Cortical Thickness Patterns of Cognitive Impairment Phenotypes in Drug-Resistant Temporal Lobe Epilepsy.

OBJECTIVE: In temporal lobe epilepsy (TLE), a taxonomy classifying patients into 3 cognitive phenotypes has been adopted: minimally, focally, or multidomain cognitively impaired (CI). We examined gray matter (GM) thickness patterns of cognitive phenotypes in drug-resistant TLE and assessed potential use for predicting postsurgical cognitive outcomes. METHODS: TLE patients undergoing presurgical evaluation were categorized into cognitive phenotypes. Network edge weights and distances were calculated using type III analysis of variance F-statistics from comparisons of GM regions within each TLE cognitive phenotype and age- and sex-matched healthy participants. In resected patients, logistic regression models (LRMs) based on network analysis results were used for prediction of postsurgical cognitive outcome. RESULTS: A total of 124 patients (63 females, mean age ± standard deviation [SD] = 36.0 ± 12.0 years) and 117 healthy controls (63 females, mean age ± SD = 36.1 ± 12.0 years) were analyzed. In the multidomain CI group (n = 66, 53.2%), 28 GM regions were significantly thinner compared to healthy controls. Focally impaired patients (n = 37, 29.8%) showed 13 regions, whereas minimally impaired patients (n = 21, 16.9%) had 2 significantly thinner GM regions. Regions affected in both multidomain and focally impaired patients included the anterior cingulate cortex, medial prefrontal cortex, medial temporal, and lateral temporal regions. In 69 (35 females, mean age ± SD = 33.6 ± 18.0 years) patients who underwent surgery, LRMs based on network-identified GM regions predicted postsurgical verbal memory worsening with a receiver operating curve area under the curve of 0.70 ± 0.15. INTERPRETATION: A differential pattern of GM thickness can be found across different cognitive phenotypes in TLE. Including magnetic resonance imaging with clinical measures associated with cognitive profiles has potential in predicting postsurgical cognitive outcomes in drug-resistant TLE. ANN NEUROL 2024;95:984-997.

Connectome reorganization associated with temporal lobe pathology and its surgical resection.

Network neuroscience offers a unique framework to understand the organizational principles of the human brain. Despite recent progress, our understanding of how the brain is modulated by focal lesions remains incomplete. Resection of the temporal lobe is the most effective treatment to control seizures in pharmaco-resistant temporal lobe epilepsy (TLE), making this syndrome a powerful model to study lesional effects on network organization in young and middle-aged adults. Here, we assessed the downstream consequences of a focal lesion and its surgical resection on the brain's structural connectome, and explored how this reorganization relates to clinical variables at the individual patient level. We included adults with pharmaco-resistant TLE (n = 37) who underwent anterior temporal lobectomy between two imaging time points, as well as age- and sex-matched healthy controls who underwent comparable imaging (n = 31). Core to our analysis was the projection of high-dimensional structural connectome data-derived from diffusion MRI tractography from each subject-into lower-dimensional gradients. We then compared connectome gradients in patients relative to controls before surgery, tracked surgically-induced connectome reconfiguration from pre- to postoperative time points, and examined associations to patient-specific clinical and imaging phenotypes. Before surgery, individuals with TLE presented with marked connectome changes in bilateral temporo-parietal regions, reflecting an increased segregation of the ipsilateral anterior temporal lobe from the rest of the brain. Surgery-induced connectome reorganization was localized to this temporo-parietal subnetwork, but primarily involved postoperative integration of contralateral regions with the rest of the brain. Using a partial least-squares analysis, we uncovered a latent clinical imaging signature underlying this pre- to postoperative connectome reorganization, showing that patients who displayed postoperative integration in bilateral fronto-occipital cortices also had greater preoperative ipsilateral hippocampal atrophy, lower seizure frequency and secondarily generalized seizures. Our results bridge the effects of focal brain lesions and their surgical resections with large-scale network reorganization and interindividual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain.

The impact of bilateral versus unilateral anterior temporal lobe damage on face recognition, person knowledge and semantic memory.

