Oxytocin modulates white matter functional connectivity tensor dynamics and circuit-targeted reconfiguration in depressive symptoms

Major depressive disorder involves disrupted neural circuit dynamics. While oxytocin has demonstrated modulatory effects on functional connectivity, its therapeutic potential for depression, particularly through white matter circuit modulation, remains poorly understood. Here we show that reduced functional connectivity tensor fractional anisotropy in the genu of the corpus callosum (GCC) serves as a candidate mechanism distinguishing major depressive disorder (N = 34) from healthy controls (N = 33), but not in generalized anxiety disorder cohort (N = 31).

This diagnostic validity was further confirmed in subclinical populations (N = 108). Crucially, oral oxytocin administration selectively increased GCC tensor metrics in individuals with high depressive traits and altered GCC-prefrontal connectivity during negative social processing (N = 69). These findings established GCC-centric WM functional connectivity tensor as a circuit-level substrate for depression in both clinical and sub-clinical populations and revealed that oral oxytocin can modulate these altered connections.

Our work therefore suggests oxytocin-sensitive GCC functional organization may represent a candidate mechanism warranting further investigation in depression-related conditions. We sincerely thank all participants for their time and contribution to this study. We are also grateful to the research assistants and MRI technicians who supported data collection and preprocessing.

Any opinions, findings, conclusions, or recommendations expressed in this publication do not reflect the views of the Government of the Hong Kong Special Administrative Region or the Innovation and Technology Commission. This work was supported by STI 2030–Major Projects [grant number 2022ZD0208500], Sichuan Science and Technology Program [grant number 2026NSFSC2068], and the Fundamental Research Funds for the Central Universities [grant number ZYGX2025K011; ZYGX2026K013]. These authors contributed equally: Xiaodong Zhang, Chunmei Lan.

The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for NeuroInformation, Brain-Apparatus Communication Institute, University of Electronic Science and Technology of China, Chengdu, China Xiaodong Zhang, Peng Qing, Dezhong Yao, Keith M. Kendrick & Weihua Zhao School of Medicine, Southwest University of Science and Technology, Mianyang, China School of Psychology, Shandong Normal University, Jinan, China Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China Yuanshu Chen, Juan Kou, Lei Xu & Xinqi Zhou The Department of Psychology, The University of Hong Kong, Hong Kong, China The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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