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• P2X7R signaling regulates both glial and neuronal genes during seizures. • P2X7R deficiency in microglia reduces seizure severity and leads to an anti-inflammatory phenotype in microglia during seizures. • P2X7R deficiency in neurons increases seizure severity. • Increased expression of P2X7Rs on GABAergic interneurons reduces seizure severity in acquired and genetic models of epilepsy. The purinergic ATP-gated P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability. P2X7R expression has been shown to be increased in the brain, including both microglia and neurons, in experimental models of epilepsy and patients. To date, the cell type-specific downstream effects of P2X7Rs during seizures remain, however, incompletely understood. Effects of P2X7R signaling on seizures and epilepsy were analyzed in induced seizure models using male mice including the kainic acid model of status epilepticus and pentylenetetrazole model and in male and female mice in a genetic model of Dravet syndrome. RNA sequencing was used to analyze P2X7R downstream signaling during seizures. To investigate the cell type-specific role of the P2X7R during seizures and epilepsy, we generated mice lacking exon 2 of the P2rx7 gene in either microglia (P2rx7 : Cx3cr1 -Cre) or neurons (P2rx7 : Thy-1 -Cre). To investigate the protective potential of overexpressing P2X7R in GABAergic interneurons, P2X7Rs were overexpressed using adeno-associated virus transduction under the mDlx promoter. RNA sequencing of hippocampal tissue from wild-type and P2X7R knock-out mice identified both glial and neuronal genes, in particular genes involved in GABAergic signaling, under the control of the P2X7R following seizures. Mice with deleted P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy, and microglia displayed an anti-inflammatory molecular profile. In contrast, mice lacking P2rx7 in neurons showed a more severe seizure phenotype when compared to epileptic wild-type mice. Analysis of single-cell expression data revealed that human P2RX7 expression is elevated in the hippocampus of patients with temporal lobe epilepsy in excitatory and inhibitory neurons. Functional studies determined that GABAergic interneurons display increased responses to P2X7R activation in experimental epilepsy. Finally, we show that viral transduction of P2X7R in GABAergic interneurons protects against evoked and spontaneous seizures in experimental temporal lobe epilepsy and in mice lacking Scn1a , a model of Dravet syndrome. Our results suggest a dual and opposing action of P2X7R in epilepsy and suggest P2X7R overexpression in GABAergic interneurons as a novel therapeutic strategy for acquired and, possibly, genetic forms of epilepsy. [ABSTRACT FROM AUTHOR]

• Gut structural alterations occur during development of acquired epilepsy in mice. • Microbiota community profiles dynamically change during epilepsy development. • The extent of structural changes and specific taxa correlate with seizure duration. • Rifaximin reverses gut alterations and shortens seizures during early disease development. • Reduced seizure duration by rifaximin correlates with rescue of hilar mossy cells. The gut microbiota is altered in epilepsy and is emerging as a potential target for new therapies. We studied the effects of rifaximin, a gastrointestinal tract-specific antibiotic, on seizures and neuropathology and on alterations in the gut and its microbiota in a mouse model of temporal lobe epilepsy (TLE). Epilepsy was induced by intra-amygdala kainate injection causing status epilepticus (SE) in C57Bl6 adult male mice. Sham mice were injected with vehicle. Two cohorts of SE mice were fed a rifaximin-supplemented diet for 21 days, starting either at 24 h post-SE (early disease stage) or at day 51 post-SE (chronic disease stage). Corresponding groups of SE mice (one each disease stage) were fed a standard (control) diet. Cortical ECoG recording was done at each disease stage (24/7) for 21 days in all SE mice to measure the number and duration of spontaneous seizures during either rifaximin treatment or control diet. Then, epileptic mice ± rifaximin and respective sham mice were sacrificed and brain, gut and feces collected. Biospecimens were used for: (i) quantitative histological analysis of the gut structural and cellular components; (ii) markers of gut inflammation and intestinal barrier integrity by RTqPCR; (iii) 16S rRNA metagenomics analysis in feces. Hippocampal neuronal cell loss was assessed in epileptic mice killed in the early disease phase. Rifaximin administered for 21 days post-SE (early disease stage) reduced seizure duration (p < 0.01) and prevented hilar mossy cells loss in the hippocampus compared to epileptic mice fed a control diet. Epileptic mice fed a control diet showed a reduction of both villus height and villus height/crypt depth ratio (p < 0.01) and a decreased number of goblet cells (p < 0.01) in the duodenum, as well as increased macrophage (Iba1)-immunostaining in the jejunum (p < 0.05), compared to respective sham mice. Rifaximin's effect on seizures was associated with a reversal of gut structural and cellular changes, except for goblet cells which remained reduced. Seizure duration in epileptic mice was negatively correlated with the number of mossy cells (p < 0.01) and with villus height/crypt depth ratio (p < 0.05). Rifaximin-treated epileptic mice also showed increased tight junctions (occludin and ZO-1, p < 0.01) and decreased TNF mRNA expression (p < 0.01) in the duodenum compared to epileptic mice fed a control diet. Rifaximin administered for 21 days in chronic epileptic mice (chronic disease stage) did not change the number or duration of seizures compared to epileptic mice fed a control diet. Chronic epileptic mice fed a control diet showed an increased crypt depth (p < 0.05) and reduced villus height/crypt depth ratio (p < 0.01) compared to respective sham mice. Rifaximin treatment did not affect these intestinal changes. At both disease stages , rifaximin modified α- and β-diversity in epileptic and sham mice compared to respective mice fed a control diet. The microbiota composition in epileptic mice, as well as the effects of rifaximin at the phylum , family and genus levels, depended on the stage of the disease. During the early disease phase, the abundance of specific taxa was positively correlated with seizure duration in epileptic mice. In conclusion, gut-related alterations reflecting a dysfunctional state, occur during epilepsy development in a TLE mouse model. A short-term treatment with rifaximin during the early phase of the disease, reduced seizure duration and neuropathology, and reversed some intestinal changes, strengthening the therapeutic effects of gut-based therapies in epilepsy. [ABSTRACT FROM AUTHOR]

• The APOE gene is associated with TLE, DRE, and LOE. • Patients with the ɛ4 allele have an earlier onset, worse cognition. • Patients with the ɛ4 allele are more likely with a history of febrile convulsion. Epilepsy is one of the most common neurological diseases. Current evidence suggests that the apolipoprotein E (APOE) gene may be related to epilepsy. The purpose was to explore whether the APOE gene is associated with the risk, characteristics, and prognosis of epilepsy. The study was a systematic review and meta -analysis. We searched WANFANG, VIP, CNKI, Embase, CENTRAL, and Medline for relevant studies published in English and Chinese inception up to December 27, 2023. Studies containing both APOE genotypes or at least one type of APOE allele and epilepsy were included. A total of 46 studies were included. Fourteen studies reported APOE genotypes and epilepsy risk (2539 patients and 2847 controls). The meta -analyses showed that the APOE 4 was higher in epilepsy (OR [95 % CI] = 1.32 [1.07, 1.62], I2 = 30 %), the APOE 2 was lower in epilepsy (OR [95 % CI] = 0.73 [0.62, 0.87], I2 = 0 %), and the APOE 3 didn't differ between epilepsy and controls (OR [95 % CI] = 1.01 [0.86, 1.19], I2 = 29 %). Our findings highlight that the risk of epilepsy is different depending on the subtype, with the APOE gene being more associated with temporal lobe epilepsy, drug-refractory epilepsy, and late-onset epilepsy. Patients with the ɛ4 allele have an earlier onset, worse cognition, and are more likely to have a history of febrile convulsion. No association between the ɛ 4 allele and psychiatric symptoms and seizure-free after surgery. These findings will help inform the provision of epilepsy services, including clinical management an important option for epilepsy patients with cognitive impairment, temporal lobe epilepsy, late-onset epilepsy, and drug-refractory epilepsy. However, whether APOE gene testing should be used as a routine test in people with epilepsy remains to be determined. [ABSTRACT FROM AUTHOR]

• Deficient auditory processing in Temporal Epilepsy is evidenced by psychoacoustic and electrophysiological evaluation. • Lack of hearing sensitivity assessment is documented in electrophysiological studies. Hearing efficiency is known to influence and interact with communication and mental health. Hearing impairment may be hidden when co-occurring with neurological disorders. We performed a systematic review and meta -analysis in order to address the following questions: 1) which specific tools of auditory processing show clear deficits, separating Temporal Lobe Epilepsy (TLE) patients from normal controls,2) How well is TLE evaluated in terms of hearing and auditory processing? The study inclusion criteria were: 1) patients diagnosed with temporal lobe epilepsy, 2) presence of a normal control group, 3) auditory processing assessment using auditory stimuli with behavioral tests and/or P300 or Mitch Match Negativity (MMN) latency and/or amplitude, 4) publications written in English, 5) publication date after 2000. 132 articles were retrieved and based on PRISMA & PICO criteria 23 articles were analyzed. Temporal resolution and processing as measured by the behavioral tests of Gaps-In-Noise (GIN) and Duration Pattern Test (DPT) document deficiencies in TLE patients and separate them from normal controls. Electrophysiology as measured by MMN & P300 shows statistically significant differences in TLE patients compared to controls with patients showing deficient auditory processing. A clear difference between studies with psychoacoustic assessment as opposed to electrophysiology ones may be due to lacking or incomplete evaluation of peripheral hearing by gold standard tools (76.9% in electrophysiology studies). Auditory processing is deficient in patients with TLE. There is a clear need to evaluate hearing efficiency before proceeding to auditory processing evaluation with behavioral or electrophysiological tests. [ABSTRACT FROM AUTHOR]

