Browsing by Author "McNeil, Elizabeth M."
Now showing 1 - 4 of 4
Results Per Page
Sort Options
- A 3-D Finite-Element Minipig Model to Assess Brain Biomechanical Responses to Blast ExposureSundaramurthy, Aravind; Kote, Vivek Bhaskar; Pearson, Noah; Boiczyk, Gregory M.; McNeil, Elizabeth M.; Nelson, Allison J.; Subramaniam, Dhananjay Radhakrishnan; Rubio, Jose E.; Monson, Kenneth; Hardy, Warren N.; VandeVord, Pamela J.; Unnikrishnan, Ginu; Reifman, Jaques (Frontiers, 2021-12-17)Despite years of research, it is still unknown whether the interaction of explosion-induced blast waves with the head causes injury to the human brain. One way to fill this gap is to use animal models to establish “scaling laws” that project observed brain injuries in animals to humans. This requires laboratory experiments and high-fidelity mathematical models of the animal head to establish correlates between experimentally observed blast-induced brain injuries and model-predicted biomechanical responses. To this end, we performed laboratory experiments on Göttingen minipigs to develop and validate a three-dimensional (3-D) high-fidelity finite-element (FE) model of the minipig head. First, we performed laboratory experiments on Göttingen minipigs to obtain the geometry of the cerebral vasculature network and to characterize brain-tissue and vasculature material properties in response to high strain rates typical of blast exposures. Next, we used the detailed cerebral vasculature information and species-specific brain tissue and vasculature material properties to develop the 3-D high-fidelity FE model of the minipig head. Then, to validate the model predictions, we performed laboratory shock-tube experiments, where we exposed Göttingen minipigs to a blast overpressure of 210 kPa in a laboratory shock tube and compared brain pressures at two locations. We observed a good agreement between the model-predicted pressures and the experimental measurements, with differences in maximum pressure of less than 6%. Finally, to evaluate the influence of the cerebral vascular network on the biomechanical predictions, we performed simulations where we compared results of FE models with and without the vasculature. As expected, incorporation of the vasculature decreased brain strain but did not affect the predictions of brain pressure. However, we observed that inclusion of the cerebral vasculature in the model changed the strain distribution by as much as 100% in regions near the interface between the vasculature and the brain tissue, suggesting that the vasculature does not merely decrease the strain but causes drastic redistributions. This work will help establish correlates between observed brain injuries and predicted biomechanical responses in minipigs and facilitate the creation of scaling laws to infer potential injuries in the human brain due to exposure to blast waves.
- Development of a Minipig Model of BINT From Blast Exposure Using a Repeatable Mobile Shock Expansion TubeMcNeil, Elizabeth M.; Walilko, Timothy; Hulbert, Lindsey E.; VanMeter, John W.; LaConte, Stephen M.; VandeVord, Pamela J.; Zai, Laila; Bentley, Timothy B. (Oxford University Press, 2021-10-22)Introduction: The Office of Naval Research (ONR) sponsored the Blast Load Assessment Sense and Test (BLAST) program to provide an approach to operationally relevant monitoring and analysis of blast exposure for optimization of service member performance and health. Of critical importance in this effort was the development of a standardized methodology for preclinical large animal studies that can reliably produce outcome measures that cannot be measured in human studies to support science-based guidelines. The primary advantage of this approach is that, because animal studies report physiological measures that correlate with human neuropathology, these data can be used to evaluate potential risks to service members by accounting for the anatomical and physiological differences between humans and large animal models. This article describes the methodology used to generate a comprehensive outcome measure dataset correlated with controlled blast exposure. Methods and materials: To quantify outcomes associated with a single exposure to blast, 23 age- and weight-matched Yucatan minipigs were exposed to a single blast event generated by a large-bore, compressed gas shock tube. The peak pressure ranged from 280 to 525 kPa. After a post-exposure 72-hour observation period, the physiological response was quantified using a comprehensive set of neurological outcome measures that included neuroimaging, histology, and behavioral measures. Responses of the blast-exposed animals were compared to the sham-treated cohort to identify statistically significant and physiologically relevant differences between the two groups. Results: Following a single exposure, the minipigs were assessed for structural, behavioral, and cellular changes for 3 days after exposure. The following neurological changes were observed: Structural- Using Diffusion Tensor Imaging, a statistically significant decrement (P < .001) in Fractional Anisotropy across the entire volume of the brain was observed when comparing the exposed group to the sham group. This finding indicates that alterations in brain tissue following exposure are not focused at a single location but instead a diffuse brain volume that can only be observed through a systematic examination of the neurological tissue. Cellular- The histopathology results from several large white matter tract locations showed varied cellular responses from six different stains. Using standard statistical methods, results from stains such as Fluoro-Jade C and cluster of differentiation 68 in the hippocampus showed significantly higher levels of neurodegeneration and increased microglia/macrophage activation in blast-exposed subjects. However, other stains also indicated increased response, demonstrating the need for multivariate analysis with a larger dataset. Behavioral- The behavior changes observed were typically transient; the animals' behavior returned to near baseline levels after a relatively short recovery period. Despite behavioral recovery, the presence of active neurodegenerative and inflammatory responses remained. Conclusions: The results of this study demonstrate that (1) a shock tube provides an effective tool for generating repeatable exposures in large animals and (2) exposure to blast overpressure can be correlated using a combination of imaging, behavioral, and histological analyses. This research demonstrates the importance of using multiple physiological indicators to track blast-induced changes in minipigs. The methodology and findings from this effort were central to developing machine-learning models to inform the development of blast exposure guidelines.
