Adaptive hub reorganization distinguishes cognitive preservation from decline in epilepsy

Cognitive impairment affects up to 80% of patients with drug resistant epilepsy (DRE), yet the basis for this impairment in patients with otherwise comparable disease characteristics remains poorly understood. Prior work has largely focused on identifying focal nodes responsible for cognitive decline, leaving the broader network reorganization associated with cognitive preservation poorly characterized. In this study, we hypothesized that the brain's capacity to reorganize its functional network hubs, rather than the degree of underlying pathology, distinguishes cognitively resilient from cognitively impaired patients. We studied a retrospective cohort of 105 DRE patients and 60 healthy controls who underwent resting-state functional neuroimaging. DRE patients were stratified into epilepsy cognitively neutral (ECN) and epilepsy cognitively impaired (ECI) subgroups based on comprehensive neuropsychological profiling spanning both domain-general and domain-specific levels. The subgroups did not differ in key disease characteristics including epilepsy duration, age of onset, seizure lateralization, and lesion status (p>0.05). We characterized hub organization across the whole brain, canonical functional networks and subcortical levels and summarized each subject's functional reorganization using the hub disruption index. We found that whole brain topology is preserved in both groups whereas disruption concentrates in the salience network and dissociates within subcortical structures with reduced hippocampal node strength in both groups and increased thalamic node strength, with the latter more pronounced with cognitive burden. Inter-network connectivity shifted from focal, selective up-regulation in ECN to diffuse hyperconnectivity in ECI. Critically, the hub disruption index (HDI) for centrality separated the groups where the ECN group showed the greatest redistribution of centrality from canonical hubs towards alternative relay regions whereas ECI demonstrated comparatively little reorganization (ECN vs ECI: d=0.52, p=0.029; Bonferroni corrected). The same pattern held within individual domains, with greater hub reorganization in patients whose language and memory function was preserved. These cross-sectional findings link cognitive impairment in epilepsy to a reduced capacity for adaptive hub reorganization rather than to pathology alone. Because the HDI for centrality is computable at the individual level, it may offer an objective imaging biomarker to complement neuropsychological testing, aid identification of patients at risk for cognitive decline, and inform prognostic counseling and surgical planning in DRE.