Research Domain One: Head and Brain Injury

1. Research Domain One: Head and Brain Injury Domain Director: David Meaney, University of Pennsylvania Susan Marguiles, University of Pennsylvania Barry Myers, Duke University Albert King and King Yang, Wayne State University Jeff Crandall and Kurosh Darvish, University of Virginia Evangelos Eleftheriou and Jean Peduzzi-Nelson, UAB Michelle LaPlaca, Georgia Institute of Technology Philip Bayly, Washington University in St. Louis Barclay Morrison, III, Columbia University

2. Long-Term Vision of Protecting the Brain Page 1 of 2 Current standards for head injury protection were reviewed to assess if substantial improvements could be made in the ability to predict conditions that will cause significant brain injuries. In the 35+ years that have elapsed since the adoption of the head injury criteria (H.I.C.) as a major standard in head protection, several important advances have been made in the laboratory toward understanding how mechanical factors further contribute to the occurrence of specific types of brain injury, the relative changes in the physical properties of selected cerebral tissues across regions, and the isolated tolerance of tissues subjected to mechanical forces that occur during impact. In parallel, computational power has grown from virtually nonexistent in the 1960’s to models in the 21st century that can accurately detail structures within the brain, its encasing structures, and the response of these model structures to impact. Clearly, there has been substantial progress in the ‘building blocks’ needed to make progress in predicting the occurrence of brain injuries. (Continued)

3. Long-Term Vision of Protecting the BrainPage 2 of 2 In the future, it is envisioned that current head injury standards will be replaced with a fundamentally new approach – a computationally based tool that will not only serve to better separate safe and unsafe environments, but will play a critical and essential role in the iterative design of products and technologies to reduce the incidence of brain injury. We use the NHTSA naming convention and refer to this tool as SIMon, an acronym for Simulated Injury Monitoring. Ideally, the tool will be widely available to manufacturers, government researchers, and academic investigators. The tool will be ‘certified’ with the appropriate research to ensure that it is reliable, will provide an excellent confidence level for predicting harmful brain injuries, and will be dynamic, i.e. the tool will be designed to allow for further upgrades as accelerations in computer hardware, intellectual knowledge and other factors become realized. With this eye towards the future, the work group organized and distilled past and current activities. From this process, several important new objectives appeared as ‘ready for action’ to enable the long-term vision of SIMon. The work group loosely organized these action items under two themes: a computational theme and an experimental theme. Today, activities in each theme area fall into one of three categories (1) better understanding the capabilities and current progress of available computational tools, (2) using or developing new experimental data to check the assumptions or features of current computational tools, and (3) exploring fundamentally new directions that may yield new insights in later generation models.

4. Evaluating and Enhancing the Predictive Capabilities of SIMonKing Yang & Albert King, Wayne State University SIMon is an acronym for a Simulated Injury Monitor which is, in injury biomechanics research circles, a “next generation” (G2) injury assessment tool. It was developed by one of the disciplines most highly regarded scientists, Dr. Rolf Eppinger, of the National Highway Transportation Safety Administration (NHTSA). Now, the Yang-King Team is evaluating, enhancing, and improving the predictive capabilities of SIMon, with the ultimate goal being replacement of existing head injury criterion (HIC) as the regulatory standard for motor vehicle safety. Thus, the major outcome for this cooperative project is to further develop the numerical, experimental, and injury prediction underpinning of SIMon, and to provide the scientific foundations for the rapid transition from HIC to SIMon. Wayne State University is leading the computational side of the SIMon validation project. The goals for the Wayne State component are to evaluate the numerical performance of the SIMon model and develop a rat finite element model for simulations of the Weight Drop Test, the Cortical Impact Test and the Vacuum Injury Test.

