Temporal Lobe Epilepsy Research Articles

Brain temperature, brain metabolites, and immune system phenotypes in temporal lobe epilepsy.

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

Focal granule cell bilamination of the dentate gyrus-its prevalence across the human age spectrum and review of the literature.

The prevalence of focal granule cell bilamination (FGCB) in the hippocampal dentate gyrus varies from 0% to 44%, depending on age and study population. FGCB is commonly thought to be a specific feature of temporal lobe epilepsy (TLE) but its prevalence in cases without TLE is unclear. Using formalin-fixed, paraffin-embedded hippocampal sections, this retrospective postmortem study evaluated the prevalence of FGCB and other granule cell pathologies in infants (1-12 months of age, n = 16), children (4-10 years, n = 6), and adults (28-91 years, n = 15) with no known history of epilepsy or seizures. We found FGCB in 6% of infants, 17% of children, and 27% of adults. We then compared our findings with those in published reports of sudden unexpected deaths in infancy (SUDI), childhood (SUDC), and epilepsy (SUDEP), and in surgical specimens from patients with TLE. The reported prevalence of FGCB in those studies was 6%-19% in infants, 0%-17% in children, and 0%-2% in adults in non-seizure-related cases and 9% in children and 3%-25% in adults with TLE. Our findings highlight the presence of FGCB in individuals with no known epilepsy/seizure-related histories in proportions similar to those reported in individuals with clinical epilepsy.

Progressive postoperative atrophy of ipsilateral thalamus, putamen, and globus pallidus in patients with temporal lobe epilepsy: A volumetric analysis.

Cortical atrophy close to medial temporal structures has been described consistently in patients with temporal lobe epilepsy (TLE). Successful TLE surgery may have a neuroprotective effect preventing further atrophy of temporal and extratemporal cortex. However, the effects of epilepsy surgery on subcortical structures demand additional enlightenment. This work aimed to determine how epilepsy surgery affects volumes of subcortical structures in medically refractory temporal lobe epilepsy patients. We compared MRI volumes of subcortical structures in 62 patients with TLE (36 left, 26 right) before and after anterior temporal lobectomy with 38 TLE patients (20 left, 18 right) who were considered to be good surgical candidates and had at least two brain MRIs. There were no volume differences in subcortical structures on preoperative and initial MRIs of non-operated TLE patients. At baseline, the ipsilateral thalamus and putamen in TLE patients were marginally smaller than contralateral structures. Operated patients showed a significant postoperative volume reduction in ipsilateral thalamus, putamen, and globus pallidus. In contrast, there were no significant volumetric reductions in non-operated patients longitudinally. There were no volumetric changes associated with different surgical outcomes or different postoperative cognitive outcomes. Our study demonstrated postoperative volume loss of thalamus, putamen and globus pallidus ipsilaterally to the side of resection. Our findings suggest surgery-related changes, likely Wallerian degeneration within subcortical networks not related to seizure or cognitive outcome. We studied 100 patients with epilepsy, comparing those who had surgery to those who did not. After surgery, the thalamus, putamen and globus pallidus on the same side as the surgery shrank significantly, but not in non-surgery patients. This suggests surgery-related changes in deeper brain structures, unrelated to seizure freedom or cognitive outcomes. This research sheds additional light on the response of the subcortical structure to epilepsy surgery, highlighting potential areas for further study.

[11C]Metoclopramide PET can detect a seizure-induced up-regulation of cerebral P-glycoprotein in epilepsy patients

BackgroundP-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [11C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [11C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB.MethodsEight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [11C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K1) and from brain to plasma (k2), and the total volume of distribution (VT = K1/k2).ResultsDRE patients but not DSE patients showed significantly higher k2 values and a trend towards lower VT values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k2: hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%).Conclusions[11C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k2 seems to be the most sensitive parameter to measure increased P-gp function with [11C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [11C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases.Trial registrationEudraCT 2019-003137-42. Registered 28 February 2020.