• Temporal lobe encephalocele is a rarely recognized cause of medically refractory epilepsy. • Temporal encephaloceles may have variable semiology, sharing features with mesial temporal lobe epilepsies. • Temporal lobe encephaloceles typically present with high-amplitude delta or medium-amplitude theta patterns on EEG. • Early detection of encephaloceles in intractable temporal lobe epilepsy can enable tailored resections with favorable outcomes. Our study aimed to investigate the management of patients with medically refractory epilepsy related to temporal encephaloceles, focusing on the use of ancillary testing in the pre-surgical evaluation to optimize surgical outcomes. We conducted a retrospective analysis of electronic medical records from the Cleveland Clinic, covering the period from January 2000 to May 2020. Patients with drug-resistant temporal lobe epilepsy were included if they had temporal lobe encephaloceles and required surgical intervention. We reviewed the results of ancillary studies, including invasive EEG. A total of 19 patients with temporal lobe encephaloceles underwent resection for drug-resistant epilepsy treatment. Among them, 63 % reported experiencing auras commonly associated with mesial temporal lobe epilepsy, such as autonomic, psychic, and abdominal symptoms, followed by dialeptic seizures. Ictal patterns were consistently ipsilateral, with high amplitude delta or medium amplitude theta activity at onset, predominantly localized to the frontotemporal region in more than half of the cases. In 35 % of these patients, encephaloceles were only diagnosed during surgery. Stereo-EEG evaluation revealed two distinct ictal patterns: one characterized by localized low voltage fast activity in the temporal pole evolving into a 3–4 Hz high amplitude diffuse spiky activity, and the other exhibiting low amplitude rhythmic theta activity in the temporal pole with late involvement of the amygdala/hippocampus. Surgical resection strategy was based on clinical history and ancillary data analysis. At one-year follow-up after resection, 63 % of the patients attained Engel I seizure control over an average duration of 44 months (ranging from 6 months to 7.3 years). Additionally, 18 % of the patients achieved an Engel II outcome. Tailored resection of the encephalocele and the surrounding temporal pole, while preserving the mesial temporal structures, can effectively control seizures in patients with temporal encephaloceles identified through MRI. Patients presenting with temporal lobe symptoms and scalp ictal patterns characterized by polymorphic high delta theta activity with frontotemporal evolution should be evaluated for temporal encephaloceles as a potential underlying cause of their seizures, especially when the MRI is otherwise unrevealing. [ABSTRACT FROM AUTHOR]

• Individuals with TLE and SE had reduced entorhinal cortex thickness compared to those with TLE and no history of SE. • Atrophy was widespread in TLE, but this did not relate to a history of SE in any other cortical regions. • Compared to those without a history of SE, individuals with SE had reduced subcortical volume in the ipsilateral hippocampus. Status epilepticus (SE) carries risks of morbidity and mortality. Experimental studies have implicated the entorhinal cortex in prolonged seizures; however, studies in large human cohorts are limited. We hypothesised that individuals with temporal lobe epilepsy (TLE) and a history of SE would have more severe entorhinal atrophy compared to others with TLE and no history of SE. 357 individuals with drug resistant temporal lobe epilepsy (TLE) and 100 healthy controls were scanned on a 3T MRI. For all subjects, the cortex was segmented, parcellated, and the thickness calculated from the T1-weighted anatomical scan. Subcortical volumes were derived similarly. Cohen's d and Wilcoxon rank-sum tests respectively were used to capture effect sizes and significance. Individuals with TLE and SE had reduced entorhinal thickness compared to those with TLE and no history of SE. The entorhinal cortex was more atrophic ipsilaterally (d = 0.51, p < 0.001) than contralaterally (d = 0.37, p = 0.01). Reductions in ipsilateral entorhinal thickness were present in both left TLE (n = 22:176, d = 0.78, p < 0.001), and right TLE (n = 19:140, d = 0.31, p = 0.04), albeit with a smaller effect size in right TLE. Several other regions exhibited atrophy in individuals with TLE, but these did not relate to a history of SE. These findings suggest potential involvement or susceptibility of the entorhinal cortex in prolonged seizures. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is a type of focal epilepsy characterized by spontaneous recurrent seizures originating from the hippocampus. The epigenetic reprogramming hypothesis of epileptogenesis suggests that the development of TLE is associated with alterations in gene transcription changes resulting in a hyperexcitable network in TLE. DNA 5-methylcytosine (5-mC) is an epigenetic mechanism that has been associated with chronic epilepsy. However, the contribution of 5-hydroxymethylcytosine (5-hmC), a product of 5-mC demethylation by the Ten-Eleven Translocation (TET) family proteins in chronic TLE is poorly understood. 5-hmC is abundant in the brain and acts as a stable epigenetic mark altering gene expression through several mechanisms. Here, we found that the levels of bulk DNA 5-hmC but not 5-mC were significantly reduced in the hippocampus of human TLE patients and in the kainic acid (KA) TLE rat model. Using 5-hmC hMeDIP-sequencing, we characterized 5-hmC distribution across the genome and found bidirectional regulation of 5-hmC at intergenic regions within gene bodies. We found that hypohydroxymethylated 5-hmC intergenic regions were associated with several epilepsy-related genes, including Gal , SV2, and Kcnj11 and hyperdroxymethylation 5-hmC intergenic regions were associated with Gad65 , TLR4 , and Bdnf gene expression. Mechanistically, Tet1 knockdown in the hippocampus was sufficient to decrease 5-hmC levels and increase seizure susceptibility following KA administration. In contrast, Tet1 overexpression in the hippocampus resulted in increased 5-hmC levels associated with improved seizure resiliency in response to KA. These findings suggest an important role for 5-hmC as an epigenetic regulator of epilepsy that can be manipulated to influence seizure outcomes. [Display omitted] • Reduced hippocampal DNA 5-hydroxymethylation levels were found in the hippocampus of people with temporal lobe epilepsy. • In the rodent experimental model of temporal lobe epilepsy, we recapitulated DNA 5-hydroxymethylation findings in human temporal lobe epilepsy. • Post-status epilepticus, the majority of genomic DNA 5-hydroxymethylation loss in the hippocampus occurs within intergenic regions. • Differential DNA 5-hydroxymethylation was found at gene regions involved in neuronal and synaptic regulation. • Manipulating TET1 expression in the rat hippocampus promotes seizure susceptibility and resiliency. [ABSTRACT FROM AUTHOR]

• Intracranial ictal onset patterns in Temporal Lobe Epilepsy depend on underlying histology and the temporal lobe structure involved in its onset. • Low-Frequency High Amplitude spike was a unique ictal pattern seen in HS. • Delta brush pattern is the signature of ictal onset within FCD. • Ictal onset in the normal Hippocampus did not include Low-Frequency, High-Amplitude periodic spikes with Slow Potential shifts or rhythmic spikes. • Low-frequency high Amplitude can be observed in ictal onset in extrahippocampal structures such as the temporal pole and the MTG. To determine the intracranial ictal onset and early spread patterns in pediatric patients with Temporal lobe epilepsy and its possible association with histopathology, temporal structure involved, mesial structural pathology, and possible implication in postsurgical outcome. A descriptive, retrospective, cross-sectional study was carried out in a group of children from Children's Wisconsin between 2016 and 2022. This study showed a strong association between ictal onset patterns and underlying histology (p < 0.05). Low-Frequency High Amplitude periodic spikes were seen only in patients with HS (20.6 %). A strong statistically significant association was found between different ictal onset patterns and the temporal lobe structure involved in the ictal onset (p < 0.001). Seizures with ictal onset consisting of Slow Potential Shift with superimposed Low Voltage Fast Activity arise from the Inferior Temporal Lobe or Middle Temporal Gyrus in a more significant proportion of seizures than those that originated from mesial temporal structures (Difference of proportion; p < 0.05). Low Voltage Fast Activity periodic spikes as an ictal pattern were seen in a patient with seizures arising outside the mesial temporal structure. The most frequent early spread pattern observed was Low Voltage Fast Activity (89.4 %); this pattern did not depend on the type of mesial structure pathology. Ictal onset patterns were associated with postsurgical outcomes (p < 0.001). The ictal onset pattern depends on the histopathology in the ictal onset zone and the temporal lobe structure involved in the ictal onset (p = 0.001). Intracranial ictal onset patterns in TEMPORAL LOBE EPILEPSY depend on underlying histology and the temporal lobe structure involved in its onset. [ABSTRACT FROM AUTHOR]

• Temporal and extra-temporal focal resistant epilepsies were compared. • Impulsivity levels and psychiatric comorbid disorders were analyzed. • Both epilepsy groups presented higher impulsivity compared to control. • A left temporal epileptogenic zone was associated with higher impulsivity. • Depressive disorders were associated with higher impulsivity. To analyze patients with drug-resistant focal epilepsy from temporal (TLE) and extra-temporal origin (ETE) and to compare the prevalence of psychiatric comorbid disorders and impulsivity between them and a control group. Consecutively studied patients with TLE and ETE confirmed with Video-EEG were included. Standardized psychiatric assessment was conducted using the Structured Clinical Interview for Axis I and II diagnosis of DSM-IV (SCID I-II), the Barrat-11 scale for impulsivity, and Beck inventory for depression. Parametric and nonparametric tests were performed. Seventy-three patients with temporal lobe epilepsy (TLE), 21 extra-temporal epilepsy (ETE) and 58 healthy control subjects were included. Both groups of patients showed a high frequency of Axis I comorbid psychiatric disorders: Depression was the most frequent disorder followed by Anxiety Disorders. Furthermore, Axis II (Personality disorders) were also diagnosed, similarly in both groups of patients (p > 0.05). In addition, both TLE and ETE groups presented higher impulsivity scores compared with the control group (p < 0.01). ETE showed a tendency to a higher impulsivity in the motor factor (p = 0.05). Among patients with TLE, a left laterality of the epileptogenic zone, and the presence of comorbid psychiatric disorders (depression), were found as independent factors associated with higher impulsivity (p < 0.05). Comorbid depression associated with higher impulsivity are important issues to consider in behavioral and clinical evaluation of patients with drug-resistant focal epilepsies, with the aim to set up a prompt treatment. [ABSTRACT FROM AUTHOR]

Mesial temporal lobe epilepsy (MTLE) is characterized by recurring focal seizures that arise from limbic areas and are often refractory to pharmacological interventions. We have reported that optogenetic stimulation of PV-positive cells in the medial septum at 0.5 Hz exerts seizure-suppressive effects. Therefore, we compared here these results with those obtained by optogenetic stimulation of medial septum PV-positive neurons at 8 Hz in male PV-ChR2 mice (P60-P100) undergoing an initial, pilocarpine-induced status epilepticus (SE). Optogenetic stimulation (5 min ON, 10 min OFF) was performed from day 8 to day 12 after SE at a frequency of 8 Hz (n = 6 animals) or 0.5 Hz (n = 8 animals). Surprisingly, in both groups, no effects were observed on the occurrence of interictal spikes and interictal high frequency oscillations (HFOs). However, 0.5 Hz stimulation induced a significant decrease of seizure occurrence (p < 0.05). Such anti-ictogenic effect was not observed in the 8 Hz protocol that instead triggered seizures (p < 0.05); these seizures were significantly longer under optogenetic stimulation compared to when optogenetic stimulation was not implemented (p < 0.05). Analysis of ictal HFOs revealed that in the 0.5 Hz group, but not in the 8 Hz group, seizures occurring under optogenetic stimulation were associated with significantly lower rates of fast ripples compared to when optogenetic stimulation was not performed (p < 0.05). Our results indicate that activation of GABAergic PV-positive neurons in the medial septum exerts seizure-suppressing effects that are frequency-dependent and associated with low rates of fast ripples. Optogenetic activation of medial septum PV-positive neurons at 0.5 Hz is efficient in blocking seizures in the pilocarpine model of MTLE, an effect that did not occur with 8 Hz stimulation. • The medial septum was shown to play a role in controlling ictogenesis. • We performed optogenetic stimulation of PV-interneurons in the medial septum. • Such procedure, at 0.5 Hz, had seizure-suppressing effects. • 8 Hz stimulation could however facilitate seizure occurrence. [ABSTRACT FROM AUTHOR]