5. Measuring Brain Tissue Injury Thresholds Susan Margulies & David Meaney, University of Pennsylvania As with other projects in the “Head-Brain Research Domain”, the Margulies-Meaney Team is also evaluating, enhancing, and improving the predictive capabilities of SIMon, with the ultimate goal of replacing the existing head injury criterion (HIC) as the regulatory standard for motor vehicle safety. The Margulies-Meaney Team is involved in research designed to contribute to the development and subsequent validation of SIMon as a rigorous tool by generating the scientific foundation to be able to predict the probability of injury. Results are being sent to the Yang-King Team at Wayne State University and are being used as input in the validation of the SIMon models. This research includes 4 areas: • Brain Injury Thresholds • Brain Injury Geometry for a more sophisticated mesh development. This is important in determining how anatomically detailed a model must be to accurately predict whether or not brain injury will occur. • Material Properties for Living Brain Tissue • Boundary Conditions specifically between brain and skull, and at the foramen magnum of the brain extruding or not through the magnum.

6. Impact Acceleration Tests & Material Properties of Rat BrainKurosh Darvish & Jeff Crandall, University of VirginiaPage 1 of 2 As with the Wayne State and University of Pennsylvania components, this project is also evaluating, enhancing, and improving the predictive capabilities of SIMon with the ultimate goal of replacing existing head injury criterion (HIC) as the regulatory standard for motor vehicle safety. The Darvish-Crandall Team is pursuing three specific objectives in support of the overall goal: • Characterization of the Kinematics of the Impact Acceleration Brain Injury Model • Quantification of the Extent of Axonal Damage to the Brain Stem • Determining the Brain Material Properties in Pre- and Post-trauma Data collected from the characterization of the kinematics of the impact acceleration test using rat brains is being used as the input to the rat brain Finite Element Model being developed by the Yang-King Team at Wayne State University. (Continued)

7. Impact Acceleration Tests & Material Properties of Rat BrainKurosh Darvish & Jeff Crandall, University of VirginiaPage 2 of 2 Previous histological studies have shown that axonal damage to the brain stem occurs as a consequence of Impact Acceleration Tests. However, previous data are for a specific point in the brain stem. More information is needed on the spatial distribution of injury which could be used to determine the effect of injury on brain material properties, and to validate a finite element model of brain injury. The purpose of this objective is to develop the topography of axonal damage in the brain stem. The last objective is to enhance knowledge of brain material properties, particularly to determine what happens to the properties of brain tissue pre- and post-injury. In other words, how injury changes brain tissue properties. Currently elastic or viscoelastic models with constant coefficients are being used in brain injury numerical models. These cannot predict any changes to the properties as a result of trauma.

8. Small Animal Model of Diffuse Axonal Injury Evangelos Eleftheriou & Jean Peduzzi-Nelson, University of Alabama at Birmingham As with the Yang-King, Margulies-Meaney and Darvish-Crandall components, this project is also evaluating, enhancing, and improving the predictive capabilities of SIMon with the ultimate goal of replacing existing head injury criterion (HIC) as the regulatory standard for motor vehicle safety. Specifically, research at the University of Alabama at Birmingham involves experiments to determine if there is a cumulative effect or cumulative damage (read: cumulative pathology) that develops as multiple injury cycles are repeated. The premise is fairly straightforward: If more axons are damaged as multiple injury cycles are repeated, they should be easier to identify with appropriate histological techniques.

9. Brain Cell and Tissue Tolerance to Traumatic LoadingMichelle LaPlaca, Georgia Institute of Technology The underlying mechanisms that lead to cell dysfunction and death after a Traumatic Brain Injury (TBI) at the molecular and biochemical level have not been extensively modeled in isolated cells. Biomechanically, well-characterized models can be used to determine both structural and functional tolerances to prescribed loading conditions. Cellular models exist, yet tolerance data have never been compared among them. Brain tissue and cellular component tolerance may be dependent on several variables, including brain region, cellular orientation, and extracellular matrix. Accurately defined cell and tissue tolerances are crucial for the input and validation of computational models and subsequent design and improvement of protective components. The overall objective of this project is to systematically subject cells and tissue specimens to biomechanically well-defined inputs in order to develop criteria that are model-independent and based on cellular properties. Specifically, the research is attempting to determine the primary mode of acute dysfunction and structural failure in neural cells subjected to prescribed traumatic mechanical loads; and, to correlate secondary cellular responses that may lead to cell dysfunction and death with load parameters in injured neural cells.

