Heterogeneity Of Traumatic Brain Injury Research Articles

Traumatic brain injury heterogeneity affects cell death and autophagy.

Traumatic brain injury (TBI) mechanism and severity are heterogenous clinically, resulting in a multitude of physical, cognitive, and behavioral deficits. Impact variability influences the origin, spread, and classification of molecular dysfunction which limits strategies for comprehensive clinical intervention. Indeed, there are currently no clinically approved therapeutics for treating the secondary consequences associated with TBI. Thus, examining pathophysiological changes from heterogeneous impacts is imperative for improving clinical translation and evaluating the efficacy of potential therapeutic strategies. Here we utilized TBI models that varied in both injury mechanism and severity including severe traditional controlled cortical impact (CCI), modified mild CCI (MTBI), and multiple severities of closed-head diffuse TBI (DTBI), and assessed pathophysiological changes. Severe CCI induced cortical lesions and necrosis, while both MTBI and DTBI lacked lesions or significant necrotic damage. Autophagy was activated in the ipsilateral cortex following CCI, but acutely impaired in the ipsilateral hippocampus. Additionally, autophagy was activated in the cortex following DTBI, and autophagic impairment was observed in either the cortex or hippocampus following impact from each DTBI severity. Thus, we provide evidence that autophagy is a therapeutic target for both mild and severe TBI. However, dramatic increases in necrosis following CCI may negatively impact the clinical translatability of therapeutics designed to treat acute dysfunction in TBI. Overall, these results provide evidence that injury sequalae affiliated with TBI heterogeneity is linked through autophagy activation and/or impaired autophagic flux. Thus, therapeutic strategies designed to intervene in autophagy may alleviate pathophysiological consequences, in addition to the cognitive and behavioral deficits observed in TBI.

Sleep, inflammation, and hemodynamics in rodent models of traumatic brain injury.

Traumatic brain injury (TBI) can induce dysregulation of sleep. Sleep disturbances include hypersomnia and hyposomnia, sleep fragmentation, difficulty falling asleep, and altered electroencephalograms. TBI results in inflammation and altered hemodynamics, such as changes in blood brain barrier permeability and cerebral blood flow. Both inflammation and altered hemodynamics, which are known sleep regulators, contribute to sleep impairments post-TBI. TBIs are heterogenous in cause and biomechanics, which leads to different molecular and symptomatic outcomes. Animal models of TBI have been developed to model the heterogeneity of TBIs observed in the clinic. This review discusses the intricate relationship between sleep, inflammation, and hemodynamics in pre-clinical rodent models of TBI.

Multifunctional Nanoparticles and Nanoclusters as a Theranostics and Symptoms Disappearing Agent for Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the most common causes of disability and mortality worldwide, creating a large socioeconomic burden annually. Secondary injury physiopathology is known to play a prominent role in exacerbating neurodegeneration post‐TBI and is potentially preventable by therapies. However, due to the heterogeneity of TBI and the complexity of the pathological mechanisms that ensue, there are currently no effective disease‐modifying treatments to prevent TBI‐associated disability and mortality. Nanotechnology has emerged in recent decades as a promising platform for the development of multifunctional neuroprotective agents for TBI. Herein, current multifunctional innovations are explored in this review in nanotechnology, which target the secondary injury pathological mechanisms of TBI and show promise in improving future post‐TBI management. Also, potential new directions for the future development of TBI treatment are discussed.

Navigating the Complexities of Traumatic Encephalopathy Syndrome (TES): Current State and Future Challenges.

Chronic traumatic encephalopathy (CTE) is a unique neurodegenerative disease that is associated with repetitive head impacts (RHI) in both civilian and military settings. In 2014, the research criteria for the clinical manifestation of CTE, traumatic encephalopathy syndrome (TES), were proposed to improve the clinical identification and understanding of the complex neuropathological phenomena underlying CTE. This review provides a comprehensive overview of the current understanding of the neuropathological and clinical features of CTE, proposed biomarkers of traumatic brain injury (TBI) in both research and clinical settings, and a range of treatments based on previous preclinical and clinical research studies. Due to the heterogeneity of TBI, there is no universally agreed-upon serum, CSF, or neuroimaging marker for its diagnosis. However, as our understanding of this complex disease continues to evolve, it is likely that there will be more robust, early diagnostic methods and effective clinical treatments. This is especially important given the increasing evidence of a correlation between TBI and neurodegenerative conditions, such as Alzheimer's disease and CTE. As public awareness of these conditions grows, it is imperative to prioritize both basic and clinical research, as well as the implementation of necessary safe and preventative measures.

