TBI in the News

Study 1:

A Magnetic Resonance Imaging-Based Classifier to Accurately Diagnose Persistent Post-Traumatic Headache and to Differentiate It From Chronic Migraine

 (PI: Dr. Todd Schwedt)

Traumatic brain injury (TBI) and post-traumatic headache (PTH) are common conditions that exert substantial impacts in the military and in the civilian population. TBI is a signature injury of U.S. Soldiers during modern warfare with 20% of Operation Enduring Freedom and Operation Iraqi Freedom Veterans having experienced TBI, 75% of which are mild TBI (mTBI). In addition, approximately 1.7 million American civilians seek medical attention each year for TBI and there are 1.6-3.8 million sports-related mTBIs annually. Headache is the most common symptom following mTBI, with estimates of headache prevalence following mTBI as high as 90%. PTH is often persistent (i.e., endures for >3 months following the injury), with about 66% of people with mTBI reporting continued headaches at 3 months post-injury. Although progress has been achieved in understanding PTH epidemiology, there are significant shortcomings in the description of PTH mechanisms, diagnosis, and treatment. A major challenge for the investigation, diagnosis, and treatment of PTH is the inability to accurately diagnose persistent post-traumatic headache (PPTH) attributed to mTBI and to reliably differentiate PPTH attributed to mTBI from chronic migraine (CM). Rationale: It is often impossible to clinically differentiate the patient who had an exacerbation of their underlying migraine pattern following TBI, from the patient who had a new onset of migraine following TBI, from the patient with true PPTH. According to International Classification of Headache Disorders diagnostic criteria, the only evidence for headache being attributable to a preceding head injury is that the headache begins within 7 days of the injury. However, a substantial proportion of military PTH starts after a longer interval (up to 60% of cases), the majority of PPTH is phenotypically indistinguishable from CM according to information typically collected in the clinical setting (60%-97%), and many Soldiers and civilians with presumed PPTH have a personal history of migraine preceding the mTBI. Thus, it is commonly challenging to differentiate PPTH from CM in the clinical setting. The inability to accurately diagnose PPTH attributed to mTBI and differentiate it from CM has substantial negative implications on patient care and the ability to conduct meaningful research on PPTH.Objective: The objective of this study is to use machine-learning algorithms to construct multivariate models of structural and functional imaging data and patient symptoms that accurately diagnose PPTH attributed to mTBI and differentiate it from CM.Study Design: Functional and structural magnetic resonance imaging (MRI) data and patient symptoms will be used to build and test automated diagnostic models that most accurately diagnose PPTH attributed to mTBI and differentiate it from CM. This investigation uses MRI sequences that could easily be employed during the clinical investigation of patients, without adding risk to the patient, without the need for contrast administration, and with little additional financial burden.

The study profile in FITBIR can be found here.

Summary Information:

Study 2:

Advanced Imaging Acquisition and Data Analysis for a Military TBI Neuroimaging Database at NICoE

 (PI: Dr. John Ollinger, DSc)

Uploading legacy clinical neuroimaging and neuropsych data from the National Intrepid Center of Excellence to FITBIR: This project establishes an accessible centralized location for legacy neuroimaging, neuropsychiatric, self-reported and demographics data from a unique military TBI population, establishing a methodology for continued data submission to FITBIR. The National Intrepid Center of Excellence (NICoE) is an institute that generates clinical knowledge, improves diagnosis and advances treatment related to the pathophysiological and natural history of comorbid mild traumatic brain injury and psychological health conditions.

The study profile in FITBIR can be found here.

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Study 3:

Objective Multimodal Assessment of Cognitive and Sensorimotor Function After Mild TBI in Static and Dynamic Environments

 (PI: Dr. Mark L. Ettenhofer)

The purpose of this study is to develop and pilot test methods for the assessment of cognitive and oculomotor performance using integrated eye tracking & electroencephalography (EEG) monitoring technologies within both static (“Fusion Rapid Clinical Assessment” [Fusion-RC]) and dynamic military/operational (“Fusion Immersive Virtual Reality Environment” [Fusion-VR]) environments. A total of 70 active duty military members between the ages of 18-45 years old will be recruited for this study. Subjects will be classified into two groups: healthy controls, or mild traumatic brain injury (mTBI). By linking Fusion-RC metrics (cognitive and oculomotor impairment and EEG signatures) to military/operational skills measured by Fusion-VR, this project will provide A) validation of Fusion-RC for rehabilitation treatment planning and return-to-duty decision making; and B) improved understanding of the functional and military/operational significance of cognitive and oculomotor impairments associated with mTBI.

The study profile in FITBIR can be found here.

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Study 4:

Automated Assessment of Visual Photosensitivity in Traumatic Brain Injury

(PI: Dr. Anat Galor)

In this study, we focus on validating a clinical automated instrument, the Ocular Photosensitivity Analyzer (OPA), to quantify an important sequela of traumatic brain injury (TBI), visual photosensitivity (i.e. photophobia). Additionally, we will also assess the effect of various light filtering eyewear with the OPA to investigate whether specific wavelengths of light have significant impact on the management of visual photosensitivity in TBI subjects. Study questionnaires will be administered in conjunction with OPA testing to better understand the complex interactions between visual photosensitivity and other TBI associated sequela (dry eye, ocular pain). We will measure VPT in healthy and TBI subjects via the OPA at Visit #1 (baseline) and Visit #2 (1 month) (both with and without light filtering eyewear, in random order) and correlate VPT to the study questionnaires. Ninety-two study participants have been recruited, screened, enrolled, and completed Visit #1 as well as eighty-eight of those study participants have completed Visit #2.

The study profile in FITBIR can be found here.

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Study 5:

Tau and beta-amyloid deposition, microhemorrhages and brain function after traumatic brain injury in war veterans

(PI: Dr. Christopher Rowe)

Studies suggest an increased risk of Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) after traumatic brain injury (TBI). Greater understanding of the chronic effects of TBI may lead to new therapies. This proposal will add a TBI cohort, tau PET imaging and 7T-MRI to the Australian Imaging Biomarkers and Lifestyle - Veterans study (AIBL-VETS) of post traumatic stress disorder and neurodegeneration. AIBL researchers have an outstanding international record in the development of tau and amyloid PET imaging.

The study profile in FITBIR can be found here.

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Study 6:

Sensory Integration Balance Deficits in Complex mTBI: Can Early Initiation of Rehabilitation With Wearable Sensor Technology Improve Outcomes?

(PI: Dr. Laurie King)

Every year 1.7 million people sustain a traumatic brain injury (TBI) in the US and of these, 84% are considered mild TBI (mTBI). Although imbalance is one of the most common and debilitating complaints after mTBI, we currently lack clear guidelines on when to initiate rehabilitation and it is unclear if early physical therapy is beneficial. Additionally, while wearable sensor data is not currently used in the clinic to assess or treat balance after mTBI, such technology may improve outcomes. Our research aligns directly with focus areas in JPC-8/CRMRP since we will study people with mTBI who also have complex, multisensory system impairments and complaints of imbalance. This call encourages studies of patients with dizziness and visual dysfunction that are slow to respond to current treatments. Our project also aligns with FY 16 PH/TBIRP CTRRA areas of encouragement for ‘interventional studies to evaluate emerging or existing rehabilitation strategies for the treatment of patients with complex TBI compared to existing standards of care.’ Our Phase 2 interventional study also addresses the interest in comorbidities (i.e. central sensory integration and/or peripheral vestibular dysfunction) that may be refractory to treatment. Our project includes a multidisciplinary team with an academic institution Oregon Health & Science university (OHSU) partnering with industry (APDM) in an effort to improve rehabilitation after mTBI. Our central hypothesis is that rehabilitation after mTBI is suboptimal due to late initiation of and inadequate performance of exercises that do not adequately challenge vestibular and sensory integration function. Our preliminary results show physical rehabilitation is initiated late (approximately 70 days post injury) and that individuals with mTBI have altered central sensorimotor integration and do not optimally perform balance exercises. We believe that wearable sensor technology could facilitate rehabilitation by monitoring the compliance and quality of balance exercises. There are 3 Aims of this proposal; Aim I. Early Intervention: To determine the effects of early vs late (standard of care) rehabilitation for balance deficits in mTBI; Aim II. Home Monitoring: To compare traditional balance rehabilitation versus balance rehabilitation with sensor-based home monitoring of the compliance and quality of prescribed exercises; Aim III. Real-time monitoring: To develop and evaluate a novel, wearable sensor system to provide real-time feedback to physical therapists on head and trunk movement during training of balance and vestibular exercises.

The study profile in FITBIR can be found here.

Summary Information:

Study 7:

Cumulative and persistent intermediate effects of concussion and head impact exposure in CARE Consortium Military Service Academy members and NCAA Athletes (CARE 2.0)

(PI: Dr. Thomas McAllister)

To better understand the risks and consequences of head impact exposure and concussion, the U.S. Department of Defense (DoD) and NCAA established the NCAA-DoD Grand Alliance and the Concussion Assessment, Research and Education (CARE) Consortium in 2014. CARE has enrolled over 55,000 male and female MSA cadets and NCAA athletes at the four MSAs and 26 NCAA institutions, and more than 5000 concussed cadets/athletes have undergone detailed post-injury study. CARE is currently addressing key knowledge gaps on the natural history of concussion, its acute effects on brain structure and function, and factors that predict health outcome in MSA members and NCAA student-athletes. There is growing concern that repeated concussions and/or cumulative head impact exposure resulting from military training or contact sports may be associated with ongoing or chronic neurologic (brain injury-related) health problems. To address this concern, the current study (CARE 2.0) used the original CARE Consortium framework and infrastructure to evaluate the cumulative effects (i.e., over the course of a MSA/collegiate career) and persistent effects (i.e., ongoing after the MSA/collegiate career) associated with concussion and/or repetitive head impact exposure. Over the period of performance, more than 14,000 cadets and athletes were studied prior to graduation and more than 3,900 were studied up to four years following graduation. Participants were evaluated for brain health in the domains of cognition, psychological health, and life function. A subset of participants were evaluated for brain structure, and function, as well as genomic and proteomic profiles.

The study profile in FITBIR can be found here.

