Modeling the Neurobehavioral Consequences of Blast-Induced Traumatic Brain Injury Spectrum Disorder and Identifying Related Biomarkers

Excerpt

Blast induced traumatic brain injury (bTBI) has become the most common type of military head injuries affecting close to 500,000 service members. bTBI is a spectrum disorder ranging from the severe form that is frequently comorbid with polytrauma to the mild form that shares symptoms and/or comorbid with post-traumatic stress disorder (PTSD). The epidemiologic scale and complexity of bTBI and closely related neuropsychiatric conditions present especially significant short- and long-term challenges for the military health care system. Due to the complexity of physical forces generated by explosive blast combined with our limited understanding how these forces interact with the biological entity (physical-to-biological coupling), modeling bTBI poses special challenges. The goal of this chapter is to: 1) familiarize readers with experimental modeling of bTBI, including physical and biological considerations toward high-fidelity modeling; 2) provide a brief overview of bTBI animal models; 3) present some of the neurobehavioral consequences of bTBI; and 4) identify related biomarkers for the diagnosis and monitoring of the disease.

Since the advent of the military conflicts in 2001, approximately 1.5 million service members were deployed to Afghanistan and Iraq where 15%–30% suffered traumatic brain injuries (TBIs) (http://www.dcoe.mil/). Approximately 80% of the injuries sustained during those wars were caused by explosive blast, resulting in a specific form of TBI called bTBI (Ling et al., 2009). Using criteria similar to other forms of TBI, bTBI is also classified as severe, moderate, or mild (Ling and Ecklund, 2011). Based on traditional assessments of injury severity, approximately 5% of documented bTBI cases (10,000–20,000 soldiers) were severe and approximately 10% (20,000–40,000 soldiers) were moderate. The overwhelming majority of bTBI cases, approximately 85% affecting 170,000–340,000 service members, were mild (Masel et al., 2012). Thus, there may be as many as 300,000 individuals who have sustained bTBIs and will be in need of some level of medical and/or rehabilitative care over the next several decades.

Depending on the severity of the injury, functional changes in bTBI span an entire spectrum of neurobehavioral symptoms and deficits: some have an acute onset and are transient in nature, whereas others develop over time and may become chronic (Marion et al., 2011). At the different ends of the spectrum, there are two important factors that confound underlying injury mechanisms, patient care, and outcome. In severe bTBI, the majority (60%–80%) of individuals sustain serious penetrating injuries to the head as well as to the extremities and body (Bass et al., 2012; Hicks et al., 2010; Ling et al., 2009). These polytrauma patients present with highly complex and critical physical and functional deficits depending on the brain region(s) (and associated circuitries) damaged by the blast (Ling and Ecklund, 2007, 2011; Ling and Marshall, 2008; Ling et al., 2010; Ling and Neal, 2005). Emotional and cognitive impairments are almost always detectable in severe bTBI.

In mild bTBI, the physical damage is minimal, but there is a significant psychological stress component that plays an important role as cofactor in the development of the condition (Chen and Huang, 2011; Elder et al., 2010; Kennedy et al., 2010b; Rosenfeld and Ford, 2010; Thompson et al., 2008). In this form of bTBI, mood, learning, and memory are primarily impaired but executive function, sleep, and social interactions are also frequently affected. Accordingly, the neurobehavioral symptoms of mild bTBI (especially when it is repeated) greatly overlap with those of PTSD, thus complicating the pathobiology, differential diagnosis, and, more importantly, the treatment of mild bTBI (Chen and Huang, 2011; Jaffee and Meyer, 2009; Peterson et al., 2011).

The behavioral symptoms observed in bTBI reflect similarly complex structural, cellular, and molecular changes in the brain. Some of these changes can be detected noninvasively by advanced imaging techniques (Benzinger et al., 2009). Various magnetic resonance imaging (MRI) modalities, predominantly diffusion tensor imaging (DTI), have identified structural anomalies in a number of brain regions, including white matter changes in the cerebrum and cerebellum. The limited number of experimental bTBI imaging studies have recapitulated some of these clinical findings. Furthermore, the nature and extent of the cellular and molecular damage can be determined by monitoring time-dependent changes in the serum and/or cerebrospinal fluid (CSF) concentrations of select protein biomarkers (Agoston and Elsayed, 2012). Several putative biomarkers have been identified in experimental bTBI, indicating complex and dynamically changing pathologies that include oxidative stress, axonal and vascular damage, and inflammation.

The epidemiologic scale and complexity of bTBI and closely related neuropsychiatric conditions have and will continue to present very significant challenges for the military health care system on a short-term as well as a long-term basis. The aim of this chapter is to (1) familiarize readers with experimental modeling of bTBI, including physical and biological considerations toward high-fidelity modeling; (2) provide a brief overview of bTBI animal models; (3) present some of the neurobehavioral consequences of bTBI; and (4) identify related biomarkers for the diagnosis and monitoring of the disease.