Topographic-prognostic gradients of cortical hypometabolism in temporal lobe epilepsy

FUNCTIONAL FRAGMENTATION AND STRUCTURAL DRIVERS OF THALAMO-CORTICAL CIRCUITS IN TEMPORAL LOBE EPILEPSY

Objective In temporal lobe epilepsy (TLE), the thalamus acts as a nexus in a pathophysiological network that implicates mesiotemporal, subcortical, and neocortical regions. Studying a large multimodal and multicentre dataset, we profiled thalamic, hippocampal, and neocortical functional connectivity (FC), assessed structural mediators, and examined clinical associations. Methods We studied resting-state FC alongside structural and diffusion MRI data in 250 unilateral TLE patients and 259 healthy controls, with measures aggregated across four independent datasets. Data were processed using open-access neuroinformatics workflows and analyzed at a subregional level to maximize anatomical precision. Statistical analysis and mediation models assessed between-group FC changes, structural contributors, and clinical correlations. Results Compared to controls, TLE patients presented with reduced thalamo-cortical FC, which was most marked in mesiotemporal, fronto-central, and occipital regions. Thalamo-hippocampal FC was also reduced, with effects seen in all CA subfields. In the thalamus, FC reductions peaked in the ventral posterior nucleus when considering neocortical target regions and in the mediodorsal nucleus when considering hippocampal target regions. While ipsilateral hippocampal volume and diffusion changes mediated thalamo-hippocampal FC, thalamo-cortical FC appeared decoupled from structural alterations. Findings were consistent in left and right TLE patients, in patients with short and long disease duration, and across imaging sites, suggesting that thalamo-cortical FC imbalances are a consistent signature of TLE. Conversely, thalamo-hippocampal FC was elevated in patients with focal-to-bilateral-tonic-clonic seizures and FC alterations were more marked in the subgroup of operated patients that became seizure-free after surgery. Conclusion Our multi-site findings demonstrate marked thalamic circuit fragmentation in TLE. Ipsilateral findings robustly showed subdivision-specific effects, which point to both mesiotemporal co-lateralization as well as broader system-level involvement. Mediation analyses furthermore confirmed a key role of hippocampal pathology in disrupted thalamo-hippocampal connectivity in TLE, while broader thalamo-cortical fragmentation becomes increasingly independent of mesiotemporal compromise. Critically, thalamic FC represents a network substrate for seizure generalization and can serve as a prognostic indicator for surgical outcome. These results underscore the contribution of the thalamus as a hub in macroscale dysfunction in TLE.

The Spatial Divergence of Hypometabolism and Atrophy in Mesial Temporal Lobe Epilepsy: Combining 18F‐FDG PET and Structural MRI for Predicting Postoperative Seizure Freedom

Surgical failure in temporal lobe epilepsy with hippocampal sclerosis (TLE‐HS) may reflect insufficient disruption of epileptogenic networks. We investigated whether integrating quantitative spatial patterns of regional atrophy and hypometabolism, along with clinical features, could provide complementary prognostic information for postoperative seizure freedom. T1‐weighted MRI, 18F‐FDG‐PET, and postoperative CT scans of patients with TLE‐HS were retrospectively analyzed against a validated healthy control cohort to compute age‐ and gender‐adjusted W‐score maps. Regional relationships of atrophy and hypometabolism were assessed using bivariate correlations and multiple regression analyses. Machine learning models integrating laterality of seizure onset, preoperative (extra‐)temporal atrophy/hypometabolism extent, seizure frequency, focal to bilateral tonic–clonic seizures during the preceding year, and resection volume were developed to predict seizure freedom 1 year after surgery. Model interpretability was assessed via permutation‐based variable importance analysis. The cohort comprised 101 patients with TLE‐HS (48 left, LHS; 53 right, RHS), including 72 patients who underwent anterior temporal lobectomy. Distinct modality‐specific patterns emerged: hypometabolism was significantly greater than local atrophy in left temporo‐limbic cortex in TLE‐LHS, while atrophy exceeded hypometabolism in bilateral occipital regions in TLE‐RHS. Positive correlations between local atrophy and hypometabolism were more robust in ipsilateral temporo‐limbic cortex in TLE‐LHS. The combined model integrating preoperative atrophy and hypometabolism features (AUC: 0.56–0.64) significantly outperformed single‐modality models (pfdr < 0.05). Notably, incorporating clinical factors further enhanced predictive performance (AUC: 0.63–0.70) and model calibration. This comprehensive preoperative clinical‐imaging model achieved robust prognostic efficacy that was not significantly improved by the addition of actual postoperative resection volumes. Structural MRI and 18F‐FDG‐PET reveal complementary facets of the epileptogenic network in TLE‐HS. While integrating multimodal imaging with clinical metrics demonstrates significant synergistic potential for predicting surgical outcomes, our models remain exploratory. External validation in independent multi‐center cohorts is required before translating these findings into precise clinical tools for surgical planning.

Ventral anterior thalamic dysfunction distinguishes seizure generalization in temporal lobe epilepsy.

