Traumatic Brain Injury Injury Research Articles

Diagnostic History of Traumatic Axonal Injury in Patients with Cerebral Concussion and Mild Traumatic Brain Injury

Cerebral concussion and mild traumatic brain injury (TBI) have been used interchangeably, although the two terms have different definitions. Traumatic axonal injury (TAI) is a more severe subtype of TBI than concussion or mild TBI. Regarding the evidence of lesions in patients with concussion or mild TBI, since the 1960's, several studies have reported on in patients with concussion who showed no radiological evidence of brain injury by autopsy. However, conventional CT and MRI are not sensitive to detection of axonal injury in concussion or mild TBI, therefore, previously, diagnosis of in live patients with concussion or mild TBI could not be demonstrated. With the development of diffusion tensor imaging (DTI) in the 1990's, in 2002, Arfanakis et al. reported on lesions in live patients with mild TBI using DTI for the first time. Subsequently, hundreds of studies have demonstrated the usefulness of DTI in detection of and lesions in patients with concussion or mild TBI. In Korea, the term TAI has rarely been used in the clinical field while diffuse axonal injury and concussion have been widely used. Rare use of in Korea appeared to be related to slow development of DTI analysis techniques in Korea. Therefore, we think that use of DTI analysis techniques for diagnosis of should be facilitated in Korea.

Longitudinal outcome and recovery of social problems after pediatric traumatic brain injury (TBI): Contribution of brain insult and family environment

Pediatric traumatic brain injury (TBI) can result in a range of social impairments, however longitudinal recovery is not well characterized, and clinicians are poorly equipped to identify children at risk for persisting difficulties. Using a longitudinal prospective design, this study aimed to evaluate the contribution of injury and non-injury related risk and resilience factors to longitudinal outcome and recovery of social problems from 12- to 24-months post-TBI. 78 children with TBI (injury age: 5.0–15.0 years) and 40 age and gender-matched typically developing (TD) children underwent magnetic resonance imaging including a susceptibility-weighted imaging (SWI) sequence 2–8 weeks post-injury (M=39.25, SD=27.64 days). At 12 and 24-months post- injury, parents completed questionnaires rating their child’s social functioning, and environmental factors including socioeconomic status, caregiver mental health and family functioning. Results revealed that longitudinal recovery profiles differed as a function of injury severity, such that among children with severe TBI, social problems significantly increased from 12- to 24-months post-injury, and were found to be significantly worse than TD controls and children with mild and moderate TBI. In contrast, children with mild and moderate injuries showed few problems at 12-months post-injury and little change over time. Pre-injury environment and SWI did not significantly contribute to outcome at 24-months, however concurrent caregiver mental health and family functioning explained a large and significant proportion of variance in these outcomes. Overall, this study shows that longitudinal recovery profiles differ as a function of injury severity, with evidence for late-emerging social problems among children with severe TBI. Poorer long-term social outcomes were associated with family dysfunction and poorer caregiver mental health at 24-months post injury, suggesting that efforts to optimize the child’s environment and bolster family coping resources may enhance recovery of social problems following pediatric TBI.

A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice.

Mild traumatic brain injury (TBI) from focal head impact is the most common form of TBI in humans. Animal models, however, typically use direct impact to the exposed dura or skull, or blast to the entire head. We present a detailed characterization of a novel overpressure blast system to create focal closed-head mild TBI in mice. A high-pressure air pulse limited to a 7.5 mm diameter area on the left side of the head overlying the forebrain is delivered to anesthetized mice. The mouse eyes and ears are shielded, and its head and body are cushioned to minimize movement. This approach creates mild TBI by a pressure wave that acts on the brain, with minimal accompanying head acceleration-deceleration. A single 20-psi blast yields no functional deficits or brain injury, while a single 25-40 psi blast yields only slight motor deficits and brain damage. By contrast, a single 50-60 psi blast produces significant visual, motor, and neuropsychiatric impairments and axonal damage and microglial activation in major fiber tracts, but no contusive brain injury. This model thus reproduces the widespread axonal injury and functional impairments characteristic of closed-head mild TBI, without the complications of systemic or ocular blast effects or head acceleration that typically occur in other blast or impact models of closed-skull mild TBI. Accordingly, our model provides a simple way to examine the biomechanics, pathophysiology, and functional deficits that result from TBI and can serve as a reliable platform for testing therapies that reduce brain pathology and deficits.

