Cortical Thickness Patterns of Cognitive Impairment Phenotypes in Drug-Resistant Temporal Lobe Epilepsy.

OBJECTIVE: In temporal lobe epilepsy (TLE), a taxonomy classifying patients into 3 cognitive phenotypes has been adopted: minimally, focally, or multidomain cognitively impaired (CI). We examined gray matter (GM) thickness patterns of cognitive phenotypes in drug-resistant TLE and assessed potential use for predicting postsurgical cognitive outcomes. METHODS: TLE patients undergoing presurgical evaluation were categorized into cognitive phenotypes. Network edge weights and distances were calculated using type III analysis of variance F-statistics from comparisons of GM regions within each TLE cognitive phenotype and age- and sex-matched healthy participants. In resected patients, logistic regression models (LRMs) based on network analysis results were used for prediction of postsurgical cognitive outcome. RESULTS: A total of 124 patients (63 females, mean age ± standard deviation [SD] = 36.0 ± 12.0 years) and 117 healthy controls (63 females, mean age ± SD = 36.1 ± 12.0 years) were analyzed. In the multidomain CI group (n = 66, 53.2%), 28 GM regions were significantly thinner compared to healthy controls. Focally impaired patients (n = 37, 29.8%) showed 13 regions, whereas minimally impaired patients (n = 21, 16.9%) had 2 significantly thinner GM regions. Regions affected in both multidomain and focally impaired patients included the anterior cingulate cortex, medial prefrontal cortex, medial temporal, and lateral temporal regions. In 69 (35 females, mean age ± SD = 33.6 ± 18.0 years) patients who underwent surgery, LRMs based on network-identified GM regions predicted postsurgical verbal memory worsening with a receiver operating curve area under the curve of 0.70 ± 0.15. INTERPRETATION: A differential pattern of GM thickness can be found across different cognitive phenotypes in TLE. Including magnetic resonance imaging with clinical measures associated with cognitive profiles has potential in predicting postsurgical cognitive outcomes in drug-resistant TLE. ANN NEUROL 2024;95:984-997.

Connectome reorganization associated with temporal lobe pathology and its surgical resection.

Network neuroscience offers a unique framework to understand the organizational principles of the human brain. Despite recent progress, our understanding of how the brain is modulated by focal lesions remains incomplete. Resection of the temporal lobe is the most effective treatment to control seizures in pharmaco-resistant temporal lobe epilepsy (TLE), making this syndrome a powerful model to study lesional effects on network organization in young and middle-aged adults. Here, we assessed the downstream consequences of a focal lesion and its surgical resection on the brain's structural connectome, and explored how this reorganization relates to clinical variables at the individual patient level. We included adults with pharmaco-resistant TLE (n = 37) who underwent anterior temporal lobectomy between two imaging time points, as well as age- and sex-matched healthy controls who underwent comparable imaging (n = 31). Core to our analysis was the projection of high-dimensional structural connectome data-derived from diffusion MRI tractography from each subject-into lower-dimensional gradients. We then compared connectome gradients in patients relative to controls before surgery, tracked surgically-induced connectome reconfiguration from pre- to postoperative time points, and examined associations to patient-specific clinical and imaging phenotypes. Before surgery, individuals with TLE presented with marked connectome changes in bilateral temporo-parietal regions, reflecting an increased segregation of the ipsilateral anterior temporal lobe from the rest of the brain. Surgery-induced connectome reorganization was localized to this temporo-parietal subnetwork, but primarily involved postoperative integration of contralateral regions with the rest of the brain. Using a partial least-squares analysis, we uncovered a latent clinical imaging signature underlying this pre- to postoperative connectome reorganization, showing that patients who displayed postoperative integration in bilateral fronto-occipital cortices also had greater preoperative ipsilateral hippocampal atrophy, lower seizure frequency and secondarily generalized seizures. Our results bridge the effects of focal brain lesions and their surgical resections with large-scale network reorganization and interindividual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain.

Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.

Mapping hippocampal and thalamic atrophy in epilepsy: A 7-T magnetic resonance imaging study.

