Development of concurrent MRI and Optical Spectroscopy for measurement of neuronal cell biophysical/microstructural changes

目前的模型和成像策略，神经元激活的基础上的瞬态电和生化事件与兴奋过程。然而，有越来越多的证据支持，往往被忽视，但非常重要的，补充生物物理微观结构的变化，兴奋的神经元组织。发展成像技术来观察这些变化在体内是非常重要的，因为它将允许一个更直接的测量神经元的事件，如膜扩张。这种成像策略提供了一种更可靠的活动测量方法，与广泛使用的血氧水平依赖（BOLD）功能磁共振成像（fMRI）信号等方法相比，具有更少的生理混淆。一种显示出巨大前景的方法是基于扩散的磁共振成像（DW-MRI）-一种对细胞结构中的这种微观结构变化敏感的成像技术;细胞膜和大分子充当阻碍水质子自由扩散的微观障碍物。在神经元活化过程中观察到的水扩散系数的降低被认为反映了皮质细胞的瞬时肿胀和细胞外空间的减少，增加了其扩散分子的曲折性。然而，DW-MRI反应的确切起源仍然不支持和不清楚。该博士项目涉及并发高场（7特斯拉）DW-MRI和空间频域光学成像（SFDI）的开发和实施，以研究神经元活动的这种潜在重要MR生物标志物的基础。SFDI是一种互补的光学成像技术，其对光散射和吸收系数的变化敏感，所述光散射和吸收系数的变化在细胞的微结构改变时（例如，在神经元细胞肿胀期间）引起。所开发的并行成像方法将在啮齿动物和神经血管耦合受损的模型中应用于体内。我们将检查两种成像方法之间的一致性程度;由于血管和细胞微观结构成分，允许分离信号源。此外，该项目将涉及开发组织模型，以3D功能磁共振成像数据为基础，分析神经元活动期间的内在光学成像信号;以期提取细胞色素氧化酶的变化，并将其与健康和疾病中的线粒体功能联系起来。数据将用于完善目前基于皮质层的神经元激活的生物物理模型，并最终加快DW-MRI在脑活动临床测量中的应用。

Current models of, and imaging strategies for, neuronal activation are based on the transient electrical and biochemical events associated with the excitation process. However, there is a growing base of evidence supporting, often ignored but extremely important, supplementary biophysical microstructural changes in excited neuronal tissue. Development of imaging techniques to observe these changes in-vivo is of great importance because it would allow a more direct measure of neuronal events, such as membrane expansion. Such imaging strategies offer a more reliable measure of activity with less physiological confounds than methods such as the widely used Blood Oxygenation Level Dependent (BOLD) functional magnetic resonance imaging (fMRI) signal. One method showing great promise is Diffusion based Magnetic Resonance Imaging (DW-MRI) - an imaging technique sensitive to such microstructural changes in cell structure; with cell membranes and macromolecules acting as microscopic obstacles that hinder the free diffusion of water protons. Observed decreases in the water diffusion coefficient during neuronal activation are presumed to reflect the transient swelling of cortical cells and reduction of the extracellular space, increasing its tortuosity for diffusing molecules. However, the exact origin of the DW-MRI response still remains unsupported and unclear. This Ph.D project involves the development and implementation of concurrent high field (7 Tesla) DW-MRI and spatial frequency domain optical imaging (SFDI) to investigate the underpinnings of this potentially important MR biomarker of neuronal activity. SFDI is a complementary optical imaging technique which is sensitive to changes in light scattering and absorption coefficients that are induced when the micro-structure of the cell changes (e.g. during neuronal cell swelling). The developed concurrent imaging method will be applied in-vivo on rodents and in models where neurovascular coupling is impaired. We will examine the degree of concordance between the two imaging methods; allowing separation of signal sources due to both the vascular and cell microstructure components. Furthermore, the project will involve the development of tissue models in the analysis of intrinsic optical imaging signals during neuronal activity, based on the 3D functional MRI data; with a view to extracting changes in cytochrome oxidase and relating that to mitochondrial function in health and disease. Data will be used to refine the current biophysical models of cortical layer based neuronal activation and ultimately expedite the use of DW-MRI in clinical measures of brain activity.