Candidate Right Locus Coeruleus-Centered Symptom Pathways in Young Major Depressive Disorder: A Multimodal Magnetic Resonance Imaging Study

Abstract

Major depressive disorder (MDD) involves network-level abnormalities that may reflect dysfunction in catecholaminergic nuclei, particularly the substantia nigra (SN) and locus coeruleus (LC), which regulate cortical gain and signal-to-noise ratio. However, whether MRI-derived SN/LC phenotypes are linked to depressive symptom severity through functional connectivity pathways in young individuals with MDD remains unclear. We studied 84 young participants (MDD, n = 46; controls, n = 38). MRI measures were extracted from the bilateral SN and LC using neuromelanin-sensitive magnetization transfer contrast (MTC) imaging and iron-sensitive quantitative susceptibility mapping (QSM). Seed-to-voxel analyses assessed associations between these phenotypes and resting-state functional connectivity. Graph-theoretical analyses extended functional connectivity findings to global network topology. Mediation analyses tested whether functional connectivity linked SN/LC MRI phenotypes to Hamilton Depression Rating Scale scores within the MDD group. Multiple comparisons were controlled using false discovery rate (FDR) at q < 0.05. Compared with controls, the MDD group exhibited reduced bilateral SN volume on QSM and decreased LC signal intensity on MTC. Neuromelanin- and iron-sensitive phenotypes showed distributed functional connectivity associations involving frontal, sensorimotor, precuneus, and cerebellar regions. Bilateral SN susceptibility showed diagnosis-dependent associations with global efficiency. Mediation analyses identified four candidate right LC functional connectivity pathways linking SN/LC qMRI phenotypes to HAMD scores, mainly involving right LC connectivity with the left precuneus, right paracentral lobule, and cerebellum.SN/LC catecholaminergic MRI phenotypes are associated with depressive severity and right LC-centered functional connectivity, supporting candidate circuit-level associations linking brainstem neuromodulatory phenotypes to clinical expression in MDD.