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Traumatic brain injury (TBI) is a key contributor to global morbidity that lacks effective treatments. Microbial infections are common in TBI patients, and their presence could modify the physiological response to TBI. It is estimated that one-third of the human population is incurably infected with the feline-borne parasite, Toxoplasma gondii, which can invade the central nervous system and result in chronic low-grade neuroinflammation, oxidative stress, and excitotoxicity-all of which are also important pathophysiological processes in TBI. Considering the large number of TBI patients that have a pre-existing T. gondii infection prior to injury, and the potential mechanistic synergies between the conditions, this study investigated how a pre-existing T. gondii infection modified TBI outcomes across acute, sub-acute and chronic recovery in male and female mice. Gene expression analysis of brain tissue found that neuroinflammation and immune cell markers were amplified in the combined T. gondii + TBI setting in both males and females as early as 2-h post-injury. Glutamatergic, neurotoxic, and oxidative stress markers were altered in a sex-specific manner in T. gondii + TBI mice. Structural MRI found that male, but not female, T. gondii + TBI mice had a significantly larger lesion size compared to their uninfected counterparts at 18-weeks post-injury. Similarly, diffusion MRI revealed that T. gondii + TBI mice had exacerbated white matter tract abnormalities, particularly in male mice. These novel findings indicate that a pre-existing T. gondii infection affects the pathophysiological aftermath of TBI in a sex-dependent manner, and may be an important modifier to consider in the care and prognostication of TBI patients., (© 2024. The Author(s).)

Research in severe traumatic brain injury (TBI) has historically been limited by studies with relatively small sample sizes that result in low power to detect small, yet clinically meaningful outcomes. Data sharing and integration from existing sources hold promise to yield larger more robust sample sizes that improve the potential signal and generalizability of important research questions. However, curation and harmonization of data of different types and of disparate provenance is challenging. We report our approach and experience integrating multiple TBI data sets containing collected physiological data, including both expected and unexpected challenges encountered in the integration process. Our harmonized data set included data on 1536 patients from the Citicoline Brain Injury Treatment Trial (COBRIT), Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial (EPO Severe TBI), BEST-TRIP, Progesterone for the Treatment of Traumatic Brain Injury III Clinical Trial (ProTECT III), Transforming Research and Clinical Knowledge in Traumatic brain Injury (TRACK-TBI), Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II (BOOST-2), and Ben Taub General Hospital (BTGH) Research Database studies. We conclude with process recommendations for data acquisition for future prospective studies to aid integration of these data with existing studies. These recommendations include using common data elements whenever possible, a standardized recording system for labeling and timing of high-frequency physiological data, and secondary use of studies in systems such as Federal Interagency Traumatic Brain Injury Research Informatics System (FITBIR), to engage investigators who collected the original data.

Background: Intracranial pressure (ICP) monitoring is widely practiced, but the indications are incompletely developed, and guidelines are poorly followed., Objective: To study the monitoring practices of an established expert panel (the clinical working group from the Seattle International Brain Injury Consensus Conference effort) to examine the match between monitoring guidelines and their clinical decision-making and offer guidance for clinicians considering monitor insertion., Methods: We polled the 42 Seattle International Brain Injury Consensus Conference panel members' ICP monitoring decisions for virtual patients, using matrices of presenting signs (Glasgow Coma Scale [GCS] total or GCS motor, pupillary examination, and computed tomography diagnosis). Monitor insertion decisions were yes, no, or unsure (traffic light approach). We analyzed their responses for weighting of the presenting signs in decision-making using univariate regression., Results: Heatmaps constructed from the choices of 41 panel members revealed wider ICP monitor use than predicted by guidelines. Clinical examination (GCS) was by far the most important characteristic and differed from guidelines in being nonlinear. The modified Marshall computed tomography classification was second and pupils third. We constructed a heatmap and listed the main clinical determinants representing 80% ICP monitor insertion consensus for our recommendations., Conclusion: Candidacy for ICP monitoring exceeds published indicators for monitor insertion, suggesting the clinical perception that the value of ICP data is greater than simply detecting and monitoring severe intracranial hypertension. Monitor insertion heatmaps are offered as potential guidance for ICP monitor insertion and to stimulate research into what actually drives monitor insertion in unconstrained, real-world conditions., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Primary Objective: This study characterized the acute and chronic effects of tau reduction in traumatic brain injury (TBI)., Research Design: A fluid percussion injury (FPI) or a sham-injury was administered to wild type (WT) or tau knockout (Tau-/-) mice. Mice were assigned to a one-week or twelve-week recovery period before behavioral testing and analysis of brain tissue., Methods and Procedures: Mice were tested on the elevated-plus maze, the Y-maze, and rotarod. The twelve-week recovery mice underwent in vivo MRI. Phosphorylated tau in brain tissue was analyzed post-mortem using western blots., Main Outcomes and Results: FPI mice, regardless of genotype, had abnormalities on the elevated-plus maze (a task to assess anxiety-like behavior) at one-week post-injury. However, after twelve-weeks recovery, the Tau-/- mice that were given an FPI were less anxious and had improved motor function compared to their WT counterparts. MRI analysis found that while all FPI mice had brain damage, the Tau-/- mice had larger hippocampal volumes. The WT+FPI mice also had increased phosphorylated tau compared to WT+sham mice at both the one-week and twelve-week recovery times., Conclusion: These findings suggest that tau may play an important role in some of the consequences of TBI, particularly the long-term functional deficits.

