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Over the past few decades, tremendous advances have been made in our understanding of the biological changes underpinning the devastating impairment of traumatic spinal cord injury (SCI). Much of this scientific research has focused on animal models of SCI, and comparatively little has been done in human SCI, largely because biospecimens from human SCI patients are not readily available. This paucity of scientific enquiry in human SCI represents an important void in the spectrum of translational research, as biological differences between animal models and the human condition need to be considered in the pre-clinical development of therapeutic approaches. The International Spinal Cord Injury Biobank (ISCIB) is a multi-user biorepository with the mission of accelerating therapeutic development in traumatic SCI through improved biological understanding of human injury, and the vision of serving as a global research resource where human SCI biospecimens are shared with researchers around the world. Aligned with internationally recognized best practices, ISCIB's formal governance structure and standard operating procedures have earned it official biobank certification through the Canadian Tissue Repository Network. Herein, we describe the translational research gap that ISCIB is helping to fill; its structure, governance and certification; how data and samples are accrued, processed and stored; and finally, the process through which samples and data are shared with global researchers. The purpose of this paper describing ISCIB is to serve as an introductory guidance document for the wider community of SCI researchers. By helping researchers understand the contents of ISCIB and the process of accessing biospecimens, we seek to further ISCIB's vision as being a resource for human and translational research in SCI, with the ultimate goal of finding disease-modifying therapies for this disabling condition.

This study investigates subacute cognitive effects of mild traumatic brain injury (MTBI) in the Trondheim Mild TBI Study, as measured, in part, by the neuropsychological test battery of the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) program, including computerized tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and traditional paper-and-pencil tests. We investigated whether cognitive function was associated with injury severity: intracranial traumatic lesions on neuroimaging, witnessed loss of consciousness (LOC), or post-traumatic amnesia (PTA) >1 h. Further, we explored which of the tests in the CENTER-TBI battery might be associated with the largest subacute effects of MTBI (i.e., at 2 weeks post-injury). We recruited 177 patients with MTBI (16-59 years of age) from a regional trauma center and an outpatient clinic,79 trauma control participants, and 81 community control participants. The MTBI group differed from community controls only on one traditional test of processing speed (coding; p  = 0.009, Cliff's delta [Δ] = 0.20). Patients with intracranial abnormalities performed worse than those without on a traditional test (phonemic verbal fluency; p  = 0.043, Δ = 0.27), and patients with LOC performed differently on the Attention Switching Task from the CANTAB ( p  = 0.020, Δ = -0.20). Patients with PTA >1 h performed worse than those with <1 h on 10 measures, from traditional tests and the CANTAB (Δ = 0.33-0.20), likely attributable, at least in part, to pre-existing differences in intellectual functioning between groups. In general, those with MTBI had good neuropsychological outcome 2 weeks after injury and no particular CENTER-TBI computerized or traditional tests seemed to be more sensitive to subtle cognitive deficits.

Chronic traumatic encephalopathy (CTE) is associated with pathological changes, yet detecting these changes during life has proven elusive. Positron emission tomography (PET) offers the potential for identifying such pathology. Few studies have been completed to date and their approaches and results have been diverse. It was the objective of this review to systematically examine relevant research using ligands for PET that bind to identified pathology in CTE. We focused on identification of patterns of binding and addressing gaps in knowledge of PET imaging for CTE. A comprehensive literature search was conducted. Data used were published on or before May 22, 2017. As the extant literature is limited, any peer-reviewed article assessing military, contact sports athletes, or professional fighters was considered for inclusion. The main outcomes were regional binding to brain regions identified through control comparisons or through clinical metrics (e.g., standardized uptake volume ratios). A total of 1207 papers were identified for review, of which six met inclusion criteria. Meta-analyses were planned but were deemed inappropriate given the small number of studies identified. Methodological concerns in these initial papers included small sample sizes, lack of a control comparison, use of nonstandard statistical procedures to quantify data, and interpretation of potentially off-target binding areas. Across studies, the hippocampi, amygdalae, and midbrain had reasonably consistent increased uptake. Evidence for increased uptake in cortical regions was less consistent. The evidence suggests that the field of PET imaging in those at risk for CTE remains nascent. As the field evolves to include more stringent studies, ligands for PET may prove an important tool in identifying CTE in vivo.

To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results.

The incidence of traumatic brain injury (TBI) in the United States was 3.5 million cases in 2009, according to the Centers for Disease Control and Prevention. It is a contributing factor in 30.5% of injury-related deaths among civilians. Additionally, since 2000, more than 260,000 service members were diagnosed with TBI, with the vast majority classified as mild or concussive (76%). The objective assessment of TBI via imaging is a critical research gap, both in the military and civilian communities. In 2011, the Department of Defense (DoD) prepared a congressional report summarizing the effectiveness of seven neuroimaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], transcranial Doppler [TCD], positron emission tomography, single photon emission computed tomography, electrophysiologic techniques [magnetoencephalography and electroencephalography], and functional near-infrared spectroscopy) to assess the spectrum of TBI from concussion to coma. For this report, neuroimaging experts identified the most relevant peer-reviewed publications and assessed the quality of the literature for each of these imaging technique in the clinical and research settings. Although CT, MRI, and TCD were determined to be the most useful modalities in the clinical setting, no single imaging modality proved sufficient for all patients due to the heterogeneity of TBI. All imaging modalities reviewed demonstrated the potential to emerge as part of future clinical care. This paper describes and updates the results of the DoD report and also expands on the use of angiography in patients with TBI.

The aim of this study was to systematically review clinical studies examining biofluid biomarkers of brain injury for concussion in athletes. Data sources included PubMed, MEDLINE, and the Cochrane Database from 1966 to October 2013. Studies were included if they recruited athletes participating in organized sports who experienced concussion or head injury during a sports-related activity and had brain injury biomarkers measured. Acceptable research designs included experimental, observational, and case-control studies. Review articles, opinion papers, and editorials were excluded. After title and abstract screening of potential articles, full texts were independently reviewed to identify articles that met inclusion criteria. A composite evidentiary table was then constructed and documented the study title, design, population, methods, sample size, outcome measures, and results. The search identified 52 publications, of which 13 were selected and critically reviewed. All of the included studies were prospective and were published either in or after the year 2000. Sports included boxing (six studies), soccer (five studies), running/jogging (two studies), hockey (one study), basketball (one study), cycling (one study), and swimming (one study). The majority of studies (92%) had fewer than 100 patients. Three studies (23%) evaluated biomarkers in cerebrospinal fluid (CSF), one in both serum and CSF, and 10 (77%) in serum exclusively. There were 11 different biomarkers assessed, including S100β, glial fibrillary acidic protein, neuron-specific enolase, tau, neurofilament light protein, amyloid beta, brain-derived neurotrophic factor, creatine kinase and heart-type fatty acid binding protein, prolactin, cortisol, and albumin. A handful of biomarkers showed a correlation with number of hits to the head (soccer), acceleration/deceleration forces (jumps, collisions, and falls), postconcussive symptoms, trauma to the body versus the head, and dynamics of different sports. Although there are no validated biomarkers for concussion as yet, there is potential for biomarkers to provide diagnostic, prognostic, and monitoring information postinjury. They could also be combined with neuroimaging to assess injury evolution and recovery.

