Showing papers in "Journal of Neurotrauma in 2009"
TL;DR: Observations suggest that the mechanism by which explosive blast injures the central nervous system may be more complex than initially assumed.
Abstract: Explosive blast traumatic brain injury (TBI) is one of the more serious wounds suffered by United States service members injured in the current conflicts in Iraq and Afghanistan. Some military medical treatments for blast TBI that have been introduced successfully in the war theater include decompressive craniectomy, cerebral angiography, transcranial Doppler, hypertonic resuscitation fluids, among others. Stateside neurosurgery, neuro-critical care, and rehabilitation for these patients have similarly progressed. With experience, military physicians have been able to clinically describe blast TBI across the entire severity spectrum. One important clinical finding is that a significant number of severe blast TBI victims develop pseudoaneurysms and vasospasm, which can lead to delayed decompensation. Another is that mild blast TBI shares clinical features with post-traumatic stress disorder (PTSD). Observations suggest that the mechanism by which explosive blast injures the central nervous system ...
413 citations
TL;DR: It is demonstrated that shock tube-generated airblast can cause TBI in rats, in part through systemic mediation, and that the resulting brain injury significantly impacts acute cardiovascular homeostatic mechanisms as well as neurobehavioral function.
Abstract: Blast injury to the brain is the predominant cause of neurotrauma in current military conflicts, and its etiology is largely undefined. Using a compression-driven shock tube to simulate blast effects, we assessed the physiological, neuropathological, and neurobehavioral consequences of airblast exposure, and also evaluated the effect of a Kevlar protective vest on acute mortality in rats and on the occurrence of traumatic brain injury (TBI) in those that survived. This approach provides survivable blast conditions under which TBI can be studied. Striking neuropathological changes were caused by both 126- and 147-kPa airblast exposures. The Kevlar vest, which encased the thorax and part of the abdomen, greatly reduced airblast mortality, and also ameliorated the widespread fiber degeneration that was prominent in brains of rats not protected by a vest during exposure to a 126-kPa airblast. This finding points to a significant contribution of the systemic effects of airblast to its brain injury pathophysiology. Airblast of this intensity also disrupted neurologic and neurobehavioral performance (e.g., beam walking and spatial navigation acquisition in the Morris water maze). When immediately followed by hemorrhagic hypotension, with MAP maintained at 30 mm Hg, airblast disrupted cardiocompensatory resilience, as reflected by reduced peak shed blood volume, time to peak shed blood volume, and time to death. These findings demonstrate that shock tube-generated airblast can cause TBI in rats, in part through systemic mediation, and that the resulting brain injury significantly impacts acute cardiovascular homeostatic mechanisms as well as neurobehavioral function.
343 citations
TL;DR: There is a paucity of randomized controlled trials for depression following TBI, and Serotonergic antidepressants and cognitive behavioral interventions appear to have the best preliminary evidence for treating depression after traumatic brain injury.
Abstract: The aim of this systematic review was to critically evaluate the evidence on interventions for depression following traumatic brain injury (TBI) and provide recommendations for clinical practice and future research We reviewed pharmacological, other biological, psychotherapeutic, and rehabilitation interventions for depression following TBI from the following data sources: PubMed, CINAHL, PsycINFO, ProQuest, Web of Science, and Google Scholar We included studies written in English published since 1980 investigating depression and depressive symptomatology in adults with TBI; 658 articles were identified After reviewing the abstracts, 57 articles met the inclusion criteria In addition to studies describing interventions designed to treat depression, we included intervention studies in which depressive symptoms were reported as a secondary outcome At the end of a full review in which two independent reviewers extracted data, 26 articles met the final criteria that included reporting data on participants with TBI, and using validated depression diagnostic or severity measures pre- and post-treatment Three external reviewers also examined the study methods and evidence tables, adding 1 article, for a total of 27 studies Evidence was classified based on American Academy of Neurology criteria The largest pharmacological study enrolled 54 patients, and none of the psychotherapeutic/rehabilitation interventions prospectively targeted depression This systematic review documents that there is a paucity of randomized controlled trials for depression following TBI Serotonergic antidepressants and cognitive behavioral interventions appear to have the best preliminary evidence for treating depression following TBI More research is needed to provide evidence-based treatment recommendations for depression following TBI
292 citations
TL;DR: In this article, the authors presented a swine model of explosive blast injury to the brain, which was developed during Phase I of the DARPA (Defense Advanced Research Projects Agency) PREVENT (Preventing Violent Explosive Neurotrauma) blast research program.
