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

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 (AXRBBB), while functional diversity was assessed via normalized entropy derived from edge functional connectivity based on overlapping community structure.

TRD patients showed elevated AXRBBB 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 AXRBBB and symptom severity in the left hippocampus and DMN.

Transcriptomic profiling revealed spatial co-localization between AXRBBB 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 AXRBBB-indexed BBB permeability alterations to disrupted functional network architecture in TRD. We would like to acknowledge all the participants in this study.

This study was supported by the National Natural Science Foundation of China (82371934), National Key Research and Development Program of China (2023YFC2414200), Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project (2022ZD0206000), National Natural Science Foundation of China (92359303), Natural Science Foundation of of Zhejiang Province (LRG25H180001), and Provincial-Ministerial Co-Construction Key Project of Henan Medical Science and Technology Research Program (SBG202602007). These authors contributed equally: Yao Ge, Zhaoqing Li. Department of Radiology, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou, China Yao Ge, Lijuan Chen, Yu Shen, Ninghua Li, Yan Bai, Wei Wei & Meiyun Wang Department of Physical Medicine and Rehabilitation of the Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China College of Biomedical Engineering and Instrument Science & Liangzhu Laboratory, Zhejiang University, Hangzhou, China MR Research Collaboration, Siemens Healthineers Ltd., Beijing, China Department of Radiology of the Second Affiliated Hospital, School of Brain Science and Brain Medicine & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou, China NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou, China Laboratory of Brain Science and Brain-Like Intelligence Technology, Institute for Integrated Medical Science and Engineering, Henan Academy of Sciences, Zhengzhou, China Correspondence to Ruiliang Bai or Meiyun Wang.

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