The focus of this paper is to identify and quantify risk factors for early hemorrhagic progression of brain contusions (HPC) in patients with traumatic brain injury (TBI) and to evaluate their impact on patients' outcome. Further, based on abnormal values in routine blood tests, the role of trauma-induced coagulopathy is analyzed in detail. Therefore, a prospective study of 153 TBI patients was completed at one institution between January 2008 and June 2012. The collected data included demographics, initial Glasgow Coma Scale pupillary response, initial and 6 h follow-up computed tomography scan findings, coagulation parameters (international normalized ratio, partial thromboplastin time, platelet count, fibrinogen, D-dimer and factor XIII), as well as outcome data using the modified Rankin score at discharge and after one year. The overall rate of early HPC within the first 6 h was 43.5%. The frequency of coagulopathy was 47.1%. When analyzing for risk factors that independently influenced outcome in the form of mRS ≥4 at both points, the following variables appeared: elevated D-dimer level (≥10,000 μg/L), HPC, and initial brain contusions ≥3 cm. Patients sustaining early HPC had a hazard ratio of 5.4 for unfavorable outcome at discharge (p=0.002) and of 3.9 after one year (p=0.006). Overall, patients who developed early HPC were significantly more likely to be gravely disabled or to die. Unfavorable neurological outcome after an isolated TBI is determined largely by early HPC and coagulopathy, which seem to occur very frequently in TBI patients, irrespective of the severity of the trauma.

"Breachers" are a unique military and law enforcement population because they are routinely exposed to low-level blast (LLB) during training and operations. This repeated exposure has been associated with symptoms similar to that of sports concussion. This study examined effects of repeated exposure to LLB during an explosive entry course. Twenty-one members of the New Zealand Defence Force volunteered for this study. Serum samples, neurocognitive performance, and self-reported symptoms were periodically measured before, during, and after a 2-week course. Serum concentrations of three biomarkers, ubiquitin C-terminal hydrolase-L1, αII-spectrin breakdown product, and glial fibrillary acidic protein, were determined with sandwich enzyme-linked immunosorbent assays, and rank scores were derived using the area under the curve (relative to baseline) for each subject. Neurocognitive performance was measured with a computer-based test battery, and symptoms were assessed by paper-based inventory. There was a significant relationship (p<0.05) between composite biomarker and neurocognitive performance and between neurocognitive performance and symptoms. The individuals with the five highest (Top 5) and lowest (Bottom 5) composite biomarker scores were identified and compared using Wilcoxon's rank-sum test. The Top 5 had significantly longer reaction times and lower percent correct on neurocognitive performance and an increase in symptom reporting. The difference between individuals expressing the highest biomarker load during breacher training (Top 5) and those with the lowest biomarker load (Bottom 5) is reflected in neurocognitive performance deficits and self-reported symptoms. This suggests a measureable degree of brain perturbation linked to LLB exposure. Follow-up studies are underway to expand upon these results.

Although research in the field of spinal cord injury (SCI) is a relatively new endeavor, a remarkable number of papers focused on this subspecialty have been published in a broad variety of journals over the last two decades. A multidisciplinary group of experts, including clinical epidemiologists, neurosurgical and orthopedic spine surgeons, basic scientists, rehabilitation specialists, intensivists, and allied health professionals (nursing and physical therapy) was assembled through the Spinal Cord Injury Solutions Network to summarize the existing literature focusing on 12 key topics related to acute traumatic SCI, which have not been recently reviewed. The objective was to develop evidence-based recommendations to help translate current science into clinical practice and to identify new directions for research. For each topic one to three specific questions were formulated by consensus through the expert panel. A systematic review of the literature was performed to determine the current evidence for the specific questions. A primary literature search was performed using MEDLINE, CINAHL, EMBASE, and Cochrane databases. A secondary search strategy incorporated additional articles referenced in significant publications (i.e., meta-analysis, systematic and nonsystematic review articles). Two reviewers independently reviewed the titles and abstracts yielded by this comprehensive search and subsequently selected articles based on the predetermined inclusion and inclusion criteria. Data were extracted for population into evidentiary tables. Selected articles were rated for level of evidence and methodological quality, information that was also included in evidentiary tables. Disagreements were resolved by a third reviewer or consensus-based discussion. Based on the evidence compiled, answers to the targeted questions were formulated and recommendations generated by consensus-based discussion and anonymized voting using Delphi methodology. A level of consensus of 80% or higher was considered to represent strong agreement.

Spinal Cord Injury (SCI) in the pediatric population is relatively rare but carries significant psychological and physiological consequences. An interdisciplinary group of experts composed of medical and surgical specialists treating patients with SCI formulated the following questions: 1) What is the epidemiology of pediatric spinal cord injury and fractures?; 2) Are there unique features of pediatric SCI which distinguish the pediatric SCI population from adult SCI?; 3) Is there evidence to support the use of neuroprotective approaches, including hypothermia and steroids, in the treatment of pediatric SCI? A systematic review of the literature using multiple databases was undertaken to evaluate these three specific questions. A search strategy composed of specific search terms (Spinal Cord Injury, Paraplegia, Quadriplegia, tetraplegia, lapbelt injuries, seatbelt injuries, cervical spine injuries and Pediatrics) returned over 220 abstracts that were evaluated and by two observers. Relevant abstracts were then evaluated and papers were graded using the Downs and Black method. A table of evidence was then presented to a panel of experts using a modified Delphi approach and the following recommendation was then formulated using a consensus approach: Pediatric patients with traumatic SCI have different mechanisms of injury and have a better neurological recovery potential when compared to adults. Patients with SCI before their adolescent growth spurt have a high likelihood of developing scoliosis. Because of these differences, traumatic SCI should be highly suspected in the presence of abnormal neck or neurological exam, a high-risk mechanism of injury or a distracting injury even in the absence of radiological anomaly.