Social-semantic knowledge in frontotemporal dementia and after anterior temporal lobe resection

Abstract Degraded semantic memory is a prominent feature of frontotemporal dementia (FTD). It is classically associated with semantic dementia and anterior temporal lobe (ATL) atrophy, but semantic knowledge can also be compromised in behavioural-variant FTD (bvFTD). Motivated by understanding behavioural change in FTD, recent research has focused selectively on social-semantic knowledge, with proposals that the right ATL is specialised for social concepts. Previous studies have assessed very different types of social concepts and have not compared performance to that on matched non-social concepts. Consequently, it remains unclear to what extent various social concepts are (i) concurrently impaired in FTD, (ii) distinct from general semantic memory and (iii) differentially supported by the left and right ATL. This study assessed multiple aspects of social-semantic knowledge and general conceptual knowledge across cohorts with ATL-damage arising from either neurodegeneration or resection. We assembled a test battery measuring knowledge of multiple types of social concept. Performance was compared to non-social general conceptual knowledge, measured using the Cambridge Semantic Memory Test Battery and other matched non-social-semantic tests. Our transdiagnostic approach included bvFTD, semantic dementia and “mixed” intermediate cases to capture the FTD clinical spectrum, as well as age-matched healthy controls. People with unilateral left or right ATL resection for temporal lobe epilepsy (TLE) were also recruited to assess how selective damage to the left or right ATL impacts social- and non-social-semantic knowledge. Social- and non-social-semantic deficits were severe and highly correlated in FTD. Much milder impairments were found after unilateral ATL resection, with no left vs. right differences in social-semantic knowledge or general semantic processing, and with only naming showing a greater deficit following left vs. right damage. A principal component analysis of all behavioural measures in the FTD cohort extracted three components, interpreted as capturing: (1) FTD severity, (2) semantic memory and (3) executive function. Social and non-social measures both loaded heavily on the same semantic memory component, and scores on this factor were uniquely associated with bilateral ATL grey matter volume but not with the degree of ATL asymmetry. Together, these findings demonstrate that both social- and non-social-semantic knowledge degrade in FTD (semantic dementia and bvFTD) following bilateral ATL atrophy. We propose that social-semantic knowledge is part of a broader conceptual system underpinned by a bilaterally-implemented, functionally-unitary semantic hub in the ATLs. Our results also highlight the value of a transdiagnostic approach for investigating the neuroanatomical underpinnings of cognitive deficits in FTD.

3D bioprinted in vitro epilepsy models for pharmacological evaluation in temporal lobe epilepsy.

This study introduces a novel in vitro model for intractable temporal lobe epilepsy (TLE) utilizing 3D bioprinting technology, aiming to replicate the complex neurobiological characteristics of TLE more accurately . Primary neural cell constructs were fabricated and subjected to epileptiform-inducing conditions, fostering synaptic proliferation and neuronal loss. Systematically electrophysiological and immunofluorescent analyses indicated that significant synaptic connectivity and sustained epileptiform activities within the constructs akin to those observed in human epilepsy models. Notably, the model responded to treatments with phenytoin and tetrodotoxin, illustrating its potential utility in drug response kinetics studies. Furthermore, we performed drug permeability simulations using COMSOL Multiphysics to analyze the diffusion characteristics of these drugs within the constructs. These results confirm that our 3D bioprinted neural model provides a physiologically relevant and ethically sustainable platform, which is beneficial for studying TLE mechanisms and developing therapeutic strategies with high accuracy and clinical relevance.&#xD.

Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus.

Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an "on-demand" treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively activates the chloride-permeable channel PSAM4-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM817 decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM817 in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM4-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.

Hippocampal microscopic fractional anisotropy is reduced in temporal lobe epilepsy

