Abstract
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.
Highlights
Metabolic activity of the brain is controlled by a complex system of neuroreceptors, small molecular regulators such as nitric oxide, hormones and proteins
When simulating blood flow as red blood cells suspended in plasma for experimental and synthetic cortical network models, we discovered that red blood cells tend to be more concentrated in deeper layers of the cortex compared to the surface
The coordination between oxygen extraction and increased cerebral blood flow after neuronal firing has garnered intense research interest in blood oxygen-level dependent (BOLD) signal, which is the basis of functional magnetic resonance imaging
Summary
Metabolic activity of the brain is controlled by a complex system of neuroreceptors, small molecular regulators such as nitric oxide, hormones and proteins. The supply, clearance, and balance of metabolites, oxygen, glucose and waste are controlled by the cerebral circulation which is coupled with the cerebrospinal and interstitial fluid (CSF/ISF) subnetworks [1,2]. The coordination between oxygen extraction and increased cerebral blood flow after neuronal firing has garnered intense research interest in blood oxygen-level dependent (BOLD) signal, which is the basis of functional magnetic resonance imaging (fMRI). The study integrated state-of-the-art neuroimaging of anatomical spaces, tissue oxygen tension measurements and a mechanistic model of blood-bound oxygen supply to convert changes in cerebral blood flow and oxygen extraction into synthetic BOLD signals using Monte Carlo simulations. The main achievement was a successful first principles correlation between measured oxygen and cerebral blood flow (CBF) levels generating fMRI signals
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