The brain's "dark energy" puzzle upgraded: [18F]FDG uptake, delivery and phosphorylation, and their coupling with resting-state brain activity.

The brain's resting-state energy consumption is expected to be driven by spontaneous activity. We previously used 50 resting-state fMRI (rs-fMRI) features to predict [¹⁸F]FDG SUVR as a proxy of glucose metabolism. Here, we expanded on our effort by estimating [¹⁸F]FDG kinetic parameters K_i (irreversible uptake), K₁ (delivery), k₃ (phosphorylation) in a large healthy control group (n = 47). Describing the parameters' spatial distribution at high resolution (216 regions), we showed that K₁ is the least redundant (strong posteromedial pattern), and K_i and k₃ have relevant differences (occipital cortices, cerebellum, thalamus). Using multilevel modeling, we investigated how much spatial variance of [¹⁸F]FDG parameters could be explained by a combination of a) rs-fMRI variables, b) cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO₂) from ¹⁵O PET. Rs-fMRI-only models explained part of the individual variance in K_i (35%), K₁ (14%), k₃ (21%), while combining rs-fMRI and CMRO₂ led to satisfactory description of K_i (46%) especially. K_i was sensitive to both local rs-fMRI variables (ReHo) and CMRO₂, k₃ to ReHo, K₁ to CMRO₂. This work represents a comprehensive assessment of the complex underpinnings of brain glucose consumption, and highlights links between 1) glucose phosphorylation and local brain activity, 2) glucose delivery and oxygen consumption.