Features Of Traumatic Brain Injury Research Articles

Neuroinflammatory Biomarkers and Their Associations With Cognitive, Affective, and Functional Outcomes 3 to 12 Months After a Traumatic Brain Injury: A Pilot Study.

Neuroinflammation is an important feature of traumatic brain injury (TBI) that remains poorly understood in the 3- to 12-month period post-TBI. The purpose of our pilot study was to examine the relationships between biomarkers of neuroinflammation and functional outcomes in TBI patients 3 to 12months postinjury. TBI patients (n =36) 3 to 12months post-TBI were recruited from a South Florida TBI clinic from May 2022 to June 2023. The Disability Rating Scale, Satisfaction with Life Scale, NIH Toolbox Sorting Working Memory, Neuro-Quality of Life Cognitive Function, Anxiety, Depression, and Sleep assessments were performed. Multiple plasma biomarkers were assayed. Analysis of variance was used to compare between-group results. Linear regression was performed to analyze relationships between biomarkers and outcomes. Brain-derived neurotrophic factor concentrations were higher as postinjury time interval increased and were associated with cognitive battery outcomes. S-100β and glial fibrillary acidic protein were associated with anxiety score and hospital length of stay; S-100β was also associated with depression. Interleukin 6 was associated with cognitive function score and time since injury. We found S-100β, glial fibrillary acidic protein, Interleukin 6, and brain-derived neurotrophic factor to play a larger role in the TBI recovery period than other biomarkers examined. Clinicians should continue to monitor for symptoms post-TBI, as the neuroinflammatory process continues to persist even into the later rehabilitation stage.

Metabotropic glutamate receptor 5 promotes blood-brain barrier recovery after traumatic brain injury

Blood-brain barrier (BBB) impairment and glutamate release are two pathophysiological features of traumatic brain injury (TBI), contributing to secondary brain damage and neuroinflammation. However, our knowledge of BBB integrity damage and dysfunction are still limited due to the diverse and fluctuating expression of glutamate receptors after trauma. Here, we confirmed the downregulation of metabotropic glutamate receptor 5 (mGluR5) on microvascular endothelial cell within the acute phase of TBI, and the recovered mGluR5 levels on BBB was positively associated with blood perfusion and neurological recovery. In whole body mGluR5-knockout mice, BBB dysfunction and neurological deficiency were exacerbated after TBI compared with wild type mice. In terms of mechanism, the amino acid sequence 201–259 of cytoskeletal protein Alpha-actinin-1 (ACTN1) interacted with mGluR5, facilitating mGluR5 translocation from cytoplasmic compartment to plasma membrane in endothelial cells. Activation of plasma membrane mGluR5 triggers the PLC/PKCμ/c-Jun signaling pathway, leading to increased expression of the tight junction-actin cytoskeleton connecting protein zonula occludens-1 (ZO-1). Our findings uncover a novel mechanism mediated by membrane and cytoplasmic mGluR5 in endothelial cell integrity maintenance and repair, providing the potential therapeutic target for TBI treatment targeting at mGluR5 and mGluR5/ACTN1 complex in BBB.

Dietary restriction mitigates phenotypes induced by traumatic brain injury (TBI) in female Drosophila.

TBI occurs when sudden trauma to the head causes damage to the brain, leading to long-term health problems. Many features of TBI can be replicated in Drosophila , making them an ideal model. Previous research on male flies showed that TBI decreases lifespan and locomotion, both of which were ameliorated by dietary restriction (DR). Considering female flies are known to be more responsive to DR, we examined whether DR ameliorates the effect of TBI in females. We found DR significantly extended lifespan and improved climbing ability at 2 weeks post-TBI, consistent with prior results in males.

Identifying the Phenotypes of Diffuse Axonal Injury Following Traumatic Brain Injury.

