Functional and effective connectivity alterations relate to cognitive performance in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder

Abstract The neural mechanisms underlying cognitive dysfunction in aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) remain unclear. Functional connectivity (FC) studies have revealed network-level alterations, but little is known about the effective interactions that support compensatory reorganization. To address this gap, we investigated how alterations in functional and effective connectivity (EC) within large-scale networks relate to cognitive performance in AQP4+NMOSD. To this end, twenty AQP4+NMOSD patients and twenty age- and sex-matched healthy controls (HCs) underwent 3-Tesla structural MRI and resting-state functional MRI. Seed-based and region-of-interest connectivity analyses focused on the default mode network (DMN) and ventral attention network (VAN). Directional interactions were assessed using Dynamic Causal Modelling (DCM). Cognitive performance was evaluated with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and the Controlled Oral Word Association Test (COWAT). Overall, cognition was quite preserved in patients, except for reduced COWAT scores. FC analyses revealed increased intra-network functional connectivity but decreased anterior–posterior DMN integration. DCM showed asymmetric prefrontal–posterior interactions, with stronger top-down excitatory influences from prefrontal to posterior regions. Taken together, these findings indicate that AQP4+NMOSD patients exhibit altered functional brain organization in the context of relatively preserved cognition, suggesting a pattern of large-scale network reorganization that may support cognitive performance.