The neural correlate for the core symptoms of depression has been located within the frontal-striatal-tegmental neural network, commonly referred to as the reward circuit¹. The ventral tegmental area and the nucleus accumbens are at the core of the reward circuit, while the orbitofrontal cortex, the anterior cingulate cortex, the dorsolateral prefrontal cortex, the hypothalamus, the thalamus, the amygdala, and the hippocampus are also included. This study aimed to investigate the brain microstructural alteration in major depressive disorder (MDD), by using neurite orientation dispersion and density imaging (NODDI)².Nineteen patients with MDD (39.8±8.3 years-old, 12 female and 7 male) and 13 age/sex-matched controls were involved. The diffusion MRI data were obtained with a 3T system, using a spin-echo echo-planar sequence. Sixty slices (2.00x2.00x2.50 mm³ voxel) were acquired at three different b-values (b=1000, 1500, and 2000 s/mm²), each with 30 non-colinear directions, and 5 b=0 volumes. Following corrections for motion and eddy current (eddy_correct in FSL), NODDI was applied to calculate neurite density index (NDI) and orientation dispersion index (ODI). The conventional DTI parameter maps (fractional anisotropy (FA), mean diffusivity (MD), and axial/radial diffusivities) were calculated from the b=0 and 1000 s/mm² data using dtifit in FSL. For tract-based spatial statistics (TBSS) analyses, Diffusion Tensor Imaging ToolKit (DTI-TK)³ was used for tensor-based spatial normalization to an iteratively optimized population-specific template, as recommended by Bach et al⁴. The NDI and ODI maps, as well as the conventional DTI parameters, were projected onto the mean FA skeleton. Then, on the skeletonized maps, permutation-based statistics were carried out (randomize in FSL, 5000 permutations) to investigate the between group differences using age and sex as nuisance covariates.In patients with MDD, significant ODI increase was identified in the white matter of bilateral frontal lobes and right occipital lobe, right internal capsule, bilateral thalamus and hypothalamus, right nucleus accumbens, and midbrain tegmentum (Fig. 1). Reduction of FA was observed in the genu of corpus callosum and the frontal white matter at a trend level, though most of the differences did not survive the correction for multiple comparisons. No significant differences were observed for mean/axial/radial diffusivities and NDI.In this study, significant increase in ODI was identified in areas of frontal-subcortical networks, including the reward circuit. The distribution of ODI increase was considered in line with the previous DTI studies that have consistently reported FA decrease in the frontal white matter^1,5. More specifically, the main fascicles reported as involved in MDD are, the frontal-subcortical network, the superior part of the cingulum, right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, and the genu and body of corpus callosum^1,5. The FA decrease did not reach the significance threshold in the present study probably due to the small sample size. Not only being more sensitive than FA, NODDI also allowed us to disentangle the two presumed factors behind FA changes, neurite density and coherence of orientation. The present result demonstrating ODI increase without NDI changes is in marked contrast with the reports on neurodegenerative diseases^6,7, and may suggest that patients with MDD are suffering from decreased coherence of neural organization, but not from neuronal cell loss.This study revealed ODI increase in patients with MDD, distributed in the frontal-subcortical networks including the reward circuit. The NODDI analyses enabled deeper interpretation of the previously reported FA decrease. Further study focusing on response to treatment, whether the ODI increase is reversible or not, would be informative.