Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics.

Traumatic brain injury (TBI) is one of the leading causes of death of young people in the developed world. In the United States alone, 1.7 million traumatic events occur annually accounting for 50,000 deaths. The etiology of TBI includes traffic accidents, falls, gunshot wounds, sports, and combat-related events. TBI severity ranges from mild to severe. TBI can induce subtle changes in molecular signaling, alterations in cellular structure and function, and/or primary tissue injury, such as contusion, hemorrhage, and diffuse axonal injury. TBI results in blood-brain barrier (BBB) damage and leakage, which allows for increased extravasation of immune cells (i.e., increased neuroinflammation). BBB dysfunction and impaired homeostasis contribute to secondary injury that occurs from hours to days to months after the initial trauma. This delayed nature of the secondary injury suggests a potential therapeutic window. The focus of this article is on the (1) pathophysiology of TBI and (2) potential therapies that include biologics (stem cells, gene therapy, peptides), pharmacological (anti-inflammatory, antiepileptic, progrowth), and noninvasive (exercise, transcranial magnetic stimulation). In final, the review briefly discusses membrane/lipid rafts (MLR) and the MLR-associated protein caveolin (Cav). Interventions that increase Cav-1, MLR formation, and MLR recruitment of growth-promoting signaling components may augment the efficacy of pharmacologic agents or already existing endogenous neurotransmitters and neurotrophins that converge upon progrowth signaling cascades resulting in improved neuronal function after injury.

Pathophysiology of battlefield associated traumatic brain injury.

As more data is accumulated from Operation Iraqi Freedom and Operation Enduring Freedom (OEF in Afghanistan), it is becoming increasing evident that traumatic brain injury (TBI) is a serious and highly prevalent battle related injury. Although traditional TBIs such as closed head and penetrating occur in the modern battle space, the most common cause of modern battle related TBI is exposure to explosive blast. Many believe that explosive blast TBI is unique from the other forms of TBI. This is because the physical forces responsible for explosive blast TBI are different than those for closed head TBI and penetrating TBI. The unique force associated with explosive blast is the blast shock pressure wave. This shock wave occurs over a very short period, milliseconds, and has a specific profile known as the Freidlander curve. This pressure-time curve is characterized by an initial very rapid up-rise followed by a longer decay that reaches a negative inflection point before returning to baseline. This is important as the effect of this shock pressure on brain parenchyma is distinct. The diffuse interaction of the pressure wave with the brain leads to a complex cascade of events that affects neurons, axons, glia cells, and vasculature. It is only by properly studying this disease will meaningful therapies be realized.

Dynamic monitoring of service members to quantify blast exposure levels during combat training using BlackBox Biometrics Blast Gauges: explosive breaching, shoulder-fired weapons, artillery, mortars, and 0.50 caliber guns.

CONQUER is a pilot blast monitoring program that monitors, quantifies, and reports to military units the training-related blast overpressure exposure of their service members. Overpressure exposure data are collected using the BlackBox Biometrics (B3) Blast Gauge System (BGS, generation 7) sensors mounted on the body during training. To date, the CONQUER program has recorded 450,000 gauge triggers on monitored service members. The subset of data presented here has been collected from 202 service members undergoing training with explosive breaching charges, shoulder-fired weapons, artillery, mortars, and 0.50 caliber guns. Over 12,000 waveforms were recorded by the sensors worn by these subjects. A maximum peak overpressure of 90.3 kPa (13.1 psi) was recorded during shoulder-fired weapon training. The largest overpressure impulse (a measure of blast energy) was 82.0 kPa-ms (11.9 psi-ms) and it was recorded during explosive breaching with a large wall charge. Operators of 0.50 caliber machine guns have the lowest peak overpressure impulse (as low as 0.62 kPa-ms or 0.09 psi-ms) of the blast sources considered. The data provides information on the accumulation of blast overpressure on service members over an extended period of time. The cumulative peak overpressure, peak overpressure impulse, or timing between exposures is all available in the exposure data.

Significant Mitigation of Blast Overpressure Exposure During Training by Adjustment of Body Position as Demonstrated With Field Data.

