Verbal memory network mapping in individual patients predicts postoperative functional impairments.

Verbal memory decline is a significant concern following temporal lobe surgeries in patients with epilepsy, emphasizing the need for precision presurgical verbal memory mapping to optimize functional outcomes. However, the inter-individual variability in functional networks and brain function-structural dissociations pose challenges when relying solely on group-level atlases or anatomical landmarks for surgical guidance. Here, we aimed to develop and validate a personalized functional mapping technique for verbal memory using precision resting-state functional MRI (rs-fMRI) and neurosurgery. A total of 38 patients with refractory epilepsy scheduled for surgical interventions were enrolled and 28 patients were analyzed in the study. Baseline 30-min rs-fMRI scanning, verbal memory and language assessments were collected for each patient before surgery. Personalized verbal memory networks (PVMN) were delineated based on preoperative rs-fMRI data for each patient. The accuracy of PVMN was assessed by comparing post-operative functional impairments and the overlapping extent between PVMN and surgical lesions. A total of 14 out of 28 patients experienced clinically meaningful declines in verbal memory after surgery. The personalized network and the group-level atlas exhibited 100% and 75.0% accuracy in predicting postoperative verbal memory declines, respectively. Moreover, six patients with extra-temporal lesions that overlapped with PVMN showed selective impairments in verbal memory. Furthermore, the lesioned ratio of the personalized network rather than the group-level atlas was significantly correlated with postoperative declines in verbal memory (personalized networks: r = -0.39, p = .038; group-level atlas: r = -0.19, p = .332). In conclusion, our personalized functional mapping technique, using precision rs-fMRI, offers valuable insights into individual variability in the verbal memory network and holds promise in precision verbal memory network mapping in individuals.

A multiscale symbolic approach to decoding delta and ripple oscillation bands as biomarkers for epileptiform discharges.

We use a multiscale symbolic approach to study the complex dynamics of temporal lobe refractory epilepsy employing high-resolution intracranial electroencephalogram (iEEG). We consider the basal and preictal phases and meticulously analyze the dynamics across frequency bands, focusing on high-frequency oscillations up to 240 Hz. Our results reveal significant periodicities and critical time scales within neural dynamics across frequency bands. By bandpass filtering neural signals into delta, theta, alpha, beta, gamma, and ripple high-frequency bands (HFO), each associated with specific neural processes, we examine the distinct nonlinear dynamics. Our method introduces a reliable approach to pinpoint intrinsic time lag scales τ within frequency bands of the basal and preictal signals, which are crucial for the study of refractory epilepsy. Using metrics such as permutation entropy (H), Fisher information (F), and complexity (C), we explore nonlinear patterns within iEEG signals. We reveal the intrinsic τmax that maximize complexity within each frequency band, unveiling the nonlinear subtle patterns of the temporal structures within the basal and preictal signal. Examining the H×F and C×F values allows us to identify differences in the delta band and a band between 200 and 220 Hz (HFO 6) when comparing basal and preictal signals. Differences in Fisher information in the delta and HFO 6 bands before seizures highlight their role in capturing important system dynamics. This offers new perspectives on the intricate relationship between delta oscillations and HFO waves in patients with focal epilepsy, highlighting the importance of these patterns and their potential as biomarkers.

Lateralizing value and clinicoradiological features of asymmetric last clonic jerks in temporal and extratemporal epilepsy.

Seizure semiology and electroencephalograph (EEG) are very important for determining seizure type, hemisphere lateralization, or localization. Clinical symptoms of focal seizures, as well as findings at the onset or end of a focal to bilateral tonic-clonic seizure (FBTCS), are highly informative for lateralization. This study aimed to investigate the relationship of asymmetric last clonic jerk in patients with temporal or extratemporal lobe epilepsy with pathologies, localization, lateralization, or other semiological findings detected in neuroimaging or neuro psychometric tests and its positive predictive value for the detection of hemisphere lateralization based on seizure onset ictal EEG activation. 44 patients with asymmetric last clonic jerks (aLCJ) who were followed up in our VEM unit were randomized 1:1 with epilepsy patients without. In patients with ipsilateral automatism and contralateral posture or gustatory and olfactory hallucinations aLCJ was less or absent. In patients with unilateral tonic activity, aLCJ was more common. The positive predictive value of aLCJ for ictal EEG activation lateralization was 86.36%. In conclusion, asymmetric last clonic beat is valuable for lateralization of FBTCS and should be considered. Its presence strongly and reliably lateralizes to the side of seizure onset.