- Development of MRI-based Yucatan Minipig Brain TemplateNorris, Caroline N. (Virginia Tech, 2019-04-05)Yucatan minipigs have become increasingly common animal models in neuroscience where recent studies, investigating blast-induced traumatic brain injury, stroke, and glioblastoma, aim to uncover brain injury mechanisms [1-3]. Magnetic Resonance Imaging (MRI) has the potential to validate and optimize unknown parameters in controlled populations. The key to group-level MRI analysis within a species is to align (or register) subject scans to the same volumetric space using a brain template. However, large animal brain templates are lacking, which limits the use of MRI as an effective research tool to study group effects. The objective of this study was to create an MRI-based Yucatan minipig brain template allowing for uniform group-level analysis of this animal model in a standard volumetric space to characterize brain mechanisms. To do this, 5-7 month old, male Yucatan minipigs were scanned using a 3 Tesla whole-body scanner (Siemens AG, Erlangen) in accordance with IACUC. T1-weighted anatomical volumes (resolution = 1×1×1 mm3; TR = 2300 ms; TE= 2.89 ms; TI = 900 ms; FOV = 256 mm2 ; FA = 8 deg) were collected with a three-dimensional magnetization prepared rapid acquisition gradient echo (MPRAGE) pulse sequence [4]. The volumes were preprocessed, co-registered, and averaged using both linear and non-linear registration algorithms in AFNI [5] to create four templates (n=58): linear brain, non-linear brain, linear head, and non-linear head. To validate the templates, tissue probability maps (TPMs) and variance maps were created, and landmark variation was measured. TPMs computed in FSL [6] and AFNI show enhanced tissue probability and contrast in the non-linear template. Additionally, variance maps showed a more uniform spatial variance in the non-linear template compared to the linear. Registration variation within the brain template was within 1.5 mm and displayed improved landmark variation in the non-linear brain template. External evaluation subjects (n=12), not included in the template, were registered to the four templates to assess functionality. The results indicate that the developed templates provide acceptable registration accuracy to enable population comparisons. With these templates, researchers will be able to use MRI as a tool to further neurological discovery and collaborate in a uniform space.
- MRI brain templates of the male Yucatan minipigNorris, Carly; Lisinski, Jonathan; McNeil, Elizabeth M.; VanMeter, John W.; VandeVord, Pamela J.; LaConte, Stephen M. (Elsevier, 2021-07-15)The pig is growing in popularity as an experimental animal because its gyrencephalic brain is similar to humans. Currently, however, there is a lack of appropriate brain templates to support functional and structural neuroimaging pipelines. The primary contribution of this work is an average volume from an iterative, non-linear registration of 70 five- to seven-month-old male Yucatan minipigs. In addition, several aspects of this study are unique, including the comparison of linear and non-linear template generation, the characterization of a large and homogeneous cohort, an analysis of effective resolution after averaging, and the evaluation of potential in-template bias as well as a comparison with a template from another minipig species using a “left-out” validation set. We found that within our highly homogeneous cohort, non-linear registration produced better templates, but only marginally so. Although our T1-weighted data were resolution limited, we preserved effective resolution across the multi-subject average, produced templates that have high gray-white matter contrast and demonstrate superior registration accuracy compared to an alternative minipig template.