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. 2021 Apr 15:12:642976.
doi: 10.3389/fpsyt.2021.642976. eCollection 2021.

Higher Levels of Pro-inflammatory Cytokines Are Associated With Higher Levels of Glutamate in the Anterior Cingulate Cortex in Depressed Adolescents

Tiffany C Ho  1 , Giana I Teresi  2 , Jillian R Segarra  2 , Amar Ojha  3 , Johanna C Walker  2 , Meng Gu  4 , Daniel M Spielman  4 , Matthew D Sacchet  5 , Fei Jiang  6 , Yael Rosenberg-Hasson  7 , Holden Maecker  7 , Ian H Gotlib  2
Affiliations

Higher Levels of Pro-inflammatory Cytokines Are Associated With Higher Levels of Glutamate in the Anterior Cingulate Cortex in Depressed Adolescents

Tiffany C Ho et al. Front Psychiatry. .

Abstract

Animal models of stress and related conditions, including depression, have shown that elevated peripheral levels of inflammatory cytokines have downstream consequences on glutamate (Glu) in the brain. Although studies in human adults with depression have reported evidence of higher inflammation but lower Glu in the anterior cingulate cortex (ACC), the extent to which peripheral inflammation contributes to glutamatergic abnormalities in adolescents with depression is not well-understood. It is also unclear whether antioxidants, such as ascorbate (Asc), may buffer against the effects of inflammation on Glu metabolism. Fifty-five depressed adolescents were recruited in the present cross-sectional study and provided blood samples, from which we assayed pro-inflammatory cytokines, and underwent a short-TE proton magnetic spectroscopy scan at 3T, from which we estimated Glu and Asc in the dorsal ACC. In the 31 adolescents with usable cytokine and Glu data, we found that IL-6 was significantly positively associated with dorsal ACC Glu (β = 0.466 ± 0.199, p = 0.029). Of the 16 participants who had usable Asc data, we found that at higher levels of dorsal ACC Asc, there was a negative association between IL-6 and Glu (interaction effect: β = -0.906 ± 0.433, p = 0.034). Importantly, these results remained significant when controlling for age, gender, percentage of gray matter in the dorsal ACC voxel, BMI, and medication (antidepressant and anti-inflammatory) usage. While preliminary, our results underscore the importance of examining both immune and neural contributors to depression and highlight the potential role of anti-inflammatory compounds in mitigating the adverse effects of inflammation (e.g., glutamatergic neuroexcitotoxicity). Future studies that experimentally manipulate levels of inflammation, and of ascorbate, and that characterize these effects on cortical glutamate concentrations and subsequent behavior in animals and in humans are needed.

Keywords: ascorbate; depression; glutamate; interleukin-6; magnetic resonance spectroscopy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Voxel placement of dorsal anterior cingulate cortex and spectra data from a representative participant.
Figure 2
Figure 2
Correlation matrix among key variables of interest. Correlation matrix of primary predictor and outcome variables of interest, covariates, and clinical characteristics. Pearson correlation coefficients are presented in black text. Significant correlations at p < 0.05 (uncorrected) are highlighted in color (blue, positive correlations; red, negative correlations).
Figure 3
Figure 3
Higher levels of IL-6 at baseline are associated with higher levels of Glu in the dorsal anterior cingulate cortex. The correlation between IL-6 and dACC Glu remained statistically significant after controlling for age, gender, percentage of gray matter volume in the dACC voxel, antidepressant medication usage, and anti-inflammatory medication usage. dACC, dorsal anterior cingulate cortex; Glu, glutamate; IL-6, interleukin-6.
Figure 4
Figure 4
Levels of Asc in the dACC moderate the association between IL-6 and glutamate in the dACC. The Johnson-Neyman procedure was used to probe the interaction effect of dACC Asc and IL-6 on dACC Glu. At lower levels of Asc (<0.16, indicated by dotted teal line, left), the correlation between IL-6 and Glu was significantly positive (p < 0.05) whereas at higher levels of Asc (>0.32, indicated by dotted teal line, right), the correlation between IL-6 and Glu was significantly negative (p < 0.05). Asc, ascorbate; dACC, dorsal anterior cingulate cortex; Glu, glutamate; IL-6, interleukin-6.
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