Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson's disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.
Mice ; Animals ; Epilepsy, Temporal Lobe/pathology* ; Parvalbumins/metabolism* ; Parkinson Disease/pathology* ; Neurons/metabolism* ; Interneurons/physiology* ; Disease Models, Animal ; Brain/pathology*

Humans ; Epilepsy, Temporal Lobe/surgery* ; Mossy Fibers, Hippocampal ; Brain-Derived Neurotrophic Factor ; Dentate Gyrus

Temporal lobe epilepsy, with a variety of etiological, symptomatic, electrophysiological characteristics, has the highest incidence among all focal epilepsy, and a high rate of progression to refractory epilepsy. Surgery is an effective treatment, but traditional methods are usually difficult to accurately locate the epileptogenic zone, which may be resolved by stereotactic-electroencephalogram(SEEG) technique. Radiofrequency thermocoagulation and MRI-guided laser interstitial thermal therapy based on SEEG provide a new accurate and minimally invasive choice for refractory epilepsy patients with high surgical risk and difficulty.
Drug Resistant Epilepsy/surgery* ; Electrocoagulation/methods* ; Electroencephalography ; Epilepsy, Temporal Lobe/surgery* ; Humans ; Stereotaxic Techniques

BACKGROUND: Deep brain stimulation (DBS) has seizure-suppressing effects but the molecular mechanisms underlying its therapeutic action remain unclear. This study aimed to systematically elucidate the mechanisms underlying DBS-induced seizure suppression at a molecular level. METHODS: We established a macaque model of mesial temporal lobe epilepsy (mTLE), and continuous high-frequency hippocampus DBS (hip-DBS) was applied for 3 months. The effects of hip-DBS on hippocampus gene expression were examined using high-throughput microarray analysis followed by bioinformatics analysis. Moreover, the microarray results were validated using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses. RESULTS: The results showed that chronic hip-DBS modulated the hippocampal gene expression. We identified 4119 differentially expressed genes and assigned these genes to 16 model profiles. Series test of cluster analysis showed that profiles 5, 3, and 2 were the predominant expression profiles. Moreover, profile 5 was mainly involved in focal adhesion and extracellular matrix-receptor interaction pathway. Nine dysregulated genes (Arhgap5, Col1a2, Itgb1, Pik3r1, Lama4, Fn1, Col3a1, Itga9, and Shc4) and three genes (Col1a2, Itgb1, and Flna) in these two pathways were further validated by qRT-PCR and Western blot analyses, respectively, which showed a concordance. CONCLUSION Our findings suggest that hip-DBS could markedly reverse mTLE-induced abnormal gene expression. Findings from this study establish the basis for further investigation of the underlying regulatory mechanisms of DBS for mTLE.
Animals ; Deep Brain Stimulation ; Epilepsy, Temporal Lobe/therapy* ; Hippocampus ; Humans ; Macaca ; Seizures

Entropy model is widely used in epileptic electroencephalogram (EEG) analysis, but there are few reports on how to objectively select the parameters to compute the entropy model in the analysis of resting-state functional magnetic resonance imaging (rfMRI). Therefore, an optimization algorithm to confirm the parameters in multi-scale entropy (MSE) model was proposed, and the location of epileptogenic hemisphere was taken as an example to test the optimization effect by supervised machine learning. The rfMRI data of 20 temporal lobe epilepsy (TLE) patients with hippocampal sclerosis, positive on structural magnetic resonance imaging, were divided into left and right groups. Then, the parameters in MSE model were optimized by the receiver operating characteristic curves (ROC) and area under ROC curve (AUC) values in sensitivity analysis, and the entropy value of the brain regions with statistically significant difference between the groups were taken as sensitive features to epileptogenic hemisphere lateral. The optimized entropy values of these bio-marker brain areas were considered as feature vectors input into the support vector machine (SVM). Finally, combining optimized MSE model with SVM could accurately distinguish epileptogenic hemisphere in TLE at an average accuracy rate of 95%, which was higher than the current level. The results show that the MSE model parameter optimization algorithm can accurately extract the functional imaging markers sensitive to the epileptogenic hemisphere, and achieve the purpose of objectively selecting the parameters for MSE in rfMRI, which provides the basis for the application of entropy in advanced technology detection.
Brain/diagnostic imaging* ; Brain Mapping ; Entropy ; Epilepsy, Temporal Lobe/diagnostic imaging* ; Humans ; Magnetic Resonance Imaging