Magnetic resonance imaging (MRI) has become the gold standard for imaging neurological tissues including the spinal cord. The use of MRI for imaging in the acute management of patients with spinal cord injury has increased significantly. This paper used a vigorous literature review with Downs and Black scoring, followed by a Delphi vote on the main conclusions. MRI is strongly recommended for the prognostication of acute spinal cord injury. The sagittal T2 sequence was particularly found to be of value. Four prognostication patterns were found to be predictive of neurological outcome (normal, single-level edema, multi-level edema, and mixed hemorrhage and edema). It is recommended that MRI be used to direct clinical decision making. MRI has a role in clearance, the ruling out of injury, of the cervical spine in the obtunded patient only if there is abnormality of the neurological exam. Patients with cervical spinal cord injuries have an increased risk of vertebral artery injuries but the literature does not allow for recommendation of magnetic resonance angiography as part of the routine protocol. Finally, time repetition (TR) and time echo (TE) values used to evaluate patients with acute spinal cord injury vary significantly. All publications with MRI should specify the TR and TE values used.

Specialized centers of care for spinal cord injury (SCI) were first established in 1944 in England. The objective of these centers is to improve care and neurological recovery of patients suffering from a spinal cord injury. An interdisciplinary group of experts composed of medical and surgical specialists treating patients with SCI formulated the following questions: (1) Is there any evidence to suggest that specialized centers of care in SCI decrease the length of patient stay? and (2) Is there evidence that specialized centers of care for SCI reduce mortality and secondary complications? A systematic review of the current evidence was performed using multiple databases to answer these two specific questions. Two independent reviewers graded each paper using the Black and Downs method. Recommendations were then formulated based on the evidence available and were reviewed by a panel of experts using a modified Delphi approach. Two recommendations were formulated and both received complete agreement from a panel of experts. The first recommendation is "Early transfer of a patient with traumatic SCI to a specialized center of care should be done promptly to decrease overall length of stay." The second recommendation is "Early transfer of patients with traumatic SCI to an integrated multidisciplinary specialized center of care decreases overall mortality, and the number and severity of complications."

Spinal cord injury (SCI) leading to neurological deficits produces long-term effects that persist over a lifetime. Survival analysis of patients with SCI, at individual and population level, is important for public health management and the assessment of treatment achievements. The current study evaluated survival following traumatic and non-traumatic SCI worldwide. A systematic review was conducted, and all included papers were assessed for quality using a purposely designed assessment form. Survival data were presented in Kaplan-Meier curves and compared using the log-rank test. Sixteen studies were included of which 11 concerned traumatic SCI, four non-traumatic SCI, and one both. Crude standard mortality rates (SMRs) revealed that overall mortality in SCI is up to three times higher than in the general population. Survival rates were statistically significantly lower in non-traumatic SCI than in traumatic SCI (log-rank p = 0.000). Age at injury, neurological level, extent of lesion, and year of injury have been described as predictors of survival. Causes of death stem from secondary complications, with failure of the respiratory system being the leading cause. This is the first systematic literature review on survival analysis following SCI worldwide. An increase in survival over time was found. However, the SMRs of individuals with SCI still exceed those of an age-matched non-disabled population, mainly due to secondary complications. Lower survival rates were observed in non-traumatic SCI compared with traumatic SCI.

Therapeutic hypothermia is a promising method for controlling intracranial pressure (ICP) in severely brain-injured patients. However, clinical data regarding the effect of brain hypothermia on overall outcome of these patients is limited. This may be because there are specific pitfalls associated with the clinical management of induced hypothermia in patients with severe traumatic brain injury (TBI). These pitfalls may be avoided by preventing specific risk factors when cooling is induced and with rewarming. However, these risk factors have not been well systematically discussed in the literature. In this paper, three categories of clinical issues regarding the management of brain hypothermia are discussed: (1) stress-induced secondary brain injury mechanisms; (2) technical aspects of intensive care unit (ICU) cooling management; and (3) rewarming rates and methods. For patients with a Glasgow Coma Scale (GCS) score of less than 8, management of stress-induced insulin-resistant hyperglycemia, and unstable systemic circulation due to impaired cardiac contractility are especially important. For example, in our experience, posttraumatic hyperglycemia, exacerbated by cooling, may be ameliorated by the administration of a ketone body with mannitol. Prevention of selective free radical damage to neurons is also an important target for successful brain hypothermia treatment. Taken together, it is clear that several orchestrated steps should be initiated to enhance the protective effects of hypothermia therapy and prevent these possible pitfalls.

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.

With the resurgence of clinical trials in spinal cord injury (SCI), there is intense interest in whether the American Spinal Injury Association (ASIA) standards are sensitive enough to discriminate neurological recovery. We conducted a systematic review to examine the psychometric properties of the ASIA Standards in assessing motor and sensory function of individuals with acute traumatic SCI. Papers, which examined the psychometric properties of the ASIA Standards, were obtained from Medline, CINAHL, and EMBASE databases (1982-2008). Of 39 publications primarily identified, 18 fulfilled the inclusion and exclusion criteria. An additional 51 publications were captured in a secondary search using the bibliographies from original articles and published reviews. The 2000 version of the ASIA Standards appear to be more reliable than the previous versions, although two prospective studies indicate that the ASIA Standards do not reliably assess children less than 4 years with SCI. Responsiveness studies indicate that (a) a detailed neurological examination using the ASIA Standards at 72 h should be obtained for comparison with subsequent neurological assessments following SCI; (b) the use of ASIA upper- and lower-extremity motor subscores instead of a single ASIA motor score is recommended; (c) further investigation of the minimal clinically important difference of the ASIA Standards is required; and (d) the functionally meaningful ASIA score threshold to document the benefit of a novel therapeutic intervention varies according to the level and severity of SCI. Although the ASIA Standards cannot be evaluated in terms of criterion validity, several studies suggested their divergent and convergent construct validity. Therefore, the ASIA Standards represent an appropriate instrument to discriminate and evaluate patients with SCI in a longitudinal manner. Nonetheless, further investigation of the ASIA Standards is recommended due to a paucity of studies focused on some key elements of the measurement responsiveness, including minimal clinically important difference.

