Association between peripheral inflammation and free-water imaging in Major Depressive Disorder before and after ketamine treatment - A pilot study

Abstract

Background: Alterations in the peripheral inflammatory profile and white matter (WM) deterioration are frequent in Major Depressive Disorder (MDD). The present study applies free-water imaging to investigate the relationship between altered peripheral inflammation and WM microstructure and their predictive value in determining response to ketamine treatment in MDD.

Methods: Ten individuals with MDD underwent diffusion-weighted magnetic resonance imaging and a blood-draw before and 24 h after ketamine infusion. We utilized MANCOVAs and ANCOVAs to compare tissue-specific fractional anisotropy (FA_T) and free-water (FW) of the forceps and cingulum, and the ratio of pro-inflammatory interleukin(IL)-8/anti-inflammatory IL-10 between individuals with MDD and 15 healthy controls at baseline. Next, we compared all baseline measures between ketamine responders (6) and non-responders (4) and analyzed changes in imaging and blood data after ketamine infusion.

Results: The MDD group exhibited an increased IL-8/IL-10 ratio compared to controls at baseline (p = .040), which positively correlated with average FW across regions of interest (p = .013). Ketamine responders demonstrated higher baseline FA_T in the left cingulum than non-responders (p = .023). Ketamine infusion did not influence WM microstructure but decreased the IL-8/IL-10 ratio (p = .043).

Limitations: The small sample size and short follow-up period limit the conclusion regarding the longer-term effects of ketamine in MDD.

Conclusions: This pilot study provides evidence for the role of inflammation in MDD by illustrating an association between peripheral inflammation and WM microstructure. Additionally, we demonstrate that free-water diffusion-weighted imaging might be a valuable tool to determine which individuals with MDD benefit from the anti-inflammatory mediated effects of ketamine treatment.

Keywords: Diffusion tensor imaging; Magnetic resonance imaging; Neuroinflammation; Treatment response; Treatment-resistant depression; White matter.

Fig. 1.

Study protocol. MDD: Major Depressive Disorder; HC: Healthy controls; MADRS: Montgomery-Åsberg Depression Rating Scale (Montgomery and Åsberg, 1979); dMRI: Diffusion-weighted magnetic resonance imaging. If possible, whole-blood samples were collected between 8 a.m. and 11 a.m. to avoid confounding through diurnal variations in circulating cytokine levels. The treatment comprised a single subanesthetic dose (0.5 mg/kg) of ketamine diluted in 60 cm³ of saline administered over 40 min via intravenous infusion with continuous clinical and hemodynamic monitoring (Ibrahim et al., 2012; Niciu et al., 2014; Zarate et al., 2006).

Fig. 2.

Baseline FA_T (A) and IL-8/IL-10 Ratio (B). FA_T: Tissue-specific fractional anisotropy; LCing: Left cingulum, cingulate gyrus portion; R: Responder; NR: Non-responder; HC: Healthy controls; MDD: Major Depressive Disorder. The post-hoc ANCOVA demonstrated significant FA_T differences between responders and non-responders in the LCing (F(1, 9) = 9.16, p = .023, ${\eta }_{\text{p}}^2:0.60$). The ANCOVA of the interleukin (IL)-8/IL-10 ratio revealed a significant difference between individuals with MDD and HC (MDD: 10.94 ± 8.86; HC: 4.26 ± 2.53; F(1, 22) = 4.87; p = .040, ${\eta }_{\text{p}}^2:0.20$).

Fig. 3.

Correlation of peripheral inflammation with average FW. Average FW: Free-water values averaged across all ROIs (forceps minor, left and right cingulum I (cingulate gyrus portion) and II (hippocampal portion)). The interleukin (IL)-8/IL-10 ratio had a significant positive correlation with average FW for all individuals with MDD (ϱ: 0.75; p = .013).