Abstract: Explosive blast has been extensively used as a tactical weapon in Operation Iraqi Freedom (OIF) and more recently in Operation Enduring Freedom(OEF). The polytraumatic nature of blast injuries is evidence of their effectiveness,and brain injury is a frequent and debilitating form of this trauma. In-theater clinical observations of brain-injured casualties have shown that edema, intracranial hemorrhage, and vasospasm are the most salient pathophysiological characteristics of blast injury to the brain. Unfortunately, little is known about exactly how an explosion produces these sequelae as well as others that are less well documented. Consequently, the principal objective of the current report is to present a swine model of explosive blast injury to the brain. This model was developed during Phase I of the DARPA (Defense Advanced Research Projects Agency) PREVENT (Preventing Violent Explosive Neurotrauma) blast research program. A second objective is to present data that illustrate the capabilities of this model to study the proximal biomechanical causes and the resulting pathophysiological, biochemical,neuropathological, and neurological consequences of explosive blast injury to the swine brain. In the concluding section of this article, the advantages and limitations of the model are considered, explosive and air-overpressure models are compared, and the physical properties of an explosion are identified that potentially contributed to the in-theater closed head injuries resulting from explosions of improvised explosive devices (IEDs).
281 citations
TL;DR: To overcome the challenges of testing combination therapies it was recommended that statisticians and the U.S. Food and Drug Administration be included in early discussions of experimental design and an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatly facilitate the development of successful combination therapies for TBI.
Abstract: Traumatic brain injury (TBI) initiates a cascade of numerous pathophysiological events that evolve over time. Despite the complexity of TBI, research aimed at therapy development has almost exclusively focused on single therapies, all of which have failed in multicenter clinical trials. Therefore, in February 2008 the National Institute of Neurological Disorders and Stroke, with support from the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, and the Department of Veterans Affairs, convened a workshop to discuss the opportunities and challenges of testing combination therapies for TBI. Workshop participants included clinicians and scientists from a variety of disciplines, institutions, and agencies. The objectives of the workshop were to: (1) identify the most promising combinations of therapies for TBI; (2) identify challenges of testing combination therapies in clinical and pre-clinical studies; and (3) propose research methodologies and study designs to overcome these challenges. Several promising combination therapies were discussed, but no one combination was identified as being the most promising. Rather, the general recommendation was to combine agents with complementary targets and effects (e.g., mechanisms and time-points), rather than focusing on a single target with multiple agents. In addition, it was recommended that clinical management guidelines be carefully considered when designing pre-clinical studies for therapeutic development. To overcome the challenges of testing combination therapies it was recommended that statisticians and the U.S. Food and Drug Administration be included in early discussions of experimental design. Furthermore, it was agreed that an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatly facilitate the development of successful combination therapies for TBI. Overall there was great enthusiasm for working collaboratively to act on these recommendations.
263 citations
TL;DR: The results show that the integrated approach with MEG and DTI is more sensitive than conventional CT and MRI in detecting subtle neuronal injury in mild TBI, and findings from the integrated imaging approach are consistent with post-concussive symptoms.
Abstract: Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild (and some moderate) TBI can be difficult to diagnose due to lack of obvious external injuries and because the injuries are often not visible on conventional acute MRI or CT. Injured brain tissues in TBI patients generate pathological low-frequency neuronal magnetic signal (delta waves 1–4 Hz) that can be measured and localized by magnetoencephalography (MEG). We hypothesize that abnormal MEG delta waves originate from gray matter neurons that experience de-afferentation due to axonal injury to the underlying white matter fiber tracts, which is manifested on diffusion tensor imaging (DTI) as reduced fractional anisotropy. The present study used a neuroimaging approach integrating findings of magnetoencephalography (MEG) and diffusion tensor imaging (DTI), evaluating their utility in diagnosing mild TBI in 10 subjects in whom conventional CT and MRI showed no visible lesions i...
210 citations
TL;DR: It is concluded that both hypoxemia and extreme hyperoxemia are associated with increased mortality and a decrease in good outcomes among TBI patients.
Abstract: An association between hypoxemia and poor outcomes from traumatic brain injury (TBI) is well documented. However, it is unclear whether hyperoxygenation is beneficial. This registry-based analysis explores the relationship between early hypoxemia and hyperoxemia on outcome from moderate-to-severe TBI. TBI patients (Abbreviated Injury Scale score 3+) were identified from the San Diego County trauma registry. Patients were stratified by arrival partial oxygen pressure (Po2) value. Trauma and injury severity score (TRISS) was then used to calculate predicted survival for each patient, with the mean observed-predicted survival differential determined for each arrival Po2 stratification. Logistic regression was used to quantify the relationship between hypoxemia, hyperoxemia, and outcome from TBI after adjusting for multiple variables including intubation and ventilation status. A total of 3420 patients were included in the analysis. TRISS calculations revealed worse outcomes than predicted for both h...
