Impairment In Temporal Lobe Epilepsy Research Articles

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

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

Altered structural network in temporal lobe epilepsy with focal to bilateral tonic-clonic seizures.

This study aims to investigate whether alterations in white matter topological networks are associated with focal to bilateral tonic-clonic seizures (FBTCS) in temporal lobe epilepsy (TLE). Additionally, we investigated the variables contributing to memory impairment in TLE. This cross-sectional study included 88 unilateral people with TLE (45 left/43 right), and 42 healthy controls. Graph theory analysis was employed to compare the FBTCS (+) group (n = 51) with the FBTCS (-) group (n = 37). The FBTCS (+) group was subcategorized into current-FBTCS (n = 31) and remote-FBTCS (n = 20), based on the history of FBTCS within 1 year or longer than 1 year before scanning, respectively. We evaluated the discriminatory power of topological network properties by receiver operating characteristic (ROC) analysis. Generalized linear models (GLMs) were employed to investigate variables associated with memory impairment in TLE. Global efficiency (Eg) was significantly reduced in the FBTCS (+) group, especially in the current-FBTCS subgroup. Greater disruption of regional properties in the ipsilateral occipital and temporal association cortices was observed in the FBTCS (+) group. ROC analysis revealed that Eg, normalized characteristic shortest path length, and nodal efficiency of the ipsilateral middle temporal gyrus could distinguish between FBTCS (+) and FBTCS (-) groups. Additionally, GLMs linked the occurrence of current FBTCS with poorer verbal memory outcomes in TLE. Our study suggests that abnormal networks could be the structural basis of seizure propagation in FBTCS. Strategies aimed at reducing the occurrence of FBTCS could potentially improve the memory outcomes in people with TLE.

Polygenic burden and its association with baseline cognitive function and postoperative cognitive outcome in temporal lobe epilepsy

ObjectiveDemographic 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. Methods202 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. ResultsNo 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. SignificanceWe 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.

Cognitive flexibility impairment in temporal lobe epilepsy: The impact of epileptic foci lateralization on executive functions

IntroductionTemporal 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. Material and MethodsA 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. ResultsThe 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. ConclusionsThis 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.

Impaired interhemispheric synchrony and effective connectivity in right temporal lobe epilepsy.

The brain functional network plays a crucial role in cognitive impairment in temporal lobe epilepsy (TLE). Based on voxel-mirrored homotopic connectivity (VMHC), this study explored how directed functional connectivity changes and is associated with impaired cognition in right TLE (rTLE). Twenty-seven patients with rTLE and twenty-seven healthy controls were included to perform VMHC and Granger causality analysis (GCA). Correlation analysis was performed based on GCA and cognitive function. Bilateral middle frontal gyrus (MFG), middle temporal gyrus, dorsolateral superior frontal gyrus (SFGdor), and supramarginal gyrus (SMG) exhibited decreased VMHC values in the rTLE group. Brain regions with altered VMHC had abnormal directed functional connectivity with multiple brain regions, mainly belonging to the default mode network, sensorimotor network, and visual network. Besides, the Montreal Cognitive Assessment (MoCA) score was positively correlated with the connectivity from the left SFGdor to the right cerebellum crus2 and was negatively correlated with the connectivity from the left SMG to the right supplementary motor area (SMA) before correction. Before correction, both phasic and intrinsic alertness reaction time were positively correlated with the connectivity from the left MFG to the left precentral gyrus (PreCG), connectivity from the left SMG to the right PreCG, and the connectivity from the left SMG to the right SMA. The executive control effect reaction time was positively correlated with the connectivity from the left MFG to the left calcarine fissure surrounding cortex before correction. The disordered functional network tended to be correlated with cognition impairment in rTLE.

Inhibitory dysfunction may cause prospective memory impairment in temporal lobe epilepsy (TLE) patients: an event-related potential study.

