Successful TLE surgery is associated with partial restoration of cholinergic arousal network connectivity, supporting the idea that seizure cessation enables recovery of brain networks disrupted by recurrent seizures.
Abstract
Objective
Resective surgery achieves seizure freedom in approximately 60%-80% of patients with drug-resistant temporal lobe epilepsy (TLE), yet the extent to which seizure cessation permits recovery of disrupted functional brain networks remains unclear. Increasing evidence suggests that recurrent seizures alter subcortical-cortical communication involved in arousal and cognition, contributing to chronic interictal deficits, such as in executive function. Prior work demonstrates that the nucleus basalis of Meynert (NBM), the primary source of cortical cholinergic input to the cortex, exhibits aberrant functional connectivity in patients with TLE. We examined NBM connectivity in patients with TLE before and after surgery using patient-specific NBM segmentations. We sought to investigate whether seizure freedom is associated with recovery of NBM functional connectivity, consistent with previous observations of interictal network dysfunction reversal in other subcortical arousal structures.
Methods
Resting-state functional magnetic resonance imaging was analyzed in 75 patients with TLE, including 34 patients postoperatively, and 106 controls. Patient-specific NBM segmentations were used to compute functional connectivity between the NBM and frontoparietal association cortex (FPAC) and across the whole brain. Subcortical arousal network community structure was assessed using community detection. Postoperative network changes were evaluated relative to seizure outcome.
Results
Prior to surgery, patients exhibited reduced bilateral NBM connectivity to the FPAC and whole brain compared to controls, indicating widespread cholinergic network disruption beyond the ipsilateral hemisphere. Following surgery, NBM connectivity increased and no longer differed from controls. Seizure-free patients demonstrated greater postoperative increases in ipsilateral NBM-FPAC connectivity than non-seizure-free patients, which was not explained by time to postoperative scan or volumetric change. Subcortical arousal community structure remained altered postoperatively.
Significance
Successful TLE surgery is associated with partial restoration of cholinergic arousal network connectivity, supporting the idea that seizure cessation enables recovery of brain networks disrupted by recurrent seizures. These findings position the NBM as a potential biomarker of network recovery following epilepsy surgery.
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.
Stacy N. Hudgins, Michael R Sperling, Hasan Ayaz et al.· Epilepsia· 0 citations
Background. Temporal lobe epilepsy (TLE) is the most common drug-resistant focal epilepsy, and a substantial subgroup develops focal-to-bilateral tonic-clonic seizures (FBTCS) carrying heightened risk for SUDEP, cognitive decline, and poor surgical outcomes. The subcortical network mechanisms that index seizure generalization, their dependence on onset laterality, and their utility as biomarkers are poorly defined. Methods. Resting-state fMRI was acquired from 166 TLE patients (120 FBTCS+, 46 FBTCS-; 71 right TLE, 95 left TLE) and 119 healthy controls. Functional network connectivity and graph-theoretic analyses quantified clustering coefficient, degree centrality, local efficiency, and intrinsic connectivity contrast across 16 bilateral thalamic regions (Aim 1) and 54 ROIs spanning thalamus, hippocampus, amygdala, caudate, putamen, globus pallidus, and nucleus accumbens (Aim 2). A prespecified rmMANCOVA cascade tested covariate robustness of FBTCS effects. Aim 3 used nested 10x5 cross-validated linear SVMs with bootstrap and DeLong inference, prespecified sensitivity analyses, and permutation testing to compare connectivity versus standard clinical features for FBTCS classification. Results. Aim 1 showed reduced cross-hemispheric ventral anterior thalamic connectivity in TLE, with more pronounced ipsilateral dysfunction in right TLE; only right-TLE FBTCS+ patients showed ipsilateral VA disruption that worsened with illness duration. Aim 2 identified six bilateral subcortical subnetworks with reduced clustering coefficient in left ventroposterior lateral thalamus, left ventral anterior caudate, and right ventroposterior putamen in FBTCS+ patients. Right TLE FBTCS+ patients showed elevated bilateral nucleus accumbens cross-hemispheric connectivity that tracked with recent seizure burden, dissociating a state-dependent accumbens marker from trait-like thalamo-striatal desegregation. In Aim 3, connectivity outperformed clinical features in pooled TLE (AUC 0.618 vs 0.418, delta-AUC = +0.200, DeLong p = .005) and most strongly in right TLE (AUC 0.657 vs 0.311, delta-AUC = +0.346, DeLong p = .002). Left TLE was null across all panels, serving as a within-study negative control. Ventroposterior thalamus and nucleus accumbens emerged as top discriminators. Conclusions. Subcortical connectivity abnormalities in TLE organize into limbic-thalamo-striatal subnetworks with state- versus trait-like dissociation. Connectivity features discriminate FBTCS status beyond clinical features in pooled and right TLE, while left TLE remains null. These signatures motivate prospective external validation as candidate FBTCS risk-stratification biomarkers and targets for personalized treatment.
