Chronic Anxiety- and Depression-Like Behaviors Are Associated With Glial-Driven Pathology Following Repeated Blast Induced Neurotrauma

Long-term neuropsychiatric impairments have become a growing concern following blast-related traumatic brain injury (bTBI) in active military personnel and Veterans. Neuropsychiatric impairments such as anxiety and depression are common comorbidities that Veterans report months, even years following injury. To understand these chronic behavioral outcomes following blast injury, there is a need to study the link between anxiety, depression, and neuropathology. The hippocampus and motor cortex (MC) have been regions of interest when studying cognitive deficits following blast exposure, but clinical studies of mood disorders such as major depressive disorder (MDD) report that these two regions also play a role in the manifestation of anxiety and depression. With anxiety and depression being common long-term outcomes following bTBI, it is imperative to study how chronic pathological changes within the hippocampus and/or MC due to blast contribute to the development of these psychiatric impairments. In this study, we exposed male rats to a repeated blast overpressure (~17 psi) and evaluated the chronic behavioral and pathological effects on the hippocampus and MC. Results demonstrated that the repeated blast exposure led to depression-like behaviors 36 weeks following injury, and anxiety-like behaviors 2-, and 52-weeks following injury. These behaviors were also correlated with astrocyte pathology (glial-fibrillary acid protein, GFAP) and dendritic alterations (Microtubule-Associated Proteins, MAP2) within the hippocampus and MC regions at 52 weeks. Overall, these findings support the premise that chronic glial pathological changes within the brain contribute to neuropsychiatric impairments following blast exposure.

Development of a new militarily-relevant whole-body low-intensity blast model for mild and subconcussive traumatic brain injury: Examination of acute neurological and multi-organ pathological outcomes

This work describes a newly developed experimental mouse model reproducing features of blast-induced neurotrauma (BINT), induced in operationally relevant manner using a compressed air-driven shock tube. Mild BINT (smBINT) was induced by one exposure to a low-intensity blast (LIB), whereas subconcussive BINT (rscBINT) was caused by repeated exposures to LIB. To mimic an operational scenario when a soldier is standing when exposed to blast using a quadruped experimental animal (mouse), a whole-body holder was developed to position mice in a bipedal stance, face-on toward the pressure wave generated in a shock tube. This restraint avoids bobble head movement, thus prevents tertiary blast effects, and allows administration of fast-acting inhaled anesthetics via nose cone. Using this model, we established and validated paradigms for primary blast-induced mild and repetitive traumatic brain injuries Our results showed that a single exposure to 69 kPa (10 psi) was capable of inducing smBINT, whereas three-rounds of exposure to 41 kPa (6 psi) caused rscBINT. Mice recovered rapidly from both types of BINT without prolonged neurological dysfunction. Mild superficial pathology was found predominantly in the lungs 24h after injury, with equivalent pathology after smBINT or repetitive rscBINT. The Purkinje layer of the cerebellum exhibited neuronal damage persisting up to 7d. Similar to some other models as well as clinical findings, this model reproduces blast-induced cerebellar pathology. In conclusion, this model positioning mice in a bipedal stance and facing front-on toward the shockwave provides realistic representation of operational scenarios and reproduces militarily-relevant smBINT and rscBINT in the laboratory.

Brain Tissue Material and Damage Properties for Blast Trauma

The aim of this study was to develop a test method to characterize the material behavior of bovine brain samples in large shear deformations and high strain rates relevant to blast-induced neurotrauma (BINT) and evaluate tissue damage. A novel shear test setup was designed and built capable of applying strain rates ranging from 300 to 1000 s−1. Based on the shear force time history and propagation of shear waves, it was found that the instantaneous shear modulus (about 6 kPa) was more than 3 times higher than the values previously reported in the literature. The shear wave velocity was found to be strain path dependent which is an indication of tissue damage at strains greater than 10%. The results of this study can help in improving finite element models of the brain for simulating tissue injury during BINT.

Military-Relevant Rodent Models of Blast-Induced Traumatic Brain Injuries

Explosive weaponry is the main cause of injuries in current military actions and terrorist attacks. Blast injuries and blast-induced neurotrauma (BINT) are caused by blast waves generated during an explosion. In both civilian and military environments, exposure to a blast may cause instant death, injuries with immediate manifestation of symptoms, and latent injuries that are initiated at the time of exposure and may manifest over a period of hours, months, or even years. Chronic health impairments due to blast often remain un- or underdiagnosed and represent significant challenges for treatment and rehabilitation. We need to advance our understanding of the mechanisms of these injuries to develop better preventive, diagnostic and treatment approaches. This could be achieved through research using clinically and militarily relevant and scientifically reliable models. This chapter provides an overview on rodent BINT models and discusses the generalizable and blast-specific factors that every rodent BINT model should fulfill.