Association between Trauma Center Type and Mortality for Injured Children with Severe Traumatic Brain Injury.

There is conflicting evidence regarding the relationship between trauma center type and mortality for children with traumatic brain injuries. Identification of mortality differences following brain injury across differing trauma center types may result in actionable quality improvement initiatives to standardize care for these children. We utilized Trauma Quality Improvement Program data from 2017-2020 to identify children with severe traumatic brain injury managed at level I and II state- or American College of Surgeon-verified trauma centers. We used a random intercept multilevel logistic regression model to assess the relationship between exposure (trauma center type either adult, pediatric or mixed) and outcome (in-hospital mortality). Several secondary analyses were performed to assess the influence of trauma center volume, age strata and traumatic brain injury heterogeneity. There were 10,105 patients identified across 512 trauma centers. Crude mortality was 25.2%, 36.2% and 28.9% for pediatric, adult, and mixed trauma centers respectively. After adjustment for confounders, odds of mortality were higher for children managed at adult trauma centers (OR 1.67; 95% CI: 1.30 - 2.13) compared to pediatric trauma centers. Male sex, self-pay insurance status, and interfacility transfers, motor vehicle, pedestrian/ cyclist and firearm injury mechanisms, presence of concomitant abdomen, lower extremity, or chest injuries, midline shift >5 mm within 24 hours, presence of age-adjusted hypotension and either pupil asymmetry or non-reactivity were all associated with a greater odds of death. Adjustment for trauma volume and subgroup analysis using a homogenous traumatic brain injury subgroup did not change the demonstrated associations. Our results suggest mortality was higher at adult trauma centers compared to mixed and pediatric trauma centers for children with traumatic brain injuries. Importantly, there exists the potential for unmeasured confounding. We aim for these findings to direct continuing quality improvement initiatives to improve outcomes for brain injured children. III; Type of study: Prognostic/ epidemiological.

Цільовий температурний менеджмент у комплексі інтенсивної терапії важкої черепно-мозкової травми

Актуальність. Гіпертермія викликає церебральне пошкодження і погіршує неврологічне відновлення при важкій черепно-мозковій травмі (ЧМТ). Метою роботи було вивчення неврологічних наслідків у пацієнтів з тяжкою ЧМТ та рефрактерною к фармакологічній корекції гіпертермією при використанні цільового температурного менеджменту з залученням езофагеального охолоджувального пристрою в комплексі інтенсивної терапії порівняно з групою контролю. Матеріали та методи. Обстежено 20 пацієнтів віком від 23 до 54 років із діагнозом «важка ЧМТ». Пацієнти були розподілені на 2 групи: пацієнтам I групи (n = 10) здійснювався стандартний комплекс інтенсивної терапії, що базується на міжнародних рекомендаціях щодо менеджменту важкої ЧМТ (2007, 2016 рр.); у II групі (n = 10) у стандартний комплекс інтенсивної терапії було включено цільовий температурний менеджмент (ЦТМ) за допомогою гіпотерма «Blanketrol II» (CSZ, США) і езофагеального пристрою для охолодження (Esophageal Cooling Device, ACT, США) з метою досягнення нормотермії у діапазоні 36,5–37 °С. У всіх пацієнтів оцінювався неврологічний статус за шкалою коми Глазго на наступних етапах: початково, на 5-ту, 10-ту добу та на момент виписки з лікувального закладу. Наслідки перенесеної ЧМТ визначалися за шкалою СРС (Сerebral Performance Categories), з оцінкою максимального балу при знаходженні у відділенні реанімації та інтенсивної терапії (ВРІТ) та на момент виписки з лікувального закладу. Результати. Аналіз динаміки неврологічного відновлення при виписці з лікувального закладу виявив достовірне поліпшення в групі пацієнтів із застосуванням ЦТМ, що знайшло відображення у середньому значенні за шкалою коми Глазго 13,50 ± 1,36 бала порівняно з 11,5 ± 1,8 бала в контрольній групі (p < 0,05). При аналізі кращих значень за шкалою СРС в період знаходження пацієнтів в умовах ВРІТ добре неврологічне відновлення, що відповідало СРС 1–2, було отримано у 20 та 50 %, погане на рівні СРС 3–4 — у 70 і 50 % пацієнтів у контрольній та групі із застосуванням ЦТМ відповідно. При виписці з лікувального закладу неврологічне відновлення на рівні СРС 1–2 було виявлено у 30 % порівняно з 80 %, на рівні СРС 3–4 — у 70 % порівняно з 20 % пацієнтів у контрольній і групі із застосуванням ЦТМ відповідно. Міжгрупові відмінності середніх значень за шкалою СРС на момент виписки з лікувального закладу мали вірогідний характер та становили 2,90 ± 0,94 і 2,00 ± 0,77 (Р = 0,02) в контрольній і основній групах відповідно. Висновки. Використання цільового температурного менеджменту з метою забезпечення нормотермії створює сприятливі умови для більш повного відновлення порушених неврологічних функцій після важкої черепно-мозкової травми.