BACKGROUND: Anterior thalamic nuclei (ATN) deep brain stimulation (DBS) is an effective method of controlling epilepsy, especially temporal lobe epilepsy. Mossy fiber sprouting (MFS) plays an indispensable role in the pathogenesis and progression of epilepsy, but the effect of ATN-DBS on MFS in the chronic stage of epilepsy and the potential underlying mechanisms are unknown. This study aimed to investigate the effect of ATN-DBS on MFS, as well as potential signaling pathways by a kainic acid (KA)-induced epileptic model. METHODS: Twenty-four rhesus monkeys were randomly assigned to control, epilepsy (EP), EP-sham-DBS, and EP-DBS groups. KA was injected to establish the chronic epileptic model. The left ATN was implanted with a DBS lead and stimulated for 8 weeks. Enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining were used to evaluate MFS and levels of potential molecular mediators in the hippocampus. One-way analysis of variance, followed by the Tukey post hoc correction, was used to analyze the statistical significance of differences among multiple groups. RESULTS: ATN-DBS is found to significantly reduce seizure frequency in the chronic stage of epilepsy. The number of ectopic granule cells was reduced in monkeys that received ATN stimulation (P < 0.0001). Levels of 3',5'-cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in the hippocampus, together with Akt phosphorylation, were noticeably reduced in monkeys that received ATN stimulation (P = 0.0030 and P = 0.0001, respectively). ATN-DBS also significantly reduced MFS scores in the hippocampal dentate gyrus and CA3 sub-regions (all P < 0.0001). CONCLUSION ATN-DBS is shown to down-regulate the cAMP/PKA signaling pathway and Akt phosphorylation and to reduce the number of ectopic granule cells, which may be associated with the reduced MFS in chronic epilepsy. The study provides further insights into the mechanism by which ATN-DBS reduces epileptic seizures.
Adenosine Monophosphate ; Anterior Thalamic Nuclei ; Cyclic AMP-Dependent Protein Kinases ; Deep Brain Stimulation ; Epilepsy/therapy* ; Epilepsy, Temporal Lobe/therapy* ; Hippocampus ; Humans ; Mossy Fibers, Hippocampal ; Signal Transduction

OBJECTIVES: To comprehensively analyze the characteristics of cognitive impairment of temporal lobe epilepsy (TLE), and to explore the effects of different lateral patients' cognitive impairment and different clinical factors on cognitive impairment of TLE. METHODS: A total of 84 patients, who met the diagnostic criteria for TLE in the Department of Neurology, Xiangya Hospital, were collected as a patient group, with 36 cases of left TLE and 48 cases of right TLE. A total of 79 healthy volunteers with matching gender, age and education level were selected as a control group. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the scores of Arithmetic Test, Information Test, Digit Symbol Substitution Test (DSST), Block Design Test (BDT), Hayling Test and Verbal Fluency Test (VFT) of the revised Chinese Adult Wechsler Intelligence scale were retrospectively analyzed in the 2 groups.Multiple regression analysis was used to analyze the relationship between the clinical factors and the cognitive impairment score. RESULTS: Compared with the control group, the TLE patient group had low scores in all neuropsychological tests, with significant difference (all CONCLUSIONS There are multiple cognitive domain dysfunctions in TLE, including language, short-term memory, long-term memory, attention, working memory, executive function and visual space function. Left TLE has greater impairment of executive function and right TLE has greater damage in working memory. Long pathography of disease, hippocampal sclerosis and a history of febrile convulsions may lead to more severe cognitive impairment. Earlier identification and earlier intervention are needed to improve prognosis of patients.
Adult ; Cognitive Dysfunction/etiology* ; Epilepsy, Temporal Lobe/complications* ; Executive Function ; Humans ; Neuropsychological Tests ; Retrospective Studies

