Journal of neurotrauma
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Journal of neurotrauma · Oct 2023
Head Kinematics, Blood Biomarkers and Histology in Large Animal Models of Traumatic Brain Injury and Hemorrhagic Shock.
Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) are each leading causes of mortality and morbidity worldwide, and present additional treatment considerations when they are comorbid (TBI+HS) as a result of competing pathophysiological responses. The current study rigorously quantified injury biomechanics with high precision sensors and examined whether blood-based surrogate markers were altered in general trauma as well as post-neurotrauma. Eighty-nine sexually mature male and female Yucatan swine were subjected to a closed-head TBI+HS (40% of circulating blood volume; n = 68), HS only (n = 9), or sham trauma (n = 12). ⋯ GFAP and NfL were both strongly associated with changes in systemic markers during general trauma and exhibited consistent time-dependent changes in individual sham animals. Finally, circulating GFAP was associated with histopathological markers of diffuse axonal injury and blood-brain barrier breach, as well as variations in device kinematics following TBI+HS. Current findings therefore highlight the need to directly quantify injury biomechanics with head mounted sensors and suggest that GFAP, NfL, and UCH-L1 are sensitive to multiple forms of trauma rather than having a single pathological indication (e.g., GFAP = astrogliosis).
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Journal of neurotrauma · Oct 2023
Modelling the inflammatory response of traumatic brain injury using human induced pluripotent stem cell derived microglia.
The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. ⋯ Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, compared with astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.
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Journal of neurotrauma · Oct 2023
Regional Cortical Thickness Correlates of Intellectual Abilities Differ in Children with Traumatic Brain Injury versus Orthopedic Injury in the Chronic Post-Injury Phase.
A decline in intellectual functioning (intelligence quotient [IQ]) is often observed following more severe forms of traumatic brain injury (TBI) and is a useful index for long-term outcome. Identifying brain correlates of IQ can serve to inform developmental trajectories of behavior in this population. Using magnetic resonance imaging (MRI), we examined the relationship between intellectual abilities and patterns of cortical thickness in children with a history of TBI or with orthopedic injury (OI) in the chronic phase of injury recovery. ⋯ This suggests that the substrates of intellectual ability are particularly susceptible to acquired injury in the integrative association cortex. Longitudinal work is needed to account for normal developmental changes and to investigate how cortical thickness and intellectual functioning and their association change over time following TBI. Improved understanding of how TBI-related cortical thickness alterations relate to cognitive outcome could lead to improved predictions of outcome following brain injury.
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Journal of neurotrauma · Oct 2023
An MR elastography-based technique to assess the biomechanics of the skull-brain interface: repeatability and age-sex characteristics.
Increasing concerns have been raised about the long-term negative effects of subconcussive repeated head impact (RHI). To elucidate RHI injury mechanisms, many efforts have studied how head impacts affect the skull-brain biomechanics and have found that mechanical interactions at the skull-brain interface dampen and isolate brain motions by decoupling the brain from the skull. Despite intense interest, in vivo quantification of the functional state of the skull-brain interface remains difficult. ⋯ Except for the temporal lobe (p = 0.0087), there was no significant difference in NOSS between men and women. This work provides motivation for utilizing MRE as a non-invasive tool for quantifying the biomechanics of the skull-brain interface. It evaluated the age and sex dependence and may lead to a better understanding of the protective role and mechanisms of the skull-brain interface in RHI and TBI, as well as improve the accuracy of computational models in simulating the skull-brain interface.
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Journal of neurotrauma · Oct 2023
Fixed time point analysis reveals repetitive mild traumatic brain injury effects on resting state fMRI connectivity and neuro-spatial protein profiles.
Repetitive mild traumatic brain injuries (rmTBIs) are serious trauma events responsible for the development of numerous neurodegenerative disorders. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps of the molecular mechanisms responsible for neurodegeneration. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. ⋯ Our analyses revealed aberrant connectivity changes in the thalamus, independent of microstructural damage or neuroinflammation. We also identified distinct changes in the levels of proteins linked to various neurodegenerative processes including total and phospho-tau species and cell proliferation markers. Together, our data show that rmTBI significantly alters brain functional connectivity and causes distinct protein changes in morphologically intact brain areas.