Cognitive and clinical dimensions of structural and functional insula alterations in patients with depression: a resting-state fMRI study

Aim: Depression is characterized by pervasive cognitive and emotional disturbances, yet the neural mechanisms underlying these deficits remain incompletely understood. Method: This study utilized multimodal neuroimaging, including resting-state functional MRI and structural T1-weighted imaging, alongside the MATRICS Consensus Cognitive Battery (MCCB) and the Hamilton Depression Rating Scale (HAMD), to delineate the structural and functional alterations in the insula in first-episode, medication-na & iuml;ve patients with depression. Result: Compared to matched healthy controls, patients with depression exhibited significant reductions in gray matter density in the left insula, which were robustly associated with impairments in reasoning and problem-solving abilities. Mediation analyses revealed that insular gray matter density mediated the relationship between depressive symptom severity and cognitive deficits, emphasizing the insula's critical role in linking emotional and cognitive dysfunctions. Furthermore, functional connectivity analyses identified disrupted insula-medial prefrontal cortex circuits, highlighting their contribution to the pathophysiology of depression. Conclusion: These findings underscore the insula's dual role as a structural and functional hub in depression, advancing our understanding of the neural substrates of cognitive dysfunction and informing potential targets for intervention.