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The piriform cortex is recognized as highly epileptogenic in rodents, yet its electrophysiological role in human epilepsy remains understudied. Recent surgical outcomes have suggested potential benefits in resecting the piriform cortex for cases of medial temporal lobe epilepsy. However, little is known about its electrophysiological activity in human epilepsy. This case-series study aimed to explore the electrophysiological role of the piriform cortex within the epileptogenic network among patients with suspected temporal lobe epilepsy. Participants were recruited from Emory University Hospital or Children's Healthcare of Atlanta, with non-lesional frontotemporal or temporal lobe hypotheses, undergoing stereoelectroencephalographic studies. Specifically, focus was placed on patients with one or more electrode contacts in the piriform cortex. Primary objectives included determining piriform cortex involvement within the electrophysiologically defined epileptogenic network and assessing the effects of electrical stimulation. Twenty-two patients were included in the study. Notably, only one patient exhibited piriform cortex involvement at seizure onset, associated with an olfactory aura. Two patients showed early piriform cortex involvement, while others displayed late or no involvement. Electrical stimulation of the piriform cortex induced after-discharges in three patients and replicated a habitual seizure in one. These findings present a contrast to surgical outcome studies, suggesting that the piriform cortex may not typically play a significant role in the epileptogenic network among patients with non-lesional temporal lobe epilepsy.

Background: The solute carrier (SLC) superfamily, which transports solutes across biological membranes, includes four members (SLC2A1, SLC6A1, SLC9A64, and SLC35A2) that have been linked to epilepsy. This study sought to examine the DNA methylation patterns near the promoters of these genes in temporal lobe epilepsy (TLE), as DNA methylation is a crucial epigenetic modification that can impact gene expression. Methods: The study comprised 38 individuals with TLE and 38 healthy controls. Methylation experiments were performed using peripheral blood, while demethylation experiments were carried out using SH-SY5Y cells with the DNA methylation inhibitor decitabine. Results: A significant difference was observed in the DNA methylation rate of SLC6A1 between TLE patients and controls, with TLE patients showing a lower rate (4.81% vs. 5.77%, p = 0.0000), which remained significant even after Bonferroni correction (p = 0.0000). Based on the hypomethylated SLC6A1 in TLE, a predictive model was established that showed promise in distinguishing and calibrating TLE. In the TLE group, there were differences in DNA methylation rates of SLC6A1 between the young patients and the older controls (4.42% vs. 5.22%, p = 0.0004). A similar trend (p = 0.0436) was noted after adjusting for sex, age at onset, and drug response. In addition, the study found that DNA methylation had a silencing impact on the expression of the SLC6A1 gene in SH-SY5Y cells, which were treated with decitabine at a set dose gradient. Conclusions: The evidence suggests that lower methylation of SLC6A1 may stimulate transcription in TLE, however, further investigation is necessary to confirm the exact mechanism. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance To date, the identification of objective biomarkers of neural epileptic activity (EA) remains challenging. We therefore investigated whether neuronal complexity could serve as an interictal electroencephalographic measure of EA, independent of interictal epileptiform discharges (IEDs). By tapering anti‐seizure medication (ASM) during video‐EEG (electroencephalography) monitoring (VEM), we studied whether changes in neuronal complexity could reliably indicate the increase in EA and identify patients with epilepsy.The study included 27 patients with unilateral mesial temporal lobe epilepsy (TLE) and 24 control patients with non‐epileptic episodes (NEEs) only, each undergoing ASM reduction during VEM. Thirteen additional patients undergoing intracranial recordings during VEM were included to study the relation of surface EEG complexity to intracranial IED. Neuronal complexity was quantified using sample entropy. Delta power served as a control parameter. Receiver‐operating characteristic (ROC) analysis was used to evaluate diagnostic performance.As ASM was reduced, patients with epilepsy showed a significant decrease in neuronal complexity over consecutive days (p = .0008). In contrast, patients with NEE showed no significant change in neuronal complexity (p = .78). Delta power in contrast increased and did not differ significantly between patients with TLE and patients with NEE (p = 1). ROC analysis demonstrated that neuronal complexity effectively distinguished between patients with epilepsy and patients with NEE (area under the curve [AUC] = .76), whereas delta power performed at chance level (AUC = .5). Analysis of simultaneously recorded surface and intracranial EEG showed that hippocampal IEDs are followed by an increase in surface EEG delta power (p = 1.8 × 10−18) without any significant change in complexity (p = .39).An increase in EA caused by ASM reduction resulted in a loss of neuronal complexity in surface EEG recordings of patients with epilepsy, independent of IEDs. These findings suggest that neuronal complexity could serve as a potential biomarker to differentiate between epilepsy patients and those with NEEs only. This holds promise for improving the clinical evaluation of EA in epilepsy, addressing the limitations of seizure frequency and IED identification. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Area tempestas, a functionally defined region in the anterior piriform cortex, was identified as a crucial ictogenic trigger zone in the rat brain in the 1980s. However, whether the primate piriform cortex can trigger seizures remains unknown. Here, in a nonhuman primate model, we aimed to localize a similar trigger zone in the piriform cortex and, subsequently, evaluated the ability of focal inhibition of the substantia nigra pars reticulata (SNpr) to suppress the evoked seizures.Focal microinjection of the γ‐aminobutyric acid type A (GABAA) antagonist bicuculline methiodide into the piriform cortex was performed, in macaque monkeys, on a within‐subject basis to map the ictogenic regions within this area. Glutamate antagonists were used to characterize the local circuit pharmacology. Focal inhibition of the substantia nigra by infusion of the GABAA agonist muscimol suppressed seizures evoked from piriform cortex.We documented a well‐defined region highly susceptible to bicuculline‐induced seizures in the piriform cortex, just posterior to the junction of the frontal and temporal lobes, indicating that a functional homolog to the rodent area tempestas is present in the primate brain. Focal infusion of glutamate receptor antagonists into the area tempestas revealed that α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor‐mediated, but not N‐methyl‐D‐aspartate‐mediated, neurotransmission was necessary for the expression of seizures. Pharmacological inhibition of the SNpr robustly suppressed area tempestas‐evoked seizures.Together, these data point to the area tempestas as a potent ictogenic zone in the primate brain and underscore the antiseizure effects of inhibition of the SNpr. Building on decades of studies in rodents, our present findings emphasize the relevance of these targets to the primate brain and provide further rationale for exploring these targets for clinical use. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance White matter abnormalities in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) are well known. Peak width of skeletonized mean diffusivity (PSMD) is a novel marker for quantifying white matter integrity that may reflect small vessel disease. In this study, we aimed to quantify the extent of white matter damage in patients with TLE and HS by using PSMD.We enrolled 52 patients with TLE with HS and 54 age‐ and sex‐matched healthy controls. Diffusion tensor imaging (DTI) was performed using a 3‐T magnetic resonance imaging scanner. We measured PSMD using DTI findings and compared PSMD between patients with TLE with HS and healthy controls. We also evaluated the correlation between PSMD and clinical factors in patients with TLE and HS.PSMD differed significantly between healthy controls and patients with TLE and HS, and it was higher in the patients (2.375 × 10−4 mm2/s vs. 2.108 × 10−4 mm2/s, p < .001). Furthermore, PSMD in the ipsilateral hemisphere of the HS was higher than in the contralateral hemisphere of the HS (2.472 × 10−4 mm2/s vs. 2.258 × 10−4 mm2/s, p = .040). PSMD was positively correlated with age (r = .512, p < .001) and age at seizure onset (r = .423, p = .002) in patients with TLE and HS.Patients with TLE and HS had higher PSMD values than healthy controls, and PSMD was positively correlated with age. These findings provide evidence of white matter damage probably due to small vessel disease in patients with TLE and HS and support the feasibility of PSMD as a promising imaging marker for epileptic disorders. [ABSTRACT FROM AUTHOR]