The functional importance of the anterior temporal lobes (ATLs) has come to prominence in two active, albeit unconnected literatures-(i) face recognition and (ii) semantic memory. To generate a unified account of the ATLs, we tested the predictions from each literature and examined the effects of bilateral versus unilateral ATL damage on face recognition, person knowledge, and semantic memory. Sixteen people with bilateral ATL atrophy from semantic dementia (SD), 17 people with unilateral ATL resection for temporal lobe epilepsy (TLE; left = 10, right = 7), and 14 controls completed tasks assessing perceptual face matching, person knowledge and general semantic memory. People with SD were impaired across all semantic tasks, including person knowledge. Despite commensurate total ATL damage, unilateral resection generated mild impairments, with minimal differences between left- and right-ATL resection. Face matching performance was largely preserved but slightly reduced in SD and right TLE. All groups displayed the familiarity effect in face matching; however, it was reduced in SD and right TLE and was aligned with the level of item-specific semantic knowledge in all participants. We propose a neurocognitive framework whereby the ATLs underpin a resilient bilateral representation system that supports semantic memory, person knowledge and face recognition.

Dynamic evolution of frontal-temporal network connectivity in temporal lobe epilepsy: A magnetoencephalography study.

Temporal lobe epilepsy (TLE) frequently involves an intricate, extensive epileptic frontal-temporal network. This study aimed to investigate the interactions between temporal and frontal regions and the dynamic patterns of the frontal-temporal network in TLE patients with different disease durations. The magnetoencephalography data of 36 postoperative seizure-free patients with long-term follow-up of at least 1 year, and 21 age- and sex-matched healthy subjects were included in this study. Patients were initially divided into LONG-TERM (n = 18, DURATION >10 years) and SHORT-TERM (n = 18, DURATION ≤10 years) groups based on 10-year disease duration. For reliability, supplementary analyses were conducted with alternative cutoffs, creating three groups: 0 < DURATION ≤7 years (n = 11), 7 < DURATION ≤14 years (n = 11), and DURATION >14 years (n = 14). This study examined the intraregional phase-amplitude coupling (PAC) between theta phase and alpha amplitude across the whole brain. The interregional directed phase transfer entropy (dPTE) between frontal and temporal regions in the alpha and theta bands, and the interregional cross-frequency directionality (CFD) between temporal and frontal regions from the theta phase to the alpha amplitude were further computed and compared among groups. Partial correlation analysis was conducted to investigate correlations between intraregional PAC, interregional dPTE connectivity, interregional CFD, and disease duration. Whole-brain intraregional PAC analyses revealed enhanced theta phase-alpha amplitude coupling within the ipsilateral temporal and frontal regions in TLE patients, and the ipsilateral temporal PAC was positively correlated with disease duration (r = 0.38, p <.05). Interregional dPTE analyses demonstrated a gradual increase in frontal-to-temporal connectivity within the alpha band, while the direction of theta-band connectivity reversed from frontal-to-temporal to temporal-to-frontal as the disease duration increased. Interregional CFD analyses revealed that the inhibitory effect of frontal regions on temporal regions gradually increased with prolonged disease duration (r = -0.36, p <.05). This study clarified the intrinsic reciprocal connectivity between temporal and frontal regions with TLE duration. We propose a dynamically reorganized triple-stage network that transitions from balanced networks to constrained networks and further develops into imbalanced networks as the disease duration increases.

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

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

Impact of white matter networks on risk for memory decline following resection versus ablation in temporal lobe epilepsy.