Drug-resistant epilepsy patients may benefit from non-pharmacological therapies, such as the ketogenic diet (KD). However, its high fat content poses compliance challenges and metabolic risks. To mitigate this, we developed a novel KD composition with less fat and additional nutrients (citrate, nicotinamide riboside, and omega-3 fatty acids) for ketone-independent neuroprotection. The efficacy, metabolic and neuropathological effects of the novel KD and a classic KD were compared to a control diet in the rapid kindling model of temporal lobe epilepsy. Both KD groups entered ketosis before kindling onset, with higher ketone levels in the classic KD group. Remarkably, rats on the novel KD had slower progression of behavioral seizures as compared to rats on a control diet, while this was not the case for rats on a classic KD. Both KDs reduced electrographic after-discharge duration, preserved neurons in the dorsal hippocampus, and normalized activity in open field tests. The novel KD, despite lower fat and ketone levels, demonstrated effective reduction of behavioral seizure severity while the classic KD did not, suggesting alternative mode(s) of action are involved. Additionally, the novel KD significantly mitigated liver triglyceride and plasma fatty acid levels compared to the classic KD, indicating a reduced risk of long-term liver steatosis. Our findings highlight the potential of the novel KD to enhance therapeutic efficacy and compliance in epilepsy patients. • Effective reduction in seizure severity by the novel KD in the rapid kindling model. • Both the novel and classic KD reduce the after-discharge duration in the rapid kindling model • Both the novel and the classic KD normalize kindling-induced behavioral alterations in the open field test. • The novel KD prevented the formation of a fatty liver. [ABSTRACT FROM AUTHOR]

While time spent in slow wave sleep (SWS) after learning promotes memory consolidation in the healthy brain, it is unclear if the same benefit is obtained in patients with temporal lobe epilepsy (TLE). Interictal epileptiform discharges (IEDs) are potentiated during SWS and thus may disrupt memory consolidation processes thought to depend on hippocampal-neocortical interactions. Here, we explored the relationship between SWS, IEDs, and overnight forgetting in patients with TLE. Nineteen patients with TLE studied object-scene pairs and memory was tested across a day of wakefulness (6 hrs) and across a night of sleep (16 hrs) while undergoing continuous scalp EEG monitoring. We found that time spent in SWS after learning was related to greater forgetting overnight. Longer duration in SWS and number of IEDs were each associated with greater forgetting, although the number of IEDs did not mediate the relationship between SWS and memory. Further research, particularly with intracranial recordings, is required to identify the mechanisms by which SWS and IEDs can be pathological to sleep-dependent memory consolidation in patients with TLE. [ABSTRACT FROM AUTHOR]

Epilepsy is characterized by recurrent, chronic, and unprovoked seizures. Epilepsy has a significant negative impact on a patient's quality of life even if seizures are well controlled. In addition to the distress caused by seizures, patients with epilepsy (PwE) may suffer from cognitive impairment with serious social consequences such as poor interpersonal relationships, loss of employment, and reduced social networks. Pathological changes and functional connectivity abnormalities observed in PwE can disrupt the neural network responsible for the theory of mind. Theory of mind is the ability to attribute mental states to other people (intentions, beliefs, and emotions). It is a complex aspect of social cognition and includes cognitive and affective constructs. In recent years, numerous studies have assessed the relationship between social cognition, including the theory of mind, in PwE, and suggested impairment in this domain. Interventions targeting the theory of mind can be potentially helpful in improving the quality of life of PwE. [ABSTRACT FROM AUTHOR]

Lewis Carroll's classic Alice in Wonderland describes Alice's fantastical experiences so similarly to the actual phenomenology of the eponymous syndrome, that it has been previously suggested that Carroll himself experienced it. The syndrome is mostly associated with migrainous aura, and naturally, Carroll was postmortemly "diagnosed" as a migraineur. However, when considering his unique personality profile, it appears that he might have had temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

• In adult patients with TLE, the SMCR test reflects a distinct cognitive domain. • Conventional rules recognition is well-retained. • Moral reasoning may be affected in right TLE if unfavorable demographics coexist. • Age, TLE side, semantic abilities, and psychoticism can predict SMCR. • However, impaired SMCR is not a marker of TLE. Sensitivity to moral and conventional rules (SMCR) is supported by bilateral brain networks and psychosocial input both of which may be altered in temporal lobe epilepsy (TLE). This study evaluated the components of SMCR in patients with TLE, aiming to clarify their preservation and link to psychopathological and cognitive aspects. Adult patients with unilateral TLE and healthy controls were evaluated using neuropsychological tests for SMCR, memory, language, and executive functions, the Empathy Questionnaire (EQ), and the Symptom Checklist-90-R (SCL-90-R). The SMCR test items showed good reliability and validity, yielding the Severity and Rules factors distinct from the Executive, Lexical and Memory factors. Patients with right TLE scored worse in moral rules recognition than controls, but this difference was nullified by a significant influence for age and sex. The Severity and Rules factors related to semantic fluency and age and, respectively, TLE side and psychoticism. However, these factors did predict TLE membership. In adult patients with TLE, the SMCR test reflects a distinct cognitive domain. Conventional rules are well-retained, while moral reasoning may be only affected in right TLE if unfavorable demographics coexist. Although age, TLE side, semantic abilities, and psychoticism cooperate to determine SMCR, impairment of such domain is not a distinctive feature of TLE. [ABSTRACT FROM AUTHOR]

• Even without IEDs, there is a generalized acceleration of brain activity in TLE patients. • Brain network in TLE patients were highly synchronized yet highly unstable, which might be related to epileptogensis. • Highly independent, highly stable, and highly synchronized activity in bilateral frontal regions and left temporal region, might be related to drug resistance in TLE. • Machine learning approach using spatiotemporal metrics can accurately distinguish TLE patients from HC and DRE patients from DSE. Temporal lobe epilepsy (TLE) stands as the predominant adult focal epilepsy syndrome, characterized by dysfunctional intrinsic brain dynamics. However, the precise mechanisms underlying seizures in these patients remain elusive. Our study encompassed 116 TLE patients compared with 51 healthy controls. Employing microstate analysis, we assessed brain dynamic disparities between TLE patients and healthy controls, as well as between drug-resistant epilepsy (DRE) and drug-sensitive epilepsy (DSE) patients. We constructed dynamic functional connectivity networks based on microstates and quantified their spatial and temporal variability. Utilizing these brain network features, we developed machine learning models to discriminate between TLE patients and healthy controls, and between DRE and DSE patients. Temporal dynamics in TLE patients exhibited significant acceleration compared to healthy controls, along with heightened synchronization and instability in brain networks. Moreover, DRE patients displayed notably lower spatial variability in certain parts of microstate B, E and F dynamic functional connectivity networks, while temporal variability in certain parts of microstate E and G dynamic functional connectivity networks was markedly higher in DRE patients compared to DSE patients. The machine learning model based on these spatiotemporal metrics effectively differentiated TLE patients from healthy controls and discerned DRE from DSE patients. The accelerated microstate dynamics and disrupted microstate sequences observed in TLE patients mirror highly unstable intrinsic brain dynamics, potentially underlying abnormal discharges. Additionally, the presence of highly synchronized and unstable activities in brain networks of DRE patients signifies the establishment of stable epileptogenic networks, contributing to the poor responsiveness to antiseizure medications. The model based on spatiotemporal metrics demonstrated robust predictive performance, accurately distinguishing both TLE patients from healthy controls and DRE patients from DSE patients. [ABSTRACT FROM AUTHOR]

• Impaired attention functions were found in patients with TLE. • Eye tracking showed significant longer MRT and MFST, and more TSC in TLE. • Lower amplitudes and longer latencies of N1 and P3, as well as higher value of theta/beta and theta/alpha were found in TLE. • The energy of beta band was sensitive to the changes of orienting network with time. To explore multiple features of attention impairments in patients with temporal lobe epilepsy (TLE). A total of 93 patients diagnosed with TLE at Xiangya Hospital during May 2022 and December 2022 and 85 healthy controls were included in this study. Participants were asked to complete neuropsychological scales and attention network test (ANT) with recording of eye-tracking and electroencephalogram. All means of evaluation showed impaired attention functions in TLE patients. ANT results showed impaired orienting (p < 0.001) and executive control (p = 0.041) networks. Longer mean first saccade time (p = 0.046) and more total saccadic counts (p = 0.035) were found in eye-tracking results, indicating abnormal alerting and orienting networks. Both alerting, orienting and executive control networks were abnormal, manifesting as decreased amplitudes (N1 & P3, p < 0.001) and extended latency (P3, p = 0.002). The energy of theta, alpha and beta were all sensitive to the changes of alerting and executive control network with time, but only beta power was sensitive to the changes of orienting network. Our findings are helpful for early identification of patients with TLE combined with attention impairments, which have strong clinical guiding significance for long-term monitoring and intervention. [ABSTRACT FROM AUTHOR]

