Abstract WP28: A Multiscale, Anatomically, and Neurochemically Realistic In Silico Toolbox for the Simulation of Cerebrovascular Ischemia

Abstract

Introduction: Despite therapeutic advances, roughly half of acute ischemic stroke (AIS) patients fail to achieve independence. Multiscale tools permitting nano- to macroscalar representations of the hemodynamic, electrical, and neurochemical disturbance in AIS are thus demanded. The vastness of potential scenarios evolving in individual patients renders full investigation into all possible courses of disease unattainable in human or animal subjects. Digital phantoms have proliferated in the precision medicine era, yet such frameworks remain immature in neuroscience. Here, we introduce a realistic simulation toolbox governed by a vast parameter space to model AIS. Methods: A numerical implementation of a 4-compartment (neuronal, astrocytic, extracellular, and capillary) model (www.cellml.org) was modified to simulate evolution of AIS, including the dynamic interplay of >80 neurochemical processes related to cellular energetics and tuned with hemodynamic (e.g. CBF) aberrations relevant to the neurovascular unit. Two different ischemic conditions are simulated to illustrate use of the framework: i. ~50% CBF reduction; ii. ~80% CBF reduction. Results: As seen in Fig. 1, while a 50% reduction in CBF reduces glucose concentration ([GLC]) in extracellular, glial, and neuronal spaces, ATP concentrations are maintained (with glial levels dropping slightly in order that glial cells can offer support to neuronal function), and sodium concentrations ([Na+]) in both cell spaces remain constant. By comparison, an 80% CBF reduction yields falling [ATP], such that Na homeostasis is disturbed and dynamic alterations in [Na+] in the cellular compartments can be observed, leading to time-dependent cytotoxicity. Conclusion: We present a digital model and generalized framework for modeling the evolution of hemodynamic, thermal, ionic, and other disturbances in AIS, conceived as a multifaceted tool for hypothesis building and testing pathologic scenarios