PROJECT SUMMARY/ABSTRACT – PROJECT 4 We propose to leverage our state-of-the-art expertise in theoretical biological physics and computational fluid dynamics to investigate fundamental aspects of the pial neurovascular circuit and its impact upon cortical blood supply and oxygenation. Project 4 will provide a quantitative path from in vivo responses in animal subjects (Projects 1 and 2) to the interpretation of fMRI data across human subjects (Project 3). This program will establish a link between observable neurovascular responses and the internal brain state. In particular, Project 4 will collaborate with Project 1 to integrate experimental knowledge of pial neurovascular circuit oscillations; it will collaborate with Project 2 to incorporate knowledge on the modulation of neuronal and vascular activity; finally, it will impact Project 3 by using blood oxygenation models to determine BOLD fMRI signals in response to pial neurovascular patterns. Project 4 features two specific aims: (ii) Capture the spatiotemporal neurovascular dynamics and the patterns of the pial vascular network, that is, the dilation and constriction of arterioles driven by their smooth muscle sheath; and (ii) Demonstrate the effects of the vasomotor dynamics onto the cortical blood supply and tissue pO2, thereby establishing a causal link between BOLD/CBV fMRI signals and neuronal activity patterns. For Aim 1, we shall rely on long standing experimental evidence for ultraslow, ~ 0.1 Hz oscillations of individual arteriole segments, as well as preliminary data of Project 1 on the pial neurovascular network. Their combination leads to our theoretical framework of brain arterioles forming a network of coupled oscillators that control the flow of blood throughout the entire brain. Our first goal is to develop coupled-oscillator-based mathematical models that capture the essence of the observed neurovascular and neuromodulatory dynamics across the cortical mantle and propose experimental tests. Our second goal is to demonstrate how the competition between modulatory drives and intrinsic oscillations of arterioles results in spatial parcellation and formation of the different constellations of temporally coherent regions, as observed in Projects 1 to 3. For Aim 2, we will use detailed hemodynamic simulations with an existing three dimensional reconstruction of the cortical microcirculation to gauge the regulatory effect of vasomotor actuation, modeled in the first aim and observed in experiments of Projects 1 and 2, on induced changes in cortical blood and oxygen supply. The effects of rhythmic changes in pial arteriole diameter upon the cerebral blood flow and dynamic resistance redistributions in microvessels will be specifically dissected to establish the feed forward regulation that vasomotor exercises upon cortical blood supply and tissue pO2. Vasomotor-modulated blood flow will be further used to compute spatiotemporal oxygenation maps throughout the depth of cortical l...