OBJECTIVE: Epilepsy patients are often grouped together by clinical variables. Quantitative neuroimaging metrics can provide a data-driven alternative for grouping of patients. In this work, we leverage ultra-high-field 7-T structural magnetic resonance imaging (MRI) to characterize volumetric atrophy patterns across hippocampal subfields and thalamic nuclei in drug-resistant focal epilepsy. METHODS: Forty-two drug-resistant epilepsy patients and 13 controls with 7-T structural neuroimaging were included in this study. We measured hippocampal subfield and thalamic nuclei volumetry, and applied an unsupervised machine learning algorithm, Latent Dirichlet Allocation (LDA), to estimate atrophy patterns across the hippocampal subfields and thalamic nuclei of patients. We studied the association between predefined clinical groups and the estimated atrophy patterns. Additionally, we used hierarchical clustering on the LDA factors to group patients in a data-driven approach. RESULTS: In patients with mesial temporal sclerosis (MTS), we found a significant decrease in volume across all ipsilateral hippocampal subfields (false discovery rate-corrected p [pFDR] < .01) as well as in some ipsilateral (pFDR < .05) and contralateral (pFDR < .01) thalamic nuclei. In left temporal lobe epilepsy (L-TLE) we saw ipsilateral hippocampal and some bilateral thalamic atrophy (pFDR < .05), whereas in right temporal lobe epilepsy (R-TLE) extensive bilateral hippocampal and thalamic atrophy was observed (pFDR < .05). Atrophy factors demonstrated that our MTS cohort had two atrophy phenotypes: one that affected the ipsilateral hippocampus and one that affected the ipsilateral hippocampus and bilateral anterior thalamus. Atrophy factors demonstrated posterior thalamic atrophy in R-TLE, whereas an anterior thalamic atrophy pattern was more common in L-TLE. Finally, hierarchical clustering of atrophy patterns recapitulated clusters with homogeneous clinical properties. SIGNIFICANCE: Leveraging 7-T MRI, we demonstrate widespread hippocampal and thalamic atrophy in epilepsy. Through unsupervised machine learning, we demonstrate patterns of volumetric atrophy that vary depending on disease subtype. Incorporating these atrophy patterns into clinical practice could help better stratify patients to surgical treatments and specific device implantation strategies.

Amygdala enlargement in temporal lobe epilepsy: Histopathology and surgical outcomes.

OBJECTIVES: Amygdala enlargement is detected on magnetic resonance imaging (MRI) in some patients with drug-resistant temporal lobe epilepsy (TLE), but its clinical significance remains uncertain We aimed to assess if the presence of amygdala enlargement (1) predicted seizure outcome following anterior temporal lobectomy with amygdalohippocampectomy (ATL-AH) and (2) was associated with specific histopathological changes. METHODS: This was a case-control study. We included patients with drug-resistant TLE who underwent ATL-AH with and without amygdala enlargement detected on pre-operative MRI. Amygdala volumetry was done using FreeSurfer for patients who had high-resolution T1-weighted images. Mann-Whitney U test was used to compare pre-operative clinical characteristics between the two groups. The amygdala volume on the epileptogenic side was compared to the amygdala volume on the contralateral side among cases and controls. Then, we used a two-sample, independent t test to compare the means of amygdala volume differences between cases and controls. The chi-square test was used to assess the correlation of amygdala enlargement with (1) post-surgical seizure outcomes and (2) histopathological changes. RESULTS: Nineteen patients with and 19 patients without amygdala enlargement were studied. Their median age at surgery was 38 years for cases and 39 years for controls, and 52.6% were male. There were no statistically significant differences between the two groups in their pre-operative clinical characteristics. There were significant differences in the means of volume difference between cases and controls (Diff = 457.2 mm3, 95% confidence interval [CI] 289.6-624.8; p < .001) and in the means of percentage difference (p < .001). However, there was no significant association between amygdala enlargement and surgical outcome (p = .72) or histopathological changes (p = .63). SIGNIFICANCE: The presence of amygdala enlargement on the pre-operative brain MRI in patients with TLE does not affect the surgical outcome following ATL-AH, and it does not necessarily suggest abnormal histopathology. These findings suggest that amygdala enlargement might reflect a secondary reactive process to seizures in the epileptogenic temporal lobe.