Introduction: There is no widely used method for communicating the possible need for surgical intervention in patients with traumatic brain injury (TBI). This study describes a scoring system designed to communicate the potential need for surgical decompression in TBI patients. The scoring system, named the Surgical Intervention for Traumatic Injury (SITI), was designed to be objective and easy to use., Methods: The SITI scale uses radiographic and clinical findings, including the Glasgow Coma Scale Score, pupil examination, and findings noted on computed tomography. To examine the scale, we used the patient database for the Progesterone for the Treatment of Traumatic Brain Injury III (ProTECT III) trial, and retrospectively applied the SITI scale to these patients., Results: Of the 871 patients reviewed, 164 (18.8%) underwent craniotomy or craniectomy, and 707 (81.2%) were treated nonoperatively. The mean SITI score was 5.1 for patients who underwent surgery and 2.5 for patients treated nonoperatively (P<0.001). The area under the receiver operating characteristic curve was 0.887., Conclusion: The SITI scale was designed to be a simple, objective, clinical decision tool regarding the potential need for surgical decompression after TBI. Application of the SITI scale to the ProTECT III database demonstrated that a score of 3 or more was well associated with a perceived need for surgical decompression. These results further demonstrate the potential utility of the SITI scale in clinical practice., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

Background: Fetal growth restriction (FGR) is a serious pregnancy complication associated with increased risk of adverse neurodevelopment and neuromorbidity. Current imaging techniques, including conventional magnetic resonance imaging (MRI), are not sensitive enough to detect subtle structural abnormalities in the FGR brain. We examined whether advanced MRI analysis techniques have the capacity to detect brain injury (particularly white matter injury) caused by chronic hypoxia-induced fetal growth restriction in newborn preterm lambs., Methods: Surgery was undertaken in twin bearing pregnant ewes at 88-90 days gestation (term = 150 days) to induce FGR in one fetus. At 127 days gestation (~32 weeks human brain development), FGR and control (appropriate for gestational age, AGA) lambs were delivered by caesarean section, intubated and ventilated. Conventional and advanced brain imaging was conducted within the first two hours of life using a 3T MRI scanner. T1-weighted (T1w) and T2-weighted (T2w) structural imaging, magnetic resonance spectroscopy (MRS), and diffusion MRI (dMRI) data were acquired. Diffusion tensor imaging (DTI) modelling and analysis of dMRI data included the following regions of interest (ROIs): subcortical white matter, periventricular white matter, cerebellum, hippocampus, corpus callosum and thalamus. Fixel-based analysis of 3-tissue constrained spherical deconvolution (CSD) of the dMRI data was performed and compared between FGR and AGA lambs. Lambs were euthanised immediately after the scans and brain histology performed in the regions of interest to correlate with imaging., Results: FGR and AGA lamb (body weight, mean (SD): 2.2(0.5) vs. 3.3(0.3) kg, p = .002) MRI brain scans were analysed. There were no statistically significant differences observed between the groups in conventional T1w, T2w or MRS brain data. Mean, axial and radial diffusivity, and fractional anisotropy indices obtained from DTI modelling also did not show any statistically significant differences between groups in the ROIs. Fixel-based analysis of 3-tissue CSD, however, did reveal a decrease in fibre cross-section (FC, p < .05) but not in fibre density (FD) or combined fibre density and cross-section (FDC) in FGR vs. AGA lamb brains. The specific tracts that showed a decrease in FC were in the regions of the periventricular white matter, hippocampus and cerebellar white matter, and were supported by histological evidence of white matter hypomyelination and disorganisation in corresponding FGR lamb brain regions., Conclusions: The neuropathology associated with FGR in neonatal preterm lambs is subtle and imaging detection may require advanced MRI and tract-based analysis techniques. Fixel-based analysis of 3-tissue CSD demonstrates that the preterm neonatal FGR brain shows evidence of macrostructural (cross-sectional) deficits in white matter subsequent to altered antenatal development. These findings can inform analysis of similar brain pathology in neonatal infants., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The frequency of head computed tomography (CT) imaging for mild head trauma patients has raised safety and cost concerns. Validated clinical decision rules exist in the published literature and on-line sources to guide medical image ordering but are often not used by emergency department (ED) clinicians. Using simulation, we explored whether the presentation of a clinical decision rule (i.e. Canadian CT Head Rule - CCHR), findings from malpractice cases related to clinicians not ordering CT imaging in mild head trauma cases, and estimated patient out-of-pocket cost might influence clinician brain CT ordering. Understanding what type and how information may influence clinical decision making in the ordering advanced medical imaging is important in shaping the optimal design and implementation of related clinical decision support systems., Methods: Multi-center, double-blinded simulation-based randomized controlled trial. Following standardized clinical vignette presentation, clinicians made an initial imaging decision for the patient. This was followed by additional information on decision support rules, malpractice outcome review, and patient cost; each with opportunity to modify their initial order. The malpractice and cost information differed by assigned group to test the any temporal relationship. The simulation closed with a second vignette and an imaging decision., Results: One hundred sixteen of the 167 participants (66.9%) initially ordered a brain CT scan. After CCHR presentation, the number of clinicians ordering a CT dropped to 76 (45.8%), representing a 21.1% reduction in CT ordering (P = 0.002). This reduction in CT ordering was maintained, in comparison to initial imaging orders, when presented with malpractice review information (p = 0.002) and patient cost information (p = 0.002). About 57% of clinicians changed their order during study, while 43% never modified their imaging order., Conclusion: This study suggests that ED clinician brain CT imaging decisions may be influenced by clinical decision support rules, patient out-of-pocket cost information and findings from malpractice case review., Trial Registration: NCT03449862 , February 27, 2018, Retrospectively registered.

Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8- to 10-week-old male C57BL/6J WT and IFNAR1(-/-) mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1(-/-) mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1(-/-) mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNFα, IL-1β and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI.

Background: Repeated mild traumatic brain injuries, such as concussions, may result in cumulative brain damage, neurodegeneration and other chronic neurological impairments. There are currently no clinically available treatment options known to prevent these consequences. However, growing evidence implicates neuroinflammation and oxidative stress in the pathogenesis of repetitive mild brain injuries; thus, these may represent potential therapeutic targets. Progesterone has been demonstrated to have potent anti-inflammatory and anti-oxidant properties after brain insult; therefore, here, we examined progesterone treatment in rats given repetitive mild brain injuries via the repeated mild fluid percussion injury model., Methods: Male Long-Evans rats were assigned into four groups: sham injury + vehicle treatment, sham injury + progesterone treatment (8 mg/kg/day), repeated mild fluid percussion injuries + vehicle treatment, and repeated mild fluid percussion injuries + progesterone treatment. Rats were administered a total of three injuries, with each injury separated by 5 days. Treatment was initiated 1 h after the first injury, then administered daily for a total of 15 days. Rats underwent behavioural testing at 12-weeks post-treatment to assess cognition, motor function, anxiety and depression. Brains were then dissected for analysis of markers for neuroinflammation and oxidative stress. Ex vivo MRI was conducted in order to examine structural brain damage and white matter integrity., Results: Repeated mild fluid percussion injuries + progesterone treatment rats showed significantly reduced cognitive and sensorimotor deficits compared to their vehicle-treated counterparts at 12-weeks post-treatment. Progesterone treatment significantly attenuated markers of neuroinflammation and oxidative stress in rats given repeated mild fluid percussion injuries, with concomitant reductions in grey and white matter damage as indicated by MRI., Conclusions: These findings implicate neuroinflammation and oxidative stress in the pathophysiological aftermath of mild brain injuries and suggest that progesterone may be a viable treatment option to mitigate these effects and their detrimental consequences.