Neurocognition in Pediatric Temporal Lobe Tumor-Related Epilepsy.

Tumor-related epilepsy is a common and understudied neurological comorbidity among pediatric temporal lobe tumor patients that poses risk for neurocognitive impairment (NCI). Forty-one youth with either TLT+ (n = 23) or nonneoplastic temporal lobe epilepsy (n = 18) ages 6-20 years completed routine neuropsychological evaluations. Rates of NCI were similar across groups; however, NCI was more common in nonneoplastic participants on a task of phonemic fluency, p = .047. Younger age of seizure onset and greater number of antiseizure medications were associated with NCI among TLT+ participants only. Preliminary findings suggest separate prognostic models of cognitive outcomes between TLT+ and nonneoplastic epilepsy populations may be needed.

The fasciola cinereum of the hippocampal tail as an interventional target in epilepsy.

Targeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of six patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy.

Atypical connectome topography and signal flow in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common pharmaco-resistant epilepsy in adults. While primarily associated with mesiotemporal pathology, recent evidence suggests that brain alterations in TLE extend beyond the paralimbic epicenter and impact macroscale function and cognitive functions, particularly memory. Using connectome-wide manifold learning and generative models of effective connectivity, we examined functional topography and directional signal flow patterns between large-scale neural circuits in TLE at rest. Studying a multisite cohort of 95 patients with TLE and 95 healthy controls, we observed atypical functional topographies in the former group, characterized by reduced differentiation between sensory and transmodal association cortices, with most marked effects in bilateral temporo-limbic and ventromedial prefrontal cortices. These findings were consistent across all study sites, present in left and right lateralized patients, and validated in a subgroup of patients with histopathological validation of mesiotemporal sclerosis and post-surgical seizure freedom. Moreover, they were replicated in an independent cohort of 30 TLE patients and 40 healthy controls. Further analyses demonstrated that reduced differentiation related to decreased functional signal flow into and out of temporolimbic cortical systems and other brain networks. Parallel analyses of structural and diffusion-weighted MRI data revealed that topographic alterations were independent of TLE-related cortical thinning but partially mediated by white matter microstructural changes that radiated away from paralimbic circuits. Finally, we found a strong association between the degree of functional alterations and behavioral markers of memory dysfunction. Our work illustrates the complex landscape of macroscale functional imbalances in TLE, which can serve as intermediate markers bridging microstructural changes and cognitive impairment.

Bilateral glymphatic dysfunction and its association with disease duration in unilateral temporal lobe epilepsy patients with hippocampal sclerosis.

OBJECTIVE: In this study, the diffusion tensor imaging along perivascular space analysis (DTI-ALPS) technique was utilized to evaluate the functional changes in the glymphatic system of the bilateral hemispheres in patients with unilateral temporal lobe epilepsy (TLE) accompanied by hippocampal sclerosis (HS). The aim was to gain insights into the alterations in the glymphatic system function in TLE patients. METHODS: A total of 61 unilateral TLE patients with HS and 53 healthy controls (HCs) from the Department of Neurosurgery at Xiangya Hospital were included in the study. All subjects underwent DTI using the same 3 T MR Scanner, and the DTI-ALPS index was calculated. Differences in the DTI-ALPS index between TLE patients and HCs were evaluated, along with the correlation between the DTI-ALPS index of TLE and clinical features of epilepsy. These features included age, age of onset, seizure duration, and neuropsychological scores. RESULTS: Compared to the bilateral means of the HCs, both the ipsilateral and contralateral DTI-ALPS index of the TLE patients were significantly decreased (TLE ipsilateral 1.41 ± 0.172 vs. HC bilateral mean: 1.49 ± 0.116, p = 0.006; TLE contralateral: 1.42 ± 0.158 vs. HC bilateral mean: 1.49 ± 0.116, p = 0.015). The ipsilateral DTI-ALPS index in TLE patients showed a significant negative correlation with disease duration (r = -0.352, p = 0.005). CONCLUSIONS: The present study suggests the presence of bilateral dysfunctions in the glymphatic system and also highlight a laterality feature in these dysfunctions. Additionally, the study found a significant negative correlation between the ipsilateral DTI-ALPS index and disease duration, underscoring the significance of early effective interventions and indicating potential for the development of innovative treatments targeting the glymphatic system.

