Mini Review of Controlled Cortical Impact: A Well-Suited Device for Concussion Research.

brain sciences Review Mini Review of Controlled Cortical Impact: A Well-Suited Device for Concussion Research Nicole Osier 1,2 and C. Edward Dixon 3,4,5, * 1 2 3 4 5 * School of Nursing, Holistic Adult Health Division, University of Texas at Austin, Austin, TX 78701, USA; Dell Medical School, Department of Neurology, University of Texas at Austin, Austin, TX 78701, USA Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15224, USA Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15260, USA VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA Correspondence: ; Tel.: +1-(412)-692-8127 Academic Editors: James M. Gurley and Brian D. Greenwald Received: 27 June 2017; Accepted: 18 July 2017; Published: 20 July 2017 Abstract: Mild traumatic brain injury (mTBI) is increasingly recognized as a significant public health problem which warrants additional research. Part of the effort to understand mTBI and concussion includes modeling in animals. Controlled cortical impact (CCI) is a commonly employed and well-characterized model of experimental TBI that has been utilized for three decades. Today, several commercially available pneumatic- and electromagnetic-CCI devices exist as do a variety of standard and custom injury induction tips. One of CCI’s strengths is that it can be scaled to a number of common laboratory animals. Similarly, the CCI model can be used to produce graded TBI ranging from mild to severe. At the mild end of the injury spectrum, CCI has been applied in many ways, including to study open and closed head mTBI, repeated injuries, and the long-term deficits associated with mTBI and concussion. The purpose of this mini-review is to introduce the CCI model, discuss ways the model can be applied to study mTBI and concussion, and compare CCI to alternative pre-clinical TBI models. Keywords: controlled cortical impact (CCI); traumatic brain injury (TBI); experimental TBI; concussion; mild TBI (mTBI) 1. Introduction Mild traumatic brain injury (mTBI) is a type of neurological event that is gaining international recognition as a significant worldwide public health problem which warrants further research. Some mTBIs are accompanied by concussion, a neurological syndrome with characteristic transient cognitive, motor, and neuropsychiatric symptoms [1]. While the symptoms associated with concussion typically resolve in the minutes-to-hours after injury [2–4], post-concussive syndrome, a neurological sequela [1], can occur and is associated with longer-term deficits. Still, despite the prevalence and increased interest in both mTBI and concussion, important gaps in the knowledge base remain, surrounding: characterizing the pathophysiology, understanding the factors that contribute to functional deficits, and developing targeted interventions capable of reducing pathology and symptoms. Pre-clinical models of TBI supplement accumulating clinical knowledge and remain an important part of the effort to generate evidence about both mTBI and concussion. There are several pre-clinical models that have been applied to study mTBI and concussion; each has unique strengths and limitations. The purpose of this mini-review is to provide an overview of the controlled cortical impact (CCI) model, discuss features that make it well-suited to studying mTBI and concussion, as well as compare CCI to available alternatives. Brain Sci. 2017, 7, 88; doi:10.3390/brainsci7070088 www.mdpi.com/journal/brainsci Brain Sci. 2017, 7, 88 2 of 7 2. Model Overview Animal models have been employed to study mTBI and concussion since the late 1800s, with efforts to refine and expand the methods in the subsequent years [5–11]. The first CCI paper published in 1988 used ferrets as the test animal [12]. During the 1990s, the model’s strengths (e.g., control and reproducibility) led others to adapt the model to rats [13], and later mice [14]. In the decades since, CCI has become a widely used model of experimental TBI that has been adapted for use in larger laboratory animals [15–17], as described in detail later (see Section 2.2). In addition to the expansion to different test animals, CCI has been modified to model closed head injury and repeated injuries (discussed in Section 3.4). 2.1. CCI Devices CCI devices induce injury by using a pneumatic piston or electromagnetic actuator to drive an injury induction tip of the desired size/shape, with a specified velocity, depth, and dwell time into the exposed dura or intact skull. The use of a stereotaxic frame allows researchers to choose whether the tip is perpendicular or angled with respect to the injury site. The CCI model was initially characterized and refined using pneumatic devices [12–14]. Today, pneumatic CCI devices remain popular [18–22], with several commercially available models. Notably, electromagnetic devices have become commercially available and have been adopted by many research teams [23–26]. Both pneumatic and electromagnetic CCI devices have been well-received by the research community. Notably, there is little empirical evidence formally comparing pneumatic and electromagnetic devices. One published study did test one commercially available pneumatic and one prototype electromagnetic device and found greater reproducibility with the electromagnetic device [23]. Specifically, the authors found the pneumatic device resulted in velocity-dependent overshoot (which was not seen in the electromagnetic model) and greater overall overshoot [23]. Notably, the proper use of either a pneumatic or electromagnetic CCI device can produce graded [23,24,27–29], reproducible injuries that model important features of mTBI and concussion that are seen in humans. 2.2. Test Animals CCI can be adapted to scale for smaller and larger animals, contributing to the model’s popularity. The initial ferret model [12] was scaled down for use in rats [13], and then further scaled down to account for the thinner cortex of mice [14]; the use of ferrets declined and smaller rodent models became the norm. Later, CCI was scaled up for use in larger laboratory animals, including nonhuman primates [17] and swine [15,16,30–33]. Ferret models have recently regained popularity with two new papers published recently [34,35]. Generally speaking, while controlling for the desired injury severity, the tip size and impact depth are scaled up with the size of the test animal. When conducting CCI in a test animal not used previously, researchers are advised to complete a thorough review of the literature and conduct pilot studies to characterize the model for the desired injury extent and specific outcomes of interest. Moreover, the experimental endpoints of interest influence the selection of which test animal to use. As part of the effort to minimize animal suffering through reduction, replacement, and refinement, the least sentient animal appropriate to address the experimental goals should be used. Still, ther (...truncated)