Background: Temporal lobe epilepsy is one of the most common types of partial epilepsy. Although surgical treatment has led to significant improvements in seizure-free rates, nearly one-third of patients still have poor seizure control after surgery. Moreover, the long-term outcome is less favorable compared to short-term outcome, with 48–58% of patients experiencing seizures five years after surgery. The aim of this study was to investigate the surgical outcomes and the predictive value of prognostic factors associated with poor surgical outcomes in temporal lobe epilepsy patients receiving surgery. Methods: We retrospectively reviewed 94 patients undergoing temporal resective surgery in the Epilepsy Center of Guangdong Provincial Hospital of Traditional Chinese Medicine between July 2016 and July 2020. Patient information including age, gender, personal and family history, as well as preoperative and postoperative clinical data (clinical type and duration of disease) was collected. Results: The differences of postoperative clinical efficacy in both seizure free group and non-seizure free group patients were observed. A log-rank test was used for univariate analysis, and a Cox proportional hazard model was used for multivariate analysis. Ninety-four patients were followed up for at least 1 years. At 12 months of follow-up, 71 (75.5%) patients achieved Engel class I, 5 (5.3%) patients were classified as Engel class II, 5 (5.3%) patients were classified as Engel class III, and 13 (13.8%) patients were classified as Engel class IV. Univariate analysis and multivariate Cox regression analysis indicated that the postoperative EEG abnormalities were significantly correlated with seizure recurrence and were significant independent predictive factors, with a hazard ratio of 12.940. Conclusions: The relapse rate in our study was similar to commonly reported overall rates in temporal lobe epilepsy patients receiving surgery. Anterior temporal lobectomy is a reliable treatment option for temporal lobe epilepsy patients. Postoperative electroencephalograph abnormalities are independent risk factors for poor surgical prognosis. [ABSTRACT FROM AUTHOR]

Objective: 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). Methods: 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. Results: 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). Significance: 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. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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. Results: 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. Significance: 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. Plain Language Summary: 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. [ABSTRACT FROM AUTHOR]

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

Objective: Frequency properties of the EEG characteristics of different seizure types including absence seizures have been described for various rodent models of epilepsy. However, little attention has been paid to the frequency properties of individual spike–wave complexes (SWCs), the constituting elements characterizing the different generalized seizure types. Knowledge of their properties is not only important for understanding the mechanisms underlying seizure generation but also for the identification of epileptiform activity in various seizure types. Here, we compared the frequency properties of SWCs in different epilepsy models. Methods: A software package was designed and used for the extraction and frequency analysis of SWCs from long‐term EEG of four spontaneously seizing, chronic epilepsy models: a post‐status epilepticus model of temporal lobe epilepsy, a lateral fluid percussion injury model of post‐traumatic epilepsy, and two genetic models of absence epilepsy—GAERS and rats of the WAG/Rij strain. The SWCs within the generalized seizures were separated into fast (three‐phasic spike) and slow (mostly containing the wave) components. Eight animals from each model were used (32 recordings, 104 510 SWCs in total). A limitation of our study is that the recordings were hardware‐filtered (high‐pass), which could affect the frequency composition of the EEG. Results: We found that the three‐phasic spike component was similar in all animal models both in time and frequency domains, their amplitude spectra showed a single expressed peak at 18–20 Hz. The slow component showed a much larger variability across the rat models. Significance: Despite differences in the morphology of the epileptiform activity in different models, the frequency composition of the spike component of single SWCs is identical and does not depend on the particular epilepsy model. This fact may be used for the development of universal algorithms for seizure detection applicable to different rat models of epilepsy. Plain Language Summary: There is a large variety between people with epilepsy regarding the clinical manifestations and the electroencephalographic (EEG) phenomena accompanying the epileptic seizures. Here, we show that one of the EEG signs of epilepsy, an epileptic spike, is universal, since it has the same shape and frequency characteristics in different animal models of generalized epilepsies, despite differences in recording sites and location. [ABSTRACT FROM AUTHOR]

Objective: Dystonic posturing (DP) is a common semiology in temporal lobe epilepsy (TLE). We aimed to explore cerebellar gradient alterations in functional connectivity in TLE patients with and without DP. Methods: Resting‐state functional MRI data were obtained in 60 TLE patients and 32 matched healthy controls. Patients were further divided into two groups: TLE with DP (TLE + DP, 31 patients) and TLE without DP (TLP‐DP, 29 patients). We explored functional gradient alterations in the cerebellum based on cerebellar–cerebral functional connectivity and combined with independent component analysis to evaluate cerebellar–cerebral functional integration and reveal the contribution of the motor components to the gradient. Results: There were no obvious differences in clinical features and postoperative seizure outcomes between TLE + DP and TLE‐DP patients. Patients and controls all showed a clear unimodal‐to‐transmodal gradient transition in the cerebellum, while TLE patients demonstrated an extended principal gradient in functional connectivity compared to healthy controls, which was more limited in TLE + DP patients. Gradient alterations were more widespread in TLE‐DP patients, involving bilateral cerebellum, while gradient alterations in TLE + DP patients were limited in the cerebellum ipsilateral to the seizure focus. In addition, more cerebellar motor components contributed to the gradient alterations in TLE + DP patients, mainly in ipsilateral cerebellum. Significance: Extended cerebellar principal gradients in functional connectivity revealed excessive functional segregation between unimodal and transmodal systems in TLE. The functional connectivity gradients were more limited in TLE + DP patients. Functional connectivity in TLE patients with dystonic posturing involved more contribution of cerebellar motor function to ipsilateral cerebellar gradient. Plain Language Summary: Dystonic posturing contralateral to epileptic focus is a common symptom in temporal lobe epilepsy, and the cerebellum may be involved in its generation. In this study, we found cerebellar gradients alterations in functional connectivity in temporal lobe epilepsy patients with and without contralateral dystonic posturing. In particular, we found that TLE patients with dystonic posturing may have more limited cerebellar gradient in functional connectivity, involving more contribution of cerebellar motor function to ipsilateral cerebellar gradient. Our study suggests a close relationship between ipsilateral cerebellum and contralateral dystonic posturing. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is the most common form of medically-intractable epilepsy. Subicular hyperexcitability is frequently observed with TLE, presumably caused by impaired inhibition of local excitatory neurons. Here, we evaluated the effectiveness of silencing subicular pyramidal neurons to treat a rodent model of TLE. First, we generated a chronic TLE mouse model via initial intrahippocampal kainic acid (IHKA) injection. In the chronic state after first IHKA injection, behavioral seizures and histological abnormalities were reliably observed. We then injected an adeno-associated viral (AAV) vector carrying an inhibitory chemogenetic element, hM4Di, directly into the subiculum. Eight weeks after the first IHKA injection, acute seizures were induced by giving a second dose of kainic acid (KA), which mimicked generalized tonic–clonic seizures. Herein, precise control over generalized tonic–clonic seizure onset was achieved via this two-step process. We found that chemogenetic suppression of subicular pyramidal neurons had a robust anti-epileptogenesis effect in this acute-chronic model of TLE. These data confirm a crucial role of the subiculum in the propagation of hippocampal seizures and highlight the potential for using subicular chemogenetic manipulation to treat generalized tonic–clonic seizures. [ABSTRACT FROM AUTHOR]