INTRODUCTION: During training and deployment, service members (SMs) experience blast exposure, which may potentially negatively impact brain health in the short and long term. This article explores if blast exposure mitigation can be effectively achieved for four different weapon training scenarios that are being monitored as part of the CONQUER (COmbat and traiNing QUeryable Exposure/event Repository) program. The training scenarios considered here are a detonating cord linear (det linear) breaching charge, a water breaching charge, a shoulder-fired weapon, and a 120-mm mortar. MATERIALS AND METHODS: This article focuses on the efficacy of modification of position and standoff distance on SMs' exposure to blast overpressure. Blast overpressure exposures were measured using BlackBox Biometrics (B3) Blast Gauge System (BGS) sensors worn by SMs during normal training. The BGS involves the use of three gauges/sensors, which are worn on the head, chest, and nondominant shoulder to record surface pressures at multiple locations on the SM. For the breaching charges, we compared the level of exposure when the SMs were directly in front of the blast with a breaching blanket to a modified standoff position around a corner from the charge without a breaching blanket. For the shoulder-fired weapon training, the modified approach simply increased the standoff distance of the SM. Finally, for mortars, blast overpressure exposures were compared for different levels of their ducking height (body position) below the mortar tube at the time of firing. RESULTS: Modification of the position of SMs during training with the det linear breaching charge had the highest measured blast exposure percent reduction, at 79%. Both the water breaching charge and shoulder-fired weapon showed lowered peak overpressures on all gauges. The measured percent reduction for the 120-mm mortar was 35%. When the blast gauges did not trigger at the modified standoff distance, the percent reduction was calculated with the assumption that the new overpressures were below ∼3.4 kPa (0.5 psi) (the lowest trigger threshold for the gauges). A figure summarizes the percent reduction for each subject in the training scenarios. CONCLUSIONS: Results show that the modification of the SMs' position effectively mitigated blast exposures for all considered weapon scenarios. There was at least a 50% overpressure reduction from the initial to modified standoff distances and a 35% reduction from the change in SM body posture. Based on these observations, new locations and body positioning of SMs during training have been suggested for blast mitigation.

Blood-Based Biomarkers of Repetitive, Subconcussive Blast Overpressure Exposure in the Training Environment: A Pilot Study.

Because of their unknown long-term effects, repeated mild traumatic brain injuries (TBIs), including the low, subconcussive ones, represent a specific challenge to healthcare systems. It has been hypothesized that they can have a cumulative effect, and they may cause molecular changes that can lead to chronic degenerative processes. Military personnel are especially vulnerable to consequences of subconcussive TBIs because their training involves repeated exposures to mild explosive blasts. In this pilot study, we collected blood samples at baseline, 6 h, 24 h, 72 h, 2 weeks, and 3 months after heavy weapons training from students and instructors who were exposed to repeated subconcussive blasts. Samples were analyzed using the reverse and forward phase protein microarray platforms. We detected elevated serum levels of glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1 (UCH-L1), nicotinic alpha 7 subunit (CHRNA7), occludin (OCLN), claudin-5 (CLDN5), matrix metalloprotease 9 (MMP9), and intereukin-6 (IL-6). Importantly, serum levels of most of the tested protein biomarkers were the highest at 3 months after exposures. We also detected elevated autoantibody titers of proteins related to vascular and neuroglia-specific proteins at 3 months after exposures as compared to baseline levels. These findings suggest that repeated exposures to subconcussive blasts can induce molecular changes indicating not only neuron and glia damage, but also vascular changes and inflammation that are detectable for at least 3 months after exposures whereas elevated titers of autoantibodies against vascular and neuroglia-specific proteins can indicate an autoimmune process.

Imaging brain trauma.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) is a leading cause of death and long-term cognitive and behavioral dysfunction in children and young adults, yet effective treatments are lacking, in part because critical aspects of TBI neurobiology and natural history are not understood. We review recent advances in neuroimaging and discuss how they are helping to address these fundamental gaps. RECENT FINDINGS: Novel imaging methods provide detailed information on how TBI affects anatomical integrity (diffusion tensor imaging; voxel-based morphometry; susceptibility-weighted imaging, magnetization transfer imaging), metabolic activity (magnetic resonance spectroscopy), perfusion (positron emission tomography, perfusion computed tomography, perfusion magnetic resonance), and patterns of functional activation (functional magnetic resonance imaging). Individually and collectively, these methods can significantly enhance TBI diagnosis and outcome prediction. SUMMARY: Refinements in neuroimaging offer a window into the complex neuroanatomical and neurophysiological disturbances induced by TBI. Research is needed to understand how these alterations evolve with time and in response to therapeutic interventions.

Initial Biphasic Fractional Anisotropy Response to Blast-Induced Mild Traumatic Brain Injury in a Mouse Model.

INTRODUCTION: Blast-induced mild traumatic brain injury was generated in a mouse model using a shock tube to investigate recovery and axonal injury from single blast. METHODS: A supersonic helium wave hit the head of anesthetized male young adult mice with a reflected pressure of 69 psi for 0.2 ms on Day 1. Subsequently, the mice were cardioperfused on Days 2, 5, or 12. The isolated brains were subjected to diffusion tensor imaging. Reduced fractional anisotropy (FA) indicated axonal injury. RESULTS: After single blast, FA showed a biphasic response in the corpus callosum with decrease on Days 2 and 12 and increase on Day 5. CONCLUSIONS: Blast-induced mild traumatic brain injury in a mouse model follows a biphasic FA response within 12 days after a single blast similar to that reported for human subjects.