Animal Models for Concussion: Molecular and Cognitive Assessments—Relevance to Sport and Military Concussions

Mild traumatic brain injury (mTBI) or concussion, the most common form of brain injury, results in a complex cascade of injurious and reparative events in the brain, and is not always as mild in nature as the mTBI term would imply. Over the last decades it has become clear that repeated mTBIs may give rise to chronic and sometimes progressive brain changes that may lead to a broad range of psychiatric and neurological symptoms. Presently, there is a convention to categorize TBI into three groups: mild, moderate, and severe, based on initial presentation. At the more severe end of the injury spectrum, the correlation between initial injury severity rating and various outcome measures is relatively robust. At the milder end of the spectrum, this correlation is less tight, and over the last 100 years this has generated confusion with regards to the typical presentation and outcome of milder injuries. For a successful translation of basic science knowledge to the clinic to occur, further techniques and models are needed that better reflect mTBI in humans. The purpose of this chapter is to overview the underlying evidence for the necessity of animal models for mTBI in sports and other high risk activities such as military service. Traumatic brain injury (TBI) occurs when an external physical force impacts the head, either causing the brain to move within the intact skull or damaging the brain by fracturing the skull (McCrory et al., 2005). Various types and levels of impact damage the brain differently. TBI may acutely alter the state of consciousness and, with time, impair cognitive abilities, behavior, and/or physical function. Annually, around 1.7 million new cases of TBI are reported in the United States (www.cdc.gov/TraumaticBrainInjury, September 2013). Mild TBI constitutes most of these; an estimated 300,000 cases take place in the setting of sports and recreation, 95% being mTBI or concussion. In Europe, these cases have reached 60,000 deaths annually, and hospitalized TBI combined was estimated to be 235/100,000 inhabitants (Marklund and Hillered, 2011); the global magnitude of TBI is unknown, but available data suggest that the number of TBI victims globally is rising sharply (Corrigan et al., 2010; Maas et al., 2008; Tagliaferri et al., 2006). TBI is not only a single pathophysiological phenomenon, but rather a complex disease process that gives rise to structural and functional damage from both primary and secondary injury mechanisms (Masel and DeWitt, 2010). The primary injury is the result of the immediate mechanical disruption of brain tissue that occurs at the time of exposure to the external force and includes contusion, damage to blood vessels (hemorrhage), and axonal shearing, in which the axons of neurons are stretched and wavering (Cernak, 2005; Gaetz, 2004). Secondary injury develops over minutes to months after the primary injury and is the result of cascades of metabolic, cellular, and molecular events that ultimately lead to brain cell death, tissue damage, and atrophy (Bramlett and Dietrich, 2007; Thompson et al., 2005). Acute assessment of injury severity is critical for the diagnosis, management, and prognosis of TBI. Currently, in TBI clinical trials, the Glasgow Coma Scale is the primary means for initial patient classification, and the Glasgow Outcome Scale or its eight-point extended version remains a primary method for assessing outcomes (Lu et al., 2010; Maas and Lingsma, 2008). In contrast, much less is known about the pathophysiology of mTBI. MTBI is characterized by a short deterioration of neural function that may or may not involve loss of consciousness (Kelly, 1997). It may result from neuropathological changes, but some believe that the acute clinical symptoms reflect a functional disorder rather than a structural damage. Generally, mTBI is associated with normal structural neuroimaging (Aubry et al., 2002; McCrory et al., 2005), but recent biomarker studies challenge the view that neurons and axons often stay intact during mTBI (Neselius et al., 2012, 2013; Zetterberg et al., 2006, 2009). In the textbook (Silver, 2010) the terms “concussion” and “mTBI” are used interchangeably. At the fourth concussion conference (McCrory et al., 2013), however, a distinction between concussion and mTBI was proposed, noting that mTBI refers to “different constructs and should not be used interchangeably” suggesting that the concussion may be followed by complete recovery, whereas mTBI may manifest persistent symptoms (McCrory et al., 2013). Regardless of the different proposals around the terminology of concussion, the most important reason for developing animal models of TBI is to open new therapeutic windows. Developments and/or modifications of new and existing animal models of TBI provide opportunities for new therapeutic strategies and to cross the therapeutic gap between preclinical studies and patient care. However, promising results from preclinical studies of potential TBI treatments have not been interpreted into successful outcomes in clinical trials. The pathophysiological heterogeneity observed in patients with TBI, the lack of adequate pharmacokinetic analyses to determine optimal doses of potential therapies, and the administration of compounds outside the therapeutic window may have led to the clinical trial failures (Schouten, 2007). The pathophysiological heterogeneity observed in patients with TBI may arise from the location, nature, and severity of the primary injury and the effects of other factors and preexisting conditions, including but not restricted to age, health, sex, medication, alcohol and drug use, and genetics (Margulies and Hicks, 2009). Animal models of TBI are each designed to produce a relatively homogeneous type of injury, with age, sex, genetic background, and the injury parameters all well controlled. Thus, any one animal model may not be able to fully recapitulate all the aspects of secondary injury development that are observed in human TBI, and this may in part explain why drugs that showed promise in preclinical studies failed in clinical studies (Marklund et al., 2006). Unquestionably, however, animal models have been fundamental for studying the biomechanical, cellular, and molecular aspects of human TBI because of the limitation of clinical setting as well as for developing and characterizing novel therapeutic interventions. To achieve new therapeutic finding and based on the study design, appropriate animal models should be selected or modified.