Models of Posttraumatic Brain Injury Neurorehabilitation

The effects of traumatic brain injury (TBI) are heterogeneous and have limited predictability, particularly in relation to neurorehabilitation. To address and treat the diverse sequelae that occur post-TBI, several experimental models have been designed to model human TBI. Yet, there is a growing gap between experimental therapeutic treatment studies and their translation to clinical TBI. As experimental models are vital to advance our understanding, management and treatment of TBI, this review aims to describe the role of experimental models in post-TBI neurorehabilitation research. We discuss important themes to consider in experimental rehabilitation modeling. Variations in models, treatment timing and chronicity, and factors like genetics, age, and gender can influence rehabilitation response and benefits. We propose more rigorous experimental rehabilitation models, integrated with a Rehabilomics-framework to examine how individual factors interact with injury to influence response to rehabilitation and outcomes following TBI, will yield important neurorehabilitation research breakthroughs and improved clinical care. TBI is a major cause of disability and death worldwide (Maas et al., 2008). The effects of TBI are heterogeneous, and in addition to damage from the direct injury, TBI facilitates the development of secondary pathologic processes in the brain, including inflammation, excitotoxicity, ischemia, edema, and many chronic secondary signaling changes (Park et al., 2008). To examine the diverse sequelae post-TBI, several experimental models, primarily in rodents, have been designed to produce injuries reflecting many components of those observed in human TBI. Experimental models are vital to the advancement of our understanding, management, and treatment of TBI. A recent example of the importance of animal models lies within work examining genetic risk factors for mortality after clinical TBI. Failla and colleagues (Failla et al., 2014) showed that genetic risk factors within the gene coding for brain-derived neurotrophic factor (BDNF) are associated with mortality risk after TBI. However, variations within the gene that reportedly increase secretion of the normally pro-survival neurotrophin were associated with reduced survival probabilities, especially in older individuals. Although this result seems to contradict reports of BDNF’s dominantly pro-survival signaling in uninjured animals, a recent study by Rostami and colleagues (2013) showed that there may actually be an injury-induced increase in BDNF’s pro-apoptotic signaling capabilities after experimental TBI. To evaluate and model this balance in BDNF signaling, and its impact on recovery post-TBI, it will be imperative to use both clinical and experimental paradigms to further contextualize and interpret the clinical genetic biomarker associations reported. While furthering our understanding of TBI mechanisms relevant to clinical care is important, there are limitations with current experimental TBI approaches. Several therapies can be neuroprotective in experimental TBI, yet most of these agents have consistently failed to translate into successful treatments in the clinic (Ikonomidou and Turski, 2002; Narayan et al., 2002). In fact, after severe TBI, only about 40% of patients have a favorable outcome (MRC CRASH Trial Collaborators et al., 2008), suggesting there is a wide gap between experimental therapeutic treatment studies and their translation to clinical TBI. This apparent disconnect may be due to heterogeneity in injury as well as a lack of consideration for covariates. Similarly, it is unclear how concurrent extracerebral injuries may influence clinical trials results (Aarabi and Simard, 2009; Kochanek and Yonas, 1999; Narayan et al., 2002). One additional limitation of successfully translating experimental clinical trials to consider is the lack of understanding of TBI as a chronic, yet rehabilitation sensitive, disease. To date, there has been a far more limited emphasis in the literature on mechanisms of chronic dysfunction after TBI. Contemporary research now suggests that TBI, in some instances including a subset of those with mild TBI (mTBI), is not simply a transient and static syndrome from which people recover, but rather a chronic and evolving disease state. Our own work suggests that TBI pathology has a dynamic time course in which secondary complications and symptoms can arise and require ongoing management (Failla et al., 2014). Within this chronic disease framework, therapeutic plasticity and recovery mechanisms interplay with ongoing neurodegenerative and other chronic state pathology to affect symptoms, complications, and function (Dixon et al., 1999; Niogi et al., 2008; Sidaros et al., 2008). Common functional impairment and disability after TBI can vary and lead to faster recovery patterns (months for motor function) (Katz et al., 1998) compared with longer recovery patterns (years for cognitive/mood recovery) (Hammond et al., 2004). This evolving understanding of the dynamic nature of TBI requires a paradigm shift in experimental TBI studies and a clear understanding of chronic states of TBI pathology and associated sequelae. However, there are numerous advantages to using established experimental models to further elucidate the mechanisms and treatment of chronic TBI through neurorehabilitation approaches. One of the most important issues is a relative lack of established neurorehabilitation methodology within the experimental literature. There are several important issues to consider when modeling neurorehabilitation strategies after experimental TBI. Many therapeutic interventions are administered briefly in experimental models, yet in clinical practice, treatments reflect a more chronic intervention period. Similarly, rehabilitation models may allow for more controlled administration compared with variable practice parameters for common rehabilitation interventions in the clinical population. Importantly, much of the experimental TBI model literature has focused on acute neuroprotection and/or management, with little consideration or understanding of how acute secondary injury and acute care practices may influence chronic TBI and neurorehabilitation effects. This lack of understanding could have important clinical implications. For example, studies suggest now that treatment with haloperidol in a limited fashion immediately following TBI may not impede recovery, but delayed administration can greatly reduce motor and cognitive recovery (Kline et al., 2007a). Given the utility of experimental models, and the need for a greater understanding of neurorehabilitation mechanisms as well as considerations and caveats for experimental rehabilitation model use, this review focuses on the current state of neurorehabilitation research in experimental TBI. We (1) provide insight into important rehabilitation-centric considerations in common TBI models, (2) summarize the current literature pairing current animal models with rehabilitation-specific interventions, and (3) identify areas of importance, impact, and improvement as a developmental guide for future integration of neurorehabilitation concepts in animal models of TBI.