Effective connectivity in the default mode network after paediatric traumatic brain injury.

Children who experience a traumatic brain injury (TBI) are at elevated risk for a range of negative cognitive and neuropsychological outcomes. Identifying which children are at greatest risk for negative outcomes can be difficult due to the heterogeneity of TBI. To address this barrier, the current study applied a novel method of characterizing brain connectivity networks, Bayesian multi-subject vector autoregressive modelling (BVAR-connect), which used white matter integrity as priors to evaluate effective connectivity-the time-dependent relationship in functional magnetic resonance imaging (fMRI) activity between two brain regions-within the default mode network (DMN). In a prospective longitudinal study, children ages 8-15 years with mild to severe TBI underwent diffusion tensor imaging and resting state fMRI 7weeks after injury; post-concussion and anxiety symptoms were assessed 7months after injury. The goals of this study were to (1) characterize differences in positive effective connectivity of resting-state DMN circuitry between healthy controls and children with TBI, (2) determine if severity of TBI was associated with differences in DMN connectivity and (3) evaluate whether patterns of DMN effective connectivity predicted persistent post-concussion symptoms and anxiety. Healthy controls had unique positive connectivity that mostly emerged from the inferior temporal lobes. In contrast, children with TBI had unique effective connectivity among orbitofrontal and parietal regions. These positive orbitofrontal-parietal DMN effective connectivity patterns also differed by TBI severity and were associated with persisting behavioural outcomes. Effective connectivity may be a sensitive neuroimaging marker of TBI severity as well as a predictor of chronic post-concussion symptoms and anxiety.

Delayed-Onset Neuropathological Complications From a Foramen Magnum and Occipital Crest Focused TBI of the Vietnam War and Other Conflicts: Part III, Critique of Existing TBI Criteria and Their Operational Controversies.

In this report, we discuss the controversy of the diverse traumatic brain injury (TBI) categorization and taxonomy and the need to develop a new multidimensional and multidisciplinary categorization system that can be an aid in improved diagnostic and prognostic outcomes. Of interest, the heterogeneity of TBI marks the major obstacle to develop effective therapeutic interventions. Currently, the Glasgow Coma Scale has been utilized to guide in the prognosis and clinical management of TBI; it does not encompass the pathophysiological mechanisms leading to neurological deficits that can impede therapeutic interventions and consequently the failure of clinical trials. An unfortunate gap exists between advances in TBI research and existing U.S. Department of Defense (DoD) definitions, categorization, and management. Part I illustrates a unique posterior-focused TBI case report that does not fit any existing TBI definitions. Part II summarizes new animal-based TBI research that supports the case report as a legitimate TBI category. Part III critiques existing TBI criteria and their controversies. Current DoD definitions and decision-making protocols based on concussion time alone are reviewed and compared to the myriad of additional TBI definitions that further illustrate the marked differences in definitions, especially in mild TBIs. The DoD definitions are not consistent with what academic research and science bring to the debate. With increasing world conflicts and wars, evaluators are not prepared to accept, evaluate, and properly manage those TBIs that are not associated with immediate levels of unconsciousness alone as the prime determinant of diagnosis and long-term severity. Despite comprehensive research, current understanding among decision-makers of progressive pathology of non-hemispheric TBIs remains limited, inconsistent, and confusing. This dilemma requires a multidisciplinary, science/medicine-led panel to actively reassess TBI criteria that take into consideration the latest research including non-cerebral hemispheric injuries. We recommend that DoD/Veterans Affairs establish a commission to regularly review the academic-related scientific evidence and incorporate these findings in a timely fashion into their operational definitions. This would guarantee that recognition, diagnosis, and follow-up of all TBIs are properly understood, managed, and documented.

