Session: 05-01-02: Injury and Damage Biomechanics: Brain Response at the Cellular Level

Paper Number: 99466

99466 - Energy Failure Causes Brain Function Disruption After Traumatic Brain Injury: Biomechanical and Neurodynamic Mechanism 

Traumatic brain injury (TBI) is a brain function disorder caused by the action of excessive external mechanical forces on the brain. Despite the increasing awareness of TBI in contact sports and combat fighting, the underlying mechanisms of TBI are not well-understood, which hinders the improvement of protective equipment and the development of therapeutic interventions. One of the important but understudied components of the pathophysiology of TBI is the perturbations to energy metabolism after TBI. The neuron cell bodies and their axonal projections form a complex neural network in which neuronal ensembles act in concert and consume around 20% of the body's substrates, primarily oxygen and glucose, through its blood supply. The disruption to the functional coupling of neuronal ensembles in the human brain can be caused not only by axonal injury (damage to the structural connections formed by axonal projections) but also by disruption to the activity of neurons, which can result from the damage to the supporting cells and vascular network after TBI. These axonal and vascular injuries would trigger and interact with each other to produce a complex pattern of evolving damage that makes its underlying causes challenging to evaluate.

To elucidate the generative mechanism of how the cognitive-emotional functions of the brain can be affected by a head impact through disruption to the neurovascular coupling and explore how this mechanism provides new insight into individual injury susceptibility, we performed a theoretical study to simulate the disruption to the large-scale spontaneous brain activity (functional connectivity) by coupling a finite element (FE) brain mechanics model with a resource-constrained neurodynamic model. The resting-state neural activity was simulated using a system of coupled Kuramoto phase oscillators representing cortical brain regions that are linked together based on structural connectivity and consume resources as a function of their oscillation frequency. The resource supplies are constrained by the vascular density in the brain region of interest. We investigated two injury methods: decline in structural connectivity caused by axonal injury and decline in resource level caused by vascular injury, informed respectively by the axonal strain and principal strain results of FE simulations. First, we simulated 53 head impacts experienced by professional American football players using a template structural connectivity, reconstructed based on diffusion magnetic resonance imaging (MRI) images of 1065 brains, and a template vascular density map, generated based on 41 time-of-flight angiography (TOF-MRA) images. Second, we simulated these head impacts using 41 individual vasculature architectures to estimate the influence of vasculature architectures. For these head impacts, the changes in simulated brain functional connectivity and neural dynamics were evaluated for their correlations with injury outcomes (no concussion, concussion). The signal propagation delays between oscillators were considered and investigated for their effects.

Our results show changes between the disrupted and healthy functional connectivity (measured by Pearson correlation) consistently correlated well with injury outcomes regardless of injury methods (AUC= 0.89 and 0.9), although axonal injury led to lower global efficiency and clustering coefficient of brain functional network while vascular injury increased network efficiency and clustering. The effects of considering delays on these results are minimal. The vasculature variability introduced a large variation in the performance of correlating injury for neural dynamics measures (synchrony: AUC=0.65-0.86 and metastability: AUC=0.47-0.84) and topological measures of functional connectivity (AUC=0.68-0.91). Intriguingly, contingent on vasculature structures, for some brains the synchronization of neuronal ensembles increases with injury while the synchronization in the other brains decreases with injury. The findings in this study provide new insight into how behaviorally relevant changes in brain function can result from energy disruption after TBI and the potential heterogeneity in injury susceptibility originating from cerebrovasculature.

Presenting Author: Taotao Wu University of Pennsylvania

Presenting Author Biography: Dr. Wu is currently a postdoc in the department of bioengineering at the University of Pennsylvania. Before joining Penn, he completed his Ph.D. in Injury Biomechanics at the University of Virginia Center for Applied Biomechanics. His research focuses on understanding the mechanisms and treatment of traumatic brain injury using interdisciplinary computational (biomechanics and neuroscience) models, in-vivo animal models, and neuroimaging techniques.

Authors:

Taotao Wu University of Pennsylvania
Jared Rifkin University of Virginia
Adam Rayfield University of Pennsylvania
Keith Kroma-Wiley University of Pennsylvania
Dani Bassett University of Pennsylvania
David Meaney University of Pennsylvania