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Study 8:

CENC Study 49: Clinical and Neuroimaging Correlates of Neurodegeneration in Military mTBI

(PI: Dr. Nicholas Davenport)

Mild traumatic brain injury (mTBI) is common among military service members returning from OEF/OIF deployments. While a history of military mTBI has been demonstrated to be associated with increased risk of negative psychological outcomes (e.g., PTSD, depression, alcohol dependence), as well as disrupted brain connectivity, it is unknown how these conditions relate to neurodegenerative conditions, such as chronic traumatic encephalopathy (CTE). The purpose of this study is to better understand biological and psychological factors contributing to progressive functional deterioration among Veterans with a history of military concussion.

The study profile in FITBIR can be found here.

Summary Information:

Study 9:

CENC Study 56: Visual Sensory Impairments and Progression Following Mild Traumatic Brain Injury

(PI: Dr. Randy Kardon)

This 3-year, prospective, case-control study of veterans will evaluate the consequences of mild TBI on the visual pathways in the eye and brain over time. Two main veteran cohorts with mild TBI and without TBI will be studied, and we will analyse visual function, eye movement and pupil recordings, and OCT imagining. An estimated 200-400 thoUnited States of Americand veterans have suffered a TBI in the Iraq and Afghanistan conflicts. Many of them have visual symptoms as a result of their TBI, but to date, a longitudinal study using quantitative visual and brain measures has not been performed.

The study profile in FITBIR can be found here.

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Study 10:

Soccer heading: potential for brain injury and opportunities for its mitigation

(PI: Dr. Michael Lipton)

Traumatic brain injury (TBI) in athletes is a major and increasingly recognized public health problem. The presumed pathologic basis of the injury is multifocal microstructural traumatic axonal injury (TAI), which can be detected in vivo using diffusion tensor MRI (DTI). These structural changes have both short-term and long-term cognitive consequences. Our preliminary studies show that amateur soccer players do head the ball frequently, up to > 5,000 per year, and those who head more than 1,000- 1,500 times per year are at increased risk for structural (TAI) and functional (poorer cognitive performance) changes. Heading exposes the brain to repeated low-level ("subconcussive") trauma. It is known that multiple head injuries in close succession are associated with worse outcomes. Additional work is needed to define exposure-response relationships for soccer heading, the time course for the onset and recovery from these structural and functional effects and particularly vulnerable populations. Herein, we use 3 integrated study designs to determine the influence of heading on brain structure and function. In a cross-sectional study (Aim 1), we assess the relationship of heading over the previous year to structural (TAI) and functional (cognition and post-concussion symptoms (PCS)) measures in a large sample (n=400) of amateur soccer players. To assess causality, we propose a longitudinal study to investigate the incremental effects of heading on changes in TAI, cognition and PCS over 2 years of follow-up (Aim 2). To assess the short-term relationship between heading and day-to-day variability in cognitive function and PCS as well as the predictive value of intensive measurement, we will assess heading, cognition and PCS on a daily basis for 14 days every 3 months using a hand-held device in a substudy of 100 players. We will also assess a number of potential modifiers of the association between heading and brain structure and function (e.g., Apolipoprotein E4 genotype).

The study profile in FITBIR can be found here.

Summary Information:

Study 11:

Human Head Impact Dose Concussion Risk Functions and Sensor-Based Military-Specific Environmental Monitoring System

(PI: Dr. Adam Bartsch)

Approximately 80% of military mTBI, affecting hundreds of thousands of soldiers, occur in non-deployed settings like combative training activities. Concussion and mTBI caused by loss of consciousness is serious concern to the Departments of Defense and Transportation because it is a major impediment to egress in aviation crashes. Military, athletic and transportation authorities have long desired a system that can monitor concussion and mTBI risk in real-time, as well as quantify head impacts that cause acute and long-term brain health decline. In spite of recent proliferation in head impact instrumentation, there still is no objective means to identify concussion risk in real-time from any single impact. In this proposal we will use valid measurements to quantify head impact severity, clinical behavioral assessments and brain damage locations in comprehensive studies of soldiers and athletes. We specifically aim to (1)Monitor dangerous head impacts to US Army Soldiers undergoing combative training without negatively impacting concept of operations. Provide head injury risk functions and dose-response relationships gathered from Modern Army Combatives Program (MACP) personnel, (2) Develop a prototype military-specific boil-and-bite Intelligent Mouthguard to instrument and monitor large numbers of personnel simultaneously without negatively impacting the concept of operations, (3) Conduct a pilot project to determine how to best monitor head impacts and quantify injury risk in Federal Service Academy personnel participating in American Football, Ice Hockey, Lacrosse, Rugby, Soccer, Wrestling and Boxing, (4) Conduct a pilot project to monitor head impacts in the airborne environment and determine how to utilize this population to best quantify dose-response relationship without negatively impacting concept of operations and (5) Assist USAARL in laboratory testing to develop standard means to quantify sensitivity and specificity of head impact dosimeters in ATD and PMHS tests. After completing these projects, we will have defined the relationship(s) between head impact kinematics, behavioral outcomes and likely locations of brain injury for US Military and athletic populations. We will be able to define performance specifications for environmental sensing instruments that can monitor US Military members at risk of short- and long-term head injury in training. We will know kinematic inputs responsible for highest head injury risk and be able to pursue subsequent projects that design military, athletic and transportation-specific protective systems to reduce impact kinematics in a physics-based manner. Finally, we will have pre-production, ruggedized and user-friendly systems ready to monitor future US Military members.

The study profile in FITBIR can be found here.

Summary Information:

Study 12:

Portable Warrior Test of Tactical Agility: POWAR-TOTAL

(PI: Dr. Karen McCulloch)

The long-term goal is to implement a clinically feasible military relevant task that can aid clinicians in RTD decisions following concussion. The overall objective is to assess the performance-based POWAR-TOTAL, building on standardized scoring and procedures from the Assessment of Military Multitask Performance (AMMP) study. This test will improve clinical feasibility over AMMP tactical agility tasks by requiring less space and time while using less expensive smartphone technology as instrumentation. The POWAR-TOTAL incorporates the most sensitive and provocative aspects of multiple AMMP tasks. The central hypothesis is that POWAR-TOTAL will be sensitive enough to identify clinically significant movement differences using a combination of Principal Component Analysis, Fast Fourier Transform and Support Vector Machine analysis that can occur in real time. This approach is reliable and valid, as previous studies with laboratory equipment found the such analysis differentiated those with injury from those without at >.80.Pilot data using our smartphone accelerometer and application further supports our hypothesis. The rationale for our project is to validate the POWAR-TOTAL in a manner that allows for portability, refining a RTD test that can be used to provide immediate feedback to clinicians and SMs alike.

The study profile in FITBIR can be found here.

Summary Information:

Study 13:

CTE and Posttraumatic Neurodegeneration: Neuropathology and Ex Vivo Imaging (UNITE)

(PI: Dr. Ann McKee)

Traumatic brain injury (TBI) is associated clinically with progressive cognitive decline and dementia and pathologically with axonal injury and the deposition of multiple aggregated proteins. Repetitive mild TBI can trigger chronic traumatic encephalopathy (CTE), a unique tauopathy, and single TBI can provoke an Alzheimer's-like neurodegeneration. Unfortunately, the only way to diagnose these posttraumatic neurodegenerations, including CTE, is by post-mortem brain examination. In order to conduct prospective research into the incidence, prevalence, risk factors, clinical course, and ultimately, treatment for posttraumatic neurodegeneration, consensus criteria for diagnosis as well as objective biomarkers for disease must first be established. This initiative will assemble a multicenter team of expert neuroscientists to evaluate the late effects of TBI, including single and repetitive TBI of varying severity, and CTE, using histological examination of postmortem biospecimens and neuroimaging tools as a foundation to develop in vivo diagnostics. As a first aim, this proposal will bring together a team of 5 accomplished neuropathologists in neurodegenerative disease to establish consensus criteria for the post-mortem diagnosis of CTE. This team will also define the stages of CTE pathology, the features that differentiate CTE from other neurodegenerations and the effects of substance abuse, and the characteristics of posttraumatic neurodegeneration after single TBI. As a second aim, this proposal will establish a national biospecimen and data bank for TBI (Understanding Neurological Injury and Traumatic Encephalopathy (UNITE) biobank) by developing a nationwide brain donor registry and hotline to acquire high quality biospecimens and data. The UNITE bank will use strictly standardized protocols and a web-based interface to ensure that tissue and data are readily available to qualified investigators. Comprehensive retrospective clinical data including clinical symptoms, brain trauma and substance abuse history, and medical records (including common data elements) will be entered into a secure database. Behavioral/ mood dysfunction, cognitive changes, substance abuse and traumatic exposure will be correlated with quantitative assessment of the multifocal tauopathy, A? deposition and axonal injury. As a third aim, neuroimaging signatures of the neuropathology will be determined in post-mortem tissue using high spatial resolution diffusion tensor imaging (DTI) and autoradiography using a highly selective PET ligand for tau. Quantitative assessment of axonal injury, tau, and A? will be correlated with ex vivo DTI abnormalities and tau ligand autoradiography. Pilot neuroimaging studies of individuals at high risk for the development of CTE will also be conducted in the final 2 years of the proposal. This proposal will determine the clinical and neuroimaging correlates of CTE and posttraumatic neurodegeneration and create the groundwork for establishing their incidence and prevalence. This study will have a tremendous impact on public health of millions of Americans and greatly increase our understanding of the latent effects of brain trauma.

The study profile in FITBIR can be found here.

Summary Information:

Study 1:

Harnessing Neuroplasticity to Promote Rehabilitation: CI Therapy for TBI

(PI: Dr. Edward Taub)

The purpose of this research was to determine the value of Constraint-Induced Movement therapy (CIMT) and Lakeshore Enriched Fitness Training (LEFT) for improving motor ability in veterans/warfighters and civilians with traumatic brain injury (TBI) and test whether any therapeutic effects observed are correlated with neuroplastic white matter or grey matter changes.

The study profile in FITBIR can be found here.

Summary Information:

Study 2:

TBI Endpoints Development (TED) Friend Controls Study

(Multi-PI: Geoffrey Manley, MD, PhD (Contact PI); Nancy Temkin, PhD; Michael McCrea, PhD; Joseph Giacino, PhD; Sureyya Dikmen, PhD; Sabrina Taylor, PhD; Pratik Mukherjee, MD, PhD; Esther Yuh, MD, PhD; Lindsay Nelson, PhD; David Okonkwo, MD, PhD; Ava Puccio, PhD; Claudia Robertson, MD; Murry Stein, MD, MPH; John Whyte, MD, PhD; Ramon Diaz-Arrastia, MD, PhD; Harvey Levin, PhD (deceased).)

