Visualization of Neuro-Molecular Targeting using Distribution-Free, High-Res fMRI

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A key in understanding the etiology and interventional outcome of neuropsychiatric diseases is the ability to analyze the brain's functional circuitry through precisely controlled stimulation mechanism, while at the same time non-invasively monitoring changes in neuronal activity. The use of conventional stimulation electrodes is constrained by the lack of its ability to selectively target different neuronal populations. Likewise, electrode-based neural stimulation does not necessarily mimic endogenous neural activity, and a spatial propagation ofthe activity in a biologically realistic fashion cannot always be guaranteed. The monitoring of the resulting brain activity on the other hand includes the use of recording electrodes that wili provide high temporal resolution measurements. However, the lack of "anatomical awareness" of recording electrodes is a limiting factor for the analysis of functional circuitry that involves multiple, and possibly elusive brain areas. Blood oxygenation level dependent (BOLD) functional MRI (fMRI) with Its non-Invasive, whole-brain coverage capability is promising for such large-scale neuronal monitoring. But current fMRI schemes struggle with problems of image distortions and lack of sufficient spatial resolution. The candidate of this K99, Pathway to Independence grant is a superbly trained MR scientist now seeking to bridge the gap between fMRI monitoring and targeted neural stimulation schemes that exist today. In this proposal, the candidate proposes a coordinated development of a highly innovative molecularly targeted neuro-optical stimulation method with a de novo distortion-free, high-resolution functional MRI technique the candidate has developed in recent years. With this new method, specific types of neurons can be molecularly targeted for interrogation, endogenous neuronal activation elicited, and the resulting pattern of neuronal activity monitored at an exceedingly high spatial resolution without distortions. This new capability to non-invasively monitor brain activity at high spatial resolution, while controlling the neuronal activity with high functional precision, will provide a powerful future tool for studying the mechanisms of neuropsychiatric diseases. This will lead to better understanding ofthe disease mechanism as well as the development of new treatments.