Youth Mental Health Screening and Linkage to Care.

One Mind, in partnership with Meadows Mental Health Policy Institute, convened several virtual meetings of mental health researchers, clinicians, and other stakeholders in 2020 to identify first steps toward creating an initiative for early screening and linkage to care for youths (individuals in early adolescence through early adulthood, ages 10-24 years) with mental health difficulties, including serious mental illness, in the United States. This article synthesizes and builds on discussions from those meetings by outlining and recommending potential steps and considerations for the development and integration of a novel measurement-based screening process in youth-facing school and medical settings to increase early identification of mental health needs and linkage to evidence-based care. Meeting attendees agreed on an initiative incorporating a staged assessment process that includes a first-stage brief screener for several domains of psychopathology. Individuals who meet threshold criteria on the first-stage screener would then complete an interview, a second-stage in-depth screening, or both. Screening must be followed by recommendations and linkage to an appropriate level of evidence-based care based on acuity of symptoms endorsed during the staged assessment. Meeting attendees proposed steps and discussed additional considerations for creating the first nationwide initiative for screening and linkage to care, an initiative that could transform access of youths to mental health screening and care.

Pre-Clinical Common Data Elements for Traumatic Brain Injury Research: Progress and Use Cases.

Traumatic brain injury (TBI) is an extremely complex condition due to heterogeneity in injury mechanism, underlying conditions, and secondary injury. Pre-clinical and clinical researchers face challenges with reproducibility that negatively impact translation and therapeutic development for improved TBI patient outcomes. To address this challenge, TBI Pre-clinical Working Groups expanded upon previous efforts and developed common data elements (CDEs) to describe the most frequently used experimental parameters. The working groups created 913 CDEs to describe study metadata, animal characteristics, animal history, injury models, and behavioral tests. Use cases applied a set of commonly used CDEs to address and evaluate the degree of missing data resulting from combining legacy data from different laboratories for two different outcome measures (Morris water maze [MWM]; RotorRod/Rotarod). Data were cleaned and harmonized to Form Structures containing the relevant CDEs and subjected to missing value analysis. For the MWM dataset (358 animals from five studies, 44 CDEs), 50% of the CDEs contained at least one missing value, while for the Rotarod dataset (97 animals from three studies, 48 CDEs), over 60% of CDEs contained at least one missing value. Overall, 35% of values were missing across the MWM dataset, and 33% of values were missing for the Rotarod dataset, demonstrating both the feasibility and the challenge of combining legacy datasets using CDEs. The CDEs and the associated forms created here are available to the broader pre-clinical research community to promote consistent and comprehensive data acquisition, as well as to facilitate data sharing and formation of data repositories. In addition to addressing the challenge of standardization in TBI pre-clinical studies, this effort is intended to bring attention to the discrepancies in assessment and outcome metrics among pre-clinical laboratories and ultimately accelerate translation to clinical research.

Guidelines for Data Acquisition, Quality and Curation for Observational Research Designs (DAQCORD).

BACKGROUND: High-quality data are critical to the entire scientific enterprise, yet the complexity and effort involved in data curation are vastly under-appreciated. This is especially true for large observational, clinical studies because of the amount of multimodal data that is captured and the opportunity for addressing numerous research questions through analysis, either alone or in combination with other data sets. However, a lack of details concerning data curation methods can result in unresolved questions about the robustness of the data, its utility for addressing specific research questions or hypotheses and how to interpret the results. We aimed to develop a framework for the design, documentation and reporting of data curation methods in order to advance the scientific rigour, reproducibility and analysis of the data. METHODS: Forty-six experts participated in a modified Delphi process to reach consensus on indicators of data curation that could be used in the design and reporting of studies. RESULTS: We identified 46 indicators that are applicable to the design, training/testing, run time and post-collection phases of studies. CONCLUSION: The Data Acquisition, Quality and Curation for Observational Research Designs (DAQCORD) Guidelines are the first comprehensive set of data quality indicators for large observational studies. They were developed around the needs of neuroscience projects, but we believe they are relevant and generalisable, in whole or in part, to other fields of health research, and also to smaller observational studies and preclinical research. The DAQCORD Guidelines provide a framework for achieving high-quality data; a cornerstone of health research.

