Inflammatory cytokines and callosal white matter microstructure in adolescents

Abstract

Adolescent depression is characterized by heightened inflammation and altered connectivity of fronto-cingulate-limbic tracts, including the genu of the corpus callosum (CCG) and the uncinate fasciculus (UF). No studies, however, have yet examined the association between inflammation, measured by peripheral levels of cytokines, and white matter connectivity of fronto-cingulate-limbic tracts in adolescents. Here, 56 depressed adolescents (32 females, 3 non-binary; 16.23 ± 1.28 years) and 19 controls (10 females; 15.72 ± 1.17 years) completed a diffusion-weighted MRI scan at 3 Tesla. We conducted deterministic tractography to segment bilateral corpus callosum (genu and splenium) and UF and computed mean fractional anisotropy (FA) in each tract. A subset of participants (43 depressed and 17 healthy controls) also provided dried blood spot samples from which we assayed interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-ɑ) using a Luminex multiplex array. Depressed participants did not differ from controls in FA of the corpus callosum or UF (all FDR-corrected ps > 0.056) but exhibited higher levels of inflammation than did controls (IL-6: β = 0.91, FDR-corrected p = 0.006; TNF-α: β = 0.76, FDR-corrected p = 0.006). Although diagnostic group did not moderate the associations between inflammatory cytokines and FA in the CCG and UF, across both groups, greater peripheral inflammation was associated with lower FA in the CCG (IL-6: β = -0.38; FDR-corrected p = 0.044; TNF-ɑ: β = -0.41, FDR-corrected p = 0.044). This study is the first to examine associations between peripheral inflammation and white matter microstructure of fronto-cingulate-limbic tracts in depressed and nondepressed adolescents. Future mechanistic studies are needed to confirm our findings; nevertheless, our results suggest that heightened inflammation is an important component of neurophenotypes that are relevant to adolescent depression.

Keywords: Adolescence; Corpus callosum; Cytokines; Depression; Diffusion tensor imaging; Interleukin-6; Tumur necrosis factor-alpha; Uncinate fasciculus; White matter microstructure.

Fig. 1.

Visualizations of corpus callosum genu (CCG), splenium (CCS), and bilateral uncinate fasciculus (UF) from a representative subject.

Fig. 2.

Correlation matrix summarizing bivariate correlations (Pearson’s r) among key variables and covariates across all participants (A), in the MDD group only (B), and in the CTL group only (C). Correlations that are significant at p < 0.05 (uncorrected) are displayed without an ‘X’.

Fig. 3.

Group differences in interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). All data displayed without adjustment covariates for visualization only.

Fig. 4.

Linear associations between interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and fractional anisotropy (FA) of the corpus callosum genu. All data displayed without adjustment covariates for visualization only. See Table 2 for more details.