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Previous structural imaging studies have found evidence of brain morphometric changes in patients with major depressive disorder (MDD), but these studies rarely excluded compounding effects of certain important factors, such as medications and long duration of illnesses. Furthermore, the neurobiological mechanism of the macroscopic findings of structural alterations in MDD patients remains unclear. In this study, we utilized magnetization transfer imaging, a quantitative measure of the macromolecular structural integrity of brain tissue, to identify biophysical alterations, which are represented by a magnetization transfer ratio (MTR), in MDD patients. To ascertain whether MTR changes occur independent of volume loss, we also conduct voxel-based morphometry (VBM) analysis. The participants included 27 first-episode, drug-naive MDD patients and 28 healthy controls matched for age and gender. Whole-brain …