Toward development of clinically translatable diagnostic and prognostic metrics of traumatic brain injury using animal models: A review and a look forward

Traumatic brain injury is a leading cause of cognitive and behavioral deficits in children in the US each year. There is an increasing interest in both clinical and pre-clinical studies to discover biomarkers to accurately diagnose traumatic brain injury (TBI), predict its outcomes, and monitor its progression especially in the developing brain. In humans, the heterogeneity of TBI in terms of clinical presentation, injury causation, and mechanism has contributed to the many challenges associated with finding unifying diagnosis, treatment, and management practices. In addition, findings from adult human research may have little application to pediatric TBI, as age and maturation levels affect the injury biomechanics and neurophysiological consequences of injury. Animal models of TBI are vital to address the variability and heterogeneity of TBI seen in human by isolating the causation and mechanism of injury in reproducible manner. However, a gap between the pre-clinical findings and clinical applications remains in TBI research today. To take a step toward bridging this gap, we reviewed several potential TBI tools such as biofluid biomarkers, electroencephalography (EEG), actigraphy, eye responses, and balance that have been explored in both clinical and pre-clinical studies and have shown potential diagnostic, prognostic, or monitoring utility for TBI. Each of these tools measures specific deficits following TBI, is easily accessible, non/minimally invasive, and is potentially highly translatable between animals and human outcomes because they involve effort-independent and non-verbal tasks. Especially conspicuous is the fact that these biomarkers and techniques can be tailored for infants and toddlers. However, translation of preclinical outcomes to clinical applications of these tools necessitates addressing several challenges. Among the challenges are the heterogeneity of clinical TBI, age dependency of some of the biomarkers, different brain structure, life span, and possible variation between temporal profiles of biomarkers in human and animals. Conducting parallel clinical and pre-clinical research, in addition to the integration of findings across species from several pre-clinical models to generate a spectrum of TBI mechanisms and severities is a path toward overcoming some of these challenges. This effort is possible through large scale collaborative research and data sharing across multiple centers. In addition, TBI causes dynamic deficits in multiple domains, and thus, a panel of biomarkers combining these measures to consider different deficits is more promising than a single biomarker for TBI. In this review, each of these tools are presented along with the clinical and pre-clinical findings, advantages, challenges and prospects of translating the pre-clinical knowledge into the human clinical setting.