Direct MRI of Neuroelectric Activity for Animal Neuroimaging

描述(申请人提供)：对动物模型的神经科学研究在改善人类神经疾病的诊断和治疗方面发挥着基础性作用，因为它具有遗传和药物操作的能力。在最广泛使用的脑功能研究方法中，电生理记录具有高时间分辨率的优点，但具有侵入性，空间覆盖有限。相反，依赖血氧水平的功能磁共振成像是无创的，可以提供全脑覆盖，但由于复杂的神经血管耦合，无法定量和准确地定位神经活动在空间和时间上的位置。一种新的磁共振成像技术，称为洛伦兹效应成像(LEI)，可以检测神经活动引起的离子电流和周围的水分子，以解决这些局限性。这项技术已经被应用于成像溶液中的离子电流，电流密度与神经活动以及感觉神经动作电位的电流密度相似，具有毫秒级的时间特异性。考虑到这些有希望的结果，可以假设LEI可以进一步发展成跨功能网络以高空间和时间特异性成像大脑中的神经活动。该项目的目标是为动物研究开发一种非侵入性和特异性的功能神经成像技术，这将对神经科学产生重大影响。由于生理噪声等潜在的混杂因素，LEI在大脑中的应用需要进一步提高灵敏度。此外，它的验证需要一个稳健的刺激范式，可以在空间和时间上精确控制。与以前使用的人类扫描仪相比，7T动物核磁共振扫描仪具有显著更高的场强和梯度幅度，以及一种新型的转基因小鼠模型，该模型在整个大脑的选定神经元中表达光激活的离子通道视紫红质-2(ChR2)，该模型可以通过可见光的光刺激在体内激活，从而满足这两个要求。提出了三个具体目标。目的1是通过对麻醉的ChR2转基因小鼠的大脑皮质表面进行光刺激，并通过仔细的实验设计来去除任何混杂的血流动力学调节，来证明LEI成像在活体大脑中神经活动的可行性。目标2是通过改变光刺激的空间范围或时间来证明LEI在空间和时间上精确定位神经活动的能力。目标3是展示LEI通过光刺激嗅球和使用不同的激活范例来跟踪和定位功能网络中的神经活动的能力，这些激活范例旨在选择性地跟踪嗅神经回路不同区域的神经活动或同时映射所有功能连接的区域。 公共卫生相关性：该项目的目标是开发一种新的动物功能神经成像的MRI技术，将电生理记录的高时间特异性与MRI固有的非侵入性和高空间覆盖率相结合。这种技术有可能无创地跟踪和绘制整个大脑中具有高度时空特异性的活体神经活动，这将显著增强我们研究神经系统功能的能力，从而提高对许多神经和精神疾病的理解、预防、诊断和治疗。

DESCRIPTION (provided by applicant): Neuroscience research on animal models plays a fundamental role in improving the diagnosis and treatment of human neurological disorders, because of the capacity for genetic and pharmacological manipulations. Among the most widely used methods to investigate brain function, electrophysiological recordings benefit from a high temporal resolution, but are invasive and have a limited spatial coverage. Conversely, blood oxygenation level-dependent functional MRI is noninvasive and provides full brain coverage, but cannot quantitatively and accurately localize neural activity in space and time because of the complex neurovascular coupling. A novel MRI technique, termed Lorentz effect imaging (LEI), which detects the ionic currents and surrounding water molecules induced by neural activity, was proposed to address these limitations. This technique has been applied to image ionic currents in solution with current densities similar to those induced by neural activity as well as sensory nerve action potentials in the human median nerve in vivo with a millisecond temporal specificity. Given these promising results, it is hypothesized that LEI can be further developed to image neural activity in the brain with a high spatial and temporal specificity across functional networks. The goal of this project is to develop such a noninvasive and specific functional neuroimaging technique for animal research, which would have a significant impact in neuroscience. Because of potential confounding factors such as physiological noise, the application of LEI to the brain requires a further increase in sensitivity. In addition, its validation requires a robust stimulation paradigm that can be accurately controlled in space and time. These two requirements can be met by using a 7 T animal MRI scanner with a significantly higher field strength and gradient amplitude as compared to the human scanner used previously, as well as a novel transgenic mouse model expressing the light-activated ion channel Channelrhodopsin-2 (ChR2) in selected neurons throughout the brain, which can be activated in vivo by photostimulation with visible light. Three specific aims are proposed. Aim 1 is to demonstrate the feasibility of LEI to image neural activity in the brain in vivo by photostimulating the cortical surface of anesthetized ChR2 transgenic mice and by using a careful experimental design to remove any confounding hemodynamic modulations. Aim 2 is to demonstrate the ability of LEI to accurately localize neural activity in space and time by varying the spatial extent or timing of the photostimulation. Aim 3 is to demonstrate the ability of LEI to track and map neural activity across functional networks by photostimulating the olfactory bulb and by using different activation paradigms designed to selectively track neural activity in different regions of the olfactory neural circuit or to simultaneously map all functionally connected areas. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a novel MRI technique for animal functional neuroimaging combining the high temporal specificity of electrophysiological recordings with the noninvasiveness and high spatial coverage inherent in MRI. Such a technique has the potential to noninvasively track and map neural activity in vivo with a high spatial and temporal specificity across the whole brain, which would significantly enhance our ability to investigate the function of the nervous system and hence improve the understanding, prevention, diagnosis, and treatment of many neurological and psychiatric disorders.