Regulator of calcineurin 1 (RCAN1) can be induced by an intracellular calcium increase and oxidative stress, which are characteristic features of temporal lobe epilepsy. Thus, we investigated the spatiotemporal expression and cellular localization of RCAN1 protein and mRNA in the mouse hippocampus after pilocarpine-induced status epilepticus (SE). Male C57BL/6 mice were given pilocarpine hydrochloride (280 mg/kg, i.p.) and allowed to develop 2 h of SE. Then the animals were given diazepam (10 mg/kg, i.p.) to stop the seizures and sacrificed at 1, 3, 7, 14, or 28 day after SE. Cresyl violet staining showed that pilocarpine-induced SE resulted in cell death in the CA1 and CA3 subfields of the hippocampus from 3 day after SE. RCAN1 immunoreactivity showed that RCAN1 was mainly expressed in neurons in the shammanipulated hippocampi. At 1 day after SE, RCAN1 expression became detected in hippocampal neuropils. However, RCAN1 signals were markedly enhanced in cells with stellate morphology at 3 and 7 day after SE, which were confirmed to be reactive astrocytes, but not microglia by double immunofluorescence. In addition, real-time reverse transcriptase–polymerase chain reaction showed a significant upregulation of RCAN1 isoform 4 (RCAN1-4) mRNA in the SE-induced hippocampi. Finally, in situ hybridization with immunohistochemistry revealed astrocytic expression of RCAN1-4 after SE. These results demonstrate astrocytic upregulation of RCAN1 and RCAN1-4 in the mouse hippocampus in the acute and subacute phases of epileptogenesis, providing foundational information for the potential role of RCAN1 in reactive astrocytes during epileptogenesis.
Animals ; Astrocytes ; Calcineurin ; Calcium ; Cell Death ; Diazepam ; Epilepsy ; Epilepsy, Temporal Lobe ; Fluorescent Antibody Technique ; Hippocampus ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Male ; Mice ; Microglia ; Neurons ; Neuropil ; Oxidative Stress ; Pilocarpine ; RNA, Messenger ; Seizures ; Status Epilepticus ; Up-Regulation ; Viola

BACKGROUND: Patients with temporal lobe epilepsy (TLE) originating from different seizure onset zones had distinct electrophysiological characteristics and surgical outcomes. In this study, we aimed to investigate the relationship between the origin and prognosis of TLE, and the stereoelectroencephalography (SEEG) features. METHODS: Thirty patients with TLE, who underwent surgical treatment in our functional neurosurgery department from January 2016 to December 2017, were enrolled in this study. All patients underwent anterior temporal lobectomy after an invasive pre-operative evaluation with SEEG. Depending on the epileptic focus location, patients were divided into those with medial temporal lobe seizures (MTLS) and those with lateral temporal lobe seizures (LTLS). The Engel classification was used to evaluate operation effectiveness, and the Kaplan-Meier analysis was used to detect seizure-free duration. RESULTS: The mean follow-up time was 25.7 ± 4.8 months. Effectiveness was 63.3% for Engel I (n = 19), 13.3% for Engel II, 3.3% for Engel III, and 20.0% for Engel IV. According to the SEEG, 60.0% (n = 18) had MTLS, and 40.0% (n = 12) had LTLS. Compared with the MTLS group, the operation age of those with LTLS was significantly greater (26.9 ± 6.9 vs. 29.9 ± 12.5 years, t = -0.840, P = 0.009) with longer epilepsy duration (11.9 ± 6.0 vs. 17.9 ± 12.1 years, t = -1.801, P = 0.038). Patients with MTLS had a longer time interval between ictal onset to seizure (67.3 ± 59.1 s vs. 29.3 ± 24.4 s, t = 2.017, P = 0.008). The most common SEEG ictal pattern was a sharp/spike-wave rhythm in the MTLS group (55.6%) and low-voltage fast activity in the LTLS group (58.3%). Compared with the LTLS group, patients with MTLS had a more favorable prognosis (41.7% vs. 77.8%, P = 0.049). Post-operative recurrence was more likely to occur within three months after the operation for both groups, and there appeared to be a stable long-term outcome. CONCLUSION Patients with MTLS, who accounted for three-fifths of patients with TLE, showed a more favorable surgical outcome.
Anterior Temporal Lobectomy ; Electroencephalography ; Epilepsy, Temporal Lobe/surgery* ; Humans ; Stereotaxic Techniques ; Treatment Outcome