The closed-head impact model of engineered rotational acceleration (CHIMERA) as an application for traumatic brain injury pre-clinical research: A status report

McNamara, Eileen H.; Grillakis, Antigone; Tucker, Laura B.; McCabe, Joseph T.

doi:10.1016/j.expneurol.2020.113409

Cited by 38 publications

(43 citation statements)

References 117 publications

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“…These models have been established for decades and have produced a wide body of literature. Although CCI and FPI have remained popular, in recent years attention has turned to less invasive and more clinically relevant "closed-head" models that produce a concussive, more diffuse injury, with or without acceleration/deceleration and rotational components (Bodnar et al, 2019;McNamara et al, 2020). Also of growing interest are animal models of blast overpressure (Skotak et al, 2019;McCabe and Tucker, 2020), as TBI from blast has been the signature wound from military conflicts for the past 20 years.…”

Section: Anxiety-like Behaviors Following Experimental Tbi Animal Models Of Experimental Tbimentioning

confidence: 99%

“…CCI is considered a focal injury, and unfortunately these inconsistencies in results extend to more diffuse and "closed-head" injury models (weightdrop, blast overpressure, and single or repeated concussive brain injury); further indicating that better standardization of TBI models and behavioral testing is needed. A newer TBI model, the Closed-Head Model of Engineered Rotational Acceleration (CHIMERA), a commercially available device that produces a contact force resulting in a rotational injury with acceleration/deceleration components, provides a more limited set of data on anxiety-like behaviors following experimental TBI (McNamara et al, 2020). To date, although more data are needed, results with the CHIMERA model have shown relative consistency: increased anxiety is measured in the OFT test up to a couple of weeks following injury, whereas decreased anxiety-like behaviors are found with the EZM or EPM at more chronic time points (e.g., Namjoshi et al, 2014;Nolan et al, 2018;McNamara et al, 2020).…”

Section: Anxiety-like Symptoms Post-tbi In Rodentsmentioning

confidence: 99%

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Measuring Anxiety-Like Behaviors in Rodent Models of Traumatic Brain Injury

Tucker

McCabe

2021

Front. Behav. Neurosci.

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Anxiety is a common complaint following acquired traumatic brain injury (TBI). However, the measurement of dysfunctional anxiety behavioral states following experimental TBI in rodents is complex. Some studies report increased anxiety after TBI, whereas others find a decreased anxiety-like state, often described as increased risk-taking behavior or impulsivity. These inconsistencies may reflect a lack of standardization of experimental injury models or of behavioral testing techniques. Here, we review the most commonly employed unconditioned tests of anxiety and discuss them in a context of experimental TBI. Special attention is given to the effects of repeated testing, and consideration of potential sensory and motor confounds in injured rodents. The use of multiple tests and alternative data analysis methods are discussed, as well as the potential for the application of common data elements (CDEs) as a means of providing a format for documentation of experimental details and procedures of each published research report. CDEs may improve the rigor, reproducibility, as well as endpoint for better relating findings with clinical TBI phenotypes and the final goal of translation. While this may not resolve all incongruities in findings across laboratories, it is seen as a way forward for standardized and universal data collection for improvement of data quality and sharing, and advance therapies for neuropsychiatric symptoms that often present for decades following TBI.

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Section: Anxiety-like Behaviors Following Experimental Tbi Animal Models Of Experimental Tbimentioning

confidence: 99%

Section: Anxiety-like Symptoms Post-tbi In Rodentsmentioning

confidence: 99%

Measuring Anxiety-Like Behaviors in Rodent Models of Traumatic Brain Injury

Tucker

McCabe

2021

Front. Behav. Neurosci.

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“…53 Pathologically, the repeated injury caused diffuse axonal injury evidenced by increased astrogliosis in the optic tracts and silver uptake in the optic tracts (OT), corpus callosum (CC), and cerebral peduncles (CP) of the brainstem. Axonal damage in the CC and OT has been reported extensively following single or repeated CHIMERA with silver staining, GFAP, Iba1, amyloid precursor protein, myelin basic protein, and neurofilament, 37 and has been suggested to be indicative of a diffuse injury pattern reflective of coup and contrecoup injuries, respectively. 14 No changes were found in any brain regions in the density of GABAergic parvalbumin (PV)-expressing interneurons.…”

