Introduction

Preliminary research suggests that major depressive disorder (MDD) is associated with structural alterations of brain regions that play a role in reward processing and emotion regulation^1,2 as well as with low-grade peripheral inflammation as indicated by high sensitive C-reactive protein (hsCRP) serum levels.^3,4 However, even though a link between inflammatory processes and altered brain structural integrity has been purported by experimental research^5,6, the biological processes underlying the associations between MDD and brain structural alterations are still poorly understood. An important question in this context is, if chronic low-grade peripheral inflammation might contribute to structural abnormalities in MDD. Well powered studies have been lacking to confirm this hypothesis in MDD patients. Therefore, we aimed to investigate the potential association between structural brain alterations and low-grade inflammation as potentially interrelated biological correlates of MDD.

Methods

In this cross-sectional study 514 MDD patients and 359 healthy controls (HC) underwent structural MRI. Voxel-based-morphometry (VBM) was used to study local differences in gray matter volume. Serum levels of high sensitive C-reactive protein (hsCRP) were assessed in each participant. Due to the not normal distribution of hsCRP, logarithmic transformed hsCRP values were used for analyses. MRI images were obtained at 3 T (Gyroscan Intera with Achieva upgrade) using a 3D T1w TFE-sequence (TR/TE/FA = 7.4 ms/3.4 ms/9°, inversion prepulse every 814.5 ms, reconstructed to voxels of .5 mm edge length). Images were preprocessed using the pipeline of the CAT12-toolbox.⁷ Imaging analyses were done in SPM12.⁸ Further statistical analyses were performed with SPSS version 25. (1) Group differences in hsCRP and log hsCRP levels between MDD and HC subjects were investigated. (2) Whole brain VBM analysis was done to investigate group differences in gray matter volume between MDD and HC subjects. (3) A multiple regression analysis of log hsCRP levels on gray matter volume was performed in the MDD group, on ROIs including the significant clusters determined in the preceding (step (2)) whole brain VBM analysis. (4) A regression analysis analog to (3) was performed in the HC group. Contributions of further potentially confounding variables were checked.

Results

(1) Compared to healthy controls, MDD patients exhibited significantly increased hsCRP and log hsCRP levels (p < .001). (2) MDD patients showed significantly decreased gray matter volume in the prefrontal cortex, temporal cortex, and the insula. (3) In MDD patients, prefrontal gray matter volume reductions were significantly associated with higher hsCRP levels (Fig. 1). The significant negative association between hsCRP and gray matter appeared independent of age, sex, body-mass-index, antidepressant load, hospitalization and medical comorbidities in the MDD sample. (4) In the HC group, no significant association between hsCRP levels and gray matter could be detected.

Discussion

The results give evidence for a relationship between peripheral low-grade inflammation and gray matter reductions in the prefrontal cortex in MDD. In line with our hypothesis and previous reports, MDD patients showed significantly altered brain structural integrity compared to HC.^2,9 Most importantly, gray matter decrease in MDD is associated with higher level of the proinflammatory marker hsCRP, while no such association is present in the HC group. The inverse association between hsCRP and gray matter was regionally specific for the prefrontal cortex, a brain region associated with MDD.^1,9 Recent evidence hints to a bidirectional communication between CNS and immune system - a pro-inflammatory environment may impair processes to maintain the integrity of gray matter in the prefrontal cortex, a brain region with pronounced structural plasticity and vulnerability to environmental influences.¹⁰ In addition, the CNS is thought to exert an influence on peripheral inflammatory processes, e.g. via activation of stress signaling pathways in response to external stress.¹¹ Considering this bidirectional communication, the MDD-specific structural alterations might in turn contribute to the maintenance of low-grade inflammation in MDD.

Conclusions

The present study highlights the role of reduced gray matter volume and low-grade peripheral inflammation as interrelated biological correlates of MDD. The reported inverse association between peripheral low-grade inflammation and brain structural integrity in depressive patients translates current knowledge from experimental studies to the bedside in MDD.

Acknowledgements

Funded by the German Federal Ministry of Education and Research (BiDirect study, grants 01ER0816, 01ER1506 and 01ER1205). Additional funding: German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 ; SFB-TRR58, Projects C09 and Z02 ) and Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17) and Deanery of the Medical Faculty of the University of Münster.

References

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