Quantitative analysis of visually normal EEG reveals spectral power abnormalities in temporal lobe epilepsy.

OBJECTIVE: To compare quantitative spectral parameters of visually-normal EEG between Mesial Temporal Lobe Epilepsy (MTLE) patients and healthy controls (HC). METHOD: We enrolled 26 MTLE patients and 26 HC. From each recording we calculated total power of all frequency bands and determined alpha-theta (ATR) and alpha-delta (ADR) power ratios in different brain regions. Group-wise differences between spectral parameters were investigated (p < 0.05). To test for associations between spectral-power and cognitive status, we evaluated correlations between neuropsychological tests and quantitative EEG (qEEG) metrics. RESULTS: In all comparisons, ATR and ADR were significantly decreased in MTLE patients compared to HC, particularly over the hemisphere ipsilateral to epileptic activity. A positive correlation was seen in MTLE patients between ATR in ipsilateral temporal lobe, and results of neuropsychological tests of auditory verbal learning (RAVLT and RAVLT-D), short term verbal memory (Digit span backwards), and executive function (Weigl's sorting test). ADR values in the contralateral posterior region correlated positively with RAVLT-D and Digit span backwards tests. DISCUSSION: Results confirmed that the power spectrum of qEEG is shifted towards lower frequencies in MTLE patients compared to HC. CONCLUSION: Of note, our results were found in visually-normal recordings, providing further evidence of the value of qEEG for longitudinal monitoring of MTLE patients over time. Exploratory analysis of associations between qEEG and neuropsychological data suggest this could be useful for investigating effects of antiseizure medications on cognitive integrity in patients.

Characterization of the intrahippocampal kainic acid model in female mice with a special focus on seizure suppression by antiseizure medications.

Despite special challenges in the medical treatment of women with epilepsy, in particular preclinical animal studies were focused on males for decades and females have only recently moved into the focus of scientific interest. The intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy (TLE) is one of the most studied models in males reproducing electroencephalographic (EEG) and histopathological features of human TLE. Hippocampal paroxysmal discharges (HPDs) were described as drug resistant focal seizures in males. Here, we investigated the IHKA model in female mice, in particular drug-resistance of HPDs and the influence of antiseizure medications (ASMs) on the power spectrum. After injecting kainic acid (KA) unilaterally into the hippocampus of female mice, we monitored the development of epileptiform activity by local field potential (LFP) recordings. Subsequently, we evaluated the effect of the commonly prescribed ASMs lamotrigine (LTG), oxcarbazepine (OXC) and levetiracetam (LEV), as well as the benzodiazepine diazepam (DZP) with a focus on HPDs and power spectral analysis and assessed neuropathological alterations of the hippocampus. In the IHKA model, female mice replicated key features of human TLE as previously described in males. Importantly, HPDs in female mice did not respond to commonly prescribed ASMs in line with the drug-resistance in males, thus representing a suitable model of drug-resistant seizures. Intriguingly, we observed an increased occurrence of generalized seizures after LTG. Power spectral analysis revealed a pronounced increase in the delta frequency range after the higher dose of 30 mg/kg LTG. DZP abolished HPDs and caused a marked reduction over a wide frequency range (delta, theta, and alpha) of the power spectrum. By characterizing the IHKA model of TLE in female mice we address an important gap in basic research. Considering the special challenges complicating the therapeutic management of epilepsy in women, inclusion of females in preclinical studies is imperative. A well-characterized female model is a prerequisite for the development of novel therapeutic strategies tailored to sex-specific needs and for studies on the effect of epilepsy and ASMs during pregnancy.