The univariate prognostic analysis of the IMPACT database on traumatic brain injury (TBI) poses the formidable challenge of how best to summarize a highly complex set of data in a way which is accessible without being overly simplistic. In this paper, we describe and illustrate the battery of statistical methods that have been used. Boxplots, histograms, tabulations, and splines were used for initial data checking and in identifying appropriate transformations for more formal statistical modeling. Imputation techniques were used to minimize the problems associated with the analysis of incomplete data due to missing values. The associations between covariates and outcome (Glasgow Outcome Scale [GOS] assessed at 6 months) were expressed as odds ratios with supporting confidence intervals when the GOS was collapsed to a dichotomous scale. This was extended to use common odds ratios from proportional odds models to express associations over the full range of the GOS. Forest plots were used to illustrate the consistency of results from study to study within the IMPACT database. The overall prognostic strength of the prognostic factors was expressed as the proportion of variance explained (Nagelkerke's R(2) statistic). Many of our approaches are based on simple graphical displays of the data, but, where appropriate, we have also used methods that although established in the statistical literature are relatively novel in their application to TBI.

Following spinal cord injury (SCI), descending axons that carry motor commands from the brain to the spinal cord are injured or transected, producing chronic motor dysfunction and paralysis. Reconnection of these axons is a major prerequisite for restoration of function after SCI. Thus far, only modest gains in motor function have been achieved experimentally or in the clinic after SCI, identifying the practical limitations of current treatment approaches. In this paper, we use an ordinary differential equation (ODE) to simulate the relative and synergistic contributions of several experimentally-established biological factors related to inhibition or promotion of axonal repair and restoration of function after SCI. The factors were mathematically modeled by the ODE. The results of our simulation show that in a model system, many factors influenced the achievability of axonal reconnection. Certain factors more strongly affected axonal reconnection in isolation, and some factors interacted in a synergistic fashion to produce further improvements in axonal reconnection. Our data suggest that mathematical modeling may be useful in evaluating the complex interactions of discrete therapeutic factors not possible in experimental preparations, and highlight the benefit of a combinatorial therapeutic approach focused on promoting axonal sprouting, attraction of cut ends, and removal of growth inhibition for achieving axonal reconnection. Predictions of this simulation may be of utility in guiding future experiments aimed at restoring function after SCI.

Quantitative neuroimaging is increasingly used to study the effects of traumatic brain injury (TBI) on brain structure and function. This paper reviews quantitative structural and functional neuroimaging studies of patients with TBI, with an emphasis on the effects of diffuse axonal injury (DAI), the primary neuropathology in TBI. Quantitative structural neuroimaging has evolved from simple planometric measurements through targeted region-of-interest analyses to whole-brain analysis of quantified tissue compartments. Recent studies converge to indicate widespread volume loss of both gray and white matter in patients with moderate-to-severe TBI. These changes can be documented even when patients with focal lesions are excluded. Broadly speaking, performance on standard neuropsychological tests of speeded information processing are related to these changes, but demonstration of specific brain-behavior relationships requires more refined experimental behavioral measures. The functional consequences of these structural changes can be imaged with activation functional neuroimaging. Although this line of research is at an early stage, results indicate that TBI causes a more widely dispersed activation in frontal and posterior cortices. Further progress in analysis of the consequences of TBI on neural structure and function will require control of variability in neuropathology and behavior.

Traumatic brain injury is a leading cause of death and disability in the United States. Pathological examinations of humans and animal models after brain injury demonstrate hippocampal neuronal damage, which may contribute to cognitive impairments. Data from our laboratories have shown that, at 1 week after brain injury, mice possess significantly fewer neurons in all ipsilateral hippocampal subregions and a cognitive impairment. Since cognitive function is distributed across both cerebral hemispheres, the present paper explores the morphological and physiological response of the contralateral hippocampus to lateral brain injury. We analyzed the contralateral hippocampus using design-based stereology, Fluoro-Jade (FJ) histochemistry, and extracellular field recordings in mice at 7 and 30 days after lateral fluid percussion injury (FPI). At 7 days, all contralateral hippocampal subregions possess significantly fewer healthy neurons compared to sham-injured animals and demonstrate FJ-positive neuronal damage, but not at 30 days. Both the ipsilateral and contralateral dentate gyri demonstrate significantly increased excitability at 7 days post-injury, but only ipsilateral dentate gyrus hyperexcitability persists at 30 days compared to sham. In the contralateral hippocampus, the transient decrease in the number of healthy neurons, concomitant with FJ damage, and electrophysiological alterations establish a stunned period of cellular and circuit dysfunction. The return of healthy neuron number, absence of FJ damage, and sham level of excitability in the contralateral hippocampus suggest recovery of structure and function by 30 days after injury. The cognitive recovery observed after human traumatic brain injury may stem from a differential injury exposure and time course of recovery between homologous regions of the two hemispheres.

Fas receptor activation has been implicated in inflammatory responses, programmed cell death, Wallerian degeneration in neural injury and the axotomy induced death of motoneurons. Recent work using transection models of spinal cord injury (SCI) demonstrated that neutralization of Fas ligand with antibodies may promote axonal regeneration and functional recovery. Moreover, recent studies from our laboratory in mutant mice with deficient expression of Fas, show reduced cell death and enhanced behavioural recovery after SCI. The present paper examines the effects of soluble Fas receptor (sFasR) administration on inhibition of Fas receptor-Fas ligand interaction in the setting of acute SCI in vitro and in vivo. An in vitro model of SCI demonstrated that sFasR administration decreases cell death as assessed by propidium iodide fluorescence. Furthermore, in a moderately severe in vivo clip compression model of SCI at C7-T1, we demonstrate that subarachnoid infusion of sFasR results in increased neuron and oligodendrocyte survival, improved tissue and long tract axonal preservation, reduced apoptotic cell death and enhanced functional neurological outcome after acute SCI. These results strongly suggest that inhibiting Fas receptor activation is neuroprotective after acute SCI and that this strategy may have important translational significance.

Previous studies have resulted in conflicting results regarding the predictive effect of various clinical symptoms, signs, and plain imaging for intracranial pathology in adults with minor head injury. We sought to perform a meta-analysis of the literature to assess the significance of these factors for the prediction of intracranial hemorrhage (ICH). The literature was searched using Medline, Embase, Experts, and the Grey literature. Reference lists of major guidelines were crosschecked. Included were control or nested case control studies of patients attending hospital with head injury that recorded clinical correlates relating to the outcome variable of presence or absence of ICH. The common relative risk ratio was calculated using the Mantel-Haenszel test with a pooled estimate. Thirty-five papers containing 83,636 patients were included in the meta-analysis after systematic review of the literature. Relative risk ratios were calculated for 23 clinical correlates from the history, the mechanism of injury, and the examination. In addition, adjusted relative risks were presented for those variables that showed significant heterogeneity across studies. Reasons for the heterogeneity are discussed. This study has determined the relative risks of 23 clinical variables that may predict the presence of an ICH in patients after minor head injury. These risks should prove invaluable to clinicians for the assessment of individual patients as well as the assessment of guidelines presented for the management of minor head injuries.