10. Biomechanics of Brain Injury: Experimental Studies Philip Bayly, Washington University in St. LouisPage 1 of 2 The objective of this research effort is to provide experimental data for validation of numerical studies of head injury. Two questions are addressed: First, what are the linear and angular accelerations of the skull during a mild head impact typical of contact sports? Second, how does the brain deform in response to angular acceleration of the skull? The specific aims are: (1) to measure the linear and angular acceleration of the head during heading of a soccer ball; and (2) to measure, non-invasively, the strain field in the human brain during voluntary head motion using tagged magnetic resonance (MR) imaging. Thus far with regard to the first specific aim, data from linear and angular accelerations of the head from 10 subjects were acquired during heading. Neuropsychological tests were also performed before and after heading. Mean (± std. dev.) peak linear acceleration of 184±42 m/s2 and peak angular accelerations of 1820 rad/s2 ±510 m/s2 have been observed. The magnitude of acceleration was similar in expert subjects compared to novice or recreational subjects. In neuropsychological tests before and after heading, a small but statistically significant increase in false identifications of a target (signifying inattention) was detected after heading. (Continued)

11. Data Archive of Non-Human Primate Brain Injury StudiesSusan Margulies, University of PennsylvaniaPage 1 of 2 Between 1976 and 1985, investigators at the University of Pennsylvania used non-human primate models to replicate specific forms of brain injury, with a focus on concussion, Diffuse Axonal Injury (DAI) and Acute Subdural Hematoma (ASDH). University of Pennsylvania scientists developed injury devices to control the rapid head motion, and loading conditions and physiological, clinical and psychological data were obtained in animal studies. These studies included a broad range of loading directions and acceleration amplitudes, as well as repeated and single loads. Squirrel, Rhesus, and Cyanomologus monkeys and baboons were followed from hours to weeks after injury. Today, those data (from approximately 150 experimental animal studies) provide a valuable if not irreplaceable resource that has the potential of being used to relate loading parameters with regional and temporal patterns of primary and secondary neuropathology. (Continued)

12. Data Archive of Non-Human Primate Brain Injury StudiesSusan Margulies, University of PennsylvaniaPage 2 of 2 However, the body of existing data in biomechanics, clinical outcome, physiology, and neuropathology has not been integrated into a single, common database. Therefore, the subset of studies that have all of these data components is not known. Although smaller groups of animals with similar pathology are now part of the scientific literature, there is emerging interest in considering the data set as a whole. This interest is stimulated by the potential use of the biomechanical information from these studies to examine new brain injury thresholds, and to use new immunohistochemistry markers on the existing tissue to identify molecular pathways of injury. In short, the goal is to extend the analysis of the historic data using 21st century computational and molecular tools. This two-year research plan will assemble loading data, physiological and clinical data, tissue data (slides, blocks), and reports from 3 institutions to create a digital database containing all available information. Thus, the objective of this research effort is to develop a high quality dataset of the integrated information from these animal experiments for use in validating injury predictions derived from the SIMon project. Moreover, it is posited that this high quality dataset represents the most complete set of data assembled for use in a model of prolonged traumatic coma, albeit no longer in use. The eventual dataset will result from an intensive examination and vetting of data from all three phases of previous experiments: the biomechanics, the neuropathology, and the clinical outcome variables. When completed from the larger set of animal experiments, this subset of data will be suitable for use as a template for assembling a Data Archive for the international research community and to allow broad access to this information.