Thromboelastography After Murine TBI and Implications of Beta-Adrenergic Receptor Knockout.

The source of coagulopathy in traumatic brain injury (TBI) is multifactorial and may include adrenergic stimulation. The aim of this study was to assess coagulopathy after TBI using thromboelastography (TEG), and to investigate the implications of β-adrenergic receptor knockout. Adult male wild type c57/bl6 (WT) and β1/β2-adrenergic receptor knockout (BKO) mice were assigned to either TBI (WT-TBI, BKO-TBI) or sham injury (WT-sham, BKO-sham). Mice assigned to TBI were subject to controlled cortical impact (CCI). At 24h post-injury, whole blood samples were obtained and taken immediately for TEG. At 24h after injury, a trend toward increased fibrinolysis was seen in WT-TBI compared to WT-sham although this did not reach significance (EPL 8.1 vs. 0%, p=0.18). No differences were noted in fibrinolysis in BKO-TBI compared to BKO-sham (LY30 2.6 vs. 2.5%, p=0.61; EPL 3.4 vs. 2.9%, p=0.61). In addition BKO-TBI demonstrated increased clot strength compared to BKO-sham (MA 76.6 vs. 68.6, p=0.03; G 18.2 vs. 11.3, p=0.03). In a mouse TBI model, WT mice sustaining TBI demonstrated a trend toward increased fibrinolysis at 24h after injury while BKO mice did not. These findings suggest β-blockade may attenuate the coagulopathy of TBI and minimize progression of intracranial hemorrhage by reducing fibrinolysis and increasing clot strength.

New Prognostic Biomarkers in Patients With Traumatic Brain Injury.

Context:Traumatic brain injury (TBI) is a leading cause of death, disability, and resource consumption per year. There are two kinds of brain injury in TBI, primary and secondary injuries. Primary injury refers to the initial physical forces applied to the brain at the moment of impact. Secondary injury occurs over a period of hours or days following the initial trauma and results from the activation of different pathways such as inflammation, coagulation, oxidation, and apoptosis.Evidence Acquisition:This review focuses on new prognostic biomarkers of mortality in TBI patients related to inflammation, coagulation, oxidation, and apoptosis.Results:Recently circulating levels of substance P (SP), soluble CD40 ligand (sCD40L), tissue inhibitor of matrix metalloproteinases (TIMP)-1, malondialdehyde (MDA), and cytokeratin (CK)-18 fragmented have been found to be associated with mortality in TBI patients. Substance P is a neuropeptide of the tachykinin family, mainly synthesized in the central and peripheral nervous system, with proinflammatory effects when binding to their neurokinin-1 receptor (NK1R). Soluble CD40 ligand, a member of the tumor necrosis factor (TNF) family that is released into circulation from activated platelets, exhibit proinflamatory, and procoagulant properties on binding to their cell surface receptor CD40. Matrix metalloproteinases (MMPs) are a family of zinc-containing endoproteinases involved neuroinflammation and TIMP-1 is the inhibitor of some of them. Malondialdehyde is an end-product formed during lipid peroxidation due to degradation of cellular membrane phospholipids, that is released into extracellular space and finally into the blood. Cytokeratin -18 is cleaved by the action of caspases during apoptosis, and CK-18 fragmented is released into the blood.Conclusions:Circulating levels of some biomarkers, such as SP, sCD40L, TIMP-1, MDA, and CK-18 fragmented, related to inflammation, coagulation, oxidation, and apoptosis have been recently associated with mortality in patients with TBI. These biomarkers could help in the prognostic classification of the patients and open new research lines in the treatment of patients with TBI.

Advances in Intracranial Pressure Monitoring and Its Significance in Managing Traumatic Brain Injury.

