Abstract Body: Intro
Resources for studying stroke are limited to clinical trials with sparse access to physiological and biochemical details, and pre-clinical animal studies with limited relation to humans. A physiologically accurate in silico model would provide a new route for study of the response to an ischemic event. Here we combine a computational model of brain tissue metabolism modified to simulate effects of ischemia (1) with an experimentally-validated approach to model the distribution of nutrients to the extravascular space as provided by a specific cerebral microvasculature network (2,3) to produce simulations of ischemic stroke showing the spatial distribution of damaged and healthy tissue.

Methods
Anatomically-accurate models of cortical microvasculature and resulting O2 concentration with consideration of oxygen consumption in tissue were developed and validated against experimental measures of pO2 (2,3, Figure 1). A numerical implementation of a 4-compartment cellular model of brain metabolism (4) was modified to simulate ischemic stroke (1), and further modified to consider effects of the local pO2 and Glucose (GLC) as provided by the vascular network by adjusting local rates of transfer of GLC and O2 into the neuronal compartment of the cell, as shown in Figure 2, bottom. Brain metabolism was simulated for cases with no ischemic event, and after CBF was reduced by 80%.

Results
Figure 2 shows timecourse of GLC, ATP, and Sodium in different compartments of the model through time in regions experiencing mild and severe ischemia. Figure 3 shows intraneuronal sodium concentration before and 2 hours after onset of an ischemic event showing failure of sodium pumps during ischemia.

Conclusion
Effects of ischemic stroke on cerebral metabolism at the cellular level with consideration of microvasculature and distribution of nutrients within the tissue can be modelled at the capillary and cellular level computationally. Future work will include linking astrocytes to local nutrient concentrations and expansion of the simulated region to include larger region of brain, so an ischemic core and penumbral region surrounded by unaffected tissue can be observed.

References
1. CM Collins et al. International Stroke Conference, February 7-9 2024, Phoenix

2. T Ventimiglia et al. Int J Numer Meth Biomed Engng. 2023;39:e3735

3. G Hartung et al. PLOS Computational Biology 2020;17(1): e1008584

4. M Cloutier et al. Journal of computational neuroscience. 2009 Dec 1;27(3):391