Diffuse axonal injury (DAI) is a significant feature of traumatic brain injury (TBI) across all injury severities and is driven by the primary mechanical insult and secondary biochemical injury phases. Axons comprise an outer cell membrane, the axolemma which is anchored to the cytoskeletal network with spectrin tetramers and actin rings. Neurofilaments act as space-filling structural polymers that surround the central core of microtubules, which facilitate axonal transport. TBI has differential effects on these cytoskeletal components, with axons in the same white matter tract showing a range of different cytoskeletal and axolemma alterations with different patterns of temporal evolution. These require different antibodies for detection in post-mortem tissue. Here, a comprehensive discussion of the evolution of axonal injury within different cytoskeletal elements is provided, alongside the most appropriate methods of detection and their temporal profiles. Accumulation of amyloid precursor protein (APP) as a result of disruption of axonal transport due to microtubule failure remains the most sensitive marker of axonal injury, both acutely and chronically. However, a subset of injured axons demonstrate different pathology, which cannot be detected via APP immunoreactivity, including degradation of spectrin and alterations in neurofilaments. Furthermore, recent work has highlighted the node of Ranvier and the axon initial segment as particularly vulnerable sites to axonal injury, with loss of sodium channels persisting beyond the acute phase post-injury in axons without APP pathology. Given the heterogenous response of axons to TBI, further characterization is required in the chronic phase to understand how axonal injury evolves temporally, which may help inform pharmacological interventions.

Differences in time-frequency characteristics between healthy controls and TBI patients during hypercapnia assessed via fNIRS

Damage to the cerebrovascular network is a universal feature of traumatic brain injury (TBI). This damage is present during different phases of the injury and can be non-invasively assessed using functional near infrared spectroscopy (fNIRS). fNIRS signals are influenced by partial arterial carbon dioxide (PaCO2), neurogenic, Mayer waves, respiratory and cardiac oscillations, whose characteristics vary in time and frequency and may differ in the presence of TBI. Therefore, this study aims to investigate differences in time–frequency characteristics of these fNIRS signal components between healthy controls and TBI patients and characterize the changes in their characteristics across phases of the injury. Data from 11 healthy controls and 21 TBI patients were collected during the hypercapnic protocol. Results demonstrated significant differences in low-frequency oscillations between healthy controls and TBI patients, with the largest differences observed in Mayer wave band (0.06 to 0.15 Hz), followed by the PaCO2 band (0.012 to 0.02 Hz). The effects within these bands were opposite, with (i) Mayer wave activity being lower in TBI patients during acute phase of the injury (d = 0.37 [0.16, 0.57]) and decreasing further during subacute (d = 0.66 [0.44, 0.87]) and postacute (d = 0.75 [0.50, 0.99]) phases; (ii) PaCO2 activity being lower in TBI patients only during acute phase of the injury (d = 0.36 [0.15, 0.56]) and stabilizing to healthy levels by the subacute phase. These findings demonstrate that TBI patients have impairments in low frequency oscillations related to different mechanisms and that these impairments evolve differently over the course of injury.

Contributions of intrinsic and extrinsic reward sensitivity to apathy: Evidence from traumatic brain injury.

Apathy is a key feature of traumatic brain injury (TBI). However, mechanisms underlying apathy are poorly understood. Evidence suggests that changes in reward may be a crucial factor. Rewards can come from two important sources: extrinsic reward (e.g., money) and intrinsic reward (e.g., enjoyment). Here, we used an experimental paradigm to examine the contributions of intrinsic-extrinsic reward sensitivity to apathy post-TBI and neurocognitive processes associated with these reward processing components. Fifty-seven patients with TBI (TBI with clinical/severe apathy [TBI + sA], TBI with subclinical/moderate apathy [TBI + mA] and TBI without apathy [TBI-A] groups), and 30 healthy individuals completed the "birthday-gift task." In the "intrinsic reward" condition, participants chose to "go" to collect the gift or "wait" for the same gift to be delivered. In the "extrinsic reward" condition, the task was identical, however, participants received monetary incentives when choosing "going" instead of "waiting." The Montreal Cognitive Assessment was utilized for cognitive examination. A smaller proportion of people in the TBI + sA group had high sensitivity to both intrinsic and extrinsic rewards than the TBI + mA, TBI-A and healthy comparison groups. The TBI+sA group also perceived the "go" option on the intrinsic reward condition as more effortful and made fewer "go" decisions on the extrinsic condition. Attention was the only predictor of intrinsic reward sensitivity, whereas executive functioning, attention and group predicted extrinsic reward. This study demonstrates the relationship between intrinsic-extrinsic reward hyposensitivity and apathy post-TBI. These results may be integrated into future trials to improve apathy in clinical practice. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Combining Multiple Indices of Diffusion Tensor Imaging Can Better Differentiate Patients with Traumatic Brain Injury from Healthy Subjects.