• Change patterns in spontaneous brain activity were similar between TLE-HS and TLE-N. • TLE-HS demonstrated more pronounced abnormalities of spontaneous brain activity. • The spontaneous brain activity alterations of TLE patients correlated with cognition. • Combination of static and dynamic metrics could better describe neuronal activity. • Voxel-mirrored homotopic connectivity (VMHC) showed promise for differential diagnosis. Hippocampal sclerosis (HS) is a prevalent cause of temporal lobe epilepsy (TLE). However, up to 30% of individuals with TLE present negative magnetic resonance imaging (MRI) findings. A comprehensive grasp of the similarities and differences in brain activity among distinct TLE subtypes holds significant clinical and scientific importance. To comprehensively examine the similarities and differences between TLE with HS (TLE-HS) and MRI-negative TLE (TLE-N) regarding static and dynamic abnormalities in spontaneous brain activity (SBA). Furthermore, we aimed to determine whether these alterations correlate with epilepsy duration and cognition, and to determine a potential differential diagnostic index for clinical utility. We measured 12 SBA metrics in 38 patients with TLE-HS, 51 with TLE-N, and 53 healthy volunteers. Voxel-wise analysis of variance (ANOVA) and post-hoc comparisons were employed to compare these metrics. The six static metrics included amplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity (VMHC), degree centrality (DC), and global signal correlation (GSCorr). Additionally, six corresponding dynamic metrics were assessed: dynamic ALFF (dALFF), dynamic fALFF (dfALFF), dynamic ReHo (dReHo), dynamic DC (dDC), dynamic VMHC (dVMHC), and dynamic GSCorr (dGSCorr). Receiver operating characteristic (ROC) curve analysis of abnormal indices was employed. Spearman correlation analyses were also conducted to examine the relationship between the abnormal indices, epilepsy duration and cognition scores. Both TLE-HS and TLE-N presented as extensive neural network disorders, sharing similar patterns of SBA alterations. The regions with increased fALFF, dALFF, and dfALFF levels were predominantly observed in the mesial temporal lobe, thalamus, basal ganglia, pons, and cerebellum, forming a previously proposed mesial temporal epilepsy network. Conversely, decreased SBA metrics (fALFF, ReHo, dReHo, DC, GSCorr, and VMHC) consistently appeared in the lateral temporal lobe ipsilateral to the epileptic foci. Notably, SBA alterations were more obvious in patients with TLE-HS than in those with TLE-N. Additionally, patients with TLE-HS exhibited reduced VMHC in both mesial and lateral temporal lobes compared with patients with TLE-N, with the hippocampus displaying moderate discriminatory power (AUC = 0.759). Correlation analysis suggested that alterations in SBA indicators may be associated with epilepsy duration and cognitive scores. The simultaneous use of static and dynamic SBA metrics provides evidence supporting the characterisation of both TLE-HS and TLE-N as complex network diseases, facilitating the exploration of mechanisms underlying epileptic activity and cognitive impairment. Overall, SBA abnormality patterns were generally similar between the TLE-HS and TLE-N groups, encompassing networks related to TLE and auditory and occipital visual functions. These changes were more pronounced in the TLE-HS group, particularly within the mesial and lateral temporal lobes. [ABSTRACT FROM AUTHOR]

• Failure to account for ATL following LITT provides an underestimate of costs. • LITT costs more if the ratio of subsequent ATLs exceeds the cost reduction of LITT. • Cost per seizure-free patient will be higher in LITT if certain relationships are met. Laser interstitial thermal therapy (LITT) is an alternative to anterior temporal lobectomy (ATL) for the treatment of temporal lobe epilepsy that has been found by some to have a lower procedure cost but is generally regarded as less effective and sometimes results in a subsequent procedure. The goal of this study is to incorporate subsequent procedures into the cost and outcome comparison between ATL and LITT. This single-center, retrospective cohort study includes 85 patients undergoing ATL or LITT for temporal lobe epilepsy during the period September 2015 to December 2022. Of the 40 patients undergoing LITT, 35 % (N = 14) underwent a subsequent ATL. An economic cost model is derived, and difference in means tests are used to compare the costs, outcomes, and other hospitalization measures. Our model predicts that whenever the percentage of LITT patients undergoing subsequent ATL (35% in our sample) exceeds the percentage by which the LITT procedure alone is less costly than ATL (7.2% using total patient charges), LITT will have higher average patient cost than ATL, and this is indeed the case in our sample. After accounting for subsequent surgeries, the average patient charge in the LITT sample ($103,700) was significantly higher than for the ATL sample ($88,548). A second statistical comparison derived from our model adjusts for the difference in effectiveness by calculating the cost per seizure-free patient outcome, which is $108,226 for ATL, $304,052 for LITT only, and $196,484 for LITT after accounting for the subsequent ATL surgeries. After accounting for the costs of subsequent procedures, we found in our cohort that LITT is not only less effective but also results in higher average costs per patient than ATL as a first course of treatment. While cost and effectiveness rates will vary across centers, we also provide a model for calculating cost effectiveness based on individual center data. [ABSTRACT FROM AUTHOR]

• The psychosocial outcome after epilepsy surgery is complex. It depends not only on seizure outcome but also on various other factors. • This study supports and strengthens the notion that the patient's coping style is a factor that affects the adaptation process after epilepsy surgery. • We contribute to the literature one of the presurgery determinants of postsurgical psychosocial status. Considering the findings of our study on the relationship between working status and social adaptation after surgery, we can infer that patients' families, healthcare professionals, and epilepsy support organizations should work collaboratively to support individuals with epilepsy in terms of providing job opportunities. Epilepsy negatively affects the social functioning of patients. Epilepsy surgery is a treatment with superior rates of seizure freedom. The psychosocial outcomes after epilepsy surgery depend on several factors, including the patient's coping style. It is important to identify the patients who are at risk of experiencing psychosocial difficulties after epilepsy surgery and consult them for psychiatric interventions. This study aimed to assess changes in social adaptation, felt stigma, self-esteem, and self-efficacy after epilepsy surgery, and the effect of coping strategies, sociodemographic and epilepsy-related variables, and post-surgical seizure outcomes on these results. Thirty adult patients with temporal lobe epilepsy who were candidates for surgery were included in the study (mean age: 33.07, mean seizure onset age: 17.2, mean duration of epilepsy: 15.8). The patients were assessed before and 6 months after epilepsy surgery using the Epilepsy Self-Efficacy Scale, Social Adaptation Self-Evaluation Scale, Rosenberg Self-Esteem Scale, Felt Stigma Scale, and Coping Orientation to Problems Experienced Inventory. The patients' self-efficacy levels were increased after surgery (p = 0.005). Postsurgical social adaptation levels were associated with higher positive reinterpretation and growth, active coping, and planning (p = 0.016, p = 0.005, p = 0.002, respectively). Postsurgical self-efficacy levels were positively associated with active coping and planning (p = 0.003, p = 0.035, respectively). Postsurgical self-esteem (p = 0.012, p = 0.049, p = 0.034, respectively) and stigma (p = 0.029, p = 0.014, p = 0.027, respectively) were negatively associated with positive reinterpretation and growth, active coping, and planning. Furthermore, being employed presurgical period was associated with better postsurgical social adaptation (p = 0.004). The psychosocial outcomes after epilepsy surgery depend not only on seizure outcomes. Understanding the factors beyond seizure freedom, allows healthcare professionals to have a pivotal role in exploring and managing patients' expectations, fostering a more comprehensive and realistic dialogue about potential outcomes. Considering employed patients had better psychosocial outcomes, we suggest patients' families, healthcare professionals, and epilepsy support organizations should work collaboratively to support people with epilepsy in terms of providing job opportunities. [ABSTRACT FROM AUTHOR]

In animal models of LGI1-dependent autosomal dominant lateral temporal lobe epilepsy, Kv 1 channels are downregulated, suggesting their crucial involvement in epileptogenesis. The molecular basis of Kv 1 channel-downregulation in LGI1 knock-out mice has not been elucidated and how the absence of this extracellular protein induces an important modification in the expression of Kv 1 remains unknown. In this study we analyse by immunofluorescence the modifications in neuronal Kv 1.1 and Kv 1.2 distribution throughout the hippocampal formation of LGI1 knock-out mice. We show that Kv 1 downregulation is not restricted to the axonal compartment, but also takes place in the somatodendritic region and is accompanied by a drastic decrease in Kv 2 expression levels. Moreover, we find that the downregulation of these Kv channels is associated with a marked increase in bursting patterns. Finally, mass spectrometry uncovered key modifications in the Kv 1 interactome that highlight the epileptogenic implication of Kv 1 downregulation in LGI1 knock-out animals. [Display omitted] • Kv 1 expression in an Autosomal Dominant Lateral Temporal Lobe Epilepsy animal model. • The delayed rectifying Kv 1 channels-interactome in LGI1 knock-out mice (LGI1-KO). • Kv1 channels distribution throughout the hippocampal formation in LGI1-KO. • Mass spectrometry analysis of Kv 1 -cytoskeletal links rearrangement in LGI1-KO. • Epileptogenic implication of Kv 1/2 downregulation and bursting patterns in LGI1-KO. [ABSTRACT FROM AUTHOR]

The Wnt signaling pathway mediates the development of dentate granule cell neurons in the hippocampus. These neurons are central to the development of temporal lobe epilepsy and undergo structural and physiological remodeling during epileptogenesis, which results in the formation of epileptic circuits. The pathways responsible for granule cell remodeling during epileptogenesis have yet to be well defined, and represent therapeutic targets for the prevention of epilepsy. The current study explores Wnt signaling during epileptogenesis and for the first time describes the effect of Wnt activation using Wnt activator Chir99021 as a novel anti-epileptogenic therapeutic approach. Focal mesial temporal lobe epilepsy was induced by intrahippocampal kainate (IHK) injection in wild-type and POMC-eGFP transgenic mice. Wnt activator Chir99021 was administered daily, beginning 3 h after seizure induction, and continued up to 21-days. Immature granule cell morphology was quantified in the ipsilateral epileptogenic zone and the contralateral peri-ictal zone 14 days after IHK, targeting the end of the latent period. Bilateral hippocampal electrocorticographic recordings were performed for 28-days, 7-days beyond treatment cessation. Hippocampal behavioral tests were performed after completion of Chir99021 treatment. Consistent with previous studies, IHK resulted in the development of epilepsy after a 14 day latent period in this well-described mouse model. Activation of the canonical Wnt pathway with Chir99021 significantly reduced bilateral hippocampal seizure number and duration. Critically, this effect was retained after treatment cessation, suggesting a durable antiepileptogenic change in epileptic circuitry. Morphological analyses demonstrated that Wnt activation prevented pathological remodeling of the primary dendrite in both the epileptogenic zone and peri-ictal zone, changes in which may serve as a biomarker of epileptogenesis and anti-epileptogenic treatment response in pre-clinical studies. These findings were associated with improved object location memory with Chir99021 treatment after IHK. This study provides novel evidence that canonical Wnt activation prevents epileptogenesis in the IHK mouse model of mesial temporal lobe epilepsy, preventing pathological remodeling of dentate granule cells. Wnt signaling may therefore play a key role in mesial temporal lobe epileptogenesis, and Wnt modulation may represent a novel therapeutic strategy in the prevention of epilepsy. [Display omitted] • There are currently no clinical treatments that prevent epileptogenesis. • Wnt signaling has been implicated in temporal lobe epileptogenesis. • Wnt activator Chir99021 prevents epileptogenesis after intrahippocampal kainate. • Granule cell remodeling may provide an experimental biomarker of treatment response. [ABSTRACT FROM AUTHOR]

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. • Female mice after IHKA reproduced key features of human TLE previously modeled in males. • In line with the drug-resistance of HPDs in males, HPDs in female IHKA mice were resistant to commonly prescribed ASMs (lamotrigine, oxcarbazepine, and levetiracetam) but reduced by diazepam. • Power spectral analysis revealed increased delta frequency after lamotrigine 30 mg/kg and a broad reduction after diazepam. [ABSTRACT FROM AUTHOR]