Traumatic brain injury (TBI) is a leading cause of death worldwide. In recent studies, we have shown that experimental TBI caused an immediate (24-h post) suppression of neuronal processing, especially in supragranular cortical layers. We now examine the long-term effects of experimental TBI on the sensory cortex and how these changes may contribute to a range of TBI morbidities. Adult male Sprague-Dawley rats received either a moderate lateral fluid percussion injury (n=14) or a sham surgery (n=12) and 12 weeks of recovery before behavioral assessment, magnetic resonance imaging, and electrophysiological recordings from the barrel cortex. TBI rats demonstrated sensorimotor deficits, cognitive impairments, and anxiety-like behavior, and this was associated with significant atrophy of the barrel cortex and other brain structures. Extracellular recordings from ipsilateral barrel cortex revealed normal neuronal responsiveness and diffusion tensor MRI showed increased fractional anisotropy, axial diffusivity, and tract density within this region. These findings suggest that long-term recovery of neuronal responsiveness is owing to structural reorganization within this region. Therefore, it is likely that long-term structural and functional changes within sensory cortex post-TBI may allow for recovery of neuronal responsiveness, but that this recovery does not remediate all behavioral deficits.

Multitrauma is a common medical problem worldwide, and often involves concurrent traumatic brain injury (TBI) and bone fracture. Despite the high incidence of combined TBI and fracture, preclinical TBI research commonly employs independent injury models that fail to incorporate the pathophysiologic interactions occurring in multitrauma. Here, we developed a novel mouse model of multitrauma, and investigated whether bone fracture worsened TBI outcomes. Male mice were assigned into four groups: sham-TBI+sham-fracture (SHAM); sham-TBI+fracture (FX); TBI+sham-fracture (TBI); and TBI+fracture (MULTI). The injury methods included a closed-skull weight-drop TBI model and a closed tibial fracture. After a 35-day recovery, mice underwent behavioral testing and magnetic resonance imaging (MRI). MULTI mice displayed abnormal behaviors in the open-field compared with all other groups. On MRI, MULTI mice had enlarged ventricles and diffusion abnormalities compared with all other groups. These changes occurred in the presence of heightened neuroinflammation in MULTI mice at 24 hours and 35 days after injury, and elevated edema and blood-brain barrier disruption at 24 hours after injury. Together, these findings indicate that tibial fracture worsens TBI outcomes, and that exacerbated neuroinflammation may be an important factor that contributes to these effects, which warrants further investigation.

