Project Summary/Abstract Recent evidence suggests that metabolic dysfunction is a crucial transdiagnostic risk factor for mental illness. Functional MRI (fMRI) measures hemodynamic changes related to metabolic shifts in the brain and could bridge a critical gap between biomarkers for mental illness and human experience and behavior; however, metabolic processes underlying the hemodynamic response have remained poorly understood. Before we can understand brain metabolic dysfunction in mental illness, we first need to understand brain metabolism during healthy cognitive function. A particular point of controversy is that the BOLD response to sensory signals and cognitive activity coincides with a substantial increase in glucose consumption, decoupled from increases in O2 metabolism. This process is called aerobic glycolysis. and its function remains disputed. We have developed a hypothesis from converging lines of neurophysiological evidence that clarifies how aerobic glycolysis serves an adaptive function in neuronal communication. The proposed research will contribute to basic science by advancing the methods and theory needed to measure and interpret task-based brain metabolic dynamics. We combine technical innovations in functional PET imaging (fPET) and dual-calibrated fMRI, to simultaneously measure absolute rates and task-based relative changes in regional glucose and O2 metabolism. Aim 1 evaluates the reliability of hybrid PET/fMRI method, within and across scan sessions, and against prior PET- derived estimates. Aim 2 tests a novel hypothesis about the role aerobic glycolysis plays in information transmission. We hypothesize that aerobic glycolysis supplements energy for communicating unpredictable sensory signals, i.e., prediction error. To test this, we will use a simple behavioral task, manipulating the predictability of auditory and visual stimuli, crossed with an attention manipulation between sensory streams. Aim 1 represents a critical advance in our ability to measure brain metabolic dynamics, as prior research has been limited to performing independent PET sessions. Aim 2 tests a key prediction in a broader theoretical framework, which has the potential to significantly reframe interpretations of existing fMRI research, recontextualizing the hemodynamic response and “brain activation” in explicit informational and metabolic terms.