• The bilateral glymphatic profile of unilateral TLE patients with histologically proved hippocampal sclerosis (HS) was evaluated by the DTI-ALPS method. • In comparison to HCs, the TLE patients with HS showed significantly reduced DTI-ALPS indices bilaterally, and the reduction was more pronounced ipsilaterally. • In TLE patients with HS, the ipsilateral DTI-ALPS index was found slightly lower than the contralateral but without evident statistical significance. • In TLE patients with HS, the ipsilateral DTI-ALPS index was significantly inversely correlated with disease duration. 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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

• The current work assessed different relational memory domains in patients with temporal lobe epilepsy (TLE). • We administered a recently developed relational memory assessment battery to examine episodic, semantic, and spatial cognition in TLE patients and healthy controls. • Comparing groups, TLE patients showed marked impairments in episodic and spatial memory, and to a lesser extent, semantic memory. • Multivariate associative techniques revealed that age, diagnostic group, and hippocampal volume significantly contributed to relational memory behavioral outcomes. Temporal lobe epilepsy (TLE) is typically associated with pathology of the hippocampus, a key structure involved in relational memory, including episodic, semantic, and spatial memory processes. While it is widely accepted that TLE-associated hippocampal alterations underlie memory deficits, it remains unclear whether impairments relate to a specific cognitive domain or multiple ones. We administered a recently validated task paradigm to evaluate episodic, semantic, and spatial memory in 24 pharmacoresistant TLE patients and 50 age- and sex-matched healthy controls. We carried out two-way analyses of variance to identify memory deficits in individuals with TLE relative to controls across different relational memory domains, and used partial least squares correlation to identify factors contributing to variations in relational memory performance across both cohorts. Compared to controls, TLE patients showed marked impairments in episodic and spatial memory, with mixed findings in semantic memory. Even when additionally controlling for age, sex, and overall cognitive function, between-group differences persisted along episodic and spatial domains. Moreover, age, diagnostic group, and hippocampal volume were all associated with relational memory behavioral phenotypes. Our behavioral findings show graded deficits across relational memory domains in people with TLE, which provides further insights into the complex pattern of cognitive impairment in the condition. [ABSTRACT FROM AUTHOR]

• This study compared visual confrontation naming and seizure control outcomes of three commonly used epilepsy surgery approaches: subtemporal approach selective amygdalohippocampectomy (subSAH), selective laser amygdalohippocampotomy (SLAH), and traditional anterior temporal lobectomy (ATL). • Group-level analyses revealed significant differences in naming outcome across the three groups: ATLs = worst naming outcome, subSAH = intermediate naming outcome, SLAH = best naming outcome. • Individual-level analyses revealed that no patient who underwent selective laser amygdalohippocampotomy (SLAH) showed significant naming decline after surgery and 36% showed improvement. • In contrast, 36% of subSAH and 82% of ATL patients showed significant postsurgical naming decline. • There were no significant differences across the three groups regarding postoperative seizure control. The purpose of this study was to systematically examine three different surgical approaches in treating left medial temporal lobe epilepsy (mTLE) (viz., subtemporal selective amygdalohippocampectomy [subSAH], stereotactic laser amygdalohippocampotomy [SLAH], and anterior temporal lobectomy [ATL]), to determine which procedures are most favorable in terms of visual confrontation naming and seizure relief outcome. This was a retrospective study of 33 adults with intractable mTLE who underwent left temporal lobe surgery at three different epilepsy surgery centers who also underwent pre-, and at least 6-month post-surgical neuropsychological testing. Measures included the Boston Naming Test (BNT) and the Engel Epilepsy Surgery Outcome Scale. Fisher's exact tests revealed a statistically significant decline in naming in ATLs compared to SLAHs, but no other significant group differences. 82% of ATL and 36% of subSAH patients showed a significant naming decline whereas no SLAH patient (0%) had a significant naming decline. Significant postoperative naming improvement was seen in 36% of SLAH patients in contrast to 9% improvement in subSAH patients and 0% improvement in ATLs. Finally, there were no statistically significant differences between surgical approaches with regard to seizure freedom outcome, although there was a trend towards better seizure relief outcome among the ATL patients. Results support a possible benefit of SLAH in preserving visual confrontation naming after left TLE surgery. While result interpretation is limited by the small sample size, findings suggest outcome is likely to differ by surgical approach, and that further research on cognitive and seizure freedom outcomes is needed to inform patients and providers of potential risks and benefits with each. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • The effects of PER on cognitive behavior and GluA1 expression in kainic acid-induced TLE were examined. • Positive effects of PER were found on cognitive behavior with improvements in memory proved using the Morris water maze. • Expression of AP-1 and GluR1 in hippocampal cells were explained to reveal the effects of PER and its internal mechanism. [ABSTRACT FROM AUTHOR]

A growing number of clinical and animal studies suggest that the nucleus accumbens (NAc), especially the shell, is involved in the pathogenesis of temporal lobe epilepsy (TLE). However, the role of parvalbumin (PV) GABAergic neurons in the NAc shell involved in TLE is still unclear. In this study, we induced a spontaneous TLE model by intrahippocampal administration of kainic acid (KA), which generally induce acute seizures in first 2 h (acute phase) and then lead to spontaneous recurrent seizures after two months (chronic phase). We found that chemogenetic activation of NAc shell PV neurons could alleviate TLE seizures by reducing the number and period of focal seizures (FSs) and secondary generalized seizures (sGSs), while selective inhibition of PV exacerbated seizure activity. Ruby-virus mapping results identified that the hippocampus (ventral and dorsal) is one of the projection targets of NAc shell PV neurons. Chemogenetic activation of the NAc-Hip PV projection fibers can mitigate seizures while inhibition has no effect on seizure ictogenesis. In summary, our findings reveal that PV neurons in the NAc shell could modulate the seizures in TLE via a long-range NAc-Hip circuit. All of these results enriched the investigation between NAc and epilepsy, offering new targets for future epileptogenesis research and precision therapy. • Chemogenetic activation of PV (+) neurons in the NAc shell attenuates seizures. • Chemogenetic inhibition of NAc shell PV (+) neurons aggravates seizures. • The ventral and dorsal hippocampus is innervated by the NAc PV projections. • Chemogenetic activation of the NAc-Hippocampal PV projection fibers also has an antiepileptic effect. [ABSTRACT FROM AUTHOR]

• Depression prevalence is slightly higher in Temporal Lobe Epilepsy with Hippocampal Sclerosis compared to other epilepsy types. • Seizure frequency and longer disease duration are predictors of Major Depressive Disorder in Temporal Lobe Epilepsy with Hippocampal Sclerosis. • Antiepileptic drugs, specifically Lamotrigine and valproate, are associated with elevated scores in the Neurological Disorders Depression Inventory for Epilepsy questionnaire. Epilepsy frequently accompanies Major Depressive Disorder (MDD). Notably, people with temporal lobe epilepsy and hippocampal sclerosis may face an increased susceptibility to MDD, as evidence indicates the involvement of the limbic system in the development of emotional symptoms. To determine the prevalence and predictors of depression in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and compare them to those of other epilepsy types. A sample of 293 epilepsy patients, including 159 non-TLE-HS and 134 TLE-HS, were recruited from three hospitals. Of these, 215 completed a two-section electronic survey. The first section collected demographic and epilepsy data, while the second used the Arabic version of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Of 215 patients, 104 (48%) had TLE-HS—38 with right TLE-HS (37%), 56 with left TLE-HS (54%), and 10 with bilateral TLE-HS (10%). The prevalence and severity of depression was assessed with an NDDI-E score of 15 or higher identified 35 patients (16%) with MDD. Valproic acid and lamotrigine were associated with higher NDDI-E scores. No such associations were found for levetiracetam or carbamazepine. Polytherapy in TLE-HS showed a significant correlation with daily poor concentration. We explored the differences in depression prevalence between TLE-HS and other epilepsy types and concluded they are minimal but slightly higher in TLE-HS. Predictors of depression such as seizure frequency and disease duration influenced MDD prevalence in TLE-HS. Lamotrigine and valproate were linked to higher NDDI-E scores. [ABSTRACT FROM AUTHOR]

• Serum APOE level of TLE patients is significantly higher than that of healthy people. • Serum APOE level is associated with cognitive dysfunction in TLE patients. • The cognitive function of APOE ε 4 allele carriers in TLE patients is poor. To investigate the effect of serum apolipoprotein E (APOE) levels on cognitive function in patients with temporal lobe epilepsy (TLE). Clinical data were collected from 190 subjects including 110 TLE patients and 80 healthy people. Cognitive function was assessed using the Addenbrooke's Cognitive Examination Revised (ACE-R) scale. Serum levels of APOE were measured using ELISA kits. Genotyping of APOE in peripheral blood was detected by microarray hybridization. Patients with TLE had significantly lower ACE-R total score, memory and verbal fluency scores compared to the healthy group. Serum levels of APOE were significantly higher in TLE patients than in the healthy subjects. Serum APOE levels were significantly negatively correlated with ACE-R total score, memory and verbal fluency scores. The cognitive function score of TLE with APOE ε 4 allele was lower than that of TLE without APOE ε 4 allele. Our study showed that serum APOE levels were higher in TLE patients than in the healthy population. And serum APOE levels were associated with cognitive dysfunction in TLE patients. APOE ε 4 allele carriers have poor cognitive function in TLE patients. [ABSTRACT FROM AUTHOR]

• Rehabilitation related improvements in memory, anxiety and quality of life were sustained at 6 months. • Culturally tailored psychoeducation was beneficial. • Lack of understanding on the role of cognition in epilepsy is prevalent in patients and caregivers. • Neuropsychology referral should be made at the time of diagnosis. • Standard deviation cut-off may be an adequate index of meaningful change. Neuropsychological Rehabilitation (NR) helps manage cognitive deficits in epilepsy. As internationally developed programs have limited applicability to resource-limited countries, we developed a program to bridge this gap. This 6-week caregiver-assisted, culturally suitable program has components of (1) psychoeducation, (2) compensatory training, and, (3) cognitive retraining and is called EMPOWER (Indig e nized Ho m e Based Attention and Memory Rehabilitation P rogram f o r Adult Patients w ith Drug R e f r actory Epilepsy). Its efficacy needs to be determined. We carried out an open-label parallel randomized controlled trial. Adults aged 18–45 years with Drug Refractory Epilepsy (DRE), fluency in Hindi and or English, with impaired attention or memory (n = 28) were randomized to Intervention Group (IG) and Control Group (CG). The primary outcomes were objective memory (Auditory Verbal Learning Test), patient and caregiver reported everyday memory difficulties (Everyday Memory Questionnaire-Revised), number of memory aids in use, depression (Hamilton Depression Rating Scale), anxiety (Hamilton Anxiety Rating Scale) and quality of life (Quality of Life in Epilepsy-31). Intention to treat was carried out for group analysis. In the absence of norms necessary for computing Reliable Change Indices (RCIs), a cut-off of +1.0 Standard Deviation (SD) was utilized to identify clinically meaningful changes in the individual analysis of objective memory. A cut-off of 11.8 points was used for quality of life. Feedback and program evaluation responses were noted. The majority of the sample comprised DRE patients with temporal lobe epilepsy who had undergone epilepsy surgery. Group analysis indicated improved learning (p = 0.013), immediate recall (p = 0.001), delayed recall (p < 0.001), long-term retention (p = 0.031), patient-reported everyday memory (p < 0.001), caregiver-reported everyday memory (p < 0.001), anxiety (p = 0.039) and total quality of life (p < 0.001). Individual analysis showed improvement in 50 %, 64 %, 71 %, 57 %, and 64 % of patients on learning, immediate recall, delayed recall, long-term retention, and total quality of life respectively. Despite improvements, themes indicative of a lack of awareness and understanding of cognitive deficits were identified. Overall, the program was rated favorably by patients and caregivers alike. NR shows promise for patients with DRE, however larger studies are warranted. The role of cognition in epilepsy needs to be introduced at the time of diagnosis to help lay the foundation for education and acceptance. [ABSTRACT FROM AUTHOR]