Traumatic brain injury is a common and serious neurodegenerative condition that lacks a pharmaceutical intervention to improve long-term outcome. Hyperphosphorylated tau is implicated in some of the consequences of traumatic brain injury and is a potential pharmacological target. Protein phosphatase 2A is a heterotrimeric protein that regulates key signalling pathways, and protein phosphatase 2A heterotrimers consisting of the PR55 B-subunit represent the major tau phosphatase in the brain. Here we investigated whether traumatic brain injury in rats and humans would induce changes in protein phosphatase 2A and phosphorylated tau, and whether treatment with sodium selenate-a potent PR55 activator-would reduce phosphorylated tau and improve traumatic brain injury outcomes in rats. Ninety young adult male Long-Evans rats were administered either a fluid percussion injury or sham-injury. A proportion of rats were killed at 2, 24, and 72 h post-injury to assess acute changes in protein phosphatase 2A and tau. Other rats were given either sodium selenate or saline-vehicle treatment that was continuously administered via subcutaneous osmotic pump for 12 weeks. Serial magnetic resonance imaging was acquired prior to, and at 1, 4, and 12 weeks post-injury to assess evolving structural brain damage and axonal injury. Behavioural impairments were assessed at 12 weeks post-injury. The results showed that traumatic brain injury in rats acutely reduced PR55 expression and protein phosphatase 2A activity, and increased the expression of phosphorylated tau and the ratio of phosphorylated tau to total tau. Similar findings were seen in post-mortem brain samples from acute human traumatic brain injury patients, although many did not reach statistical significance. Continuous sodium selenate treatment for 12 weeks after sham or fluid percussion injury in rats increased protein phosphatase 2A activity and PR55 expression, and reduced the ratio of phosphorylated tau to total tau, attenuated brain damage, and improved behavioural outcomes in rats given a fluid percussion injury. Notably, total tau levels were decreased in rats 12 weeks after fluid percussion injury, and several other factors, including the use of anaesthetic, the length of recovery time, and that some brain injury and behavioural dysfunction still occurred in rats treated with sodium selenate must be considered in the interpretation of this study. However, taken together these data suggest protein phosphatase 2A and hyperphosphorylated tau may be involved in the neurodegenerative cascade of traumatic brain injury, and support the potential use of sodium selenate as a novel traumatic brain injury therapy., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Research in acute illness often requires an exception from informed consent. Few studies have assessed the views of patients enrolled in exception from informed consent trials. This study was designed to assess the views of patients and their surrogates of exception from informed consent enrollment within the context of a randomized, placebo-controlled trial of an investigational agent for traumatic brain injury., Design: Interactive interview study., Setting: Nested within the Progesterone for the Treatment of Traumatic Brain Injury trial, a Phase III randomized controlled trial in acute traumatic brain injury., Subjects: Patients and surrogates (for patients incapable of being interviewed) enrolled in Progesterone for the Treatment of Traumatic Brain Injury under exception from informed consent at 12 sites., Interventions: None., Measurements and Main Results: Interviews focused on respondents' acceptance of exception from informed consent enrollment in Progesterone for the Treatment of Traumatic Brain Injury, use of placebo and randomization, understanding of major study elements, and views regarding regulatory protections. Descriptive statistical analysis was performed; textual data were analyzed thematically. Eighty-five individuals were interviewed. Eighty-four percent had positive attitudes toward Progesterone for the Treatment of Traumatic Brain Injury inclusion. Seventy-eight percent found their inclusion under exception from informed consent acceptable, and 72% found use of exception from informed consent in Progesterone for the Treatment of Traumatic Brain Injury acceptable in general. Only two respondents clearly disagreed with both personal and general exception from informed consent enrollment. The most common concerns (26%) related to absence of consent. Eighty percent and 92% were accepting of placebo use and randomization, respectively. Although there were few black respondents (n = 11), they were less accepting of personal exception from informed consent enrollment than white respondents (55% vs 83%; p = 0.0494)., Conclusions: Acceptance of exception from informed consent in this placebo-controlled trial of an investigational agent was high and exceeded acceptance among community consultation participants. Exception from informed consent enrollment appears generally consistent with patients' preferences., Competing Interests: Dr. Wright is entitled to royalty through Emory University, derived from any BHR Pharma sales of progesterone for use in traumatic brain injury. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. The authors report no additional conflicts of interest relevant to this manuscript. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Background: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI., Methods: We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score., Results: A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes., Conclusions: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. There is strong evidence that gender and sex play an important role across the spectrum of TBI, from pathophysiology to clinical care. In May 2014, Academic Emergency Medicine held a consensus conference "Gender-Specific Research in Emergency Care: Investigate, Understand, and Translate How Gender Affects Patient Outcomes." A TBI working group was formed to explore what was known about the influence of sex and gender on TBI and to identify gaps for future research. The findings resulted in four major recommendations to guide the TBI research agenda., (© 2014 by the Society for Academic Emergency Medicine.)

Traumatic brain injury (TBI) is an international health concern with a complex pathogenesis resulting in major long-term neurological, neurocognitive, and neuropsychiatric outcomes. Although neuroinflammation has been identified as an important pathophysiological process resulting from TBI, the function of specific inflammatory mediators in the aftermath of TBI remains poorly understood. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an inflammatory cytokine that has been reported to have neuroprotective effects in various animal models of neurodegenerative disease that share pathological similarities with TBI. The importance of GM-CSF in TBI has yet to be studied, however. We examined the role of GM-CSF in TBI by comparing the effects of a lateral fluid percussion (LFP) injury or sham injury in GM-CSF gene deficient (GM-CSF(-/-)) versus wild-type (WT) mice. After a 3-month recovery interval, mice were assessed using neuroimaging and behavioral outcomes. All mice given a LFP injury displayed significant brain atrophy and behavioral impairments compared with those given sham-injuries; however, this was significantly worse in the GM-CSF(-/-) mice compared with the WT mice. GM-CSF(-/-) mice given LFP injury also had reduced astrogliosis compared with their WT counterparts. These novel findings indicate that the inflammatory mediator, GM-CSF, may have significant protective properties in the chronic sequelae of experimental TBI and suggest that further research investigating GM-CSF and its potential benefits in the injured brain is warranted.

Background: Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury., Findings: Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes., Conclusions: This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.

The sex hormone progesterone has been shown to improve outcomes in animal models of a number of neurologic diseases, including traumatic brain injury, ischemia, spinal cord injury, peripheral nerve injury, demyelinating disease, neuromuscular disorders, and seizures. Evidence suggests it exerts its neuroprotective effects through several pathways, including reducing edema, improving neuronal survival, and modulating inflammation and apoptosis. In this review, we summarize the functional outcomes and pathophysiologic mechanisms attributed to progesterone treatment in neurologic disease. We then comment on the breadth of evidence for the use of progesterone in each neurologic disease family. Finally, we provide support for further human studies using progesterone to treat several neurologic diseases., (© 2013 Elsevier B.V. All rights reserved.)