Serum biomarkers in severe paediatric traumatic brain injury-a narrative review.

Severe traumatic brain injury continues to present complex management and prediction challenges for the clinician. While there is some evidence that better systems of care can improve outcome, multiple multi-centre randomised controlled trials of specific therapies have consistently failed to show benefit. In addition, clinicians are challenged in attempting to accurately predict which children will recover well and which children will have severe and persisting neurocognitive deficits. Traumatic brain injury is vastly heterogeneous and so it is not surprising that one therapy or approach, when applied to a mixed cohort of children in a clinical trial setting, has yielded disappointing results. Children with severe traumatic brain injury have vastly different brain injury pathologies of widely varying severity, in any number of anatomical locations at what may be disparate stages of brain development. This heterogeneity may also explain why clinicians are unable to accurately predict outcome. Biomarkers are objective molecular signatures of injury that are released following traumatic brain injury and may represent a way of unifying the heterogeneity of traumatic brain injury into a single biosignature. Biomarkers hold promise to diagnose brain injury severity, guide intervention selection for clinical trials, or provide vital prognostic information so that early intervention and rehabilitation can be planned much earlier in the course of a child’s recovery. Serum S100B and serum NSE levels show promise as a diagnostic tool with biomarker levels significantly higher in children with severe TBI including children with inflicted and non-inflicted head injury. Serum S100B and serum NSE also show promise as a predictor of neurodevelopmental outcome. The role of biomarkers in traumatic brain injury is an evolving field with the potential for clinical application within the next few years.

Phenotyping the Spectrum of Traumatic Brain Injury: A Review and Pathway to Standardization.

It is widely appreciated that the spectrum of traumatic brain injury (TBI), mild through severe, contains distinct clinical presentations, variably referred to as subtypes, phenotypes, and/or clinical profiles. As part of the Brain Trauma Blueprint TBI State of the Science, we review the current literature on TBI phenotyping with an emphasis on unsupervised methodological approaches, and describe five phenotypes that appear similar across reports. However, we also find the literature contains divergent analysis strategies, inclusion criteria, findings, and use of terms. Further, whereas some studies delineate phenotypes within a specific severity of TBI, others derive phenotypes across the full spectrum of severity. Together, these facts confound direct synthesis of the findings. To overcome this, we introduce PhenoBench, a freely available code repository for the standardization and evaluation of raw phenotyping data. With this review and toolset, we provide a pathway toward robust, data-driven phenotypes that can capture the heterogeneity of TBI, enabling reproducible insights and targeted care.

Secreted Peptides for Diagnostic Trajectory Assessments in Brain Injury Rehabilitation

Background Rehabilitation following traumatic brain injury (TBI) significantly improves outcomes; yet TBI heterogeneity raises the need for molecular evidence of brain recovery processes to better track patient progress, evaluate therapeutic efficacy, and provide prognostication. Objective Here, we assessed whether the trajectory of TBI-responsive peptides secreted into urine can produce a predictive model of functional recovery during TBI rehabilitation. Methods The multivariate urinary peptidome of 12 individuals with TBI was examined using quantitative peptidomics. Measures were assessed upon admission and discharge from inpatient rehabilitation. A combination of Pavlidis template matching and partial least-squares discriminant analysis was used to build models on Disability Rating Scale (DRS) and Functional Independence Measure (FIM) scores, with participants bifurcated into more or less functional improvement groups. Results The produced models exhibited high sensitivity and specificity with the area under the receiver operator curve being 0.99 for DRS- and 0.95 for FIM-based models using the top 20 discriminant peptides. Predictive ability for each model was assessed using robust leave-one-out cross-validation with Q2 statistics of 0.64 (P = .00012) and 0.62 (P = .011) for DRS- and FIM-based models, respectively, both with a high predictive accuracy of 0.875. Identified peptides that discriminated improved functional recovery reflected heightened neuroplasticity and synaptic refinement and diminished cell death and neuroinflammation, consistent with postacute TBI pathobiology. Conclusions Produced models of urine-based peptide measures reflective of ongoing recovery pathobiology can inform on rehabilitation progress after TBI, warranting further study to assess refined stratification across a larger population and efficacy in assessing therapeutic interventions.

Comparative transcriptomic analysis of rat versus mouse cerebral cortex after traumatic brain injury.

