According to the World Health Organization (WHO), major depressive disorder (MDD) is the current leading cause of disability worldwide and adolescence is a vulnerable period for onset of depression, affecting more than 10% of adolescents in the US [1]. Uncovering the neuroanatomical basis of MDD is essential for the development of novel effective treatment paradigms. It is likely that differences between a depressed and non-depressed adolescent brain are not confined to a specific brain region but involve communication pathways between different regions. MRI connectomics views the brain as a network and has been successfully applied to studying brain network development [2] and disruption in neurological and psychiatric disorders [3].

The goal of this study was to perform DTI-based connectome analysis in a cohort of depressed adolescents and matched non-depressed controls.

T1-weighted and DTI data were obtained on 57 adolescents with MDD and 41 well-matched controls. T1-weighted image parameters: 3T, fast spoiled gradient echo, TR/TE=8.1/3.17 ms, flip angle=12°, 256x256, 1x1x1mm voxels. The images were bias-field-corrected, skull-stripped, and transformed to MNI152 space using an affine transform. DTI parameters: dual spin echo EPI, 30 directions, b-value=1500 s/mm², TR/TE=7200/86.5ms, 96x96, 1.875x1.875x2.5mm voxels. A quality assurance step was performed as previously described [4]. Individual brains were segmented into 90 ROIs using Automated Anatomical Labeling (AAL) atlas [5], which were dilated by 1 voxel and used as network nodes. DTI reconstruction and deterministic whole-brain streamline fiber tractography were performed using the Diffusion Toolkit [6]. Connections between AAL ROIs were calculated, with the number of connecting streamlines (scaled by total brain volume) and average FA serving as edge weights. Weighted local and global network properties normalized by random networks were examined using the Brain Connectivity Toolbox [7]. Network-Based Statistic (NBS) [8] was utilized to assess edge-wise differences in the connectivity matrices between the two groups. We performed a t-test with 5000 permutations and tested a range of primary thresholds 3, 3.1, … 6 to determine the highest threshold value at which the number of significantly different connections plateaued.While there were no significant group differences in the global network properties, the local measure of node strength of the right caudate weighted by FA was significantly lower in the depressed subjects (p<0.01, corrected for multiple comparisons). Edge-based FA-weighted connectome analysis using NBS at primary threshold 5.5 (resulting in p-value=0.0000) revealed a right caudate-centered network comprising 13 nodes and 12 connections with lower FA in MDD (Figs. 1,2). In particular, connections between right caudate and frontal gyri (superior, medial, and inferior), between right caudate and insula, and between right caudate and anterior cingulate had significantly lower FA in adolescents with MDD. Age was positively associated with the FA-based node strength of the right caudate (Fig. 3). Reynolds Adolescent Depression Scale (RADS-2) scores in MDD subjects didn’t show any significant correlation with the right caudate node strength. There was no significant gender difference in the right caudate node strength. There were also no significant differences in global mean FA or caudate volume between groups.This is the first report of DTI-based connectome analysis of adolescent MDD and our findings highlight the role of right caudate connectivity, in particular to frontal gyri, insula, and anterior cingulate, in this population. Our findings are similar to the results of a recent DTI-based NBS study of adult MDD, in which two networks with lower connectivity were identified in the depressed group, also including right caudate, frontal gyri, and anterior cingulate [9]. Caudate is part of the striatum, and a critical component of the reward system. Altered reward function has been previously found in adolescent depression using fMRI studies [10], with a pattern of low striatal response and high medial prefrontal response to reward, potentially due to disrupted balance of corticostriatal circuit function. In the AAL atlas the caudate includes the Nucleus accumbens (NAcc), which is thought to act as a motivation gateway between systems involved in emotion and motor control. Interestingly, the NAcc has previously been identified as a key center of the adult depression network and has been a target for deep brain stimulation in treatment-resistant depression [11]. Our results also demonstrated a positive correlation of the right caudate node strength with age (Fig. 3), suggesting a developmental delay of its connections in adolescent MDD. This is in line with the finding that the fibers connecting striatum to prefrontal regions continue to mature through adolescence [12]. Given the relatively recent onset of depression in our sample, our findings may indicate that reduced structural connectivity of the right caudate could be a risk factor for developing adolescent MDD.