Circadian changes in aperiodic activity are correlated with seizure reduction in patients with mesial temporal lobe epilepsy treated with responsive neurostimulation.

OBJECTIVES: Responsive neurostimulation (RNS) is an established therapy for drug-resistant epilepsy that delivers direct electrical brain stimulation in response to detected epileptiform activity. However, despite an overall reduction in seizure frequency, clinical outcomes are variable, and few patients become seizure-free. The aim of this retrospective study was to evaluate aperiodic electrophysiological activity, associated with excitation/inhibition balance, as a novel electrographic biomarker of seizure reduction to aid early prognostication of the clinical response to RNS. METHODS: We identified patients with intractable mesial temporal lobe epilepsy who were implanted with the RNS System between 2015 and 2021 at the University of Utah. We parameterized the neural power spectra from intracranial RNS System recordings during the first 3 months following implantation into aperiodic and periodic components. We then correlated circadian changes in aperiodic and periodic parameters of baseline neural recordings with seizure reduction at the most recent follow-up. RESULTS: Seizure reduction was correlated significantly with a patient's average change in the day/night aperiodic exponent (r = .50, p = .016, n = 23 patients) and oscillatory alpha power (r = .45, p = .042, n = 23 patients) across patients for baseline neural recordings. The aperiodic exponent reached its maximum during nighttime hours (12 a.m. to 6 a.m.) for most responders (i.e., patients with at least a 50% reduction in seizures). SIGNIFICANCE: These findings suggest that circadian modulation of baseline broadband activity is a biomarker of response to RNS early during therapy. This marker has the potential to identify patients who are likely to respond to mesial temporal RNS. Furthermore, we propose that less day/night modulation of the aperiodic exponent may be related to dysfunction in excitation/inhibition balance and its interconnected role in epilepsy, sleep, and memory.

Low frequency stimulation for seizure suppression: Identification of optimal targets in the entorhinal-hippocampal circuit.

BACKGROUND: Mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is a common form of drug-resistant focal epilepsy in adults. Treatment for pharmacoresistant patients remains a challenge, with deep brain stimulation (DBS) showing promise for alleviating intractable seizures. This study explores the efficacy of low frequency stimulation (LFS) on specific neuronal targets within the entorhinal-hippocampal circuit in a mouse model of MTLE. OBJECTIVE: Our previous research demonstrated that LFS of the medial perforant path (MPP) fibers in the sclerotic hippocampus reduced seizures in epileptic mice. Here, we aimed to identify the critical neuronal population responsible for this antiepileptic effect by optogenetically stimulating presynaptic and postsynaptic compartments of the MPP-dentate granule cell (DGC) synapse at 1 Hz. We hypothesize that specific targets for LFS can differentially influence seizure activity depending on the cellular identity and location within or outside the seizure focus. METHODS: We utilized the intrahippocampal kainate (ihKA) mouse model of MTLE and targeted specific neural populations using optogenetic stimulation. We recorded intracranial neuronal activity from freely moving chronically epileptic mice with and without optogenetic LFS up to 3 h. RESULTS: We found that LFS of MPP fibers in the sclerotic hippocampus effectively suppressed epileptiform activity while stimulating principal cells in the MEC had no impact. Targeting DGCs in the sclerotic septal or non-sclerotic temporal hippocampus with LFS did not reduce seizure numbers but shortened the epileptiform bursts. CONCLUSION: Presynaptic stimulation of the MPP-DGC synapse within the sclerotic hippocampus is critical for seizure suppression via LFS.

Ictal Central Apnea Is Predictive of Mesial Temporal Seizure Onset: An Intracranial Investigation.