The Biological Basis of Chronic Traumatic Encephalopathy following Blast Injury: A Literature Review.

The United States Department of Defense Blast Injury Research Program Coordinating Office organized the 2015 International State-of-the-Science meeting to explore links between blast-related head injury and the development of chronic traumatic encephalopathy (CTE). Before the meeting, the planning committee examined articles published between 2005 and October 2015 and prepared this literature review, which summarized broadly CTE research and addressed questions about the pathophysiological basis of CTE and its relationship to blast- and nonblast-related head injury. It served to inform participants objectively and help focus meeting discussion on identifying knowledge gaps and priority research areas. CTE is described generally as a progressive neurodegenerative disorder affecting persons exposed to head injury. Affected individuals have been participants primarily in contact sports and military personnel, some of whom were exposed to blast. The symptomatology of CTE overlaps with Alzheimer's disease and includes neurological and cognitive deficits, psychiatric and behavioral problems, and dementia. There are no validated diagnostic criteria, and neuropathological evidence of CTE has come exclusively from autopsy examination of subjects with histories of exposure to head injury. The perivascular accumulation of hyperphosphorylated tau (p-tau) at the depths of cortical sulci is thought to be unique to CTE and has been proposed as a diagnostic requirement, although the contribution of p-tau and other reported pathologies to the development of clinical symptoms of CTE are unknown. The literature on CTE is limited and is focused predominantly on head injuries unrelated to blast exposure (e.g., football players and boxers). In addition, comparative analyses of clinical case reports has been challenging because of small case numbers, selection biases, methodological differences, and lack of matched controls, particularly for blast-exposed individuals. Consequently, the existing literature is not sufficient to determine whether the development of CTE is associated with head injury frequency (e.g., single vs. multiple exposures) or head injury type (e.g., impact, nonimpact, blast-related). Moreover, the incidence and prevalence of CTE in at-risk populations is unknown. Future research priorities should include identifying additional risk factors, pursuing population-based longitudinal studies, and developing the ability to detect and diagnose CTE in living persons using validated criteria.

The 5th Annual One Mind Summit: Lessons Learned About "Science Informing Brain Health Policies and Practice".

Advances in science frequently precede changes in clinical care by several years or even decades. To better understand the path to translation, we invited experts to share their perspectives at the 5th Annual One Mind Summit: "Science Informing Brain Health Policies and Practice," which was held on May 24-25, 2016, in Crystal City, VA. While the translation of brain research throughout the pipeline-from basic science research to patient care-was discussed, the focus was on the implementation of "best evidence" into patient care. The Summit identified key steps, including the need for professional endorsement and clinical guidelines or policies, acceptance by regulators and payers, dissemination and training for clinicians, patient advocacy, and learning healthcare models. The path to implementation was discussed broadly, as well as in the context of a specific project to implement concussion screening in emergency and urgent care centers throughout the United States.

Pre-Clinical Traumatic Brain Injury Common Data Elements: Toward a Common Language Across Laboratories.

Traumatic brain injury (TBI) is a major public health issue exacting a substantial personal and economic burden globally. With the advent of "big data" approaches to understanding complex systems, there is the potential to greatly accelerate knowledge about mechanisms of injury and how to detect and modify them to improve patient outcomes. High quality, well-defined data are critical to the success of bioinformatics platforms, and a data dictionary of "common data elements" (CDEs), as well as "unique data elements" has been created for clinical TBI research. There is no data dictionary, however, for preclinical TBI research despite similar opportunities to accelerate knowledge. To address this gap, a committee of experts was tasked with creating a defined set of data elements to further collaboration across laboratories and enable the merging of data for meta-analysis. The CDEs were subdivided into a Core module for data elements relevant to most, if not all, studies, and Injury-Model-Specific modules for non-generalizable data elements. The purpose of this article is to provide both an overview of TBI models and the CDEs pertinent to these models to facilitate a common language for preclinical TBI research.

Ethical and regulatory considerations in the design of traumatic brain injury clinical studies.