• Little is understood about genetic factors in cognitive function and outcomes in TLE. • Results did not identify any significant relationship between PGS and cognition in TLE. • More research is needed to examine the role of genetic variation in cognition in TLE. • Future studies should seek to develop PGS specific to cognition in epilepsy. Demographic and disease factors are associated with cognitive deficits and postoperative cognitive declines in adults with pharmacoresistant temporal lobe epilepsy (TLE), but the role of genetic factors in cognition in TLE is not well understood. Polygenic scores (PGS) for neurological and neuropsychiatric disorders and IQ have been associated with cognition in patient and healthy populations. In this exploratory study, we examined the relationship between PGS for Alzheimer's disease (AD), depression, and IQ and cognitive outcomes in adults with TLE. 202 adults with pharmacoresistant TLE had genotyping and completed neuropsychological evaluations as part of a presurgical work-up. A subset (n = 116) underwent temporal lobe resection and returned for postoperative cognitive testing. Logistic regression was used to determine if PGS for AD, depression, and IQ predicted baseline domain-specific cognitive function and cognitive phenotypes as well as postoperative language and memory decline. No significant findings survived correction for multiple comparisons. Prior to correction, higher PGS for AD and depression (i.e., increased genetic risk for the disorder), but lower PGS for IQ (i.e., decreased genetic likelihood of high IQ) appeared possibly associated with baseline cognitive impairment in TLE. In comparison, higher PGS for AD and IQ appeared as possible risk factors for cognitive decline following temporal lobectomy, while the possible relationship between PGS for depression and post-operative cognitive outcome was mixed. We did not observe any relationships of large effect between PGS and cognitive function or postsurgical outcome; however, results highlight several promising trends in the data that warrant future investigation in larger samples better powered to detect small genetic effects. [ABSTRACT FROM AUTHOR]

Epilepsy is a chronic neurologic disorder characterized by abnormal functioning of brain networks, making it a complex research topic. Recent advancements in neuroimaging technology offer an effective approach to unraveling the intricacies of the human brain. Within different types of epilepsy, there is growing recognition regarding ongoing changes in the default mode network (DMN). However, little is known about the shared and distinct alterations of static functional connectivity (sFC) and dynamic functional connectivity (dFC) in DMN among epileptic subtypes, especially in children with epilepsy. Here, 110 children with epilepsy at a single center, including idiopathic generalized epilepsy (IGE), frontal lobe epilepsy (FLE), temporal lobe epilepsy (TLE), and parietal lobe epilepsy (PLE), as well as 84 healthy controls (HC) underwent resting-state functional magnetic resonance imaging (fMRI) scan. We investigated both sFC and dFC between groups of the DMN. Decreased static and dynamic connectivity within the DMN subsystem were shared by all subtypes. In each epilepsy subtype, children with epilepsy displayed significant and distinct patterns of DMN connectivity compared to the control group: the IGE group showed reduced interhemispheric connectivity, the FLE group consistently demonstrated disturbances in frontal region connectivity, the TLE group exhibited significant disruptions in hippocampal connectivity, and the PLE group displayed a notable decrease in parietal-temporal connectivity within the DMN. Some state-specific FC disruptions (decreased dFC) were observed in each epilepsy subtype that cannot detect by sFC. To determine their uniqueness within specific subtypes, bootstrapping methods were employed and found the significant results (IGE: between PCC and bilateral precuneus, FLE: between right middle frontal gyrus and bilateral middle temporal gyrus, TLE: between left Hippocampus and right fusiform, PLE: between left angular and cingulate cortex). Furthermore, only children with IGE exhibited dynamic features associated with clinical variables. Our findings highlight both shared and distinct FC alterations within the DMN in children with different types of epilepsy. Furthermore, our work provides a novel perspective on the functional alterations in the DMN of pediatric patients, suggesting that combined sFC and dFC analysis can provide valuable insights for deepening our understanding of the neuronal mechanism underlying epilepsy in children. • Decreased static and dynamic connectivity within the DMN subsystem were shared by all children with epilepsy • State-specific FC disruptions were observed in each patient group that were not detected by state FC • Epilepsy children in each subtype also showed unique connectivity patterns of the DMN that reflect their epilepsy types • The findings of static and dynamic functional abnormalities in DMN confirmed the essential role of DMN in children with epilepsy [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNA) are believed to play a crucial role in the cause and treatment of temporal lobe epilepsy (TLE) by controlling gene expression in different stages of the disease. To investigate role of miRNA in the latent stage following status epilepticus, we first compared microRNA expression profiles in mice hippocampus at 1 week after pilocarpine-induced status epilepticus (SE) vs. controls in hippocampal tissues using Exiqon miRCURY LNA™ miRNAs Array. Then, the target genes of altered miRNAs were predicted using both TargetScan 7.1 and miRDB V5, and were further selected by intersecting with another independent mRNA expression profile dataset from the samples at the same time point. We found out 14 common genes as down miRNA target (up-mRNA) and 4 common genes as up miRNA target (down mRNA) in SE mice. miR-669m-3p-TRHR (thyrotropin releasing hormone receptor), miR-669m-3p-B3galt2 (β-1,3-Galactosyltransferase 2), miR-105-PDPN (Podoplanin) and miR-883b-3p-CLEC-2 (C-type-lectin-like-2) were found to be potential molecular mechanisms to modulate the calcium signaling pathway, glycosylation pathways and chemokine mediated inflammatory processes in mice hippocampus at 1 week after pilocarpine-induced SE, respectively. Our results offered potential novel insights into the cellular events in the mice hippocampus mediated by miRNASs-target genes that shape SE-evoked epileptogenesis. • At 1 w after pilocarpine-induced SE, 1 up-regulated miRNA and 8 down-regulated miRNAs were identified in the mice hippocampus. • 4 genes were selected as up miRNA target and 14 genes were selected as down miRNA target respectively. • miR-669m-3p-TRHR, miR-669m-3p-B3galt2 and miR-105-PDPN may be involved in SE-evoked epileptogenesis [ABSTRACT FROM AUTHOR]

Adherens junction-associated protein-1 (AJAP1), also called SHREW1, was first discovered as a novel component of adherens junctions in 2004. In later studies, AJAP1 was found to suppress invasion and predict recurrence of some tumors. Apart from its function as a putative tumor suppressor, AJAP1 is still poorly understood. Schwenk et al. recently found that AJAP1 was tightly associated with the γ-Aminobutyric acid type B receptor subunit 1(GABA B R1). It is well known that GABA B R plays a vital role in epilepsy as an inhibitory transmitter receptor. Structurally adjacent, possibly functionally interacting, therefore, we hypothesize that AJAP1 participates in the onset and progression of epilepsy. We designed this experiment to investigate the expression and location of AJAP1 in temporal lobe epilepsy (TLE) patients and kainic acid(KA)-induced epilepsy animal models by immunofluorescence and Western blot analyses. We overexpressed and inhibited AJAP1 through lentiviruses in KA-induced models and observed the corresponding effects on epileptic animals. Double-label immunofluorescence showed that AJAP1 was expressed mainly in neurons. Western blot analysis revealed that AJAP1 expression was downregulated in the neocortex of TLE patients and the hippocampus and neocortex of epileptic animal models. The overexpression of AJAP1 can reduce the frequency of spontaneous seizures, whereas the inhibition of AJAP1 expression can increase the incidence rate. Our study demonstrated that AJAP1 may be involved in the pathogenic process of epilepsy and may represent a novel antiepileptic target. • Our study confirms that AJAP1 is closely related to epilepsy. • The expression of AJAP1 decreased in epileptic patients and animal models. • We have recorded the behavioral changes in epileptic mice with different levels of AJAP1. • We found that epilepsy was negatively correlated with the level of AJAP1. • In epileptic mice, different expression of AJAP1 affects the levels of GABA B R1. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is the most prevalent and often devastating form of epilepsy. The molecular mechanism underlying the development of TLE remains largely unclear, which hinders the discovery of effective antiepileptogenic drugs. Here we adopted a systems-level approach integrating transcriptomic profiles of three epileptogenesis stages to identify key regulators underlying epilepsy progression. Associating stage-specific gene meta-signatures with brain cell-specialized modules revealed positive regulation of glial migration and adhesion, cytokine production, and neuron death, and downregulation of synaptic transmission and ion transport during epileptogenesis. We identified 265 key regulators driving these processes and 72 of them were demonstrated associating with seizure frequency and/or hippocampal sclerosis in human TLE. Importantly, the upregulation of FAM107A , LAMB2, LTBP1 and TGIF1, which are mainly involved in nervous system development, were found contributing to both conditions. Our findings present the evolution landscape of epileptogenesis and provide candidate regulators that may serve as potential antiepileptogenic targets. • Specific gene signatures are identified for different stages of epileptogenesis. • Expression dynamics of modules depict the evolution process of epilepsy. • Key regulators driving the epileptogenic process are inferred and validated. • Four regulators related to clinical symptoms may serve as new therapeutic targets. [ABSTRACT FROM AUTHOR]