The TBI Endpoints Development is an initiative to improve the design of clinical trials that will lead to successful treatments of traumatic brain injury (TBI). While building the TED Metadataset, a compendium of datasets of individual, similarly characterized TBI studies, it became apparent that there is a dearth of data on control subjects in legacy TBI studies. To address this, 300 adult ‘friend’ and family member controls were recruited from and matched with the adult TBI patients that were enrolled in the NIH-funded Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. The controls underwent the same study milestones as 2,539 adult TBI subjects and the 299 adult controls with only orthopedic injuries. Recruiting and enrolling these 300 friend controls leveraged the existing infrastructure of the TRACK-TBI network at 12 trauma centers across the country.

Friend controls were matched according to demographic and background characteristics that were similar to the participants with TBI. Visits were conducted at baseline and 3, 6, and 12-months. In an effort to fuel progress towards precision medicine models for TBI, data collection included: medical histories; structural and functional neuroimaging; proteomic and genomic biomarkers; and the TRACK-TBI Comprehensive Assessment Battery (CAB) which consists of standardized neuropsychological, neurocognitive, and quality of life questionnaires.

• A total of nearly 40,000 records are shared among 43 form structures.
• For the CAB, 16 assessments were administered by the outcomes core examiners for a total of over 30,000 records submitted from more than 1,000 follow-up visits.
• Results of selected proteomic assays processed to date by the biomarker core are shared for 105 subjects.
• The imaging core submitted readings for MRI scans from 280 subjects that participated in the imaging protocol. Of these, nearly 2,700 structural, functional, and diffusion magnetic resonance sequences are currently being curated. These imaging datasets will be released in the near future upon completion of work for the quality assurance procedures.
• For more information about TBI Endpoints Development, please visit: https://tbiendpoints.ucsf.edu/

The study profile for the TBI Endpoint Study can be found here:

• https://fitbir.nih.gov/study_profile/384

Summary Information

Study 3:

Development and validation of spreading depolarization monitoring for TBI management

(PI: Jed Hartings, PhD)

Abstract

The goal of acute traumatic brain injury (TBI) treatment is to minimize secondary damage that evolves over hours to days after the primary injury. Until now, however, there have been no methods for monitoring heterogeneous pathomechanisms to identify patients for appropriate neuroprotection therapies. Using invasive monitoring in TBI patients requiring craniotomy, we have documented that spreading depolarizations (SD), a seizure-like pathology of cerebral gray matter that has been well-characterized through 60 years of research in animal models, are the dominant pathophysiologic process in peri-lesion cortex of many, but not all, severe TBI patients. Furthermore, we found that the occurrence of SD as a secondary injury process in patients is an independent predictor of worse neurologic outcomes. Thus, monitoring of SD provides the first real-time measure of neuronal secondary injury processes in patients to determine the selective application and benefit of neuroprotective therapies. However, since surgical patients are <10% of all TBI, less invasive and non-invasive techniques for SD monitoring are now required to generalize these findings. The premise of this proposal is that SD occurs across the spectrum of TBI severity as a pathologic mechanism of disease process and outcome heterogeneity.

Study Aims

Aim 1: Develop signal processing methods for automated bedside detection of spreading depolarizations in both electrocorticographic (ECoG) and non-invasive EEG recordings.

Aim 2: Determine the incidence of spreading depolarizations in TBI patients requiring intensive care.

Aim 3: Determine whether spreading depolarizations are independently associated with worse neurologic outcomes across the continuum of moderate-severe TBI.

Study Design: To achieve the specific aims, we will conduct an observational multi-center clinical study of patients admitted to intensive care for treatment of TBI. Severe TBI patients will undergo both invasive ECoG (depth or strip electrodes) and non-invasive EEG monitoring, and mild-moderate TBI patients will undergo EEG monitoring only.

Overview of Dataset Submission

The study was undertaken as a subprotocol of the “Transforming Research and Clinical Knowledge in Traumatic Brain Injury” (TRACK-TBI) initiative at 7 Level I Trauma Centers. A total of 153 TRACK-TBI subjects were co-enrolled into the SD protocol. Data collected in accordance with the TRACK-TBI protocol includes clinical histories, laboratory results, vital signs and Glasgow Coma Score assessments. Follow-up visits were conducted using the TRACK-TBI Flexible Outcome battery at 2-weeks and 3,6 and 12-months.

Sharing of the raw and preprocessed data collected from the high resolution ECoG and EEG monitoring is not currently possible within the FITBIR platform. Preprocessing and analysis are ongoing. Investigators interested in proposing a research collaboration for sharing the data may contact the PI.

Summary Information

*An additional 33 subjects were co-enrolled into TRACK-TBI study before enrollment in that study was closed. Those data were submitted to FITBIR Study ID 267.

Study 4:

Cortical GABA in pediatric sports concussion

(PI: Dr. Jeffrey Ojemann, MD)

Pediatric concussion remains without a reliable scanning tool to image injury or guide therapies. Previous studies with MRI use methods, such as diffusion tensor imaging, functional MRI and functional connectivity MRI, that have not yet been sensitive or specific enough to be used as clinical scans. MR spectroscopy allows measures of the chemical composition in parts of the brain. Recent advances in MR spectroscopy allow for the detection of levels of neurotransmitters, including gamma-amino butyric acid (GABA) which is a widespread inhibitory transmitter. GABA function is critical for cognition and may be abnormal in trauma. Abnormal GABA levels may impair recovery in animal models of injury. Our group combines a dedicated sports concussion program, a work-in-progress collaboration with Siemens Medical Imaging group, and an advanced imaging system (3T magnet with 32 channel head coil) along with a radiology research group with expertise in pediatric neuroimaging. We will address several areas of research interest by developing and studying MR spectroscopy of GABA in a tightly defined pediatric sports concussion population, with appropriate controls.

The study profile in FITBIR can be found here.

Study 5:

Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) High Definition Fiber Tracking (HDFT): Neuroimaging, Biospecimen, and Data Informatics Repositories

(PI: Dr. David Okonkwo, MD, PhD)

Grant/Project ID: W911QY-14-C-0070

Abstract

Effective treatment of traumatic brain injury (TBI) remains one of the great unmet needs of wounded warriors and in public health. Each year in the US, at least 2.5 million people suffer TBI; an estimated 3.2 to 5.3 million people live with the long-term physical, cognitive, and psychological health disabilities of TBI. This study expanded the scope of TRACK-TBI, the parent study (FITBIR Study ID 267), delivering on three core missions that harmonized TRACK-TBI resources and infrastructure: 1) advancing diagnostic neuroimaging by applying 3T structural MRI followed by High Definition Fiber Tracking (HDFT); 2) creation of a Biospecimen Repository of blood and DNA samples to validate proteomic and genetic biomarkers of TBI from 3000 subjects; and 3) foundation of a Bioinformatics Core necessary for validating neuroimaging, proteomic and genetic biomarkers of TBI.

Study Aims

Specific Aim 1: Perform advanced neuroimaging including 3T structural MRI and High Definition Fiber Tracking (HDFT) with subsequent analysis to accelerate the development and clinical adoption of technology that will provide a quantitative diagnosis of structural white matter injury after TBI to further improve diagnosis and prognosis of TBI patients.

Specific Aim 2: Create a Biospecimen Repository of blood and DNA samples collected from subjects that will enable validation of proteomic and genetic biomarkers to improve classification of TBI and lead to targeted therapies.

Specific Aim 3: Create a Data Informatics Core that will accelerate input of TRACK-TBI data into the Federal Interagency Traumatic Brain Injury Research Informatics System (FITBIR) and create a legacy database with analytic tools and resources to support TBI research.

Study Design

To achieve the specific aims, we conducted an observational multi-center clinical study of subjects treated at 7 Level I Trauma Centers. Subjects were enrolled into the study within the first 24-hours from the time of injury. Follow-up assessments were conducted during the acute phase in the hospital and at 2-weeks; 3-months; 6-months; and 12-months.

Overview of Dataset Submission

During Phase I, a total of 388 TBI subjects were co-enrolled into the TRACK-TBI Adult protocol. Data for the Phase I subjects have been shared within FITBIR Study ID 267. Enrollment into Phase II of the HDFT protocol continued when Study ID 267 closed to enrollments in July of 2018. The additional 113 TBI and 42 orthopedic control subjects were enrolled into the HDFT protocol between July of 2018 and September of 2019 and are shared within FITBIR Study ID 411.

Over 8,000 structural, functional and diffusion magnetic resonance sequences continue to undergo processing and curation for the Phase II subjects. The imaging datasets will be released upon completion of the quality assurance procedures. Investigators interested accessing the imaging datasets may contact the Principal Investigator to submit a collaboration proposal. Details for the protocols used by clinical and outcomes cores have been provided in the study documentation module.

The study profile in FITBIR can be found here.

Summary Information

*Clinical, Outcome and Biomarker forms shared.

Study 6:

Patterns of Tinnitus and Hearing Loss secondary to Blast Injury

(PI: Dr. Dewleen Baker)

Blast injuries are deemed signature wounds of recent wars; 12%-23% of returning Service members report traumatic brain injury (TBI), the majority mild TBI (mTBI). Of military personnel exposed to explosions, up to 77% sustain permanent hearing loss and 60%-75% report tinnitus. Patients with blast-related TBI are at least 2.5 times more likely to sustain tinnitus than patients with non-blast TBI. Despite the high prevalence of tinnitus, it remains a subjective syndrome that is not well characterized and for which there is no definitive treatment. This application makes use of the applied (human) TBI-related research Congressionally Directed Medical Research Programs request for proposals to focus upon the area of hearing loss/dysfunction and tinnitus, with the prime goal being to better understand underlying neural mechanisms of tinnitus.Objective/Hypotheses: As a primary objective of the study, we propose to obtain Department of Veterans Affairs (VA) and Department of Defense (DoD) audiology exam data, administer (via telephone and internet) an interview and questionnaires (Objective 1). We hypothesize that: (1.1) deployment-related TBI will increase likelihood of post-deployment hearing loss, defined as a "notch" at 6000 Hz; (1.2) hearing loss will increase as a function of injury etiology (i.e., blast vs. non-blast) (Aim 1); and (2.1) deployment-related TBI (versus no TBI) will be associated with greater tinnitus symptom severity controlling for relevant variables (i.e., prior noise exposure, hearing loss, and post-traumatic stress disorder [PTSD] status); (2.2) current tinnitus severity will vary as a function of injury etiology (Aim 2). As a second objective, we propose to invite four groups of participants to San Diego for comprehensive assessments including Magnetoencephalogram (MEG) scans to better understand underlying brain mechanisms (Objective 2). We hypothesize that: (3.1) resting-state MEG activity from individuals with blast-related tinnitus will show hyper-activity in beta (15-30 Hz) and gamma (30-80 Hz) bands from the auditory cortices in superior temporal gyri (STG), but hypo-activity from ventro-medial as well as dorso-lateral pre-frontal cortex (vmPFC and dlPFC) when compared with asymptomatic control subjects, suggesting local disinhibition at the auditory cortex and lack of top-down inhibition from pre-frontal cortex (PFC); (3.2) compared to asymptomatic controls, individuals with tinnitus and no hearing loss will show distorted tonotopic organization in the auditory cortices related to the tone of their tinnitus to MEG steady-state sound stimuli and abnormal responses to MEG paired-click sound stimuli; (3.3) MEG slow-wave generation (suggesting TBI) from vmPFC and dlPFC areas will correlate with MEG measures of disinhibition in tinnitus in these regions. Hypo-activity in high frequency bands from vmPFC will also correlate with PTSD symptoms; (3.4) Abnormal MEG resting-state signals and evoked responses from auditory cortices in STG as well as PFC will correlate with tinnitus symptom scores, behavioral deficits, and audiology data including tinnitus pitch, severity matching, and tinnitus masking scores (Aim 3).

