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Effect of selective serotonin reuptake inhibitor on prefrontal-striatal connectivity is dependent on the level of TNF-α in patients with major depressive disorder

  • Kai Liu (a1) (a2), Xiaohua Zhao (a1), Xiaobing Lu (a3), Xiaoxia Zhu (a1), Hui Chen (a2), Mengmeng Wang (a1), Weixin Yan (a1), Linlin Jing (a4), Yanjia Deng (a2), Lin Yu (a3), Huawang Wu (a3), Ge Wen (a2), Xuegang Sun (a1) (a5) and Zhiping Lv (a1)...



We hypothesize that the tumor necrosis factor-α (TNF-α) may play a role in disturbing the effect of selective serotonin reuptake inhibitor (SSRI) on the striatal connectivity in patients with major depressive disorder (MDD).


We performed a longitudinal observation by combining resting-state functional magnetic resonance imaging (rs-fMRI) and biochemical analyses to identify the abnormal striatal connectivity in MDD patients, and to evaluate the effect of TNF-α level on these abnormal connectivities during SSRI treatment. Eighty-five rs-fMRI scans were collected from 25 MDD patients and 35 healthy controls, and the scans were repeated for all the patients before and after a 6-week SSRI treatment. Whole-brain voxel-wise functional connectivity (FC) was calculated by correlating the rs-fMRI time courses between each voxel and the striatal seeds (i.e. spherical regions placed at the striatums). The level of TNF-α in serum was evaluated by Milliplex assay. Factorial analysis was performed to assess the interaction effects of ‘TNF-α × treatment’ in the regions with between-group FC difference.


Compared with controls, MDD patients showed significantly higher striatal FC in the medial prefrontal cortex (MPFC) and bilateral middle/superior temporal cortices before SSRI treatment (p < 0.001, uncorrected). Moreover, a significant interaction effect of ‘TNF-α × treatment’ was found in MPFC-striatum FC in MDD patients (p = 0.002), and the significance remained after adjusted for age, gender, head motion, and episode of disease.


These findings provide evidence that treatment-related brain connectivity change is dependent on the TNF-α level in MDD patients, and the MPFC-striatum connectivities possibly serve as an important target in the brain.


Corresponding author

Author for correspondence: Zhiping Lv, E-mail: and Ge Wen, E-mail:; Xuegang Sun, E-mail:


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These authors contributed equally to this paper.



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