Project Summary / Abstract: The blood oxygenation level dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) signal source has been long debated since the invention of fMRI in the early 90s. While fMRI is one of the most successful technologies utilized in numerous studies, the debate over the source of fMRI signal source continue to generate controversies over the utility of fMRI and the interpretation of fMRI studies. One important aspect in the study of fMRI signal source is that it is fundamentally difficult to study the fMRI signal source in isolation in one brain region with one cell type. fMRI signal represents an intricate interaction between the vascular system and the neural activity and it is bound to depend on cell type and vascular composition of each region of the brain. In this context, basal ganglia thalamo-cortical circuit provides a unique opportunity to understand the fMRI signal source. Many of the basal ganglia circuit elements contain largely inhibitory cell populations with remote projections. This enables the possibility of driving neural activity throughout the brain with distinct temporal dynamics, which can potentially help delineate fMRI signal with more specificity on each cell type’s role. In addition, the basal ganglia thalamo-cortical system is an important network in the brain that consists of multiple nodes throughout the brain forming a distributed network that real- time controls important behavior such as movement. It is one of the key networks that require large-scale imaging methods such as fMRI to understand its overall dynamics. Specifically, studying the fMRI signal source associated with this network function will directly enable us to apply the knowledge to understanding an important neurobiological question. Our experimental strategy consists of three main components. In the first aim, we will measure cell type specific whole brain network function during D1- or D2- MSN stimulation utilizing simultaneous ofMRI and electrophysiology. In the second aim, we will conduct optical imaging at locations identified by preliminary ofMRI studies to confirm sources of fMRI signal with cell type specificity at each location. Then, we will computationally model the measurements to systematically understand the source of the fMRI signal against frequency components of the electrophysiology signal and also cell types at each downstream location from the stimulation site. We will utilize this knowledge to then construct models of whole brain circuit function with both stimulation cell type and downstream locations cell type specificity These aims are designed to understand the fMRI signal source in the context of D1 and D2 MSN regulation of global brain function across multiple synapses. We will also demonstrate the power of such studies in enabling a comprehensive model that can describe the interactions among all regions involved with both stimulation cell type and downstream local regional cell type specificity. This study will provide an important groundwork for understanding fMRI signal sources and how it can enable cell type specific whole brain function investigation with unprecedented precision.

Project Narrative Utilizing a novel technology that enables precise, selective excitation and/or inhibition of brain cells while measuring high-resolution videos of the associated whole brain interactions, we aim to understand the source of the functional magnetic resonance imaging signal. Upon success, these measurements will help us interpret the fMRI signal beyond simple correlative measures. Furthermore, we will demonstrate that such understanding can be utilized to uncover comprehensive whole brain circuit functions, which in turn will enable us to systematically design therapies that can restore normal brain circuit function in neurological diseases such as Parkinson’s disease.