Combining magnetic resonance fingerprinting with voxel-based morphometric analysis to reduce false positives for focal cortical dysplasia detection.

OBJECTIVE: We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis. METHODS: We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level. RESULTS: MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients. SIGNIFICANCE: This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy.

Structural disconnection relates to functional changes after temporal lobe epilepsy surgery.

Epilepsy surgery consists of surgical resection of the epileptic focus and is recommended for patients with drug-resistant focal epilepsy. However, focal brain lesions can lead to effects in distant brain regions. Similarly, the focal resection in temporal lobe epilepsy surgery has been shown to lead to functional changes distant from the resection. Here we hypothesize that there are changes in brain function caused by temporal lobe epilepsy surgery in regions distant from the resection that are due to their structural disconnection from the resected epileptic focus. Therefore, the goal of this study was to localize changes in brain function caused by temporal lobe epilepsy surgery and relate them to the disconnection from the resected epileptic focus. This study takes advantage of the unique opportunity that epilepsy surgery provides to investigate the effects of focal disconnections on brain function in humans, which has implications in epilepsy and broader neuroscience. Changes in brain function from pre- to post-epilepsy surgery were quantified in a group of temporal lobe epilepsy patients (n = 36) using a measure of resting state functional MRI activity fluctuations. We identified regions with significant functional MRI changes that had high structural connectivity to the resected region in healthy controls (n = 96) and patients based on diffusion MRI. The structural disconnection from the resected epileptic focus was then estimated using presurgical diffusion MRI and related to the functional MRI changes from pre- to post-surgery in these regions. Functional MRI activity fluctuations increased from pre- to post-surgery in temporal lobe epilepsy in the two regions most highly structurally connected to the resected epileptic focus in healthy controls and patients-the thalamus and the fusiform gyrus ipsilateral to the side of surgery (PFWE < 0.05). Broader surgeries led to larger functional MRI changes in the thalamus than more selective surgeries (P < 0.05), but no other clinical variables were related to functional MRI changes in either the thalamus or fusiform. The magnitude of the functional MRI changes in both the thalamus and fusiform increased with a higher estimated structural disconnection from the resected epileptic focus when controlling for the type of surgery (P < 0.05). These results suggest that the structural disconnection from the resected epileptic focus may contribute to the functional changes seen after epilepsy surgery. Broadly, this study provides a novel link between focal disconnections in the structural brain network and downstream effects on function in distant brain regions.

Spectrum, Evolution, and Clinical Relationship of Magnetic Resonance Imaging in 31 Children with Febrile Infection-Related Epilepsy Syndrome.

OBJECTIVE: Describing spectrum, evolution, and clinical relationship of brain magnetic resonance imaging (MRI) findings in a large case series of children with febrile infection-related epilepsy syndrome (FIRES). METHODS: This retrospective study included 31 children with FIRES. Clinical data and MRI findings of the brain were evaluated. Poor clinical outcome was defined as severe disability, persistent vegetative state or stupor, very low intelligence quotient (<80), or death (modified Rankin scale 4-6 and Glasgow Outcome Score 1-3). RESULTS: Seventeen (54.8%) children with FIRES showed no abnormalities in the initial MRI, whereas 28 (90.3%) children showed MRI abnormalities at follow-up. The most frequent abnormalities were brain atrophy (74.2%) and T2/fluid-attenuated inversion recovery changes (64.5%), mostly hippocampal (45.2%). Generalized brain atrophy was the most frequent type of atrophy (58%). The earliest atrophy was recorded 9 days after the onset of disease. It progressed even beyond the acute phase in most children (51.6%). The exploratory data analysis revealed nominal significance between all MRI abnormalities considered together and poor outcome (p = 0.049) and between generalized brain atrophy and anesthesia (p = 0.024). After adjustment for multiple testing, the p-values were not significant. The outcome in four (12.9%) children was not poor despite generalized brain atrophy. CONCLUSION: In contrast to the uniform clinical course, MRI demonstrated a broad spectrum of findings. Initially, these were mostly normal and therefore indicative of FIRES but then changed rapidly and were mostly progressive despite the stable chronic course. The cause may be ongoing disease, treatment intensity, or both. Future studies should focus on what process underlies the onset and the progression of brain atrophy. However, brain atrophy was not always related to poor outcomes in children despite FIRES.