Purpose: Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE., Methods: Adult male Wistar rats underwent LFPI or sham injury. Serial magnetic resonance (MR) and positron emission tomography (PET) imaging, and behavioral analyses were performed over 6 months postinjury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video-electroencephalography (EEG) to assess for PTE. Of the LFPI rats, 52% (n = 12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings., Key Findings: MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, (18) F-fluorodeoxyglucose (FDG)-PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at 1 week, and 1, 3, and 6 months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and nonepileptic groups. However, hippocampal surface shape analysis using large-deformation high-dimensional mapping identified significant changes in the ipsilateral hippocampus at 1 week postinjury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the 1 week, and 1 and 3 month (18) F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination., Significance: These findings suggest that PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest that more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and nonepileptic animals into the correct group., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Background: Recent research has proposed a new method for defining a favorable outcome in traumatic brain injury and stroke research., Purpose: This new method is called the sliding dichotomy, and it is suggested as a potential solution to the problem of underpowered clinical trials., Methods: We present a brief simulation study and graphical comparison of the power of each method to detect varying treatment effect sizes., Results: Simulations of a patient population similar to the National Acute Brain Injury Study: Hypothermia (NABISH) study indicate that the sliding dichotomy method does not result in higher power than traditional methods., Conclusions: Although the sliding dichotomy may present gains in power in some cases, several aspects of the patient population need to be considered in choosing between sliding dichotomy and traditional definitions of favorable outcomes.

Objectives: The objective was to determine if geospatial techniques can be used to inform targeted community consultation (CC) and public disclosure (PD) for a clinical trial requiring emergency exception from informed consent (EFIC)., Methods: Data from January 2007 to December 2009 were extracted from a Level I trauma center's trauma database using the National Trauma Registry of the American College of Surgeon (NTRACS). Injury details, demographics, geographic codes, and clinical data necessary to match core elements of the clinical trial inclusion criteria (Glasgow Coma Scale [GCS] 3-12 and blunt head injury) were collected on all patients. Patients' home zip codes were geocoded to compare with population density and clustering analysis., Results: Over a 2-year period, 179 patients presented with moderate to severe traumatic brain injury (TBI). Mapping the rate and frequency of TBI patients presenting to the trauma center delineated at-risk populations for moderate to severe head injury. Four zip codes had higher incidences of TBI than the rest, with one zip code having a very high rate of 80 per 100,000 population., Conclusions: Geospatial techniques and hospital data records can be used to characterize potential subjects and delineate a high-risk population to inform directed CC and public disclosure strategies., (© 2011 by the Society for Academic Emergency Medicine.)

Collaboration among investigators, centers, countries, and disciplines is essential to advancing the care for traumatic brain injury (TBI). It is thus important that we "speak the same language." Great variability, however, exists in data collection and coding of variables in TBI studies, confounding comparisons between and analysis across different studies. Randomized controlled trials can never address the many uncertainties concerning treatment approaches in TBI. Pooling data from different clinical studies and high-quality observational studies combined with comparative effectiveness research may provide excellent alternatives in a cost-efficient way. Standardization of data collection and coding is essential to this end. Common data elements (CDEs) are presented for demographics and clinical variables applicable across the broad spectrum of TBI. Most recommendations represent a consensus derived from clinical practice. Some recommendations concern novel approaches, for example assessment of the intensity of therapy in severely injured patients. Up to three levels of detail for coding data elements were developed: basic, intermediate, and advanced, with the greatest level of detail attained in the advanced version. More detailed codings can be collapsed into the basic version. Templates were produced to summarize coding formats, explanation of choices, and recommendations for procedures. Endorsement of the recommendations has been obtained from many authoritative organizations. The development of CDEs for TBI should be viewed as a continuing process; as more experience is gained, refinement and amendments will be required. This proposed process of standardization will facilitate comparative effectiveness research and encourage high-quality meta-analysis of individual patient data.