BACKGROUND: With expanding neurosurgical options in epilepsy, it is important to characterise each options' risk for postoperative cognitive decline. Here, we characterise how patients' preoperative white matter (WM) networks relates to postoperative memory changes following different epilepsy surgeries. METHODS: Eighty-nine patients with temporal lobe epilepsy with T1-weighted and diffusion-weighted imaging as well as preoperative and postoperative verbal memory scores (prose recall) underwent either anterior temporal lobectomy (ATL: n=38) or stereotactic laser amygdalohippocampotomy (SLAH; n=51). We computed laterality indices (ie, asymmetry) for volume of the hippocampus and fractional anisotropy (FA) of two deep WM tracts (uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF)). RESULTS: Preoperatively, left-lateralised FA of the ILF was associated with higher prose recall (p<0.01). This pattern was not observed for the UF or hippocampus (ps>0.05). Postoperatively, right-lateralised FA of the UF was associated with less decline following left ATL (p<0.05) but not left SLAH (p>0.05), while right-lateralised hippocampal asymmetry was associated with less decline following both left ATL and SLAH (ps<0.05). After accounting for preoperative memory score, age of onset and hippocampal asymmetry, the association between UF and memory decline in left ATL remained significant (p<0.01). CONCLUSIONS: Asymmetry of the hippocampus is an important predictor of risk for memory decline following both surgeries. However, asymmetry of UF integrity, which is only severed during ATL, is an important predictor of memory decline after ATL only. As surgical procedures and pre-surgical mapping evolve, understanding the role of frontal-temporal WM in memory networks could help to guide more targeted surgical approaches to mitigate cognitive decline.

Defining benchmark outcomes for mesial temporal lobe epilepsy surgery: A global multicenter analysis of 1119 cases.

OBJECTIVE: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff. RESULTS: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months). SIGNIFICANCE: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques.

Indirect structural changes and reduced controllability after temporal lobe epilepsy resection.

OBJECTIVE: To understand the potential behavioral and cognitive effects of mesial temporal resection for temporal lobe epilepsy (TLE) a method is required to characterize network-wide functional alterations caused by a discrete structural disconnection. The objective of this study was to investigate network-wide alterations in brain dynamics of patients with TLE before and after surgical resection of the seizure focus using average regional controllability (ARC), a measure of the ability of a node to influence network dynamics. METHODS: Diffusion-weighted imaging (DWI) data were acquired in 27 patients with drug-resistant unilateral mesial TLE who underwent selective amygdalohippocampectomy. Imaging data were acquired before and after surgery and a presurgical and postsurgical structural connectome was generated from whole-brain tractography. Edge-wise strength, node strength, and node ARC were compared before and after surgery. Direct and indirect edge-wise strength changes were identified using patient-specific simulated resections. Direct edges were defined as primary edges disconnected by the resection zone itself. Indirect edges were secondary measured edge strength changes. Changes in node strength and ARC were then related to both direct and indirect edge changes. RESULTS: We found nodes with significant postsurgical changes in both node strength and ARC surrounding the resection zone (paired t tests, p < .05, Bonferroni corrected). ARC identified additional postsurgical changes in nodes outside of the resection zone within the ipsilateral occipital lobe, which were associated with indirect edge-wise strength changes of the postsurgical network (Fisher's exact test, p < .001). These indirect edge-wise changes were facilitated through the "hub" nodes including the thalamus, putamen, insula, and precuneus. SIGNIFICANCE: Discrete network disconnection from TLE resection results in widespread structural and functional changes not predicted by disconnection alone. These can be well characterized by dynamic controllability measures such as ARC and may be useful for investigating changes in brain function that may contribute to seizure recurrence and behavioral or cognitive changes after surgery.

Semiautomated electric source imaging determines epileptogenicity of encephaloceles in temporal lobe epilepsy.