Background: This study compares Selective Amygdalohippocampectomy (SAHE) and Anterior Temporal Lobectomy (ATL) for temporal lobe epilepsy (TLE), focusing on seizure control and visual field deficits (VFD). While previous research suggests potential benefits of SAHE, this meta-analysis aims to clarify the comparative effectiveness of bothprocedures. Methods: This study adhered to PRISMA guidelines, comparing seizure outcomes and VFDs between SAHE and ATL for temporal lobe epilepsy. Comprehensive data extraction and meta-analysis revealed comparable efficacy, with SAHE potentially offering advantages in VFD risk reduction. Quality assessment ensured methodological rigor. Results: 29 studies comparing SAHE and ATL for TLE. Seizure freedom analysis encompassed 23 studies (n = 3238), showing no significant difference between SAHE and ATL (RR = 0.96, 95% CI = 0.89–1.03, P = 0.26). SAHE exhibited significantly lower visual field deficits (RR = 0.87, 95% CI = 0.78–0.97, P = 0.01). Subgroup analyses highlighted differences between transsylvian SAHE and ATL but not transcortical SAHE. No significant difference was found in seizure freedom between SAHE and ATL in patients with hippocampal sclerosis. Conclusions: ATL is more effective than transsylvian SAHE in achieving seizure freedom. However, no significant difference in seizure freedom was observed between transcortical SAHE and ATL. There were no notable differences in seizure outcomes between the two techniques in patients with hippocampal sclerosis. In contrast, SAHE carries a lower risk of postoperative visual field deficits compared to ATL. [ABSTRACT FROM AUTHOR]

Background: Transcranial direct current stimulation (tDCS) has recently become a novel and non-invasive treatment option for refractory epilepsy. Previous systematic reviews have suggested that tDCS may be effective in treating epilepsy, this study presents the first meta-analysis on its effectiveness. Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science for relevant randomized controlled trials (RCTs) from database inception to May 2024. The Cochrane risk of bias tool RoB2.0 was used to assess the risk of bias. Primary outcomes included changes in seizure frequency from baseline and the proportion of patients with a ≥50% reduction in seizure frequency. Results: Of the 608 studies initially identified, 14 were finally included. The pooled results from the random-effects model indicated that tDCS significantly reduced seizure frequency (WMD 0.41, 95% CI 0.24, 0.59). Further subgroup analysis revealed that tDCS significantly reduced seizure frequency in temporal lobe epilepsy, and seizure frequency was more alleviated in studies that had treatment sessions of fewer than 5 times, and followed up within 2 months' post-treatment. Only four studies provided data on patients with a ≥50% reduction in seizure frequency, showing no significant difference (RR 2.96, 95% CI 0.85, 10.32). In the systematic review, three studies analyzed cognitive function changes after tDCS treatment, but none reported significant improvements. The most common side effect during tDCS treatment was transient tingling, and no patients required additional life-support measures due to side effects. Conclusion: The current meta-analysis on available trials indicates that tDCS can effectively reduce seizure frequency in the short term and is well-tolerated. However, its impact on cognitive improvement in epilepsy patients requires further investigation. Systematic review registration: https://inplasy.com/inplasy-2024-6-0033/, identifier INPLASY202460033. [ABSTRACT FROM AUTHOR]

Background/Objectives: In this study, a medical decision support system is presented to assist physicians in epileptic focus detection by correlating MRI and EEG data of temporal lobe epilepsy patients. Methods: By exploiting the asymmetry in the hippocampus in MRI images and using voxel-based morphometry analysis, gray matter reduction in the temporal and limbic lobes is detected, and epileptic focus prediction is realized. In addition, an epileptic focus is also determined by calculating the asymmetry score from EEG channels. Finally, epileptic focus detection was performed by associating MRI and EEG data with a decision tree. Results: The results obtained from the proposed algorithm provide 100% overlap with the physician's finding on the EEG data. Conclusions: MRI and EEG correlation in epileptic focus detection was improved compared with physicians. The proposed algorithm can be used as a medical decision support system for epilepsy diagnosis, treatment, and surgery planning. [ABSTRACT FROM AUTHOR]