The heterogeneity of traumatic brain injury (TBI)-induced secondary injury has greatly hampered the development of effective treatments for TBI patients. Targeting common processes across species may be an innovative strategy to combat debilitating TBI. In the present study, a cross-species transcriptome comparison was performed for the first time to determine the fundamental processes of secondary brain injury in Sprague-Dawley rat and C57/BL6 mouse models of TBI, caused by acute controlled cortical impact. The RNA sequencing data from the mouse model of TBI were downloaded from the Gene Expression Omnibus (ID: GSE79441) at the National Center for Biotechnology Information. For the rat data, peri-injury cerebral cortex samples were collected for transcriptomic analysis 24 hours after TBI. Differentially expressed gene-based functional analysis revealed that common features between the two species were mainly involved in the regulation and activation of the innate immune response, including complement cascades as well as Toll-like and nucleotide oligomerization domain-like receptor pathways. These findings were further corroborated by gene set enrichment analysis. Moreover, transcription factor analysis revealed that the families of signal transducers and activators of transcription (STAT), basic leucine zipper (BZIP), Rel homology domain (RHD), and interferon regulatory factor (IRF) transcription factors play vital regulatory roles in the pathophysiological processes of TBI, and are also largely associated with inflammation. These findings suggest that targeting the common innate immune response might be a promising therapeutic approach for TBI. The animal experimental procedures were approved by the Beijing Neurosurgical Institute Animal Care and Use Committee (approval No. 201802001) on June 6, 2018.

Neuroimaging and Psychometric Assessment of Mild Cognitive Impairment After Traumatic Brain Injury.

Traumatic brain injury (TBI) can be serious partly due to the challenges of assessing and treating its neurocognitive and affective sequelae. The effects of a single TBI may persist for years and can limit patients’ activities due to somatic complaints (headaches, vertigo, sleep disturbances, nausea, light or sound sensitivity), affective sequelae (post-traumatic depressive symptoms, anxiety, irritability, emotional instability) and mild cognitive impairment (MCI, including social cognition disturbances, attention deficits, information processing speed decreases, memory degradation and executive dysfunction). Despite a growing amount of research, study comparison and knowledge synthesis in this field are problematic due to TBI heterogeneity and factors like injury mechanism, age at or time since injury. The relative lack of standardization in neuropsychological assessment strategies for quantifying sequelae adds to these challenges, and the proper administration of neuropsychological testing relative to the relationship between TBI, MCI and neuroimaging has not been reviewed satisfactorily. Social cognition impairments after TBI (e.g., disturbed emotion recognition, theory of mind impairment, altered self-awareness) and their neuroimaging correlates have not been explored thoroughly. This review consolidates recent findings on the cognitive and affective consequences of TBI in relation to neuropsychological testing strategies, to neurobiological and neuroimaging correlates, and to patient age at and assessment time after injury. All cognitive domains recognized by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) are reviewed, including social cognition, complex attention, learning and memory, executive function, language and perceptual-motor function. Affect and effort are additionally discussed owing to their relationships to cognition and to their potentially confounding effects. Our findings highlight non-negligible cognitive and affective impairments following TBI, their gravity often increasing with injury severity. Future research should study (A) language, executive and perceptual-motor function (whose evolution post-TBI remains under-explored), (B) the effects of age at and time since injury, and (C) cognitive impairment severity as a function of injury severity. Such efforts should aim to develop and standardize batteries for cognitive subdomains—rather than only domains—with high ecological validity. Additionally, they should utilize multivariate techniques like factor analysis and related methods to clarify which cognitive subdomains or components are indeed measured by standardized tests.

Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI.