Prospective memory (PM) is the ability to remember future intentions, and PM function is closely related to independence in daily life, particularly in patients with temporal lobe epilepsy (TLE). As PM involves various cognitive components of attention, working memory, inhibition and other executive functions, this study investigated how TLE may affect PM components and the underlying neural mechanisms. Sixty-four subjects were recruited, including 20 refractory TLE patients, 18 well-controlled TLE patients and 26 age-matched healthy controls. A set of neuropsychological tests was administered to assess specific brain functions. An event-related potential (ERP) task was used to further explore how PM and its components would be differentially affected in the two TLE types. Our findings revealed that: (1) refractory TLE patients scored lower than the healthy controls in the digit span, Verbal Fluency Test and Symbol Digit Modalities Test; (2) refractory TLE patients exhibited impaired PM performance and reduced prospective positivity amplitudes over the frontal, central and parietal regions in ERP experiments when compared to the healthy controls; and (3) decreased P3 amplitudes in the nogo trials were observed over the frontal-central sites in refractory but not in well-controlled TLE patients. To our knowledge, this is the first ERP study on PM that has specifically identified PM impairment in refractory but not in well-controlled TLE patients. Our finding of double dissociation in PM components suggests that inhibition dysfunction may be the main reason for PM deficit in refractory TLE patients. The present results have clinical implications for neuropsychological rehabilitation in TLE patients.

Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model.

Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα+ glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα+ neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

The role of the thalamus in modular functional networks in temporal lobe epilepsy with cognitive impairment.

Cognitive deficit is common in patients with temporal lobe epilepsy (TLE). Here, we aimed to investigate the modular architecture of functional networks associated with distinct cognitive states in TLE patients together with the role of the thalamus in modular networks. Resting-state functional magnetic resonance imaging scans were acquired from 53 TLE patients and 37 matched healthy controls. All patients received the Montreal Cognitive Assessment test and accordingly were divided into TLE patients with normal cognition (TLE-CN, n = 35) and TLE patients with cognitive impairment (TLE-CI, n = 18) groups. The modular properties of functional networks were calculated and compared including global modularity Q, modular segregation index, intramodular connections, and intermodular connections. Thalamic subdivisions corresponding to the modular networks were generated by applying a 'winner-take-all' strategy before analyzing the modular properties (participation coefficient and within-module degree z-score) of each thalamic subdivision to assess the contribution of the thalamus to modular functional networks. Relationships between network properties and cognitive performance were then further explored. Both TLE-CN and TLE-CI patients showed lower global modularity, as well as lower modular segregation index values for the ventral attention network and the default mode network. However, different patterns of intramodular and intermodular connections existed for different cognitive states. In addition, both TLE-CN and TLE-CI patients exhibited anomalous modular properties of functional thalamic subdivisions, with TLE-CI patients presenting a broader range of abnormalities. Cognitive performance in TLE-CI patients was not related to the modular properties of functional network but rather to the modular properties of functional thalamic subdivisions. The thalamus plays a prominent role in modular networks and potentially represents a key neural mechanism underlying cognitive impairment in TLE.

Cognitive impairment in temporal lobe epilepsy

Cognitive impairment (CI) is a common comorbid pathology in epilepsy patients that exerts profound negative impact on quality of life. The CI causes may be due to various factors related to etiology, clinical manifestations, and treatment of epilepsy. A typical disorder in temporal lobe epilepsy is memory impairment. However, neuropsychological impairments may be more extensive and involve other neuropsychological domains. The risk of CI in patients with temporal lobe epilepsy may increase in structural brain disorders such as hippocampal sclerosis as well as in frequent seizures, early onset and long course of the disease. Surgical treatment of epilepsy may positively or negatively impact the cognitive function. In recent years, due to development of neurosciences as well as advances in the field of medical technologies, particularly neuroimaging, genetics, immunology, and biochemistry, new data emerged regarding potential mechanisms for developing CI in patients with epilepsy. The aim of the review is to assess available ideas about neurophysiological mechanisms of CI development, cues influencing emergence of neuropsychological disorders in patients with temporal lobe epilepsy.

