A Systematic Review of Closed Head Injury Models of Mild Traumatic Brain Injury in Mice and Rats

Abstract

Mild TBI (mTBI) is a significant health concern. Animal models of mTBI are essential for understanding mechanisms, and pathological outcomes, as well as to test therapeutic interventions. A variety of closed head models of mTBI that incorporate different aspects (i.e., biomechanics) of the mTBI have been reported. The aim of the current review was to compile a comprehensive list of the closed head mTBI rodent models, along with the common data elements, and outcomes, with the goal to summarize the current state of the field. Publications were identified from a search of PubMed and Web of Science and screened for eligibility following PRISMA guidelines. Articles were included that were closed head injuries in which the authors classified the injury as mild in rats or mice. Injury model and animal-specific common data elements, as well as behavioral and histological outcomes, were collected and compiled from a total of 402 articles. Our results outline the wide variety of methods used to model mTBI. We also discovered that female rodents and both young and aged animals are under-represented in experimental mTBI studies. Our findings will aid in providing context comparing the injury models and provide a starting point for the selection of the most appropriate model of mTBI to address a specific hypothesis. We believe this review will be a useful starting place for determining what has been done and what knowledge is missing in the field to reduce the burden of mTBI.

Keywords: animal models; common data elements; concussion.

FIG. 1.

Methods flow chart. Identification through searches on two separate web-based platforms yielded 1,890 articles which were screened by abstract and then eligibility was determined via full text examination to exclude 1,403 articles. Removing mTBI articles in which repeat injuries were sustained, a total of 402 single mTBI articles were included in our review. mTBI, mild traumatic brain injury.

FIG. 2.

Overall summary of included studies. Of the 402 articles included in our final analysis, 3 major categories of models were found (A). Within the piston category (B) and the “other” models (C) there was considerable variability. A breakdown by year of publication (D) demonstrated the weight drop model over the last four decades and the increase in use of piston driven models over the last decade. TBI, traumatic brain injury. Color image is available online.

FIG. 3.

Example experimental set-up for weight drop and piston mTBI models. In the weight drop model (A), a variable weight is dropped from a variable height, onto the head of the animal and the animal can be on either a hard surface or a foam pad. Piston driven models (B), use either an electromagnetic (C) or a pneumatic (D) driven piston that is set to a specified velocity and impact depth and strikes the head of the animal. In piston driven models, the impact angle (E) can vary between study designs. In both the weight drop and the piston driven models the impact surface can vary with either a helmet or no helmet on the intact scalp or the exposed skull (F). Further, the head can be either fixed or free to rotate after the impact (G). The impact tip which contacts the head of the animal to induce injury can be either flexible or rigid (H) causing different injury biomechanics. An emerging model utilizes rotation following impact by placing the animal on a thin sheet following impact the animal falls through the sheet onto a foam pad (I). Color image is available online.

FIG. 4.

Common data elements for the weight drop model. Weight drop models have been used with a variety of different weights (A) and heights (B). Mice were injured typically using lower weights and heights, while rats were injured using heavier weights and heights. Injuries were induced on different surfaces (C) with the head either fixed or unfixed (D). A majority of papers used male (E), adult animals (F). Total numbers for (E) and (F) are greater than the 335 total publications because several publications reported using more than one sex or age of animals. N.R., not reported. Color image is available online.

FIG. 5.

Functional and Pathological deficits observed in the weight drop models of mTBI. Outcome measures collected included motor function (A), cognitive function (B), affective behaviors (C), and histology measures (D). Numbers indicate the number of studies with / without deficits. mTBI, mild traumatic brain injury.

FIG. 6.

Piston driven CHI models of mTBI common data elements. Most animals were male (A) and adult (B). The head was most often fixed (C) and the impact surface varied (D). The impact tip size when reported was typically 5 mm or less (E). Impact velocity (F) and depth (G) were smaller for mice than rats. Numbers indicate the number of studies using rats / mice. Total numbers are greater than the 43 total publications because several publications reported using more than one sex or age. CHI, closed head injury; N.R., not reported. Color image is available online.

FIG. 7.

Outcome measures for piston driven injury models. Common tests typically reported for motor function (A), cognitive function (B), affective behaviors (C), and histological measures (D) were reported. Numbers indicate the number of studies with / without deficits.

FIG. 8.

“Other” models common data elements. Most publications used anesthesia (A). Impact locations varied between models (B). However, most publications used males (C), and rats (D). Motor function (E), cognitive function (F), affective behaviors (G), and histological changes (H) were recorded for all “other” models. Numbers indicate the number of studies with / without deficits. Total numbers are greater than the 25 total publications in (C) and (D) because several publications reported using more than one sex and species. N.R., not reported. Color image is available online.