Spatial Intracranial Pressure Fields Driven by Blast Overpressure in Rats.

Free-field blast exposure imparts a complex, dynamic response within brain tissue that can trigger a cascade of lasting neurological deficits. Full body mechanical and physiological factors are known to influence the body's adaptation to this seemingly instantaneous insult, making it difficult to accurately pinpoint the brain injury mechanisms. This study examined the intracranial pressure (ICP) profile characteristics in a rat model as a function of blast overpressure magnitude and brain location. Metrics such as peak rate of change of pressure, peak pressure, rise time, and ICP frequency response were found to vary spatially throughout the brain, independent of blast magnitude, emphasizing unique spatial pressure fields as a primary biomechanical component to blast injury. This work discusses the ICP characteristics and considerations for finite element models, in vitro models, and translational in vivo models to improve understanding of biomechanics during primary blast exposure.

Quantifying acute changes in neurometabolism following blast-induced traumatic brain injury.

Brain health is largely dependent on the metabolic regulation of amino acids. Brain injuries, diseases, and disorders can be detected through alterations in free amino acid (FAA) concentrations; and thus, mapping the changes has high diagnostic potential. Common methods focus on optimizing neurotransmitter quantification; however, recent focus has expanded to investigate the roles of molecular precursors in brain metabolism. An isocratic method using high performance liquid chromatography with electrochemical cell detection was developed to quantify a wide range of molecular precursors and neurotransmitters: alanine, arginine, aspartate, serine, taurine, threonine, tyrosine, glycine, glutamate, glutamine, and γ-Aminobutyric acid (GABA) following traumatic brain injury. First, baseline concentrations were determined in the serum, cerebrospinal fluid, hippocampus, cortex, and cerebellum of naïve male Sprague Dawley rats. A subsequent study was performed investigating acute changes in FAA concentrations following blast-induced traumatic brain injury (bTBI). Molecular precursor associated FAAs decreased in concentration at 4 h after injury in both the cortex and hippocampus while those serving as neurotransmitters remained unchanged. In particular, the influence of oxidative stress on the observed changes within alanine and arginine pathways following bTBI should be further investigated to elucidate the full therapeutic potential of these molecular precursors at acute time points.

A closed-body preclinical model to investigate blast-induced spinal cord injury.

Blast-induced spinal cord injuries (bSCI) are common and account for 75% of all combat-related spinal trauma. It remains unclear how the rapid change in pressure contributes to pathological outcomes resulting from these complex injuries. Further research is necessary to aid in specialized treatments for those affected. The purpose of this study was to develop a preclinical injury model to investigate the behavior and pathophysiology of blast exposure to the spine, which will bring further insight into outcomes and treatment decisions for complex spinal cord injuries (SCI). An Advanced Blast Simulator was used to study how blast exposure affects the spinal cord in a non-invasive manner. A custom fixture was designed to support the animal in a position that protects the vital organs while exposing the thoracolumbar region of the spine to the blast wave. The Tarlov Scale and Open Field Test (OFT) were used to detect changes in locomotion or anxiety, respectively, 72 h following bSCI. Spinal cords were then harvested and histological staining was performed to investigate markers of traumatic axonal injury (ß-APP, NF-L) and neuroinflammation (GFAP, Iba1, S100ß). Analysis of the blast dynamics demonstrated that this closed-body model for bSCI was found to be highly repeatable, administering consistent pressure pulses following a Friedlander waveform. There were no significant changes in acute behavior; however, expression of ß-APP, Iba1, and GFAP significantly increased in the spinal cord following blast exposure (p < 0.05). Additional measures of cell count and area of positive signal provided evidence of increased inflammation and gliosis in the spinal cord at 72 h after blast injury. These findings indicated that pathophysiological responses from the blast alone are detectable, likely contributing to the combined effects. This novel injury model also demonstrated applications as a closed-body SCI model for neuroinflammation enhancing relevance of the preclinical model. Further investigation is necessary to assess the longitudinal pathological outcomes, combined effects from complex injuries, and minimally invasive treatment approaches.

Defining Experimental Variability in Actuator-Driven Closed Head Impact in Rats.

