Metabolic activity diffusion imaging (MADI): II. Noninvasive, high-resolution human brain mapping of sodium pump flux and cell metrics

We introduce a new ¹H₂O magnetic resonance approach: metabolic activity diffusion imaging (MADI). Numerical diffusion-weighted imaging decay simulations characterized by the mean cellular water efflux (unidirectional) rate constant (k_io), mean cell volume (V), and cell number density (ρ) are produced from Monte Carlo random walks in virtual stochastically sized/shaped cell ensembles. Because of active steady-state trans-membrane water cycling (AWC), k_io reflects the cytolemmal Na⁺, K⁺ATPase (NKA) homeostatic cellular metabolic rate (^cMR_NKA). A digital 3D “library” contains thousands of simulated single diffusion-encoded (SDE) decays. Library entries match well with disparate, animal, and human experimental SDE decays. The V and ρ values are consistent with estimates from pertinent in vitro cytometric and ex vivo histopathological literature: in vivo V and ρ values were previously unavailable. The library allows noniterative pixel-by-pixel experimental SDE decay library matchings that can be used to advantage. They yield proof-of-concept MADI parametric mappings of the awake, resting human brain. These reflect the tissue morphology seen in conventional MRI. While V is larger in gray matter (GM) than in white matter (WM), the reverse is true for ρ. Many brain structures have k_io values too large for current, invasive methods. For example, the median WM k_io is 22s⁻¹; likely reflecting mostly exchange within myelin. The k_io•V product map displays brain tissue ^cMR_NKA variation. The GM activity correlates, quantitatively and qualitatively, with the analogous resting-state brain ¹⁸FDG-PET tissue glucose consumption rate (^tMR_glucose) map; but noninvasively, with higher spatial resolution, and no pharmacokinetic requirement. The cortex, thalamus, putamen, and caudate exhibit elevated metabolic activity. MADI accuracy and precision are assessed. The results are contextualized with literature overall homeostatic brain glucose consumption and ATP production/consumption measures. The MADI/PET results suggest different GM and WM metabolic pathways. Preliminary human prostate results are also presented.