AimDiffuse axonal injury (DAI) is one of the most common pathological features of traumatic brain injury (TBI). Diffusion tensor imaging (DTI) indices can be used to identify and quantify white matter microstructural changes following DAI. Recently, many studies have used DTI with various machine learning approaches to predict white matter microstructural changes following TBI. The current study sought to examine whether our classification approach using multiple DTI indices in conjunction with machine learning is a useful tool for diagnosing/classifying TBI patients and healthy controls.MethodsParticipants were adult patients with chronic TBI (n = 26) with DAI pathology, and age- and sex-matched healthy controls (n = 26). DTI images were obtained from all participants. Tract-based spatial statistics analyses were applied to DTI images. Classification models were built using principal component analysis and support vector machines. Receiver operator characteristic curve analysis and area under the curve were used to assess the classification performance of the different classifiers.ResultsTract-based spatial statistics revealed significantly decreased fractional anisotropy, as well as increased mean diffusivity, axial diffusivity, and radial diffusivity in patients with TBI compared with healthy controls (all p-values < 0.01). The principal component analysis and support vector machine-based machine learning classification using combined DTI indices classified patients with TBI and healthy controls with an accuracy of 90.5% with an area under the curve of 93 ± 0.09.ConclusionThese results highlight the potential of our approach combining multiple DTI measures to identify patients with TBI.

Chronic Cortical Inflammation, Cognitive Impairment, and Immune Reactivity Associated with Diffuse Brain Injury Are Ameliorated by Forced Turnover of Microglia.

Traumatic brain injury (TBI) is associated with an increased risk of cognitive, psychiatric, and neurodegenerative complications that may develop after injury. Increased microglial reactivity following TBI may underlie chronic neuroinflammation, neuropathology, and exaggerated responses to immune challenges. Therefore, the goal of this study was to force turnover of trauma-associated microglia that develop after diffuse TBI and determine whether this alleviated chronic inflammation, improved functional recovery and attenuated reduced immune reactivity to lipopolysaccharide (LPS) challenge. Male mice received a midline fluid percussion injury (mFPI) and 7 d later were subjected to a forced microglia turnover paradigm using CSF1R antagonism (PLX5622). At 30 d postinjury (dpi), cortical gene expression, dendritic complexity, myelin content, neuronal connectivity, cognition, and immune reactivity were assessed. Myriad neuropathology-related genes were increased 30 dpi in the cortex, and 90% of these gene changes were reversed by microglial turnover. Reduced neuronal connectivity was evident 30 dpi and these deficits were attenuated by microglial turnover. TBI-associated dendritic remodeling and myelin alterations, however, remained 30 dpi independent of microglial turnover. In assessments of functional recovery, increased depressive-like behavior, and cognitive impairment 30 dpi were ameliorated by microglia turnover. To investigate microglial priming and reactivity 30 dpi, mice were injected intraperitoneally with LPS. This immune challenge caused prolonged lethargy, sickness behavior, and microglial reactivity in the TBI mice. These extended complications with LPS in TBI mice were prevented by microglia turnover. Collectively, microglial turnover 7 dpi alleviated behavioral and cognitive impairments associated with microglial priming and immune reactivity 30 dpi.SIGNIFICANCE STATEMENT A striking feature of traumatic brain injury (TBI), even mild injuries, is that over 70% of individuals have long-term neuropsychiatric complications. Chronic inflammatory processes are implicated in the pathology of these complications and these issues can be exaggerated by immune challenge. Therefore, our goal was to force the turnover of microglia 7 d after TBI. This subacute 7 d postinjury (dpi) time point is a critical transitional period in the shift toward chronic inflammatory processes and microglia priming. This forced microglia turnover intervention in mice attenuated the deficits in behavior and cognition 30 dpi. Moreover, microglia priming and immune reactivity after TBI were also reduced with microglia turnover. Therefore, microglia represent therapeutic targets after TBI to reduce persistent neuroinflammation and improve recovery.

Mechanical threshold for concussion based on computation of axonal strain using a finite element rat brain model