Cerebral blood flow (CBF) alterations following post-traumatic contusions have been demonstrated in recent papers. We evaluated regional CBF (rCBF) by means of Xenon-enhanced computerized tomography (Xe-CT) in 29 traumatic intracerebral hematomas, from 22 patients with severe head injury (GCS < or = 8). Fifty traumatic hematoma/Xe-CT CBF measurements were obtained from 39 Xe-CT studies performed during the acute phase (corresponding to the first 20 days post-injury). The rCBF was measured in three different regions of interest: the hemorrhagic core, the perihematoma edematous low-density area, and a 1-cm rim of perihematoma normal-appearing brain tissue, surrounding the edematous low-density area. We found a centrifugal improvement of rCBF as well as a decrease in the rates of CBF levels below 18 mL/100 g/min from the core to the periphery (p < 0.0001), which persisted over time. Ischemic rCBF values were detected in the perihematoma low-density area only in 24% of the traumatic hematomas. The time course of rCBF levels showed a reduced flow in the first 24 h, with a recovery of flow from day 2 to day 4, followed by another reduced flow (p < or = 0.0001) both in the perihematoma edematous low-density area and in the non-lesioned tissue. Our findings suggest that the only area with persistent ischemic values was the hemorrhagic core. Low rCBF levels seen in the perihematoma low-density area may only be ascribed partially to ischemia and can possibly recover over time. These results could encourage a surgical approach based on an early evacuation of the hemorrhagic core associated to a preservation of the surrounding edematous tissue.

Olfactory ensheathing cells (OECs) have recently been shown to have a remarkable ability to repair spinal cord injury. These cells were originally selected for transplant-mediated repair as their inherent behavior in the olfactory system is to support continual regeneration of olfactory receptor neurons throughout life. What is unique about this system is that olfactory receptor neurons, from the PNS are able to extend primary axons from the olfactory mucosa into the central nervous system (CNS) tissue of the olfactory bulb and synapse with second order neurons. This is one of the rare instances of axons crossing from the peripheral neurons system (PNS) into the CNS in the adult animal. In this paper the basic biology of these cells is described, making comparison with another promising candidate for transplant-mediated repair, the Schwann cell. The growth factor requirement for OECs is summarized detailing the influence of these factors on their antigenic and morphological characteristics. Evidence that OECs have distinct glial cell properties is provided with emphasis on their unique ability to interact with astrocytes. A brief background is given of the data obtained using OECs in transplantation studies and the resulting pros and cons discussed with emphasis on limitations of functional recovery.

Selection and implementation of behavioral tests in spinal cord injury research is an important process, and yet few papers have focused on these issues. The critical component of any behavioral experiment is the ability to produce reliable, reproducible, and worthwhile data. Unfortunately, the difference between worthwhile and worthless data is often subtle. This paper describes factors that must be considered in order to select the most sensitive behavioral tests to match the hypothesis of the experiment and apply any test in a standardized, consistent manner. Classifications of behavioral tests, their strengths and limitations, as well as methods to overcome these limitations are discussed. Recent work in translating behavioral tests from rats to mice is also provided. The purpose of this article is to provide a framework by which behavioral testing can be standardized within and across spinal cord injury labs.

It is the aim of the present paper to correlate clinical symptoms of auditory dysfunction (tinnitus, hyperacusis, hearing loss) one year on average after a blunt trauma of the head with objective audiological test results (otoacoustic emission and auditory brainstem response testing, impedance audiometry) and to compare these findings to controls without history of head trauma. Thirty-one patients (24-56 years) were included. They were largely female (n = 26). The clinical and otolaryngological examination (including otoscopy) of all patients revealed no pathological abnormalities. Pure-tone audiograms were normal with one exception (pre-existing noise-induced hearing loss) as well as tympanograms. The main auditory symptoms were tinnitus (n = 9), hyperacusis (n = 2) and a reported transient hearing loss immediately after the trauma (n = 16) (which had improved at the time of examination). The results of testing the central auditory pathway showed that the transiently evoked otoacoustic emissions (otoemissions) revealed statistically significant differences between amplitude differences of all patients as well as patients with tinnitus and controls in the linear, but not in the non-linear stimulation mode. A complete loss of stapedial reflex responses was found in 12 of the patients and a partial (irregular) loss (in at least more than two frequencies) in four additional patients. Auditory brainstem responses (ABR) were normal in all patients, but 76% had lowered loudness discomfort levels (LDL). Blunt trauma of the head can lead to auditory dyfunction, probably as a result of diffuse axonal injury of the central auditory pathway. An initial sensorineural hearing loss after the trauma (as a result of the inner ear fluid concussion) was transiently reported only. Auditory symptoms play a minor role in the so-called "postconcussive syndrome," but should be considered and evaluated fully.

Traumatic brain injury is known to cause several secondary effects, one of which is altered drug clearance. Given the fact that patients who sustain TBI are subsequently treated with a variety of pharmacological agents for the purpose of either neuroprotection or physiological support, it is imperative to clarify changes in expression and/or activities of enzymes involved in clearing drugs. The mixed function oxidase system, which consists of cytochrome P450 and cytochrome P450 reductase, plays a vital role in phase I drug metabolism. This paper addresses the issue as to what extent TBI affects the levels and activity of various rat CYP450 subfamilies. Our results show that TBI induces tissue-specific and time-dependent alterations. Total hepatic CYP450 content showed a biphasic response with a decrease seen at 24 h followed by an increase at 2 weeks. CYP450 reductase, in contrast, showed an opposite temporal profile. Immunoblot analyses and marker substrate metabolism demonstrated a clear decrease in hepatic CYP1A levels while a significant increase in kidney was seen at both 24 h and 2 weeks. A dramatic induction of CYP3A was evident at 2 weeks in liver, while no changes were noticed in CYP2B or CYP2D subfamilies. CYP4F subfamily showed induction in kidney only. Collectively, the data reveal the differential effects of TBI on hepatic and renal drug metabolism.