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluRI MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Hippocampal sclerosis (HS), the most common pathology associated with temporal lobe epilepsy (TLE), is not always visible on magnetic resonance imaging (MRI), causing surgical delays and reduced postsurgical seizure‐freedom. We developed an open‐source software to characterize and localize HS to aid the presurgical evaluation of children and adults with suspected TLE.We included a multicenter cohort of 365 participants (154 HS; 90 disease controls; 121 healthy controls). HippUnfold was used to extract morphological surface‐based features and volumes of the hippocampus from T1‐weighted MRI scans. We characterized pathological hippocampi in patients by comparing them to normative growth charts and analyzing within‐subject feature asymmetries. Feature asymmetry scores were used to train a logistic regression classifier to detect and lateralize HS. The classifier was validated on an independent multicenter cohort of 275 patients with HS and 161 healthy and disease controls.HS was characterized by decreased volume, thickness, and gyrification alongside increased mean and intrinsic curvature. The classifier detected 90.1% of unilateral HS patients and lateralized lesions in 97.4%. In patients with MRI‐negative histopathologically‐confirmed HS, the classifier detected 79.2% (19/24) and lateralized 91.7% (22/24). The model achieved similar performances on the independent cohort, demonstrating its ability to generalize to new data. Individual patient reports contextualize a patient's hippocampal features in relation to normative growth trajectories, visualise feature asymmetries, and report classifier predictions.Automated and Interpretable Detection of Hippocampal Sclerosis (AID‐HS) is an open‐source pipeline for detecting and lateralizing HS and outputting clinically‐relevant reports. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Clinical studies have shown that epileptic seizures worsen Alzheimer's disease (AD) pathology and related cognitive deficits; however, the underlying mechanism is unclear. To assess the effects of seizures on the progression of AD, chronic temporal lobe epilepsy was induced in five familial AD mutation (5×FAD) mice by kindling with the chemoconvulsant pentylenetetrazole (PTZ) at 3–3.5 months of age. The amyloidogenic pathway, tauopathy, synaptic damage, neuronal death, neurological inflammatory response and associated kinase signaling pathway dysregulation were examined at 9 months of age. We found that APP, p-APP, BACE1, Aβ and kinase-associated p-tau levels were elevated after PTZ kindling in 5×FAD mice. In addition, PTZ kindling exacerbated hippocampal synaptic damage and neuronal cell death, as determined by scanning electron microscopy and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, respectively. Finally, the levels of the neuroinflammation markers GFAP and Iba1, as well as the inflammatory cytokine IL-1β, were increased after PTZ insult. PTZ kindling profoundly exacerbated extracellular regulated kinase (ERK)-death-associated protein kinase (DAPK) signaling pathway overactivation, and acute ERK inhibitor treatment downregulated Aβ production and p-APP and p-tau levels in epileptic 5×FAD mice. In addition, long-term use of the antiseizure drug carbamazepine (CBZ) alleviated seizure-induced accelerated amyloid and tau pathology and ERK-DAPK overactivation in 5×FAD mice. Collectively, these results demonstrate that seizure-induced increases in AD-like neuropathology in 5×FAD mice are partially regulated by the ERK-DAPK pathway, suggesting that the ERK-DAPK axis could be a new therapeutic target for the treatment of AD patients with comorbid seizures. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Riluzole exhibits neuroprotective and therapeutic effects in several neurological disease models associated with excessive synaptic glutamate (Glu) release. We recently showed riluzole prevents acute excitotoxic hippocampal neural injury at 3 days in the kainic acid (KA) model of temporal lobe epilepsy (TLE). Currently, it is unknown if preventing acute neural injury and the neuroinflammatory response is sufficient to suppress epileptogenesis. Methods: The KA rat model of TLE was used to determine if riluzole attenuates acute hippocampal neural injury and reactive gliosis. KA was administered to adult male Sprague-Dawley (250 g) rats at 5 mg/kg/hr until status epilepticus (SE) was observed, and riluzole was administered at 10 mg/kg 1 h and 4 h after SE and once per day for the next 2 days. Immunostaining was used to assess neural injury (FJC and NeuN), microglial activation (Iba1 and ED-1/CD68) and astrogliosis (GFAP and vimentin) at day 7 and day 14 after KA-induced SE. Learning and memory tests (Y-maze, Novel object recognition test, Barnes maze), behavioral hyperexcitability tests, and spontaneous generalized recurrent seizure (SRS) activity (24-hour video monitoring) were assessed at 11–15 weeks. Results: Here we show that KA-induced hippocampal neural injury precedes the neuroimmune response and that riluzole attenuates acute neural injury, microglial activation, and astrogliosis at 7 and 14 days. We find that reducing acute hippocampal injury and the associated neuroimmune response following KA-induced SE by riluzole attenuates hippocampal-dependent cognitive impairment, behavioral hyperexcitability, and tonic/clonic generalized SRS activity after 3 months. We also show that riluzole attenuates SE-associated body weight loss during the first week after KA-induced SE. Discussion: Riluzole acts on multiple targets that are involved to prevent excessive synaptic Glu transmission and excitotoxic neuronal injury. Attenuating KA-induced neural injury and subsequent microglia/astrocyte activation in the hippocampus and extralimbic regions with riluzole reduces TLE-associated cognitive deficits and generalized SRS and suggests that riluzole could be a potential antiepileptogenic drug. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)‐AS‐1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.(R)‐AS‐1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents. The effect of (R)‐AS‐1 on glutamate uptake was assessed in COS‐7 cells expressing the transporter. WAY 213613, a selective competitive EAAT2 inhibitor, was used to probe the reversal of the enhanced glutamate uptake in the same transporter expression system. Confocal microscopy and Western blotting analyses were used to study a potential influence of (R)‐AS‐1 on GLT‐1 expression in mice.(R)‐AS‐1 showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock‐ and 6 Hz‐induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine‐resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, (R)‐AS‐1 displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. (R)‐AS‐1 enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT‐1 expression in vivo was observed after repeated treatment.Collectively, our results show that (R)‐AS‐1 has favorable tolerability and provides robust preclinical efficacy against seizures. Thus, allosteric enhancement of EAAT2 function could offer a novel therapeutic strategy for treatment of epilepsy and potentially other neurological disorders associated with glutamate excitotoxicity. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Mesial temporal lobe epilepsy (mTLE) is a debilitating disease characterized by recurrent seizures originating from temporal lobe structures such as the hippocampus. The pathogenic mechanisms underlying mTLE are incompletely understood but include changes in the expression of non-coding RNAs in affected brain regions. Previous work indicates that some of these changes may be selective to specific sub-cellular compartments, but the full extent of these changes and how these sub-cellular compartments themselves are affected remains largely unknown. Here, we performed small RNA sequencing (RNA-seq) of sub-cellular fractions of hippocampal tissue from mTLE patients and controls to determine nuclear and cytoplasmic expression levels of microRNAs (miRNAs). This showed differential expression of miRNAs and isomiRs, several of which displayed enriched nuclear expression in mTLE. Subsequent analysis of miR-92b, the most strongly deregulated miRNA in the nucleus, showed accumulation of this miRNA in the nucleolus in mTLE and association with snoRNAs. This prompted us to further study the nucleolus in human mTLE which uncovered several defects, such as altered nucleolar size or shape, mis-localization of nucleolar proteins, and deregulation of snoRNAs, indicative of nucleolar stress. In a rat model of epilepsy, nucleolar phenotypes were detected in the latency period before the onset of spontaneous seizures, suggesting that nucleolar changes may contribute to the development of seizures and mTLE. Overall, these data for the first time implicate nucleolar defects in the pathogenesis of mTLE and provide a valuable framework for further defining the functional consequences of altered sub-cellular RNA profiles in this disease. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Anterior temporal lobe resection (ATLR) is an effective treatment for drug‐resistant temporal lobe epilepsy (TLE), although language deficits may occur after both left and right ATLR. Functional reorganization of the language network has been observed in the ipsilateral and contralateral hemispheres within 12 months after ATLR, but little is known of longer‐term plasticity effects. Our aim was to examine the plasticity of language functions up to a decade after ATLR, in relation to cognitive profiles.We examined 24 TLE patients (12 left [LTLE]) and 10 controls across four time points: pre‐surgery, 4 months, 12 months, and ~9 years post‐ATLR. Participants underwent standard neuropsychological assessments (naming, phonemic, and categorical fluency tests) and a verbal fluency functional magnetic resonance imaging (fMRI) task. Using a flexible factorial design, we analyzed longitudinal fMRI activations from 12 months to ~9 years post‐ATLR, relative to controls, with separate analyses for people with hippocampal sclerosis (HS). Change in cognitive profiles was correlated with the long‐term change in fMRI activations to determine the “efficiency” of reorganized networks.LTLE patients had increased long‐term engagement of the left extra‐temporal and contralateral temporal regions, with better language performance linked to bilateral activation. Those with HS exhibited more widespread bilateral activations. RTLE patients showed plasticity in the left extra‐temporal regions, with better language outcomes associated with these areas. Both groups of patients achieved cognitive stability over 9 years, with more than 50% of LTLE patients improving. Older age, longer epilepsy duration, and lower pre‐operative cognitive reserve negatively affected long‐term language performance.Neuroplasticity continues for up to ~9 years post‐epilepsy surgery in LTLE and RTLE, with effective language recovery linked to bilateral engagement of temporal and extra‐temporal regions. This adaptive reorganization is associated with improved cognitive outcomes, challenging the traditional view of localized surgery effects. These findings emphasize the need for early intervention, tailored pre‐operative counseling, and the potential for continued cognitive gains with extended post‐ATLR rehabilitation. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance This study was undertaken to analyze the histology underlying increased T2 signal intensity (iT2SI) in anterior temporal lobe white matter (aTLWM) epilepsy due to hippocampal sclerosis (TLE/HS).Twenty‐three patients were included: 16 with increased T2 signal in the aTLWM and seven with HS only. Magnetic resonance imaging (MRI) findings were consistent across two neuroradiologists (kappa = .89, p < .001). Quantification of neuronal cells, astrocytes, oligodendrocytes, and vacuolization in the white matter of temporal lobe specimens was performed by immunohistochemistry (neuronal nuclear antigen, glial fibrillary acidic protein, oligodendrocyte transcription factor, and basic myelin protein, respectively). Surgical specimens from TLE/HS patients with and without iT2SI in the aTLWM were compared. Samples of aTLWM were divided into three groups, according to MRI features: G1 = samples of iT2SI, G2 = samples with normal T2 signal intensity from patients without white matter imaging abnormalities, and G3 = samples with normal T2 signal intensity adjacent to areas with iT2SI.Patients with increased T2 signal had a significantly younger age at epilepsy onset (p < .035). Histological analysis revealed a higher percentage of vacuolar area in these patients (p < .004) along with a lower number of ectopic neurons (p = .042). No significant differences were found in astrocyte or oligodendrocyte counts among groups.A higher proportion of vacuoles in regions with iT2SI may be the histopathologic substrate of this signal alteration in the white matter of the temporal lobe in patients with TLE/HS. This method of quantifying vacuoles using digital image analysis proved reliable and cost‐effective. [ABSTRACT FROM AUTHOR]