Traumatic brain injury (TBI) is the largest cause of death and disability of persons under 45 years old, worldwide. Independent of the distribution, outcomes such as disability are associated with huge societal costs. The heterogeneity of TBI and its complicated biological response have helped clarify the limitations of current pharmacological approaches to TBI management. Five decades of effort have made some strides in reducing TBI mortality but little progress has been made to mitigate TBI-induced disability. Lessons learned from the failure of numerous randomized clinical trials and the inability to scale up results from single center clinical trials with neuroprotective agents led to the formation of organizations such as the Neurological Emergencies Treatment Trials (NETT) Network, and international collaborative comparative effectiveness research (CER) to re-orient TBI clinical research. With initiatives such as TRACK-TBI, generating rich and comprehensive human datasets with demographic, clinical, genomic, proteomic, imaging, and detailed outcome data across multiple time points has become the focus of the field in the United States (US). In addition, government institutions such as the US Department of Defense are investing in groups such as Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug-screening consortium to address the barriers in translation. The consensus from such efforts including “The Lancet Neurology Commission” and current literature is that unmitigated cell death processes, incomplete debris clearance, aberrant neurotoxic immune, and glia cell response induce progressive tissue loss and spatiotemporal magnification of primary TBI. Our analysis suggests that the focus of neuroprotection research needs to shift from protecting dying and injured neurons at acute time points to modulating the aberrant glial response in sub-acute and chronic time points. One unexpected agent with neuroprotective properties that shows promise is transplantation of neural stem cells. In this review we present (i) a short survey of TBI epidemiology and summary of current care, (ii) findings of past neuroprotective clinical trials and possible reasons for failure based upon insights from human and preclinical TBI pathophysiology studies, including our group's inflammation-centered approach, (iii) the unmet need of TBI and unproven treatments and lastly, (iv) present evidence to support the rationale for sub-acute neural stem cell therapy to mediate enduring neuroprotection.

Multi-Center Pre-clinical Consortia to Enhance Translation of Therapies and Biomarkers for Traumatic Brain Injury: Operation Brain Trauma Therapy and Beyond.

Current approaches have failed to yield success in the translation of neuroprotective therapies from the pre-clinical to the clinical arena for traumatic brain injury (TBI). Numerous explanations have been put forth in both the pre-clinical and clinical arenas. Operation Brain Trauma Therapy (OBTT), a pre-clinical therapy and biomarker screening consortium has, to date, evaluated 10 therapies and assessed three serum biomarkers in nearly 1,500 animals across three rat models and a micro pig model of TBI. OBTT provides a unique platform to exploit heterogeneity of TBI and execute the research needed to identify effective injury specific therapies toward precision medicine. It also represents one of the first multi-center pre-clinical consortia for TBI, and through its work has yielded insight into the challenges and opportunities of this approach. In this review, important concepts related to consortium infrastructure, modeling, therapy selection, dosing and target engagement, outcomes, analytical approaches, reproducibility, and standardization will be discussed, with a focus on strategies to embellish and improve the chances for future success. We also address issues spanning the continuum of care. Linking the findings of optimized pre-clinical consortia to novel clinical trial designs has great potential to help address the barriers in translation and produce successes in both therapy and biomarker development across the field of TBI and beyond.

Altered cortical activation and connectivity patterns for visual attention processing in young adults post-traumatic brain injury: A functional near infrared spectroscopy study.

This study aimed at understanding the neurobiological mechanisms associated with inattention induced by traumatic brain injury (TBI). To eliminate the potential confounding caused by the heterogeneity of TBI, we focused on young adults postsports-related concussion (SRC). Functional near-infrared spectroscopy (fNIRS) data were collected from 27 young adults post-SRC and 27 group-matched normal controls (NCs), while performing a visual sustained attention task. Task responsive cortical activation maps and pairwise functional connectivity among six regions of interest were constructed for each subject. Correlations among the brain imaging measures and clinical measures of attention were calculated in each group. Compared to the NCs, the SRC group showed significantly increased brain activation in left middle frontal gyrus (MFG) and increased functional connectivity between right inferior occipital cortex (IOC) bilateral calcarine gyri (CG). The left MFG activation magnitude was significantly negatively correlated with the hyperactive/impulsive symptom severity measure in the NCs, but not in the patients. The right hemisphere CG-IOC functional connectivity showed a significant positive correlation with the hyperactive/impulsive symptom severity measure in patients, but not in NCs. The current data suggest that abnormal left MFG activation and hyper-communications between right IOC and bilateral CG during visual attention processing may significantly contribute to behavioral manifestations of attention deficits in patients with TBI.

Effects of dextroamphetamine in subacute traumatic brain injury: A randomized, placebo-controlled pilot study.