This paper describes a biomechanical study of axonal injury due to a blunt impact to the head. The aim of the experimental model was to produce axonal injury analogous to that seen in human trauma while measuring the dynamics of the impact and the subsequent kinematics of the head. These measurements were made in a way to facilitate the simulation of these experiments using the finite element method. Sheep were anaesthetised and ventilated, and subjected to a single impact to the lateral aspect of their skull. The impact force was measured throughout the duration of the impact and the kinematics of the head was measured using a novel implementation of a nine-accelerometer array. The axonal injury was identified using amyloid precursor protein (APP) as a marker, intensified using antigen retrieval techniques. Axonal injury was consistently produced in all animals. Commonly injured regions included the sub-cortical and deep white matter, and the periventricular white matter surrounding the lateral ventricles. The observed axonal injury was mapped and quantified on three coronal sections of each brain. The measure used to describe the injury severity correlated with the peak magnitude of the impact force and with peak values of kinematic parameters, particularly the peak change of linear and angular velocity.

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate significant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.

This paper describes a modification of a balloon-compression technique to produce spinal cord injury in adult rats. A 2-French Fogarty catheter is inserted into the dorsal epidural space through a small hole made in T10 vertebral arch, advanced cranially to T8-9 spinal level, and inflated for 5 min. Spinal cord damage is graded by increasing the volume of saline used to inflate the balloon. Quantitative neurological and histopathological outcomes are presented with three different volumes (10, 15, and 20 microl of saline) to characterize the gradation of injury. Volume of 15 microl produced complete paraplegia followed by gradual recovery, finally reaching approximately the middle of the scale used to quantitate the locomotor performance. With these animals, after 4 weeks, the center of the lesion shows complete loss of grey matter and partial sparing of the white matter. We conclude that 15 microl volume produced submaximal injury that will be useful for studying the pathophysiology and effects of protective therapies with this compression-injury model.

Repinotan is a high-affinity, selective, full agonist of the 5HT1A-receptor subtype with neuroprotective properties. This paper presents the results of a randomized, double-blind, placebo-controlled study examining the safety and tolerability of three different doses of repinotan in patients with severe traumatic brain injury. Sixty patients were enrolled to receive repinotan (0.5, 1.25, or 2.50 mg/day) or placebo, by continuous i.v. infusion for 7 days. Repinotan treatment had no apparent adverse effects on intracranial pressure, hemodynamic parameters or laboratory parameters. No seizures occurred during treatment, and the incidence and severity of adverse events was as expected for this indication. No serious adverse events were considered related to drug treatment, with the possible exception of one case of inappropriate ADH secretion. No further safety concerns were raised during the 3 months following treatment. On a descriptive basis, the proportion of patients having good outcome or moderate disability (Glasgow Outcome Scale) was somewhat greater in repinotan-treated patients (60%) than in placebo (50%).

Neurobehavioral assessment of outcome has played an integral part in traumatic brain injury (TBI) research. Given the fundamental role of neurobehavioral measurement, it is critical that the tasks used are of the highest psychometric quality. The purpose of this paper is to evaluate several, commonly used neurobehavioral measures along the dimensions of reliability, sensitivity, and validity. Using both the midline and lateral fluid-percussion injury models, nine neurobehavioral measures were evaluated that assessed three different neurobehavioral constructs. Reflex suppression was measured by the duration of the suppression of the pinna, corneal, and righting reflexes. Vestibulomotor function was assessed with the beam-balance, beam-walking, and rotorod tasks. Cognitive function was evaluated by three measures of Morris water maze performance (goal latency, path length, cumulative distance). The evaluation of the reliability of the nine neurobehavioral measures found that all had acceptably high reliability coefficients (0.79 or higher). The analysis of each measure's sensitivity to injury found that all measures were capable of detecting injury-induced impairments. However, there were some substantial differences in the sensitivity of the measures of vestibulomotor and maze performance: the rotorod was the most sensitive vestibulomotor measure and goal latency and path length were equally sensitive measures of maze performance. In the assessment of validity, the results of a factor analysis supported the convergent and discriminative validity of the measures. And in cases in which the preclinical and clinical research have assessed the same construct, the animal model neurobehavioral measures had predictive (or external) validity. Thus, according to the psychometric standards by which measurement instruments are evaluated, the results indicated that these measures provide a valid assessment of neurobehavioral function after fluid percussion TBI.

Flexion injury and/or whiplash injury to the neck in car accidents are usually trivial injuries with no serious neurological deficits. Our intention was to point out the importance to proceed with diagnostic procedures if neurological deficits do occur in order to reveal the true cause of the deficit. The paper presents the case of a 35-year-old woman who sustained a flexion injury to the neck. A relatively trivial injury to the neck promoted a progressive neurological deterioration. The standard diagnostic procedures (x-ray, computed tomography scan) were normal. Further diagnostics with magnetic resonance imaging was required to reveal an underlying Chiari I malformation. Finally, the operative decompression of the craniocervical junction was performed. Following the surgical treatment, the patient's clinical symptoms regressed. One year after her discharge, she remains in good physical condition. To our knowledge, this case is the first report of the manifestation of Chiari I malformation in the adult as a result of a flexion or whiplash injury of the neck. This unusual case suggests that in a trivial flexion injury to the neck sustained in a car accident, which presents with serious neurological dysfunction, and where the standard diagnostic procedures are normal, the possibility of underlying congenital abnormality, such as Chiari I malformation should be considered.

Analysis of locomotion is an important tool in the study of peripheral and central nervous system damage. Most locomotor scoring systems in rodents are based either upon open field locomotion assessment, for example, the BBB score or upon foot print analysis. The former yields a semiquantitative description of locomotion as a whole, whereas the latter generates quantitative data on several selected gait parameters. In this paper, we describe the use of a newly developed gait analysis method that allows easy quantitation of a large number of locomotion parameters during walkway crossing. We were able to extract data on interlimb coordination, swing duration, paw print areas (total over stance, and at 20-msec time resolution), stride length, and base of support: Similar data can not be gathered by any single previously described method. We compare changes in gait parameters induced by two different models of spinal cord injury in rats, transection of the dorsal half of the spinal cord and spinal cord contusion injury induced by the NYU or MASCIS device. Although we applied this method to rats with spinal cord injury, the usefulness of this method is not limited to rats or to the investigation of spinal cord injuries alone.