The study profile in FITBIR can be found here.

Summary Information:

Study 7:

Objective Translational Multi-domain Early Concussion Assessment

(PI: Dr. Susan Margulies)

In the US, there are more than four sports-related traumatic brain injuries every minute. Sports-related concussion (SRC) in youth has received heightened attention due to emerging evidence that SRCs can affect academics, behavior, and neurocognitive processes, such as working memory, concentration, processing speed, and eye and motor function. A recent Institute of Medicine report on SRCs in youth revealed how little is known about concussion in the young brain, and called for urgent attention to determine the incidence of SRCs in boys and girls by sport and demographic; research to identify unbiased, sensitive prognostic and diagnostic metrics/markers; longitudinal studies to determine outcomes; and to delineate age- and sex-related biomechanical determinants of injury risk. This innovative hypothesis-driven Bioengineering Research Grant will generate objective diagnostic tools for use in concussion (Aim 1), new technologies to translate human outcome metrics to animals to provide a human-like platform to develop and test injury treatments in the future (Aim 2), and new knowledge regarding high-risk sports settings for youth (Aim 3) that will drive safety equipment design. The most innovative feature of the study is the integration across Aims to use BOTH male and female high school students and piglets in a deliberately parallel study design to determine optimal SRC assessments and identify mechanistic relationships between sex, loading conditions, and SRC symptoms. The integration of human and animal studies which employ similar neuro-functional assessments leverages the strengths of each approach: human studies ensure the study of biofidelic physiologic processes, and animal studies allow application of specific loading conditions and outcomes not easily measured in living humans, such as neuropathology. Extensive pilot data establish feasibility and sample sizes in all Aims. In Aim 1 an unbiased numerical assessment suite for SRC will be developed and independently validated to establish ≥95% sensitivity, and determine if these metrics are predictive of days-to-clearance for sports. Because the Aim 1 objective metrics are nonverbal and effort-independent, they have been ?translated? to animals and reveal human-like physical, cognitive, and sleep symptoms of SRC in animals after rapid controlled head rotations. In Aim 2, single head rotations and multiple sub-concussive rotations are computationally scaled from teens to an immature large animal model of mild TBI, to identify the effects of sex and load frequency, magnitude and direction on neuro-function, biomarkers and neuropathology. Aim 2 will identify biomechanical settings of greatest risk for the young brain. The biomechanical insights from pigs in Aim 2 are translated to teens in Aim 3, where head impact sensors are used to quantify biomechanical load exposure by sport and sex, and the relationships between load exposure and neuro-functional metrics. The proposed studies in animals and humans will have broad impact ? by reducing the healthcare burden of SRC, enhancing accurate and objective diagnosis, and identifying gender-specific prevention and intervention strategies.

The study profile in FITBIR can be found here.

Summary Information:

Study 1:

Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI)

(Multi-PI: Geoffrey Manley, MD, PhD (Contact PI), Ramon Diaz-Arrastia, MD, PhD, Joe Giacino, PhD, Pratik Mukherjee, MD, PhD, David Okonkwo, MD, PhD, Claudia Robertson, MD, Nancy Temkin PhD

The unique public-private partnership of investigators, philanthropy, government, and industry leaders, along with the Multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) proposal, share a mission to accelerate clinical research in TBI. Our goal is to create an extensive, high-quality TBI database that integrates clinical, imaging, proteomic and genomic, and outcome biomarkers. We hope to provide analytic tools and resources to the research community through precise TBI diagnosis and prognosis methods that enhance outcome assessment and compares the effectiveness and costs of tests, treatments, and services. The investigators hypothesize that this approach will permit better characterization and stratification of patients, allowing meaningful comparisons of treatments and outcomes to improve the future generation of clinical trials.

The four specific aims of the study are:

• Specific Aim 1. To create a widely accessible, comprehensive TBI Information Commons that integrates clinical, imaging, proteomic, genomic, and outcome biomarkers from subjects across the age and injury spectra and provides analytic tools and resources to support TBI research.
• Specific Aim 2. To validate imaging, proteomic, and genetic biomarkers that will improve classification of TBI, permit appropriate choice and stratification of patients for clinical trials, and contribute to the development of a new taxonomy for TBI.
• Specific Aim 3. To evaluate a flexible outcome assessment battery comprised of a broad range of TBI common data elements that enables assessment of multiple outcome domains across all phases of recovery and at all levels of TBI severity.
• Specific Aim 4. To determine which tests, treatments, and services are effective and appropriate for which TBI patients and use this evidence to recommend practices that offer the best value.

The TRACK-TBI study was conducted at 18 level 1 trauma centers, representing the efforts of hundreds of investigators and research coordinators to screen and recruit subjects within the first 24-hours post-injury. Between February 26, 2014, and August 8, 2018, adult and pediatric TBI subjects were enrolled from across the injury spectrum from concussion to coma, along with a separate orthopedic control cohort.

Follow-up visits were conducted at 2-weeks and 3,6 and 12-months. In an effort to fuel progress towards precision medicine models for TBI, data collection included clinical indicators; serial imaging; proteomic and genomic biomarkers; and multidimensional outcome data using the NINDS Common Data Elements for TBI. Key data from the TRACK-TBI Cohort has contributed the following:

• Detailed clinical histories with inpatient and outpatient laboratory, vital sign and Glasgow Coma Score assessments during hospitalization.
• Candidate SNP array dataset for investigation of genetic associations that will improve the understanding of the role of genes in the pathophysiology of TBI.
• Neuroimaging sequences from standardized protocols across all study sites with demonstrated inter-rater reliability for using the TBI imaging CDEs for the study of associations between structural MRI findings, biomarkers and outcome measures.
• Development of a flexible outcome assessment battery to enable on research participants who are too impaired to complete standardized neurocognitive testing across all phases of recovery.

The data for the TRACK-TBI U01 Study are split into two study profiles within the FITBIR Data Repository, Adult and Pediatrics.

• The Adult study will have submissions to 87 form structures with a total of 1,271,936 records of data for 2,838 TBI and Orthopedic Control study participants. As of March 1^st, this is the largest study submission submitted to FITBIR accounting for 26% of the total number of records within FITBIR.
• The Pediatric study will have submissions to 43 form structures with a total of 30,839 records of data for 145 study participants.

For more information about TRACK-TBI, please visit: https://tracktbi.ucsf.edu

The study profiles for the two TRACK-TBI study profiles can be found here:

• Adult: https://fitbir.nih.gov/study_profile/267
• Pediatrics: https://fitbir.nih.gov/study_profile/409

Summary Information

Study 2:

Visual Deficits in Traumatic Brain Injury

(PI: Dr. Reza Farivar & Dr. Robert Hess)

The purpose of this study was to evaluate the impact of a traumatic brain injury on vision and characterize and measure possible visual deficits following a traumatic brain injury. A second component of the study investigated mechanisms of recovery of visual deficits following traumatic brain injury. We aimed to characterize and measure visual deficits following TBI, as correlated with injury location and severity. This knowledge will then be helpful in developing specific and individualized rehabilitation programs when patients are faced with visual deficits.

The study profile in FITBIR can be found here. 

Summary Information:

Study 3:

The use of VOMS tool with military personnel to track mTBI recovery and RTD status

(PI: Dr. Anthony Kontos)

Vestibular impairment and symptoms are prevalent following mild traumatic brain injury (mTBI) (Hoffer et al., 2010) and may play a role in prolonged recovery (Lau et al., 2011; Sheedy et al., 2009). Researchers have indicated that ocular motor dysfunction and symptoms are common among personnel exposed to blast mTBI (Capo-Aponte et al., 2012). In fact, researchers have suggested that vestibular and ocular motor outcomes such as VOR and vestibule-spinal reflex (VSR) may be useful in identifying the effects of blast from blunt mTBI (Hoffer et al., 2009). There are currently no brief, clinical screening tools to identify vestibular/ocular motor impairment and symptoms in military personnel following mTBI. Our research team recently developed the Vestibular/Ocular Motor Screening (VOMS) tool to screen for vestibular/ocular motor impairment and symptoms following mTBI (Mucha et al., 2014). Our preliminary research indicates that VOMS -- a 5-min clinical screening tool that can be deployed by corpsman-level (i.e., Special Operation Combat Medics [SOCM], Special Forces Medical Sergeants [18D]) medical personnel with minimal training and materials -- was nearly 90% accurate in identifying patients with mTBI from healthy controls (Mucha et al., 2014). These preliminary findings suggest that VOMS may augment current clinical screening tools such as the MACE used by the U.S. Military.

The study profile in FITBIR can be found here. 