Abstract Surgical resection is the method of choice for treating drug-resistant focal temporal lobe epilepsy (TLE). Postsurgical outcomes are better when magnetic resonance imaging (MRI) findings can localize the seizure focus for resection. However, many patients are MR-negative, meaning the focus cannot be differentiated from normal tissue in relaxation-weighted MRI. Diffusion MRI shows promise as a preoperative marker of neuronal abnormalities due to its sensitivity to cellular changes such as axon damage, indexed by fractional anisotropy. Microscopic fractional anisotropy is a recently introduced diffusion MRI metric that is sensitive to axon integrity regardless of axon orientation in both grey and white matter. In contrast, regular fractional anisotropy is only sensitive to axon integrity in coherently oriented bundles of fibers. This work investigated whether microscopic fractional anisotropy is sensitive to hippocampal abnormalities in drug-resistant TLE. Diffusion MRI was performed on a 3T scanner in 19 patients (age = 31±10 years) with drug-resistant TLE (of which 10 were MR-negative) and 18 healthy volunteers (age = 38±15). A deep-learning method was employed to segment the hippocampus into smaller subregions corresponding to the subiculum, cornu ammonis (CA) 1, CA2/3, and CA4 plus dentate gyrus (DG). Mean measurements of subregion volume, diffusivity, fractional anisotropy, and microscopic fractional anisotropy were compared between cohorts. In a subset of the TLE cohort suspected to have unilateral pathology (n=15, age = 32±10 years), the percentage differences between measurements ipsilateral and contralateral to the epileptogenic zone were evaluated to assess asymmetry. Microscopic fractional anisotropy was reduced in the hippocampus of drug-resistant TLE patients relative to healthy volunteers. In subregion-specific analysis, microscopic fractional anisotropy was significantly reduced in only the CA4/DG region in patients compared to healthy volunteers, after corrections for multiple comparisons. In the 15 patients with suspected unilateral pathology, microscopic fractional anisotropy was reliably and statistically lower in the ipsilateral CA4/DG region compared to the contralateral side. Significant differences were not observed between TLE patients and healthy volunteers, or between hemispheres for patients with suspected unilateral pathology, for the fractional anisotropy or volume metrics. Diffusion MRI may complement standard imaging procedures by detecting abnormalities in MRI-negative patients. Due to its ability to detect abnormality regardless of axon orientation, microscopic fractional anisotropy may improve seizure focus localization in surgical candidates.

Non-classical event-related potentials reveal attention network alteration in patients with temporal lobe epilepsy

ObjectiveTo explore the characteristic changes of multiple ERP components associated with attention impairments in patients with temporal lobe epilepsy (TLE). MethodsA total of 92 patients diagnosed with TLE at Xiangya Hospital during May 2022 and January 2023 and 85 healthy controls were included in this study. Participants were asked to complete attention network test with recording of electroencephalogram. ResultsCompared with healthy controls, significant lower amplitudes (cue-related N1, N2 and CNV) and longer latencies (target-related N2) were found in TLE patients. Besides classical components, other components could also reveal the impairments of attention function. Cue-related N1 (p ≤ 0.007) and N2 (p ≤ 0.01) components indicated impaired alerting and orienting network in TLE. And cue-related CNV-E component (p = 0.003) promoted the alerting network was damaged and target-related N2 component (p = 0.008) indicated the executive control network was impaired. ConclusionThese findings consummate the non-classical ERP features of attention impairments in TLE patients. SignificanceThe above findings have strong clinical guiding significance for early identification and intervention.

Effect of Cardarin on Gene Expression of Proteins Involved in Epileptogenesis in Rat Hippocampus in the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

In recent years, the role of astro- and microglial cells and associated neuroinflammation in the pathogenesis of epilepsy has been extensively discussed. These cells can be in different functional states, the extreme A1 and M1 phenotypes producing predominantly pro-inflammatory (promoting epileptogenesis) proteins, and the A2 and M2 phenotypes producing anti-inflammatory (preventing epileptogenesis) proteins. It has been suggested that the use of drugs that can stimulate polarisation from M1 and A1 to M2 and A2 phenotypes may be a successful strategy for the treatment of epilepsy. Such drugs include agonists of peroxisome proliferator-activated receptor nuclear receptors (PPARs). The aim of this study was to investigate changes in the expression of micro- and astroglial proteins involved in the regulation of epileptogenesis in the dorsal hippocampus of rats in the lithium-pilocarpine model of temporal lobe epilepsy (TLE) and to investigate the effect of the PPAR agonist beta/delta cardarine on these processes. Cardarin was administered at the initial stages of epileptogenesis (within 7 days after induction of the TLE model), and two months later (chronic phase of the model) we analysed the expression of genes of interest in the dorsal hippocampus by real-time RT-PCR. The performed study revealed changes in gene expression of astro- and microglial proteins during epileptogenesis, mainly associated with the enhancement of neuroinflammatory processes and weakening of neuroprotective properties of these cells. In TLE rats the expression of genes of markers of astro- (Gfap) and microglia activation (Aif1), pro- (Il1b, Nlrp3) and anti-inflammatory (Il1rn) proteins, markers of the A1 phenotype of astrocytes (Lcn2, Gbp2) and growth factors (Bdnf, Fgf2) was increased. Gene expression of the protective M2 phenotype Arg1 gene was decreased in TLE rats. The most striking effect of cardarine administration was manifested in the enhanced expression of the marker A2 gene of the S100a10 astrocyte phenotype.

