Table 2.

Actionable Research Recommendations for Pre-Clinical Studies in TBI

Recommendation	Action
Comprehensive assessment of the validity of accepted animal models	• Conduct comprehensive assessments within existing models across the core neurophysiological and -psychiatric sequelae of TBI.
	• Consider how population characteristics affect the etiology of the course and outcome of TBI.
	• Support the performance of cross-species validation of phenotypes/models.
	• Integrate appropriate animal models of mTBI and repetitive mTBI for assessment of new rehabilitation approaches across laboratories, particularly with incorporation of long-term outcome assessments.
Cross-validate and standardize behavioral tests in animal models to recapitulate deficits found in humans after TBI	• Develop models that account for relevant patient variables, such as previous history of TBI, age, sex, and comorbidities (e.g., PTSD, substance abuse, and major depressive disorder).
	• Develop validated and standardized behavioral tests that can reliably recapitulate higher cognitive deficits displayed by humans, especially in larger non-rodent models such as ferrets and porcine.
	• Consider genetic manipulation to model particular aspects of human TBI, such as humanized tau or TDP-43 to reliably recapitulate TBI-dependent proteinopathy or APOE genotype to incorporate the risk of poor recovery post-TBI.
Evaluate candidate therapies to assess acute and chronic effects of TBI across multiple models	• Screen putative therapies on a variety of relevant models in order to assess interventions based on different endophenotypes.
	• Incorporate assessments of brain pharmacokinetics and pharmacodynamics along with confirmation of target engagement when testing therapies—this should be pursued in both forward and reverse translation.
	• Evaluate therapies in pre-clinical models using strategies that expand upon the traditional early post-TBI administration—including assessment of acute and/or chronic administration.
Standardize experimental variables to improve research rigor, transparency, and reproducibility and guide future model development	• Adopt new pre-clinical Common Data Elements to improve standardization of data collection.
	• Apply best practices for reproducibility and quality assurance in model generation.
	• Ensure that negative data are published or available and searchable in a database.
	• Promote data sharing of pre-clinical data under FAIR principles.

TBI, traumatic brain injury; mTBI, mild TBI; PTSD, post-traumatic stress disorder; TDP-43, transactive response DNA binding protein 43; APOE, apolipoprotein E; FAIR, Findability, Accessibility, Interoperability, and Reusability.