Journal of neurotrauma
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Journal of neurotrauma · May 2019
Biophysical modeling suggests optimal drug combinations for improving the efficacy of GABA agonists after traumatic brain injuries.
Traumatic brain injuries (TBI) lead to dramatic changes in the surviving brain tissue. Altered ion concentrations, coupled with changes in the expression of membrane-spanning proteins, create a post-TBI brain state that can lead to further neuronal loss caused by secondary excitotoxicity. Several GABA receptor agonists have been tested in the search for neuroprotection immediately after an injury, with paradoxical results. ⋯ The likelihood of prolonged, excitotoxic depolarization block is further exacerbated by the extremely high levels of extracellular potassium seen after TBI. Our modeling results predict that the neuroprotective efficacy of GABA receptor agonists can be substantially enhanced when they are combined with NKCC1 co-transporter inhibitors. This suggests a rational, biophysically principled method for identifying drug combinations for neuroprotection after TBI.
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Journal of neurotrauma · May 2019
Rapid Repeat Exposure to Subthreshold Trauma Causes Synergistic Axonal Damage and Functional Deficits in the Visual Pathway in a Mouse Model.
We examined the effect of repeat exposure to a non-damaging insult on central nervous system axons using the optic projection as a model. The optic projection is attractive because its axons are spatially separated from the cell bodies, it is easily accessible, it is composed of long axons, and its function can be measured. We performed closed-system ocular neurotrauma in C57Bl/6 mice using bursts of 15 or 26-psi (pounds per square inch) overpressure air that caused no gross damage. ⋯ Therefore, repeat mild trauma within an interinjury interval of 1 min or less causes synergistic axon damage, whereas mild trauma repeated at a longer interinjury interval causes additive, cumulative damage. The synergistic damage may underlie the high incidence of traumatic brain injury and traumatic optic neuropathy in blast-injured service members given that explosive blasts are multiple injury events that occur in a very short time span. This study also supports the use of the VEP as a biomarker for traumatic optic neuropathy.
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Journal of neurotrauma · May 2019
Headache trigger sensitivity and avoidance after mild traumatic brain injury.
Most patients with primary headache disorders identify environmental stimuli (e.g., visual glare), situational factors (e.g., stress), physiological states (e.g., hormones), or activities (e.g., exercise) as triggers that elicit or worsen headache episodes. Headache triggers have not been previously studied in post-traumatic headache (PTH). The present study explored the frequency of headache triggers and their avoidance in PTH. ⋯ Headache severity was more associated with trigger sensitivity [F(2,49) = 13.45, p < 0.001] than trigger avoidance [F(2,47) = 2.97, p = 0.062]. In summary, the pattern of headache triggers in persistent PTH after mild TBI appears somewhat different from that in primary headache disorders, with mental exertion emerging as uniquely important. Pervasive avoidance of mental exertion to prevent headaches (cogniphobia) might be a worthwhile behavioral intervention target after mild TBI.
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Journal of neurotrauma · May 2019
Evaluating Cerebrovascular Reactivity during the Early Symptomatic Phase of Sport Concussion.
Cerebrovascular reactivity (CVR) indexes the ability of blood vessels to respond to vasoactive stimuli and may be a sensitive biomarker of concussion. However, alterations in whole-brain CVR remain poorly understood during the early symptomatic phase of injury. In this study, CVR was assessed using blood-oxygenation-level dependent functional magnetic resonance imaging (BOLD fMRI) combined with a respiratory challenge paradigm; resting cerebral blood flow (CBF) was also evaluated using arterial spin labeling (ASL). ⋯ In addition, greater symptom severity was associated with greater reductions in BOLD response, with effects distributed throughout the brain. This study establishes fMRI with respiratory challenge as a robust method for assessing acute concussion-related alterations in CVR. Moreover, it highlights the importance of examining neurovascular response to physiological stressors after a concussion.
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Journal of neurotrauma · May 2019
Proteomic Analysis and Biochemical Correlates of Mitochondrial Dysfunction following Low-Intensity Primary Blast Exposure.
Service members during military actions or combat training are frequently exposed to primary blasts by weaponry. Most studies have investigated moderate or severe brain injuries from blasts generating overpressures >100 kPa, whereas understanding the pathophysiology of low-intensity blast (LIB)-induced mild traumatic brain injury (mTBI) leading to neurological deficits remains elusive. Our recent studies, using an open-field LIB-induced mTBI mouse model with a peak overpressure at 46.6 kPa, demonstrated behavioral impairments and brain nanoscale damages, notably mitochondrial and axonal ultrastructural changes. ⋯ With observations of proteomic changes, we found LIB-induced oxidative stress associated with mitochondrial dysfunction mainly at 7 and 30 DPI. These dysfunctions included impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated respiration-relevant enzyme activities. Insights on the early pathogenesis of primary LIB-induced brain damage provide a template for further characterization of its chronic effects, identification of potential biomarkers, and targets for intervention.