Intracranial pressure (ICP) measurements are essential in evaluation and treatment of neurological disorders such as subarachnoid and intracerebral hemorrhage, ischemic stroke, hydrocephalus, meningitis/encephalitis, and traumatic brain injury (TBI). The techniques of ICP monitoring have evolved from invasive to non-invasive—with both limitations and advantages. Some limitations of the invasive methods include short-term monitoring, risk of infection, restricted mobility of the subject, etc. The invasiveness of a method limits the frequency of ICP evaluation in neurological conditions like hydrocephalus, thus hampering the long-term care of patients with compromised ICP. Thus, there has been substantial interest in developing noninvasive techniques for assessment of ICP. Several approaches were reported, although none seem to provide a complete solution due to inaccuracy. ICP measurements are fundamental for immediate care of TBI patients in the acute stages of severe TBI injury. In severe TBI, elevated ICP is associated with mortality or poor clinical outcome. ICP monitoring in conjunction with other neurological monitoring can aid in understanding the pathophysiology of brain damage. This review article presents: (a) the significance of ICP monitoring; (b) ICP monitoring methods (invasive and non-invasive); and (c) the role of ICP monitoring in the management of brain damage, especially TBI.

Socio Economic Status and Traumatic Brain Injury amongst Pediatric Populations: A Spatial Analysis in Greater Vancouver

Introduction: Within Canada, injuries are the leading cause of death amongst children fourteen years of age and younger, and also one of the leading causes of morbidity. Low Socio Economic Status (SES) seems to be a strong indicator of a higher prevalence of injuries. This study aims to identify hotspots for pediatric Traumatic Brain Injury (TBI) and examines the relationship between SES and pediatric TBI rates in greater Vancouver, British Columbia (BC), Canada. Methods: Pediatric TBI data from the BC Trauma Registry (BCTR) was used to identify all pediatric TBI patients admitted to BC hospitals between the years 2000 and 2013. Spatial analysis was used to identify hotspots for pediatric TBI. Multivariate analysis was used to distinguish census variables that were correlated with rates of injury. Results: Six hundred and fifty three severe pediatric TBI injuries occurred within the BC Lower Mainland between 2000 and 2013. High rates of injury were concentrated in the East, while low rate clusters were most common in the West of the region (more affluent neighborhoods). A low level of education was the main predictor of a high rate of injury (OR = 1.13, 95% CI = 1.03–1.23, p-Value 0.009). Conclusion: While there was a clear relationship between different SES indicators and pediatric TBI rates in greater Vancouver, income-based SES indicators did not serve as good predictors within this region.

Automated Perimetry and Visual Dysfunction in Blast-Related Traumatic Brain Injury

To evaluate feasibility and results of automated perimetry in veterans with combat blast neurotrauma. Prospective, longitudinal, observational case series. Sixty-one patients in a Veterans Affairs Polytrauma Center diagnosed with traumatic brain injury (TBI) from combat blast exposure. Study participants underwent automated perimetry at baseline (median interval, 2 months after injury) (Humphrey Field Analyzer, Carl Zeiss Meditec, Dublin, CA, Swedish Interactive Threshold Algorithm 30-2 Standard or Fast), and 36 of them were followed up (median interval, 10 months after baseline). Presence of significant mean deviation and pattern standard deviation was determined for testing with reliability indices ≤20% for fixation loss, 15% for false-positives, and 33% for false-negatives. Test-retest stability of global visual field indices was assessed for tests with these cutoffs or with elevated fixation loss. Associations between global visual field defects and predictors were examined. Global visual field indices (mean deviation and pattern standard deviation). Among 61 study participants (109 study eyes) with baseline testing, a field that met reliability cutoffs was obtained for 48 participants (79%) and 78 eyes (72%). Fixation loss was found in 29% of eyes in initial testing. Nine study participants (15%) demonstrated hemianopia or quadrantanopia, and an additional 36% had an abnormal global visual field index. Global indices were relatively stable at follow-up testing for tests meeting fixation-loss cutoffs and tests that did not. Visual scotomas due to post-chiasmal lesions were associated with moderate to severe TBI or penetrating head injury, but other visual field deficits were prevalent across the range of mild to severe TBI. Ocular injury to the retina or choroid, poorer visual acuity, and pupillary defect were associated with visual field defects. Participants with depressed visual field sensitivity reported lower visual quality of life. Reliable automated perimetry can be accomplished in most patients with TBI from combat blast exposure and reveals high rates of visual field deficits, indicating that blast forces may significantly affect the eye and visual pathways.

Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate.

There is currently no therapeutic drug treatment for traumatic brain injury (TBI) despite decades of experimental clinical trials. This may be because the mechanistic pathways for improving TBI outcomes have yet to be identified and exploited. As such, there remains a need to seek out new molecular targets and their drug candidates to find new treatments for TBI. This review presents supporting evidence for cathepsin B, a cysteine protease, as a potentially important drug target for TBI. Cathepsin B expression is greatly up-regulated in TBI animal models, as well as in trauma patients. Importantly, knockout of the cathepsin B gene in TBI mice results in substantial improvements of TBI-caused deficits in behavior, pathology, and biomarkers, as well as improvements in related injury models. During the process of TBI-induced injury, cathepsin B likely escapes the lysosome, its normal subcellular location, into the cytoplasm or extracellular matrix (ECM) where the unleashed proteolytic power causes destruction via necrotic, apoptotic, autophagic, and activated glia-induced cell death, together with ECM breakdown and inflammation. Significantly, chemical inhibitors of cathepsin B are effective for improving deficits in TBI and related injuries including ischemia, cerebral bleeding, cerebral aneurysm, edema, pain, infection, rheumatoid arthritis, epilepsy, Huntington’s disease, multiple sclerosis, and Alzheimer’s disease. The inhibitor E64d is unique among cathepsin B inhibitors in being the only compound to have demonstrated oral efficacy in a TBI model and prior safe use in man and as such it is an excellent tool compound for preclinical testing and clinical compound development. These data support the conclusion that drug development of cathepsin B inhibitors for TBI treatment should be accelerated.

Prevalence and determinants of depression and its association with quality of life in Traumatic Brain Injury (TBI) patients

Abstract Introduction: Traumatic brain injury (TBI) is a major cause of disability. Assessment and treatment of TBI typically focus on physical and cognitive impairments, yet psychological impairments represent significant causes of disability. Depression may be the most common and disabling psychiatric condition in individuals with TBI. Objective: This cross-sectional study was design to investigate prevalence and risk factors of depression in Traumatic brain injury (TBI). Material and method: The Group studied consists of 204 patients of mild and moderate TBI between 14-days to one-year post injury. Demographic characteristics of the participants were assessed on a self-designed semi structured performa. Interviews focused on assessment of severity of TBI, depression and quality of life (Qol) using GCS, PHQ-9 and WHOBREF-QOL respectively. Results: Total 204 patients were included. 42.15% participants were found to have depression. None of the demographic variables were associated with depression except female sex, severity and time since injury. Moderate TBI patient (55.80%) had significantly higher occurrence of depression than the mild cases (44.2%). Patients with lesser duration (time since injury) of TBI had high incidence (50.2%) of depression compare to longer duration of TBI. Depressed patients also had poor Qol than those without depression in all domains except physical health domain. Neuroanatomical localization was also correlated with depression. Cerebral contusions were the most common (44.24%) lesions associated with depression. Conclusion: Depression is commonly associated, yet under diagnosed clinical entities in head injury and have tremendous impact in overall outcome measures. Every patient of head injury warrants psychiatric evaluation and concomitant treatment if required to ensure the attainment of not only neuroanatomical intact but overall productive and qualitative life vindicating the holistic and multidisciplinary treatment approach.

Brainstem white matter integrity is related to loss of consciousness and postconcussive symptomatology in veterans with chronic mild to moderate traumatic brain injury.

