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.