PROJECT SUMMARY/ABSTRACT – PROJECT 3 We propose to leverage our state-of-the-art functional MRI (fMRI) tools combined with electroencephalography (EEG) to investigate the pial neurovascular circuit in humans. This circuit is composed of a network of pial arterioles that integrate neuronal activity with the intrinsic arteriolar vasomotion, producing dynamic patterns of coherent oscillations in arteriolar diameter that effectively parcellate the cortical mantle. Today fMRI is the most widespread tool for measuring neural activity noninvasively across the entire human brain. All fMRI signals are vascular in origin, thus proper interpretation of these hemodynamic signals is key to understanding the underlying neural activity. Our team has demonstrated that spontaneous oscillations in arterial vascular diameter, or vasomotion, in the cerebral cortex is entrained by local neural activity, and that arterioles behave as coupled oscillators with other connected arterioles via active signaling along the vascular endothelium. This motivates the central hypothesis of this U19—that local neuronal drive and neuromodulatory inputs with ultralow-frequency components compete with the intrinsic oscillatory properties of arterioles. This allows different cortical regions to oscillate at different frequencies and results in spatial parcellation of vasodynamics and the formation of different constellations of temporally coherent regions. The coupling of arterial oscillations will induce coupling of the downstream venous blood oxygenation that is the basis of Blood- Oxygenation Level Dependent (BOLD) contrast, the most commonly used fMRI signal. In Aim 1, we will adapt our noninvasive imaging tools to image the anatomy and dynamics of the human pial arterial vascular network. We will then develop novel tools to measure diameter changes of pial arterioles to directly track vasomotion in humans, and link these dynamics to standard fMRI measures. Our Aim 2 is a human counterpart of Project 1; we will study vascular integration of multiple sensory drives by the pial neurovascular circuit and its reflection in large-scale hemodynamics. Our Aim 3 is the human counterpart of Project 2; we will record BOLD fMRI and EEG simultaneously during spontaneous fluctuations in arousal state, and identify how internal brain states are linked to spatial patterns of our imaging readouts. Similar to Project 2, we will test whether these hemodynamic patterns, alone or in combination with EEG signals, can be used to predict cognitive performance. Finally, we will work throughout with Project 4 to devise a phenomenological mathematical model that captures the essence of a brain state from the standpoint of the vascular integrator producing large-scale patterns of coherent vascular/hemodynamic fluctuations. Impact: Project 3 will offer a strong physiological foundation for the interpretation of large-scale fMRI signals in humans and better understanding of the mechanisms linking spontaneous ...