A clear, concise definition of traumatic brain injury (TBI) is fundamental for reporting, comparison, and interpretation of studies on TBI. Changing epidemiologic patterns, an increasing recognition of significance of mild TBI, and a better understanding of the subtler neurocognitive neuroaffective deficits that may result from these injuries make this need even more critical. The Demographics and Clinical Assessment Working Group of the International and Interagency Initiative toward Common Data Elements for Research on Traumatic Brain Injury and Psychological Health has therefore formed an expert group that proposes the following definition: In this article, we discuss criteria for considering or establishing a diagnosis of TBI, with a particular focus on the problems how a diagnosis of TBI can be made when patients present late after injury and how mild TBI may be differentiated from non-TBI causes with similar symptoms. Technologic advances in magnetic resonance imaging and the development of biomarkers offer potential for improving diagnostic accuracy in these situations., (Copyright © 2010 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Comparing results across studies in traumatic brain injury (TBI) has been difficult because of the variability in data coding, definitions, and collection procedures. The global aim of the Working Group on Demographics and Clinical Assessment was to develop recommendations on the coding of clinical and demographic variables for TBI studies applicable across the broad spectrum of TBI, and to classify these as core, supplemental, or emerging. The process was consensus driven, with input from experts over a broad range of disciplines. Special consideration was given to military and pediatric TBI. Categorizing clinical elements as core versus supplemental proved difficult, given the great variation in types of studies and their interests. The data elements are contained in modules, which are grouped together in categories. Three levels of detail for coding data elements were developed: basic, intermediate, and advanced, with the greatest level of detail in the advanced version. In every case, the more detailed coding can be collapsed into the basic version. Templates were produced to summarize coding formats, motivation of choices, and recommendations for procedures. Work is ongoing to include more international participation and to provide an electronic data entry format with pull-down menus and automated data checks. This proposed standardization will facilitate comparison of research findings across studies and encourage high-quality meta-analysis of individual patient data., (Copyright © 2010 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Importance of the Field: Traumatic brain injury (TBI) has yet to find a safe and effective acute-stage neuroprotective treatment. Experimental drugs targeting a single receptor mechanism, gene, or brain locus have failed., Areas Covered in This Review: We review the latest clinical trials using progesterone (PROG) to treat moderate to severe TBI, and present background showing why this hormone and some of its metabolites should be considered as candidates for neuroprotective therapy. TBI is a complex disease caused by a cascade of systemic toxic events in the brain and throughout the body. Attention is now turning to combinatorial or pleiotropic drugs that act on multiple genomic, proteomic and metabolic pathways to enhance morphological and functional outcomes., What the Reader Will Gain: PROG has long been considered merely a female reproductive hormone with little role in neuroprotection after brain injury. This review will help readers to understand that PROG and its metabolites have multiple neuroprotective mechanisms, and may be among the first safe, low-cost, easily administered, effective treatments for a variety of CNS disorders., Take Home Message: The idea that PROG is just a female reproductive hormone is outdated. We propose that PROG has substantial pleiotropic properties as a neuroprotective agent in a variety of CNS injury models.

This clinical policy provides evidence-based recommendations on select issues in the management of adult patients with mild traumatic brain injury (TBI) in the acute setting. It is the result of joint efforts between the American College of Emergency Physicians and the Centers for Disease Control and Prevention and was developed by a multidisciplinary panel. The critical questions addressed in this clinical policy are: (1) Which patients with mild TBI should have a noncontrast head computed tomography (CT) scan in the emergency department (ED)? (2) Is there a role for head magnetic resonance imaging over noncontrast CT in the ED evaluation of a patient with acute mild TBI? (3) In patients with mild TBI, are brain specific serum biomarkers predictive of an acute traumatic intracranial injury? (4) Can a patient with an isolated mild TBI and a normal neurologic evaluation result be safely discharged from the ED if a noncontrast head CT scan shows no evidence of intracranial injury? Inclusion criteria for application of this clinical policy's recommendations are nonpenetrating trauma to the head, presentation to the ED within 24 hours of injury, a Glasgow Coma Scale score of 14 or 15 on initial evaluation in the ED, and aged 16 years or greater. The primary outcome measure for questions 1, 2, and 3 is the presence of an acute intracranial injury on noncontrast head CT scan; the primary outcome measure for question 4 is the occurrence of neurologic deterioration.