OBJECTIVE Focal-to-bilateral tonic-clonic seizures (FBTCS) in temporal lobe epilepsy (TLE) involve thalamocortical networks, yet the functional integrity and role of specific thalamic subregions in seizure generalization remain unclear. In this cross-sectional study, we investigated whether thalamic subregion functional connectivity patterns distinguish TLE patients with and without FBTCS and tested for laterality-specific differences between right TLE (RTLE) and left TLE (LTLE. METHODS We analyzed resting-state functional magnetic resonance imaging (fMRI) data from 166 patients with TLE (71 RTLE, 95 LTLE; 120 FBTCS+, and 46 FBTCS-) and 119 healthy participants. Thalamic parcellation identified eight bilateral regions of interest. We computed graph theory measures of regional segregation, connection density, and integration, as well as intrinsic connectivity contrast to characterize thalamic subregion network topology. Sensitivity analyses controlled for pathology subgroup and anti-seizure medication burden. RESULTS TLE patients exhibited reduced cross-hemispheric functional connectivity between bilateral ventral anterior (VA) thalamic regions compared with controls. Compared with patients with LTLE, patients with RTLE showed more pronounced ipsilateral VA hypoconnectivity and more disrupted nodal topology (clustering coefficient, degree centrality, local efficiency) in the ipsilateral VAia. Within RTLE, FBTCS+ patients (vs FBTCS-) showed ipsilateral connectivity reductions and cross-hemispheric VA reductions that increased with illness duration. Within LTLE, FBTCS+ patients (vs FBTCS-) showed bilateral connectivity increases in the ventral posterior medial subregion. Sensitivity analyses confirmed that these findings were robust across pathology subtypes and independent of anti-seizure medication burden. SIGNIFICANCE These findings provide initial evidence that intra-thalamic functional connectivity, particularly within the bilateral VA complex, is associated with FBTCS history in TLE and varies with lateralization of seizureonset. The observations may represent a biomarker for FBTCS, but whether this is causal or an epiphenomenon of this seizure type remains to be determined.

Subtle Hippocampal Subfield Volumetric Alterations in Clinically Diagnosed MRI-Negative Temporal Lobe Epilepsy.

Introduction Approximately 20-30% of temporal lobe epilepsy (TLE) cases present with no visible abnormalities on conventional magnetic resonance imaging (MRI). When interictal electroencephalography (EEG) recordings are also persistently normal, the diagnosis and lateralization become major clinical challenges. We aimed to investigate whether automated hippocampal subfield volumetry could detect subtle structural alterations in these "electro-clinically silent" MRI-negative cases and to correlate these findings with seizure semiology. Methods We analyzed 24 patients with clinically diagnosed MRI-negative/EEG-negative TLE and 26 age-matched healthy controls. Despite normal visual inspection on 1.5-T MRI, hippocampal subfield volumes were extracted using an automated segmentation pipeline (volBrain). Seizure semiology was systematically categorized to provide clinical-anatomical correlation. Results TLE patients exhibited a significant and selective volume reduction in the right CA4-dentate gyrus (CA4-DG) subfield compared to healthy controls (p=0.003), even after adjusting for age, sex, and total intracranial volume (p=0.002). No statistically significant differences were observed in other hippocampal subfields (CA1, CA2/3, or subiculum), indicating a highly localized pattern of structural alteration. Conclusion These results imply that selective CA4-DG atrophy is a defining characteristic of the MRI-negative TLE phenotype, thereby corroborating the "dentate gate" failure hypothesis. Quantitative volumetry provides a crucial diagnostic tool in settings with limited resources, where advanced techniques like 3-T MRI or invasive monitoring are not accessible. This objective structural marker, when integrated with comprehensive semiological analysis, improves diagnostic accuracy and facilitates early clinical intervention in difficult non-lesional TLE cases.

Multiscale alterations and cortex-wide organizational trends in focal cortical dysplasia

Preoperative Neuropsychology Subtypes Predict Neuropsychological Change after Temporal Lobe resection

Cognitive outcomes following temporal lobe epilepsy surgery are highly heterogeneous and remain difficult to predict using traditional threshold-based neuropsychological classifications. Here, we implemented Subtype and Stage Inference (SuStaIn) on preoperative neuropsychology to model cognitive function as a continuous network-level process reflecting both pathological burden and compensatory reserve. We identified three distinct latent trajectories: Verbal, Naming, and Visual. The Verbal subtype reflected classic mesial temporal pathology, where postoperative decline aligned with functional adequacy of residual hippocampal tissue. Conversely, the Naming subtype represented a neocortical-predominant 'Temporal Plus' phenotype; despite lower rates of hippocampal sclerosis, these individuals showed severe postoperative verbal memory vulnerability due to un-reorganized frontotemporal language networks. The Visual trajectory demonstrated progressive visuospatial decline with distinct sex-specific reserve profiles and poorer visual recall outcomes. Crucially, these progression-based trajectories outperformed conventional static classifications in predicting 12-month postoperative outcomes on unseen test data. Operating directly on routine preoperative evaluations without requiring additional testing, this computational framework disentangles pathological burden from network reserve, providing scalable, biologically interpretable biomarkers to guide personalized risk counselling and network-informed surgical planning.