Evaluation the cognition-improvement effects of N-acetyl cysteine in experimental temporal lobe epilepsy in rat

Memory impairment is a critical issue in patients with temporal lobe epilepsy (TLE). Neuronal loss within the hippocampus and recurrent seizures may cause cognitive impairment in TLE. N -acetyl cysteine (NAC) is a sulfur-containing amino acid cysteine that is currently being investigated due to its protective effects on neurodegenerative disorders. NAC was orally administrated at a dose of 100 mg/kg for 8 days (7-day pretreatment and 1-day post-surgery). Neuronal viability, mTOR protein level, and spatial memory were detected in the kainite temporal epilepsy model via Nissl staining, western blot method, and Morris water maze task, respectively. Results showed that NAC delayed seizure activity and ameliorated memory deficit induced by Kainic acid. Histological analysis showed that NAC significantly increased the number of intact neurons in CA3 and hilar areas of the hippocampus following the induction of epilepsy. NAC also modulated the mTOR protein level 5 days after epilepsy compared to the KA-induced group. ConclusionThese results suggest that NAC improved memory impairment via anticonvulsant and neuroprotective activity and, in all probability, by lowering the level of mTOR.

Molecular and subregion mechanisms of episodic memory phenotypes in temporal lobe epilepsy.

Memory dysfunction is prevalent in temporal lobe epilepsy, but little is known about the underlying pathophysiological etiologies. Here, we use spatial quantitation to examine differential expression of targeted proteins and transcripts in four brain regions essential for episodic memory (dentate gyrus, CA3, CA1, neocortex) between temporal lobe epilepsy patients with and without episodic memory impairment. Brain tissues were obtained from dominant temporal lobectomies in 16 adults with pharmacoresistant temporal lobe epilepsy associated with hippocampal sclerosis. Verbal memory tests from routine pre-operative clinical care were used to classify episodic memory as impaired or intact. Digital spatial profiling of a targeted protein panel and the whole transcriptome was performed using tissue sections from the temporal neocortex and hippocampus. We performed differential expression and pathway enrichment analysis between the memory groups within each temporal lobe region. Several proteins associated with neurodegenerative disease were overexpressed in the neocortex of patients with impaired memory, corroborating our prior findings using bulk transcriptomics. Spatial transcriptomics identified numerous differentially expressed transcripts in both neocortical and hippocampal subregions between memory groups, with little overlap across subregions. The strongest molecular signal was observed in the CA3 hippocampal subregion, known to play an essential role in memory encoding. Enrichment analyses revealed BDNF as a central hub in CA3-related networks regulating phenotype-relevant processes such as cognition, memory, long-term potentiation and neuritogenesis (Padj < 0.05). Results suggest memory impairment in temporal lobe epilepsy with hippocampal sclerosis is associated with molecular alterations within temporal lobe subregions that are independent from hippocampal cell loss, demographic variables and disease characteristics. Importantly, each temporal subregion shows a unique molecular signature associated with memory impairment. While many differentially expressed transcripts and proteins in the neocortex have been associated with neurodegenerative disorders/processes, differentially expressed transcripts in hippocampal subregions involve genes associated with neuritogenesis and long-term potentiation, processes essential for new memory formation.

Alterations in Neural Networks During Working Memory Encoding Related to Cognitive Impairment in Temporal Lobe Epilepsy.

Objective: The aim of the current study was to investigate the alterations in the neural networks of patients with temporal lobe epilepsy (TLE) during working memory (WM) encoding.Methods: Patients with TLE (n = 52) and healthy volunteers (n = 35) completed a WM task, during which 34-channel electroencephalogram signals were recorded. The neural networks during WM encoding were calculated in TLE patients with (TLE-WM) and without (TLE-N) WM deficits.Results: Functional connectivity strength decreased, and the theta network was altered in the TLE-WM group, although no significant differences in clinical features were observed between the TLE-N and TLE-WM groups.Conclusions: Not all patients with TLE present with cognitive impairments and alterations in the theta network were identified in TLE patients with functional cognitive deficits.Significance: The theta network may represent a sensitive measure of cognitive impairment and could predict cognitive outcomes among patients with TLE.

Low prevalence of amyloid and tau pathology in drug-resistant temporal lobe epilepsy.