206 citations
TL;DR: The objective of this study was to evaluate the relationship between QA and serum concentrations of monomeric transthyretin (TTR) or S100B, and to establish a gold-standard measure, the cerebrospinal fluide-serum albumin quotient (QA).
Abstract: The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most water-soluble molecules over 500 Da, is often disrupted after trauma Post-traumatic BBB disruption may have important implications for prognosis and therapy Assessment of BBB status is not routine in clinical practice because available techniques are invasive The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (QA), requires the measurement of albumin in CSF and serum collected contemporaneously Accurate, less invasive techniques are necessary The objective of this study was to evaluate the relationship between QA and serum concentrations of monomeric transthyretin (TTR) or S100B Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score ≤ 8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled Serum and CSF were collected at the time of LP for headache subjects and
191 citations
TL;DR: The probability of a depolarization occurring increased significantly as a function of declining mean arterial pressure and cerebral perfusion pressure and increasing core temperature, and the relationship to systemic physiologic values during neurointensive care was investigated.
Abstract: Here we investigated the incidence of cortical spreading depolarizations (spreading depression and peri-infarct depolarization) after traumatic brain injury (TBI) and their relationship to systemic physiologic values during neurointensive care. Subdural electrode strips were placed on peri-contusional cortex in 32 patients who underwent surgical treatment for TBI. Prospective electrocorticography was performed during neurointensive care with retrospective analysis of hourly nursing chart data. Recordings were 84 hr (median) per patient and 2,503 hr in total. In 17 patients (53%), 280 spreading depolarizations (spreading depressions and peri-infarct depolarizations) were observed. Depolarizations occurred in a bimodal pattern with peak incidence on days 1 and 7. The probability of a depolarization occurring increased significantly as a function of declining mean arterial pressure (MAP; R2 = 0.78; p < 0.001) and cerebral perfusion pressure (R2 = 0.85; p < 0.01), and increasing core temperature (R2 ...
181 citations
TL;DR: Preliminary findings indicate significantly lower levels of gray matter Glx and higher levels of white matter creatine-phosphocreatine in mTBI subjects relative to healthy controls and Cr levels were predictive of executive function and emotional distress in the combined groups.
Abstract: Single-voxel proton magnetic resonance imaging (1H-MRS) and proton MR spectroscopic imaging (1H-MRSI) were used to compare brain metabolite levels in semi-acute mild traumatic brain injury (mTBI) patients (n = 10) and matched healthy controls (n = 9). The 1H-MRS voxel was positioned in the splenium, a region known to be susceptible to axonal injury in TBI, and a single 1H-MRSI slice was positioned above the lateral ventricles. To increase sensitivity to the glutamate (Glu) and the combined glutamate-glutamine (Glx) signal, an inter-pulse echo time shown to emphasize the major Glu signals was used along with an analysis method that reduces partial volume errors by using water as a concentration standard. Our preliminary findings indicate significantly lower levels of gray matter Glx and higher levels of white matter creatine-phosphocreatine (Cr) in mTBI subjects relative to healthy controls. Furthermore, Cr levels were predictive of executive function and emotional distress in the combined groups....
179 citations
TL;DR: The results show that treatment of TBI with hMSCs during the acute phase of injury can enhance neurological functional outcome, and suggest that increased levels of neurotrophic factors in the i...
Abstract: To investigate the therapeutic effects and mechanisms of action of human mesenchymal stem cells (hMSCs), rats were intravenously treated with hMSCs 24 h after traumatic brain injury (TBI). Neurological function was significantly recovered in the hMSC-treated group by 15 days after TBI compared to the placebo group treated with saline. Quantitative ELISA of extracts from the entire traumatized cerebral hemispheres showed significantly increased expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) in the hMSC group at 2 days after TBI, with expression decreasing over time. Western blot analysis demonstrated that pAkt expression was upregulated at 2 days after TBI, and caspase-3 cleavage was significantly decreased at 8 days after TBI in the hMSC group. Our results show that treatment of TBI with hMSCs during the acute phase of injury can enhance neurological functional outcome, and suggest that increased levels of neurotrophic factors in the i...
TL;DR: DTI demonstrates axonopathy in the acute stage, as well as at secondary stages, at 6 months post-injury in the corpus callosum and peri-ventricular white matter in regions of normal-appearing white matter on conventional MRI.