Summary Information:

Study 4:

Development of a Brief Version of Compensatory Cognitive Training for Veterans with Mild Traumatic Brain Injury

(PI: Kathleen Pagulayan, PhD)

Persisting cognitive difficulties are frequently reported by Veterans with a history of mild TBI (mTBI), and can have a significant and wide ranging impact on day to day functioning. Empirically validated treatment options for cognitive rehabilitation (CR) exist for this population, but the length of treatment often pose a financial and time barrier. A brief CR intervention has the potential to significantly improve access to care for persisting cognitive difficulties among individuals with a history of mTBI and improve overall functioning and quality of life as well as serving as a possible gateway for engagement in other needed treatments. but interventions that are both accessible and effective remain limited. This study built on the existing literature, which supports the effectiveness of longer/more intensive CR interventions for Veterans to develop a brief CR intervention that is specifically targeted to the unique needs of this population. Using an empirically validated 10-week CR intervention called Compensatory Cognitive Training (CCT) as the starting point, a 5-session intervention called On-TRACC (Tools for Recovery and Clinical Care) was developed using a multi-faceted approach to identify the content for this intervention that was specifically designed to address the needs and treatment goals of Veterans who have persisting cognitive difficulties secondary to mTBI. In particular, information for this intervention was derived from  (1) a survey of Veterans who were previously diagnosed with mTBI and endorsed persisting symptoms in order to assess treatment preferences, barriers to care, and the nature/functional impact of ongoing cognitive difficulties and other symptoms, (2) a survey of clinicians who currently provide CR interventions in VA settings, (3) review and comparison of findings from step 1 and 2 with the completed full-length CCT randomized controlled trial in Veterans with a history of mTBI, and (4) feedback from Veterans who received the newly developed On-TRACC intervention.

The study profile for this study in FITBIR can be found here.

Summary Information:

Study 5:

Comprehensive study of acute effects and recovery after concussion: An integrated investigation of head impact sensor technology, blood biomarkers, advanced neuroimaging, genetic testing and clinical outcome metrics

(PI: Michael McCrea, PhD)

During the acute phase, mild traumatic brain injury (mTBI) is known to cause serious disruption in normal biological, cognitive, and behavioral function. While research over the last decade has significantly advanced the science of mTBI, a comprehensive neurobiopsychosocial model of mTBI is yet to be achieved. Objective/Hypothesis: With the goal of conducting the most comprehensive study of mTBI to date, this proposal leverages the existing infrastructure of a current DoD-funded study by ?piggy-backing? additional scientific aims that have major significance to our scientific understanding of mTBI. We hypothesize that there will be a significant correlation between biomechanical, clinical, neurobiological, and neuroradiological markers of mTBI, which will more fully inform a neurobiopsychosocial model of mTBI. Study Design: This is a prospective, cohort study that will include pre-exposure baseline assessment of a large sample of athletes enrolled, as well as acute and longitudinal follow-up assessment of a cohort with concussion, a matched control group of non- concussed athlete from the same contact sport, and a noncontact sport athlete control groups. 900 athletes participating in contact sports will undergo extensive pre-exposure baseline clinical, genetic, and biological studies. A subgroup of 50 contact sport athletes and the noncontact sport control group (n=50) will undergo preseason MRI studies as well. All participating athletes will be dually-equipped with the Riddell Head Impact Telemetry (HIT) system and non-helmet based sensor technologies to record biomechanical measurements of head impact exposure. Concussed athletes (n=50), a matched contact sport athlete control (n=50), and noncontact sport athlete control (n=50) will then undergo extensive post-injury follow-up studies at multiple time points. An array of blood biomarkers will be collected in concussed and control athletes within 6 hours of injury. Both groups will also then undergo clinical, blood biomarker, and advanced neuroimaging studies again at 24 hours, 8 days, 15 days and 45 days postinjury. Our study design will allow us to analyze the diagnostic and predictive value of each mTBI biomarker domain over time, as well as create a correlative, multi-dimensional diagnostic and prognostic model of mTBI.

The study profile for this study in FITBIR can be found here.

Summary Information:

Study 6:

AIM: TBI Impact of Aging on the Immune Response to Traumatic Brain Injury

(PI: Dr. Hillaire J. Thompson)

The aims of this prospective cohort study are to: 1) Compare cellular immune responses, plasma inflammatory biomarker concentrations, and measures of impairments, disability and health-related quality of life up to 6 months post-injury in young and older adults with and without mild TBI (75 per group) and 2) Determine the association between selected cellular immune and plasma biomarkers and impairments, disability and health- related quality of life at 3 and 6 months post-injury in older adults with mild TBI.

The study profile in FITBIR can be found here.

Summary Information:

Study 7:

Improving Cognitive and Functional Deficits after TBI Using Virtual Technology (Pilot and Core Studies)

(PI: Dr. Daniel )

We propose to improve cognitive difficulties in individuals with chronic TBI through training of strategies to accomplish complex real-life tasks. The interventions will be remotely delivered via virtual reality (VR) technology. The VR-technology allows the interventionist to simulate real-life tasks in an environment that allows careful modulation of task difficulty and collection of quantitative performance metrics. Remote deployment will make the intervention more accessible to individual who are resistant to clinical appointments or for whom transportation or work constraints render in-office visits impractical. If successful, we will be able to provide a set of tools to help an underserved group of wounded warriors. Improvements in daily life abilities will also likely impact the family lives of the individuals we are able to reach, as better daily life goal management, task performance, and task scheduling will have a positive impact for spouses, caregivers, and families of our military.

The study profile in FITBIR can be found here for the Pilot Study.

Summary Information:

The study profile in FITBIR can be found here for the Core Study.

Summary Information:

Study 1:

Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT) (PIs: Stephen Wisniewski, Ph.D., and Michael J Bell, MD)

ADAPT is an international research study designed to evaluate the impact of interventions on the outcomes of children with severe traumatic brain injury. The study was funded by the National Institutes of Neurological Disorders and Stroke (1 U01 NS081041-01A1).   

The study tested three aims:   

Specific Aim 1: Compare the effectiveness of first-line intracranial hypertension strategies.  

Specific Aim 2: Compare the effectiveness of strategies that mitigate iatrogenic ischemia and hypoxia.  

Specific Aim 3: Compare the effectiveness of strategies that provide metabolic support on outcome.  

40 clinical assessment form structures totaling 20,335 data records for 1000 subjects are now available in the FITBIR Data Repository. Imaging data will be shared at a later date.  

For more study information, please visit the site: https://www.adapttrial.org/  

The study profile for ADAPT in FITBIR can be found at: https://fitbir.nih.gov/study_profile/231  

Summary Information:

Study 2:

Chronic Effects of Neurotrauma Consortium (CENC) Study 08: Otolith Dysfunction and Postural Stability (Principal Investigator:  Faith Akin, PhD)

Chronic Effects of Neurotrauma Consortium (CENC) Study 08: Otolith Dysfunction and Postural Stability is a prospective case-controlled study to determine the effect of inner ear (vestibular) dysfunction on balance, gait and quality of life in Veterans. The specific aims are designed to determine the effect of otolith dysfunction on postural stability at the levels of impairment (Specific Aim 1), activity and participation (Specific Aim 2), and determine the interaction of age and otolith dysfunction on postural stability (Specific Aim 3). Balance measures, gait and mobility measures and self-report questionnaires were compared between vestibular groups and across a wide age range.

The study profile for the CENC Study 08 in FITBIR can be found here.

Summary Information:

Study 3:

MicroRNA in cerebral spinal fluid as biomarkers of Alzheimer's disease risk after brain injury (PI: Joseph Quinn, M.D.)

Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD), the most common neurodegenerative disease and a major public health problem. The mechanistic link between TBI and AD is not clear, and there is a long latency between TBI and AD, during which individuals are largely asymptomatic. The clinician's ultimate goal is to define interventions to reduce the risk of AD associated with TBI, but this will require definition of biomarkers of disease activity, especially during the prolonged latent period between the TBI and onset of dementia. While a variety of candidate biomarkers exist, the recent discovery of extracellular microRNAs in cerebrospinal fluid represents an opportunity to rapidly define candidate biomarkers of TBI and TBI-associated neurodegeneration.

To identify biomarkers specific to TBI, we examined miRNA expression in banked CSF obtained from and representing 3 groups: (i) deployed Iraq/Afghanistan Veterans who suffered repetitive blast mTBI, (ii) deployed Veterans with no lifetime history of TBI, and (iii) age-matched community controls with no lifetime history of TBI to identify whether miRNAs are dysregulated as a consequence of brain injury.

The study profile in FITBIR can be found here.

Summary Information:

Study 4:

Soccer heading: potential for brain injury and opportunities for its mitigation (PI: Michael Lawrence Lipton, MD)

Soccer heading: potential for brain injury and opportunities for its mitigation is a research study designed to evaluate the impact of Traumatic brain injury (TBI) in athletes as a major and increasingly recognized public health problem.  The study was funded by the National Institutes of Neurological Disorders and Stroke (1R01Ns082432-01).   

The study tested three aims:   

Study Aim 1: (Cross-sectional): Determine the relationship of heading exposure to MRI evidence of traumatic axonal injury (TAI), cognitive function and post-concussion symptoms (PCS).

Study Aim 2: (Longitudinal): Determine the longitudinal relationships between heading and incremental changes in TAI, cognitive function, and PCS in a prospective study.

Study Aim 3: (Intensive measurement): Determine the short-term effects on and variability in day-to-day cognitive function and PCS using an intensive measurement design.

17 clinical assessment form structures totaling 11,977 data records for 355 subjects are now available in the FITBIR Data Repository. Imaging data will be shared at a later date.  

For more study information, please visit Albert Einstein College  of Medicine website.

The study profile in FITBIR can be found here.

Summary Information:

Study 5:

Mechanisms of Photophobia in Mild Traumatic Brain Injury in Human Subjects: Therapeutic Implications (PI: Lora Likova, Ph.D.)

The purpose of this study was to identify the mechanisms responsible for generating photophobia, or abnormal light sensitivity, in patients who have suffered mild traumatic injury to the brain (or 'concussion').

Study Aim 1: Determine if there is functional damage to the retina and its the melanopsin-containing retinal ganglion cells (mRGCs), using  electroretinography (ERG).

Study Aim 2:  Determine if different cortical areas are affected by changes in mRGC function using high-density electroencephalography (EEG).

Study Aim 3: Determine changes in core brain function (functional MRI).

Study Aim 4: Determine if there are changes due to tissue swelling using the structural MRI technique of tensor-based morphometry (TBM)

The study profile in FITBIR can be found here.