Association of glymphatic system dysfunction with cognitive impairment in temporal lobe epilepsy

ObjectivesTo explore the relationship between glymphatic dysfunction and cognitive impairment in unilateral temporal lobe epilepsy (TLE).MethodsThis study retrospectively included 38 patients with unilateral TLE and 26 age- and gender-matched healthy controls (HCs). The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, choroid plexus volume (CPV), and cognitive assessment were obtained for each participant. Neuropsychological test batteries included Montreal Cognitive Assessment (MoCA), Minimum Mental State Examination, Arithmetic Test (AT), Digit Symbol Substitution Test (DSST), Digit Span Test (DST), Boston Naming Test, Block design, Phonological Fluency Test (PFT), and Semantic Verbal Fluency (SVF).ResultsCompared to HCs, TLE patients had lower scores of MoCA, AT, DSST, DST, Block design, PFT and SVF (all p < 0.05) and lower values of mean DTI-ALPS index (1.491 ± 0.142 vs. 1.642 ± 0.123, p < 0.001). Significantly lower DTI-ALPS index values were observed in the ipsilateral hemisphere than in the contralateral hemisphere (1.466 ± 0.129 vs. 1.517 ± 0.175, p = 0.013) for patients with unilateral TLE. Correlation analyses found that SVF performance was significantly or borderline significantly associated with glymphatic function (FDR-corrected p < 0.05 for all DTI-ALPS index and FDR-corrected p = 0.057 for CPV) in TLE patients. Linear regression analyses showed that increased CPV and decreased DTI-ALPS index were independent risk factors for semantic fluency impairment (all p < 0.05). Furthermore, mediation analyses found the mediator role of the mean DTI-ALPS index in the relationship between choroid plexus enlargement and semantic fluency impairment (indirect effect: β = −0.182, 95%CI = −0.486 to −0.037).ConclusionThese findings reveal the important role of the DTI-ALPS index and CPV in SVF performance in unilateral TLE. Decreased DTI-ALPS index and increased CPV are the independent risk factors for semantic fluency impairment. The DTI-ALPS index may fully mediate the relationship between CP enlargement and SVF performance. These insights provide a radiological foundation for further investigations into the mechanism of the glymphatic system in TLE pathophysiology.

Lesion and lesion network localization of dysnomia after epilepsy surgery.

Temporal lobe (TL) epilepsy surgery is an effective treatment option for patients with drug-resistant epilepsy. However, neurosurgery poses a risk for cognitive deficits - up to one third of patients have a decline in naming ability following TL surgery. In this study, we aimed to better understand the neural correlates associated with reduced naming performance after TL surgery, with the goal of informing surgical planning strategies to mitigate the risk of dysnomia. We retrospectively identified 85 patients who underwent temporal lobe (TL) resective surgery (49 left TL, 36 right TL) for whom naming ability was assessed before and >3 months post-surgery using the Boston Naming Test (BNT). We used multivariate lesion-symptom mapping to identify resection sites associated with naming decline, and we used lesion-network mapping to evaluate the broader functional and structural connectivity profiles of resection sites associated with naming decline. We validated our findings in an independent cohort of 59 individuals with left temporal lobectomy, along with repeating all analyses after combining the cohorts. Lesion laterality and location were important predictors of post-surgical naming performance. Naming performance significantly improved after right temporal lobectomy (P = 0.015) while a decrement in performance was observed following left temporal lobectomy (P = 0.002). Declines in naming performance were associated with surgical resection of the left anterior middle temporal gyrus (Brodmann area 21, r =0.41, P = <.001), along with a previously implicated basal temporal language area. Resection sites linked to naming decline showed a functional connectivity profile featuring a left-lateralized network closely resembling the extended semantic \ default mode network, and a structural connectivity profile featuring major temporo-frontal association white matter tracts coursing through the temporal stem. This extends prior work by implicating the left anterior middle temporal gyrus in naming decline and provides additional support for the role of the previously identified basal temporal language area in naming decline. Importantly, the structural and functional connectivity profiles of these regions suggest they are key nodes of a broader extended semantic network. Together these regional and network findings may help in surgical planning and discussions of prognosis.

