Functional impairment following axonal injury

Following trauma or other neurological disorders, a series of events happen that cause axonal dysfunction or ultimately lead to axonal death. Computational modeling of the nervous system facilitates systematic study of the effects of each injury parameter on the output. The overall goal of this research was to develop a new method of simulating axon damage in a biophysical model and quantify the effects of structural damage on signal conduction. To achieve this, three objectives were addressed 1) quantify the effects of normal morphological variation and demyelination on axonal conduction characteristics, 2) develop a new computationally efficient method for modeling damage in axons, and 3) characterize the structure changes observed in human axons and quantify the relationship between these observed changes and axonal function. Biophysical computational models developed in NEURON were employed to characterize morphological changes in damaged axons and study the effects of some of the most common axonal injuries such as myelin damage and spheroid formation on signal propagation in axons with different calibers. To facilitate efficient computational simulation, a new approach for increasing geometrical resolution in NEURON was developed and assessed. To investigate the effects of axonal swelling on action potential conduction in myelinated axons, the morphological properties of axonal spheroids were characterized by analyzing a series of confocal images captured from post-mortem human brain samples of patients with MS and infarction. Our results indicate that subtle abnormalities in nodal, paranodal and juxtaparanodal regions may have sizable effects on action potential amplitude and velocity and more targeted treatments need to be developed that focus on these regions. In addition, the results of our histopathological and computational studies suggest that axons with different diameters may respond differently to injuries and diseases. Therefore, it is important to perform experimental injury models across a wide range of axons to get a more comprehensive understanding of the relationship between axonal morphological features, injury parameters and functional responses. We expect this research to lay the quantitative foundation for finding new potential functional markers of white matter tissue damage and provide further insights into how myelin damage and axonal spheroids may affect function.