Background/Objectives: Epilepsy is a chronic brain disease characterized by recurrent epileptic seizures. It affects roughly 50 million people worldwide and around one third of the patients have drug-resistant epilepsy (DRE). The current study aimed to find differences in the whole-brain functional connectivity (FC) in patients with DRE compared to patients with well-controlled epilepsy (WCE) and healthy controls (HCs). Methods: This explorative, cross-sectional study included 92 participants (nDRE = 30; nWCE = 30; nHC = 32) who underwent resting-state functional magnetic resonance imaging (fMRI). The CONN Toolbox was used to process and analyze the FC changes among the three groups. Results: There was a statistically significant increase of the FC between the left lateral prefrontal cortex, left inferior temporal gyrus (temporo-occipital), left lobules IV and V of the cerebellum and multiple cortical and subcortical structures in patients with DRE as opposed to WCE and HC. On the other hand, decreased FC was observed between three seeds (the posterior cingulate cortex, precuneus cortex, the right planum polare) and different frontal, temporal and occipital regions. Interestingly, the right nucleus accumbens (r_NAc) showed increased FC with the inferior frontal gyrus in DRE compared to WCE, whereas the r_NAc-left precentral gyrus FC was reduced in DRE as opposed to HC. Conclusions: The acquired information offers valuable insights into the neuronal networks associated with DRE. These data could be used for advancing diagnostic accuracy and future therapeutic strategies.
Petar Vasilev, E. Viteva, A. Todeva-Radneva et al.· Neurology International· 0 citations
The model achieved high specificity in predicting long-term seizure recurrence, which supports its potential clinical utility for postoperative risk stratification and counseling rather than surgical exclusion and underscores the translational potential of network-level biomarkers to complement conventional predictors.
V.Yu. Karpychev, Rebecca W. Roth, William Yun et al.· Neurology· 0 citations
OBJECTIVE
Memory impairment is a common comorbidity in temporal lobe epilepsy (TLE) and is thought to arise from hippocampal dysfunction and disrupted interactions within a distributed memory network involving medial temporal, frontal, and parietal cortical regions. However, the network-level mechanisms underlying memory impairment in TLE remain poorly understood. Leveraging complementary intracranial electroencephalography (iEEG) and resting-state functional magnetic resonance imaging (rsfMRI), this study aimed to investigate hippocampal network alterations associated with memory dysfunction in TLE and characterize hippocampal-cortical connectivity patterns linked to individual differences in memory performance.
METHODS
This retrospective study included 29 patients with TLE who underwent structural MRI and rsfMRI, 13 of whom also underwent interictal iEEG. For each participant, 94 subject-specific regions of interest (ROIs) were generated, including 92 cortical ROIs from individualized rsfMRI parcellation and bilateral hippocampal ROIs defined using FreeSurfer subcortical segmentation. iEEG signals were projected onto these ROIs for cross-modal alignment. Hippocampal-cortical connectivity was estimated using rsfMRI functional connectivity and iEEG imaginary coherence, with hemispheres standardized relative to the epileptogenic side. Memory-related connectivity within the hippocampal network was then identified through behavioral-connectivity correlation analysis followed by Elastic Net regularization.
RESULTS
Increased ipsilesional hippocampal-cortical alpha-band (8-12 Hz) connectivity derived from interictal iEEG was significantly correlated with worse Logical Memory performance. Consistently, rsfMRI analyses revealed a significant epileptogenic side (ipsilesional vs. contralesional) and connection type (within- vs. between-hemisphere) interaction, with stronger within-hemispheric hippocampal-cortical connectivity in the ipsilesional hemisphere. Behavioral-connectivity analyses indicate that immediate and delayed recall shared a core episodic memory architecture, but delayed recall relied more on large-scale network coordination supporting retrieval after a delay.
SIGNIFICANCE
Our multimodal findings suggest that increased hippocampal connectivity in the epileptogenic hemisphere may reflect pathological hypersynchronization that disrupts efficient memory network coordination in TLE and highlight hippocampal connectivity as a promising candidate biomarker for characterizing individual memory outcomes.
Ruxue Gong, Xiaolong Peng, Rebecca W. Roth et al.· Epilepsia· 0 citations
Temporal lobe epilepsy (TLE) is increasingly recognized as a distributed network disorder extending beyond mesial temporal structures. Among the brain regions implicated in epileptic network organization, the thalamus has emerged as a key hub due to its extensive structural and functional connections with cortical, limbic, and subcortical systems.This integrative review aimed to synthesize current evidence regarding nucleus-specific thalamic abnormalities and thalamocortical connectivity alterations in TLE.A literature search was conducted following PRISMA guidelines using PubMed and Google Scholar databases. Twenty-eight studies were included in the qualitative synthesis, with nineteen studies providing detailed nucleus-specific structural, functional, or electrophysiological characterization of thalamic involvement.Across structural MRI, diffusion imaging, resting-state functional MRI, magnetoencephalography, and stereo-electroencephalography studies, convergent evidence indicated preferential involvement of the anterior thalamic nucleus (ANT), mediodorsal nucleus (MD), pulvinar, and intralaminar nuclei. TLE with mesial temporal sclerosis generally exhibited more extensive thalamic atrophy and thalamotemporal disconnection, whereas MRI-negative TLE showed more heterogeneous functional and network-level abnormalities. Electrophysiological studies demonstrated dynamic thalamic participation in seizure propagation and network synchronization, supporting an active role of thalamic nuclei in epileptic processes. Emerging longitudinal evidence further suggests that thalamocortical networks may undergo postoperative reorganization following successful epilepsy surgery.Overall, the available evidence supports a transition from a predominantly hippocampocentric framework toward a distributed thalamocortical network model of TLE. Nucleus-specific thalamic dysfunction appears to contribute to seizure propagation, cognitive impairment, and large-scale network dysregulation, highlighting the importance of multimodal approaches for understanding epileptic network organization.
Giuseppina Bevacqua, Marco Ciavarro, L. Gaetani et al.· Brain Structure and Function· 0 citations