The overall goal of this work is to develop functional magnetic resonance imaging (MRI) and optical imaging techniques that allow non-invasive assessment of brain and heart function. MRI technqiues are having a broad impact on understanding brain. Anatomical based MRI has been very useful for separating gray and white matter and detecting numerous brain disorders. Functional MRI techniques enable detection of regions of the brain that are active during a task. Molecular MRI is an emerging area, whose major goal is to image a large variety of processes in tissues. Our goal is to impact MRI developments in all these areas. Over the past several years we have demonstrated that manganese chloride gives MRI contrast that defines neural architecture, can monitor activity, and can be used to trace neural connections. Over the last couple of years we have completed the assignment of cortical layers detected using manganese enhanced MRI by comparison to histology and have demonstrated that functional anatomy of some cortical regions of the rodent brain can be defined in individual animals. We have also demonstrated, in collaboration with Leo Belluscio, that activity in the olfactory bulb can be imaged to the level of single glomeruli using manganese enhanced MRI. Finally, we have developed sensitive MRI techniques to monitor manganese levels and can now track neural connections from the olfactory bulb to the amygdala in individual animals and cortical-cortical connections.? ? Over the past few years, we have completed studies in the rodent brain that acquired very high temporal and spatial resolution functional MRI (fMRI) to monitor changes in hemodynamics as a surrogate marker of electrical activity during forepaw stimulation. Work over the past year has acquired very high signal to noise fMRI maps to determine if the borders of activated areas can be detected. fMRI results can be compared to manganese enhanced MRI determination of anatomical borders to get a non-invasive view of the functional dynamics that can occur in the rodent brain under a variety of conditions. Functional MRI studies were performed to measure changes in brain activation that occur after denervation of peripheral nerves. After severing the saphanous and sciatic nerve of one hindpaw, the good hindpaw is now able to cause activation of about 50% of the damaged hindpaw's cortical representation even though it is in the opposite brain hemisphere. Lesion experiments support the model that cortical-cortical communication via the corpus collosum is responsible for this plasticity. High resolution fMRI indicates that the cortical layers responisble for this communication can be detected and electrophysiology is being performed to confirm the fMRI results.? ? Over the past couple of years we have demonstrated that micron sized iron oxide particles are useful as cellular MRI contrast agents. Over the past year we have been successful at detecting single cells migrating in the brain and to the liver using micron sized iron oxide particles. These are very potent MRI contrast agents that have enbaled us to label endogenous neural stem cells in the subventricular zone and then detect migration of these cells to the olfactory bulb. Over the past year we have verified the localization of the particles and quantitated the neural stem cells and neurons that arise from these cells. We have begun to test conditions under which the distribution of these cells change based on changes in brain activity during learning and plasticity. We have also successfully co-labeled these endogenous cells with fluorescence as well as MRI markers to enable optical studies to be done at subcellular resolution. The ability to monitor the migration of these important cells in the same animal that we can perform functional MRI and manganese based neural tracing should give us a unique view of the rodent brain. The usefulness of detecting single cells in MRI is being explored in projects to assess metastatic potential of cancer cells in collaboration with Katherine Kelley in NCI and the potential to label specific blood cells in collaboration with Cynthia Dunbar in NHLBI.
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