Cognitive impairment is common in patients with chronic drug-resistant temporal lobe epilepsy (TLE). Hyperphosphorylated tau (pTau) and amyloid-β (Aβ) plaques, pathological hallmarks of Alzheimer disease, have been hypothesized to play a mechanistic role. We investigated Aβ plaques and pTau prevalence in TLE patients who underwent resective surgery and correlated their presence with preoperative psychometric test scores and clinical factors. Patients were retrospectively selected from the epilepsy surgery register of the Royal Melbourne Hospital, Australia. Sections from the resected temporal lobe were immunostained for pTau and Aβ plaques (antibodies: AT8, 1E8). The presence and severity of pathology were correlated with clinical characteristics, and verbal and visual learning functions as measured by the Verbal Pair Associates (VPA) test and Rey Complex Figure Test. Fifty-six patients (55% female) aged 20-68years (median = 34years) at surgery were included. Aβ plaques were detected in four patients (7%), all at the moderate level. There was no difference in duration, age at onset of epilepsy, or side of resection between patients with and without Aβ plaques. Sparse pTau was found in two patients (3.5%). Both had moderate Aβ plaques and were >50years of age. Patients with Aβ plaques had a lower median score for the VPA hard assessment compared to those without (0 vs. 4; p=.02). There was otherwise no correlation between pathology and psychometric test scores. Aβ plaques and pTau were uncommon in the resected brain tissue of patients who have undergone temporal lobectomy, and did not correlate with clinical characteristics or preoperative psychometric test scores, except for a lower VPA median score in patients with Aβ plaques. Therefore, considering the low prevalence of Aβ plaques and pTau herein observed, it is unlikely that cognitive impairment in TLE is driven by the same mechanisms as in Alzheimer disease.

Memory Deficit in Patients With Temporal Lobe Epilepsy: Evidence From Eye Tracking Technology.

Objective: To explore quantitative measurements of the visual attention and neuroelectrophysiological relevance of memory deficits in temporal lobe epilepsy (TLE) by eye tracking and electroencephalography (EEG).Methods: Thirty-four TLE patients and twenty-eight healthy controls were invited to complete neurobehavioral assessments, cognitive oculomotor tasks, and 24-h video EEG (VEEG) recordings using an automated computer-based memory assessment platform with an eye tracker. Visit counts, visit time, and time of first fixation on areas of interest (AOIs) were recorded and analyzed in combination with interictal epileptic discharge (IED) characteristics from the bilateral temporal lobes.Results: The TLE patients had significantly worse Wechsler Digit Span scores [F(1, 58) = 7.49, p = 0.008]. In the Short-Term Memory Game with eye tracking, TLE patients took a longer time to find the memorized items [F(1, 57) = 17.30, p < 0.001]. They had longer first fixation [F(1, 57) = 4.06, p = 0.049] and more visit counts [F(1, 57) = 7.58, p = 0.008] on the target during the recall. Furthermore, the performance of the patients in the Digit Span task was negatively correlated with the total number of IEDs [r(28) = −0.463, p = 0.013] and the number of spikes per sleep cycle [r(28) = −0.420, p = 0.026].Conclusion: Eye tracking appears to be a quantitative, objective measure of memory evaluation, demonstrating memory retrieval deficits but preserved visual attention in TLE patients. Nocturnal temporal lobe IEDs are closely associated with memory performance, which might be the electrophysiological mechanism for memory impairment in TLE.

Hippocampal atrophy and quantitative EEG markers in mild cognitive impairment in temporal lobe epilepsy versus extra-temporal lobe epilepsy.

Cognitive impairment in temporal lobe epilepsy is widely acknowledged as one of the most well-known comorbidities. This study aimed to explore cognitive impairment and to determine the potential clinical, radiological, and quantitative electroencephalography markers for cognitive impairment in temporal lobe epilepsy patients versus extra-temporal lobe epilepsy. Forty-five patients with temporal lobe epilepsy and forty-five patients with extra-temporal lobe epilepsy were recruited for an administered digit span test, verbal fluency test, mini-mental state examination, digital symbol test, and Montreal cognitive assessment. Also, they were subjected to magnetic resonance imaging assessment for hippocampal atrophy and a quantitative electroencephalography assessment for electroencephalography markers (median frequency, peak frequency, and the alpha-to-theta ratio). Patients with extra-temporal lobe epilepsy showed non-significant higher epilepsy durations and a higher frequency of seizures. Temporal lobe epilepsy patients showed a more statistically significant family history of epilepsy (37.7%), more history of febrile convulsions (13.3%), higher hippocampal atrophy (17.8%), and lower cognitive scales, especially mini-mental state examination and Montreal cognitive assessment; lower digital symbol test, verbal fluency test, and backward memory of digit span test. Also, temporal lobe epilepsy patients had a strong negative correlation with electroencephalography markers: median frequency, peak frequency, and the alpha-to-theta ratio (r = - 0.68, P < 0.005 and r = - 0.64, P < 0.005 and r = - 0.66, P < 0.005 respectively). Cognitive impairment in patients with temporal lobe epilepsy was correlated with hippocampal atrophy and quantitative electroencephalography abnormalities, especially peak frequency, median frequency, and alpha-to-theta ratio that could be used alone for the identification of early cognitive impairment. Clinicaltrials.gov: NCT04376671.