In a study involving the statistical modeling of potential head injury trials, we explore approaches to trial design that could enhance their power to detect treatment-related effects on clinical outcome. The study uses a survey organized by the European Brain Injury Consortium of over 1,000 head-injured patients to characterize the population from which trial participants can be selected. A variety of models are postulated for the effects of "neuroprotective" treatment on outcome, and their interaction with a range of strategies for targeting patients for inclusion in the trial is evaluated. A very simple strategy of targeting patients with an intermediate prognosis was found to allow a reduction in sample size by 30%, with no reduction in statistical power. This paper illustrates an important methodology for studying the characteristics of competing trial designs.

Transplantation of myelin-forming cells into the demyelinated spinal cord results in remyelination. This paper reviews the electrophysiological properties of demyelinated axons remyelinated by transplantation of myelin-forming cells. Conduction velocity and frequency-response properties of the remyelinated axons are restored to near normal values. Moreover, conduction block can be overcome by remyelination, and no abnormal firing is observed. There is discussion of the challenges of a potential cell therapy approach in human demyelinating disease.

This paper further characterizes the response to axotomy of mouse transcallosal cortical neurons, a population of neurons that seems to be particularly refractory to regeneration. Mouse transcallosal cortical neurons did not upregulate mRNA for the growth-associated protein alpha 1-tubulin following axotomy, even when the axonal distance from injury to cell body was only 100-300 microns. Previous experiments had found no upregulation of another growth-associated protein, GAP-43, by transcallosal neurons following axotomy 1-2 mm from the cell body. These latest results establish that this population of neurons fails to respond to axotomy even when it is extremely proximal and that this failure is not a peculiarity specific to one growth-associated protein but is indicative of a generally poor regenerative response.

Previous reports have demonstrated that some focal brain injuries increase amyloid precursor protein (APP) immunoreactivity in the region surrounding the injury where it was localized, in damaged axons and in pre-alpha 2 cells of the entorhinal cortex. However, to date, APP expression in the hippocampus remote from the impact site has not been comprehensively studied. Therefore, we have evaluated APP expression not only in the locally injured cerebral cortex but also in the hippocampus remote from the impact site. In the present paper, diffuse axonal injury was induced in rats in midline fluid percussion injury. APP expression was examined post injury using Western blot analysis and immunohistochemistry. Western blot analysis demonstrated that the expression of 100-kd APP was increased in both the cerebral cortex and hippocampus 24 h after injury. It then decreased in the hippocampus, but did not change in the cerebral cortex, 7 days after injury. Immunohistochemical studies showed increased immunoreactivity of APP in the neuronal perikarya and reactive astrocytes near the region of injury in the cerebral cortex 24 h to 7 days after injury. In the hippocampus, APP accumulated in the CA3 neurons 24 h and 3 days after injury, although no hemorrhagic lesions were seen at that site. The APP positive neurons in CA3 showed shrunken cell bodies and pyknotic nuclei 3 days after injury, and some of the neurons in CA3 had disappeared by 7 days postinjury. The results of present study suggest that traumatic brain injury induces overexpression and accumulation of APP in neuronal perikarya and that these events are followed by degeneration of CA3 neurons. Further, the decline in APP expression in the hippocampus is thought to be due to neuronal loss in CA3 subsector.

A novel concussive-like brain injury (CLBI) model characterized by transient neurobehavioral depression, short duration of brain edema, and long-lasting memory deficits has been reported in our companion paper. This was achieved by dropping a 21-g weight from a height of 25 cm onto the head of a mouse. In the present study, we examined the histopathological changes in this model. Male ddY mice were subjected to either the trauma or sham injury. Gross pathological examination of the brain 1 h posttrauma did not demonstrate subdural, subarachnoid, intraventricular, periventricular, and intraparenchymatous hemorrhage, focal lesions or contusions. Microscopic examination 24 h posttrauma with Nissl staining (cresyl violet), however, revealed a selective bilateral neuronal cell loss in the cerebral cortex and hippocampus but not in the regions of the thalamus, cerebellum, and brain stem. The characteristics of neuronal cell loss in the cortex suggested that this pathology was related in part, to the head impact dynamics, since the cell loss was noted in the central portion of the supraventricular cerebral cortex (p < 0.001), the site of the weight impact, gradually decreasing peripheral to this site, and disappearing in the areas remote from this locus. In contrast, neuronal cell loss seen in the hippocampus did not suggest that this pathology was directly associated with the impact site. Neuronal cell loss was concentrated in the pyramidal cell layer of CA2 (p < 0.01) and CA3 (p < 0.01), and a lesser degree was noted in the subfields of CA3c (p < 0.05) and the hilar region (p < 0.05) but not in the subfields of CA1 and the dentate gyrus layers. The present study characterized the histopathological change seen in the CLBI model, demonstrating the selective neuronal cell loss following weight-drop concussion in mice.

This paper briefly reviews general principles of gene therapy with emphasis on the therapeutic potential of cationic liposome-mediated neurotrophin gene transfer to treat central nervous system (CNS) injury. Current developments in studies of gene therapy for CNS injury are both impressive and promising. Ex vivo gene transfer into the CNS is relatively mature in animal studies following more than a decade of experimental studies. In vivo gene transfer into the CNS has gained more attention recently. Although progress has been made using viral vectors, rapid advances in transfection technologies employing cationic liposomes, together with the relatively low toxicity of these nonviral vector systems, suggest that liposomes may have significant potential for clinical applications. Although many investigators have recognized that gene therapy may be useful for treatment of certain genetic defect diseases or cancer, gene therapy for CNS injury is relatively novel. In contrast to genetic defect disorders, temporary induction of transgenes may have therapeutic applications for CNS injuries such as stroke and trauma. Employing gene transfer techniques to achieve therapeutically useful levels of expression of neurotrophins in the CNS could provide a new strategy for treatment of the traumatically injured CNS.

This paper reviews changes in gene expression produced by two rodent models of traumatic brain injury: cortical impact injury and fluid-percussion injury. Cortical impact injury produces transient increases in c-fos mRNA expression, which begin as early as 5 min after injury and subsides by 1 day after injury in the cerebral cortex ipsilateral to injury. In addition, AP-1 transcription factor binding is greatly increased in the injured cerebral cortex at 1, 3, and 5 h post-injury. AP-1 binding remains increased for at least 1 day after injury, while SP-1 transcription factor binding activity does not increase. Additional studies have confirmed increases in c-fos mRNA expression in the hippocampus at 30 min, 1 h, and 3 h after injury. These increases in c-fos mRNA in the hippocampus preceded increased levels of NGF mRNA that were detected at 1 and 3 h but not at 30 min following injury. Following fluid-percussion injury, increases in c-fos mRNA can be detected as early as 2 h following injury in the cortex ipsilateral to the site of injury as well as in the hippocampus. Heat-shock protein (hsp72) mRNA is also increased in the ipsilateral cortex and hippocampus following fluid percussion injury. By 24 h post-injury, both c-fos and hsp72 gene expression return to control levels. Severe but not moderate fluid percussion injury produces increased gene expression for glucose-regulated proteins (grp78, grp94) 12 h following injury. Fluid-percussion injury also produces significant increases in expression of both interleukin-1 beta and tumor necrosis factor-alpha in the injured cortex and ipsilateral hippocampus as early as 1 h post-injury, that remains elevated up to 6 h in the injured cortex and hippocampus.

