Network localization of functional brain changes associated with ketamine's therapeutic effects in depression

Shaoqiang Han; Ya Tian; Huiting Yang; Ruiping Zheng; Shuying Li; Keke Fang; Baohong Wen; Liang Liu; Yarui Wei; Yuan Chen; Huafu Chen; Jingliang Cheng; Yong Zhang

doi:10.1016/j.biopsych.2025.06.006

Network localization of functional brain changes associated with ketamine's therapeutic effects in depression

Biol Psychiatry. 2025 Jun 13:S0006-3223(25)01249-1. doi: 10.1016/j.biopsych.2025.06.006. Online ahead of print.

Authors

Shaoqiang Han¹, Ya Tian¹, Huiting Yang¹, Ruiping Zheng¹, Shuying Li², Keke Fang³, Baohong Wen¹, Liang Liu¹, Yarui Wei¹, Yuan Chen¹, Huafu Chen⁴, Jingliang Cheng⁵, Yong Zhang⁶

Affiliations

¹ Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University; Key Laboratory for functional magnetic resonance imaging and molecular imaging of Henan Province; Engineering Technology Research Center for detection and application of brain function of Henan Province; Engineering Research Center of medical imaging intelligent diagnosis and treatment of Henan Province; Key Laboratory of magnetic resonance and brain function of Henan Province; Key Laboratory of brain function and cognitive magnetic resonance imaging of Zhengzhou; Key Laboratory of Imaging Intelligence Research medicine of Henan Province; Henan Engineering Research Center of Brain Function Development and Application.
² Department of Psychiatry, the First Affiliated Hospital of Zhengzhou University.
³ Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
⁴ Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University; The Clinical Hospital of Chengdu Brain Science Institute, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, PR China.
⁵ Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University; Key Laboratory for functional magnetic resonance imaging and molecular imaging of Henan Province; Engineering Technology Research Center for detection and application of brain function of Henan Province; Engineering Research Center of medical imaging intelligent diagnosis and treatment of Henan Province; Key Laboratory of magnetic resonance and brain function of Henan Province; Key Laboratory of brain function and cognitive magnetic resonance imaging of Zhengzhou; Key Laboratory of Imaging Intelligence Research medicine of Henan Province; Henan Engineering Research Center of Brain Function Development and Application. Electronic address: fccchengjl@zzu.edu.cn.
⁶ Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University; Key Laboratory for functional magnetic resonance imaging and molecular imaging of Henan Province; Engineering Technology Research Center for detection and application of brain function of Henan Province; Engineering Research Center of medical imaging intelligent diagnosis and treatment of Henan Province; Key Laboratory of magnetic resonance and brain function of Henan Province; Key Laboratory of brain function and cognitive magnetic resonance imaging of Zhengzhou; Key Laboratory of Imaging Intelligence Research medicine of Henan Province; Henan Engineering Research Center of Brain Function Development and Application. Electronic address: zzuzhangyong2013@163.com.

PMID: 40518102
DOI: 10.1016/j.biopsych.2025.06.006

Abstract

Background: Although numerous studies have attempted to identify the functional pathways underlying the rapid antidepressant effects of ketamine, their findings remain inconsistent, limiting our understanding of the neural mechanisms involved.

Methods: This study aims to delineate a specific brain circuit by integrating diverse functional findings related to ketamine's efficacy in depression. We conducted a systematic review of multimodal neuroimaging studies reporting brain locations associated with ketamine's effects on depression. Using functional connectivity network mapping and a large-scale normative connectome database, we mapped these locations onto a ketamine functional brain network. We tested the robustness of this network by evaluating its stability under parameter perturbations and leave-one-study-out validation, and assessed its specificity for depression relative to other mental disorders. We further identified the ketamine-specific brain circuit compared with an antidepressant functional brain network constructed using the same methodology.

Results: Our review included 18 multimodal neuroimaging studies with 440 depression individuals and 174 healthy controls. The heterogeneous brain locations localized to a connected network primarily involving regions implicated in the default mode, ventral attention, and frontoparietal networks. This network demonstrated robustness to minor perturbations and validation, and was specifically linked to depression. Compared with the antidepressant functional brain network, the ketamine-specific brain circuit predominantly encompassed brain regions such as the subgenual cingulate cortex and dorsolateral prefrontal cortex, which aligned with optimal brain stimulation sites for depression.

Conclusions: These findings help reconcile seemingly inconsistent neuroimaging results and provide new insights into the neuropathology of ketamine's therapeutic effects from a network perspective.

Keywords: brain network; depression; functional connectivity; ketamine.