgical epilepsy. Confidently lateralizing mTLE preoperatively may be challenging with only noninvasive evaluations. Resting-state fMRI has been used to identify connectivity abnormalities in mTLE, involving mesial temporal structures and other networks such as default mode network (DMN). METHODS: We acquired 20 minutes of resting-state fMRI in 52 mTLE patients (28 females, 39.5 ± 12.2 years) and 52 age/gender matched controls. In mTLE patients versus controls, we evaluated fMRI functional connectivity of bilateral hippocampi/amygdalae and resting-state networks (default mode, central executive, salience, visual) using non-directed Pearson correlation (Z-scored), network-based statistic (NBS), and directed dynamic causal modeling (DCM). We separately acquired 2 minutes of resting-state SEEG in 17 unilateral mTLE patients (10 females, 34.6 ± 12.5 years). Using SEEG, we measured hippocampal versus extrahippocampal inward partial directed coherence (PDC) strength. RESULTS: Right mTLE patients demonstrated reduced undirected functional connectivity (Z) between right hippocampus and DMN compared to left mTLE patients and controls (p &lt; 0.001, corrected, ANOVA). These were not seen between the hippocampus and other resting-state networks. Focusing on mesial temporal and DMN nodes, NBS analysis demonstrated the network with most decreased connectivity in right versus left mTLE included right hippocampus/amygdala, bilateral inferior parietal, precuneus, and medial orbitofrontal, and right lateral orbitofrontal regions (9 of 14 nodes, p = 0.006, corrected). With model exceedance probabilities, DCM analysis revealed cross-hemispheric connectivity between hippocampi/amygdalae was mostly inward to epileptogenic-side. FMRI finding resembled SEEG findings, where inward PDC strength was higher in epileptogenic hippocampi compared to other regions in right/left mTLE (p &lt; 0.05, t-tests, corrected). CONCLUSION: If improved, this may aid surgical planning and reduce need for intracranial monitoring. Inward patterns using fMRI and SEEG appear altered at epileptogenic hippocampi, warranting further comparative study of directional connectivity between fMRI and SEEG.

Characterization of resting functional MRI activity alterations across epileptic foci and networks.

Brain network alterations have been studied extensively in patients with mesial temporal lobe epilepsy (mTLE) and other focal epilepsies using resting-state functional magnetic resonance imaging (fMRI). However, little has been done to characterize the basic fMRI signal alterations caused by focal epilepsy. Here, we characterize how mTLE affects the fMRI signal in epileptic foci and networks. Resting-state fMRI and diffusion MRI were collected from 47 unilateral mTLE patients and 96 healthy controls. FMRI activity, quantified by amplitude of low-frequency fluctuations, was increased in the epileptic focus and connected regions in mTLE. Evidence for spread of this epileptic fMRI activity was found through linear relationships of regional activity across subjects, the association of these relationships with functional connectivity, and increased activity along white matter tracts. These fMRI activity increases were found to be dependent on the epileptic focus, where the activity was related to disease severity, suggesting the focus to be the origin of these pathological alterations. Furthermore, we found fMRI activity decreases in the default mode network of right mTLE patients with different properties than the activity increases found in the epileptic focus. This work provides insights into basic fMRI signal alterations and their potential spread across networks in focal epilepsy.

Decreased Intrinsic Neural Timescales in Mesial Temporal Lobe Epilepsy.

It is well established that epilepsy is characterized by the destruction of the information capacity of brain network and the interference with information processing in regions outside the epileptogenic focus. However, the potential mechanism remains poorly understood. In the current study, we applied a recently proposed approach on the basis of resting-state fMRI data to measure altered local neural dynamics in mesial temporal lobe epilepsy (mTLE), which represents how long neural information is stored in a local brain area and reflect an ability of information integration. Using resting-state-fMRI data recorded from 36 subjects with mTLE and 36 healthy controls, we calculated the intrinsic neural timescales (INT) of neural signals by summing the positive magnitude of the autocorrelation of the resting-state brain activity. Compared to healthy controls, the INT values were significantly lower in patients in the right orbitofrontal cortices, right insula, and right posterior lobe of cerebellum. Whereas, we observed no statistically significant changes between patients with long- and short-term epilepsy duration or between left-mTLE and right-mTLE. Our study provides distinct insight into the brain abnormalities of mTLE from the perspective of the dynamics of the brain activity, highlighting the significant role of intrinsic timescale in understanding neurophysiological mechanisms. And we postulate that altered intrinsic timescales of neural signals in specific cortical brain areas may be the neurodynamic basis of cognitive impairment and emotional comorbidities in mTLE patients.

Detection of Hippocampal Subfield Asymmetry at 7T With Automated Segmentation in Epilepsy Patients With Normal Clinical Strength MRIs.

