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

理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。常规刺激电极的使用受到其选择性地靶向不同神经元群体的能力的缺乏的限制。同样地，基于电极的神经刺激不一定模仿内源性神经活动，并且空间神经刺激不一定模仿内源性神经活动。 不能总是保证以生物学上真实的方式传播活性。另一方面，对所得到的大脑活动的监测包括使用将提供高时间分辨率测量的记录电极。然而，缺乏对记录电极的“解剖意识”是分析涉及多个且可能难以捉摸的大脑区域的功能电路的限制因素。 血氧水平依赖（BOLD）功能磁共振成像（fMRI）以其非侵入性，全脑覆盖的能力是有希望的，这样的大规模神经元监测。但目前的功能磁共振成像方案与图像失真和缺乏足够的空间分辨率的问题作斗争。这个K99的候选人，独立之路赠款是一个训练有素的MR科学家现在寻求弥合功能磁共振成像监测和有针对性的神经刺激计划之间的差距，今天存在。在这份提案中，候选人提议 高度创新的分子靶向神经光学刺激方法与候选人近年来开发的从头无失真、高分辨率功能性MRI技术的协调发展。通过这种新方法，可以在分子上靶向特定类型的神经元进行询问，引发内源性神经元激活，并以极高的空间分辨率无失真地监测神经元活动的结果模式。这种以高空间分辨率非侵入性监测大脑活动的新能力，同时以高功能精度控制神经元活动，将为研究神经精神疾病的机制提供强大的未来工具。这将导致更好地理解疾病机制以及新治疗方法的开发。

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.