[Advances of pathological research and classification in malformations of cortical development associated with refractory epilepsy].

With rapid development of genetic testing techniques, neuroimaging and neuroelectrophysiological technologies, our understanding of malformations of cortical development continues to be deepened and updated. In particular, mutations in genes related to the mammalian target of rapamycin (mTOR) signaling pathway have been successively discovered in focal cortical dysplasia (FCD). At the same time, the classification consensus on FCD issued by the International League Against Epilepsy (ILAE) in 2011 has encountered problems and challenges in diagnostic practice. Therefore, in 2022, ILAE proposed an updated version of the FCD classification based on the progress in molecular genetics over the past decade. The main addition to the classification system is "white matter lesions, " and it is also suggested to integrate histopathological, neuroimaging, and molecular testing results for multi-level integrated diagnosis to achieve reliable, clinically relevant, and therapeutic targeted final diagnosis.

[Focal cortical dysplasia: visual assessment of MRI and MR morphometry data]. / Fokal'naya kortikal'naya displaziya: sravnitel'nyi analiz vizual'noi otsenki dannykh magnitno-rezonansnoi tomografii i magnitno-rezonansnoi morfometrii.

OBJECTIVE: Assessing the diagnostic significance of MR morphometry in determining the localization of focal cortical dysplasias (FCD). MATERIAL AND METHODS: The study included 13 children after surgery for drug-resistant epilepsy caused by FCD type II and stable postoperative remission of seizures (Engel class IA, median follow-up 56 months). We analyzed the results of independent expert assessment of native MR data by three radiologists (HARNESS protocol) and MR morphometry data regarding accuracy of FCD localization. We considered 2 indicators, i.e. local cortical thickening and gray-white matter blurring. RESULTS: FCD detection rate was higher after MR morphometry compared to visual analysis of native MR data using the HARNESS protocol. MR morphometry also makes it possible to more often identify gray-white matter blurring as a sign often missed by radiologists (p<0.05). CONCLUSION: MR morphometry is an additional non-invasive method for assessing the localization of FCD.

A multi-scale cortical wiring space links cellular architecture and functional dynamics in the human brain.

The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here, we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico-cortical wiring established by postmortem anatomical studies and capitalises on cutting-edge in vivo neuroimaging and machine learning. The new model expands the currently prevailing diffusion magnetic resonance imaging (MRI) tractography approach by incorporation of additional features of cortical microstructure and cortico-cortical proximity. Studying several datasets and different parcellation schemes, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior-posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics based on resting-state functional magnetic resonance imaging (rs-fMRI) and human intracranial electroencephalography (EEG) coherence. Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals.

Decomposing MRI phenotypic heterogeneity in epilepsy: a step towards personalized classification.

In drug-resistant temporal lobe epilepsy, precise predictions of drug response, surgical outcome and cognitive dysfunction at an individual level remain challenging. A possible explanation may lie in the dominant 'one-size-fits-all' group-level analytical approaches that does not allow parsing interindividual variations along the disease spectrum. Conversely, analysing inter-patient heterogeneity is increasingly recognized as a step towards person-centred care. Here, we used unsupervised machine learning to estimate latent relations (or disease factors) from 3 T multimodal MRI features [cortical thickness, hippocampal volume, fluid-attenuated inversion recovery (FLAIR), T1/FLAIR, diffusion parameters] representing whole-brain patterns of structural pathology in 82 patients with temporal lobe epilepsy. We assessed the specificity of our approach against age- and sex-matched healthy individuals and a cohort of frontal lobe epilepsy patients with histologically verified focal cortical dysplasia. We identified four latent disease factors variably co-expressed within each patient and characterized by ipsilateral hippocampal microstructural alterations, loss of myelin and atrophy (Factor 1), bilateral paralimbic and hippocampal gliosis (Factor 2), bilateral neocortical atrophy (Factor 3) and bilateral white matter microstructural alterations (Factor 4). Bootstrap analysis and parameter variations supported high stability and robustness of these factors. Moreover, they were not expressed in healthy controls and only negligibly in disease controls, supporting specificity. Supervised classifiers trained on latent disease factors could predict patient-specific drug response in 76 ± 3% and postsurgical seizure outcome in 88 ± 2%, outperforming classifiers that did not operate on latent factor information. Latent factor models predicted inter-patient variability in cognitive dysfunction (verbal IQ: r = 0.40 ± 0.03; memory: r = 0.35 ± 0.03; sequential motor tapping: r = 0.36 ± 0.04), again outperforming baseline learners. Data-driven analysis of disease factors provides a novel appraisal of the continuum of interindividual variability, which is probably determined by multiple interacting pathological processes. Incorporating interindividual variability is likely to improve clinical prognostics.