We investigated associations between DTI indices of three brainstem white matter tracts, traumatic brain injury (TBI) injury characteristics, and postconcussive symptomatology (PCS) in a well-characterized sample of veterans with history of mild to moderate TBI (mTBI). 58 military veterans (mTBI: n = 38, mean age = 33.2, mean time since injury = 90.9months; military controls [MC]; n = 20; mean age = 29.4) were administered 3T DTI scans as well as a comprehensive neuropsychiatric evaluation including evaluation of TBI injury characteristics and PCS symptoms (e.g., negative mood, dizziness, balance and coordination difficulties). Tractography was employed by seeding ROIs along 3 brainstem white matter tracts (i.e., medial lemniscus-central tegmentum tract [ML-CTT]; corticospinal tracts [CST], and pontine tegmentum [PT]), and mean DTI values were derived from fractional anisotropic (FA) maps. Results showed that there were no significant difference in FA between the MC and TBI groups across the 3 regions of interest; however, among the TBI group, CST FA was significantly negatively associated with LOC duration. Additionally, lower FA of certain tracts-most especially the PT-was significantly associated with increased PCS symptoms (i.e., more severe vestibular symptoms, poorer physical functioning, and greater levels of fatigue), even after adjusting for PTSD symptoms. Our findings show that, in our sample of veterans with mTBI, tractography-based DTI indices of brainstem white matter tracts of interest are related to the presence and severity of PCS symptoms. Findings are promising as they show linkages between brainstem white matter integrity and injury severity (LOC), and they raise the possibility that the pontine tegmentum in particular may be a useful marker of PCS symptoms. Collectively, these data point to important neurobiological substrates of the chronic and complex constellation of symptoms following the 'signature injury' of our combat-exposed veterans.

When Injury Clouds Understanding of Others: Theory of Mind after Mild TBI in Preschool Children.

There is evidence to suggest that social skills, such as the ability to understand the perspective of others (theory of mind), may be affected by childhood traumatic brain injuries; however, studies to date have only considered moderate and severe traumatic brain injury (TBI). This study aimed to assess theory of mind after early, mild TBI (mTBI). Fifty-one children who sustained mTBI between 18 and 60 months were evaluated 6 months post-injury on emotion and desires reasoning and false-belief understanding tasks. Their results were compared to that of 50 typically developing children. The two groups did not differ on baseline characteristics, except for pre- and post-injury externalizing behavior. The mTBI group obtained poorer scores relative to controls on both the emotion and desires task and the false-belief understanding task, even after controlling for pre-injury externalizing behavior. No correlations were found between TBI injury characteristics and theory of mind. This is the first evidence that mTBI in preschool children is associated with theory of mind difficulties. Reduced perspective taking abilities could be linked with the social impairments that have been shown to arise following TBI.

Traumatic Brain Injury–Practice Based Evidence Study: Design and Patients, Centers, Treatments, and Outcomes

ObjectivesTo describe study design, patients, centers, treatments, and outcomes of a traumatic brain injury (TBI) practice-based evidence (PBE) study and to evaluate the generalizability of the findings to the U.S. TBI inpatient rehabilitation population. DesignProspective, longitudinal, observational study. SettingTen inpatient rehabilitation centers. ParticipantsPatients (N=2130) enrolled between October 2008 and September 2011 and admitted for inpatient rehabilitation after an index TBI injury. InterventionsNot applicable. Main Outcome MeasuresReturn to acute care during rehabilitation, rehabilitation length of stay, FIM at discharge, residence at discharge, and 9 months postdischarge rehospitalization, FIM, participation, and subjective well-being. ResultsThe level of admission FIM cognitive score was found to create relatively homogeneous subgroups for the subsequent analysis of best treatment combinations. There were significant differences in patient and injury characteristics, treatments, rehabilitation course, and outcomes by admission FIM cognitive subgroups. TBI-PBE study patients were overall similar to U.S. national TBI inpatient rehabilitation populations. ConclusionsThis TBI-PBE study succeeded in capturing naturally occurring variation in patients and treatments, offering opportunities to study best treatments for specific patient impairments. Subsequent articles in this issue report differences between patients and treatments and associations with outcomes in greater detail.

