Continuous and Longitudinal Monitoring of Cerebral Blood Flow and Metabolism in Freely Moving Rodents

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ABSTRACT Measurements of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMRO2) in response to brain activity allows investigation of underlying excitatory and inhibitory neural responses and holds the key to optimizing novel therapies for neurological disorders and cerebrovascular diseases. Rodents (mice and rats) have been helping scientists investigate human diseases for well over a century and still make up 95% of the animal models used today. Major limitations with these rodent models are that cerebral hemodynamics is measured mostly in anesthetized animals and at limited time points. However, anesthesia impacts cerebral hemodynamics profoundly and interferes with studies of behavioral health, cognitive function, and sleep disorder. A few methods available for cerebral hemodynamic monitoring in conscious rodents require invasive craniotomy with installation of various opto-electrode/ultrasound probes onto the brain, which restrains animal’s head or body during measurements. Supported by NIH (R21), we have recently developed an innovative, noninvasive, low-cost, fiber-free, near-infrared diffuse speckle contrast flowmetry (DSCF) probe, which affixes on the heads of anesthetized rodents and awake humans for continuous monitoring of CBF. The goal of this proposal is to extend, optimize, and validate this novel technology toward a dual-wavelength, multi-channel, diffuse speckle contrast flow-oximetry (DSCFO) system for simultaneous regional mapping of CBF, cerebral oxygenation, and CMRO2 in conscious, freely moving rodents. DSCFO uses small near-infrared laser diodes at different wavelengths as point sources and a tiny CMOS camera as a 2D detector array to detect spatial dynamic light scattering by intrinsic motions of red blood cells (i.e., CBF) and light attenuations by oxy- and deoxy- hemoglobin absorptions ([HbO2] and [Hb]). Combination of CBF, [HbO2], and [Hb] enables derivation of CMRO2 based on established models. The 2D camera array enables 2D mapping of cerebral responses over two hemispheres and at different depths of the rodent head. Importantly, connections between the DSCFO probe and control unit are all electrical wires/cables (i.e., fiber-free), thereby offering the promise for continuous cerebral monitoring in freely moving subjects. After calibrating and optimizing the DSCFO system using head-simulating phantoms and validation in anesthetized rodents against established techniques, we will evaluate its performance for continuous and longitudinal cerebral monitoring in conscious, freely moving rodents with or without ischemic stroke insult. While we explore stroke-induced cerebral outcomes in this project, the DSCFO technology is applicable for studying other neurological disorders and cerebrovascular diseases. In combination with our ongoing R21 studies in human subjects, completion of this study in rodents will generate a unique noninvasive, fast, low-cost, multiscale, and multimodal brain mapping tool for both neuroscience research and clinical applications. Ultimately, the levels/variations and combination of CBF, [HbO2], [Hb], and CMRO2 may serve as biomarkers for assessing brain health and outcomes of cerebral pathological conditions and interventions.