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Understanding how neural activity augments blood flow (CBF) to support metabolism of glucose (CMR\n                    <jats:sub>glc<\/jats:sub>\n                    ) and oxygen (CMR\n                    <jats:sub>O2<\/jats:sub>\n                    ) can help unravel mysteries of neurovascular and neurometabolic couplings underlying functional MRI (fMRI) with blood oxygenation level\u2010dependent (BOLD) contrast. Key to this enigma is oxygen extraction fraction (OEF). Fundamentally, OEF is defined by flow\u2010metabolism (i.e., CBF\u2010CMR\n                    <jats:sub>O2<\/jats:sub>\n                    ) coupling generating mitochondrial ATP to signify limits of hypoxia and ischemia. However, to fully account for observed CBF\u2010CMR\n                    <jats:sub>O2<\/jats:sub>\n                    coupling, the OEF must include a term for oxygen diffusivity (D\n                    <jats:sub>O2<\/jats:sub>\n                    ) 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\n                    <jats:sub>O2<\/jats:sub>\n                    , 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\u2010based and gas\u2010free methods. CMR\n                    <jats:sub>O2<\/jats:sub>\n                    by gas\u2010free calibrated fMRI easily and reproducibly tracks neural activity, while combining it with CMR\n                    <jats:sub>glc<\/jats:sub>\n                    can also reveal aerobic glycolysis. In summary, there is translational potential of gas\u2010free calibrated fMRI for metabolic imaging in the resting and stimulated brain, from neurodegeneration to neurological disorders.\n                  <\/jats:p>","DOI":"10.1111\/jnc.70217","type":"journal-article","created":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T04:14:49Z","timestamp":1759551289000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Fundamentals of Gas\u2010Free Calibrated\n                    <scp>fMRI<\/scp>\n                    for Oxidative Metabolic Neuroimaging"],"prefix":"10.1111","volume":"169","author":[{"given":"Fahmeed","family":"Hyder","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Yale University  New Haven Connecticut USA"},{"name":"Department of Radiology &amp; Biomedical Imaging  New Haven Connecticut USA"},{"name":"Magnetic Resonance Research Center Yale University  New Haven 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