The goal of this application is to develop and validate spectral-domain imaging technology at visible wavelengths to collect and reconstruct 2-dimensional topographic and 3-dimensional tomographic images of the oxidation state of mitochondrial cytochrome c and cytochrome oxidase, as well as the absolute hemoglobin concentration and saturation and the concentration of extrinsic chromophores. The technology will have the spatial and depth precision sufficient to resolve the columnar and laminar structure of the mammalian neocortex, and have the temporal precision to resolve events at the timescale of the neuronal circuits. It could be applied minimally invasively in mice and neonatal rats where the skull is sufficiently thin to be transparent, on rats using a standard thinned skull preparation, on awake non-human primates using a window preparation and on patients under going neurosurgery. We anticipate that this technology will be able to address fundamental issues in brain physiology such as mitochondrial oxygenation during neuronal activation, the magnitude of oxygen gradients in the brain, mechanisms of activation-flow coupling, the role of the blood flow increases during activation, the apparent shift from oxidative to glycolytic metabolism during focal activation and the origin of the elusive """"""""initial dip"""""""" observed in some but not all functional activation studies. The ability to image the columnar and laminar structure of the cortex with the temporal precision of the neuronal circuits has the potential to unravel the manner in which the cortex processes information. Furthermore, the technology has an application during neurosurgery to locate the boundaries of a tumor or to precisely locate a seizure focus during a lesionectomy. We have four specific aims (i) Construct a raster scanning visible spectral domain imaging system, (ii) Develop high resolution spectral-domain topographic and tomographic reconstruction algorithms based on a rapid Monte Carlo forward model, (iii) Develop methods to image total blood volume and tissue hematocrit and test the hypothesis that changes in the tissue hematocrit are insensitive to changes in the draining venules and so provide more localized vascular images of activation (iv) Develop techniques to image the cortex on the timescale of the neuronal circuits and test the hypothesis that a component of the fast optical signal is metabolic in origin and can be imaged with the mitochondrial signals.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biomedical Imaging Technology Study Section (BMIT)
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Stewart, Randall R
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Dartmouth College
Schools of Medicine
United States
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Ripple, Maureen O; Kim, Namjoon; Springett, Roger (2013) Acute mitochondrial inhibition by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitors regulates proliferation. J Biol Chem 288:2933-40
Ripple, Maureen O; Kim, Namjoon; Springett, Roger (2013) Mammalian complex I pumps 4 protons per 2 electrons at high and physiological proton motive force in living cells. J Biol Chem 288:5374-80
Kim, N; Ripple, M O; Springett, R (2011) Spectral components of the ?-band of cytochrome oxidase. Biochim Biophys Acta 1807:779-87
Ripple, Maureen O; Abajian, Michelle; Springett, Roger (2010) Cytochrome c is rapidly reduced in the cytosol after mitochondrial outer membrane permeabilization. Apoptosis 15:563-73
Davis, Scott C; Pogue, Brian W; Springett, Roger et al. (2008) Magnetic resonance-coupled fluorescence tomography scanner for molecular imaging of tissue. Rev Sci Instrum 79:064302
Springett, Roger; Swartz, Harold M (2007) Measurements of oxygen in vivo: overview and perspectives on methods to measure oxygen within cells and tissues. Antioxid Redox Signal 9:1295-301