Psychostimulants that affect neurotransmitters implicated in cognitive function and neural plasticity have potential to enhance the rate and extent of recovery after traumatic brain injury (TBI). Ten milligrams dextroamphetamine (DEX) or an identical placebo was administered daily for 3 weeks to 32 participants with moderate to severe TBI, engaged in inpatient rehabilitation, at a mean of 2 months post injury. A variety of outcome measures assessing cognitive function and overall functional status was administered at weekly intervals, to examine effect sizes that may inform a larger trial, and to evaluate safety. Results indicated trivial-to-small effect sizes for DEX-placebo differences, with the largest effects seen on speed of information processing (more improvement with DEX) and agitation (exacerbation with DEX). Examination of adverse events and vital signs suggested safety of DEX, but the pattern of results did not suggest accelerated recovery due to the drug. Future trials of DEX in this population need to consider the impact of floor effects of commonly used measures of cognitive and physical function, and the heterogeneity of TBI. Although the small sample precludes definitive conclusions, these findings are not encouraging with regard to clinical trials of DEX in subacute TBI.

Classification of traumatic brain injury severity using retrospective data

Objective: Accurate classification of traumatic brain injury (TBI) severity is essential to brain injury research. TBI heterogeneity complicates classification of the injury; is a significant barrier in the design of therapeutic interventions; and results in retrospective data which is difficult to translate. The objective of this study is to describe the differences in two current tools used in the classification of TBI severity, the Glasgow Coma Scale (GCS) and the head Abbreviated Injury Score (AIS), using retrospective data to compare their performance.Methods: Using correlational and descriptive statistics, this study examined two TBI severity classification methods across a large sample of TBI patients (N = 56,131), who were treated at level I and level II trauma centers in the United States and were included in the 2010 National Sample Program (NSP) of the National Trauma Data Bank (NTDB®).Results: The study population was 67% male, 67% non-Hispanic white, treated most often in trauma centers in the South (38%), with blunt trauma (93%) and from non-motor vehicle collisions (MVC’s) (56%). Observation of the AIS classification system demonstrated that it tends to over-score TBI severity compared to the GCS classification. The methods (GCS & AIS) had a weak, inverse relationship with a correlation coefficient (Pearson’s r) of -0.3980, which was significant at p < .001.Conclusions: The current study addressed the difficulties associated with categorizing TBI severity when analyzing retrospective data. Although AIS is commonly used to classify severity in retrospective data when GCS is unavailable, the relationship between the two scales is relatively unknown. Results show that AIS and GCS are more closely related for severely brain injured patients but in cases of mild and moderate injury, AIS is less predictive of GCS. Since they are often used in conjunction in identifying brain injured severity in retrospective data, researchers cannot be certain that the tools are similarly classifying mild, moderate, and severe injuries. This study reinforces the need for additional TBI severity classification methods, such as neuroimaging techniques and biomarkers.

Alcohol and mortality after moderate to severe traumatic brain injury: a meta-analysis of observational studies

OBJECT Experimental studies have shown numerous neuroprotective properties of alcohol ("ethanol") after TBI, but clinical studies have provided conflicting results. The authors aimed to assess the relationship between positive blood alcohol concentration (BAC) on hospital admission and mortality after moderate to severe traumatic brain injury (TBI). METHODS The authors searched 8 databases for observational studies reported between January 1, 1990, and October 7, 2013, and investigated the effect of BAC on mortality after moderate to severe TBI. Reviews of each study were conducted, and data were extracted according to the MOOSE and PRISMA guidelines. Study quality was assessed using the Newcastle-Ottawa scale. The Mantel-Haenszel fixed effect methodology was used to generate pooled estimates. Heterogeneity was dealt with by multiple sensitivity analyses. RESULTS Eleven studies with a total of 95,941 patients (42% BAC positive and 58% BAC negative) were identified for the primary analysis (overall mortality 12%). Primary analysis showed a significantly lower risk of death for BAC-positive patients compared with BAC-negative patients (crude mortality 11.0% vs 12.3%, pooled OR 0.84 [95% CI 0.81-0.88]), although flawed by heterogeneity (I(2) = 68%). Multiple sensitivity analyses, including 55,949 and 51,772 patients, yielded similar results to the primary analysis (crude mortality 12.2% vs 14.0%, pooled OR 0.87 [95% CI 0.83-0.92] and crude mortality 8.7% vs 10.7%, pooled OR 0.78 [95% CI 0.74-0.83]) but with good study homogeneity (I(2) = 36% and 14%). CONCLUSIONS Positive BAC was significantly associated with lower mortality rates in moderate to severe TBI. Whether this observation is due to selection bias or neuroprotective effects of alcohol remains unknown. Future prospective studies adjusting for TBI heterogeneity is advocated to establish the potential favorable effects of alcohol on outcome after TBI.

A Review of the Effectiveness of Neuroimaging Modalities for the Detection of Traumatic Brain Injury.

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.