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.