Background Objectives Animals Methods Results Conclusions and Clinical Importance Lesions causing refractory epilepsy, often associated with temporal lobe epilepsy (TLE), can be undetectable on standard magnetic resonance imaging (MRI) in dogs. Automated brain volumetry, widely used in human medicine, can now be applied in veterinary medicine because of the availability of brain atlases.This study aimed to develop an automatic volumetry method, translate the outcomes into the assessment of temporal lobe volumes in dogs with idiopathic epilepsy, and correlate the results with the electroencephalography (EEG) data of epileptiform discharges (EDs).Thirty‐one dogs of various breeds with dominant temporal lobe discharge.Retrospective, observational study. The MRI and EEG examination results of dogs referred for neurological diagnosis data between 2016 and 2021 were retrospectively analyzed. An automated volumetry method was developed, which allowed the evaluation of temporal lobe volumes of the dogs. The asymmetric ratio (AR) was then estimated, and the results were correlated with the EEG EDs.12/31 (38%; 95% CI: 21.8%‐57.8%) dogs had an asymmetric ratio >6%. Among them, reduction in temporal lobe volumes correlated with the side of the EEG EDs in 7 cases. There was no statistical correlation between temporal lobe volume changes and ED location.Preliminary volumetric analysis of the temporal lobes indicates the presence of volume differences between the lobes in some dogs with idiopathic epilepsy. Diagnosis of TLE in dogs based on MRI volumetry in correlation with EEG examination, especially for dogs with drug‐resistant epilepsy, can influence the development of new therapeutic options, such as surgery. [ABSTRACT FROM AUTHOR]

The study analyzed the impact of SEEG-guided RFTC on brain connectivity in patients with drug-resistant epilepsy, finding alterations in brain connectivity post-RFTC. Bexicaserin showed a reduction in motor seizures in patients with DEEs, supporting further investigation as a potential treatment. A network-based approach successfully predicted DRE in children based on their first EEG recording, highlighting the potential for early identification and personalized treatment strategies. The study on FND aimed to address misconceptions and stigma associated with the disorder, providing a more nuanced understanding of FND through evolutionary psychology principles. Gene therapy targeting GABAA receptors showed promise in enhancing the response to AEDs in treating epilepsy, suggesting a potential therapeutic strategy. [Extracted from the article]

Anterior temporal lobectomy (ATL) is the most common surgical treatment for temporal lobe epilepsy (TLE), and Stereoelectroencephalography (SEEG) plays a critical role in precisely localizing the epileptogenic zone (EZ). This study aimed to explore the effect of SEEG on the long-term outcomes of different side ATL. From March 2012 to February 2020, a retrospective analysis was conducted on 231 TLE patients who underwent standard ATL surgery. According to the surgical sides and the utilization of SEEG during preoperative evaluation, the patients were categorized into 4 groups, with a follow-up period exceeding 2 years. Among the 231 TLE patients, the probability of being seizure-free 2 years after the surgery was 80.52%, which decreased to 65.65% after 5 years. There was no significant difference in outcomes between SEEG and non-SEEG patients. For overall and non-SEEG patients, there was no significant difference in short-term outcomes between different surgical sides. However, the long-term outcomes of right ATL patients were significantly better than left. Interestingly, for patients who underwent SEEG, there was no significant difference in both short-term and long-term outcomes between different surgical sides. Some TLE patients encounter challenges in localizing the EZ through noninvasive evaluation, necessitating the use of SEEG for precise localization. Furthermore, their seizure outcomes after surgery can be the same with the patients who have a clear EZ in noninvasive evaluation. And SEEG patients can achieve a more stable long-term prognosis than non-SEEG patients. [ABSTRACT FROM AUTHOR]

Objective: E2730, an uncompetitive γ‐aminobutyric acid (GABA) transporter‐1 (GAT‐1) inhibitor, has potent anti‐seizure effects in a rodent model of chronic temporal lobe epilepsy, the kainic acid status epilepticus (KASE) rat model. In this study, we examined purported neuroimaging and physiological surrogate biomarkers of the effect of E2730 on brain GABAergic function. Methods: We conducted a randomized cross‐over study, incorporating 1‐week treatments with E2730 (100 mg/kg/day subcutaneous infusion) or vehicle in epileptic post‐KASE rats. KASE rats underwent serial 9.4 T magnetic resonance spectroscopy (MRS) measuring GABA and other brain metabolites, [18F]Flumazenil positron emission tomography (PET) quantifying GABAA receptor availability, quantitative electroencephalography (qEEG) and transcranial magnetic stimulation (TMS)–mediated motor activity, as well as continuous video‐EEG recording to measure spontaneous seizures during each treatment. Age‐matched, healthy control animals treated with E2730 or vehicle were also studied. Results: E2730 treatment significantly reduced spontaneous seizures, with 8 of 11 animals becoming seizure‐free. MRS revealed that E2730‐treated animals had significantly reduced taurine levels. [18F]Flumazenil PET imaging revealed no changes in GABA receptor affinity or density during E2730 treatment. The power of gamma frequency oscillations in the EEG was decreased significantly in the auditory cortex and hippocampus of KASE and control rats during E2730 treatment. Auditory evoked gamma frequency power was enhanced by E2730 treatment in the auditory cortex of KASE and healthy controls, but only in the hippocampus of KASE rats. E2730 did not influence motor evoked potentials triggered by TMS. Significance: This study identified clinically relevant changes in multimodality imaging and functional purported biomarkers of GABAergic activity during E2730 treatment in epileptic and healthy control animals. These biomarkers could be utilized in clinical trials of E2730 and potentially other GABAergic drugs to provide surrogate endpoints, thereby reducing the cost of such trials. [ABSTRACT FROM AUTHOR]

Objective: The single‐center retrospective cohort study investigated underlying pathogenic mechanisms and clinical significance of patients with temporal lobe epilepsy and hippocampal sclerosis (TLE‐HS), in the presence/absence of gray–white matter abnormalities (usually called "blurring"; GMB) in ipsilateral temporopolar region (TPR) on MRI. Methods: The study involved 105 patients with unilateral TLE‐HS (60 GMB+ and 45 GMB−) who underwent standard anterior temporal lobectomy, along with 61 healthy controls. Resected specimens were examined under light microscope. With combined T1‐weighted and DTI data, we quantitatively compared large‐scale morphometric features and exacted diffusion parameters of ipsilateral TPR‐related superficial and deep white matter (WM) by atlas‐based segmentation. Along‐tract analysis was added to detect heterogeneous microstructural alterations at various points along deep WM tracts, which were categorized into inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and temporal cingulum. Results: Comparable seizure semiology and postoperative seizure outcome were found, while the GMB+ group had significantly higher rate of HS Type 1 and history of febrile seizures, contrasting with significantly lower proportion of interictal contralateral epileptiform discharges, HS Type 2, and increased wasteosomes in hippocampal specimens. Similar morphometric features but greater WM atrophy with more diffusion abnormalities of superficial WM was observed adjacent to ipsilateral TPR in the GMB+ group. Moreover, microstructural alterations resulting from temporopolar GMB were more localized in temporal cingulum while evenly and widely distributed along ILF and UF. Interpretation: Temporopolar GMB could signify more severe and widespread microstructural damage of white matter rather than a focal cortical lesion in TLE‐HS, affecting selection of surgical procedures. [ABSTRACT FROM AUTHOR]