Traumatic Brain Injury Patient, Injury, Therapy, and Ancillary Treatments Associated With Outcomes at Discharge and 9 Months Postdischarge

ObjectiveTo examine associations of patient and injury characteristics, inpatient rehabilitation therapy activities, and neurotropic medications with outcomes at discharge and 9 months postdischarge for patients with traumatic brain injury (TBI). DesignProspective, longitudinal observational study. SettingInpatient rehabilitation centers. ParticipantsConsecutive patients (N=2130) enrolled between 2008 and 2011, admitted for inpatient rehabilitation after an index TBI injury. InterventionsNot applicable. Main Outcome MeasuresRehabilitation length of stay, discharge to home, and FIM at discharge and 9 months postdischarge. ResultsThe admission FIM cognitive score was used to create 5 relatively homogeneous subgroups for subsequent analysis of treatment outcomes. Within each subgroup, significant associations were found between outcomes and patient and injury characteristics, time spent in therapy activities, and medications used. Patient and injury characteristics explained on average 35.7% of the variation in discharge outcomes and 22.3% in 9-month outcomes. Adding time spent and level of effort in therapy activities and percentage of stay using specific medications explained approximately 20% more variation for discharge outcomes and 12.9% for 9-month outcomes. After patient, injury, and treatment characteristics were used to predict outcomes, center differences added only approximately 1.9% additional variance explained. ConclusionsAt discharge, greater effort during therapy sessions, time spent in more complex therapy activities, and use of specific medications were associated with better outcomes for patients in all admission FIM cognitive subgroups. At 9 months postdischarge, similar but less pervasive associations were observed for therapy activities, but not classes of medications. Further research is warranted to examine more specific combinations of therapy activities and medications that are associated with better outcomes.

Study of Quality of Life in Traumatic Brain Injury

Objective To assess quality of life (QOL) in individuals with mild and moderate traumatic brain injury (TBI) and their relationship with demographic, posttraumatic insomnia, and injury-related factors. Method The present study was a cross-sectional study conducted at Sawai Man Singh Medical College and group of hospitals over a period of 6 months from January 2013 to June 2013. The groups studied consists of 204 patients of mild and moderate TBI between 14 days and 1 year postinjury and equal number of controls by recruiting close relatives of the patients for comparison. Patients were assessed on semistructured sociodemographic proforma along with WHOQOL BREF, insomnia severity index, and GCS to assess QOL, insomnia, and severity of TBI, respectively. Result The number of participants included was 204. Mean age was 33.34 years. QOL was found impaired in all four domains of patients with TBI as compared with control group. The most unsatisfying domain among all was environmental health. None of the sociodemographic variables were associated with impaired QOL in TBI except duration and severity of head injury. Patients with longer duration (time since injury) of TBI and higher GCS had better QOL. Patients with insomnia had significantly poor QOL compared with those with TBI without insomnia. Conclusion QOL is an important aspect to be considered while management of TBI is performed especially during follow-ups. Impact of severity and the duration of injury with associated sleep problems have significant bearing on QOL.

Associations between a History of Traumatic Brain Injuries and Current Cigarette Smoking, Substance Use, and Elevated Psychological Distress in a Population Sample of Canadian Adults.

This study describes the prevalence of reported history of traumatic brain injury (TBI) and its association with reports of current substance use, cigarette smoking, and psychological distress among Canadian adults in a population sample. A cross-sectional sample of 1999 Ontario adults 18-93 years of age were surveyed by telephone in 2011 as part of the Center for Addiction and Mental Health's ongoing representative survey of adult mental health and substance use in Ontario, Canada. Loss of consciousness for at least 5 min or at least one overnight hospitalization resulting from symptoms associated with the TBI injury represented minimum criteria for TBI. An estimated 16.8% (95% confidence interval, 14.8, 19.0) of adults reported a TBI in their lifetime. Men had higher prevalence of TBI than women. Adults who reported a history of TBI had higher odds of reported past-year daily smoking (adjusted odds ratio [AOR] = 2.15), using cannabis (AOR = 2.80) and nonmedical opioids (AOR = 2.90), as well as screened significantly for recent elevated psychological distress (AOR = 1.97) in the past few weeks, compared to adults without a history of TBI. Co-occurrence of a history of TBI with current elevated psychological distress and substance use warrants vigilance among medical practitioners to assess the possibility of a history of TBI during reviews of the history leading to the occurrence of these conditions.

Systematic review and meta-analysis of efficacy of mesenchymal stem cells on locomotor recovery in animal models of traumatic brain injury.