Abstract: Diffuse axonal injury (DAI) that follows traumatic brain injury (TBI) is thought to be a major contributor to neurocognitive dysfunction that sometimes follows TBI. Conventional magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and neuropsychological tests (NPT) were performed on 38 TBI patients [hemorrhagic DAI (H-DAI, n = 8), non-hemorrhagic (Nh-DAI, n = 7), with no apparent DAI on conventional MRI (NA-DAI, n = 23)] with a Glasgow Coma Scale score ranging between 9 and 13. The fractional anisotropy (FA) and mean diffusivity (MD) were quantified from different regions of the corpus callosum (CC), and peri-ventricular white matter (PWM) within 5–14 days and 6 months following TBI. Patients in all three groups showed decreased FA in the anterior limb of the internal capsule (ALIC) and the posterior limb of the internal capsule (PLIC), while the genu of the CC showed a decrease in the H-DAI group during the early period following TBI that persisted 6 months later, which appeared to b...
TL;DR: It is demonstrated that brain networks involved in different demands of motor control remain responsive even in chronic paralysis, implying that therapeutic strategies aimed at restoring spinal cord function, even in people with chronic SCI, can build on preserved competent brain control.
Abstract: Reorganization of brain function in people with CNS damage has been identified as one of the fundamental mechanisms involved in the recovery of sensorimotor function. Spinal cord injury (SCI) brain mapping studies during motor tasks aim for assessing the reorganization and preservation of brain networks involved in motor control. Revealing the activation of cortical and subcortical brain areas in people with SCI can indicate principal patterns of brain reorganization when the neurotrauma is distal to the brain. This review assessed brain activation after SCI in terms of intensity, volume, and somatotopic localization, as well as preservation of activation during attempted and/or imagined movements. Twenty-five studies meeting the inclusion criteria could be identified in Medline (1980 to January 2008). Relevant characteristics of studies (level of lesion, time after injury, motor task) and mapping techniques varied widely. Changes in brain activation were found in both cortical and subcortical ar...
TL;DR: Comparing the results provided by the different assessment tools used in the scientific literature in order to gain a better understanding of the sequelae and recovery following a concussion suggests that cognitive testing should be viewed as one of several complementary tools necessary for a comprehensive assessment of concussion.
Abstract: Given that the incidence of sports-related concussion is considered to have reached epidemic proportions, in the past 15 years we have witnessed an explosion of research in this field. The purpose of the current review is to compare the results provided by the different assessment tools used in the scientific literature in order to gain a better understanding of the sequelae and recovery following a concussion. Until recently, the bulk of the has literature focused on the immediate outcome in the hours and days post-injury as a means to plan the safest return-to-play strategy. This has led to the development of several assessment batteries that are relatively easy and rapid to administer and that allow for multiple testing sessions. The main conclusion derived from that literature is that cognitive symptoms tend to resolve within 1 week. However, accumulating evidence indicates that cognitive testing should be viewed as one of several complementary tools necessary for a comprehensive assessment o...
TL;DR: The results identify neuron-enriched proteins that may serve as a panel of CSF and blood surrogate markers for the minimally invasive detection, management, mechanistic, and therapeutic evaluation of human TBI.
Abstract: Surrogate markers have enormous potential for contributing to the diagnosis, prognosis, and therapeutic evaluation of acute brain damage, but extensive prior study of individual candidates has not yielded a biomarker in widespread clinical practice. We hypothesize that a panel of neuron-enriched proteins measurable in cerebrospinal fluid (CSF) and blood should vastly improve clinical evaluation and therapeutic management of acute brain injuries. Previously, we developed such a panel based initially on the study of protein release from degenerating cultured neurons, and subsequently on rodent models of traumatic brain injury (TBI) and ischemia, consisting of 14-3-3β, 14-3-3ζ, three distinct phosphoforms of neurofilament H, ubiquitin hydrolase L1, neuron-specific enolase, α-spectrin, and three calpain- and caspase-derived fragments of α-spectrin. In the present study, this panel of 11 proteins was evaluated as CSF and serum biomarkers for severe TBI in humans. By quantitative Western blotting and s...
TL;DR: Evaluating young adults with and without a history of concussion using a standard clinical assessment and highly sensitive electrophysiological measures for persistent changes in cognitive functioning suggested an increased risk for late life cognitive dysfunction in those with previous injuries.
