Neurotransmitter-associated structural remodeling of the insula-hippocampus mediates cognitive impairment in age-related hearing loss

Age-related hearing loss is a major modifiable risk factor for cognitive decline, yet the dynamic trajectory of brain structural evolution and its underlying neurochemical basis remain poorly understood. This study investigated gray matter (GM) atrophy patterns and their causal relationships in 134 elderly participants, categorized by hearing loss severity, using voxel-based morphometry and causal structural covariance networks (CaSCN). We further explored spatial correlations between these structural changes and neurotransmitter systems using the JuSpace toolbox. Results identified a distinct "insula-initiated and hippocampus-terminated" structural atrophy cascade. Bilateral insular atrophy emerged during mild hearing loss and persisted throughout disease progression, while significant hippocampal atrophy primarily appeared in moderate-to-severe stages. CaSCN analysis identified the left insula as a primary "output hub" initiating a pathological cascade that converged on the hippocampus as the terminal "target node". Critically, the spatial pattern of GM atrophy was significantly coupled with specific neurotransmitter systems, including 5-HT1b, GABAa, and cannabinoid CB1 receptors, particularly in advanced stages. Furthermore, GM volumes of the insula and hippocampus were negatively correlated with high-frequency hearing thresholds and executive dysfunction. These findings reveal an insula-hippocampus axis of structural remodeling in ARHL, offering new insights into the neurobiological mechanisms of cognitive impairment and providing potential imaging biomarkers for early diagnosis.