OBJECTIVE: We aimed to assess the ability of semiautomated electric source imaging (ESI) from long-term video-electroencephalographic (EEG) monitoring (LTM) to determine the epileptogenicity of temporopolar encephaloceles (TEs) in patients with temporal lobe epilepsy. METHODS: We conducted a retrospective study involving 32 temporal lobe epilepsy patients with TEs as potentially epileptogenic lesions in structural magnetic resonance imaging scans. Findings were validated through invasive intracerebral stereo-EEG in six of 32 patients and postsurgical outcome after tailored resection of the TE in 17 of 32 patients. LTM (mean duration = 6 days) was performed using the 10/20 system with additional T1/T2 for all patients and sphenoidal electrodes in 23 of 32 patients. Semiautomated detection and clustering of interictal epileptiform discharges (IEDs) were carried out to create IED types. ESI was performed on the averages of the two most frequent IED types per patient, utilizing individual head models, and two independent inverse methods (sLORETA [standardized low-resolution brain electromagnetic tomography], MUSIC [multiple signal classification]). ESI maxima concordance and propagation in spatial relation to TEs were quantified for sources with good signal quality (signal-to-noise ratio > 2, explained signal > 60%). RESULTS: ESI maxima correctly colocalized with a TE in 20 of 32 patients (62.5%) either at the onset or half-rising flank of at least one IED type per patient. ESI maxima showed propagation from the temporal pole to other temporal or extratemporal regions in 14 of 32 patients (44%), confirming propagation originating in the area of the TE. The findings from both inverse methods validated each other in 14 of 20 patients (70%), and sphenoidal electrodes exhibited the highest signal amplitudes in 17 of 23 patients (74%). The concordance of ESI with the TE predicted a seizure-free postsurgical outcome (Engel I vs. >I) with a diagnostic odds ratio of 2.1. SIGNIFICANCE: Semiautomated ESI from LTM often successfully identifies the epileptogenicity of TEs and the IED onset zone within the area of the TEs. Additionally, it shows potential predictive power for postsurgical outcomes in these patients.

Preoperative structural-functional coupling at the default mode network predicts surgical outcomes of temporal lobe epilepsy.

OBJECTIVE: Structural-functional coupling (SFC) has shown great promise in predicting postsurgical seizure recurrence in patients with temporal lobe epilepsy (TLE). In this study, we aimed to clarify the global alterations in SFC in TLE patients and predict their surgical outcomes using SFC features. METHODS: This study analyzed presurgical diffusion and functional magnetic resonance imaging data from 71 TLE patients and 48 healthy controls (HCs). TLE patients were categorized into seizure-free (SF) and non-seizure-free (nSF) groups based on postsurgical recurrence. Individual functional connectivity (FC), structural connectivity (SC), and SFC were quantified at the regional and modular levels. The data were compared between the TLE and HC groups as well as among the TLE, SF, and nSF groups. The features of SFC, SC, and FC were categorized into three datasets: the modular SFC dataset, regional SFC dataset, and SC/FC dataset. Each dataset was independently integrated into a cross-validated machine learning model to classify surgical outcomes. RESULTS: Compared with HCs, the visual and subcortical modules exhibited decoupling in TLE patients (p < .05). Multiple default mode network (DMN)-related SFCs were significantly higher in the nSF group than in the SF group (p < .05). Models trained using the modular SFC dataset demonstrated the highest predictive performance. The final prediction model achieved an area under the receiver operating characteristic curve of .893 with an overall accuracy of .887. SIGNIFICANCE: Presurgical hyper-SFC in the DMN was strongly associated with postoperative seizure recurrence. Furthermore, our results introduce a novel SFC-based machine learning model to precisely classify the surgical outcomes of TLE.

Amygdala enlargement in temporal lobe epilepsy: Histopathology and surgical outcomes.