Abstract: Mild traumatic brain injuries (mTBIs) that result from participation in sports are a major public health issue affecting 1.6–3.8 million individuals annually. The injury has been postulated as transient and void of long-term consequences when rapidly diagnosed and properly managed. Emerging evidence, however, has suggested an increased risk for late life cognitive dysfunction in those with previous injuries. The purpose of this investigation was to evaluate young adults with and without a history of concussion using a standard clinical assessment and highly sensitive electrophysiological measures for persistent changes in cognitive functioning. Ninety participants (19.7 ±1.3 years; 44 without mTBI and 46 with previous mTBI) were evaluated using the ImPACT and event-related brain potentials (ERPs) that were recorded during a three-stimulus oddball task. Those with a history of concussion reported an average of 3.4 years post-injury. No significant differences were found between groups on the ImPAC...
TL;DR: Experimental data obtained in animal models of brain and SCI demonstrating the benefits of mild to moderate hypothermia are reviewed and critical data for the translation of this therapy to the clinical arena are provided.
Abstract: For the past 20 years, various laboratories throughout the world have shown that mild to moderate levels of hypothermia lead to neuroprotection and improved functional outcome in various models of brain and spinal cord injury (SCI) Although the potential neuroprotective effects of profound hypothermia during and following central nervous system (CNS) injury have long been recognized, more recent studies have described clinically feasible strategies for protecting the brain and spinal cord using hypothermia following a variety of CNS insults In some cases, only a one or two degree decrease in brain or core temperature can be effective in protecting the CNS from injury Alternatively, raising brain temperature only a couple of degrees above normothermia levels worsens outcome in a variety of injury models Based on these data, resurgence has occurred in the potential use of therapeutic hypothermia in experimental and clinical settings The study of therapeutic hypothermia is now an international area of investigation with scientists and clinicians from every part of the world contributing to this important, promising therapeutic intervention This paper reviews the experimental data obtained in animal models of brain and SCI demonstrating the benefits of mild to moderate hypothermia These studies have provided critical data for the translation of this therapy to the clinical arena The mechanisms underlying the beneficial effects of mild hypothermia are also summarized
TL;DR: The results indicate that moderate brain injury produces temperature-sensitive acute, as well as more long-lasting vascular perturbations associated with secondary injury mechanisms.
Abstract: We investigated the temporal and regional profile of blood-brain barrier (BBB) permeability to both large and small molecules after moderate fluid percussion (FP) brain injury in rats and determined the effects of post-traumatic modest hypothermia (33 degrees C/4 h) on these vascular perturbations. The visible tracers biotin-dextrin-amine 3000 (BDA-3K, 3 kDa) and horseradish peroxidase (HRP, 44 kDa) were injected intravenously at 4 h or 3 or 7 days post-TBI. At 30 min after the tracer infusion, both small and large molecular weight tracers were detected in the contusion area as well as remote regions adjacent to the injury epicenter in both cortical and hippocampal structures. In areas adjacent to the contusion site, increased permeability to the small molecular weight tracer (BDA-3K) was evident at 4 h post-TBI and remained visible after 7 days survival. In contrast, the larger tracer molecule (HRP) appeared in these remote areas at acute permeable sites but was not detected at later post-traumatic time periods. A regionally specific relationship was documented at 3 days between the late-occurring permeability changes observed with BDA-3K and the accumulation of CD68-positive macrophages. Mild hypothermia initiated 30 min after TBI reduced permeability to both large and small tracers and the infiltration of CD68-positive cells. These results indicate that moderate brain injury produces temperature-sensitive acute, as well as more long-lasting vascular perturbations associated with secondary injury mechanisms.
TL;DR: These findings provide novel insights into molecular mechanisms responsible for PSH associated with hemorrhagic contusions, and point to SUR1 as a potential therapeutic target in TBI.
Abstract: An important but poorly understood feature of traumatic brain injury (TBI) is the clinically serious problem of spatiotemporal progression ("blossoming") of a hemorrhagic contusion, a phenomenon we term progressive secondary hemorrhage (PSH). Molecular mechanisms of PSH are unknown and efforts to reduce it by promoting coagulation have met with equivocal results. We hypothesized that PSH might be due to upregulation and activation of sulfonylurea receptor 1 (SUR1)-regulated NC(Ca-ATP) channels in capillary endothelial cells, predisposing to oncotic death of endothelial cells and catastrophic failure of capillary integrity. Anesthetized adult male rats underwent left parietal craniectomy for induction of a focal cortical contusion. The regulatory subunit of the channel, SUR1, was prominently upregulated in capillaries of penumbral tissues surrounding the contusion. In untreated rats, PSH was characterized by progressive enlargement of the contusion deep into the site of cortical impact, including corpus callosum, hippocampus, and thalamus, by progressive accumulation of extravasated blood, with a doubling of the volume during the first 12 h after injury, and by capillary fragmentation in penumbral tissues. Block of SUR1 using low-dose (non-hypoglycemogenic) glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in the size of the necrotic lesion and in preservation of neurobehavioral function. Antisense oligodeoxynucleotide against SUR1, administered after injury, reduced both SUR1 expression and PSH, consistent with a requirement for transcriptional upregulation of SUR1. Our findings provide novel insights into molecular mechanisms responsible for PSH associated with hemorrhagic contusions, and point to SUR1 as a potential therapeutic target in TBI.