Detection of seizure clustering using ultralong-term subcutaneous EEG monitoring

AbstractEpileptic seizures usually occur unpredictably yet not necessarily at random times. Cyclical patterns of seizure recurrence have been broadly described. Long-term seizure documentation may reveal individual cyclical seizure patterns; however, seizure reporting by patients or their caregivers is often inaccurate. Modern technologies for at-home monitoring of epileptic seizures enable continuous EEG recording for objective seizure counts over long-term timescales. Here, we present the clinical case of a patient with temporal lobe epilepsy due to hippocampal sclerosis who underwent ultralong-term subcutaneous EEG recording over a 1-year period, which revealed the occurrence of seizure clusters at three- to four-weekly intervals. The case demonstrates the possibility of detection of subject-specific seizure timing using a minimally invasive subcutaneous EEG recorder for ultralong-term at-home seizure monitoring. Information about individual seizure timing may contribute to a more personalized chronotherapeutic treatment approach in which antiseizure medication can be maintained at low doses during the low-risk periods and increased briefly before the anticipated seizures.

Value of Quantitative Intraoperative Electrocorticography During Anterior Temporal Lobectomy in Temporal Lobe Epilepsy Patients

Introduction: There is debate on the predictive usefulness of electrocorticography (ECoG) during anterior temporal lobectomy (ATL) in temporal lobe epilepsy (TLE) patients. The purpose of this study was to determine the usefulness of quantitative intraoperative ECoG monitoring for postoperative seizure outcomes after ATL in TLE patients. Methods: The study enrolled thirteen TLE patients who underwent ECoG-assisted ATL. Pre- and post-resection ECoG spike frequency (/min) and spike amplitude (μv/mm) were analyzed with histopathological and preoperative video-electroencephalography (EEG) data. After one year of follow-up, patients were classified as seizure-free (Engel Class I) or with residual seizure outcomes using the Engel Seizure Outcome Classification Scheme. Results: The pre-resection and post-resection ECoG showed significant differences in spike frequency (/min) and amplitude (μv/mm) (P-value &lt; 0.001). Patients with residual seizures (15.4%) showed significantly greater pre- and post-resection ECoG spike frequency and amplitude, as well as significantly higher seizure frequency before surgery, compared to patients with postoperative seizure freedom (84.6%). The pre-resection ECoG spike frequency was significantly greater in TLE patients with histopathology focal cortical dysplasia (FCD) than in those with non-FCD. The post-resection ECoG revealed a sensitivity of 100%, a specificity of 50%, a negative predictive value of 100%, and a positive predictive value of 91.67%. Conclusions: Pre-resection ECoG spike frequency and amplitude can be used as a predictive tool for postoperative seizure outcomes, particularly when video-EEG can't identify the epileptogenic zone (EZ) in TLE patients undergoing ATL.

Retraction Note: MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR-34a-targeted neuroprotection against hippocampal neurone cell apoptosis post-status epilepticus

Retraction Note: MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR-34a-targeted neuroprotection against hippocampal neurone cell apoptosis post-status epilepticus

Exogenous ketones exert antiseizure effects and modulate the gut microbiome and mycobiome in a clinically relevant murine model of epilepsy.

