Mathematical synthesis of the cortical circulation for the whole mouse brain-part I. theory and image integration.

Microcirculation plays a significant role in cerebral metabolism and blood flow control, yet explaining and predicting functional mechanisms remains elusive because it is difficult to make physiologically accurate mathematical models of the vascular network. As a precursor to the human brain, this paper presents a computational framework for synthesizing anatomically accurate network models for the cortical blood supply in mouse. It addresses two critical deficiencies in cerebrovascular modeling. At the microscopic length scale of individual capillaries, we present a novel synthesis method for building anatomically consistent capillary networks with loops and anastomoses (=microcirculatory closure). This overcomes shortcomings in existing algorithms which are unable to create closed circulatory networks. A second critical innovation allows the incorporation of detailed anatomical features from image data into vascular growth. Specifically, computed tomography and two photon laser scanning microscopy data are input into the novel synthesis algorithm to build the cortical circulation for the entire mouse brain in silico. Computer predictions of blood flow and oxygen exchange executed on synthetic large-scale network models are expected to elucidate poorly understood functional mechanisms of the cerebral circulation.

Simulations of blood as a suspension predicts a depth dependent hematocrit in the circulation throughout the cerebral cortex.

Recent advances in modeling oxygen supply to cortical brain tissue have begun to elucidate the functional mechanisms of neurovascular coupling. While the principal mechanisms of blood flow regulation after neuronal firing are generally known, mechanistic hemodynamic simulations cannot yet pinpoint the exact spatial and temporal coordination between the network of arteries, arterioles, capillaries and veins for the entire brain. Because of the potential significance of blood flow and oxygen supply simulations for illuminating spatiotemporal regulation inside the cortical microanatomy, there is a need to create mathematical models of the entire cerebral circulation with realistic anatomical detail. Our hypothesis is that an anatomically accurate reconstruction of the cerebrocirculatory architecture will inform about possible regulatory mechanisms of the neurovascular interface. In this article, we introduce large-scale networks of the murine cerebral circulation spanning the Circle of Willis, main cerebral arteries connected to the pial network down to the microcirculation in the capillary bed. Several multiscale models were generated from state-of-the-art neuroimaging data. Using a vascular network construction algorithm, the entire circulation of the middle cerebral artery was synthesized. Blood flow simulations indicate a consistent trend of higher hematocrit in deeper cortical layers, while surface layers with shorter vascular path lengths seem to carry comparatively lower red blood cell (RBC) concentrations. Moreover, the variability of RBC flux decreases with cortical depth. These results support the notion that plasma skimming serves a self-regulating function for maintaining uniform oxygen perfusion to neurons irrespective of their location in the blood supply hierarchy. Our computations also demonstrate the practicality of simulating blood flow for large portions of the mouse brain with existing computer resources. The efficient simulation of blood flow throughout the entire middle cerebral artery (MCA) territory is a promising milestone towards the final aim of predicting blood flow patterns for the entire brain.