TL;DR: The purpose of this review is to consider the mechanical phases of bTBI, how these phases are reproduced with in-vitro models, and to review findings from these models to assess how each phase ofbTBI can be examined in more detail.
Abstract: Traumatic brain injury caused by explosive or blast events is currently divided into four phases: primary, secondary, tertiary, and quaternary blast injury. These phases of blast-induced traumatic brain injury (bTBI) are biomechanically distinct, and can be modeled in both in-vivo and in-vitro systems. The purpose of this review is to consider the mechanical phases of bTBI, how these phases are reproduced with in-vitro models, and to review findings from these models to assess how each phase of bTBI can be examined in more detail. Highlighted are some important gaps in the literature that may be addressed in the future to better identify the exact contributing mechanisms for bTBI. These in-vitro models, viewed in combination with in-vivo models and clinical studies, can be used to assess both the mechanisms and possible treatments for this type of trauma.
TL;DR: It is concluded that little is known regarding the directionality of TBI increasing drug abuse, and that collaborative research in this area is critically needed.
Abstract: Wars in Afghanistan and Iraq have resulted in thousands of military personnel suffering traumatic brain injury (TBI), including closed-head injuries. Of interest is whether these individuals and other TBI survivors are at increased risk for substance use disorder (SUD). While it has been well established that drug or alcohol intoxication itself increases probability of suffering a TBI in accidents or acts of violence, little is known about whether the brain insult itself increases the likelihood that a previously non-drug-abusing individual would develop SUD. Might TBI survivors be unusually vulnerable to addiction to opiate analgesics compared to other pain patients? Similarly, it is not known if TBI increases the likelihood of relapse among persons with SUD in remission. We highlight challenges in answering these questions, and review neurochemical and behavioral evidence that supports a causal relationship between TBI and SUD. In this review, we conclude that little is known regarding the directionality of TBI increasing drug abuse, and that collaborative research in this area is critically needed.
TL;DR: Mortality rates among older people (≥65 years) were significantly greater than those of younger individuals at 6 weeks, at 6 months, and at 1 year following SCI (38.6% versus 3.1%; p < 0.0001).
Abstract: Given the potential effects of age on mortality, impairment, and disability among individuals with traumatic spinal cord injury [(SCI), we examined these issues using a large, prospectively accrued clinical database. This study includes all patients who were enrolled in the Third National Spinal Cord Injury Study (NASCIS 3). Motor, sensory, and pain outcomes were assessed using NASCIS scores. Functional outcome was evaluated using the Functional Independence Measure (FIM). Data analyses included regression models adjusted for major potential confounders (i.e., sex, ethnicity, Glasgow Coma Scale [GCS] score, blood alcohol concentration on admission, drug protocol, cause, and level and severity of SCI). Mortality rates among older people (≥65 years) were significantly greater than those of younger individuals at 6 weeks, at 6 months, and at 1 year following SCI (38.6% versus 3.1%; p < 0.0001). Among survivors, age was not significantly correlated with motor recovery or change in pain scores in the ...
TL;DR: It is hypothesized that expression of tight junction protein ZO-1 and occludin, responsible for intestinal architectural and functional integrity, will decrease following TBI and increase intestinal permeability.