Summary Information:

Study 6:

Concussion Assessment, Research and Education (CARE) Consortium (Principal Investigators: Thomas W. McAllister, MD; Michael McCrea, PhD, ABPP; Steven Broglio PhD, ATC; Colonel (Ret.) Paul. F. Pasquina, MD)

Mild traumatic brain injury (TBI) and sport-related concussion (SRC) are major public health problems. Although significant advances have been made in our understanding of concussion, to date, the natural history of concussion remains poorly defined, no objective biomarker of physiological recovery exists for clinical use, and athlete knowledge of the injury remains low. This investigation is poised to address the true natural history of clinical and physiological recovery of SRC, which has critical implications for improving safety, injury prevention, and medical care in athletes and military personnel. Objective: In keeping with the identified priorities of the National Collegiate Athletic Association (NCAA) and Department of Defense (DoD), we propose the Concussion Assessment, Research and Education (CARE) Consortium as a scientific and operational framework for the NCAA-DoD Grand Alliance. Hypotheses: There are two over-arching hypotheses driving this proposal:(1) Neurophysiological recovery from concussion extends beyond clinical signs and symptoms resolution.(2) A multidimensional combination of biomechanical, genetic, neuroradiological, biological, and clinical variables will be more strongly predictive of concussion risk and recovery than any single predictor variable. This study led by the Indiana University School of Medicine, Medical College of Wisconsin, and University of Michigan marks what is considered to be the most comprehensive investigation of sport-related concussion (SRC) ever conducted. This study will allow scientists to better understand the true natural history of concussion in athletes and investigate the correlation between multi-dimensional predictor and outcome variables associated with SRC from a fully neurobiopsychosocial perspective in a common injured sample and single study design.

Additional information about the study can be found here.

The study profile for the CARE Study in FITBIR can be found here.

Summary Information:

Study 7:

TBI Assessment of Readiness using a Gait Evaluation Test (TARGET): Development of a Portable mTBI Screening Device (PI: Christopher Rhea, PhD)

It is estimated that up to 320,000 service members in OEF/OIF have sustained some form of traumatic brain injury. The lack of an objective measurement tool for evaluation and monitoring of a suspected mild traumatic brain injury (mTBI) is of great concern to the military. Accurate diagnosis of an acute mTBI should involve detailed head injury history documentation and an assessment of a range of domains, including motor deficits. Assessments of motor functioning can detect neurophysiological impairments which may negatively impact the military personnel's ability to function in full military capacity. The NeuroCom Sensory Organization Test (SOT) is the current gold standard for assessing mTBI-related motor impairments; however, the equipment's size and logistical footprint makes it impractical for field deployment. An objective and clinically valid, yet field deployable assessment of motor functioning would greatly assist military medical personnel with return to duty (RTD) decisions. The AccWalker smartphone app taps into accelerometry and orientation data in order to assess an individual's neuromotor functioning by focusing on movement variability. Clinical research shows increased movement variability emerges in motor tasks after a neurological insult. This is likely due to reduced capacity of the central nervous system (CNS) to control movement. Thus, variability in motor tasks such as walking, has been used to identify neurological impairment from mTBI. Gait tasks have been used to identify motor impairment following mTBI, however, a large overground space or a treadmill is needed to properly assess gait variability. In pursuit of a simple motor task that encompasses a movement variability profile comparable to gait behavior, we adopted a stepping-in-place task. Gait and stepping-in-place exhibit similar variability characteristics, making the stepping-in-place task a proxy for gait behavior. Therefore, the study will seek to assess the use of the AccWalker smartphone app during a stepping-in-place task as a means of screening for mTBI-related motor impairments.

The primary objectives of this effort will be to establish the: (1) reliability (both inter-rater and test-retest), (2) criterion validity (both concurrent and predictive), 3) reliable change estimates, and (4) diagnostic utility of the reliable change estimates. Phase 1 of this proposal will establish the test-retest reliability, criterion validity, reliable change estimates, and diagnostic utility in a civilian population. If the reliability, criterion validity, and diagnostic utility are deemed acceptable, Phase 2 will establish the diagnostic utility of the TARGET in a military population. This approach will demonstrate if performance on the TARGET can identify mTBI related neuromotor deficits during post-injury in military population.

The study profile in FITBIR can be found here.

Summary Information:                                                                    

Study 8:

Quantitative MRI and 1H MRS in Traumatic Brain Injury (Principal Investigator: Yvonne Lui, MD)

Mild traumatic brain injury (MTBI) is a major public health problem with close to 1.5 million cases a year that can result in long-term complications including Post-Concussive Syndrome and Chronic Traumatic Encephalopathy. Concerns such as these have brought MTBI to public attention. There is evidence from our group and others that even a single concussive episode can cause long-term changes in the brain that can be visualized by Magnetic Resonance Imaging (MRI). Brain iron is highly regulated and has been shown to be abnormal after traumatic brain injury in both animal and human studies. Though iron is essential for a number of normal cellular processes, it is also implicated in a number of neurodegenerative disorders as causing toxicity to the brain via the production of oxygen free radicals. Abnormal iron in the brain associated with traumatic brain injury may be a link between trauma and a host of neurodegenerative conditions which have been associated with trauma, including Chronic Traumatic Encephalopathy and Alzheimer's Disease. This study was conducted to help characterize tissue distribution of susceptibility, a marker of brain iron in vivo, after a single concussive episode and to follow such changes over time. The project application has a translational focus and we also study the relationship to long-term changes in brain structure as well as the predictive value of brain iron in determining functional brain changes and outcome.

AIM: The primary long-term objective of the study is to characterize tissue distribution of susceptibility, a marker for brain iron in vivo, in MTBI using MRI.

The study profile for this study in FITBIR can be found here.

Summary Information:

Study 9:

Enhancing the detection and management of mTBI in military personnel (Principal Investigator: Jay Alberts, PhD)

Approximately 28,000 service members sustain a traumatic brain injury (TBI) each year in the US military. TBI results in multi-system impairments, including declines in postural stability, information processing, goal-directed movements, vision, vestibular function, and cognition (attention, working memory, set-switching, recall, dual-task performance). Commanders have called for objective and valid measures to quantify these deficits, to help determine the degree of recovery and most importantly, to provide quantifiable benchmarks to guide return-to-duty decisions. Current testing approaches to assessing TBI have been found to correlate only modestly to traditional neuropsychological tests, and their utility in assisting with clinical decision making has been called into question; furthermore, these tests lack precision and specificity, which exposes a fundamental gap in the management of concussion or mild TBI (mTBI) in a military population. The proposed project will address this gap by validating, in a military population, a portable tool that evaluates cognitive function, postural stability, reaction time, dual-task constructs, vestibular function, dynamic visual acuity and provides a mechanism for documenting the specifics of the incident. Our preliminary data indicate that the Cleveland Clinic Concussion Application (C3 App) is sensitive in identifying the specific changes in cognitive, motor, and visual-vestibular function following a concussion, which has the potential to detect undiagnosed mTBI, guide treatment of injured soldiers, inform return-to-duty decisions, and facilitate sharing of objective test assessments across providers. We propose to develop and validate a military-grade specific version of the C3 App to ensure that mTBI assessment as it relates to military-related injuries is comprehensively addressed and outcome measures validated for use in the military are included. To accomplish this aim, baseline assessments using the C3 App will be completed on 300 soldiers at Camp Lejeune as part of their basic training processing. An age and gender-matched non-military control sample of 300 participants will also be collected.

Three technical objectives will be completed within a project period of 2 years. Technical Objective 1: To determine if performance in each domain of neurological function assessed by the C3 App is consistent with age- and gender-matched civilians. Technical Objective 2: To develop and validate a neurocognitive assessment module that is sensitive in detecting impairments in high-level cognitive function. Technical Objective 3: To validate the use of the C3 App in detecting and managing neurological impairments as a result of mTBI in military service members.

The study profile in FITBIR can be found here.

Summary Information:

Study 10:

The Quantification of Visual Function and Postural Stability Under Single- and Dual-Task Conditions Using Mobile Technology (Principal Investigator: Jay Alberts, PhD)

Recent studies have demonstrated that following mild traumatic brain injury (mTBI), Soldiers often experience declines in postural stability under single- and dual-task conditions. Similarly, oculomotor and visual impairments are prevalent following mTBI; however, the primary care clinic environment often lacks technology of sufficient resolution and sophistication to accurately detect the subtle abnormalities associated with mTBI-related visual dysfunction. The lack of scalable and adoptable approaches to the objective quantification of postural stability visual function represent fundamental gaps in the detection, assessment, and management of military mTBI and potentially prolongs and complicates the return-to-duty process. The proposed project will address these fundamental diagnostic and treatment gaps. Specifically, our existing validated mobile device assessment of balance and vision will be leveraged to develop "mobile devices to test balance that can be administered by corpsman-level medical personnel" and provide "diagnostic methods" for the mitigation and treatment of visual dysfunction associated with mTBI that are specifically designed for the unique demands of a military population. Our initial studies and experience clearly indicate this technology is scalable across a large health system and is effectively utilized by all members of the providers including athletic trainers, pediatricians, neurologists, sports medicine physicians, physical therapists, and occupational therapists to ensure continuity of care from injury to return to learn/play. The results from this project will provide the military with a scalable, reliable, affordable, and accurate solution to evaluating postural stability and visual function to aid in optimizing care and return-to-duty.Hypotheses: The fundamental hypotheses being tested are: (1) effective and informative dual-task paradigms can be developed using a mobile device to characterize motor (postural stability) and cognitive (executive function) simultaneously and (2) a mobile device can be used to characterize visual dysfunction that has the potential to aid in the diagnosis and treatment of mTBI.

The study profile in FITBIR can be found here.