OBJECTIVES: Amygdala enlargement is detected on magnetic resonance imaging (MRI) in some patients with drug-resistant temporal lobe epilepsy (TLE), but its clinical significance remains uncertain We aimed to assess if the presence of amygdala enlargement (1) predicted seizure outcome following anterior temporal lobectomy with amygdalohippocampectomy (ATL-AH) and (2) was associated with specific histopathological changes. METHODS: This was a case-control study. We included patients with drug-resistant TLE who underwent ATL-AH with and without amygdala enlargement detected on pre-operative MRI. Amygdala volumetry was done using FreeSurfer for patients who had high-resolution T1-weighted images. Mann-Whitney U test was used to compare pre-operative clinical characteristics between the two groups. The amygdala volume on the epileptogenic side was compared to the amygdala volume on the contralateral side among cases and controls. Then, we used a two-sample, independent t test to compare the means of amygdala volume differences between cases and controls. The chi-square test was used to assess the correlation of amygdala enlargement with (1) post-surgical seizure outcomes and (2) histopathological changes. RESULTS: Nineteen patients with and 19 patients without amygdala enlargement were studied. Their median age at surgery was 38 years for cases and 39 years for controls, and 52.6% were male. There were no statistically significant differences between the two groups in their pre-operative clinical characteristics. There were significant differences in the means of volume difference between cases and controls (Diff = 457.2 mm3, 95% confidence interval [CI] 289.6-624.8; p < .001) and in the means of percentage difference (p < .001). However, there was no significant association between amygdala enlargement and surgical outcome (p = .72) or histopathological changes (p = .63). SIGNIFICANCE: The presence of amygdala enlargement on the pre-operative brain MRI in patients with TLE does not affect the surgical outcome following ATL-AH, and it does not necessarily suggest abnormal histopathology. These findings suggest that amygdala enlargement might reflect a secondary reactive process to seizures in the epileptogenic temporal lobe.

Mesial temporal lobe spiking reveals distinct patterns of blood oxygen level-dependent functional magnetic resonance imaging activation using simultaneous intracranial electroencephalography-functional magnetic resonance imaging.

OBJECTIVE: Temporal lobe epilepsy (TLE) has a high probability of becoming drug resistant and is frequently considered for surgical intervention. However, 30% of TLE cases have nonlesional magnetic resonance imaging (MRI) scans, which is associated with worse surgical outcomes. Characterizing interactions between temporal and extratemporal structures in these patients may help understand these poor outcomes. Simultaneous intracranial electroencephalography-functional MRI (iEEG-fMRI) can measure the hemodynamic changes associated with interictal epileptiform discharges (IEDs) recorded directly from the brain. This study was designed to characterize the whole brain patterns of IED-associated fMRI activation recorded exclusively from the mesial temporal lobes of patients with nonlesional TLE. METHODS: Eighteen patients with nonlesional TLE undergoing iEEG monitoring with mesial temporal IEDs underwent simultaneous iEEG-fMRI at 3 T. IEDs were marked, and statistically significant clusters of fMRI activation were identified. The locations of IED-associated fMRI activation for each patient were determined, and patients were grouped based on the location and pattern of fMRI activation. RESULTS: Two patterns of IED-associated fMRI activation emerged: primarily localized (n = 7), where activation was primarily located within the ipsilateral temporal lobe, and primarily diffuse (n = 11), where widespread bilateral extratemporal activation was detected. The primarily diffuse group reported significantly fewer focal to bilateral tonic-clonic seizures and had better postsurgical outcomes. SIGNIFICANCE: Simultaneous iEEG-fMRI can measure the hemodynamic changes associated with focal IEDs not visible on scalp EEG, such as those arising from the mesial temporal lobe. Significant fMRI activation associated with these IEDs was observed in all patients. Two distinct patterns of IED-associated activation were seen: primarily localized to the ipsilateral temporal lobe and more widespread, bilateral activation. Patients with widespread IED associated-activation had fewer focal to bilateral tonic-clonic seizures and better postsurgical outcome, which may suggest a neuroprotective mechanism limiting the spread of ictal events.

[18F]FDG PET metabolic patterns in mesial temporal lobe epilepsy with different pathological types.