Despite growing interest in the potential use of exogenous ketones for the treatment of epilepsy, their impact on seizures and the gut microbiome and mycobiome remain unclear. Here, we examined the effects of both oral gavage and subcutaneous (SC) injection of a ketone ester (KE) in spontaneously epileptic Kcna1-null (KO) mice that model seminal aspects of human temporal lobe epilepsy. Electroencephalographic recordings and biochemical analyses were performed in KE-treated KO mice. Fecal microbial and fungal communities were profiled to determine whether the antiseizure activity of KE involves changes in the gut microbiome. We found that exogenous KE administration by SC injection was more effective than oral gavage in terms of rendering antiseizure effects while generating similar degrees of ketonemia. However, reductions in mean daily seizure counts were accompanied by overall alterations in the fecal bacterial microbiome. Either oral or SC injection imposed a greater impact on the microbiome in male than female mice. In males, oral KE decreased Bacteroidota phylum and genera of Ligilactobacillus and Muribaculaceae, whereas SC injection decreased Bacteroides, Lactobacillus, and Lachnospiraceae. The fecal mycobiome was affected by KE injection to a greater degree than by oral gavage, and more in females than in males, as reflected by an increase in Ascomycota and Saccharomyces. Correlation analysis between microbiome and seizure counts revealed that in mice receiving KE injection, the seizure count was positively correlated with an amplicon sequencing variant of Lactobacillus (Spearman rho = .64, p = .03) and tended toward a negative correlation with Saccharomyces (Spearman rho = -.57, p = .057). Our findings demonstrate that exogenous ketone administration alone can induce antiseizure effects equally via different routes of administration, and that they induce differential shifts in both the bacterial microbiome and mycobiome.

Amyloid deposition in adults with drug-resistant temporal lobe epilepsy.

Pathological amyloid-β (Aβ) accumulation and hyperphosphorylated tau proteins have been described in resected temporal lobe specimens of epilepsy patients. We aimed to determine cerebrospinal fluid (CSF) Aβ1-42 and p181-tau levels and cerebral Aβ deposits on positron emission tomography (Aβ PET) and correlate these findings with cognitive performance in adults with drug-resistant temporal lobe epilepsy (TLE). In this cross-sectional study, we enrolled individuals with drug-resistant TLE who were 25-55 years old. Each participant underwent 18F-flutemetamol PET, determination of CSF Aβ1-42, p181-tau, and total tau, and a comprehensive neuropsychological assessment. We evaluated normalized standard uptake value ratios (SUVRs) for different brain regions on Aβ PET. Thirty patients (mean age = 41.9 ± SD 8.1 years, 57% men) were included. The median disease duration was 9.5 (interquartile range = 4-24) years. Twenty-six patients (87%) had a clinically significant cognitive impairment on neuropsychological evaluation, 18 (69%) of the amnesic type. On Aβ PET, high uptake was observed in both mesial temporal regions (ipsilateral: SUVR z-score = .90, 95% confidence interval [CI] = .60-1.20; contralateral: SUVR z-score = .92, 95% CI = .57-1.27; p < .001), which was higher when compared to SUVR z-scores in all the remaining regions (p < .001) and in the ipsilateral anterior cingulate (SUVR z-score = .27, 95% CI = .04-.49, p = .020). No significant deposition was observed in other regions. Seven patients (23%) had low Aβ1-42 levels, and two (7%) had elevated p181-tau levels in CSF. Higher p181-tau levels correlated with poorer verbal fluency (R = -.427, p = .044). Our findings reveal a considerable Aβ deposition in mesial temporal regions and ipsilateral anterior cingulate among adults with drug-resistant TLE. Additionally, abnormal CSF Aβ1-42 levels were observed in a significant proportion of patients, and p181-tau levels were associated with verbal fluency. These results suggest that markers of neuronal damage can be observed in adults with TLE, warranting further investigation.

On-Demand Seizures Facilitate Rapid Screening of Therapeutics for Epilepsy.

Animal models of epilepsy are critical in drug development and therapeutic testing, but dominant methods for pharmaceutical evaluation face a tradeoff between higher throughput and etiological relevance. For example, in temporal lobe epilepsy, a type of epilepsy where seizures originate from limbic structures like the hippocampus, the main screening models are either based on acutely induced seizures in wild type, naïve animals or spontaneous seizures in chronically epileptic animals. Both types have their disadvantages - the acute convulsant or kindling induced seizures do not account for the myriad neuropathological changes in the diseased, epileptic brains, and spontaneous behavioral seizures are sparse in the chronically epileptic models, making it time-intensive to sufficiently power experiments. In this study, we took a mechanistic approach to precipitate seizures "on demand" in chronically epileptic mice. We briefly synchronized principal cells in the CA1 region of the diseased hippocampus to reliably induce stereotyped on-demand behavioral seizures. These induced seizures resembled naturally occurring spontaneous seizures in the epileptic animals and could be stopped by commonly prescribed anti-seizure medications such as levetiracetam and diazepam. Furthermore, we showed that seizures induced in chronically epileptic animals differed from those in naïve animals, highlighting the importance of evaluating therapeutics in the diseased circuit. Taken together, we envision our model to advance the speed at which both pharmacological and closed loop interventions for temporal lobe epilepsy are evaluated.