Summary Information:

Study 11:

FRONTOPARIETAL PRIORITY MAPS AS BIOMARKERS FOR MTBI (PI: Cheryl Olman, PhD)

During viewing of complex scenes, eye movements are planned in high-level regions of the brain. Just as eye movements are directed towards particular locations in space, attention can be focused on discrete locations in a visual scene; the neural mechanisms of visual spatial attention and eye movements strongly indicates that there is a great deal of overlap between the two systems. Accurate eye movements and successful re-direction of attention therefore require intact function in frontal and parietal cortical regions. We propose a series of behavioral and magnetic resonance imaging (MRI) experiments that will determine the degree to which difficulties with visual attention, saccade targeting and motion perception associated with mild traumatic brain injury (mTBI) can be attributed to damaged cortical brain networks serving attention and eye movement planning. Broadly, the Focus Area is mitigation and treatment of visual dysfunction associated with mTBI. Specifically: the objective of this research is to identify biomarkers of visual system injuries in the brain associated with mTBI. Objective/Hypothesis: The proposed research will test the hypothesis that spatial attention and eye movement deficits associated with mTBI result from disruption of the gray matter and/or the white matter in cortical networks that control attention allocation and eye movements. A combination of functional MRI and diffusion-weighted imaging will allow us to measure (1) integrity in cortical networks in frontal and parietal brain regions responsible for attention allocation and eye-movement planning, and (2) integrity in the white matter that contains the axons that carry the outputs of these cortical computations to the sub-cortical nuclei that actually control eye movements. Specific Aim 1 is to establish a measure of the health of visual spatial attention and eye-movement planning networks. In this aim, we hypothesize that fronto-parietal priority networks show reduced selectivity for spatial location in subjects who demonstrate relatively weak spatial attention performance. Our objective is to quantify(1) performance on tasks that require either spatial attention allocation or eye movements and (2) contrast-to-noise ratio, as measured with functional MRI, in brain regions with spatial attention and eye movement. Specific Aim 2 is to determine strength of correlation between frontoparietal white matter fractional anisotropy and accuracy of eye movements. We hypothesize that damage to cortical white matter impairs eye-movement. Our objective is to measure, in the same scanning session as Aim 1, the white matter integrity in the WM tracts carrying information within and from the fronto-parietal priority network. Study design: For Aim 1, the association between behavioral and neuroimaging measures (assessed in two study visits, each 2h long) will be measured within a group of 24 subjects with mTBI and weak spatial attention skills. Results will be compared against a control group of 24 subjects with TBI but no visual complaints. Performance on static tasks that do not require attention shifting, eye movement or motion perception will be measured to test whether association with neuroimaging data is specific to oculomotor skills. For Aim 2, the associations between successful eye movements, successful visual attention allocation, and white matter integrity in four a priori frontoparietal regions of interest (and 2 control regions) will be quantified. Again, performance on static tasks that do not require eye movement or motion perception will be measured to test whether the association with fronto-parietal FA measurements is specific to oculomotor skills.

The study profile in FITBIR can be found here.

Summary Information: 

Study 12:

REHABILITATION OF CENTRAL SENSORY IMPAIRMENTS FOR BALANCE IN MTBI (PI: Laurie King, PhD)

Control of balance requires complex integration of sensory and motor systems. In the clinic or in the field, balance measurement is often over-simplified, preventing balance deficits from being identified and treated after mTBI. Our central hypothesis is that chronic balance deficits after mTBI result from impairments in central sensorimotor integration that may be helped by rehabilitation. There are two objectives of this proposal; the first objective is to characterize balance deficits in people with mTBI. The second objective is to use a novel ABF device to improve measures central sensorimotor integration and balance control. Plan: The proposed 4-year study has two parts: 1) Cross-sectional study (Aim I: Balance Assessment) to identify and characterize maladaptive balance control strategies after mTBI compared to healthy controls and 2) Interventional randomized pilot study (Aim II: Balance Rehabilitation) using a novel ABF rehabilitation technique to ameliorate maladaptive balance control strategies after TBI. Subjects in Aim II will be a subset from Aim I and studies will occur simultaneously. Methods: I) Balance Assessment: To characterize balance deficits in people with mTBI who have chronic, non-resolving balance deficits compared to healthy control subjects without a history of mTBI. We hypothesize that a) objective measures of central sensorimotor integration, static and dynamic balance will better distinguish people with mTBI from control subjects than clinical measures, b) a subset of people with mTBI will have abnormal CSMI test measures, even without peripheral vestibular or ocular motor deficits c) the relationship between poorer static/dynamic balance performance and mTBI is regulated/mediated by CSMI. We will test 130 subjects between the ages of 21 and 50; 65 with chronic (> 3 months) mTBI and non-resolving balance deficits and 65 healthy age and gender matched control subjects without a history of mTBI. We will obtain objective measures of static and dynamic balance using wearable inertial sensors and determine how these measures relate to central sensorimotor integration. We will also obtain laboratory measures of peripheral vestibular function and ocular motor function to help classify people and to consider as potential covariates in rehabilitation efficacy. II) Balance Rehabilitation: To determine the efficacy of a novel, ABF balance rehabilitation program to improve central sensorimotor integration, static and dynamic balance, and functional activity in patients with chronic mTBI. We hypothesize that a) CSMI scores will improve with rehabilitation and ABF will increase the improvement of CSMI scores beyond the standard of care, b) ABF intervention will improve objective summary measures of balance and c) people with central sensorimotor integration impairment will show sustained improvement in CSMI scores and balance after rehabilitation. We will randomize 40 subjects between the ages of 18 and 60; 65 with chronic (> 3 months) mTBI and non-resolving balance deficits from Aim I who have abnormal CSMI into either the ABF rehabilitation group or the standard of care group. People will be tested before and after a 6-week intervention period and again 6 week later to determine long-term changes. Normal/abnormal vestibular and ocular motor function will be used as covariates to determine if peripheral deficits affect the efficacy of ABF rehabilitation.

The profile in FITBIR can be found here.

Summary Information: 

Study 13:

THE EPIDEMIOLOGY OF EPILEPSY AND TRAUMATIC BRAIN INJURY (PI: Mary Jo Pugh, PhD)

The proposed project is designed to examine the epidemiology of epilepsy and mild traumatic brain injury (mTBI) in Post-9/11 Veterans using available data from the Departments of Defense (DoD) and Veterans Affairs (VA), and primary data collection. Research Plan: Comprehensive evaluation of epilepsy in Military and Veteran populations should: 1) incorporate both DoD and VA data in a longitudinal record, if possible; 2) include primary data collection including lifetime history of TBI and patient reported outcomes for a sample of the population; and 3) include imaging and neuropsychological evaluations for a small subset of the sample for whom lifetime TBI status is known. Methods: In Aim 1, we will identify a cohort of all Post-9/11 Veterans who receive VA Care (2 or more years 2002-2015), obtain VA and DoD health care system data for that cohort, and identify epilepsy and TBI over the longitudinal data record. Using those data we will examine the relationship between TBI severity (with emphasis on mTBI) and epilepsy. From that cohort we will select a sub-sample of Veterans based on mTBI and epilepsy status, conduct telephone interviews to identify lifetime TBI exposure (including mechanisms of exposure), seizure history and functional status related to work, and physical, mental health and social functioning. We will use these data in Aim 2 to determine if deployment related mTBI exposure is associated with epilepsy after controlling for greatest lifetime TBI severity, and if blast-related TBI (BR-TBI)/multiple mTBI are associated with increased odds of epilepsy compared to non- BR-TBI. In Aim 3, we will compare self-reported work, physical, mental health and social functional status in a stratified random sample of veterans with epilepsy to controls without epilepsy. For the final aspect of the study we will enroll 200 individuals who were surveyed and who are interested in participating in the Chronic Effects of Neurotrauma Consortium (CENC) Longitudinal study where they will undergo magnetic resonance imaging, neuropsychological testing, collection of blood for later biomarker analysis and other clinical evaluations. Clinical Relevance: Together these aims address the DoD Epilepsy Research Program, Idea Development Award (ERP-IDA) focus area of epilepsy epidemiology using a comprehensive approach that ranges from population-based surveillance using existing data, to a case-control approach that more carefully characterizes epilepsy cases and controls to evaluate patient reported outcomes that have been identified by our patient advisory board as being relevant, to a comprehensive longitudinal evaluation that uses the power of cutting-edge neuroimaging (and eventually biomarker/genomic data developed through CENC) that may provide insights into post-traumatic epilepsy (PTE) etiology and ultimately identify specific aspects of mTBI (and other risk factors) that will allow early identification of those at greatest risk of PTE.

The study profile in FITBIR can be found here.

Summary Information: 

Study 1:

Targeted Evaluation, Action, and Monitoring of Traumatic Brain Injury (TEAM-TBI) (Principal Investigator: David O Okonkwo, MD, PhD)

TEAM-TBI is a research study that ran from 2014-2018 and brought together TBI patients, advanced evaluation methods, and clinical experts in a multi-faceted study to address the heterogeneity of TBI and the effects of targeted rehabilitation, interventional, and social strategies have on TBI outcomes. The study involved a comprehensive 3-4 day intake evaluation and a multi-disciplinary adjudication of clinical profiles, followed by targeted therapies during a 6-9 month follow-up period. The interventions were individualized to each participant based on intake evaluations and reviewed by investigators specialized in each trajectory (i.e. cognitive therapy, vestibular therapy, sleep therapy, etc.). Participants were monitored during the remote portion via telemonitoring and telemedicine modalities, and returned after approximately 6 months for a follow-up to their initial assessment. Study data in the FITBIR repository includes numerous clinical assessments as well as MRI and MEG.

The study profile for the TEAM-TBI Study in FITBIR can be found here.

Summary Information:

Study 2:

Cognitive rehabilitation: ACTION training for soldiers with executive dysfunction (Principal Investigator: Mary Vining Radomski, PhD, OTR/L)

This study evaluated the feasibility (acceptability, implementability, and preliminary impact) of a one-to-one, 8-session metacognitive strategy instruction (MSI) intervention that incorporated training in implementation intentions (II) called ACTION (AutomatiC iniTiation of IntentiONs). Thirty-eight consenting soldiers with mild traumatic brain injury-symptom complex who were referred to cognitive rehabilitation at the Fort Campbell Intrepid Spirit (FCIS) were randomized to the ACTION condition (MSI plus II) or to MSI-alone; 34 completed the study. Responses from a post-test experience survey suggest that the ACTION intervention was acceptable to those who received it. Both the manualized ACTION and MSI-alone interventions were implementable (mean of 98.31% of the 113 elements administered across ACTION participants; 99% of 78 elements for MSI-alone). All sessions were 60 minutes in duration. Overall, SM who received ACTION were able to learn to write II for self- selected goals. Thirteen of the 16 SM in ACTION met criteria for II competence (achieving >=80% of correctness points). SM who received ACTION demonstrated statistically significant pre-post changes in implementing a goal behavior (shifting) in a novel task (p=0.005) at posttest; those in the control condition did not (p=0.210). Goal achievement appeared to be influenced by nature of goals, group assignment, homework adherence.  Further study is warranted.

The study profile in FITBIR can be found here.

Summary Information:

Study 3:

Development and Validation of the Virtual Environment TBI Screen (VETS) for Postural Control Testing (Principal Investigator: Geoffrey Wright, PhD)

This study evaluated the validity of the Virtual Environment Traumatic brain injury (TBI) Screen (VETS) as a new assessment tool that can potentially be used to measure postural stability in healthy and neurologically impaired individuals. Study participants performed standing postural tasks using the VETS, clinical examination and neurocognitive tests.