Association between serum apolipoprotein E and cognitive functions in temporal lobe epilepsy

Objective The aim was to estimate serum level of apolipoprotein E (Apo E) in patients with temporal lobe epilepsy (TLE) and to investigate the association between Apo E and cognitive functions in patients with TLE. Background There is a relation between Apo E and TLE, which has led to increased attention for examination. Apo E may exacerbate epilepsy and promote memory impairment in patients with long-standing TLE. Patients and methods A total of 40 patients with TLE and 40 normal participants were included. Interictal electroencephalogram and magnetic resonance imaging were done. Brain cognitive assessment was done using minimental state examination and Addenbrooke's cognitive examination revised (ACE-R). Serum Apo E was done using enzyme-linked immunosorbent assay technique. Results Minimental state examination and ACE-R scores were significantly less in the patients with TLE compared with the controls (P Conclusion There is a cognitive impairment in patients with TLE especially for memory, verbal fluency, and visuospatial activity. Serum Apo E was associated with cognitive impairment in TLE, which may suggest its possible role in cognitive impairment in patients with TLE.

The impact of hippocampal impairment on task-positive and task-negative language networks in temporal lobe epilepsy

ObjectiveTo study hippocampal integration within task-positive and task-negative language networks and the impact of a diseased left and right hippocampus on the language connectome in temporal lobe epilepsy (TLE). MethodsWe used functional magnetic resonance imaging (fMRI) to study a homogenous group of 32 patients with TLE (17 left) and 14 healthy controls during a verb-generation task. We performed functional connectivity analysis and quantified alterations within the language connectome and evaluated disruptions of the functional dissociation along the anterior-posterior axis of the hippocampi. ResultsConnectivity analysis revealed significant differences between left and right TLE compared to healthy controls. Left TLE showed widespread impairment of task-positive language networks, while right TLE showed less pronounced alterations. Particularly right TLE showed altered connectivity for cortical regions that were part of the default mode network (DMN). Left TLE showed a disturbed functional dissociation pattern along the left hippocampus to left and right inferior frontal language regions, while left and right TLE revealed an altered dissociation pattern along the right hippocampus to regions associated with the DMN. ConclusionsOur results showed an impaired hippocampal integration into active language and the default mode networks, which both may contribute to language impairment in TLE. SignificanceOur results emphasize the direct role of the left hippocampus in language processing, and the potential role of the right hippocampus as a modulator between DMN and task-positive networks.

Cognitive impairment in temporal lobe epilepsy: contributions of lesion, localization and lateralization.

Cognitive impairment is an importantcomorbidityof refractory temporal lobe epilepsy (TLE). We aimed to explore the impact of (i) specific lesions, such as dysembryoplastic neuroepithelial tumor (DNET), dysplasia, or hippocampal sclerosis, (ii) focus localization (medial versus lateral) and (iii) focus lateralization (right versus left) on the neuropsychological profile of refractory TLE adult patients. We examined the neuropsychological characteristics of 312 adults with refractory TLE: 100 patients without hippocampal sclerosis (HS) and 212 with HS. Scores on tests of intelligence (Global IQ, Verbal IQ and Performance IQ), working memory, episodic memory (verbal and visual learning and forgetting), executive functions and language abilities were analyzed. Three main factors influenced the neuropsychological profile of refractory TLE patients: (i) the lesion, patients with HS obtaining poorer cognitive performances than patients without HS and specifically DNET patients performing better than patients with HS, (ii) the focus side, that seems only relevant for verbal memory abilities which are affected in left but not right TLE patients and (iii) the localization of seizure focus, patients with medial TLE exhibiting lower memory performances than patients with lateral TLE. Lesion, localization and lateralization are major contributors of the cognitive impairment depicted in TLE. Hippocampal sclerosis appears as the main contributor.