The association between structural connectivity and anti-seizure medication response in patients with temporal lobe epilepsy.

This study aimed to investigate the differences in structural connectivity and glymphatic system function between patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) and healthy controls. Additionally, we analyzed the association between structural connectivity, glymphatic system function, and antiseizure medication (ASM) response. We retrospectively enrolled patients with TLE and HS and healthy controls who underwent diffusion tensor imaging at our hospital. We assessed structural connectivity in patients with TLE and HS and healthy controls by calculating network measures using graph theory and evaluated glymphatic system function using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Patients with TLE and HS were categorized into two groups: ASM poor and good responders. We enrolled 55 patients with TLE and HS and 53 healthy controls. Of the 55 patients with TLE and HS, 39 were ASM poor responders, and 16 were ASM good responders. The assortativity coefficient in patients with TLE and HS was higher than that in healthy controls (0.004 vs. -0.007, p = 0.004), and the assortativity coefficient in ASM poor responders was lower than that in ASM good responders (-0.001 vs. -0.197, p = 0.003). The DTI-ALPS index in patients with TLE and HS was lower than that in healthy controls (1.403 vs. 1.709, p < 0.001); however, the DTI-ALPS index did not differ between ASM poor and good responders (1.411 vs. 1.385, p = 0.628). The DTI-ALPS index had a significant negative correlation with age in patients with TLE and HS (r = -0.267, p = 0.049). We confirmed increased assortativity coefficient in structural connectivity and decreased DTI-ALPS index in patients with TLE and HS compared with healthy controls. Additionally, we demonstrated an association between decreased assortativity coefficient in structural connectivity and ASM poor response in patients with TLE patients and HS. This study investigates the relationship between brain connectivity changes and glymphatic system function with antiseizure medication response in patients with temporal lobe epilepsy and hippocampal sclerosis. The research reveals that these patients show altered brain connectivity and glymphatic function compared to healthy individuals. A key finding is the strong link between a specific connectivity measure (assortativity coefficient) and antiseizure medication response, providing valuable insights that could influence epilepsy treatment and future research directions.

Bibliometric analysis of the interplay between epilepsy and microglia: trends, hotspots, and emerging research areas.

Epilepsy, a common neurological disorder, has been increasingly associated with neuroinflammation, especially microglia activation. To gain insights into the research trends and patterns in this intersection, we conducted a bibliometric analysis of studies published between 2005 and 2024. Using the Web of Science Core Collection, we identified 1,229 relevant articles and reviews, focusing on the relationship between epilepsy and microglia. We employed the Bibliometrix R package and VOSviewer to analyze the data. Our search strategy combined epilepsy-related terms with microglia and microglial cell keywords. The analysis encompassed publication trends, country and institutional contributions, journal sources, authors, keywords, and thematic evolution. The number of publications has steadily increased, particularly after 2019, indicating growing research interest. The United States, China, and Germany emerged as the most productive countries, with extensive collaboration between China and the United States. Epilepsia and Journal of Neuroinflammation were the most influential journals. Aronica E, Vezzani A, and Engel T were the most prolific authors. Thematic analysis revealed clusters focused on temporal lobe epilepsy, epilepsy-related disorders, and microglia activation. Over the past several years, research has shifted from fundamental brain function studies to in-vivo investigations of specific molecular mechanisms. The CSTB (-) mouse model and NF-κB signaling pathway both merit further in-depth investigation. In conclusion, this bibliometric study reveals a surge in epilepsy-microglia research, led by key countries, journals, and researchers. Temporal lobe epilepsy, epilepsy-related disorders, and microglia activation are focal themes. Future directions include exploring microglia activation mechanisms, utilizing animal models, and interdisciplinary approaches.