Multiscale Model of Cerebral Blood Flow Control: Application to Small Vessel Disease and Cortical Spreading Depression

An in-time delivery of oxygen-rich blood into areas of high metabolic demand is pivotal in proper functioning of the brain and neuronal health. This highly precise communication between neuronal activity and cerebral blood flow (CBF) is termed as neurovascular coupling (NVC) or functional hyperemia. NVC is disrupted in major pathological conditions including Alzheimer’s disease, dementia, small vessel pathologies (SVD) and cortical spreading depression. Despite the utmost importance of NVC, its underlying mechanisms are not fully understood. This dissertation presents a multiscale mathematical modeling framework for studying unresolved mechanisms of NVC with major focus on K+ ions as a mediator of this process. To this end, models of single-cell electrophysiology are developed for endothelial (EC) and smooth muscle (SMC) cells of capillaries and parenchymal arterioles (PAs). Cells are electrically coupled, and large-scale geometrically-accurate models of microvascular networks are constructed. Model simulations predict an important role of capillary inward rectifying potassium channels (Kir) to sense neuronally-induced changes in extracellular potassium concentrations ([K+]o) and conduct hyperpolarizing signals over long distances to upstream PAs. Simulation results demonstrate a “tug-of-war” dynamic between Kir and voltage-gated potassium (Kv) channels in determining the Vm and myogenic tone of PA SMCs during NVC in SVD. Results also predict a key role of Kir channels in the experimentally observed multiphasic vascular response during high elevations of [K+]o in cortical spreading depression. The multiscale models presented in this study were able to accurately capture several experimentally observed responses during NVC and provided insights into their potential underlying mechanisms in health and disease. These models provide a theoretical platform where macroscale, tissue-level responses can be related to microscale, single-cell signaling pathways