Section: Summary Of Pathological Findingsmentioning

confidence: 99%

“…CHIMERA was introduced approximately 7 years ago 14 and has since been demonstrated in approximately 20 publications to date to reliably elicit diffuse white matter injury and cognitive deficits in rodents. 37 Learning and memory deficits after CHIMERA injuries, single or repeated, have been shown with the Morris water maze (MWM), Barnes maze, and passive avoidance behavioral tests in mice, 37 all of which depend on intact sensory and motor function during test performance. Recently, Desai and colleagues showed that following three CHIMERA injuries, male mice were impaired on a visible platform test in the MWM and on the visual cliff test of visual acuity, and also had reduced visual evoked potentials.…”

Section: Introductionmentioning

confidence: 99%

Hippocampal-Dependent Cognitive Dysfunction following Repeated Diffuse Rotational Brain Injury in Male and Female Mice

Tucker

McCabe

2021

Journal of Neurotrauma

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Cognitive dysfunction is a common, often long-term complaint following acquired traumatic brain injury (TBI). Cognitive deficits suggest dysfunction in hippocampal circuits. The goal of the studies described here is to phenotype in both male and female mice the hippocampal-dependent learning and memory deficits resulting from TBI sustained by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) device-a model that delivers both a contact-concussion injury as well as unrestrained rotational head movement. Mice sustained either sham procedures or four injuries (0.7 J, 24-h intervals). Spatial learning and memory skills assessed in the Morris water maze (MWM) approximately 3 weeks following injuries were significantly impaired by brain injuries; however, slower swimming speeds and poor performance on visible platform trials suggest that measurement of cognitive impairment with this test is confounded by injury-induced motor and/or visual impairments. A separate experiment confirmed hippocampal-dependent cognitive deficits with trace fear conditioning (TFC), a behavioral test less dependent on motor and visual function. Male mice had greater injury-induced deficits on both the MWM and TFC tests than female mice. Pathologically, the injury was characterized by white matter damage as observed by silver staining and glial fibrillary acidic protein (astrogliosis) in the optic tracts, with milder damage seen in the corpus callosum, and fimbria and brainstem (cerebral peduncles) of some animals. No changes in the density of GABAergic parvalbumin-expressing cells in the hippocampus, amygdala, or parietal cortex were found. This experiment confirmed significant sexually dimorphic cognitive impairments following a repeated, diffuse brain injury.

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“…Acceleration injuries have traditionally been classified (see Table 1 for a review) into impact (e.g., bolt guns, sled models with impact) vs. non-impact models (e.g., HYGE, sled models without impact) and can be performed with or without protective equipment (1,67). Although rodent acceleration models have been proposed (70), examination of the effects of linear and rotational accelerative forces is more practical in gyrencephalic animal species with a larger brain mass (11,71).…”

Section: Introductionmentioning

confidence: 99%

Reproducibility and Characterization of Head Kinematics During a Large Animal Acceleration Model of Traumatic Brain Injury

et al. 2021

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Acceleration parameters have been utilized for the last six decades to investigate pathology in both human and animal models of traumatic brain injury (TBI), design safety equipment, and develop injury thresholds. Previous large animal models have quantified acceleration from impulsive loading forces (i.e., machine/object kinematics) rather than directly measuring head kinematics. No study has evaluated the reproducibility of head kinematics in large animal models. Nine (five males) sexually mature Yucatan swine were exposed to head rotation at a targeted peak angular velocity of 250 rad/s in the coronal plane. The results indicated that the measured peak angular velocity of the skull was 51% of the impulsive load, was experienced over 91% longer duration, and was multi- rather than uni-planar. These findings were replicated in a second experiment with a smaller cohort (N = 4). The reproducibility of skull kinematics data was mostly within acceptable ranges based on published industry standards, although the coefficients of variation (8.9% for peak angular velocity or 12.3% for duration) were higher than the impulsive loading parameters produced by the machine (1.1 vs. 2.5%, respectively). Immunohistochemical markers of diffuse axonal injury and blood–brain barrier breach were not associated with variation in either skull or machine kinematics, suggesting that the observed levels of variance in skull kinematics may not be biologically meaningful with the current sample sizes. The findings highlight the reproducibility of a large animal acceleration model of TBI and the importance of direct measurements of skull kinematics to determine the magnitude of angular velocity, refine injury criteria, and determine critical thresholds.

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The closed-head impact model of engineered rotational acceleration (CHIMERA) as an application for traumatic brain injury pre-clinical research: A status report

Cited by 38 publications

References 117 publications

Measuring Anxiety-Like Behaviors in Rodent Models of Traumatic Brain Injury

Measuring Anxiety-Like Behaviors in Rodent Models of Traumatic Brain Injury

Hippocampal-Dependent Cognitive Dysfunction following Repeated Diffuse Rotational Brain Injury in Male and Female Mice

Reproducibility and Characterization of Head Kinematics During a Large Animal Acceleration Model of Traumatic Brain Injury

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