Topographic-prognostic gradients of cortical hypometabolism in temporal lobe epilepsy

Abstract Anterior temporal lobectomy (ATL) remains the standard surgical treatment for pharmacoresistant temporal lobe epilepsy (TLE), yet long-term seizure freedom remains suboptimal. Neuroimaging studies show neocortical metabolic abnormalities beyond the mesiotemporal epicentre, but how such patterns inform resection extent remains unclear. We hypothesized that neocortical hypometabolism in TLE follows a quantifiable spatial gradient that can be translated into personalized surgical strategies. Our multicentre study included 358 participants across discovery, validation, and sensitivity analyses. Multimodal MRI and FDG-PET data were processed to derive vertex-wise structural, intensity, and metabolic features. Individual metabolic abnormalities were quantified using a normative asymmetry modelling approach. In the discovery cohort (227 patients undergoing ATL and 37 healthy controls), we characterized the topography of neocortical hypometabolism, and evaluated its correspondence to cytoarchitectural profiles, multimodal MRI features, and hippocampal measures. Three gradient-informed surgical metrics were evaluated in relation to seizure outcomes, with replication in an independent prospective validation cohort of 38 patients undergoing ATL. An additional sensitivity cohort comprising 56 surgical candidates, whose procedure spared the temporal neocortex was included to assess the robustness. Neocortical hypometabolism in TLE followed a spatially organized gradient, with the most severe hypometabolism at the hippocampal-neocortical interface that diminished with increasing geodesic distance (r = 0.955, Pperm < 0.001). Regions closer to the interface exhibited lower cytoarchitectonic differentiation and stronger FLAIR-related alterations. Hippocampal abnormalities also showed distance-dependent coupling with neocortical metabolism (r = 0.871, Pperm < 0.001). Among surgical metrics, greater resection of severe hypometabolism was associated with seizure freedom (OR = 1.448, P = 0.022). The association was replicated in the validation cohort. The present study identified a hypometabolic gradient in TLE, which covaries with cytoarchitectonic organization, microstructural changes, and hippocampal-neocortical interactions. The gradient provides a biologically grounded framework for precise surgical planning, emphasizing that targeting severe hypometabolism may optimize prognosis.