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Merging pathology with biomechanics using CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): a novel, surgery-free model of traumatic brain injury.

Namjoshi DR, Cheng WH, McInnes KA, Martens KM, Carr M, Wilkinson A, Fan J, Robert J, Hayat A, Cripton PA, Wellington CL - Mol Neurodegener (2014)

Bottom Line: Traumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment.Despite promising outcomes from many preclinical studies, clinical evaluations have failed to identify effective pharmacological therapies, suggesting that the translational potential of preclinical models may require improvement.Injured mouse brains also showed significantly increased levels of TNF-α and IL-1β and increased endogenous tau phosphorylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. wcheryl@mail.ubc.ca.

ABSTRACT

Background: Traumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment. Despite promising outcomes from many preclinical studies, clinical evaluations have failed to identify effective pharmacological therapies, suggesting that the translational potential of preclinical models may require improvement. Rodents continue to be the most widely used species for preclinical TBI research. As most human TBIs result from impact to an intact skull, closed head injury (CHI) models are highly relevant, however, traditional CHI models suffer from extensive experimental variability that may be due to poor control over biomechanical inputs. Here we describe a novel CHI model called CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) that fully integrates biomechanical, behavioral, and neuropathological analyses. CHIMERA is distinct from existing neurotrauma model systems in that it uses a completely non-surgical procedure to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement. In this study, we characterized head kinematics as well as functional, neuropathological, and biochemical outcomes up to 14d following repeated TBI (rTBI) in adult C57BL/6 mice using CHIMERA.

Results: Head kinematic analysis showed excellent repeatability over two closed head impacts separated at 24h. Injured mice showed significantly prolonged loss of righting reflex and displayed neurological, motor, and cognitive deficits along with anxiety-like behavior. Repeated TBI led to diffuse axonal injury with extensive microgliosis in white matter from 2-14d post-rTBI. Injured mouse brains also showed significantly increased levels of TNF-α and IL-1β and increased endogenous tau phosphorylation.

Conclusions: Repeated TBI using CHIMERA mimics many of the functional and pathological characteristics of human TBI with a reliable biomechanical response of the head. This makes CHIMERA well suited to investigate the pathophysiology of TBI and for drug development programs.

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Head kinematics during rTBI. Head kinematic parameters during impacts were assessed in 8 mice subjected to rTBI. Data are represented as the means for each impact. (A) Head trajectory during the maximum acceleration phase in the sagittal plane following impact. (B) Head displacement-time graph following impact. (C) Head deflection is measured as the angle between the snout, side marker and the horizontal plane. Linear head velocity and linear head acceleration are depicted in (D) and (E), respectively. (F) and (G) show angular head velocity and angular acceleration, respectively. Data in (A) are represented as mean ± 95% CI in both X- and Y- direction, respectively. Data in B-G are represented as mean ± 95% CI. (H) Summary of peak values of kinematic parameters averaged across all 8 rTBI mice. The coefficient of variation (CV) was calculated as the average of day 1 and day 2 peak values from all available recordings.
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Fig1: Head kinematics during rTBI. Head kinematic parameters during impacts were assessed in 8 mice subjected to rTBI. Data are represented as the means for each impact. (A) Head trajectory during the maximum acceleration phase in the sagittal plane following impact. (B) Head displacement-time graph following impact. (C) Head deflection is measured as the angle between the snout, side marker and the horizontal plane. Linear head velocity and linear head acceleration are depicted in (D) and (E), respectively. (F) and (G) show angular head velocity and angular acceleration, respectively. Data in (A) are represented as mean ± 95% CI in both X- and Y- direction, respectively. Data in B-G are represented as mean ± 95% CI. (H) Summary of peak values of kinematic parameters averaged across all 8 rTBI mice. The coefficient of variation (CV) was calculated as the average of day 1 and day 2 peak values from all available recordings.

Mentions: Analysis of high-speed videography (5,000 fps) was used to assess the biomechanical responses of the head in a group of 8 mice during CHIMERA rTBI at an impact energy of 0.5 J (Figure 1; peak kinematic parameters depicted in Figure 1H). Trajectories of the mouse head in the sagittal plane during peak acceleration following two impacts spaced at 24h are depicted in Figure 1A. Following vertical impact, the head followed a looped trajectory in the sagittal plane (Additional file 1: Figure S1, and Additional file 2: Movie S4). The average head trajectories following two repetitive TBIs in 8 mice were highly consistent (Figure 1A). The head traveled a peak linear displacement of 49.6 ± 3.5 mm (mean ± SD, same below) in 15.7 ± 2.4 ms (Figure 1B) and exhibited a peak angular deflection of 2.6 ± 0.28 rad in 24.8 ± 3.1 ms (Figure 1C). Peak linear velocity was 6.6 ± 0.8 m/s at 3.4 ± 1.0 ms (Figure 1D), and peak angular velocity was 305.8 ± 73.7 rad/s at 2.8 ± 1.9 ms following initial impactor contact (Figure 1F). The head experienced large linear and angular accelerations following impact, achieving peak linear acceleration of 385.3 ± 52 g at 1.5 ± 0.3 ms (Figure 1E), whereas the peak angular acceleration of 253.6 ± 69.0 krad/s2 was observed at 0.8 ± 1.1 ms (Figure 1G). As the head was stationary before impact, the change in head velocity (ΔV) equals peak head velocity and was found to be 6.6 m/s. The energy transferred from the piston to the head was 0.07 J.Figure 1


Merging pathology with biomechanics using CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): a novel, surgery-free model of traumatic brain injury.