IntroductionThe therapeutic potential of mesenchymal stem cells (MSCs) for traumatic brain injury (TBI) is attractive. Conducting systematic review and meta-analyses based on data from animal studies can be used to inform clinical trial design. To conduct a systematic review and meta-analysis to (i) systematically review the literatures describing the effect of MSCs therapy in animal models of TBI, (ii) determine the estimated effect size of functional locomotor recovery after experimental TBI, and (iii) to provide empirical evidence of biological factors associated with greater efficacy.MethodsWe conducted a systematic search of PubMed, EMBASE, and Web of Science and hand searched related references. Studies were selected if they reported the efficacy of MSCs in animal models of TBI. Two investigators independently assessed the identified studies. We extracted the details of individual study characteristics from each publication, assessed study quality, evaluated the effect sizes of MSCs treatment, and performed stratified meta-analysis and meta-regression, to assess the influence of study design on the estimated effect size. The presence of small effect sizes was investigated using funnel plots and Egger’s tests.ResultsTwenty-eight eligible controlled studies were identified. The study quality was modest. Between-study heterogeneity was large. Meta-analysis showed that MSCs exert statistically significant positive effects on sensorimotor and neurological motor function. For sensorimotor function, maximum effect size in studies with a quality score of 5 was found in the weight-drop impact injury TBI model established in male SD rats, to which syngeneic umbilical cord-derived MSCs intracerebrally at cell dose of (1–5) × 106 was administered r 6 hours following TBI, using ketamine as anesthetic agent. For neurological motor function, effect size was maximum for studies with a quality score of 5, in which the weight-drop impact injury TBI models of the female Wistar rats were adopted, with administration syngeneic bone marrow-derived MSCs intravenously at cell dose of 5 × 106 at 2 months after TBI, using sevofluorane as anesthetic agent.ConclusionsWe conclude that MSCs therapy may improve locomotor recovery after TBI. However, additional well-designed and well-reported animal studies are needed to guide further clinical studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0034-0) contains supplementary material, which is available to authorized users.

Inter-hemispheric wave propagation failures in traumatic brain injury are indicative of callosal damage

Approximately 3.2–5.3million Americans live with the consequences of a traumatic brain injury (TBI), making TBI one of the most common causes of disability in the world. Visual deficits often accompany TBI but physiological and anatomical evidence for injury in mild TBI is lacking. Axons traversing the corpus callosum are particularly vulnerable to TBI. Hemifield representations of early visual areas are linked by bundles of fibers that together cross the corpus callosum while maintaining their topographic relations. Given the increased vulnerability of the long visual axons traversing the corpus callosum, we hypothesized that inter-hemispheric transmission for vision will be impaired following mild TBI. Using the travelling wave paradigm (Wilson, Blake, & Lee 2001), we measured inter-hemispheric transmission in terms of both speed and propagation failures in 14 mild TBI patients and 14 age-matched controls. We found that relative to intra-hemispheric waves, inter-hemispheric waves were faster and that the inter-hemispheric propagation failures were more common in TBI patients. Furthermore, the transmission failures were topographically distributed, with a bias towards greater failures for transmission across the upper visual field. We discuss the results in terms of increased local inhibition and topographically-selective axonal injury in mild TBI.

Neuroinflammatory responses to traumatic brain injury.

