Paper 1) Bayly, Philip V et al. “In vivo imaging of rapid deformation and strain in an animal model of traumatic brain injury.” Journal of biomechanics vol. 39,6 (2006): 1086-95.
This study aimed to quantify the rapid deformation of brain tissue in traumatic brain injury (TBI) by estimating strain fields in the perinatal rat brain. The researchers used magnetic resonance (MR) images obtained during and after rapid indentation to obtain high spatial and temporal resolution images. The strain fields were estimated using harmonic phase (HARP) analysis, which was then filtered and Fourier-transformed to obtain HARP images. The study found maximum principal Lagrangian strains of >0.20 at strain rates >40/s during indentations of 2 mm depth and 21 ms duration. This approach will help with quantitative information on strain levels experienced in single impacts.
Paper 2) Bennett, Rachel E et al. “Diffusion tensor imaging detects axonal injury in a mouse model of repetitive closed-skull traumatic brain injury.” Neuroscience letters vol. 513,2 (2012): 160-5.
The study demonstrates that diffusion tensor imaging (DTI) is a sensitive method for detecting axonal injury in mice, despite the absence of conventional APP pathology. At 7 days, axial and mean diffusivity reduced, and mean diffusivity was elevated in the ipsilateral cortex. Essentially this study shows that the impacts of a concussion continue to worsen parts of the brain. This highlights the need to better understand the histological basis for DTI signal changes in mild repetitive closed-skull brain injury. I can relate this to my topic because, we need to be able to see signal changes when children come in with a concussion.
Paper 3) Bolton Hall, Amanda N et al. “Repeated Closed Head Injury in Mice Results in Sustained Motor and Memory Deficits and Chronic Cellular Changes.” PloS one vol. 11,7 e0159442 (2016).
This study looked at behavioral differences when a repeated concussion was induced. They looked at beam walking, novel object recognition, and gaits. These behaviors represent behaviors that humans have difficulty with when diagnosed with a TBI. They found that even after 10 weeks, the mice that sustained repeated head injury had a deficit in motor function. They conclude by saying that, longer studies need to occur for us to understand how the injuries will change over time.
Paper 4) Clevenger, Amy C et al. “Carotid artery blood flow decreases after rapid head rotation in piglets.” Journal of neurotrauma vol. 32,2 (2015):120-6.
This study looks at carotid arteries because it is a major source of cerebral blood flow. Backround knowledge is that a low CBF is common in pediatric sTBI. The researchers wanted to make sure that the blood flow would decrease after the head rotation without spine injury. This study used 4-week-old piglets and the underwent a head rotation that produces diffuse TBI. They found that the decrease in blood flow is rapid and persistent over the first hour. This supports the idea that timing of treatment is crucial in children with TBIs. This study can also help shed light on other parts of CBF because the study did not look for a correlation between CBF and Carotid artery blood flow.
Paper 5) Cole, Jeffrey T et al. “Craniotomy: true sham for traumatic brain injury, or a sham of a sham?.” Journal of neurotrauma vol. 28,3 (2011): 359-69.
The study involved 38 adult female rats found that both manual trephine and electric dental drill methods resulted in visible MRI lesions that persist for 14 days. The drill technique caused significantly larger initial lesions and impaired sensory and motor responses. Additionally, cytokines KC-GRO and IFN-γ increased significantly in both craniotomy models compared to naïve rats. The study concluded that traditional sham operations cause significant proinflammatory damage which can complicate the interpretation of brain injury models. Therefore, when looking at sham, one has to remember that mocking the model is still invasive.
Paper 6) Creeley, Catherine E et al. “Multiple episodes of mild traumatic brain injury result in impaired cognitive performance in mice.” Academic emergency medicine : official journal of the Society for Academic Emergency Medicine vol. 11,8 (2004): 809-19.
This study aimed to determine how these parameters relate to transient loss of consciousness, cognitive deficits, and potential neuropathologic effects in mice. Seven-week-old male C57BL/6 mice were randomly assigned to experimental conditions involving three impacts to the head to induce mild traumatic brain injury or to sham control procedures. The mean force of impact was 19 (63.5) N, and impacted mice took longer to regain consciousness compared to sham control mice. They also exhibited impaired spatial learning performance during place trials in the Morris water maze. The study concluded that this multiple-impact model results in transient, reversible loss of consciousness, a contra-coup brain injury, and cognitive impairment.
Paper 7) Duhaime, Ann-Christine. "Large Animal Models of Traumatic Injury to the Immature Brain." Developmental neuroscience, vol. 28, no. 4-5, (2006), pp. 380-7.
This paper shows how large animal models can actually be more helpful when looking at TBI in children because larger animals tend to develop slower which means they are more similar to a human child. This paper specifically talks about using pigs as an animal model of pediatric TBIs because although it is more expensive than smaller animals, we do not have a lot of information on the behavioral effects to TBI before the brain is fully developed. Since researchers are limited to hospital records for humans, it makes more sense to use an animal model that can show some similarities. However, there is something to be said about the ethics of inflicting a concussion on a pig versus a rodent. Ergo, the majority of studies use rodents but, using pigs could be more helpful.
Paper 8) Fijalkowski, Ronald J et al. “New rat model for diffuse brain injury using coronal plane angular acceleration.” Journal of neurotrauma vol. 24,8 (2007): 1387-98.
