Methods in molecular biology
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Traumatic brain injury (TBI) has been named the most complex disease in the most complex organ of the body. It is the most common cause of death and disability in the Western world in people <40 years old and survivors commonly suffer from persisting cognitive deficits, impaired motor function, depression and personality changes. TBI may vary in severity from uniformly fatal to mild injuries with rapidly resolving symptoms and without doubt, it is a markedly heterogeneous disease. ⋯ Since TBI is not one disease, refined animal models must take into account the clinical features and complexity of human TBI. To enhance the possibility of establishing preclinical efficacy of a novel treatment, the preclinical use of several different experimental models is encouraged as well as varying the species, gender, and age of the animal. In this chapter, the methods, limitations, and challenges of the CCI and FPI models of TBI used in rodents are described.
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Despite prodigious advances in TBI neurobiology research and a broad arsenal of animal models mimicking different aspects of human brain injury, this field has repeatedly experienced collective failures to translate from animals to humans, particularly in the area of therapeutics. This lack of success stems from variability and inconsistent standardization across models and laboratories, as well as insufficient objective and quantifiable diagnostic measures (biomarkers, high-resolution imaging), understanding of the vast clinical heterogeneity, and clinically centered conception of the TBI animal models. Significant progress has been made by establishing well-defined standards for reporting animal studies with "preclinical common data elements" (CDE), and for the reliability and reproducibility in preclinical TBI therapeutic research with the Operation Brain Trauma Therapy (OBTT) consortium. However, to break the chain of failures and achieve a therapeutic breakthrough in TBI will probably require the use of higher species models, specific mechanism-based injury models by which to theranostically targeted treatment portfolios are tested, more creative concepts of therapy intervention including combination therapy and regeneration neurobiology strategies, and the adoption of dosing regimens based upon pharmacokinetic-pharmacodynamic (PK-PD) studies and guided by the injury severity and TBI recovery process.
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The brain has different responses to traumatic injury as a function of its developmental stage. As a model of injury to the immature brain, the piglet shares numerous similarities in regards to morphology and neurodevelopmental sequence compared to humans. This chapter describes a piglet scaled focal contusion model of traumatic brain injury that accounts for the changes in mass and morphology of the brain as it matures, facilitating the study of age-dependent differences in response to a comparable mechanical trauma.
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Animal models play a critical role in understanding the biomechanical, pathophysiological, and behavioral consequences of traumatic brain injury (TBI). In preclinical studies, cognitive impairment induced by TBI is often assessed using the Morris water maze (MWM). ⋯ We include a theoretical framework for examining deficits in discrete stages of cognitive function and offer suggestions for how to make inferences regarding the specific nature of TBI-induced cognitive impairment. The ultimate goal is more precise modeling of the animal equivalents of the cognitive deficits seen in human TBI.
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Traumatic brain injury (TBI) is one of the most common causes of death and disability, and cerebral hypoxia is a frequently occurring harmful secondary event in TBI patients. The hypoxic conditions that occur on the scene of accident, where the airways are often obstructed or breathing is in other ways impaired, could be reproduced using animal TBI models where oxygen delivery is strictly controlled throughout the entire experimental procedure. ⋯ Different models of traumatic brain injury could be used to inflict desired injury type, whereas effects then could be studied using radiological, physiological and functional tests. In order to confirm that the brain has been affected by a hypoxic injury, appropriate substances in the affected cerebral tissue, cerebrospinal fluid, or serum should be analyzed.