Cortical hemodynamic dysregulation is linked to peripheral NIMETOX pathways in major depressive disorder: an 89-channel fNIRS systems-biology study.

Background: Major depressive disorder (MDD) is clinically heterogeneous, but relationships among cortical hemodynamic abnormalities, peripheral neuroimmune, metabolic, and oxidative stress (NIMETOX) processes, and clinical phenome features remain unclear. We applied a systems-biology approach integrating functional near-infrared spectroscopy (fNIRS), peripheral NIMETOX biomarkers, and multidimensional clinical phenomes. Methods: Patients with MDD (n = 86) and demographically matched healthy controls (HC, n = 40) underwent 89-channel high-density fNIRS during resting-state and verbal fluency task (VFT) conditions. Temporal hemodynamic variability (Difference) and area under the concentration-time curve (AUC) were derived from oxygenated hemoglobin (HbO), deoxygenated hemoglobin (HbR), and total hemoglobin (HbT) signals. NIMETOX assessments included inflammatory biomarkers, generalized and lipophilic antioxidant defenses, oxidized lipids, lipidomics, and 16S rRNA amplicon sequencing of the stool microbiome. Results: MDD showed reduced VFT Difference and AUC across HbO, HbR, and HbT. Difference reductions were widespread across prefrontal, frontal eye field, language-related, and sensorimotor cortices, whereas AUC abnormalities were more restricted and resting-state alterations were limited. VFT differences significantly differentiated MDD from HC, with further improvement after integrating NIMETOX biomarkers. Lower antioxidants, carnitines/acetylcarnitines, polyunsaturated and even-chain saturated fatty acids, inflammation, indices of gut dysbiosis and leaky gut, and adverse childhood experiences explained substantial variance in HbO, HbR, and HbT Difference. Integrated fNIRS-NIMETOX profiles explained substantial variance in overall illness severity (cross-validated R2= 0.62) and physiosomatic symptoms (cross-validated R2= 0.48). Conclusions: Systems-biology integration identified a multilevel MDD phenotype linking peripheral NIMETOX dysregulation with task-evoked cortical hemodynamic abnormalities and clinical phenome heterogeneity, supporting an interconnected gut-NIMETOX-brain pathophysiology. Key words: major depressive disorder, biomarkers, redox mechanisms, lipophilic antioxidants, oxidized lipids