• Cognitive impairment in people with epilepsy is common but access to neuropsychological screenings is limited by cost and time. • We evaluated cognition in people with temporal lobe epilepsy using neuropsychological screening tools and robotic (Kinarm) assessment. • Robotic assessment can assess executive function, attention, visuospatial and motor performance in a comparable manner to neuropsychological screenings in patients with temporal lobe epilepsy. • Technology-based assessment of cognition may be an effective tool to screen for cognitive impairment in people with epilepsy. Individuals with temporal lobe epilepsy (TLE) frequently demonstrate impairments in executive function, working memory, and/or declarative memory. It is recommended that screening for cognitive impairment is undertaken in all people newly diagnosed with epilepsy. However, standard neuropsychological assessments are a limited resource and thus not available to all. Our study investigated the use of robotic technology (the Kinarm robot) for cognitive screening. 27 participants with TLE (17 left) underwent both a brief neuropsychological screening and a robotic (Kinarm) assessment. The degree of impairments and correlations between standardized scores from both approaches to assessments were analysed across different neurocognitive domains. Performance was compared between people with left and right TLE to look for laterality effects. Finally, the association between the duration of epilepsy and performance was assessed. Across the 6 neurocognitive domains (attention, executive function, language, memory, motor and visuospatial) assessed by our neuropsychological screening, all showed scores that significantly correlated with Kinarm tasks assessing the same cognitive domains except language and memory that were not adequately assessed with Kinarm. Participants with right TLE performed worse on most tasks than those with left TLE, including both visuospatial (typically considered right hemisphere), and verbal memory and language tasks (typically considered left hemisphere). No correlations were found between the duration of epilepsy and either the neuropsychological screening or Kinarm assessment. Our findings suggest that Kinarm may be a useful tool in screening for neurocognitive impairment in people with TLE. Further development may facilitate an easier and more rapid screening of cognition in people with epilepsy and distinguishing patterns of cognitive impairment. [ABSTRACT FROM AUTHOR]

• Four patients with mixed TLE and IGE were identified; 0.1% of all epilepsies. • We could identify genes that are shared between TLE and syndromes of IGE. • While coexistence of TLE and IGE is a rare phenomenon, this could be explained by shared genetic variations. We investigated the frequency of coexistence of temporal lobe epilepsy (TLE) and idiopathic generalized epilepsy (IGE) in a retrospective database study. We also explored the underlying pathomechanisms of the coexistence of TLE and IGE based on the available information, using bioinformatics tools. The first phase of the investigation was a retrospective study. All patients with an electro-clinical diagnosis of epilepsy were studied at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2023. In the second phase, we searched the following databases for genetic variations (epilepsy-associated genetic polymorphisms) that are associated with TLE or syndromes of IGE: DisGeNET, genome-wide association study (GWAS) Catalog, epilepsy genetic association database (epiGAD), and UniProt. We also did a separate literature search using PubMed. In total, 3760 patients with epilepsy were registered at our clinic; four patients with definitely mixed TLE and IGE were identified; 0.1% of all epilepsies. We could identify that rs1883415 of ALDH5A1, rs137852779 of EFHC1, rs211037 of GABRG2, rs1130183 of KCNJ10, and rs1045642 of ABCB1 genes are shared between TLE and syndromes of IGE. While coexistence of TLE and IGE is a rare phenomenon, this could be explained by shared genetic variations. [ABSTRACT FROM AUTHOR]

• Probabilistic fiber tracking and functional connectivity (FC) analysis were performed to investigate brain network changes in epilepsy. • The left precuneus volumes in epilepsy groups were lower than that in healthy controls. • Temporal lobe epilepsy (TLE) patients and frontal lobe epilepsy (FLE) patients showed structural and functional changes in the DMN. • Compared with FLE patients, TLE patients showed reduced structural and functional connection strengths between the left hippocampus and precuneus. • We provided new insights into the underlying pathological changes in TLE patients. To investigate brain network properties and connectivity abnormalities of the default mode network (DMN) in drug-resistant epilepsy (DRE). The study was based on probabilistic fiber tracking and functional connectivity (FC) analysis, to explore the structural and functional connectivity patterns change between frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). A total of 33 DRE patients (18 TLE and 15 FLE) and 30 healthy controls (HCs) were recruited. The volume fraction of the septal brain region of the DMN in DRE was calculated using FreeSurfer. The FC analysis was performed using Data Processing and Analysis for Brain Imaging in MATLAB. The structural connections between brain regions of the DMN were calculated based on probabilistic fiber tracking. The left precuneus (PCUN) volumes in epilepsy groups were lower than that in HCs. Compared with FLE, TLE showed reduced FC between the left hippocampus (HIP) and PCUN/medial frontal gyrus, and between the right inferior parietal lobule (IPL) and right superior temporal gyrus. Compared with HCs, FLE showed increased FCs between the right IPL and occipital lobe, and between the left superior frontal gyrus (SFG) and bilateral superior temporal gyrus. In terms of structural connectivity, TLE exhibited increased connectivity strength between the left SFG and left PCUN, and showed reduced connection strength between the left HIP and left posterior cingulate gyrus/left PCUN, when compared with the FLE. TLE and FLE patients showed structural and functional changes in the DMN. Compared with FLE patients, the TLE patients showed reduced structural and functional connection strengths between the left HIP and PCUN. These alterations in connection strengths holds promise for the identification of TLE and FLE. [ABSTRACT FROM AUTHOR]

• TLE patients exhibit poorer executive performance compared to healthy controls. • Right-TLE patients showed lower performance than left-TLE in cognitive flexibility. • Lateralization of temporal focus helps to precise neuropsychological cognitive profile. • Comprehensive assessment of EF is vital for understanding cognitive phenotypes in TLE. Temporal Lobe Epilepsy (TLE) has been associated with memory impairments, which are typically linked to hippocampal and mesial temporal cortex lesions. Considering the presence of extensive bidirectional frontotemporal connections, it can be hypothesized that executive dysfunction in TLE is modulated by the lateralization of the epileptic foci. A comprehensive neuropsychological executive functions protocol was administered to 63 participants, including 42 individuals with temporal lobe epilepsy (20 with right-TLE and 22 with left-TLE) and 21 healthy controls aged 20–49. The results indicate that TLE patients exhibit poorer executive performance compared to healthy controls in working memory (F(2,60) = 4.18, p <.01), planning (F(2,60) = 4.71, p <.05), set shifting (F(2,60) = 10.1, p <.001), phonetic verbal fluency (F(2,60) = 11.71, p <.01) and semantic verbal fluency (F(2,60) = 9.61, p <.001. No significant differences were found in cognitive inhibition. Furthermore, right-TLE patients showed lower performance than left-TLE in set shifting (F(1,61) = 6.45, p <.05), while no significant differences were observed in working memory, planning, inhibition, and verbal fluency. This research emphasize the importance of considering the lateralization of the temporal lobe focus to achieve a more accurate neuropsychological characterization. The cognitive differences between left and right TLE patients highlight the need for individualized approaches in their treatment and care. [ABSTRACT FROM AUTHOR]

• Complex automatic behavior (automatism) may occur in seizure. • Complex automatism can mimic modern behaviors such as smartphone use. • Complex automatism may be related to seizure spread to the non-dominant hemisphere. To describe a novel set of gestural automatisms related to the use of digital screens on smartphones and tablets in patients with epilepsy. Representative patients were selected from among those admitted to the Epilepsy Monitoring Unit at the Toronto Western Hospital between April 2016 and January 2020, and included if they exhibited automatisms clearly related to or mimicking digital device use. In total 5 patients were included, 4 female. All had temporal lobe epilepsy: 2 had left mesial temporal sclerosis and 3 had normal imaging. Nearly equal numbers of seizures began with right (5/9) and left (4/9) temporal onsets, with most automatisms occurring after seizure propagation to bilateral temporal involvement (6/9). Left-handed automatisms were most common (8/9). The majority of the automatisms (7/9) were perseverative on device usage prior to the seizure. Gestural automatisms appear related to the contemporary lived experience, culture, and habitual behaviour of patients with epilepsy. In the modern era, the use of smartphones and tablets are both common and habitual for many, and this case series shows that touch-screen automatisms may be added to the semiological panoply of temporal lobe seizures. [ABSTRACT FROM AUTHOR]

Studying the development of brain network disruptions in epilepsy is challenged by the paucity of data before epilepsy onset. Here, we used the unilateral, kainate mouse model of hippocampal epilepsy to investigate brain network changes before and after epilepsy onset and their stability across time. Using 32 epicranial electrodes distributed over the mouse hemispheres, we analyzed EEG epochs free from epileptic activity in 15 animals before and 28 days after hippocampal injection (group 1) and in 20 animals on two consecutive days (d28 and d29, group 2). Statistical dependencies between electrodes were characterized with the debiased-weighted phase lag index. We analyzed: a) graph metric changes from baseline to chronic stage (d28) in group 1; b) their reliability across d28 and d29, in group 2; c) their correlation with epileptic activity (EA: seizure, spike and fast-ripple rates), averaged over d28 and d29, in group 2. During the chronic stage, intra-hemispheric connections of the non-injected hemisphere strengthened, yielding an asymmetrical network in low (4–8 Hz) and high theta (8–12 Hz) bands. The contralateral hemisphere also became more integrated and segregated within the high theta band. Both network topology and EEG markers of EA were stable over consecutive days but not correlated with each other. Altogether, we show reproducible large-scale network modifications after the development of focal epilepsy. These modifications are mostly specific to the non-injected hemisphere. The absence of correlation with epileptic activity does not allow to specifically ascribe these network changes to mechanisms supporting EA or rather compensatory inhibition but supports the notion that epilepsy extends beyond the sole repetition of EA and impacts network that might not be involved in EA generation. • The contralateral hemisphere of a TLE mouse model is more integrated and segregated. • EEG-network changes (4–12 Hz) at the chronic stage are reproducible across two days. • 40 mins EEG recording yield stable signatures of epileptic activity over two days. • No correlation is found between network changes and epileptic activity. [ABSTRACT FROM AUTHOR]

Many adults with temporal lobe epilepsy (TLE) report subjective cognitive impairment; however, prior studies have shown a discrepancy between these subjective complaints and objective cognitive deficits on neuropsychological measures. Mood disorders/symptoms are also common in TLE and have been linked to greater subjective cognitive difficulties. To further understand these relationships, this retrospective study sought to determine if symptoms of depression and anxiety moderate or mediate the relationship between subjective cognitive impairment and objective cognitive performance in adults with TLE. Participants were 345 adults (mean age = 40.7; 55 % female) with pharmacoresistant TLE who completed self-report screening measures of depression, anxiety, and subjective cognitive function along with objective memory measures as part of a pre-surgical clinical neuropsychological evaluation. A series of linear regression analyses was conducted to examine the potential moderating and mediating effects of mood on the relationship between subjective and objective memory function after adjusting for relevant covariates. Consistent with existing literature, self-reported depression and anxiety symptoms were significantly correlated with subjective memory difficulties across all scales (all p <.001). Subjective memory impairment was also significantly correlated with objective memory performance on neuropsychological measures, albeit with small effect sizes (estimate range 0.04-0.20). Contrary to our hypothesis, depression and anxiety did not moderate or mediate the relationship between subjective memory complaints and objective memory performance. While symptoms of depression and anxiety were associated with subjective memory ability in this cohort of adults with TLE, this study suggests that mood symptoms do not fully explain the relationship between subjective and objective memory function, likely reflecting the complex and multifactorial relationships among these variables. Nevertheless, our results highlight the importance of screening for depression and anxiety symptoms and assessing patients' subjective memory complaints as part of a neuropsychological evaluation as each of these factors tap into a different aspect of the patient functioning. [ABSTRACT FROM AUTHOR]

