Impaired regional structure-function coupling as novel neurophenotype: mechanistic insights and diagnostic exploration in treatment-resistant depression

Treatment‑resistant depression (TRD) is one of the toughest clinical challenges in psychiatry, characterized by high recurrence, heavy disease burden, and elevated suicide risk. Neuroimaging studies have mainly focused on single‑modality data, overlooking interactions between brain structure and function. This cross‑sectional study integrated multimodal MRI to examine alterations of structure–function coupling (SFC) and their associations with symptoms and diagnostic potential in TRD and non‑treatment‑resistant depression (nTRD). A total of 72 TRD patients, 152 nTRD patients, and 84 healthy controls were recruited. SFC was computed for each brain region from whole‑brain structural and functional data, and group differences, symptom correlations, and diagnostic classification were analyzed. TRD patients showed marked SFC decoupling in the right middle frontal gyrus, left inferior parietal lobule, left precentral gyrus, and right superior temporal gyrus. In nTRD, higher hippocampal SFC correlated with suicidal ideation and despair. Machine‑learning models based on SFC achieved high accuracy in distinguishing TRD from nTRD, outperforming previous unimodal approaches. These findings indicate that altered structure–function coordination represents a specific neural phenotype of TRD, linking network‑level decoupling with clinical symptoms and supporting its potential as an imaging‑based biomarker for individualized treatment. Trial Registration: ChiCTR2200055320, https://www.chictr.org.cn/showproj.aspx?proj=132558 . Registration date: January 1, 2022.