Linking Electrophysiological Metrics to Oxidative Metabolism: Implications for EEG–fMRI Association

Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study brain function, yet its biophysiological basis remains incompletely understood. Building on our recent work, we investigated how EEG activity and cerebral metabolic rate of oxygen (CMRO ₂ ) are related to one another, and how they jointly underpin rs-fMRI metrics. Using a multimodal dataset with macrovascular correction applied to all rs-fMRI metrics, we first examined associations between EEG metrics and CMRO ₂ , then applied mediation analysis to evaluate how CMRO ₂ mediates EEG–fMRI associations. We found that bandlimited EEG theta and alphafractional power was significantly associated with CMRO ₂ . Bandlimited EEG coherence was also associated with CMRO ₂ across all the bands. Bandlimited EEG fractional power and coherence were also significantly associated with cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in a manner that varied by frequency. EEG broadband temporal complexity was positively associated with CMRO₂ and EEG coherence was negatively associated with OEF. Notably, there are pronounced sex differences in these relationships, which suggests that the biophysical underpinnings of rs-fMRI are sex dependent. Moreover, the baseline metabolic and hemodynamic variables did partially mediate EEG–fMRI associations, with CMRO ₂ serving as the primary mediator. However, most of the mediations are partial, highlighting the complex interplay among electrophysiological activity, oxidative metabolism, and hemodynamics. This study advances our understanding of the biophysical basis of rs-fMRI and provides a foundation for developing sex-specific diagnostic and therapeutic strategies for neurological disorders.