Connectivity is critical to understanding how the brain works. Currently, most connectivity data is obtained in post-mortem histology studies, which are labor intensive, require the use of many animals, and can only be performed once per animal. Magnetic resonance imaging methods offer much increased efficiency and, because they are performed entirely in vivo, can be repeated as often as desired on the same animal. Diffusion tensor imaging is useful for studying brain connectivity in humans, but in animals, increased resolution and specificity can be obtained by injecting an MR-lucent tracer substance directly into the brain area whose connectivity is in question. Manganese has been used for this purpose in rats and birds, and has been used to trace large subcortical connections in monkeys. We propose to develop a methodology for studying detailed cortical connectivity in living primates, using cerebral manganese injections coupled with MRI analysis and visualization. We will optimize injection techniques, data acquisition and post-processing for intracortical and cortical-subcortical projections. In order to validate our results, we will co-inject manganese with histologic tracers and then compare the results of standard post-mortem histologic analysis with the manganese-enhanced MRI data. Successful development of this method could revolutionize the study of connectivity in monkeys, permitting, for example, precise determinations of how the cortex is rewired in development, skill acquisition and in recovery from lesions. It will also facilitate determinations of areal boundaries in relation to physiologically determined functions, and has the potential to greatly increase our understanding of how circuits in the brain process information. Perhaps the greatest health-related impact of this work will be on rehabilitation after brain injury, since this method will allow us to interrogate brain connectivity as individual subjects respond to and recover from, or fail to recover from, brain insults.
