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Traumatic brain injury (TBI) is a leading cause of death and disability in pediatric patients and often results in delayed neural development and altered connectivity, leading to lifelong learning, memory, behavior, and motor function deficits. Induced pluripotent stem cell-derived neural stem cells (iNSCs) may serve as a novel multimodal therapeutic as iNSCs possess neuroprotective, regenerative, and cell-replacement capabilities post-TBI. In this study, we evaluated the effects of iNSC treatment on cellular, tissue, and functional recovery in a translational controlled cortical impact TBI piglet model. Five days post-craniectomy (n = 6) or TBI (n = 18), iNSCs (n = 7) or PBS (n = 11) were injected into perilesional brain tissue. Modified Rankin Scale (mRS) neurological evaluation, magnetic resonance imaging, and immunohistochemistry were performed over the 12-week study period. At 12-weeks post-transplantation, iNSCs showed long-term engraftment and differentiation into neurons, astrocytes, and oligodendrocytes. iNSC treatment enhanced endogenous neuroprotective and regenerative activities indicated by decreasing intracerebral immune responses, preserving endogenous neurons, and increasing neuroblast formation. These cellular changes corresponded with decreased hemispheric atrophy, midline shift, and lesion volume as well as the preservation of cerebral blood flow. iNSC treatment increased piglet survival and decreased mRS scores. The results of this study in a predictive pediatric large-animal pig model demonstrate that iNSC treatment is a robust multimodal therapeutic that has significant promise in potentially treating human pediatric TBI patients. [ABSTRACT FROM AUTHOR]

Aims Alcohol is the most commonly abused substance leading to significant economic and medical burdens. Pigs are an attractive model for studying alcohol abuse disorder due to the comparable alcohol metabolism and consumption behavior, which are in stark contrast to rodent models. This study investigates the usage of a porcine model for voluntary binge drinking (BD) and a detailed analysis of gait changes due to motor function deficits during alcohol intoxication. Methods Adolescent pigs were trained to drink increasing concentration (0–8%) of alcohol mixed in a 0.2% saccharin solution for 1 h in a two bottle choice test for 2 weeks. The training period was followed by a 3-week alcohol testing period, where animals were given free access to 8% alcohol in 0.2% saccharin solution and 0.2% saccharin water solution. Blood alcohol levels were tested and gait analysis was performed pre-alcohol consumption, last day of training, and Day 5 of each testing period. Results Pigs voluntarily consumed alcohol to intoxication at all timepoints with blood alcohol concentration (BAL) ≥80 mg/dl. Spatiotemporal gait parameters including velocity, cadence, cycle time, swing time, stance time, step time, and stride length were perturbed as a result of intoxication. The stratification of the gait data based on BAL revealed that the gait parameters were affected in a dose-dependent manner. Conclusion This novel adolescent BD porcine model with inherent anatomical and physiological similarities to humans display similar consumption and intoxication behavior that is likely to yield results that are translatable to human patients. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, with children who sustain a TBI having a greater risk of developing long-lasting cognitive, behavioral, and motor function deficits. This has led to increased interest in utilizing large animal models to study pathophysiologic and functional changes after injury in hopes of identifying novel therapeutic targets. In the present study, a controlled cortical impact (CCI) piglet TBI model was utilized to evaluate cognitive, motor, and histopathologic outcomes. CCI injury (4 m/sec velocity, 9 mm depression, 400 msec dwell time) was induced at the parietal cortex. Compared with normal pigs (n = 5), TBI pigs (n = 5) exhibited appreciable cognitive deficiencies, including significantly impaired spatial memory in spatial T-maze testing and a significant decrease in exploratory behaviors followed by marked hyperactivity in open field testing. Additionally, gait analysis revealed significant increases in cycle time and stance percent, significant decreases in hind reach, and a shift in the total pressure index from the front to the hind limb on the affected side, suggesting TBI impairs gait and balance. Pigs were sacrificed 28 days post-TBI and histological analysis revealed that TBI lead to a significant decrease in neurons and a significant increase in microglia activation and astrogliosis/astrocytosis at the perilesional area, a significant loss in neurons at the dorsal hippocampus, and significantly increased neuroblast proliferation at the subventricular zone. These data demonstrate a strong relationship between TBI-induced cellular changes and functional outcomes in our piglet TBI model that lay the framework for future studies that assess the ability of therapeutic interventions to contribute to functional improvements. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) at a young age can lead to the development of long-term functional impairments. Severity of injury is well demonstrated to have a strong influence on the extent of functional impairments; however, identification of specific magnetic resonance imaging (MRI) biomarkers that are most reflective of injury severity and functional prognosis remain elusive. Therefore, the objective of this study was to utilize advanced statistical approaches to identify clinically relevant MRI biomarkers and predict functional outcomes using MRI metrics in a translational large animal piglet TBI model. TBI was induced via controlled cortical impact and multiparametric MRI was performed at 24 hours and 12 weeks post-TBI using T1-weighted, T2-weighted, T2-weighted fluid attenuated inversion recovery, diffusion-weighted imaging, and diffusion tensor imaging. Changes in spatiotemporal gait parameters were also assessed using an automated gait mat at 24 hours and 12 weeks post-TBI. Principal component analysis was performed to determine the MRI metrics and spatiotemporal gait parameters that explain the largest sources of variation within the datasets. We found that linear combinations of lesion size and midline shift acquired using T2-weighted imaging explained most of the variability of the data at both 24 hours and 12 weeks post-TBI. In addition, linear combinations of velocity, cadence, and stride length were found to explain most of the gait data variability at 24 hours and 12 weeks post-TBI. Linear regression analysis was performed to determine if MRI metrics are predictive of changes in gait. We found that both lesion size and midline shift are significantly correlated with decreases in stride and step length. These results from this study provide an important first step at identifying relevant MRI and functional biomarkers that are predictive of functional outcomes in a clinically relevant piglet TBI model. This study was approved by the University of Georgia Institutional Animal Care and Use Committee (AUP: A2015 11-001) on December 22, 2015., Competing Interests: None

Traumatic brain injury (TBI) is a major contributor of long-term disability and a leading cause of death worldwide. A series of secondary injury cascades can contribute to cell death, tissue loss, and ultimately to the development of functional impairments. However, there are currently no effective therapeutic interventions that improve brain outcomes following TBI. As a result, a number of experimental TBI models have been developed to recapitulate TBI injury mechanisms and to test the efficacy of potential therapeutics. The pig model has recently come to the forefront as the pig brain is closer in size, structure, and composition to the human brain compared to traditional rodent models, making it an ideal large animal model to study TBI pathophysiology and functional outcomes. This review will focus on the shared characteristics between humans and pigs that make them ideal for modeling TBI and will review the three most common pig TBI models-the diffuse axonal injury, the controlled cortical impact, and the fluid percussion models. It will also review current advances in functional outcome assessment measures and other non-invasive, translational TBI detection and measurement tools like biomarker analysis and magnetic resonance imaging. The use of pigs as TBI models and the continued development and improvement of translational assessment modalities have made significant contributions to unraveling the complex cascade of TBI sequela and provide an important means to study potential clinically relevant therapeutic interventions., Competing Interests: None