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.

Highlights

• MDD is characterized by reduced temporal hemodynamic variability and impaired task-evoked recruitment across oxygenated (HbO) and deoxygenated (HbR) hemoglobin.

• Multidimensional fNIRS features discriminate MDD from controls, with further improvement after integration with peripheral neuroimmune, metabolic and oxidative stress (NIMETOX) pathways.

• Peripheral NIMETOX biomarkers, particularly lipophilic antioxidants, oxidized lipids, inflammation, and gut-microbiome related indices, explain substantial variation in HbO/HbR hemodynamic abnormalities and the clinical features of MDD.

• Multilevel systems-biological aberrations link peripheral NIMETOX pathways with brain hemodynamic abnormalities and the symptoms of MDD.