Contribution of cell-specific activity to functional MRI

Resting state functional magnetic resonance imaging (rs-fMRI) contains a wealth of information about the large-scale structure of intrinsic neural activity in the brain and is widely used to study alterations in neurological or psychiatric disorders. Our prior work demonstrates that intrinsic brain activity is dominated by a few whole- brain spatiotemporal patterns that occur repeatedly over time, but little is known about the mechanisms that coordinate these patterns and therefore about how altered patterns in brain disorders should be interpreted. The spatiotemporal patterns exhibit features that are undetectable with time-averaged analysis methods (e.g., functional connectivity) and which may provide important insight into underlying neurophysiology. Three prominent features in need of explanation are sparse instances of strong transient network activity; variability in the amplitude of the rs-fMRI signal across brain areas and over time; and propagation along the cortex that happens concurrently with network interactions. We have developed an innovative method for simultaneous wide-field optical imaging (WOI) and rs-fMRI that will allow us to test potential explanations for these features of intrinsic activity. WOI can detect fluorescence from activity in specific types of cells over the entire cortex, obtaining images of spatial patterns rather than the localized measurements obtained with electrophysiology. Functional connectivity has been observed in WOI of excitatory and inhibitory activity, suggesting that transient network activation patterns of both types of neurons may underlie the strong transient activations observed with rs-fMRI. Aim 1 utilizes simultaneous rs-fMRI and WOI of excitatory and inhibitory neurons to determine if the transient patterns of activity are common and synchronous across modalities. Aim 2 uses the same method to investigate the relationship between the amplitudes of excitatory and inhibitory activity and the amplitudes of the rs-fMRI fluctuations. Finally, we hypothesize that signal propagation is mediated by astrocytes, which have been shown to give rise to traveling waves. Aim 3 applies simultaneous rs-fMRI and WOI to determine the role of astrocytes in the propagation of signal across the cortex. This proposal will make strides toward understanding the coordination of intrinsic brain activity, which is altered in nearly every psychiatric and neurodegenerative disorder. The proposed experiments provide insight into these alterations for the purposes of diagnosing, evaluating, and treating dysfunction in the brain. The knowledge gained about the large-scale organization of brain activity will help to bridge the gap between fundamental studies of activity in local circuits and the whole-brain activity detectable with noninvasive imaging techniques. As experiments proceed, we will further refine the cutting-edge technologies that we have developed for multi-modal WOI and rs-fMRI studies, and we will make the methods and the resulting data freely available. Project Number: 1R01NS140219-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Shella Keilholz | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $577,611 | Activity Code: R01 | Study Section: Imaging Technology for Neuroscience Study Section[ITN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296530