Research is essential for improving outcomes after traumatic brain injury (TBI). However, the ubiquity, variability, and nature of TBI create many ethical issues and accompanying regulations for research. To capture the complexity and importance of designing and conducting TBI research within the framework of key ethical principles, a few highly relevant topics are highlighted. The selected topics are: (1) research conducted in emergency settings; (2) maintaining equipoise in TBI clinical trials; (3) TBI research on vulnerable populations; and (4) ethical considerations for sharing data. The topics aim to demonstrate the dynamic and multifaceted challenges of TBI research, and also to stress the value of addressing these challenges with the key ethical principles of respect, beneficence, and justice. Much has been accomplished to ensure that TBI research meets the highest ethical standards and has fair and enforceable regulations, but important challenges remain and continued efforts are needed by all members of the TBI research community.

Toward an international initiative for traumatic brain injury research.

The European Commission (EC) and the National Institutes of Health (NIH) jointly sponsored a workshop on October 18-20, 2011 in Brussels to discuss the feasibility and benefits of an international collaboration in the field of traumatic brain injury (TBI) research. The workshop brought together scientists, clinicians, patients, and industry representatives from around the globe as well as funding agencies from the EU, Spain, the United States, and Canada. Sessions tackled both the possible goals and governance of a future initiative and the scientific questions that would most benefit from an integrated international effort: how to optimize data collection and sharing; injury classification; outcome measures; clinical study design; and statistical analysis. There was a clear consensus that increased dialogue and coordination of research at an international level would be beneficial for advancing TBI research, treatment, and care. To this end, the EC, the NIH, and the Canadian Institutes of Health Research expressed interest in developing a framework for an international initiative for TBI Research (InTBIR). The workshop participants recommended that InTBIR initially focus on collecting, standardizing, and sharing clinical TBI data for comparative effectiveness research, which will ultimately result in better management and treatments for TBI.

Progress in developing common data elements for traumatic brain injury research: version two--the end of the beginning.

To accelerate data sharing and research on traumatic brain injury (TBI), several federal agencies have been collaborating to support the development and implementation of common data elements (CDEs). The first recommendations for CDEs were made in 2010, and were well suited for hospital-based studies of acute TBI in adults. To broaden the utility of the TBI CDEs, experts were asked to update the recommendations to make them relevant to all ages, levels of injury severity, and phases of recovery. The second version of the TBI CDEs (v.2) was organized around four major study types: 1) epidemiological research; 2) studies on acute, hospitalized patients; 3) studies of the rehabilitation for moderate/severe TBI; and 4) mild TBI/concussion research. Given the heterogeneity of TBI, only a small set of core CDEs were found to be relevant across all study types. However, within groups, a much larger set of highly relevant CDEs were identified, and these were called basic CDEs. In addition, an expanded number of supplemental CDEs were specified and recommended for use depending upon the study goals. Version 2 provides a rich data dictionary for TBI research with about 900 CDEs. Many of the CDEs overlap across the study types, which will facilitate comparisons and meta-analysis across studies. Further modifications of the CDEs should be based on evaluation of their usefulness following implementation across a range of studies.

Therapy development for diffuse axonal injury.

Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

Common data elements for research on traumatic brain injury: pediatric considerations.

Traumatic brain injury (TBI) is a significant global health problem, with a notably high incidence in children and adolescents. Despite the prevalence of TBI and the disabilities that often follow, research on which to base effective treatment is limited by several challenges, including but not limited to the complexity and heterogeneity of TBI. Even when rigorous methods are employed, the utility of the research may be limited by difficulties in comparing findings across studies resulting from the use of different measures to assess similar TBI study variables. Standardization of definitions and data elements is an important step toward accelerating the process of data sharing that will ultimately lead to a stronger evidence base for treatment advances. To address this need, recommendations for common data elements (CDEs) for research on TBI were developed through a 2009 national initiative. To ensure that the TBI CDE recommendations are relevant to pediatric populations, the National Institute on Disability and Rehabilitation Research (NIDRR) and the National Institute of Neurological Disorders and Stroke (NINDS) called for a review of the original recommendations. Following the process used for the original initiative, multidisciplinary work groups composed of pediatric TBI experts were formed (Demographics and Clinical Assessment; Biomarkers; Neuroimaging; and Outcomes Assessment). Recommendations for modifications and additions to the original CDEs were developed by the work groups, vetted at a 2010 workshop and further refined in preparation for publication. The pediatric considerations for TBI CDEs are described in a series of articles in this journal. This article describes the efforts leading to this pediatric CDE initiative and the CDE review and development process. It concludes with general recommendations for future iterations of the CDE initiative.