The epileptogenic network in temporal lobe epilepsy (TLE) contains structures of the primary and secondary olfactory cortex such as the piriform and entorhinal cortex, the amygdala, and the hippocampus. Olfactory auras and olfactory dysfunction are relevant symptoms of TLE. This study aims to characterize olfactory function in TLE using olfactory testing and olfactory functional magnetic resonance imaging (fMRI). We prospectively enrolled 20 individuals with unilateral TLE (age 45 ± 20 years [mean ± SD], 65% female, 90% right‐handed) and 20 healthy individuals (age 33 ± 15 years [mean ± SD], 35% female, 90% right‐handed). In the TLE group, the presumed seizure onset zone was left‐sided in 75%; in 45% of the individuals with TLE limbic encephalitis was the presumed etiology; and 15% of the individuals with TLE reported olfactory auras. Olfactory function was assessed with a Screening Sniffin' Sticks Test (Burkhart, Wedel, Germany) during a pre‐assessment. During a pre‐testing, all individuals were asked to rate the intensity, valence, familiarity, and associated memory of five different odors (eugenol, vanillin, phenethyl alcohol, decanoic acid, valeric acid) and a control solution. During the fMRI experiment, all individuals repeatedly smelled eugenol (positively valenced odor), valeric acid (negatively valenced odor), and the control solution and were asked to rate odor intensity on a five‐point Likert scale. We acquired functional EPI sequences and structural images (T1, T2, FLAIR). Compared to healthy individuals, individuals with TLE rated the presented odors as more neutral (two‐sided Mann–Whitney U tests, FDR‐p < 0.05) and less familiar (two‐sided Mann–Whitney U tests, FDR‐p < 0.05). fMRI data analysis revealed a reduced response contrast in secondary olfactory areas (e.g., hippocampus) connected to the limbic system when comparing eugenol and valeric acid in individuals with TLE when compared with healthy individuals. However, no lateralization effect was obtained when calculating a lateralization index by the number of activated voxels in the olfactory system (two‐sided Mann–Whitney U test; U = 176.0; p = 0.525). TLE is characterized by olfactory dysfunction and associated with hypoactivation of secondary olfactory structures connected to the limbic system. These findings contribute to our understanding of the pathophysiology of TLE. This study was preregistered on OSF Registries (www.osf.io). [ABSTRACT FROM AUTHOR]

Declarative memory encompasses episodic and semantic divisions. Episodic memory captures singular events with specific spatiotemporal relationships, whereas semantic memory houses context-independent knowledge. Behavioural and functional neuroimaging studies have revealed common and distinct neural substrates of both memory systems, implicating mesiotemporal lobe (MTL) regions such as the hippocampus and distributed neocortices. Here, we explored declarative memory system reorganization in patients with unilateral temporal lobe epilepsy (TLE) as a human disease model to test the impact of variable degrees of MTL pathology on memory function. Our cohort included 31 patients with TLE and 60 age- and sex-matched healthy controls, and all participants underwent episodic and semantic retrieval tasks during a multimodal MRI session. The functional MRI tasks were closely matched in terms of stimuli and trial design. Capitalizing on non-linear connectome gradient-mapping techniques, we derived task-based functional topographies during episodic and semantic memory states, in both the MTL and neocortical networks. Comparing neocortical and hippocampal functional gradients between TLE patients and healthy controls, we observed a marked topographic reorganization of both neocortical and MTL systems during episodic memory states. Neocortical alterations were characterized by reduced functional differentiation in TLE across lateral temporal and midline parietal cortices in both hemispheres. In the MTL, in contrast, patients presented with a more marked functional differentiation of posterior and anterior hippocampal segments ipsilateral to the seizure focus and pathological core, indicating perturbed intrahippocampal connectivity. Semantic memory reorganization was also found in bilateral lateral temporal and ipsilateral angular regions, whereas hippocampal functional topographies were unaffected. Furthermore, leveraging MRI proxies of MTL pathology, we observed alterations in hippocampal microstructure and morphology that were associated with TLE-related functional reorganization during episodic memory. Moreover, correlation analysis and statistical mediation models revealed that these functional alterations contributed to behavioural deficits in episodic memory, but again not in semantic memory in patients. Altogether, our findings suggest that semantic processes rely on distributed neocortical networks, whereas episodic processes are supported by a network involving both the hippocampus and the neocortex. Alterations of such networks can provide a compact signature of state-dependent reorganization in conditions associated with MTL damage, such as TLE. [ABSTRACT FROM AUTHOR]

Temporal Lobe Epilepsy (TLE) is a severe neurological condition characterized by recurrent seizures that often do not respond well to available anti-seizure medications. TLE has been associated with epileptogenesis, a process that starts during the latent period following a neurologic insult and is followed by chronic phase. Recent research has linked canonical Wnt signaling to the pathophysiology of epileptogenesis and TLE. Our previous study demonstrated differential regulation of canonical Wnt signaling during early and late stage post status epilepticus (SE) induction. Building on these findings, our current study utilized Wnt modulators: GSK-3β inhibitor 6-bromoindirubin-3'-oxime (6-Bio) and disheveled inhibitor niclosamide and investigated their impact on canonical Wnt signaling during the early (30 days) and later stages (60 days) following SE induction. We assessed several parameters, including seizure frequency, astrogliosis, synaptic density, and neuronal counts in hippocampal tissue. We used immunohistochemistry and Nissl staining to evaluate gliosis, synaptic density, and neuronal counts in micro-dissected hippocampi. Western blotting was used to examine the expression of proteins involved in canonical Wnt/β-catenin signaling, and real-time PCR was conducted to analyze their relative mRNA expression. Wnt modulators, 6-Bio and Niclosamide were found to reduce seizure frequency and various other parameters including behavioral parameters, hippocampal morphology, astrogliosis and synaptic density at different stages of TLE. [ABSTRACT FROM AUTHOR]

Objectives: To explore the relationship between glymphatic dysfunction and cognitive impairment in unilateral temporal lobe epilepsy (TLE). Methods: This 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). Results: Compared 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). Conclusion: These 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. [ABSTRACT FROM AUTHOR]