High b-value diffusion tractography: Abnormal axonal network organization associated with medication-refractory epilepsy.

Diffusion magnetic resonance imaging (dMRI) tractography has played a critical role in characterizing patterns of aberrant brain network reorganization among patients with epilepsy. However, the accuracy of dMRI tractography is hampered by the complex biophysical properties of white matter tissue. High b-value diffusion imaging overcomes this limitation by better isolating axonal pathways. In this study, we introduce tractography derived from fiber ball imaging (FBI), a high b-value approach which excludes non-axonal signals, to identify atypical neuronal networks in patients with epilepsy. Specifically, we compared network properties obtained from multiple diffusion tractography approaches (diffusion tensor imaging, diffusion kurtosis imaging, FBI) in order to assess the pathophysiological relevance of network rearrangement in medication-responsive vs. medication-refractory adults with focal epilepsy. We show that drug-resistant epilepsy is associated with increased global network segregation detected by FBI-based tractography. We propose exploring FBI as a clinically feasible alternative to quantify topological changes that could be used to track disease progression and inform on clinical outcomes.

High-resolution hippocampal diffusion tensor imaging of mesial temporal sclerosis in refractory epilepsy.

OBJECTIVE: We explore the possibility of using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to discern microstructural abnormalities in the hippocampus indicative of mesial temporal sclerosis (MTS) at the subfield level. METHODS: We analyzed data from 57 patients with refractory epilepsy who previously underwent 3.0-T magnetic resonance imaging (MRI) including DTI as a standard part of presurgical workup. We collected information about each subject's seizure semiology, conventional electroencephalography (EEG), high-density EEG, positron emission tomography reports, surgical outcome, and available histopathological findings to assign a final diagnostic category. We also reviewed the radiology MRI report to determine the radiographic category. DTI- and NODDI-based metrics were obtained in the hippocampal subfields. RESULTS: By examining diffusion characteristics among subfields in the final diagnostic categories, we found lower orientation dispersion indices and elevated axial diffusivity in the dentate gyrus in MTS compared to no MTS. By similarly examining among subfields in the different radiographic categories, we found all diffusion metrics were abnormal in the dentate gyrus and CA1. We finally examined whether diffusion imaging would better inform a radiographic diagnosis with respect to the final diagnosis, and found that dentate diffusivity suggested subtle changes that may help confirm a positive radiologic diagnosis. SIGNIFICANCE: The results suggest that diffusion metric analysis at the subfield level, especially in dentate gyrus and CA1, maybe useful for clinical confirmation of MTS.

Effects of GABAB receptor positive allosteric modulator BHF177 and IRS-1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway.

