Multimodal neuroimaging reveals brain neurochemical disturbances associated with superoxide dismutase in first-episode drug-naïve schizophrenia

Reduced antioxidant defense observed in first-episode drug-naïve schizophrenia (SCZ) may contribute to impaired cognition of SCZ. However, the underlying relationships among antioxidant stress-neuroimaging-cognition pathway and neurotransmitter dysfunction remain unclear. In this study, 75 patients with first-episode drug-naïve SCZ and 85 age and sex matched healthy controls underwent clinical evaluation and brain MRI. Two brain imaging measurements, including gray matter volume (GMV) from structural MRI (sMRI) and fractional amplitude of low frequency fluctuations (fALFF) from resting-state functional MRI, were jointly analyzed with a data-driven multivariate fusion method. Serum superoxide dismutase (SOD) levels was used as a reference to guide fusion of two MRI features. To investigate specific neurotransmitter system alterations associated with SOD-related SCZ patients, we used the JuSpace toolbox for cross-modal correlations between two MRI-based modalities with nuclear imaging derived estimates. Two multimodal components (IC5 and IC7) show significant group difference in loadings. We found significant associations of SOD with both GMV and fALFF within the frontoparietal and default mode networks (DMN). Furthermore, the covariant structural-functional components linked with reduced SOD levels were associated with deficits in cognitive function in speed of processing and visual learning. Moreover, the spatial correlation analysis identified associations of altered neuroimaging fusion biomarkers with disrupted excitatory-inhibitory neurotransmitter receptor distribution. This study unveils the complex alterations in SCZ across structural, functional, and neurochemical dimensions through multimodal analysis, highlighting the association between SOD-induced oxidative stress and imbalances in the excitatory/inhibitory ratio in the core brain regions of the DMN. Antioxidant therapy may have the potential to alleviate cognition deficit in SCZ patients in the future.