Background: P-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. Methods: Eight 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). Results: DRE 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 registration: EudraCT 2019-003137-42. Registered 28 February 2020. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy （TLE） is a common type of epilepsy. It may lead to cognitive impairment when it becomes recurrent. However, how it happens remains unclear. Recently, noninvasive resting-state functional magnetic resonance imaging （rs-fMRI） has been used comprehensively in the clinical diagnosis of temporal lobe epilepsy-associated cognitive impairment for its high temporal and spatial resolution. To better understand the effectiveness of rs-fMRI in the diagnosis, his paper reviews the relevant literature, comprehensively analyzing the epileptogenic foci localization and neural network alterations displayed by rs-fMRI and exploring the insight to the mechanism of temporal lobe epilepsy-associated cognitive impairment. Moreover, the paper has discussed the rs-fMRI's potential in predicting surgical outcomes and machine learning applications. This review is hoped to be conducive to improving treatment outcomes and providing novel approaches for more precise and intelligent interventions in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: People with epilepsy (PWE) have been hypothesized to have higher prevalence of personality disorders and cognitive disorders. The objective of this study was to investigate the controversial notion of “epileptic personality,” a series of supposedly specific personality traits of people with epilepsy (PWE). Methods: For this purpose, 29 individuals with Mesial Temporal lobe Epilepsy (MTLE) and 23 with Juvenile myoclonic epilepsy (JME) as confirmed by electroencephalography (EEG), MRI scans and clinical examination, underwent a thorough neuropsychological and personality assessment. The resulting neuropsychological profiles were statistically analyzed considering possible personality disorders, character traits, cognitive and linguistic deviations from 20 healthy controls (HC). Results: Our findings suggest accumulative cognitive and linguistic deficits in individuals with epilepsy compared to controls. It is possible that these might be misinterpreted as personality disorders. Specifically, personality traits (p  =  0.049) and verbal fluency (p  =  0.013), were significantly different between PWEs and controls. Also, the type of epilepsy and lateralization seem to affect executive function (p  =  0.049) and pragmatology scores (p  <  0.001), exhibiting differences in subgroup analysis. Discussion: Different theories are considered as plausible pathophysiological explanations for the aforementioned differences. This research might serve as a basis to further investigate the cognitive aspects of epilepsy and possible pharmacological interventions, which are currently lacking. [ABSTRACT FROM AUTHOR]

Central and systemic inflammation play pivotal roles in epileptogenesis and proepileptogenesis in temporal lobe epilepsy (TLE). The interplay between peripheral CD4+ T cells and central microglia orchestrates the "systemic‐central" immune response in TLE. However, the precise molecular mechanisms linking central and systemic inflammation in TLE remain unknown. This preliminary findings revealed an imbalance in Th1/Th2 subsets in the periphery，accompanied by related cytokines release in TLE patients. they proposed that this peripheral Th1/Th2 imbalance may influence central inflammation by mediating microglial state dynamics within epileptic foci and distant brain regions. In Li‐pilocarpine‐induced TLE rats, a peripheral Th1/Th2 imbalance and observed corresponding central and systemic responses is confirmed. Notably, CD4+ T cells infiltrated through the compromised blood‐brain barrierand are spatially close to microglia around epileptic foci. Intravenous depletion and reinfusion of CD4+ T cells modulated microglia state dynamics and altered neuroinflammatory cytokines secretion. Moreover, mRNA sequencing of the human hippocampus identified Notch1 as a key regulator of Th1/Th2 differentiation, CD4+ T cell recruitment to brain infiltration sites, and the regulation of microglial responses, seizure frequency, and cognition. This study underscores the significance of Th1/Th2 imbalance in modulating the "systemic‐central" response in TLE, highlighting Notch1 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: In conclusion, this bibliometric study reveals a surge in epilepsymicroglia 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. [ABSTRACT FROM AUTHOR]

The article discusses a case report of a 36-year-old male with drug-resistant post-traumatic epilepsy who achieved seizure freedom without medication after stereoelectroencephalography (sEEG) implantation. The patient underwent sEEG monitoring, which captured a single event without sEEG correlate, prompting further investigation. Despite discontinuing all seizure medications, the patient remained seizure-free for over 3.5 years. The article highlights the potential benefits and risks of sEEG procedures in drug-resistant epilepsy cases, emphasizing the need for further research into potential tissue injury caused by depth electrode insertion. [Extracted from the article]

Objective Methods Results Significance 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. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) has identified epilepsy as a significant public health issue that requires urgent attention. Epilepsy is a neurological disorder that affects millions of people worldwide and can lead to social, economic, and health challenges. The WHO emphasizes the need for improved awareness, diagnosis, treatment, and support for individuals with epilepsy. Neurosurgical interventions for epilepsy include removing or altering brain regions that generate seizures or implanting devices to regulate abnormal electrical activity. These interventions have advanced with technologies such as robotic assistance and neuromodulation devices. Neurosurgical treatment can significantly improve the quality of life for patients with drug-resistant epilepsy, even leading to complete seizure freedom. However, there are risks and challenges associated with these interventions, and careful patient selection and support are crucial. The future of epilepsy management may involve advances in neurotechnology, a focus on comorbidities, and continued research and clinical trials. The goal is to empower individuals with epilepsy to lead meaningful lives through personalized medicine, innovative treatments, and compassionate care. [Extracted from the article]

Background: Mesial temporal lobe epilepsy (MTLE) epileptiform discharges have been reported to arise from the hippocampus or the extrahippocampal medial temporal cortex, such as the amygdala, and then propagate to the temporal lobe cortex. The surgical ablation of which of these structures would result in a better postoperative outcome is debatable. Objective: To assess the possible factors that might have influenced the postoperative outcome of a group of drug-resistant mesial MTLE patients who underwent stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC). Design: Single-center, retrospective. Methods: The present study utilized a pre- and postoperative gray matter voxel-by-voxel ablation mapping comparison approach, along with a white matter mapping of longitudinal changes in the native space technique, to evaluate the association between the post-SEEG implantation signal recordings (obtained from clinically relevant electrode contacts used during RFTC) and the post-RFTC ablation volume of the different selected regions of interest (ROIs). Results: The study included 22 patients (12 men and 10 women, mean age 28.86 ± 14.04 years). Sixteen patients (72.72%) were seizure-free (SF), and six patients (27.27%) were non-SF. Five patients (22.72%) experienced mild side effects following RFTC. The post-RFTC follow-up period varied from 12 to 48 months, with an average of 24.17 ± 9.86 months. The SF group was associated with a higher number of implanted electrode contacts in the amygdala that were used during RFTC, a larger preoperative volume of the amygdala; a larger ablation volume of both the amygdala and rhinal cortex. The ablation volume of the white matter was statistically similar between both groups. Conclusion: This study provides valuable insights into the significance of the amygdala and rhinal cortex as ROIs in the preoperative evaluation of patients with MTLE. Future implantation scheme plans should consider evaluating the preoperative volume of these ROIs. Additionally, increasing the number of electrode contacts implanted within these regions might be beneficial to capture more clinically relevant signals and enhance their ablation volume. [ABSTRACT FROM AUTHOR]

Background: Visual perception of face images or face pareidolia can be evaluated with event-related potentials (ERP) for healthy subjects and patients with neurological conditions. In this study, we aimed to analyse event-related potential components such as P100, N100, N170, and vertex-positive potential (VPP) in response to face pareidolia perception in temporal lobe epilepsy (TLE) patients. Methods: ERPs were recorded during the pareidolia test. Waveforms were analzyed and current source density (CSD) maps were generated. Results: CSD profiles were shown to be interpretable when face and face pareidolia conditions. N100, P100, and N170 components showed larger amplitudes and longer latency in epilepsy patients in response to face pareidolia stimuli compared to real face images. However, the N170 component latency did not differ significantly between epilepsy patients and healthy participants, while the larger amplitude and longer latency of N100 and P100 responses were evoked in healthy patients. Conclusions: Our results indicate a difference in the neural mechanisms of processing real face information and pareidolia face-like information in TLE patients. [ABSTRACT FROM AUTHOR]