The present study was conducted to determine the effects of the γ-aminobutyric acid B (GABAB ) receptor positive allosteric modulator BHF177 on refractory epilepsy (RE). An RE rat model was initially established via treatment with lithium-pilocarpine. The RE rats were then treated with BHF177 or the GABAB receptor antagonist CGP46381, followed by recording of their seizure rate and assessment of their spatial learning in the Morris water maze test. Treatment of BHF177 reduced the seizure intensity, whereas this effect was revered upoj treatment with CGP46381. Immunohistochemistry revealed that BHF177 treatment diminished P-glycoprotein (P-gp) expression in the hippocampal tissues of RE rats. Next, we found that BHF177 activated GABAB receptor, resulting in upregulated expression of insulin receptor substrate 1 (IRS-1) and PI3K, as well as antiapoptotic factors (Bcl-2 and mTOR), along with suppression of the apoptosis factors Bax and cleaved caspase-3 in the hippocampal tissues. Further, activation of GABAB receptors by BHF177 alleviated the inflammatory response in hippocampal tissues of RE rats, as evidenced by reduced VCAM-1, ICAM-1, and tumor necrosis factor-α levels. Next, we treated primary cultured rat hippocampal neurons with BHF177 and the IRS-1 selective inhibitor NT157. BHF177 inhibited hippocampal apoptosis in rat hippocampal neurons by regulating the IRS-1/PI3K/Akt axis through crosstalk between GABAB and insulin-like growth factor-1 receptors. Collectively, our findings indicate that the BHF177 inhibited neuron apoptosis, thus protecting against RE through the IRS-1/PI3K/Akt axis, which may present a new therapeutic channel for RE.

Local and distant responses to single pulse electrical stimulation reflect different forms of connectivity.

Measuring connectivity in the human brain involves innumerable approaches using both noninvasive (fMRI, EEG) and invasive (intracranial EEG or iEEG) recording modalities, including the use of external probing stimuli, such as direct electrical stimulation. To examine how different measures of connectivity correlate with one another, we compared 'passive' measures of connectivity during resting state conditions to the more 'active' probing measures of connectivity with single pulse electrical stimulation (SPES). We measured the network engagement and spread of the cortico-cortico evoked potential (CCEP) induced by SPES at 53 out of 104 total sites across the brain, including cortical and subcortical regions, in patients with intractable epilepsy (N=11) who were undergoing intracranial recordings as a part of their clinical care for identifying seizure onset zones. We compared the CCEP network to functional, effective, and structural measures of connectivity during a resting state in each patient. Functional and effective connectivity measures included correlation or Granger causality measures applied to stereoEEG (sEEGs) recordings. Structural connectivity was derived from diffusion tensor imaging (DTI) acquired before intracranial electrode implant and monitoring (N=8). The CCEP network was most similar to the resting state voltage correlation network in channels near to the stimulation location. In contrast, the distant CCEP network was most similar to the DTI network. Other connectivity measures were not as similar to the CCEP network. These results demonstrate that different connectivity measures, including those derived from active stimulation-based probing, measure different, complementary aspects of regional interrelationships in the brain.

Fiber ball white matter modeling in focal epilepsy.

Multicompartment diffusion magnetic resonance imaging (MRI) approaches are increasingly being applied to estimate intra-axonal and extra-axonal diffusion characteristics in the human brain. Fiber ball imaging (FBI) and its extension fiber ball white matter modeling (FBWM) are such recently described multicompartment approaches. However, these particular approaches have yet to be applied in clinical cohorts. The modeling of several diffusion parameters with interpretable biological meaning may offer the development of new, noninvasive biomarkers of pharmacoresistance in epilepsy. In the present study, we used FBI and FBWM to evaluate intra-axonal and extra-axonal diffusion properties of white matter tracts in patients with longstanding focal epilepsy. FBI/FBWM diffusion parameters were calculated along the length of 50 white matter tract bundles and statistically compared between patients with refractory epilepsy, nonrefractory epilepsy and controls. We report that patients with chronic epilepsy had a widespread distribution of extra-axonal diffusivity relative to controls, particularly in circumscribed regions along white matter tracts projecting to cerebral cortex from thalamic, striatal, brainstem, and peduncular regions. Patients with refractory epilepsy had significantly greater markers of extra-axonal diffusivity compared to those with nonrefractory epilepsy. The extra-axonal diffusivity alterations in patients with epilepsy observed in the present study could be markers of neuroinflammatory processes or a reflection of reduced axonal density, both of which have been histologically demonstrated in focal epilepsy. FBI is a clinically feasible MRI approach that provides the basis for more interpretive conclusions about the microstructural environment of the brain and may represent a unique biomarker of pharmacoresistance in epilepsy.

ATP-evoked intracellular Ca2+ transients shape the ionic permeability of human microglia from epileptic temporal cortex.