While the etiology of hippocampal sclerosis (HS) in epilepsy patients remains unknown, distinct phenotypes of hippocampal subfield atrophy have been associated with different clinical presentations and surgical outcomes. The advent of novel techniques including ultra-high field 7T magnetic resonance imaging (MRI) and automated subfield volumetry have further enabled detection of hippocampal pathology in patients with epilepsy, however, studies combining both 7T MRI and automated segmentation in epilepsy patients with normal-appearing clinical MRI are limited. In this study, we present a novel application of the automated segmentation of hippocampal subfields (ASHS) software to determine subfield volumes of the CA1, CA2/3, CA4/DG, and the subiculum using ultra high-field 7T MRI scans, including T1-weighted MP2RAGE and T2-TSE sequences, in 27 patients with either mesial temporal lobe epilepsy (mTLE) or neocortical epilepsy (NE) compared to age and gender matched healthy controls. We found that 7T improved visualization of structural abnormalities not otherwise seen on clinical strength MRIs in patients with unilateral mTLE. Additionally, our automated segmentation algorithm was able to detect structural differences in volume and asymmetry across hippocampal subfields in unilateral mTLE patients compared to controls. Specifically, amongst unilateral mTLE patients with longer disease durations, volume loss was observed in the ipsilateral CA1 and CA2/3 subfields and contralateral CA1. There were no differences in subfield volumes in patients with NE compared to controls. We report the first application of 7T with automated segmentation to characterize the relationship between disease duration burden and asymmetry across specific hippocampal subfields in this population. Disease duration was found to have a statistically significant positive relationship with subfield asymmetry within the unilateral mTLE cohort. These findings highlight the ability of 7T MRI and automated segmentation to provide novel qualitative and quantitative information in epilepsy patients who are otherwise MRI-negative at clinical field strengths.

Mechanistic Analysis of Micro-Neurocircuits Underlying the Epileptogenic Zone in Focal Cortical Dysplasia Patients.

We aim to explore the microscopic neurophysiology of focal cortical dysplasia (FCD) induced epileptogenesis in specific macroscopic brain regions, therefore mapping a micro-macro neuronal network that potentially indicates the epileptogenic mechanism. Epileptic and relatively non-epileptic temporal neocortex specimens were resected from FCD and mesial temporal lobe epilepsy (mTLE) patients, respectively. Whole-cell patch-clamping was performed on cells from the seizure onset zone (SOZ) and non-SOZ inside the epileptogenic zone (EZ) of FCD patients, as well as the non-epileptic neocortex of mTLE patients. Microscopic data were recorded, including membrane characteristics, spontaneous synaptic activities, and evoked action potentials. Immunohistochemistry was also performed on parvalbumin-positive (PV+) interneurons. We found that SOZ interneurons exhibited abnormal neuronal expression and distribution as well as reduced overall function compared with non-SOZ and mTLE interneurons. The SOZ pyramidal cells experienced higher excitation but lower inhibition than the mTLE controls, whereas the non-SOZ pyramidal cells exhibited intermediate excitability. Action potential properties of both types of neurons also suggested more synchronized neuronal activity inside the EZ, particularly inside the SOZ. Together, our research provides evidence for a potential neurocircuit underlying SOZ epileptogenesis and non-SOZ seizure susceptibility. Further investigation of this microscopic network may promote understanding of the mechanism of FCD-induced epileptogenesis.

Causal Network Connectivity Patterns in Autism Spectrum Disorder Based on the Liang-Kleeman Information Flow Theory

To explore the structural and functional reorganization of contralateral hippocampus in patients with unilateral mesial temporal lobe epilepsy (mTLE) who achieved seizure-freedom after anterior temporal lobectomy (ATL).We obtained high-resolution structural MRI and resting-state functional MRI data in 28 unilateral mTLE patients and 29 healthy controls. Patients were scanned before and three and 24 months after surgery while controls were scanned only once. Hippocampal gray matter volume (GMV) and functional connectivity (FC) were assessed.No obvious GMV changes were observed in contralateral hippocampus before and after successful surgery. Before surgery, ipsilateral hippocampus showed increased FC with ipsilateral insula (INS) and temporoparietal junction (TPJ), but decreased FC with widespread bilateral regions, as well as contralateral hippocampus. After successful ATL, contralateral hippocampus showed: (1) decreased FC with ipsilateral INS at three months follow-up, without further changes; (2) decreased FC with ipsilateral TPJ, postcentral gyrus and rolandic operculum at three months, with an obvious increase at 24 months follow-up; (3) increased FC with bilateral medial prefrontal cortex (MPFC) and superior frontal gyrus (SFG) at three months follow-up, without further changes.Successful ATL may not lead to an obvious structural reorganization in contralateral hippocampus. Surgical manipulation may lead to a transient FC reduction of contralateral hippocampus. Increased FC between contralateral hippocampus and bilateral MPFC and SFG may be related to postoperative functional remodeling.

Reelin Is Required for Maintenance of Granule Cell Lamination in the Healthy and Epileptic Hippocampus.