Concussion, in spite of being a mild traumatic brain injury, involves serious long term consequences and can adversely affect the life of an individual, their family and the wider society. Since, diffuse axonal injury (DAI) is known to be one of the most frequent pathological features of traumatic brain injury (TBI), knowledge of the mechanical threshold for concussion in terms of axonal strain can help in developing better brain injury prediction tools in the context of head protection system optimization and the management of sport related concussions. This paper presents development, validation and utilization of an anisotropic viscous hyperelastic finite element rat brain model for investigation of the mechanical threshold for concussion in terms of axonal strain. For the investigation, twenty-six well documented cases of experimental concussion were simulated. A thorough statistical analysis of global kinematic parameters (maximum rotational acceleration and duration) and intra-cerebral parameters (maximum axonal strain, maximum strain energy, maximum von Mises stress, maximum von Mises strain, maximum shear stress, maximum shear strain, maximum principal stress, maximum principal strain, minimum pressure and maximum pressure) revealed that intra-cerebral parameters are better suited for the prediction of concussion than the global kinematic parameters. The estimated tolerance level for a 50% risk of concussion was found to be 8.97% of maximum axonal strain. The results are promising and hence, this study is not only a key step towards better understanding of concussion, but it also contributes towards concussion related investigations. Statement of SignificanceA number of studies have identified axonal strain as one of the key metrics for the prediction of concussion through biomechanical simulations. Where infeasibility of experimentation on in-vivo human brain limits the in-depth investigation, animal models have proved to be efficient. None of the existing finite element rat brain models have taken anisotropy, based on the rat brain DTI, into account, which is rather a crucial aspect for the fidelity. The present study provides a validated anisotropic viscous hyperelastic finite element rat brain model, which was successfully applied for the simulations of experimental concussive loadings on the rat brain and furnished promising results that are in accordance with the literature. As such, it is helpful in developing more accurate brain injury prediction tools in the context of head protection system optimization and for the management of sport related concussions.

Loss of the Antimicrobial Peptide Metchnikowin Protects Against Traumatic Brain Injury Outcomes in Drosophila melanogaster.

Neuroinflammation is a major pathophysiological feature of traumatic brain injury (TBI). Early and persistent activation of innate immune response signaling pathways by primary injuries is associated with secondary cellular injuries that cause TBI outcomes to change over time. We used a Drosophila melanogaster model to investigate the role of antimicrobial peptides (AMPs) in acute and chronic outcomes of closed-head TBI. AMPs are effectors of pathogen and stress defense mechanisms mediated by the evolutionarily conserved Toll and Immune-deficiency (Imd) innate immune response pathways that activate Nuclear Factor kappa B (NF-κB) transcription factors. Here, we analyzed the effect of null mutations in 10 of the 14 known Drosophila AMP genes on TBI outcomes. We found that mutation of Metchnikowin (Mtk) was unique in protecting flies from mortality within the 24 h following TBI under two diet conditions that produce different levels of mortality. In addition, Mtk mutants had reduced behavioral deficits at 24 h following TBI and increased lifespan either in the absence or presence of TBI. Using a transcriptional reporter of gene expression, we found that TBI increased Mtk expression in the brain. Quantitative analysis of mRNA in whole flies revealed that expression of other AMPs in the Toll and Imd pathways as well as NF-κB transcription factors were not altered in Mtk mutants. Overall, these results demonstrate that Mtk plays an infection-independent role in the fly nervous system, and TBI-induced expression of Mtk in the brain activates acute and chronic secondary injury pathways that are also activated during normal aging.

Clinical Features of Traumatic Brain Injury in Various Kinds of Brain Damage

Various circumstances of the injury lead to various types of brain damage. The main types of destructive effects are countracoup effect and acceleration/deceleration. The high intensity injuring force creates conditions for occurrence of combinations of different types of damage leading to aggravation of pathological processes caused by trauma, complication of clinical picture, difficulties of diagnosis and treatment, prolongation of hospital stay, and requires an additional methods of research and treating the injured. Finding the genesis of symptoms observed upon neurologic examination, and especially the differential diagnosis between primary and secondary lesions of the brain stem are nessesary to choose the emergency care for victims with severe traumatic brain injury, as well as to forecast the outcomes of treatment. The dynamics of neurological symptoms (level of wakefulness, pupil size, eyeball mobility, muscle tone and limb movement disorders, pathological plantar reflexes) have significant differences in patients with various types of brain damage, which makes a regular assessment of neurological status extremely important in these patients.