BACKGROUND: Intracellular Ca2+ modulates several microglial activities, such as proliferation, migration, phagocytosis, and inflammatory mediator secretion. Extracellular ATP, the levels of which significantly change during epileptic seizures, activates specific receptors leading to an increase of intracellular free Ca2+ concentration ([Ca2+]i). Here, we aimed to functionally characterize human microglia obtained from cortices of subjects with temporal lobe epilepsy, focusing on the Ca2+-mediated response triggered by purinergic signaling. METHODS: Fura-2 based fluorescence microscopy was used to measure [Ca2+]i in primary cultures of human microglial cells obtained from surgical specimens. The perforated patch-clamp technique, which preserves the cytoplasmic milieu, was used to measure ATP-evoked Ca2+-dependent whole-cell currents. RESULTS: In human microglia extracellular ATP evoked [Ca2+]i increases depend on Ca2+ entry from the extracellular space and on Ca2+ mobilization from intracellular compartments. Extracellular ATP also induced a transient fivefold potentiation of the total transmembrane current, which was completely abolished when [Ca2+]i increases were prevented by removing external Ca2+ and using an intracellular Ca2+ chelator. TRAM-34, a selective KCa3.1 blocker, significantly reduced the ATP-induced current potentiation but did not abolish it. The removal of external Cl- in the presence of TRAM-34 further lowered the ATP-evoked effect. A direct comparison between the ATP-evoked mean current potentiation and mean Ca2+ transient amplitude revealed a linear correlation. Treatment of microglial cells with LPS for 48 h did not prevent the ATP-induced Ca2+ mobilization but completely abolished the ATP-mediated current potentiation. The absence of the Ca2+-evoked K+ current led to a less sustained ATP-evoked Ca2+ entry, as shown by the faster Ca2+ transient kinetics observed in LPS-treated microglia. CONCLUSIONS: Our study confirms a functional role for KCa3.1 channels in human microglia, linking ATP-evoked Ca2+ transients to changes in membrane conductance, with an inflammation-dependent mechanism, and suggests that during brain inflammation the KCa3.1-mediated microglial response to purinergic signaling may be reduced.

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

OBJECTIVE: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Magnetic resonance imaging findings and clinical characteristics in mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy in a predominantly adult cohort.

OBJECTIVE: We aimed to better characterize the magnetic resonance imaging (MRI) findings of mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE), a rare clinicopathological entity associated with pharmacoresistance recently described in patients with frontal lobe epilepsy. METHODS: We studied 12 patients who underwent epilepsy surgery and whose surgical specimens showed histopathological findings of MOGHE, characterized by preserved cortical lamination, blurred gray-white matter interface due to increased number of oligodendrocytes, and heterotopic neurons in the white matter. The age at MRI evaluation ranged from 11 to 58 years, except for one 4.5-year-old patient. RESULTS: Following a detailed MRI analysis using an in-house protocol, we found abnormalities in all cases. The lesion was circumscribed in the frontal lobe in six (50%) and in the temporal lobe in three (25%) patients. In the remaining three patients (25%), the lesion was multilobar (frontotemporal and temporoparieto-occipital). Cortical thickening was mild in all patients, except in the 4.5-year-old patient, who had pronounced cortical thickening and white matter blurring. We also identified cortical/subcortical hyperintense T2/fluid-attenuated inversion recovery signal associated with gray/white matter blurring in all but one patient. When present, cleft cortical dimple, and deep sulci aided in localizing the lesion. Overall, the MRI findings were like those in focal cortical dysplasia (FCD) Type IIa. Surgical outcome was excellent in five patients (Engel Class I in 25% and II in 17%). The remaining seven patients (58%) had worthwhile seizure reduction (Engle Class III). Incomplete lesion resection was significantly associated with worse outcomes. SIGNIFICANCE: MRI findings associated with MOGHE are similar to those described in FCD Type IIa. Although more frequent in the frontal lobe, MOGHE also occurred in the temporal lobe or involved multiple lobes. Multilobar or extensive MOGHE MRI lesions are associated with less favorable surgical outcomes. Because this is a rare condition, multicenter studies are necessary to characterize MOGHE further.