Blood-brain barrier permeability is associated with edge-centric functional connectivity and depressive symptoms in treatment-resistant depression

Abstract Blood-brain barrier (BBB) dysfunction and associated cerebral inflammation have emerged as contributing factors in depression pathophysiology, yet human evidence for BBB dysfunction in treatment-resistant depression (TRD), including its spatial distribution and interaction with functional network dysregulation, remains unexplored. We hypothesized that disrupted BBB permeability is related to the aberrant functional network architecture observed in TRD. In 44 TRD patients and 62 healthy controls, regional BBB permeability was quantified using a contrast-agent free MRI technique measuring apparent water exchange across the BBB (AXR BBB ), while functional diversity was assessed via normalized entropy derived from edge functional connectivity based on overlapping community structure. TRD patients showed elevated AXR BBB across visual, somatomotor, ventral attention, frontoparietal, and default mode networks (DMN) regions. Normalized entropy was significantly increased within the DMN and left hippocampus, indicating disrupted functional community architecture. Mediation analyses showed that normalized entropy partially mediated the relationship between AXR BBB and symptom severity in the left hippocampus and DMN. Transcriptomic profiling revealed spatial co-localization between AXR BBB alterations and normative astrocyte-specific gene expression topography, with spatial correlations to normative serotonergic, dopaminergic, and glutamatergic receptor distributions. These findings provide the first evidence linking AXR BBB -indexed BBB permeability alterations to disrupted functional network architecture in TRD.