A Mechanistic End-to-End Concussion Model That Translates Head Kinematics to Neurologic Injury.

Past concussion studies have focused on understanding the injury processes occurring on discrete length scales (e.g., tissue-level stresses and strains, cell-level stresses and strains, or injury-induced cellular pathology). A comprehensive approach that connects all length scales and relates measurable macroscopic parameters to neurological outcomes is the first step toward rationally unraveling the complexity of this multi-scale system, for better guidance of future research. This paper describes the development of the first quantitative end-to-end (E2E) multi-scale model that links gross head motion to neurological injury by integrating fundamental elements of tissue and cellular mechanical response with axonal dysfunction. The model quantifies axonal stretch (i.e., tension) injury in the corpus callosum, with axonal functionality parameterized in terms of axonal signaling. An internal injury correlate is obtained by calculating a neurological injury measure (the average reduction in the axonal signal amplitude) over the corpus callosum. By using a neurologically based quantity rather than externally measured head kinematics, the E2E model is able to unify concussion data across a range of exposure conditions and species with greater sensitivity and specificity than correlates based on external measures. In addition, this model quantitatively links injury of the corpus callosum to observed specific neurobehavioral outcomes that reflect clinical measures of mild traumatic brain injury. This comprehensive modeling framework provides a basis for the systematic improvement and expansion of this mechanistic-based understanding, including widening the range of neurological injury estimation, improving concussion risk correlates, guiding the design of protective equipment, and setting safety standards.