The computational properties of the human brain arise from an intricate interplay between billions of neurons connected in complex networks. However, our ability to study these networks in healthy human brain is limited by the necessity to use noninvasive technologies. This is in contrast to animal models where a rich, detailed view on the cellular level brain function has become available due to recent advances in microscopic optical imaging and genetics. Thus, a central challenge facing neuroscience today is leveraging these mechanistic insights from animal studies to accurately draw physiological inferences from human noninvasive signals. In the proposed project, we focus on the “Calibrated” Blood Oxygenation Level Dependent (BOLD) fMRI technology asking the questions: “Which aspects of the underlying neuronal activity can be reliably inferred from noninvasive cerebral blood flow (CBF) and Cerebral Metabolic Rate of O2 (CMRO2) observables?” and “What further information can be obtained from combining Calibrated BOLD with Magnetoencephalography (MEG)?” Our central hypothesis is that specific neuronal cell types have identifiable “signatures” in the way they drive changes in energy metabolism (CMRO2), blood flow (CBF) and contribute to macroscopic electrical signals (MEG current dipole dynamics). Because other factors may affect baseline flow and metabolism, our focus is on the evoked absolute CMRO2 and CBF changes associated with increased or decreased neuronal activity. We will perform parallel experiments in mice and humans to empirically connect the dots between the microscopic properties of brain's functional organization and their manifestation on the macroscopic level of noninvasive observables. Based on the experimental results, we will then develop a computational framework that will establish connections between scales and measurement modalities enabling robust estimation of the critical aspects of neuronal circuit activity from noninvasive measurements in humans. The proposed project will deliver a quantitative probe for neuronal activity of known cell types in human brain enabling a paradigm shift in human fMRI studies: from a simple mapping of fMRI signal change to the explicit estimation of the respective activity levels of specific neuronal cell types without confounding effects of the baseline state of flow and metabolism.

Noninvasive imaging technologies have become as ubiquitous to psychologists and psychiatrists as microscopes are to basic biologists. And yet, despite this widespread adoption, the power of available human neuroimaging methods remains limited, leaving a gap between the macroscopic activity patterns available in humans and the rich, detailed view achievable in model organisms. The proposed project will deliver a quantitative probe for neuronal activity of known cell types in human brain enabling a paradigm shift in human fMRI studies: from a simple mapping of fMRI signal change to the explicit estimation of the respective activity levels of specific neuronal cell types without confounding effects of the baseline state of flow and metabolism.