Alterations in white matter microstructure and structural network topology associated with cortisol level in major...

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation, neuroinflammation are associated with the development of major depressive disorder (MDD). In MDD patients, the relationships among cortisol (CORT), neuroinflammation, and white matter (WM) microstructural damage remain unclear.

We recruited 59 MDD patients (20 MDD patients with high CORT [high-CORTs], 39 MDD patients with normal CORT [normal-CORTs]) and 29 healthy controls (HCs). Tract-Based Spatial Statistics (TBSS) and structural network analyses were performed. Partial correlation, linear regression, mediation analyses were applied to investigate the relationships among the TBSS and structural network topology results with clinical symptoms.

TBSS analysis revealed a significant cluster in axial diffusivity (AD) values across the three groups. In the global network metrics, high-CORTs exhibited significantly lower clustering coefficient (Cp) than normal-CORTs in the mean diffusivity (MD) and radial diffusivity (RD) weighted networks. In the nodal metrics, high-CORTs demonstrated significantly increased nodal clustering coefficient (Ncp) at left rostral temporal thalamus (rTtha_L) and right caudal temporal thalamus (cTtha_R) compared to normal-CORTs and higher Ncp at rTtha_L compared to HCs in the fibers number (FN) weighted network. Normal-CORTs exhibited higher degree centrality (Dc) at cTtha_R than HCs across MD, AD, and RD weighted networks. Additionally, high-CORTs had increased betweenness centrality (Bc) at left rostral cuneus gyrus (rCunG_L) compared to HCs in the FN-weighted network. All false discovery rate (FDR)-corrected P < 0.001. AD and network measures correlated with CORT levels and were associated with neuropsychological performance. In the mediation analysis, AD values also showed significant mediating effects on the relationship between CORT and HAMD-Retardation (indirect effects = 0.0027 (95 % confidence interval: 0.0012-0.0045) in all participants.

MDD patients with different CORT levels show WM microstructure alterations and structural network topology differences, particularly in high-CORTs. These alterations were associated with CORT levels and neuropsychological performance and could have implications for future diagnosis and treatment.