When light hurts:\xa0Comparative Morphometry of Human Brainstem in Traumatic Photalgia

Traumatic brain injury is an increasingly common affliction, although many of its serious repercussions are still underappreciated. A frequent consequence is the development of light-induced pain, or ‘photalgia’, which can often lead to prolonged debilitation. The mechanism underlying the sensitivity to light, however, remains unresolved. Since tissue oedema (swelling) is a common feature of traumatic brain injury, we propose that the brainstem oedema, in particular, might sensitize the brainstem trigeminal complex to signals from ocular mechanisms activated in bright light. To assess this hypothesis, we ran high-resolution Magnetic Resonance Imaging of the brainstems of concussion groups with mild and severe photalgia, without photalgia, and healthy controls. The 3D configuration of the brainstem was determined by Tensor-Based Morphometry (TBM) for each participant. The TBM revealed significant deviations in the brainstem morphology of all concussion groups, with a characteristic signature for each group. In particular, concussion without photalgia showed bilateral expansion at the pontine/medulla junction, whereas concussion with photalgia showed mid-pontine shrinkage, consistent with degeneration of nuclei of the trigeminal complex. These results support the hypothesis that brainstem shrinkage/degeneration represents a morphological substrate of the photalgic sensitization of the trigeminal pathway.

Significance of the number of vomiting episodes as an indication for imaging in paediatric traumatic brain injury

Background: Vomiting is a nonspecific clinical feature of traumatic brain injury and considered as an indication for imaging the brain in suspected traumatic brain injury. Number of vomiting episodes is discussed as a tool to predict the severity of injury and currently three episodes of vomiting is accepted as an indication for computerized tomography in paediatric head injury assessment

Electro-mechanical response of a 3D nerve bundle model to mechanical loads leading to axonal injury.

Axonal damage is one of the most common pathological features of traumatic brain injury, leading to abnormalities in signal propagation for nervous systems. We present a 3D fully coupled electro-mechanical model of a nerve bundle, made with the finite element software Abaqus 6.13-3. The model includes a real-time coupling, modulated threshold for spiking activation and independent alteration of the electrical properties for each 3-layer fibre within the bundle. Compression and tension are simulated to induce damage at the nerve membrane. Changes in strain, stress distribution and neural activity are investigated for myelinated and unmyelinated nerve fibres, by considering the cases of an intact and of a traumatized nerve membrane. Results show greater changes in transmitting action potential in the myelinated fibre.

Concussion Induces Hippocampal Circuitry Disruption in Swine.

Hippocampal-dependent deficits in learning and memory formation are a prominent feature of traumatic brain injury (TBI); however, the role of the hippocampus in cognitive dysfunction after concussion (mild TBI) is unknown. We therefore investigated functional and structural changes in the swine hippocampus following TBI using a model of head rotational acceleration that closely replicates the biomechanics and neuropathology of closed-head TBI in humans. We examined neurophysiological changes using a novel ex vivo hippocampal slice paradigm with extracellular stimulation and recording in the dentate gyrus and CA1 occurring at 7 days following non-impact inertial TBI in swine. Hippocampal neurophysiology post-injury revealed reduced axonal function, synaptic dysfunction, and regional hyperexcitability at one week following even "mild" injury levels. Moreover, these neurophysiological changes occurred in the apparent absence of intra-hippocampal neuronal or axonal degeneration. Input-output curves demonstrated an elevated excitatory post-synaptic potential (EPSP) output for a given fiber volley input in injured versus sham animals, suggesting a form of homeostatic plasticity that manifested as a compensatory response to decreased axonal function in post-synaptic regions. These data indicate that closed-head rotational acceleration-induced TBI, the common cause of concussion in humans, may induce significant alterations in hippocampal circuitry function that have not resolved at 7 days post-injury. This circuitry dysfunction may underlie some of the post-concussion symptomatology associated with the hippocampus, such as post-traumatic amnesia and ongoing cognitive deficits.

Protection of FK506 against neuronal apoptosis and axonal injury following experimental diffuse axonal injury.

Diffuse axonal injury (DAI) is the most common and significant pathological features of traumatic brain injury (TBI). However, there are still no effective drugs to combat the formation and progression of DAI in affected individuals. FK506, also known as tacrolimus, is an immunosuppressive drug, which is widely used in transplantation medicine for the reduction of allograft rejection. Previous studies have identified that FK506 may play an important role in the nerve protective effect of the central nervous system. In the present study, apoptosis of neuronal cells was observed following the induction of experimental DAI. The results demonstrated that it was closely related with the upregulation of death-associated protein kinase 1 (DAPK1). It was hypothesized that FK506 may inhibit the activity of DAPK1 by inhibiting calcineurin activity, which may be primarily involved in anti-apoptosis following DAI induction. Through researching the expression of nerve regeneration associated proteins (NF-H and GAP-43) following DAI, the present study provides novel data to suggest that FK506 promotes axon formation and nerve regeneration following experimental DAI. Therefore, FK506 may be a potent therapeutic for inhibiting nerve injury, as well as promoting the nerve regeneration following DAI.