This paper encompasses the prediction of early and late recovery from traumatic brain injury (TBI). Predictors of the duration of coma and the utilization of posttraumatic amnesia duration to predict residual memory function are discussed. The issues surrounding prediction of long-term neurobehavioral recovery from TBI are considered, particularly the patient and clinical variables that are related to intellectual recovery. Findings from the NIH Traumatic Coma Data are reviewed pertaining to testability as a criterion for outcome. In addition to discussing the relationship of specific neurologic indices of TBI as predictors, the results obtained using a regression model are summarized. Finally, the relationship of neuroimaging findings to neurobehavioral outcome is discussed including directions for future research.

This paper reviews important new evidence indicating that traumatic brain injury can produce more widespread derangements to the neuronal cytoskeleton than previously recognized. Although cytoskeletal derangements in axons have long been documented, recent data suggest that traumatic brain injury can produce structural derangements to dendrites and cell bodies as well. Many of these investigations have employed in vivo models to provide important insights into mechanisms possibly mediating the acute loss of cytoskeletal proteins, including disturbances in calcium homeostasis and activation of calcium-dependent proteolytic enzymes. However, we have little understanding of processes mediating the recovery of cytoskeletal proteins following injury. This paper provides recent evidence from in vitro models of central nervous system injury that neurotrophic proteins can enhance the recovery of the neuronal cytoskeleton. Neurotrophin-based therapy could employ either administration of exogenous neurotrophic proteins and/or transfection of cDNA for appropriate neurotrophins.

This manuscript reviews current experience with a large-scale clinical trial of the nonglucocorticoid 21-aminosteroid compound, tirilazad mesylate (U-74,006F). The trial itself now encompasses 15 countries with all central coordination conducted in the Data Coordinating Center at the University of California, San Diego. To date, the conduct of this trial has shown that diverse groups of clinicians in multiple countries have been able to work together to adhere to a tightly defined research protocol. Despite the success in initiating and conducting this trial, however, there have been several unanticipated problems that have complicated its progress. In this regard, difficulties have been associated with the use of mean Glasgow coma scores for data analysis. Similarly, a prospective identification of the risk variables was found necessary to preclude the potential for serious errors in data analysis. Lastly, a differential effect of the drug was noted in women compared to men in the European subarachnoid hemorrhage trial where a significant improvement in outcome was observed in males. This differential response appears to be linked to drug metabolism, but the problem may be further compounded by improper dosing because of failure to weigh many patients. Women appear to be routinely underdosed because their weights are routinely underestimated. Overall, this paper shows the feasibility of conducting such a large scale international trial, while also highlighting some of the potential pitfalls and problems that should be avoided in future trials of this nature.

Biomechanics of cerebral trauma attempts to delineate the dynamic response of the cranial vault contents to a direct or indirect impact to the head. Consequently, brain injury mechanisms and associated tolerance to impact can be deduced by establishing a relationship between neurological deficit and mechanical dosage. The resulting information is invaluable to brain injury prevention and diagnosis. This paper presents an overview of our recent research on head injury focusing on establishing brain injury biomechanics by developing a comprehensive and validated mathematical model. To achieve our goal, we developed a comprehensive three-dimensional finite element human head model, finite element porcine head models, and sensors to monitor head kinematics and brain strains by neutral density accelerometers. The information obtained from this research thus far provided a predictive and somewhat validated mathematical model of the head, which clearly shows a correspondence between brain mechanical response and experimentally observed injuries.

Head injury is the most frequent injury resulting from traffic accidents. Head injury mechanisms are difficult to study experimentally due to the variety of impact conditions involved, as well as ethical issues, such as the use of human cadavers and animals. Finite element modeling is a comprehensive technique through which human head impact tolerance can be studied. A finite element human head model would ideally allow for the assessment of the injurious effects of different impact conditions and enable the development of enhanced head injury and protection criteria. The paper describes the development of a three-dimensional finite element model based on the anatomical features of the adult human cranium. The complex cranial geometry was measured from a series of two-dimensional computer tomography images. The CT scans were transformed with a self-developed preprocessor into a finite element mesh. To model the skull's impact responses, valid material properties are required. The mechanical characteristics of cranial bone were investigated experimentally at Heidelberg University's Institute for Forensic Medicine. To create a sample of material properties for use in the human head model, statistical analyses of the experimental results were undertaken. The tests were modeled with the finite element method and a numerical material model representing the mechanical properties of the human skull bone was developed. The first approach to validate the model and to investigate different boundary conditions by using experimental data is shown.

The purpose of this paper is to present results from methodologies used in our laboratory that are targeted toward identifying specific brain injury thresholds. Results from studying one form of brain injury, diffuse axonal injury, are presented in this report. Physical models, or surrogates, of the skull-brain complex are used to estimate the relationship between inertial loading and brain deformation. A porcine model of diffuse axonal injury, developed with information from these physical models and earlier in vitro tissue modeling studies, is used to correlate histologic and radiologic evidence of axonal injury to predicted regions of injury from the experimental and theoretical analysis. These results form the basis for developing improved diffuse brain injury tolerance levels, as well as identifying new means of diagnostic and treatment techniques for diffuse axonal injury.

This review encompasses the neurobehavioral sequelae of moderate to severe closed head injury (CHI). Following a discussion of posttraumatic amnesia and its measurement, the paper discusses assessment of the global outcome of CHI using the Glasgow Outcome Scale. Domains of residual neurobehavioral sequelae that are reviewed include attention/information processing speed, memory, language, intellectual ability, executive functions, and motor speed. The contribution of behavioral disturbance and psychosocial maladjustment to overall outcome is reviewed, as is the impact on the family. Finally, the neurobehavioral outcome measures for clinical trials involving moderate to severe head-injured patients are presented. Caveats for completing clinical trials that involve assessment of neurobehavioral functioning are provided.