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

了解神经精神疾病的病因和干预结果的关键是能够通过精确控制的刺激机制分析大脑的功能电路，同时非侵入性地监测神经元活动的变化。传统刺激电极的使用受到其缺乏选择性地针对不同神经元群体的能力的限制。同样，基于电极的神经刺激不一定模仿内源性神经活动，并且空间 不能总是保证以生物上真实的方式传播这项活动。另一方面，对由此产生的大脑活动的监测包括使用记录电极，这些电极将提供高时间分辨率测量。然而，缺乏对记录电极的“解剖学意识”是分析涉及多个可能难以捉摸的大脑区域的功能电路的一个限制因素。 血氧水平依赖(BOLD)功能磁共振成像(FMRI)以其无创、全脑覆盖的能力，在大规模神经元监测中具有广阔的应用前景。但目前的功能磁共振成像方案正在努力解决图像失真和缺乏足够空间分辨率的问题。K99《独立之路》的候选人是一位训练有素的MR科学家，他正在寻求弥合功能磁共振监测和目前存在的有针对性的神经刺激计划之间的差距。在这份提案中，候选人提议 一种高度创新的分子靶向神经光学刺激方法与无从头失真、高分辨率功能磁共振技术的协调开发是该候选人近年来开发的。使用这种新方法，特定类型的神经元可以作为询问的分子靶点，引发内源性神经元激活，并以极高的空间分辨率监测由此产生的神经元活动模式，而不会发生扭曲。这种以高空间分辨率非侵入性监测大脑活动，同时以高功能精度控制神经元活动的新能力，将为研究神经精神疾病的机制提供强大的未来工具。这将有助于更好地了解疾病的机制以及开发新的治疗方法。

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.