Abstract: Traumatic brain injury (TBI) can lead to several physiologic complications including gastrointestinal dysfunction. Specifically, TBI can induce an increase in intestinal permeability, which may lead to bacterial translocation, sepsis, and eventually multi-system organ failure. However, the exact mechanism of increased intestinal permeability following TBI is unknown. We hypothesized that expression of tight junction protein ZO-1 and occludin, responsible for intestinal architectural and functional integrity, will decrease following TBI and increase intestinal permeability. BALB/c mice underwent a weight drop TBI model following anesthesia. Brain injury was confirmed by a neurologic assessment and gross brain pathology. Six hours following injury, FITC-dextran (25 mg 4.4 kDa FITC-dextran) was injected into the intact lumen of the isolated ileum. Intestinal permeability was measured in plasma 30 min following injection, by using spectrophotometry to determine plasma FITC-dextran concentrations. Whole ileum extracts were used to measure expression of tight junction proteins ZO-1 and occludin by Western blot. TBI caused a significant increase in intestinal permeability (110.0 microg/mL +/-22.2) compared to sham animals (29.4 microg/mL +/- 9.7) 6 h after injury (p = 0.016). Expression of ZO-1 was decreased by 49% relative to sham animals (p < 0.02), whereas expression of occludin was decreased by 73% relative to sham animals (p < 0.001). An increase in intestinal permeability corresponds with decreased expression of tight junction proteins ZO-1 and occludin following TBI. Expression of intestinal tight junction proteins may be an important factor in gastrointestinal dysfunction following brain injury.
TL;DR: While current research suggests that blast injury impairs cerebral vascular compensatory responses, thereby leaving the brain vulnerable to secondary insults, the effects of blast injury on the cerebral vascular reactivity have not been investigated and it is clear that further research is necessary to address these critical concerns.
Abstract: Explosive munitions account for more than 50% of all wounds sustained in military combat, and the proportion of civilian casualties due to explosives is increasing as well. But there has been only limited research on the pathophysiology of blast-induced brain injury, and the contributions of alterations in cerebral blood flow (CBF) or cerebral vascular reactivity to blast-induced brain injury have not been investigated. Although secondary hypotension and hypoxemia are associated with increased mortality and morbidity after closed head injury, the effects of secondary insults on outcome after blast injury are unknown. Hemorrhage accounted for approximately 50% of combat deaths, and the lungs are one of the primary organs damaged by blast overpressure. Thus, it is likely that blast-induced lung injury and/or hemorrhage leads to hypotensive and hypoxemic secondary injury in a significant number of combatants exposed to blast overpressure injury. Although the effects of blast injury on CBF and cerebral vascular reactivity are unknown, blast injury may be associated with impaired cerebral vascular function. Reactive oxygen species (ROS) such as the superoxide anion radical and other ROS, likely major contributors to traumatic cerebral vascular injury, are produced by traumatic brain injury (TBI). Superoxide radicals combine with nitric oxide (NO), another ROS produced by blast injury as well as other types of TBI, to form peroxynitrite, a powerful oxidant that impairs cerebral vascular responses to reduced intravascular pressure and other cerebral vascular responses. While current research suggests that blast injury impairs cerebral vascular compensatory responses, thereby leaving the brain vulnerable to secondary insults, the effects of blast injury on the cerebral vascular reactivity have not been investigated. It is clear that further research is necessary to address these critical concerns.
TL;DR: While SWI rarely discriminated by outcome, it was very sensitive to intraparenchymal injury and its optimal use in evaluating TBI is unclear.
Abstract: Early prediction of outcomes after traumatic brain injury (TBI) is often difficult. To improve prognostic accuracy soon after trauma, we compared different radiological modalities and anat...
TL;DR: The therapeutic effect of the ketogenic diet on beam walking and cognitive performance was not observed in PND75 animals, which supports the theory about age-dependent utilization and effectiveness of ketones as an alternative fuel after TBI.
Abstract: The ketogenic diet has been shown to have unique properties that make it a more suitable cerebral fuel under various neuropathological conditions (e.g., starvation, ischemia, and traumatic brain injury (TBI). Recently, age-dependent ketogenic neuroprotection was shown among postnatal day 35 (PND35) and PND45 rats after TBI, but not in PND17 and PND65 animals (Prins et al., 2005). The present study addresses the therapeutic potential of a ketogenic diet on motor and cognitive deficits after TBI. PND35 and PND75 rats received sham or controlled cortical impact (CCI) surgery and were placed on either standard (Std) or ketogenic (KG) diet for 7 days. Beam walking and the Morris water maze (MWM) were used to assess sensory motor function and cognition, respectively. PND35 CCI Std animals showed significantly longer traverse times than sham and CCI KG animals at the beginning of motor training. Footslip analysis revealed better performance among the sham and the CCI KG animals compared to the CCI Std group. In the MWM PND35 CCI KG animals showed significantly shorter escape latencies compared to CCI Std-fed animals. During the same time period there was no significant difference between sham animals and CCI KG animals. The therapeutic effect of the ketogenic diet on beam walking and cognitive performance was not observed in PND75 animals. This finding supports our theory about age-dependent utilization and effectiveness of ketones as an alternative fuel after TBI.