Gamma oscillation regularity (GOR) indicates the synchronization of inhibitory interneurons, while the reactivity of cortico-cortical evoked potentials (CCEPs) is supposed to reflect local cortical excitability. Under the assumption that the early response of CCEP near the stimulation site also indicates excitatory activity primarily mediated by pyramidal cells, we aimed to visualize the cortical inhibitory and excitatory activities using GOR and CCEP in combination and to use them to predict the epileptogenic zone (EZ) in mesial temporal lobe epilepsy (MTLE). In five patients who underwent intracranial electrode implantation, GOR and CCEP reactivity in the vicinity of the stimulation site was quantified. The interictal GOR was calculated using multiscale entropy (MSE), the decrease of which was related to the enhanced GOR. These parameters were compared on an electrode-and-electrode basis, and spatially visualized on the brain surface. As a result, elevated GOR and CCEP reactivities, indicative of enhanced inhibitory and excitatory activities, were observed in the epileptogenic regions. Elevated CCEP reactivity was found to be localized to a restricted area centered on the seizure onset region, whereas GOR elevation was observed in a broader region surrounding it. Although these parameters independently predicted the EZ with high specificity, we combined the two to introduce a novel parameter, the excitatory and inhibitory (EI) index. The EI index predicted EZ with increased specificity compared with GOR or CCEP reactivity alone. Our results demonstrate that GOR and CCEP reactivity provided a quantitative visualization of the distribution of cortical inhibitory and excitatory activities and highlighted the relationship between the two parameters. The combination of GOR and CCEP reactivities are expected to serve as biomarkers for localizing the epileptogenic zone in MTLE from interictal intracranial electroencephalograms. [ABSTRACT FROM AUTHOR]

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE. [ABSTRACT FROM AUTHOR]

Executive function (EF) deficits are common in epilepsy and impact quality of life. This study compares EF in idiopathic generalized epilepsy (IGE) and temporal lobe epilepsy (TLE) patients to healthy controls. Fifty-six IGE patients, 56 TLE patients, and 60 controls (matched by age) completed cognitive tests assessing attention, memory, learning, and verbal fluency. Both epilepsy groups performed worse than controls, with TLE patients showing significantly poorer verbal learning and memory compared to IGE patients. These findings suggest that TLE patients have more severe EF impairments, likely due to focal temporal lobe dysfunction and disruptions in EF networks. [ABSTRACT FROM AUTHOR]

Background/Objectives: Although the involvement of progressive brain alterations in epilepsy was recently suggested, individual patients' trajectories of white matter (WM) disruption are not known. Methods: We investigated the disease progression patterns of WM damage and its associations with clinical metrics. We examined the cross-sectional diffusion tensor imaging (DTI) data of 155 patients with unilateral temporal lobe epilepsy (TLE) and 270 age/gender-matched healthy controls, and we then calculated the average fractional anisotropy (FA) values within 20 WM tracts of the whole brain. We used the Subtype and Stage Inference (SuStaIn) program to detect the progression trajectory of FA changes and investigated its association with clinical parameters including onset age, disease duration, drug-responsiveness, and the number of anti-seizure medications (ASMs). Results: The SuStaIn algorithm identified a single subtype model in which the initial damage occurs in the ipsilateral uncinate fasciculus (UF), followed by damage in the forceps, superior longitudinal fasciculus (SLF), and anterior thalamic radiation (ATR). This pattern was replicated when analyzing TLE with hippocampal sclerosis (n = 50) and TLE with no lesions (n = 105) separately. Further-progressed stages were associated with longer disease duration (p < 0.001) and a greater number of ASMs (p = 0.001). Conclusions: the disease progression model based on WM tracts may be useful as a novel individual-level biomarker. [ABSTRACT FROM AUTHOR]

Background: Temporal lobe epilepsy (TLE), a prevalent chronic neurological disorder, affects millions of individuals and is often resistant to anti‐epileptic drugs. Increasing evidence has shown that acetylcholine (ACh) and cholinergic neurotransmission play a role in the pathophysiology of epilepsy. Tropisetron, an antiemetic drug used for chemotherapy in clinic, has displayed potential in the treatment of Alzheimer's disease, depression, and schizophrenia in animal models. However, as a partial agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), whether tropisetron possesses the therapeutic potential for TLE has not yet been determined. Methods: In this study, tropisetron was intraperitoneally injected into pilocarpine‐induced epileptic rats for 3 weeks. Alpha‐bungarotoxin (α‐bgt), a specific α7nAChR antagonist, was applied to investigate the mechanism of tropisetron. Rats were assessed for spontaneous recurrent seizures (SRS) and cognitive function using video surveillance and Morris's water maze testing. Hippocampal impairment and synaptic structure were evaluated by Nissl staining, immunohistochemistry, and Golgi staining. Additionally, the levels of glutamate, γ‐aminobutyric acid (GABA), ACh, α7nAChRs, neuroinflammatory cytokines, glucocorticoids and their receptors, as well as synapse‐associated protein (F‐actin, cofilin‐1) were quantified. Results: The results showed that tropisetron significantly reduced SRS, improved cognitive function, alleviated hippocampal sclerosis, and concurrently suppressed synaptic remodeling and the m6A modification of cofilin‐1 in TLE rats. Furthermore, tropisetron lowered glutamate levels without affecting GABA levels, reduced neuroinflammation, and increased ACh levels and α7nAChR expression in the hippocampi of TLE rats. The effects of tropisetron treatment were counteracted by α‐bgt. Conclusion: In summary, these findings indicate that tropisetron exhibits an anti‐epileptic effect and provides neuroprotection in TLE rats through the activation of α7nAChRs. The potential mechanism may involve the reduction of glutamate levels, enhancement of cholinergic transmission, and suppression of synaptic remodeling. Consequently, the present study not only highlights the potential of tropisetron as an anti‐epileptic drug but also identifies α7nAChRs as a promising therapeutic target for the treatment of TLE. [ABSTRACT FROM AUTHOR]

Objective: The piriform cortex is considered to be highly epileptogenic. Its resection during epilepsy surgery is a predictor for postoperative seizure freedom in temporal lobe epilepsy. Epilepsy is associated with a dysfunction of the blood–brain barrier. We investigated blood–brain barrier dysfunction in the piriform cortex of people with temporal lobe epilepsy using quantitative T1‐relaxometry. Methods: Gadolinium‐based contrast agent was administered ictally and interictally in 37 individuals before undergoing quantitative T1‐relaxometry. Postictal and interictal images were co‐registered, and subtraction maps were created as biomarkers for peri‐ictal (∆qT1interictal‐postictal) and interictal (∆qT1noncontrast‐interictal) blood–brain barrier dysfunction. Values were extracted for the piriform cortex, hippocampus, amygdala, and the whole cortex. Results: In temporal lobe epilepsy (n = 14), ∆qT1noncontrast‐interictal was significantly higher in the piriform cortex than in the whole cortex (p = 0.02). In extratemporal lobe epilepsy (n = 23), ∆qT1noncontrast‐interictal was higher in the hippocampus than in the whole cortex (p = 0.05). Across all individuals (n = 37), duration of epilepsy was correlated with ∆qT1noncontrast‐interictal (ß = 0.001, p < 0.001) in all regions, while the association was strongest in the piriform cortex. Impaired verbal memory was associated with ∆qT1noncontrast‐interictal only in the piriform cortex (p = 0.04). ∆qT1interictal‐postictal did not show differences in any region. Interpretation: Interictal blood–brain barrier dysfunction occurs in the piriform cortex in temporal lobe epilepsy. This dysfunction is linked to longer disease duration and worse cognitive deficits, emphasizing the central role of the piriform cortex in the epileptogenic network of temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]