OBJECTIVES: To investigate [18F]FDG PET patterns of mesial temporal lobe epilepsy (MTLE) patients with distinct pathologic types and provide possible guidance for predicting long-term prognoses of patients undergoing epilepsy surgery. METHODS: This was a retrospective review of MTLE patients who underwent anterior temporal lobectomy between 2016 and 2021. Patients were classified as having chronic inflammation and gliosis (gliosis, n = 44), hippocampal sclerosis (HS, n = 43), or focal cortical dysplasia plus HS (FCD-HS, n = 13) based on the postoperative pathological diagnosis. Metabolic patterns and the severity of metabolic abnormalities were investigated among MTLE patients and healthy controls (HCs). The standardized uptake value (SUV), SUV ratio (SUVr), and asymmetry index (AI) of regions of interest were applied to evaluate the severity of metabolic abnormalities. Imaging processing was performed with statistical parametric mapping (SPM12). RESULTS: With a mean follow-up of 2.8 years, the seizure freedom (Engel class IA) rates of gliosis, HS, and FCD-HS were 54.55%, 62.79%, and 69.23%, respectively. The patients in the gliosis group presented a metabolic pattern with a larger involvement of extratemporal areas, including the ipsilateral insula. SUV, SUVr, and AI in ROIs were decreased for patients in all three MTLE groups compared with those of HCs, but the differences among all three MTLE groups were not significant. CONCLUSIONS: MTLE patients with isolated gliosis had the worst prognosis and hypometabolism in the insula, but the degree of metabolic decrease did not differ from the other two groups. Hypometabolic regions should be prioritized for [18F]FDG PET presurgical evaluation rather than [18F]FDG uptake values. CLINICAL RELEVANCE STATEMENT: This study proposes guidance for optimizing the operation scheme in patients with refractory MTLE and emphasizes the potential of molecular neuroimaging with PET using selected tracers to predict the postsurgical histology of patients with refractory MTLE epilepsy. KEY POINTS: • MTLE patients with gliosis had poor surgical outcomes and showed a distinct pattern of decreased metabolism in the ipsilateral insula. • In the preoperative assessment of MTLE, it is recommended to prioritize the evaluation of glucose hypometabolism areas over [18F]FDG uptake values. • The degree of glucose hypometabolism in the epileptogenic focus was not associated with the surgical outcomes of MTLE.

Cell-type specific and multiscale dynamics of human focal seizures in limbic structures.

The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the transition to seizure is complex, potentially leading to imprecise delineation of epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing and others suggesting reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principle applies in limbic structures. We analysed simultaneous electrocorticography (ECoG) and neuronal recordings of 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, which at times co-existed within seizures. Overall, 156 single units were isolated, subclassified by cell-type and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (P < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition, with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (P = 0.014). This study provides evidence for entrained high-gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, reduced neuronal firing suggested preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or indicates a 'seizure-responsive' state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help to refine the surgical treatment of mesial temporal lobe epilepsy.

Structural disconnection relates to functional changes after temporal lobe epilepsy surgery.

Epilepsy surgery consists of surgical resection of the epileptic focus and is recommended for patients with drug-resistant focal epilepsy. However, focal brain lesions can lead to effects in distant brain regions. Similarly, the focal resection in temporal lobe epilepsy surgery has been shown to lead to functional changes distant from the resection. Here we hypothesize that there are changes in brain function caused by temporal lobe epilepsy surgery in regions distant from the resection that are due to their structural disconnection from the resected epileptic focus. Therefore, the goal of this study was to localize changes in brain function caused by temporal lobe epilepsy surgery and relate them to the disconnection from the resected epileptic focus. This study takes advantage of the unique opportunity that epilepsy surgery provides to investigate the effects of focal disconnections on brain function in humans, which has implications in epilepsy and broader neuroscience. Changes in brain function from pre- to post-epilepsy surgery were quantified in a group of temporal lobe epilepsy patients (n = 36) using a measure of resting state functional MRI activity fluctuations. We identified regions with significant functional MRI changes that had high structural connectivity to the resected region in healthy controls (n = 96) and patients based on diffusion MRI. The structural disconnection from the resected epileptic focus was then estimated using presurgical diffusion MRI and related to the functional MRI changes from pre- to post-surgery in these regions. Functional MRI activity fluctuations increased from pre- to post-surgery in temporal lobe epilepsy in the two regions most highly structurally connected to the resected epileptic focus in healthy controls and patients-the thalamus and the fusiform gyrus ipsilateral to the side of surgery (PFWE < 0.05). Broader surgeries led to larger functional MRI changes in the thalamus than more selective surgeries (P < 0.05), but no other clinical variables were related to functional MRI changes in either the thalamus or fusiform. The magnitude of the functional MRI changes in both the thalamus and fusiform increased with a higher estimated structural disconnection from the resected epileptic focus when controlling for the type of surgery (P < 0.05). These results suggest that the structural disconnection from the resected epileptic focus may contribute to the functional changes seen after epilepsy surgery. Broadly, this study provides a novel link between focal disconnections in the structural brain network and downstream effects on function in distant brain regions.