Traumatic brain injury (TBI) is a world-wide health challenge that lacks tools for diagnosis and treatment. There is a need for translational preclinical models to effectively design clinical tools, however, the diversity of models is a barrier to reproducible studies. Actuator-driven closed head impact (AD-CHI) models have translational advantages in replicating the pathophysiological and behavioral outcomes resulting from impact TBI. The main advantages of AD-CHI protocols include versatility of impact parameters such as impact angle, velocity, depth, and dwell time with the ability to interchange tip types, leading to consistent outcomes without the need for craniectomy. Sources of experimental variability within AD-CHI rat models are identified within this review with the aim of supporting further characterization to improve translational value. Primary areas of variability may be attributed to lack of standardization of head stabilization methods, reporting of tip properties, and performance of acute neurological assessments. AD-CHI models were also found to be more prevalently used among pediatric and repeated TBI paradigms. As this model continues to grow in use, establishing the relationships between impact parameters and associated injury outcomes will reduce experimental variability between research groups and encourage meaningful discussions as the community moves towards common data elements.

Defining community revitalization in Great Lakes Areas of Concern and investigating how revitalization can be catalyzed through remediation and restoration.

An international effort to restore contaminated areas across the Great Lakes has been underway for over 50 years. Although experts have increasingly recognized the inherent connections between ecological conditions and community level benefits, Great Lakes community revitalization continues to be a broad and complex topic, lacking a comprehensive definition. The purpose of this study was to generate a testable "AOC-Revitalization Framework" for linking remediation and restoration success, represented by Beneficial Use Impairment (BUI) removal in U.S. Great Lakes Areas of Concern (AOC), to community revitalization. Using directed content analysis, we conducted a literature review and identified 433 potential revitalization metrics and indicators and grouped them into 15 broader community revitalization attributes to develop the following definition of Great Lakes community revitalization: "locally driven community resurgence resulting in resilient and equitable enhancements to social, economic, and environmental community structures." We surveyed experts within the Great Lakes AOC program on the likelihood remediation and restoration success, would positively impact revitalization attributes. Focus groups triangulated survey results. Results identified BUI removal was expected to positively affect revitalization, but the type of revitalization outcome was based on the BUI being removed. The AOC-Revitalization Framework is the first to empirically outline these possible linkages, providing a clear testable structure for future research; it can be used to better understand how environmental improvements are or are not leading to community revitalization and more accurately identify components of revitalization impacted, thus supporting more equitable representation, communication, and measurement of the relationship.

MRI brain templates of the male Yucatan minipig.

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.

Hemostatic nanoparticles increase survival, mitigate neuropathology and alleviate anxiety in a rodent blast trauma model.

Explosions account for 79% of combat related injuries and often lead to polytrauma, a majority of which include blast-induced traumatic brain injuries (bTBI). These injuries lead to internal bleeding in multiple organs and, in the case of bTBI, long term neurological deficits. Currently, there are no treatments for internal bleeding beyond fluid resuscitation and surgery. There is also a dearth of treatments for TBI. We have developed a novel approach using hemostatic nanoparticles that encapsulate an anti-inflammatory, dexamethasone, to stop the bleeding and reduce inflammation after injury. We hypothesize that this will improve not only survival but long term functional outcomes after blast polytrauma. Poly(lactic-co-glycolic acid) hemostatic nanoparticles encapsulating dexamethasone (hDNPs) were fabricated and tested following injury along with appropriate controls. Rats were exposed to a single blast wave using an Advanced Blast Simulator, inducing primary blast lung and bTBI. Survival was elevated in the hDNPs group compared to controls. Elevated anxiety parameters were found in the controls, compared to hDNPs. Histological analysis indicated that apoptosis and blood-brain barrier disruption in the amygdala were significantly increased in the controls compared to the hDNPs and sham groups. Immediate intervention is crucial to mitigate injury mechanisms that contribute to emotional deficits.

Distinguishing the Unique Neuropathological Profile of Blast Polytrauma.

Traumatic brain injury sustained after blast exposure (blast-induced TBI) has recently been documented as a growing issue for military personnel. Incidence of injury to organs such as the lungs has decreased, though current epidemiology still causes a great public health burden. In addition, unprotected civilians sustain primary blast lung injury (PBLI) at alarming rates. Often, mild-to-moderate cases of PBLI are survivable with medical intervention, which creates a growing population of survivors of blast-induced polytrauma (BPT) with symptoms from blast-induced mild TBI (mTBI). Currently, there is a lack of preclinical models simulating BPT, which is crucial to identifying unique injury mechanisms of BPT and its management. To meet this need, our group characterized a rodent model of BPT and compared results to a blast-induced mTBI model. Open field (OF) performance trials were performed on rodents at 7 days after injury. Immunohistochemistry was performed to evaluate cellular outcome at day seven following BPT. Levels of reactive astrocytes (GFAP), apoptosis (cleaved caspase-3 expression), and vascular damage (SMI-71) were significantly elevated in BPT compared to blast-induced mTBI. Downstream markers of hypoxia (HIF-1α and VEGF) were higher only after BPT. This study highlights the need for unique therapeutics and prehospital management when handling BPT.