OBJECTIVE: Ictal central apnea (ICA) is a semiological sign of focal epilepsy, associated with temporal and frontal lobe seizures. In this study, using qualitative and quantitative approaches, we aimed to assess the localizational value of ICA. We also aimed to compare ICA clinical utility in relation to other seizure semiological features of focal epilepsy. METHODS: We analyzed seizures in patients with medically refractory focal epilepsy undergoing intracranial stereotactic electroencephalographic (SEEG) evaluations with simultaneous multimodal cardiorespiratory monitoring. A total of 179 seizures in 72 patients with reliable artifact-free respiratory signal were analyzed. RESULTS: ICA was seen in 55 of 179 (30.7%) seizures. Presence of ICA predicted a mesial temporal seizure onset compared to those without ICA (odds ratio = 3.8, 95% confidence interval = 1.3-11.6, p = 0.01). ICA specificity was 0.82. ICA onset was correlated with increased high-frequency broadband gamma (60-150Hz) activity in specific mesial or basal temporal regions, including amygdala, hippocampus, and fusiform and lingual gyri. Based on our results, ICA has an almost 4-fold greater association with mesial temporal seizure onset zones compared to those without ICA and is highly specific for mesial temporal seizure onset zones. As evidence of symptomatogenic areas, onset-synchronous increase in high gamma activity in mesial or basal temporal structures was seen in early onset ICA, likely representing anatomical substrates for ICA generation. INTERPRETATION: ICA recognition may help anatomoelectroclinical localization of clinical seizure onset to specific mesial and basal temporal brain regions, and the inclusion of these regions in SEEG evaluations may help accurately pinpoint seizure onset zones for resection. ANN NEUROL 2024;95:998-1008.

Low-frequency Stimulation at the Subiculum Prevents Extensive Secondary Epileptogenesis in Temporal Lobe Epilepsy.

Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary focus. It is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy, but still lacks effective treatments. Here, we aimed to test the effects of low-frequency stimulation (LFS) at the subiculum for secondary epileptogenesis in a mouse model. Here, secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling stimuli. Mice kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive mice. LFS at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex, characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary foci. Only application along with the primary epileptogenesis was effective. Notably, the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary foci. These results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance.

Reduced eye gaze fixation during emotion recognition among patients with temporal lobe epilepsy.

OBJECTIVES: To investigate the facial scan patterns during emotion recognition (ER) through the dynamic facial expression task and the awareness of social interference test (TASIT) using eye tracking (ET) technology, and to find some ET indicators that can accurately depict the ER process, which is a beneficial supplement to existing ER assessment tools. METHOD: Ninety-six patients with TLE and 88 healthy controls (HCs) were recruited. All participants watched the dynamic facial expression task and TASIT including a synchronized eye movement recording and recognized the emotion (anger, disgust, happiness, or sadness). The accuracy of ER was recorded. The first fixation time, first fixation duration, dwell time, and fixation count were selected and analyzed. RESULTS: TLE patients exhibited ER impairment especially for disgust (Z = - 3.391; p = 0.001) and sadness (Z = - 3.145; p = 0.002). TLE patients fixated less on the face, as evidenced by the reduced fixation count (Z = - 2.549; p = 0.011) of the face and a significant decrease in the fixation count rate (Z = - 1.993; p = 0.046). During the dynamic facial expression task, TLE patients focused less on the eyes, as evidenced by the decreased first fixation duration (Z = - 4.322; p = 0.000), dwell time (Z = - 4.083; p = 0.000), and fixation count (Z = - 3.699; p = 0.000) of the eyes. CONCLUSION: TLE patients had ER impairment, especially regarding negative emotions, which may be attributable to their reduced fixation on the eyes during ER, and the increased fixation on the mouth could be a compensatory effect to improve ER performance. Eye-tracking technology could provide the process indicators of ER, and is a valuable supplement to traditional ER assessment tasks.

Imaging visuospatial memory in temporal lobe epilepsy-Results of an fMRI study.