Harnessing neuroplasticity for clinical applications.

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

Proceedings of the military mTBI Diagnostics Workshop, St. Pete Beach, August 2010.

Approximately 28,000 service members (SMs) sustain a traumatic brain injury (TBI) each year in the U.S. military. The majority of the injuries result either in a brief or no loss of consciousness, and are classified as a mild TBI (mTBI or concussion). Current evaluation guidelines of SMs suspected of having a mTBI rely heavily on self-reports. However, there is concern that SMs typically minimize or do not report their symptoms of mTBI for fear that doing so will result in being removed from the battlefield. Because mTBI often results in headaches, cognitive dysfunction, attention difficulties, and balance problems, returning to the battlefield before resolution of their symptoms can be dangerous for the SM and for their unit. Sustaining a second concussion before resolution of a previous mTBI also may make long-term neuronal injury more likely. The mTBI Diagnostics Workshop was designed as a forum where civilian and military experts from a variety of TBI-related clinical and basic science disciplines could meet to define the diagnostic tools, alone or in combination, that were most likely to result in an acute, objective diagnosis of mTBI. The premise of the meeting was that a small number of well-focused research projects conducted over the next 2-3 years could be done to validate the optimal test, or more likely combination of tests, that would be practical and reliable for the acute diagnosis of mTBI within 2-3 h of injury in theater. The recommendations of the Workshop are provided in this report.

Advancing integrated research in psychological health and traumatic brain injury: common data elements.

In civilian, military, and veteran populations, there is increased recognition of the interrelationship between traumatic brain injury (TBI) and some psychological health (PH) disorders and the need to better understand the relationships by integrating research for these topics. The use of different measures to assess similar study variables and/or assess outcomes may limit important advances in PH and TBI research. Without a set of common data elements (CDEs; to include variable definitions and recommended measures for the purpose of this discussion), comparison of findings across studies is challenging. The federal agencies involved in PH and TBI research, the National Institute of Neurological Disorders and Stroke, Department of Veterans Affairs, National Institute on Disability and Rehabilitation Research, Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, and Defense and Veterans Brain Injury Center, therefore cosponsored a scientific initiative to develop CDEs for PH and TBI research. Scientific experts were invited to participate in 1 of 8 working groups to develop recommendations for specific topic-driven CDEs. Draft recommendations were presented and discussed in the workshop "Advancing Integrated Research in Psychological Health and Traumatic Brain Injury: Common Data Elements (CDE)" held on March 23-24, 2009, in Silver Spring, MD. The overall process leading to the workshop and subsequent recommendations by the working groups are presented in this article. Topic-driven recommendations for CDEs are presented in individual reports in this edition.

Common data elements in radiologic imaging of traumatic brain injury.

Radiologic brain imaging is the most useful means of visualizing and categorizing the location, nature, and degree of damage to the central nervous system sustained by patients with traumatic brain injury (TBI). In addition to determining acute patient management and prognosis, imaging is crucial for the characterization and classification of injuries for natural history studies and clinical trials. This article is the initial result of a workshop convened by multiple national health care agencies in March 2009 to begin to make recommendations for potential data elements dealing with specific radiologic features and definitions needed to characterize injuries, as well as specific techniques and parameters needed to optimize radiologic data acquisition. The neuroimaging work group included professionals with expertise in basic imaging research and physics, clinical neuroradiology, neurosurgery, neurology, physiatry, psychiatry, TBI research, and research database formation. This article outlines the rationale and overview of their specific recommendations. In addition, we review the contributions of various imaging modalities to the understanding of TBI and the general principles needed for database flexibility and evolution over time to accommodate technical advances.

Neurological effects of blast injury.

