The goal of this project is to create noninvasive methodology to image the connectional neuroanatomy of the human brain using diffusion MRI. Two recent developments make this possible. First, we have shown in macaque that every region of the cerebral cortex reliably gives rise to a predictable number of fiber tracts connecting it with unique sets of neuronal subpopulations distributed within cortical and subcortical regions. Second, we have shown, also in macaque, that novel forms of high angular resolution diffusion spectrum MRI (DSI) have the unique capacity to define connectional neuroanatomy non-invasively. The goal of the present project is to define, for the first time, the connectional neuroanatomy of the monkey brain non-invasively, and to build a bridge from the macaque brain to the human brain in order to accomplish a previously impossible goal - the determination of connectional neuroanatomy in the human brain. To achieve this goal, three steps are necessary. First, we will validate diffusion MRI in macaque by comparison to the gold standard of isotope tract tracer injections, the tracer injections and MRI to be performed in the same animals. The technical parameters that optimally and most accurately replicate the findings of the tract tracer studies will be determined, and potential sources of MRI error quantified and minimized. Second, post-mortem human brains will be imaged to achieve the highest possible resolution of these human brains, with the aim of replicating the mandatory principles of organization of the white matter pathways identified as defining the connections of the monkey brain. Next, the brains of living human subjects will be imaged, to attempt to replicate the findings in the post-mortem specimens, in order to establish the limitations of the methodology in vivo. To convey this technology into the broader imaging arena, we will investigate the hypothesis that structural and functional connectivity are correlated by comparing the results with those of resting state connectivity in the living human brain.
- RELEVANCE TO PUBLIC HEALTH All conscious human activity depends on a normally functioning nervous system. Diseases that affect the brain have very different manifestations, depending on which part of the brain is involved. This is the basis for the realization that the anatomical organization of the brain is of paramount importance for nervous system function in the healthy brain and in disease states. Functional imaging studies of the human brain have made it clear that many different brain regions are engaged in actions ranging in complexity from what appears to be a simple movement, to complex types of higher order behaviors including language and thinking strategies required for planning and memory. It is possible to see the major structures of the human brain at post-mortem, and during life with radiological techniques such as computerized axial tomography (CT) scans and magnetic resonance imaging (MRI) scans. It has been impossible, though, to know how the brain is hard wired using these techniques, and there have been no methods to allow scientists to develop this knowledge. For at least two centuries scientists have had to use animal models to explore the anatomy of the brain to understand how the nervous system works, and what the relationships are between the different brain regions. This anatomical approach has shown that the different areas of the brain are linked together in a very precisely organized manner. This science of connectional neuroanatomy has led to the understanding that every area of the cerebral cortex is linked in a unique manner with other cortical areas and also with subcortical structures. The pathways that link these different parts of the networks, or the distributed neural circuits, are also very precisely arranged. This deeper understanding of the pathways and networks of the brain have helped explain the functions of the brain in the realms of motor control, cognitive processing and emotional regulation. But the problem with this approach is that all this work has been performed in monkeys, cats, rats, mice and other animals - but not in humans. The ability to converse, think rationally, engage in complex behaviors, build societies, and enjoy rich emotional lives are human traits that are likely to have anatomical foundations quite different from that in animals. And how does one person differ from another - what is the brain basis of musical skill or mathematical ability;what are the differences in the wiring of the brain between individuals who develop obsessive compulsive disorder, schizophrenia or dyslexia;and what happens to the brain circuits in disease that devastate the nervous system such as Alzheimer disease or Lou Gherig disease? All these questions are of fundamental significance, and scientists, as well as society at large, have long been curious to know the answer - not for curiosity's sake alone, but because knowing how the brain is constructed in people, as opposed to animals, is likely to have profound significance for understanding the human condition in health and disease and developing new approaches to diagnosis, management and prevention of disease. The development of the techniques that we are proposing in this grant has the demonstrated potential to shed light on these questions, and indeed, achieve the goal of performing connectional neuroanatomy in the human brain. Our preliminary studies show that this can be achieved to a reasonable degree in many areas in the monkey brain, and with the further refinement of the techniques and the validation of the new imaging methods (DSI - diffusion spectrum imaging) we are confident that the results will match the enthusiasm with which this team of investigators is embarking on this scientific journey. The team is headed by two of the leading scientists in their respective research fields - improvement in imaging methods, and the neuroanatomy and connections of the brain - collaborating together in a scientific environment that is conducive to this kind of novel exploration and discovery. The ability to engage in connectional neuroanatomy - the definition of brain circuits in humans in health and disease, has long been an elusive goal of neuroscience that is about to be realized within the time frame of this grant cycle.