Namjoshi DR, Cheng WH, McInnes KA, Martens KM, Carr M, Wilkinson A, Fan J, Robert J, Hayat A, Cripton PA, Wellington CL - Mol Neurodegener (2014)

Head kinematics during rTBI. Head kinematic parameters during impacts were assessed in 8 mice subjected to rTBI. Data are represented as the means for each impact. (A) Head trajectory during the maximum acceleration phase in the sagittal plane following impact. (B) Head displacement-time graph following impact. (C) Head deflection is measured as the angle between the snout, side marker and the horizontal plane. Linear head velocity and linear head acceleration are depicted in (D) and (E), respectively. (F) and (G) show angular head velocity and angular acceleration, respectively. Data in (A) are represented as mean ± 95% CI in both X- and Y- direction, respectively. Data in B-G are represented as mean ± 95% CI. (H) Summary of peak values of kinematic parameters averaged across all 8 rTBI mice. The coefficient of variation (CV) was calculated as the average of day 1 and day 2 peak values from all available recordings.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig1: Head kinematics during rTBI. Head kinematic parameters during impacts were assessed in 8 mice subjected to rTBI. Data are represented as the means for each impact. (A) Head trajectory during the maximum acceleration phase in the sagittal plane following impact. (B) Head displacement-time graph following impact. (C) Head deflection is measured as the angle between the snout, side marker and the horizontal plane. Linear head velocity and linear head acceleration are depicted in (D) and (E), respectively. (F) and (G) show angular head velocity and angular acceleration, respectively. Data in (A) are represented as mean ± 95% CI in both X- and Y- direction, respectively. Data in B-G are represented as mean ± 95% CI. (H) Summary of peak values of kinematic parameters averaged across all 8 rTBI mice. The coefficient of variation (CV) was calculated as the average of day 1 and day 2 peak values from all available recordings.
Mentions: Analysis of high-speed videography (5,000 fps) was used to assess the biomechanical responses of the head in a group of 8 mice during CHIMERA rTBI at an impact energy of 0.5 J (Figure 1; peak kinematic parameters depicted in Figure 1H). Trajectories of the mouse head in the sagittal plane during peak acceleration following two impacts spaced at 24h are depicted in Figure 1A. Following vertical impact, the head followed a looped trajectory in the sagittal plane (Additional file 1: Figure S1, and Additional file 2: Movie S4). The average head trajectories following two repetitive TBIs in 8 mice were highly consistent (Figure 1A). The head traveled a peak linear displacement of 49.6 ± 3.5 mm (mean ± SD, same below) in 15.7 ± 2.4 ms (Figure 1B) and exhibited a peak angular deflection of 2.6 ± 0.28 rad in 24.8 ± 3.1 ms (Figure 1C). Peak linear velocity was 6.6 ± 0.8 m/s at 3.4 ± 1.0 ms (Figure 1D), and peak angular velocity was 305.8 ± 73.7 rad/s at 2.8 ± 1.9 ms following initial impactor contact (Figure 1F). The head experienced large linear and angular accelerations following impact, achieving peak linear acceleration of 385.3 ± 52 g at 1.5 ± 0.3 ms (Figure 1E), whereas the peak angular acceleration of 253.6 ± 69.0 krad/s2 was observed at 0.8 ± 1.1 ms (Figure 1G). As the head was stationary before impact, the change in head velocity (ΔV) equals peak head velocity and was found to be 6.6 m/s. The energy transferred from the piston to the head was 0.07 J.Figure 1

Bottom Line: Traumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment.Despite promising outcomes from many preclinical studies, clinical evaluations have failed to identify effective pharmacological therapies, suggesting that the translational potential of preclinical models may require improvement.Injured mouse brains also showed significantly increased levels of TNF-α and IL-1β and increased endogenous tau phosphorylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. wcheryl@mail.ubc.ca.

ABSTRACT

Background: Traumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment. Despite promising outcomes from many preclinical studies, clinical evaluations have failed to identify effective pharmacological therapies, suggesting that the translational potential of preclinical models may require improvement. Rodents continue to be the most widely used species for preclinical TBI research. As most human TBIs result from impact to an intact skull, closed head injury (CHI) models are highly relevant, however, traditional CHI models suffer from extensive experimental variability that may be due to poor control over biomechanical inputs. Here we describe a novel CHI model called CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) that fully integrates biomechanical, behavioral, and neuropathological analyses. CHIMERA is distinct from existing neurotrauma model systems in that it uses a completely non-surgical procedure to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement. In this study, we characterized head kinematics as well as functional, neuropathological, and biochemical outcomes up to 14d following repeated TBI (rTBI) in adult C57BL/6 mice using CHIMERA.

Results: Head kinematic analysis showed excellent repeatability over two closed head impacts separated at 24h. Injured mice showed significantly prolonged loss of righting reflex and displayed neurological, motor, and cognitive deficits along with anxiety-like behavior. Repeated TBI led to diffuse axonal injury with extensive microgliosis in white matter from 2-14d post-rTBI. Injured mouse brains also showed significantly increased levels of TNF-α and IL-1β and increased endogenous tau phosphorylation.

Conclusions: Repeated TBI using CHIMERA mimics many of the functional and pathological characteristics of human TBI with a reliable biomechanical response of the head. This makes CHIMERA well suited to investigate the pathophysiology of TBI and for drug development programs.

Show MeSH
Related in: MedlinePlus