Introduction
Major depressive disorder (MDD) in adolescence is a prevalent and disabling psychiatric illness associated with serious consequences including academic failure, social withdrawal, substance abuse, and most critically, suicide (1–5). Converging evidence derived from neuroimaging studies suggests that adolescent MDD entails morphological, functional, and neurochemical alterations (6–10). Importantly, since adolescence represents a critical period of rapid neuroplasticity [e.g., increased myelination, synaptic pruning; (11–13)], white matter (WM) alterations can contribute to the neurobiology of adolescent MDD. Indeed, in our prior investigation of gamma-Aminobutyric acid in the anterior cingulate cortex (ACC), we incidentally found reduced WM volume in adolescents with MDD compared to healthy controls [HC; (9)]. However, there has been sparse research focusing on WM alterations in this age group.
Diffusion tensor imaging (DTI) enables the non-invasive examination of in vivo structural connectivity by providing measures of WM microstructure and integrity based on the extent of water diffusion (14). Several DTI measures are typically quantified, with fractional anisotropy (FA) being the most commonly used to reflect WM integrity. Higher FA values suggest greater diffusion in the direction of the axon, and thus greater WM integrity. Other measures, including mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), can also be determined to investigate different aspects of WM microstructure.
To date, most DTI research in MDD has investigated adults and consistently reported decreased FA in tracts connected to the prefrontal cortex (PFC) or tracts connecting the two hemispheres within the PFC (15, 16). Only one DTI study was carried out in adolescents with depression, demonstrating a similar pattern to adult MDD of reduced FA in tracts connected to the subgenual ACC and the PFC [i.e., uncinate fasciculus, inferior-fronto-occipital fasciculus, anterior cingulum, superior longitudinal fasciculus; (17)]. However, results may have been impacted by the concurrent use of psychotropic medication and past substance abuse in some subjects. Relatedly, medication-naïve adolescents with a familial risk for unipolar depression also demonstrated reduced FA compared to HC in similar tracts (18).
In this study, we aimed to expand on prior work by examining WM integrity in psychotropic medication-free adolescents with MDD compared to HC. Given the inherent heterogeneity of adolescent MDD, we further sought to identify specific WM alterations in relation to MDD severity as well as anhedonia and irritability – two core symptoms of adolescent MDD. Due to our desire to explore a range in depression severity, we included patients with mild to moderate severity. Based on others’ and our prior findings (8, 15–17), we hypothesized that adolescents with MDD would manifest less restricted diffusion (i.e., decreased WM integrity) compared to HC in tracts connecting frontal, striatal, and limbic regions. We also predicted that similar tracts would be associated with depression severity. For anhedonia, we expected reduced WM integrity in tracts that have been implicated in reward-related processing in the ventral striatum [i.e., subgenual cingulate, forceps minor, inferior-fronto-occipital fasciculus, anterior thalamic radiation (ATR), anterior limb of the internal capsule; (19)], and that these would be distinct from those associated with irritability. Finally, only one study has examined irritability in a clinical population [i.e., Huntington’s disease; (20)] and found involvement of the amygdala. As such, we predicted the impairment of tracts connecting to the amygdala (e.g., uncinate fasciculus, inferior-fronto-occipital fasciculus, inferior longitudinal fasciculus).