Spatially Resolved Diffuse Correlation Spectroscopy for Cerebral Blood Flow Monitoring in Mouse Stroke Model

Animal stroke models have contributed greatly to our understanding of the pathophysiological outcomes of stroke and its interventions, and can provide an exploratory environment for potential clinical applications. Transient occlusion models are widely used, particularly in mice, as they can mimic acute occlusion and subsequent thrombolysis in humans, thereby facilitating the design and optimization of stroke interventions. Cerebral blood flow (CBF) can change not only during occlusion and reperfusion, but also in response to reactivity patterns of cerebrovascular vasodilatation, which have been associated with neuron protection or injury. Continuous measurements of CBF variations during occlusion studies of stroke, as well as their correlations with pathophysiological consequences would present a significant advancement for clinical stroke management and research. Unfortunately, the ideal technologies to measure CBF in animal models are still not established. Our research has centered on developing near-infrared diffuse correlation spectroscopy (DCS) that enables the noninvasive measurement of CBF variations in deep animal and human tissues (millimeters to centimeters). Our preliminary studies, supported by the American Heart Association, have demonstrated high sensitivity of DCS in detecting transient forebrain ischemia in mice. While our investigations are extremely promising, we have found recently that the most widely used semi-infinite homogenous solutions for DCS data analysis can lead to large errors in quantifying CBF in the mouse head which exhibits layered heterogeneous properties and irregular geometries. We propose to address this critical issue by mathematically modeling autocorrelation function distributions in the layered tissues (i.e., scalp, skull, brain cortex) of each individual head whose geometry will be obtained by MRI (Specific Aim 1). Accordingly, we will extend our prototype DCS device to a multi-channel parallel detection system to create a spatially-resolved DCS device (SR-DCS), which will enable accurate measurement and online reporting of blood flow values in multiple layered tissues. The improved optical measurements will allow us to calibrate the SR-DCS against arterial-spin-labeling magnetic resonance imaging (ASL-MRI) to achieve absolute CBF measurements, which is essential for inter-subject comparison and longitudinal monitoring. The calibrated DCS system will then be used to continuously monitor CBF variations in mice undergoing transient forebrain ischemia/stroke (Specific Aim 2). We hypothesize that CBF responses to ischemia/stroke will correlate with infarct volume and functional neurologic deficits post procedures, thus providing valuable information for noninvasive prediction and evaluation of ischemic stroke. Specific Aim 1: Develop and Calibrate a SR-DCS System for Quantifying the Heterogeneity of CBF in the Scalp-Skull-Brain Structure of Mouse Head. Based on our newly developed linear layer algorithm, we will construct a highly accurate SR-DCS device with parallel measurements at multiple source-detector distances to simultaneously solve for the unknown blood flow indices in the scalp, skull and brain tissues. We will also develop a user-friendly interface to control the SR-DCS device for continuous monitoring and online reporting of CBF. We will then calibrate the SR-DCS for the absolute measurement of CBF variations in anesthetized mice during occlusion of the left common carotid artery (LCCA) against concurrent ASL-MRI (as a gold standard). The key outcome from this aim will be the determination of calibration parameters that relate absolute CBF values from both optical and ASL-MRI measurements. Specific Aim 2: Assess SR-DCS for Monitoring CBF in Acute Stroke Mouse Model. We will use the MRI-calibrated SR-DCS device to track CBF in mice with transient ischemic stroke in tandem occlusions of the ipsilateral common carotid artery (CCA) and the middle cerebral artery (MCA). CBF measurements will be continuously recorded before, during, and immediately after vessel occlusions as well as on post-stroke days 1 and 7. We will test the sensitivity of the calibrated SR-DCS measurements in determining the success of CCA/MCA occlusion and recovery reperfusion. We will also correlate CBF variation patterns during occlusions to the infarct brain volumes and functional neurologic deficits post procedure to establish highly sensitive benchmarks in the mouse stroke model. We have previously verified that DCS can probe CBF signals from cortexes of adult heads (see B.3). Our novel linear layer algorithm for SR-DCS can be used in both animal and human heads (with simple probe modifications). As such, research on SR-DCS for absolute hemodynamic quantification of layered head tissues has great potential for significantly advancing the accurate diagnosis and therapeutic monitoring of various cerebral diseases in clinic.