Severe depressive disorder is associated with smaller hippocampal volumes. We hypothesized that Neurite Orientation Dispersion and Density Imaging (NODDI) could provide in vivo evidence of decreased hippocampal neuroplasticity in patients with depression.

This cross-sectional study evaluated 43 patients with treatment-resistant depression eligible for electroconvulsive therapy and 24 controls. MRI evaluations included a 3T scan with 3DT1-weighted and multi-shell diffusion sequences (b = 200/1500/2500 s/mm², 30/45/60 directions). Q-ball, diffusion tensor, and NODDI models were used to obtain axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), fractional anisotropy (FA), generalized FA (GFA), neurite density index (NDI), isotropic fraction (Fiso), and orientation dispersion index (ODI). Hippocampal volumes were extracted using FreeSurfer from T1-weighted images. Pearson correlations adjusted for sex and group analyzed the relationship between age and bilateral hippocampal diffusion. Mixed-effects models assessed the impact of depression, hemisphere, sex, and age on eight diffusion metrics. Correlation matrices and group-specific correlograms analyzed diffusion metrics across both hippocampi. Principal component analysis (PCA) reduced these metrics to components explaining ‘95% of the variance.

A total of 107 MRIs from patients and 24 MRIs from controls were analyzed. Hippocampal NDI was negatively correlated with age (r = -0.41, p = 0.002), while hippocampal Fiso was positively correlated (r = 0.45, p = 0.001). FA, GFA, AD, NDI, and ODI showed significant differences between patients and controls, despite comparable hippocampal volumes. PCA analysis effectively distinguished the two groups, achieving a diagnostic accuracy of 1.

Diffusion microstructural analyses reveal hippocampal alterations in severely depressed patients, potentially reflecting decreased neuroplasticity.