TL;DR: Evidence is strongest for prehospital cardiac arrest and neonatal hypoxic-ischemic encephalopathy, while for many of the other indications, such as stroke and spinal cord injury, trials are ongoing, but the data are insufficient to recommend routine use of hypothermia at this time.
Abstract: Therapeutic moderate hypothermia has been advocated for use in traumatic brain injury, stroke, cardiac arrest-induced encephalopathy, neonatal hypoxic-ischemic encephalopathy, hepatic encephalopathy, and spinal cord injury, and as an adjunct to aneurysm surgery. In this review, we address the trials that have been performed for each of these indications, and review the strength of the evidence to support treatment with mild/moderate hypothermia. We review the data to support an optimal target temperature for each indication, as well as the duration of the cooling, and the rate at which cooling is induced and rewarming instituted. Evidence is strongest for prehospital cardiac arrest and neonatal hypoxic-ischemic encephalopathy. For traumatic brain injury, a recent meta-analysis suggests that cooling may increase the likelihood of a good outcome, but does not change mortality rates. For many of the other indications, such as stroke and spinal cord injury, trials are ongoing, but the data are insufficient to recommend routine use of hypothermia at this time.
TL;DR: The impact of TBI on traditional measures, self-assessed health function status using the SF-36 version 2 (SF-36V2), and self-Assessed health preference using two generic utility instruments, the assessment of quality of life (AQoL) and the SF6D are reported.
Abstract: Recent calls have been made for the inclusion of health-related quality of life (HRQoL) in traumatic brain injury studies. This study reports the impact of TBI on traditional measures (general health, depression, social isolation, labor force participation), self-assessed health function status using the SF-36 version 2 (SF-36V2), and self-assessed health preference using two generic utility instruments, the assessment of quality of life (AQoL) and the SF6D. A random sample of TBI cases (n = 66) was drawn from a trauma registry and matched (gender, age, education, and relationship status) with non-trauma-exposed cases from a population health survey. All participants were interviewed and the two cohorts compared. When compared with matched comparators, TBI cases experienced worse general health, elevated probabilities of depression, social isolation, and worse labor force participation rates. The TBI-cohort reported worse health status on the SF-36V2. The most affected areas were social function,...
TL;DR: The study represents the largest, modern series of hypothermia treatment of acute spinal cord injury with intravascular cooling techniques and provides needed baseline data for outcome studies to include larger multi-center, randomized trials.
Abstract: There is widespread interest in the use of hypothermia in the treatment of CNS injury. While there is considerable experience in the use of cooling for a variety of brain pathologies, limited data exist after spinal cord injury. In the past few years, technological advances in the induction and maintenance of cooling have been achieved and can potentially allow for a more accurate evaluation of this form of treatment. We report a series of 14 patients with an average age of 39.4 years (range, 16–62 years) with acute, complete (AIS A) cervical spinal cord injuries who underwent a protocol using an intravascular cooling catheter to achieve modest (33°C) systemic hypothermia. There was an excellent correlation between intravascular and intrathecal cerebrospinal fluid temperature. The average time between injury and induction of hypothermia was 9.17 ± 2.24 h (mean ± SEM); the time to target temperature was 2.72 ± 0.42 h; the duration of cooling at target temperature was 47.6 ± 3.1 h; the average tota...
TL;DR: This study is the first to systematically determine relative recovery in vitro for a wide range of cytokines using both crystalloid and colloid perfusate, and the two forms of perfusion fluid require direct comparison in vivo.
Abstract: Cerebral microdialysis is a monitoring technique with expanding clinical and research utility following traumatic brain injury. This study's aim was to determine the relative recovery for 12 cytokines using both crystalloid (CNS perfusion fluid) and colloid (CNS perfusion fluid supplemented with 3.5% human serum albumin) perfusate. Six CMA71 microdialysis catheters (nominal molecular weight cut-off 100 kDa) were perfused in vitro with either crystalloid or colloid and the relative recovery (%) determined for the cytokines as follows (crystalloid/colloid perfusate): IL-1α (50.6/48), IL-1β (34.6/38.4), IL-1ra (21.9/38.4), IL-2 (17.1/52.8), IL-4 (26/56.7), IL-6 (9.8/25.5), IL-8 (47.7/73.4), IL-10 (2.9/8.7), IL-17 (14.4/43.7), TNF-α (4.4/31.2), MIP-1α (31.8/55.6), and MIP-1β (31.9/50.1). The colloid perfusate significantly improved relative recovery for nine of these cytokines (p < 0.05), but not for IL-1α, IL-1β, and IL-8. Relative recovery was related to apparent molecular weight of cytokine and to...