One characteristic feature of mesial temporal lobe epilepsy is granule cell dispersion (GCD), a pathological widening of the granule cell layer in the dentate gyrus. The loss of the extracellular matrix protein Reelin, an important positional cue for neurons, correlates with GCD formation in MTLE patients and in rodent epilepsy models. Here, we used organotypic hippocampal slice cultures (OHSC) from transgenic mice expressing enhanced green fluorescent protein (eGFP) in differentiated granule cells (GCs) to monitor GCD formation dynamically by live cell video microscopy and to investigate the role of Reelin in this process. We present evidence that following treatment with the glutamate receptor agonist kainate (KA), eGFP-positive GCs migrated mainly toward the hilar region. In the hilus, Reelin-producing neurons were rapidly lost following KA treatment as shown in a detailed time series. Addition of recombinant Reelin fragments to the medium effectively prevented the KA-triggered movement of eGFP-positive GCs. Placement of Reelin-coated beads into the hilus of KA-treated cultures stopped the migration of GCs in a distance-dependent manner. In addition, quantitative Western blot analysis revealed that KA treatment affects the Reelin signal transduction pathway by increasing intracellular adaptor protein Disabled-1 synthesis and reducing the phosphorylation of cofilin, a downstream target of the Reelin pathway. Both events were normalized by addition of recombinant Reelin fragments. Finally, following neutralization of Reelin in healthy OHSC by incubation with the function-blocking CR-50 Reelin antibody, GCs started to migrate without any direction preference. Together, our findings demonstrate that normotopic position of Reelin is essential for the maintenance of GC lamination in the dentate gyrus and that GCD is the result of a local Reelin deficiency.

Comparison of multimodal findings on epileptogenic side in temporal lobe epilepsy using self-organizing maps.

To develop a decision-making tool to evaluate and compare the performance of neuroimaging markers with clinical findings and the significance of attributes for presurgical lateralization of mesial temporal lobe epilepsy (mTLE). Thirty-five unilateral mTLE patients who qualified as candidates for surgical resection were studied. Seizure semiology, ictal EEG, ictal epileptogenic zone, interictal-irritative zone, and MRI findings were used as clinical markers. Hippocampal T1 volumetry and FLAIR intensity, DTI estimated; mean diffusivity (MD) in the hippocampus and fractional anisotropy (FA) in posteroinferior cingulum and crus of fornix, and the output of logistic regression method on volumetrics of the hippocampus, amygdala, and thalamus were adopted as neuroimaging markers. The self-organizing map (SOM) method was applied to markers to provide predictive methods for mTLE lateralization. The SOM clustered all clinical attributes correctly with 100% accuracy and sensitivity for both the left and right mTLE. Among the clinical markers, seizure semiology and interictal-irrelative zone are the most sensitive attribute for the left-mTLE group lateralization. The accuracy achieved by applying the SOM method to the neuroimaging attributes was 94%, while the sensitivity was achieved 90% for left and 100% for right mTLE. SOM evidence indicated that the hippocampal volume is the most sensitive attribute for the prediction of the laterality in left-mTLE groups. The proposed SOM method showed that neuroimaging markers may not replace with clinical findings. Nevertheless, multimodal neuroimaging can play an effective role in preoperative lateralization to reduce the costs and risks of surgical resection.

A Systematic Review of Minimally Invasive Procedures for Mesial Temporal Lobe Epilepsy: Too Minimal, Too Fast?

Cortico-amygdalohippocampectomy (CAH) is effective for mesial temporal lobe epilepsy (mTLE). Concerns regarding surgical morbidity have generated enthusiasm for more minimally invasive interventions. A careful analysis of current data is warranted before widespread adoption of these techniques. To systematically review the use of laser interstitial thermal therapy (LITT), stereotactic radiosurgery (SRS), radiofrequency thermocoagulation (RF-TC), and focused ultrasound for mTLE. Major online databases were searched for prospective observational studies, randomized clinical trials, and retrospective studies (>50 patients), including mTLE patients. Outcomes of interest were seizure freedom (Engel I), complications and re-operation rates, and neuropsychological and quality-of-life (QoL) data. Nineteen publications were identified. At ≥6 mo postoperatively, LITT (9/19) Engel I outcomes ranged from 52% to 80%. SRS (3/19) has a latency period (52%-67%, 24-36 mo postoperatively) and the radiosurgery vs. open surgery for epilepsy (ROSE) trial reported inferiority of SRS compared to CAH. RF-TC (7/19) demonstrated variable seizure freedom rates (0%-79%) and high re-operation rates (0%-90%). Twelve studies reported neuropsychological outcomes but QoL (4/19) was not widely reported, and few studies (3/19) assessed both. Study quality ranged from fair to good. Based on nonrandomized data, LITT has compelling evidence of efficacy; however, comparisons to surgical resection are lacking. SRS has a latency period and is inferior to CAH (ROSE trial). RF-TC is a less resource-intensive alternative to LITT; however, comparisons of efficacy are limited. Additional studies are needed before minimally invasive procedures can supplant standard surgery.