Verbal memory dysfunction is associated with alterations in brain transcriptome in dominant temporal lobe epilepsy.

Memory dysfunction is prevalent in many neurological disorders and can have a significant negative impact on quality of life. The genetic contributions to memory impairment in epilepsy, particularly temporal lobe epilepsy (TLE), remain poorly understood. Here, we compare the brain transcriptome between TLE patients with and without verbal memory impairments to identify genes and signaling networks important for episodic memory. Brain tissues were resected from 23 adults who underwent dominant temporal lobectomy for treatment of pharmacoresistant epilepsy. To control for potential effects of APOE on memory, only those homozygous for the APOE ε3 allele were included. A battery of memory tests was performed, and patients were stratified into two groups based on preoperative memory performance. The groups were well matched on demographic and disease-related variables. Total RNA-Seq and small RNA-Seq were performed on RNA extracted from the brain tissues. Pathway and integrative analyses were subsequently performed. We identified 1092 differentially expressed transcripts (DETs), with the majority (71%) being underexpressed in brain tissues from patients with impaired memory compared to those from patients with intact memory. Enrichment analysis revealed overrepresentation of genes in pathways pertaining to brain-related neurological dysfunction, including a subset associated with neurodegenerative diseases, memory, and cognition (APP, MAPT, PINK1). Despite including patients with identical APOE genotypes, we identify APOE as a differentially expressed gene associated with memory status. Small RNA-Seq identified four differentially expressed microRNAs (miRNAs) that were predicted to target a subset (22%) of all DETs. Integrative analysis showed that these miRNA-predicted DET targets impact brain-related pathways and biological processes also pertinent to memory and cognition. TLE-associated memory status may be influenced by differences in gene expression profiles within the temporal lobe. Upstream processes influencing differential expression signatures, such as miRNAs, could serve as biomarkers and potential treatment targets for memory impairment in TLE.

The white matter connectome as an individualized biomarker of language impairment in temporal lobe epilepsy.

The distributed white matter network underlying language leads to difficulties in extracting clinically meaningful summaries of neural alterations leading to language impairment. Here we determine the predictive ability of the structural connectome (SC), compared with global measures of white matter tract microstructure and clinical data, to discriminate language impaired patients with temporal lobe epilepsy (TLE) from TLE patients without language impairment. T1- and diffusion-MRI, clinical variables (CVs), and neuropsychological measures of naming and verbal fluency were available for 82 TLE patients. Prediction of language impairment was performed using a robust tree-based classifier (XGBoost) for three models: (1) a CV-model which included demographic and epilepsy-related clinical features, (2) an atlas-based tract-model, including four frontotemporal white matter association tracts implicated in language (i.e., the bilateral arcuate fasciculus, inferior frontal occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus), and (3) a SC-model based on diffusion MRI. For the association tracts, mean fractional anisotropy was calculated as a measure of white matter microstructure for each tract using a diffusion tensor atlas (i.e., AtlasTrack). The SC-model used measurement of cortical-cortical connections arising from a temporal lobe subnetwork derived using probabilistic tractography. Dimensionality reduction of the SC was performed with principal components analysis (PCA). Each model was trained on 49 patients from one epilepsy center and tested on 33 patients from a different center (i.e., an independent dataset). Randomization was performed to test the stability of the results. The SC-model yielded a greater area under the curve (AUC; .73) and accuracy (79%) compared to both the tract-model (AUC: .54, p<.001; accuracy: 70%, p<.001) and the CV-model (AUC: .59, p<.001; accuracy: 64%, p<.001). Within the SC-model, lateral temporal connections had the highest importance to model performance, including connections similar to language association tracts such as links between the superior temporal gyrus to pars opercularis. However, in addition to these connections many additional connections that were widely distributed, bilateral and interhemispheric in nature were identified as contributing to SC-model performance. The SC revealed a white matter network contributing to language impairment that was widely distributed, bilateral, and lateral temporal in nature. The distributed network underlying language may be why the SC-model has an advantage in identifying sub-components of the complex fiber networks most relevant for aspects of language performance.