A new experimental model has been developed to induce diffuse brain injury (DBI) in rats through pure coronal plane angular acceleration. The model was created to protect the rat when they are induced with a concussion. Twenty-six rats were subjected to peak angular accelerations, resulting in a short period of unconsciousness which lasted 8.8+/- 3.7 min. Macroscopic damage was noted in 51% of animals, with 38% subarachnoid hemorrhage and 15% intraparenchymal lesion. Microscopic analysis showed no evidence of axonal swellings at sacrifice times of up to 4 days. All rats survived rotational loading without skull fracture. This study will be helpful when trying to figure out how to protect the head of the rat because I want to study the rats for a longer period of time.
Paper 9) Friess, Stuart H et al. “Repeated traumatic brain injury affects composite cognitive function in piglets.” Journal of neurotrauma vol. 26,7 (2009): 1111-21.
This paper inflicted TBIs on 3-5-day-old piglets to see what cognitive dysfunction will occur. This study was done because there is not a lot of information on repetitive mTBI in pediatric literature. The white matter injuries in piglets are more similar to humans than rodents. This study required the pigs to go through a T-maze test which also tests the novel object task. The study euthanized the pigs on the 12th day after the last head injury. If the pigs were unable to feed and ambulate, they were euthanized. This paper is helpful in deciding when to euthanize the animal because they wanted to see the development of the white matter.
Paper 10) Friess, Stuart H et al. “Differing effects when using phenylephrine and norepinephrine to augment cerebral blood flow after traumatic brain injury in the immature brain.” Journal of neurotrauma vol. 32,4 (2015): 237-43.
This study was done because in children inflicted with a TBI can have low cerebral blood flow and increases the mortality rate. This study found that giving phenylephrine to the pigs significantly increases the cerebral blood flow. They believe that this could be applied to a clinical setting in the ICU is they use an opioid-benzodiazepine-based anesthetic. This is because it is more volatile and volatile anesthetics have cerebral autoregulation effects as well as neuroprotection. However, volatile an opiod-based drugs may not be the best thing for an infant.
Paper 11) Kallakuri, Srinivasu et al. “The effect of varying impact energy on diffuse axonal injury in the rat brain: a preliminary study.” Experimental brain research vol. 148,4 (2003): 419-24.
Diffuse axonal injury (DAI) is a brain injury characterized by morphological changes in axons. This study investigated the impact energy on DAI in the corpus callosum (CC) of adult male Sprague-Dawley rats. The rats were induced with a brass weight dropped from different heights, and their brains were sectioned and stained with silver impregnation. The CC showed DAI in the form of beaded axons, retraction balls, and vacuole-like enlargements. The severity of the injury was highest in the 2-m group, while the 1-m group was mildest. The data will be useful for figuring out how much force is required for the rat brains.
Paper 12) Kilbourne, Michael et al. “Novel model of frontal impact closed head injury in the rat.” Journal of neurotrauma vol. 26,12 (2009): 2233-43
This study investigated the impact energy on DAI in the frontal lobe of adult male Sprague-Dawley rats. The rats were induced with a brass weight dropped from different heights, and their brains were sectioned and stained with silver impregnation. The scans showed DAI in the form of beaded axons, retraction balls, and vacuole-like enlargements. Regions affected including the orbitofrontal cortex (coup), corpus callosum, caudate, putamen, thalamus, cerebellum, and brainstem. The Maryland model offers unique pathophysiological features not encountered in previous models of closed head injury. This can be useful when choosing where I want to inflict brain trauma.
Paper 13) Oeur, Anna et al. “Altered Auditory and Visual Evoked Potentials following Single and Repeated Low-Velocity Head Rotations in 4-Week-Old Swine.” Biomedicines vol. 11,7 1816. (2023).
This paper looked at the auditory and visual evoked potentials in 4 week old pigs to see cognitive changes after a TBI. The reason this study was done is because auditory and visual dysfunctions are common in children who sustain a TBI. This study looked at the changes within a week. They found that the anaesthesia had an effect of corticol activations and only the auditory stimuli decreased after anaesthesia. The visual evoked potentials remained unaffected which mimics humans. This also shows the similarity between humans and pigs.
Paper 14) Smith, Douglas H., Masahiro Nonaka, Reid Miller, Matthew Leoni, Xiao-Han Chen, David Alsop, and David F. Meaney. "Immediate coma following inertial brain injury dependent on axonal damage in the brainstem". Journal of Neurosurgery 93.2 (2000): 315-322.
The study involved 38 adult female rats who underwent craniotomy performed by manual trephine or electric dental drill. The results showed that inertial loading applied to the heads of pigs along either the coronal or axial plane induced diffuse axonal injury (DAI) throughout the white matter. However, immediate and persistent coma was only observed in animals injured by head axial plane rotation. The study suggests that coma may be more of a reflection of the severity of axonal damage in specific regions, most notably the brainstem, rather than the total sum of axonal injury distributed throughout the brain. This is helpful because that means I do not necessarily need to induce a coma when doing the research.
Paper 15) To, Xuan Vinh, and Fatima A Nasrallah. “A roadmap of brain recovery in a mouse model of concussion: insights from neuroimaging.” Acta neuropathologica communications vol. 9, 2 (2021).
This study looked at a multi-modal examination in behavioral and brain changes using MRI and fMRI. When it came to behavioral changes, they found that motor-balance deficits were significant following a single TBI and the deficits were fully recovered by 14 days. They also used the open field test and found that the mice would spend more time in the centre but after 14 days they went back to typical behavior. They also found anxiety like behaviors (with the open field task) only lasted a week (while recoving). They also found structural imaging similar to humans: there was enlargment in the ventricles. They conclude that this study has important implications for clinical settings especially with the behavioral assessment.