Over the last few years, thousands of soldiers and an even greater number of civilians have suffered traumatic injuries due to blast exposure, largely attributed to improvised explosive devices in terrorist and insurgent activities. The use of body armor is allowing soldiers to survive blasts that would otherwise be fatal due to systemic damage. Emerging evidence suggests that exposure to a blast can produce neurologic consequences in the brain but much remains unknown. To elucidate the current scientific basis for understanding blast-induced traumatic brain injury (bTBI), the NIH convened a workshop in April 2008. A multidisciplinary group of neuroscientists, engineers, and clinicians were invited to share insights on bTBI, specifically pertaining to: physics of blast explosions, acute clinical observations and treatments, preclinical and computational models, and lessons from the international community on civilian exposures. This report provides an overview of the state of scientific knowledge of bTBI, drawing from the published literature, as well as presentations, discussions, and recommendations from the workshop. One of the major recommendations from the workshop was the need to characterize the effects of blast exposure on clinical neuropathology. Clearer understanding of the human neuropathology would enable validation of preclinical and computational models, which are attempting to simulate blast wave interactions with the central nervous system. Furthermore, the civilian experience with bTBI suggests that polytrauma models incorporating both brain and lung injuries may be more relevant to the study of civilian countermeasures than considering models with a neurologic focus alone.

Combination therapies for traumatic brain injury: prospective considerations.

Traumatic brain injury (TBI) initiates a cascade of numerous pathophysiological events that evolve over time.Despite the complexity of TBI, research aimed at therapy development has almost exclusively focused on single therapies, all of which have failed in multicenter clinical trials. Therefore, in February 2008 the National Institute of Neurological Disorders and Stroke, with support from the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, and the Department of Veterans Affairs, convened a workshop to discuss the opportunities and challenges of testing combination therapies for TBI. Workshop participants included clinicians and scientists from a variety of disciplines, institutions, and agencies. The objectives of the workshop were to: (1) identify the most promising combinations of therapies for TBI; (2) identify challenges of testing combination therapies in clinical and pre-clinical studies; and (3) propose research methodologies and study designs to overcome these challenges. Several promising combination therapies were discussed, but no one combination was identified as being the most promising. Rather, the general recommendation was to combine agents with complementary targets and effects (e.g., mechanisms and time-points), rather than focusing on a single target with multiple agents. In addition, it was recommended that clinical management guidelines be carefully considered when designing pre-clinical studies for therapeutic development.To overcome the challenges of testing combination therapies it was recommended that statisticians and the U.S. Food and Drug Administration be included in early discussions of experimental design. Furthermore, it was agreed that an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatly facilitate the development of successful combination therapies for TBI. Overall there was great enthusiasm for working collaboratively to act on these recommendations.

Environmental enrichment increases progenitor cell survival in the dentate gyrus following lateral fluid percussion injury.

Neurons in the hilus of the dentate gyrus are lost following a lateral fluid percussion injury. Environmental enrichment is known to increase neurogenesis in the dentate in intact rats, suggesting that it might also do so following fluid percussion injury, and potentially provide replacements for lost neurons. We report that 1 h of daily environmental enrichment for 3 weeks increased the number of progenitor cells in the dentate following fluid percussion injury, but only on the ipsilesional side. In the dentate granule cell layer, but not the hilus, most progenitors had a neuronal phenotype. The rate of on going cell proliferation was similar across groups. Collectively, these results suggest that the beneficial effects of environmental enrichment on behavioral recovery following FP injury are not attributable to neuronal replacement in the hilus but may be related to increased neurogenesis in the granule cell layer.

Potential intervention by vaccinia virus complement control protein of the signals contributing to the progression of central nervous system injury to Alzheimer's disease.

Traumatic brain injury (TBI) is one of the few known risk factors for Alzheimers disease (AD) and for depression. The mechanisms by which trauma causes delayed cognitive deficits are largely unknown. In recent studies, it was demonstrated that the complement system (an important component of the immune system and a mediator of inflammation) is activated both in human AD and following experimental TBI in rats. Amyloid proteins are also present in AD and following TBI, and are known to activate complement in vitro. Based on these and other previous studies, it was hypothesized that regulation of the complement system will attenuate the long-term consequences of TBI. Vaccinia virus complement control protein (VCP) is a protein encoded by vaccinia virus. It blocks both the classic and alternative pathways of complement activation in vitro, and by doings so prevents the generation of proinflammatory chemotactic factors. Based on in vitro studies VCP can block the complement activation by the amyloid beta peptide. Using a fluid percussion rat model that causes traumatic brain injury (TBI), it was found that VCP significantly enhances functional recovery as determined by the Morris Water Maze test. Taken togther these studies indicate that potentially VCP could block molecular signals such as the formation of amyloid beta or the activation of complement to inhibit formation of AD following TBI.