Dear editor We read with great interest the recent study by Lozano et al1 published in the Neuropsychiatric Disease and Treatment. The recovery after traumatic brain injury (TBI) is related to severity of the initial injury (primary injury) and the presence of secondary injury.2 Evidences suggest that inflammation, oxidative stress, excitotoxicity, apoptosis, and neuroendocrine responses play an important role in the development of secondary brain injury.3 Therefore, an important part in the management of patients with TBI is trying to minimize the occurrence of deleterious secondary lesions. Lozano et al’s1 paper focused on the role of neuroinflammation in brain injury. Although some studies have described experimental drugs which may eventually have neuroprotective effects in patients with TBI,2–4 there is currently no approved pharmacological treatment for neuroinflammatory effects of the acute phase of the injury. The dissociation between experimental data with positive results and consecutive clinical trials with negative results leads to a dilemma for the treatment of patients with TBI. And, we agree with Lozano et al1 that further clarification of the neuroinflammatory mechanisms could be the basis for addressing the gap between bench and clinical results to provide better treatment and reduce death and sequelae of TBI. A strong point of the paper1 is the detailed description of signaling pathways of biochemical cascades of secondary injury in TBI, highlighting the metabolic and cellular processes. The discussion about cell death mechanisms is comprehensive and in simple language, which makes it accessible for clinical teams. The description of acute excitatory mechanisms, oxidative stress, and mitochondrial dysfunction is broad and interesting. Another prominent aspect in the review is the section “Neuroinflammation-based therapies”, which allows an analysis of the current status and perspectives for treatment of post-traumatic neuroinflammation. Our group has a particular interest in the role of MMPs, zinc-dependent peptides capable to break down most of the extracellular matrix components such as COL, ELN, and FN, in the mechanisms of enhancement of brain injury. As discussed by Lozano et al many processes in secondary injury depends on the integrity of the blood–brain barrier,5 an anatomical structure formed by tight junctions, basement membrane, podocyte and glial cells that prevents the passive transport of hydrophilic molecules larger than 500 Da between brain structures and blood.5,6 Experimental studies have shown that MMP-9 levels increase after TBI, breaking down basal lamina components and disrupting the blood–brain barrier.7 In animal studies, Wang et al8 demonstrated increased levels of MMP-9 after TBI which persisted for up to 1 week and such an increase also occurred in the contralateral hemisphere, suggesting that after trauma, changes in cerebral state are not restricted to the injured area. Suehiro et al7 found high levels of MMP-9 in TBI patients in the acute phase correlated with high levels of IL-6. They suggested that MMP-9 might play a role in the damage of TBI and be associated with inflammatory events post-TBI. Moreover, during normal development and physiological conditioning of the cell, activated metalloproteinases are required to break down extracellular matrix molecules to allow cell migration.6 In this context, metalloproteinases may also play a role in allowing the interaction of different types of cells during brain injury or repair. Inflammatory process, as reported by the authors, is a double-edged sword, good toward neuroregeneration and bad toward enhancing brain damage. The comprehension of the mechanisms that rule this subtle switch to one side or the other should be the goal of this group and others working in this challenging domain.

The effect of traumatic brain injury on bone healing: an experimental study in a novel in vivo animal model

IntroductionAmong many factors determining the outcome of complex fractures in polytrauma patients, the role of traumatic brain injury (TBI) remains only partly understood. The aim of the present study was to examine the effect of traumatic brain injury on bone healing through the establishment of a novel standardised animal model that sequentially combines traumatic brain injury (TBI) with a long bone injury. Materials and methodsThirty-six female twelve-week old C57/BL6 mice were randomised in two groups (fracture (Fx)-group and combined-trauma (Fx/TBI) group). The methods of the Control Cortical Impact Injury for induction of TBI and of the femoral osteotomy, fixed with an external fixator for the simulation of the long bone fracture, were combined. No TBI was induced in the Fx-group. Bone healing was examined using in vivo micro-CT measurements over a period of three weeks. ResultsThe severity of the TBI was sufficient to stimulate a significantly increased callus formation in the Fx/TBI-group with an acceptable mortality rate. The micro-CT analysis of fracture healing displayed a significantly increased callus volume in the Fx/TBI-group already from the second postoperative week. This difference remained significant throughout the entire study period. DiscussionThe successful and standardised combination of TBI and fracture in a mouse model allows systematic and quantitative in vivo analysis of underlying pathways that trigger the mutual interaction between musculoskeletal trauma and brain injury, as well as, corresponding differences in fracture healing using micro-CT methods. ConclusionThe present study offers three new aspects: a standardised model for combined injury of TBI and femoral osteotomy; direct and serial in vivo imaging and quantification of fracture healing response using micro-CT; testing of potentially beneficial therapeutic regimens for fracture treatment in presence of TBI. Thus this model provides a valuable basic approach for the study of the amplifying effect of TBI on callus formation seen in patients with craniocerebral injury and concomitant skeletal trauma.