PURPOSE: Impairment of cognitive functions is commonly observed in temporal lobe epilepsy (TLE). The aim of this study was to assess visuospatial memory functions and memory-related networks using an adapted version of Roland's Hometown Walking (RHWT) functional MRI (fMRI) task in patients with TLE. METHODS: We used fMRI to study activation patterns based on a visuospatial memory paradigm in 32 TLE patients (9 right; 23 left) and also within subgroups of lesional and non-lesional TLE. To test for performance, a correlational analysis of fMRI activation patterns and out-of-scanner neuropsychological visuospatial memory testing was performed. Additionally, we assessed memory-related networks using functional connectivity (FC). RESULTS: Greater contralateral than ipsilateral mesiotemporal (parahippocampal gyrus/hippocampus) activation was observed in left (n = 23)/right (n = 9) TLE. In lesional left TLE (n = 17), significant activations were seen in right more than left mesiotemporal areas (parahippocampal gyrus), while non-lesional left TLE patients (n = 6) showed significant bilateral (left>right) activations in mesiotemporal structures (parahippocampal gyrus). In left TLE, visuospatial cognitive testing correlated with fMRI activations in left (parahippocampal gyrus) and right mesiotemporal structures (hippocampus), characterized by greater fMRI activation being associated with better memory scores. In right TLE, higher scores in visuospatial memory testing were associated with greater fMRI activations in left and right insular regions. FC patterns of memory-related networks differ in right and left TLE. CONCLUSION: While TLE in general leads to asymmetrical mesiotemporal activation, lesion-induced and non-lesional TLE patients reveal different memory fMRI activation patterns. In right TLE, insular regions try to compensate for impaired right mesiotemporal structures during the performance of visuospatial tasks. Underlying functional visuospatial memory networks differ in right and left TLE.

Investigation of synapses in the cortical white matter in human temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is one of the most common focal pharmacotherapy-resistant epilepsy in adults. Previous studies have shown significantly higher numbers of neurons in the neocortical white matter in TLE patients than in controls. The aim of this work was to investigate whether white matter neurons are part of the neuronal circuitry. Therefore, we studied the distribution and density of synapses in surgically resected neocortical tissue of pharmacotherapy-resistant TLE patients. Neocortical white matter of temporal lobe from non-epileptic patients were used as controls. Synapses and neurons were visualized with immunohistochemistry using antibodies against synaptophysin and NeuN, respectively. The presence of synaptophysin in presynaptic terminals was verified by electron microscopy. Quantification of immunostaining was performed and the data of the patients' cognitive tests as well as clinical records were compared to the density of neurons and synapses. Synaptophysin density in the white matter of TLE patients was significantly higher than in controls. In TLE, a significant correlation was found between synaptophysin immunodensity and density of white matter neurons. Neuronal as well as synaptophysin density significantly correlated with scores of verbal memory of TLE patients. Neurosurgical outcome of TLE patients did not significantly correlate with histological data, although, higher neuronal and synaptophysin densities were observed in patients with favorable post-surgical outcome. Our results suggest that white matter neurons in TLE patients receive substantial synaptic input and indicate that white matter neurons may be integrated in epileptic neuronal networks responsible for the development or maintenance of seizures.

Oral glutamine supplementation increases seizure severity in a rodent model of mesial temporal lobe epilepsy.

Background: Glutamine synthetase (GS) is the only enzyme known to synthesize significant amounts of glutamine in mammals, and loss of GS in the hippocampus has been implicated in the pathophysiology of medication refractory mesial temporal lobe epilepsy (MTLE). Moreover, loss-of-function mutations of the GS gene causes severe epileptic encephalopathy, and supplementation with glutamine has been shown to normalize EEG and possibly improve the outcome in these patients. Here we examined whether oral glutamine supplementation is an effective treatment for MTLE by assessing the frequency and severity of seizures after supplementation in a translationally relevant model of the disease.Methods: Male Sprague Dawley rats (380-400 g) were allowed to drink unlimited amounts of glutamine in water (3.6% w/v; n = 8) or pure water (n = 8) for several weeks. Ten days after the start of glutamine supplementation, GS was chronically inhibited in the hippocampus to induce MTLE. Continuous video-intracranial EEG was collected for 21 days to determine the frequency and severity of seizures.Results: While there was no change in seizure frequency between the groups, the proportion of convulsive seizures was significantly higher in glutamine treated animals during the first three days of GS inhibition.Conclusion: The results suggest that oral glutamine supplementation transiently increases seizure severity in the initial stages of an epilepsy model, indicating a potential role of the amino acid in seizure propagation and epileptogenesis.

