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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.

SUBMITTER: Bodnar CN

PROVIDER: S-EPMC6555186 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Bodnar Colleen N CN Roberts Kelly N KN Higgins Emma K EK Bachstetter Adam D AD

Journal of neurotrauma 20190306 11

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 t ...[more]

PMID: 30661454

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Project description:BackgroundIndividuals who have experienced mild traumatic brain injuries (mTBIs) suffer from several comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated chronic pain, the role of inflammation in long-term pain after mTBIs is not fully elucidated. Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes in inflammatory processes following mTBIs and their effects on TBI-related pain.MethodsWe utilized a recently developed transgenic caspase-1 luciferase reporter mouse model to monitor caspase-1 activation through a thinned skull window in the in vivo setting following three closed-head mTBI events. Organotypic coronal brain slice cultures and acutely dissociated dorsal root ganglion (DRG) cells provided tissue-relevant context of inflammation signal. Mechanical allodynia was assessed by mechanical withdrawal threshold to von Frey and thermal hyperalgesia withdrawal latency to radiant heat. Mouse grimace scale (MGS) was used to detect spontaneous or non-evoked pain. In some experiments, mice were prophylactically treated with MCC950, a potent small molecule inhibitor of NLRP3 inflammasome assembly to inhibit injury-induced inflammatory signaling. Bioluminescence spatiotemporal dynamics were quantified in the head and hind paws, and caspase-1 activation was confirmed by immunoblot. Immunofluorescence staining was used to monitor the progression of astrogliosis and microglial activation in ex vivo brain tissue following repetitive closed-head mTBIs.ResultsMice with repetitive closed-head mTBIs exhibited significant increases of the bioluminescence signals within the brain and paws in vivo for at least one week after each injury. Consistently, immunoblotting and immunofluorescence experiments confirmed that mTBIs led to caspase-1 activation, astrogliosis, and microgliosis. Persistent changes in MGS and hind paw withdrawal thresholds, indicative of pain states, were observed post-injury in the same mTBI animals in vivo. We also observed enhanced inflammatory responses in ex vivo brain slice preparations and DRG for at least 3 days following mTBIs. In vivo treatment with MCC950 significantly reduced caspase-1 activation-associated bioluminescent signals in vivo and decreased stimulus-evoked and non-stimulus evoked nociception.ConclusionsOur findings suggest that the inflammatory states in the brain and peripheral nervous system following repeated mTBIs are coincidental with the development of nociceptive sensitization, and that these events can be significantly reduced by inhibition of NLRP3 inflammasome activation.

Project description:The underlying pathophysiology of paediatric mild traumatic brain injury and the time-course for biological recovery remains widely debated, with clinical care principally informed by subjective self-report. Similarly, clinical evidence indicates that adolescence is a risk factor for prolonged recovery, but the impact of age-at-injury on biomarkers has not been determined in large, homogeneous samples. The current study collected diffusion MRI data in consecutively recruited patients (n = 203; 8-18 years old) and age and sex-matched healthy controls (n = 170) in a prospective cohort design. Patients were evaluated subacutely (1-11 days post-injury) as well as at 4 months post-injury (early chronic phase). Healthy participants were evaluated at similar times to control for neurodevelopment and practice effects. Clinical findings indicated persistent symptoms at 4 months for a significant minority of patients (22%), along with residual executive dysfunction and verbal memory deficits. Results indicated increased fractional anisotropy and reduced mean diffusivity for patients, with abnormalities persisting up to 4 months post-injury. Multicompartmental geometric models indicated that estimates of intracellular volume fractions were increased in patients, whereas estimates of free water fractions were decreased. Critically, unique areas of white matter pathology (increased free water fractions or increased neurite dispersion) were observed when standard assumptions regarding parallel diffusivity were altered in multicompartmental models to be more biologically plausible. Cross-validation analyses indicated that some diffusion findings were more reproducible when ∼70% of the total sample (142 patients, 119 controls) were used in analyses, highlighting the need for large-sample sizes to detect abnormalities. Supervised machine learning approaches (random forests) indicated that diffusion abnormalities increased overall diagnostic accuracy (patients versus controls) by ∼10% after controlling for current clinical gold standards, with each diffusion metric accounting for only a few unique percentage points. In summary, current results suggest that novel multicompartmental models are more sensitive to paediatric mild traumatic brain injury pathology, and that this sensitivity is increased when using parameters that more accurately reflect diffusion in healthy tissue. Results also indicate that diffusion data may be insufficient to achieve a high degree of objective diagnostic accuracy in patients when used in isolation, which is to be expected given known heterogeneities in pathophysiology, mechanism of injury and even criteria for diagnoses. Finally, current results indicate ongoing clinical and physiological recovery at 4 months post-injury.

Project description:Background: Mild traumatic brain injury (mTBI) results from an external force to the head or body causing neurophysiological changes within the brain. The number and severity of symptoms can vary, with some individuals experiencing rapid recovery, and others having persistent symptoms for months to years, impacting their quality of life. Current rehabilitation is limited in its ability to treat persistent symptoms and novel approaches are being sought to improve outcomes following mTBI. Neuromodulation is one technique used to encourage adaptive neuroplasticity within the brain. Objective: To systematically review the literature on the efficacy of neuromodulation in the mTBI population. Method: A systematic review was conducted using Medline, Embase, PsycINFO, PsycARTICLES and EBM Review. Preferred Reporting Items for Systematic Reviews and the Synthesis Without Meta-analysis reporting guidelines were used and a narrative review of the selected studies was completed. Fourteen articles fulfilled the inclusion criteria which were published in English, investigating an adult sample and using a pre- and post-intervention design. Studies were excluded if they included non-mild TBI severities, pediatric or older adult populations. Results: Thirteen of fourteen studies reported positive reductions in mTBI symptomatology following neuromodulation. Specifically, improvements were reported in post-concussion symptom ratings, headaches, dizziness, depression, anxiety, sleep disturbance, general disability, cognition, return to work and quality of life. Normalization of working memory activation patterns, vestibular field potentials, hemodynamics of the dorsolateral prefrontal cortex and excessive delta wave activity were also seen. The studies reviewed had several methodological limitations including small, heterogenous samples and varied intervention protocols, limiting generalisability. Further research is required to understand the context in which neuromodulation may be beneficial. Conclusions: While these positive effects are observed, limitations included unequal representation of neuromodulation modalities in the literature, and lack of literature describing the efficacy of neuromodulation on the development or duration of persistent mTBI symptoms. Better clarity regarding neuromodulation efficacy could have a significant impact on mTBI patients, researchers, clinicians, and policy makers, facilitating a more productive post-mTBI population. Despite the limitations, the literature indicates that neuromodulation warrants further investigation. PROSPERO registration number: CRD42020161279.

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

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

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