Age-Dependent Effects of Haptoglobin Deletion in Neurobehavioral and Anatomical Outcomes Following Traumatic Brain Injury.

Cerebral hemorrhages are common features of traumatic brain injury (TBI) and their presence is associated with chronic disabilities. Recent clinical and experimental evidence suggests that haptoglobin (Hp), an endogenous hemoglobin-binding protein most abundant in blood plasma, is involved in the intrinsic molecular defensive mechanism, though its role in TBI is poorly understood. The aim of this study was to investigate the effects of Hp deletion on the anatomical and behavioral outcomes in the controlled cortical impact model using wildtype (WT) C57BL/6 mice and genetically modified mice lacking the Hp gene (Hp−∕−) in two age cohorts [2–4 mo-old (young adult) and 7–8 mo-old (older adult)]. The data obtained suggest age-dependent significant effects on behavioral and anatomical TBI outcomes and recovery from injury. Moreover, in the adult cohort, neurological deficits in Hp−∕− mice at 24 h were significantly improved compared to WT, whereas there were no significant differences in brain pathology between these genotypes. In contrast, in the older adult cohort, Hp−∕− mice had significantly larger lesion volumes compared to WT, but neurological deficits were not significantly different. Immunohistochemistry for ionized calcium-binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) revealed significant differences in microglial and astrocytic reactivity between Hp−∕− and WT in selected brain regions of the adult but not the older adult-aged cohort. In conclusion, the data obtained in the study provide clarification on the age-dependent aspects of the intrinsic defensive mechanisms involving Hp that might be involved in complex pathways differentially affecting acute brain trauma outcomes.

Combined Magnesium/Polyethylene Glycol Facilitates the Neuroprotective Effects of Magnesium in Traumatic Brain Injury at a Reduced Magnesium Dose

While a number of studies have shown that free magnesium (Mg) decline is a feature of traumatic brain injury (TBI), poor central penetration of Mg has potentially limited clinical translation. This study examines whether polyethylene glycol (PEG) facilitates central penetration of Mg after TBI, increasing neuroprotection while simultaneously reducing the dose requirements for Mg. Rats were exposed to diffuse TBI and administered intravenous MgCl2 either alone (254 μmol/kg or 25.4 μmol/kg) or in combination with PEG (1 g/kg PEG) at 30-min postinjury. Vehicle-treated (saline or PEG) and sham animals served as controls. All animals were subsequently assessed for blood-brain barrier permeability and edema at 5 h, and functional outcome for 1 week postinjury. Optimal dose (254 μmol/kg) MgCl2 or Mg PEG significantly improved all outcome parameters compared to vehicle or PEG controls. Intravenous administration of 10% MgCl2 alone (25.4 μmol/kg) had no beneficial effect on any of the outcome parameters, whereas 10% Mg in PEG had the same beneficial effects as optimal dose Mg administration. Polyethylene glycol facilitates central penetration of Mg following TBI, reducing the concentration of Mg required to confer neuroprotection while simultaneously reducing the risks associated with high peripheral Mg concentration.

Developing a Cognition Endpoint for Traumatic Brain Injury Clinical Trials.

Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint.

Prevalence of traumatic brain injury in children of Russian Federation: epidemiology and economic aspects

Aim. To define epidemiological features of traumatic brain injury in children and to assess economic losses caused by this condition.&#x0D; Methods. The prevalence of traumatic brain injury in children for the period of 2003-2012 in Russia according to State Statistical Database. Direct and indirect economic losses (overall and per patient) were calculated for 2012.&#x0D; Results. The study revealed an increase of traumatic brain injury prevalence in children for the analyzed period, with the domestic traumatism prevailing among all brain trauma injuries, especially in girls. The amount of economic losses due to traumatic brain injury in children of Russian Federation in 2012 was about 4 milliard roubles. However, this figure is considerably underestimated, because the amount of expenses per one patient with traumatic brain injury is a quarter less compared to the standard sum per one case traumatic brain injury according to the standards of obligatory health insurance. On the one hand, it may be explained by high admission rate in children with minor head injury. On the other hand, it may be a result of insufficient healthcare funding as well as unaccounted expenses for medical care and drug coverage, especially in children with severe traumatic brain injury.&#x0D; Conclusion. The reduction of economic losses due to pediatric traumatic brain injury is possible not only by preventing new cases of traumatic brain injury but also by optimizing medical care.