Multiscale computer modeling of penumbral zones in brain ischemia

On a cellular level, molecular cascades produce damage that can lead to apoptosis, necrosis or necroptosis. Damage propagates due to a combination of extracellular diffusion and synaptic connectivity. Temporally, we are interested in aberrant spiking activity over milliseconds up to the progression of ischemia extending over a period of hours. Spatial scales range from subcellular changes in ion concentrations to large regions of brain tissue. Tissue affected by ischemic stroke is divided into three regions; 1. the core where cells suffer irreparable damage and death, 2. a penumbra where cells may recover with reperfusion, 3. a further region of edema where spontaneous recovery is expected.We extended the NEURON reaction-diffusion modules (NRxD) to include the extracellular space (ECS), providing a platform for modeling ischemia, with the penumbra cells and embedded in its extracellular environment. Here, we explored cellular failure initiated by ATP depletion at a central location. Ischemia impedes ATP production which results in a failure of the Na+/K+-ATPase pump and a rise in extracellular K+. Once extracellular K+ exceeds a threshold it will cause neurons to depolarize, further increasing extracellular K+. The cell network was created using NetPyNE in order to model the spreading depression seen in ischemic stroke by coupling a detailed biophysical model of cortical pyramidal neurons equipped with Na+/K+-ATPase pumps with reaction-diffusion of ions in the ECS.Multiscale modeling of ischemia combines the dynamics of rapid synaptic connectivity and slower extracellular diffusion of ions and toxic products of cell death, giving varying effects of core on the penumbra. Different penumbral subzones will produce differing intracellular dynamics biasing the cell to either cell death or potential recovery. The tools presented in this model allow for more efficacious experimentation and understanding of potential mechanisms to prevent permanent penumbra cell death.