Convergent functional networks of intrinsic activity alterations in temporal lobe epilepsy and their molecular correlates

Abstract

Background Temporal lobe epilepsy (TLE) is increasingly recognized as a network disorder, yet reported regional intrinsic neural activity alterations from resting-state fMRI studies remain spatially heterogeneous. This study aimed to determine whether these heterogeneous alterations converge onto a shared functional network and to characterize its normative transcriptomic and neurochemical correlates. Methods Using a coordinate-based network mapping approach (functional connectivity network mapping, FCNM), we delineated a common brain network functionally connected to regional intrinsic neural activity alterations reported across 20 published neuroimaging studies. The robustness of the resulting network was assessed in an independent cross-scanner validation connectome and across different seed sizes. We further characterized this TLE-related network by correlating its spatial topography with microscale gene expression data from the Allen Human Brain Atlas (AHBA) and with normative neurotransmitter receptor and transporter distributions derived from the JuSpace toolbox. Results Twenty studies comprising 345 foci of regional intrinsic neural activity alteration in TLE were included. The FCNM analysis revealed that heterogeneous regional alterations in TLE converged onto a common functional brain network. This network exhibited the greatest spatial overlap with the default mode network (DMN), while also showing substantial overlap with the limbic network (LN). Transcriptomic analysis revealed that the network’s topography was spatially correlated with gene expression profiles significantly enriched in adaptive immune response pathways, particularly antigen processing and presentation. Neurochemically, the TLE-related network exhibited a significant positive spatial correlation with the distribution of the 5-hydroxytryptamine receptor 1A (5-HT1A). Conclusion Our findings reconcile previously inconsistent reports of regional intrinsic neural activity alterations in TLE by demonstrating their convergence onto a shared brain network, primarily the DMN and LN. By linking this TLE-related network to specific normative transcriptomic and neurochemical signatures, we propose a multi-scale neurobiological framework for the disorder. These findings should be interpreted as spatial associations based on normative datasets rather than direct evidence of disease-specific molecular alterations. This framework reframes TLE from a collection of disparate regional changes toward a core network dysfunction with distinct molecular correlates, thereby opening new avenues for targeted, network-based interventions.