This clinical policy provides evidence-based recommendations on select issues in the management of adult patients with mild traumatic brain injury (TBI) in the acute setting. It is the result of joint efforts between the American College of Emergency Physicians and the Centers for Disease Control and Prevention and was developed by a multidisciplinary panel. The critical questions addressed in this clinical policy are: (1) Which patients with mild TBI should have a noncontrast head computed tomography (CT) scan in the emergency department (ED)? (2) Is there a role for head magnetic resonance imaging over noncontrast CT in the ED evaluation of a patient with acute mild TBI? (3) In patients with mild TBI, are brain specific serum biomarkers predictive of an acute traumatic intracranial injury? (4) Can a patient with an isolated mild TBI and a normal neurologic evaluation result be safely discharged from the ED if a noncontrast head CT scan shows no evidence of intracranial injury? Inclusion criteria for application of this clinical policy's recommendations are nonpenetrating trauma to the head, presentation to the ED within 24 hours of injury, a Glasgow Coma Scale score of 14 or 15 on initial evaluation in the ED, and aged 16 years or greater. The primary outcome measure for questions 1, 2, and 3 is the presence of an acute intracranial injury on noncontrast head CT scan; the primary outcome measure for question 4 is the occurrence of neurologic deterioration.

Study Objective: For clinical research, the consent process plays a critical role in protecting human subjects. In emergency research, proxy consent can impose substantial delays or even render a study infeasible if the intervention involves a highly time-sensitive treatment. The objective of this study is to compare the time required to enroll brain-injured trauma patients in a study with proxy consent versus exception from consent., Methods: We analyzed data from a clinical trial (Progesterone for Traumatic brain injury-Experimental Clinical Treatment-ProTECT) of a promising treatment for acute brain injury that used proxy consent for subject enrollment. Performance metrics using proxy consent (actual study) were compared to assumptions of what would have happened if the study had been conducted with exception from consent (hypothetical study). The total number and monthly rate of enrollees, mean time from injury to initiation of the study treatment, and number of subjects receiving unwanted treatment for any span of time were compared., Results: During the 30-month enrollment period, the actual study accrued 100 consenting subjects (3.3 per month) compared with 122 subjects (4.1 per month) for the hypothetical study. Mean time from injury to initiation of experimental treatment in the actual study was 379.2 standard deviation 118.0 minutes, approximately 6.3 hours, compared with 122 minutes in the hypothetical study., Conclusion: Exception from consent can reduce mean time from injury to initiation of study treatment of trauma patients by 4 hours or more. For a time-critical trauma care intervention, this difference may justify elaborate efforts to comply with the Final Rule.

Background: Given after brain injury (TBI), progesterone reduces cerebral oedema and facilitates functional recovery. Progesterone analogues have been synthesized for use in many medical conditions and exhibit different chemical and biological properties. Medroxyprogesterone acetate (MPA) is widely used in clinical practice, but oestrogen/MPA combinations may increase the risk of stroke and cardiovascular disease rather than preventing them. In some conditions, MPA can exhibit pharmacological actions that are different from those of natural progesterone. PRIMARY OBJECTIVE AND HYPOTHESIS: Using laboratory rats, this study assessed the efficacy of MPA to determine whether this progestin and natural progesterone exert similar effects as a treatment after bilateral injury to the frontal cortex., Main Outcomes and Results: MPA produced a dose-related reduction of cerebral oedema at 48 hours post-TBI but neither 4 nor 16 mg/kg doses of MPA enhanced behavioural recovery., Conclusion: These findings help to clarify the divergent results from prior positive progesterone studies and the negative MPA clinical trials for hormone replacement therapy. The results can be taken to suggest that the control of cerebral oedema, while clearly desirable, is not the only contributor to progesterone-induced behavioural recovery.

Objective: To examine the relationship between gender and cognitive recovery 1 year following traumatic brain injury (TBI)., Methods: Patients with blunt TBI were identified from the TBI Model Systems of Care National Database, multi-centre cohort study. The included patients (n = 325) were 16-45 years at injury, admitted to an acute care facility within 24 hours, received inpatient rehabilitation, had documented admission Glasgow Coma Scale (GCS) scores, completed neuropsychological follow-up 1 year post-injury and did not report pre-morbid learning problems. Multivariate analyses of variance examined the unadjusted association between gender and six cognitive domains examining attention/working memory, verbal memory, language, visual analytic skills, problem-solving and motor functioning. Analyses of covariance models were constructed to determine if confounding factors biased the observed associations., Results: Females performed significantly better than males on tests of attention/working memory and language. Males outperformed females in visual analytic skills. Gender remained significantly associated with performance in these areas when controlling for confounding variables., Conclusions: These results suggest a better cognitive recovery of females than males following TBI. However, future studies need to include non-TBI patients to control for possible pre-injury gender-related differences, as well as to conduct extended follow-ups to determine the stability of the observed differences.

Study Objective: Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering progesterone to patients with acute traumatic brain injury., Methods: This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale-Extended 30 days postinjury., Results: Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale-Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo., Conclusion: In this small study, progesterone caused no discernible harm and showed possible signs of benefit.