Persistent homology offers a powerful tool for extracting hidden topological signals from brain networks. It captures the evolution of topological structures across multiple scales, known as filtrations, thereby revealing topological features that persist over these scales. These features are summarized in persistence diagrams, and their dissimilarity is quantified using the Wasserstein distance. However, the Wasserstein distance does not follow a known distribution, posing challenges for the application of existing parametric statistical models. To tackle this issue, we introduce a unified topological inference framework centered on the Wasserstein distance. Our approach has no explicit model and distributional assumptions. The inference is performed in a completely data driven fashion. We apply this method to resting-state functional magnetic resonance images (rs-fMRI) of temporal lobe epilepsy patients collected from two different sites: the University of Wisconsin-Madison and the Medical College of Wisconsin. Importantly, our topological method is robust to variations due to sex and image acquisition, obviating the need to account for these variables as nuisance covariates. We successfully localize the brain regions that contribute the most to topological differences. A MATLAB package used for all analyses in this study is available at https://github.com/laplcebeltrami/PH-STAT. • Proposed topological data analysis (TDA) framework for analyzing collection of brain networks. • TDA is robust to site affects. No need to account for sites as nuisance covariates. • Our method can localize brain regions that is responsible for topological changes. [ABSTRACT FROM AUTHOR]

The subiculum, a key output region of the hippocampus, is increasingly recognized as playing a crucial role in seizure initiation and spread. The subiculum consists of glutamatergic pyramidal cells, which show alterations in intrinsic excitability in the course of epilepsy, and multiple types of GABAergic interneurons, which exhibit varying characteristics in epilepsy. In this study, we aimed to assess the role of the vasoactive intestinal peptide interneurons (VIP-INs) of the ventral subiculum in the pathophysiology of temporal lobe epilepsy. We observed that an anatomically restricted inhibition of VIP-INs of the ventral subiculum was sufficient to reduce seizures in the intrahippocampal kainic acid model of epilepsy, changing the circadian rhythm of seizures, emphasizing the critical role of this small cell population in modulating TLE. As we expected, permanent unilateral or bilateral silencing of VIP-INs of the ventral subiculum in non-epileptic animals did not induce seizures or epileptiform activity. Interestingly, transient activation of VIP-INs of the ventral subiculum was enough to increase the frequency of seizures in the acute seizure model. Our results offer new perspectives on the crucial involvement of VIP-INs of the ventral subiculum in the pathophysiology of TLE. Given the observed predominant disinhibitory role of the VIP-INs input in subicular microcircuits, modifications of this input could be considered in the development of therapeutic strategies to improve seizure control. [Display omitted] • First long-term study of VIP-expressing interneurons of ventral subiculum in epilepsy. • Permanent silencing of VIP-expressing interneurons dampened seizure activity. • Short-term activation of VIP-expressing interneurons increased seizure severity. • Disinhibitory role of VIP-expressing interneurons of ventral subiculum in epilepsy. [ABSTRACT FROM AUTHOR]

• We used beta coherence of stereotaxic EEG to create functional connectomes and diffusion and T1 weighted MR images to create structural connectomes. • We then examined the structure-functional coupling at rest and at various ictal time points. • We found an association between lower coupling at rest and during ictal timepoints and seizure freedom status following surgical intervention. This proof-of-concept study aimed to examine the overlap between structural and functional activity (coupling) related to surgical response. We studied intracranial rest and ictal stereoelectroencephalography (sEEG) recordings from 77 seizures in thirteen participants with temporal lobe epilepsy (TLE) who subsequently underwent resective/laser ablation surgery. We used the stereotactic coordinates of electrodes to construct functional (sEEG electrodes) and structural connectomes (diffusion tensor imaging). A Jaccard index was used to assess the similarity (coupling) between structural and functional connectivity at rest and at various intraictal timepoints. We observed that patients who did not become seizure free after surgery had higher connectome coupling recruitment than responders at rest and during early and mid seizure (and visa versa). Structural networks provide a backbone for functional activity in TLE. The association between lack of seizure control after surgery and the strength of synchrony between these networks suggests that surgical intervention aimed to disrupt these networks may be ineffective in those that display strong synchrony. Our results, combined with findings of other groups, suggest a potential mechanism that explains why certain patients benefit from epilepsy surgery and why others do not. This insight has the potential to guide surgical planning (e.g., removal of high coupling nodes) following future research. [ABSTRACT FROM AUTHOR]

Epilepsy and psychiatric comorbidities have a complex relation, which can be manifested by their relatively high comorbid occurrence and the existence of a bidirectional relation, whereby not only are people with epilepsy (PWE) at greater risk of developing psychiatric disorders, but patients with primary psychiatric disorders are at higher risk of developing epilepsy. The existence of common pathogenic mechanisms operant in primary psychiatric disorders and epilepsy has been postulated as one of the leading hypothesis to explain their close and very complex relation. The neurobiologic characteristics of mood disorders can be used as a model to test this hypothesis. In this manuscript, we highlight data that suggest how several neurobiologic aspects of mood disorders can facilitate the epileptogenic process in animal models and explain the increased risk of patients with primary mood disorders to develop epilepsy in general and treatment-resistant epilepsy in particular. It is our hope that the inclusion of these data in this Special Issue will motivate neurologists to screen common psychiatric comorbidities in PWE. This article is part of the Special Issue "Obstacles of Treatment of Psychiatric Comorbidities in Epilepsy". • Mood disorders share common pathogenic mechanisms with epilepsy. • High glutamatergic, low GABAergic and low serotonergic activities are common in depression and epilepsy. • Hyperactive pituitary-adrenal occurs in major depression and the epileptogenic process in animal models of epilepsy. [ABSTRACT FROM AUTHOR]

Finding new targets to control or reduce seizure activity is essential to improve the management of epileptic patients. We hypothesized that activation of the pre-synaptic and inhibitory metabotropic glutamate receptor type 7 (mGlu7) reduces spontaneous seizures. We tested LSP2-9166, a recently developed mGlu7/4 agonist with unprecedented potency on mGlu7 receptors, in two paradigms of epileptogenesis. In a model of chemically induced epileptogenesis (pentylenetetrazole systemic injection), LSP2-9166 induces an anti-epileptogenic effect rarely observed in preclinical studies. In particular, we found a bidirectional modulation of seizure progression by mGlu4 and mGlu7 receptors, the latter preventing kindling. In the intra-hippocampal injection of kainic acid mouse model that mimics the human mesial temporal lobe epilepsy, we found that LSP2-9166 reduces seizure frequency and hippocampal sclerosis. LSP2-9166 also acts as an anti-seizure drug on established seizures in both models tested. Specific modulation of the mGlu7 receptor could represent a novel approach to reduce pathological network remodeling. Unlabelled Image • mGlu7 receptors reduce neurotransmitter release at presynaptic sites • Invalidation of mGlu7 renders mice over-responsive to chemical kindling • A new mGlu7/4 agonist, LSP2-9166, counteracts kindling progression in mice • The agonist modifies the development of KA-induced hippocampal seizures • LSP2-9166 has a strong anti-seizure effect in both epilepsy models [ABSTRACT FROM AUTHOR]

Astrocytes serve many functions in the human brain, many of which focus on maintenance of homeostasis. Astrocyte dysfunction in Tuberous Sclerosis Complex (TSC) has long been appreciated with activation of the mTORC1 signaling pathway resulting in gliosis and possibly contributing to the very frequent phenotype of epilepsy. We hypothesized that aberrant expression of the astrocyte protein aquaporin-4 (AQP4) may be present in TSC and contribute to disease pathology. Characterization of AQP4 expression in epileptic cortex from TSC patients demonstrated a diffuse increase in AQP4. To determine if this was due to exposure to seizures, we examined Aqp4 expression in mouse models of TSC in which Tsc1 or Tsc2 inactivation was targeted to astrocytes or glial progenitors, respectively. Loss of either Tsc1 or Tsc2 from astrocytes resulted in a marked increase in Aqp4 expression which was sensitive to mTORC1 inhibition with rapamycin. Our findings in both TSC epileptogenic cortex and in a variety of astrocyte culture models demonstrate for the first time that AQP4 expression is dysregulated in TSC. The extent to which AQP4 contributes to epilepsy in TSC is not known, though the similarities in AQP4 expression between TSC and temporal lobe epilepsy supports further studies targeting AQP4 in TSC. • AQP4 dysregulation may contribute to epilepsy. • AQP4 expression is increased in cerebral cortex in TSC patients. • Increased Aqp4 expression is seen in astrocytes from mouse models of TSC. • Aqp4 expression is decreased with mTOR inhibition in mouse models. [ABSTRACT FROM AUTHOR]

Behavioral and personality disorders in temporal lobe epilepsy (TLE) have been a topic of interest and controversy for decades, with less attention paid to alterations in normal personality structure and traits. In this investigation, core personality traits (the Big 5) and their neurobiological correlates in TLE were explored using the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) and structural magnetic resonance imaging (MRI) through the Epilepsy Connectome Project (ECP). NEO-FFI scores from 67 individuals with TLE (34.6 ± 9.5 years; 67% women) were compared to 31 healthy controls (32.8 ± 8.9 years; 41% women) to assess differences in the Big 5 traits (agreeableness, openness, conscientiousness, neuroticism, and extraversion). Individuals with TLE showed significantly higher neuroticism, with no significant differences on the other traits. Neural correlates of neuroticism were then determined in participants with TLE including cortical and subcortical volumes. Distributed reductions in cortical gray matter volumes were associated with increased neuroticism. Subcortically, hippocampal and amygdala volumes were negatively associated with neuroticism. These results offer insight into alterations in the Big 5 personality traits in TLE and their brain-related correlates. • Individuals with Temporal Lobe Epilepsy (TLE) show higher levels of neuroticism in the NEO-Five Factor Inventory. • Higher neuroticism is associated with earlier age of epilepsy onset. • Distributed reductions in cortical gray matter volumes were associated with increased neuroticism in TLE. • Hippocampal and amygdala volume were negatively associated with neuroticism in TLE. [ABSTRACT FROM AUTHOR]