Visualization of the Spatiotemporal Propagation of Interictal Spikes in Temporal Lobe Epilepsy: A MEG Pilot Study.

Magnetoencephalography (MEG) is clinically used to localize interictal spikes in discrete brain areas of epilepsy patients through the equivalent current dipole (ECD) method, but does not account for the temporal dynamics of spike activity. Recent studies found that interictal spike propagation beyond the temporal lobe may be associated with worse postsurgical outcomes, but studies using whole-brain data such as in MEG remain limited. In this pilot study, we developed a tool that visualizes the spatiotemporal dynamics of interictal MEG spikes normalized to spike-free sleep activity to assess their onset and propagation patterns in patients with temporal lobe epilepsy (TLE). We extracted interictal source data containing focal epileptiform activity in awake and asleep states from seven patients whose MEG ECD clusters localized to the temporal lobe and normalized the data against spike-free sleep recordings. We calculated the normalized activity over time per cortical label, confirmed maximal activity at onset, and mapped the activity over a 10 ms interval onto each patient's brain using a custom-built Multi-Modal Visualization Tool. The onset of activity in all patients appeared near the clinically determined epileptogenic zone. By 10 ms, four of the patients had propagated source activity restricted to within the temporal lobe, and three had propagated source activity spread to extratemporal regions. Using this tool, we show that noninvasively identifying the onset and propagation of interictal spike activity in MEG can be achieved, which may help provide further insight into epileptic networks and guide surgical planning and interventions in patients with TLE.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. SIGNIFICANCE: 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.

An "epileptic scent": Olfactory auras in tumor-related epilepsy.

OBJECTIVES: To characterize a profile for patients with tumor-related epilepsy presenting olfactory auras. MATERIALS AND METHODS: We conducted a monocentric, retrospective study on patients who underwent surgery in the Neurosurgery Unit of Udine University Hospital (Udine, Italy), between the 1st of January 2010 and the 1st of January 2019, for primary brain tumors (PBTs) involving the temporal lobe and the insula. All patients were affected by tumor-related epilepsy; the study group presented olfactory auras as well. We collected neuroradiological, neuropsychological and neurophysiological data from patients' medical charts. RESULTS: The subtraction analysis of MRI data shows maximum lesion overlay in left olfactory cortex, left and right hippocampus, left amygdala, right rolandic operculum, right inferior frontal gyrus and right middle temporal gyrus. The presence of olfactory auras did not influence seizure outcome (p = 0.500) or tumor recurrence after surgery (p = 0.185). The type of auras (elementary vs. complex), also, did not influence seizure control (p = 0.222). DISCUSSION: In presence of olfactory auras, anterior and mesial temporal regions are mainly involved, such as olfactory cortex, amygdala, and anterior hippocampus, together with right rolandic operculum, right inferior frontal gyrus and right middle temporal gyrus, suggesting their possible role in the genesis of olfactory auras. Post-surgical seizure outcome and disease relapse are not influenced by neither the presence nor the type of olfactory auras. CONCLUSIONS: Olfactory auras are rare event, however they may be often underestimated by the patients and under-investigated by the clinicians, even when their occurrence can represent a useful localizing tool.

Comparison of minimally invasive to standard temporal lobectomy approaches to epilepsy surgery: Seizure relief and visual confrontation naming outcomes.

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.

Accounting for repeat intervention costs in the economic comparison of laser interstitial thermal therapy and anterior temporal lobectomy for treatment of refractory temporal lobe epilepsy.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. SIGNIFICANCE: 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.