A novel LGI1 mutation causing autosomal dominant lateral temporal lobe epilepsy confirmed by a precise knock-in mouse model.

AIMS: This study aimed to explore the pathomechanism of a mutation on the leucine-rich glioma inactivated 1 gene (LGI1) identified in a family having autosomal dominant lateral temporal lobe epilepsy (ADLTE), using a precise knock-in mouse model. METHODS AND RESULTS: A novel LGI1 mutation, c.152A>G; p. Asp51Gly, was identified by whole exome sequencing in a Chinese family with ADLTE. The pathomechanism of the mutation was explored by generating Lgi1D51G knock-in mice that precisely phenocopied the epileptic symptoms of human patients. The Lgi1D51G/D51G mice showed spontaneous recurrent generalized seizures and premature death. The Lgi1D51G/+ mice had partial epilepsy, with half of them displaying epileptiform discharges on electroencephalography. They also showed enhanced sensitivity to the convulsant agent pentylenetetrazole. Mechanistically, the secretion of Lgi1 was impaired in the brain of the D51G knock-in mice and the protein level was drastically reduced. Moreover, the antiepileptic drugs, carbamazepine, oxcarbazepine, and sodium valproate, could prolong the survival time of Lgi1D51G/D51G mice, and oxcarbazepine appeared to be the most effective. CONCLUSIONS: We identified a novel epilepsy-causing mutation of LGI1 in humans. The Lgi1D51G/+ mouse model, precisely phenocopying epileptic symptoms of human patients, could be a useful tool in future studies on the pathogenesis and potential therapies for epilepsy.

Effects of perampanel on cognitive behavior and GluR1 expression in immature mice of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) has a low antiepileptic drug (AED) treatment response rate, and about 70% of patients eventually progress to refractory epilepsy. Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, which is used clinically for the treatment of partially refractory epilepsy, but its mechanism of action is not completely clear. In this study, kainic acid (KA) was successfully used to induce TLE in 3-week-old C57BL/6 immature mice, and the effects of PER on the cognitive behavior of the epileptic mice were characterized using the Morris water maze paradigm. To determine the mechanism underlying the therapeutic effects of PER, the morphological evolution of the hippocampus and the expression of AP-1 and GluR1 were systematically evaluated. Compared to control TLE mice, escape latency was reduced and the number of target platform crossings was increased in the Morris water maze by treatment with PER. The therapeutic effects of PER were mediated mainly via inhibition of the expression of AP-1 and GluR1, as the TLE mice showed significantly improved learning and memory and decreased seizure frequency after treatment with PER.

Impairments of Long-Term Synaptic Plasticity in the Hippocampus of Young Rats during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy.

Status epilepticus (SE) causes persistent abnormalities in the functioning of neuronal networks, often resulting in worsening epileptic seizures. Many details of cellular and molecular mechanisms of seizure-induced changes are still unknown. The lithium-pilocarpine model of epilepsy in rats reproduces many features of human temporal lobe epilepsy. In this work, using the lithium-pilocarpine model in three-week-old rats, we examined the morphological and electrophysiological changes in the hippocampus within a week following pilocarpine-induced seizures. We found that almost a third of the neurons in the hippocampus and dentate gyrus died on the first day, but this was not accompanied by impaired synaptic plasticity at that time. A diminished long-term potentiation (LTP) was observed following three days, and the negative effect of SE on plasticity increased one week later, being accompanied by astrogliosis. The attenuation of LTP was caused by the weakening of N-methyl-D-aspartate receptor (NMDAR)-dependent signaling. NMDAR-current was more than two-fold weaker during high-frequency stimulation in the post-SE rats than in the control group. Application of glial transmitter D-serine, a coagonist of NMDARs, allows the enhancement of the NMDAR-dependent current and the restoration of LTP. These results suggest that the disorder of neuron-astrocyte interactions plays a critical role in the impairment of synaptic plasticity.