High-density optical tomography of cerebral blood flow and metabolism in small animals

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ABSTRACT Many clinical situations, including stroke, expose the brain to insufficient cerebral blood flow (CBF) that cannot maintain normal cerebral metabolic rate of oxygen consumption (CMRO2) requirements, thereby leading to cerebral ischemic/hypoxic stresses and neurological disorders. Effective interventions are dependent on the findings of CBF/CMRO2 improvement and eventually neural recovery. Rodents (mice and rats) make up 95% of research animals. However, one major limitation with neuroscience research in rodent models is lack of affordable noninvasive imaging technologies for continuous and longitudinal monitoring of CBF and CMRO2 variations. Large imaging modalities (e.g., CT, PET, and MRI) require expensive instrumentation, and are difficult to use for longitudinal monitoring. Portable, inexpensive optical/ultrasonic technologies greatly expand choices for continuous cerebral monitoring although most systems lack the combination of high tempo-spatial resolution, wide field-of-view, and proper penetration depth into deep brains. Moreover, none of currently available techniques enable simultaneous imaging of CBF, cerebral tissue oxygen saturation (StO2), and CMRO2. To overcome these limitations, researchers at University of Kentucky (UK) have developed an innovative CCD/CMOS based speckle contrast diffuse correlation tomography (scDCT: US Patent #9861319) technique to accommodate noninvasive, noncontact, fast, high-density 3D imaging of CBF distributions in mice, rats, piglets, and human neonates. While effective, scDCT has not been optimized for dissemination and commercialization in terms of imaging performance (signal-to-noise ratio, temporal-spatial resolution, accuracy, easy-to-use), and instrument cost and portability. In collaboration with UK, Bioptics Technology LLC (BOT) proposes to develop, optimize, validate, and commercialize an affordable, portable, easy-to-use, multi-wavelength scDCT (MW- scDCT) technique for repeated, longitudinal imaging of CBF, StO2, and CMRO2 distributions in rodents. New methodologies and algorithms will be developed to achieve a nearly real-time, high-density, 3D imaging of cerebral function. The MW-scDCT will be rigorously tested and optimized using head-simulating phantoms with known optical and hemodynamic properties (Aim 1). In vivo calibration and evaluation of absolute measurements with MW-scDCT will be conducted against standard perfusion MRI and histological examination in rats with or without stroke (Aim 2). Finally, optimized MW-scDCT devices will be disseminated to several neuroscience researchers inside and outside UK to collect feedback regarding instrument applicability and user experience. With preliminary feedback from these selected end-users, we expect to identify refinements and improvements needed for the MW-scDCT in a continued Phase-II study to produce an optimal product-level device for commercialization. The ultimate use will be expanded to larger animal models and human subjects. However, this Phase-I project will begin with rodents as using small animals is easier, more economical and efficient for commercializing the device, thereby paving the way for future commercialization of clinical-level devices.