Fundamentals of Gas-Free Calibrated fMRI for Oxidative Metabolic Neuroimaging

Brain's high energy demands require abundant production of ATP from glucose oxidation, mandating coupling between neural activity and nutrient supply. Understanding how neural activity augments blood flow (CBF) to support metabolism of glucose (CMR_glc) and oxygen (CMR_O2) can help unravel mysteries of neurovascular and neurometabolic couplings underlying functional MRI (fMRI) with blood oxygenation level-dependent (BOLD) contrast. Key to this enigma is oxygen extraction fraction (OEF). Fundamentally, OEF is defined by flow-metabolism (i.e., CBF-CMR_O2) coupling generating mitochondrial ATP to signify limits of hypoxia and ischemia. However, to fully account for observed CBF-CMR_O2 coupling, the OEF must include a term for oxygen diffusivity (D_O2) that is regulated by rheological properties of blood. BOLD contrast depends on intravoxel spin dephasing of tissue water protons due to paramagnetic fields generated by deoxyhemoglobin. During augmented neural activity, if CBF increases more than CMR_O2, then deoxyhemoglobin (paramagnetic) is replaced by perfusing oxyhemoglobin (diamagnetic) to increase BOLD signal. Calibrated fMRI converts BOLD contrast into OEF according to the deoxyhemoglobin dilution model. Agreement across these OEF models (i.e., OEF trifecta) authenticates calibrated fMRI, both gas-based and gas-free methods. CMR_O2 by gas-free calibrated fMRI easily and reproducibly tracks neural activity, while combining it with CMR_glc can also reveal aerobic glycolysis. In summary, there is translational potential of gas-free calibrated fMRI for metabolic imaging in the resting and stimulated brain, from neurodegeneration to neurological disorders.