The study profile in FITBIR can be found here.

Summary Information:

Study 1:

Integrating Traumatic Brain Injury Model Systems Data into the Federal Interagency Traumatic Brain Injury Research Informatics System (Principal Investigator: Cynthia Harrison-Felix, Ph.D)

Traumatic Brain Injury Model Systems is the first prospective, longitudinal multi-center study ever conducted which examines the course of recovery and outcomes following the delivery of a coordinated system of acute neurotrauma and inpatient rehabilitation. The study started in 1989 and has enrolled over 12,000 adult study participants with moderate to severe TBI. The data from study participants (N = 14,152) include preinjury, injury, acute care, rehabilitation, and outcomes at 1, 2, and 5 years post-injury. Currently, the Data Repository consists of data that spans from the beginning of the study to the year 2015. Study data within the Repository will be updated as additional data becomes available to FITBIR.

Additional information about the study can be found at https://www.tbindsc.org/ .

The study profile for the TBIMS Study in FITBIR can be found here.

Summary Information:

Study 2:

Automated Comprehensive Evaluation of Mild Traumatic Brain Injury Visual Dysfunction (Principal Investigator: Jose Capo-Aponte, Ph.D.)

This study expanded on previous studies completed by Dr. Capo-Aponte which includes a 2012 computerized oculomotor and vision screening (COVS) study of mTBI (Capo-Aponte et al. 2012) and the 2014 article titled "Proposed objective visual system biomarkers for mild traumatic brain injury" by Ciuffreda and Capo-Aponte et al. (Ciuffreda et al. 2014). Study data is comprised of 15 clinical assessments for active duty personnel (N=120). The purpose of this study is to validate the Neuro-Ophthalmic Device (NODe) test battery that provides the highest sensitivity and specificity for the detection of oculomotor and high order visual processing dysfunctions on a large population of Warfighters with acute mTBI as compared to healthy age-matched controls.

The study profile for this study can be found here.

Summary Information:

Thor Release Notes 2024.pdf

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NEO Minor Release Notes 2022  

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Jubilee Release Notes 2019 

TBI Endpoints Development (TED) Friend Controls Study

Multi-PI: Geoffrey Manley, MD, PhD (Contact PI); Nancy Temkin, PhD; Michael McCrea, PhD; Joseph Giacino, PhD; Sureyya Dikmen, PhD; Sabrina Taylor, PhD; Pratik Mukherjee, MD, PhD; Esther Yuh, MD, PhD; Lindsay Nelson, PhD; David Okonkwo, MD, PhD; Ava Puccio, PhD; Claudia Robertson, MD; Murry Stein, MD, MPH; John Whyte, MD, PhD; Ramon Diaz-Arrastia, MD, PhD; Harvey Levin, PhD (deceased).

The TBI Endpoints Development is an initiative to improve the design of clinical trials that will lead to successful treatments of traumatic brain injury (TBI). While building the TED Metadataset, a compendium of datasets of individual, similarly characterized TBI studies, it became apparent that there is a dearth of data on control subjects in legacy TBI studies. To address this, 300 adult ‘friend’ and family member controls were recruited from and matched with the adult TBI patients that were enrolled in the NIH-funded Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. The controls underwent the same study milestones as 2,539 adult TBI subjects and the 299 adult controls with only orthopedic injuries. Recruiting and enrolling these 300 friend controls leveraged the existing infrastructure of the TRACK-TBI network at 12 trauma centers across the country.

Friend controls were matched according to demographic and background characteristics that were similar to the participants with TBI. Visits were conducted at baseline and 3, 6, and 12-months. In an effort to fuel progress towards precision medicine models for TBI, data collection included: medical histories; structural and functional neuroimaging; proteomic and genomic biomarkers; and the TRACK-TBI Comprehensive Assessment Battery (CAB) which consists of standardized neuropsychological, neurocognitive, and quality of life questionnaires.

• A total of nearly 40,000 records are shared among 43 form structures.
• For the CAB, 16 assessments were administered by the outcomes core examiners for a total of over 30,000 records submitted from more than 1,000 follow-up visits.
• Results of selected proteomic assays processed to date by the biomarker core are shared for 105 subjects.
• The imaging core submitted readings for MRI scans from 280 subjects that participated in the imaging protocol. Of these, nearly 2,700 structural, functional, and diffusion magnetic resonance sequences are currently being curated. These imaging datasets will be released in the near future upon completion of work for the quality assurance procedures.
• For more information about TBI Endpoints Development, please visit: https://tbiendpoints.ucsf.edu/

The study profile for the TBI Endpoint Study can be found here:

• https://fitbir.nih.gov/study_profile/384

Summary Information

Development and validation of spreading depolarization monitoring for TBI management

(PI: Jed Hartings, PhD)

Abstract

The goal of acute traumatic brain injury (TBI) treatment is to minimize secondary damage that evolves over hours to days after the primary injury. Until now, however, there have been no methods for monitoring heterogeneous pathomechanisms to identify patients for appropriate neuroprotection therapies. Using invasive monitoring in TBI patients requiring craniotomy, we have documented that spreading depolarizations (SD), a seizure-like pathology of cerebral gray matter that has been well-characterized through 60 years of research in animal models, are the dominant pathophysiologic process in peri-lesion cortex of many, but not all, severe TBI patients. Furthermore, we found that the occurrence of SD as a secondary injury process in patients is an independent predictor of worse neurologic outcomes. Thus, monitoring of SD provides the first real-time measure of neuronal secondary injury processes in patients to determine the selective application and benefit of neuroprotective therapies. However, since surgical patients are <10% of all TBI, less invasive and non-invasive techniques for SD monitoring are now required to generalize these findings. The premise of this proposal is that SD occurs across the spectrum of TBI severity as a pathologic mechanism of disease process and outcome heterogeneity.

Study Aims

Aim 1: Develop signal processing methods for automated bedside detection of spreading depolarizations in both electrocorticographic (ECoG) and non-invasive EEG recordings.

Aim 2: Determine the incidence of spreading depolarizations in TBI patients requiring intensive care.

Aim 3: Determine whether spreading depolarizations are independently associated with worse neurologic outcomes across the continuum of moderate-severe TBI.

Study Design: To achieve the specific aims, we will conduct an observational multi-center clinical study of patients admitted to intensive care for treatment of TBI. Severe TBI patients will undergo both invasive ECoG (depth or strip electrodes) and non-invasive EEG monitoring, and mild-moderate TBI patients will undergo EEG monitoring only.

Overview of Dataset Submission

The study was undertaken as a subprotocol of the “Transforming Research and Clinical Knowledge in Traumatic Brain Injury” (TRACK-TBI) initiative at 7 Level I Trauma Centers. A total of 153 TRACK-TBI subjects were co-enrolled into the SD protocol. Data collected in accordance with the TRACK-TBI protocol includes clinical histories, laboratory results, vital signs and Glasgow Coma Score assessments. Follow-up visits were conducted using the TRACK-TBI Flexible Outcome battery at 2-weeks and 3,6 and 12-months.

Sharing of the raw and preprocessed data collected from the high resolution ECoG and EEG monitoring is not currently possible within the FITBIR platform. Preprocessing and analysis are ongoing. Investigators interested in proposing a research collaboration for sharing the data may contact the PI.

Summary Information

*An additional 33 subjects were co-enrolled into TRACK-TBI study before enrollment in that study was closed. Those data were submitted to FITBIR Study ID 267.

Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) High Definition Fiber Tracking (HDFT): Neuroimaging, Biospecimen, and Data Informatics Repositories

(PI: Dr. David Okonkwo, MD, PhD)

Grant/Project ID: W911QY-14-C-0070

Abstract

Effective treatment of traumatic brain injury (TBI) remains one of the great unmet needs of wounded warriors and in public health. Each year in the US, at least 2.5 million people suffer TBI; an estimated 3.2 to 5.3 million people live with the long-term physical, cognitive, and psychological health disabilities of TBI. This study expanded the scope of TRACK-TBI, the parent study (FITBIR Study ID 267), delivering on three core missions that harmonized TRACK-TBI resources and infrastructure: 1) advancing diagnostic neuroimaging by applying 3T structural MRI followed by High Definition Fiber Tracking (HDFT); 2) creation of a Biospecimen Repository of blood and DNA samples to validate proteomic and genetic biomarkers of TBI from 3000 subjects; and 3) foundation of a Bioinformatics Core necessary for validating neuroimaging, proteomic and genetic biomarkers of TBI.

Study Aims

Specific Aim 1: Perform advanced neuroimaging including 3T structural MRI and High Definition Fiber Tracking (HDFT) with subsequent analysis to accelerate the development and clinical adoption of technology that will provide a quantitative diagnosis of structural white matter injury after TBI to further improve diagnosis and prognosis of TBI patients.

Specific Aim 2: Create a Biospecimen Repository of blood and DNA samples collected from subjects that will enable validation of proteomic and genetic biomarkers to improve classification of TBI and lead to targeted therapies.

Specific Aim 3: Create a Data Informatics Core that will accelerate input of TRACK-TBI data into the Federal Interagency Traumatic Brain Injury Research Informatics System (FITBIR) and create a legacy database with analytic tools and resources to support TBI research.

Study Design

To achieve the specific aims, we conducted an observational multi-center clinical study of subjects treated at 7 Level I Trauma Centers. Subjects were enrolled into the study within the first 24-hours from the time of injury. Follow-up assessments were conducted during the acute phase in the hospital and at 2-weeks; 3-months; 6-months; and 12-months.

Overview of Dataset Submission

During Phase I, a total of 388 TBI subjects were co-enrolled into the TRACK-TBI Adult protocol. Data for the Phase I subjects have been shared within FITBIR Study ID 267. Enrollment into Phase II of the HDFT protocol continued when Study ID 267 closed to enrollments in July of 2018. The additional 113 TBI and 42 orthopedic control subjects were enrolled into the HDFT protocol between July of 2018 and September of 2019 and are shared within FITBIR Study ID 411.

Over 8,000 structural, functional and diffusion magnetic resonance sequences continue to undergo processing and curation for the Phase II subjects. The imaging datasets will be released upon completion of the quality assurance procedures. Investigators interested accessing the imaging datasets may contact the Principal Investigator to submit a collaboration proposal. Details for the protocols used by clinical and outcomes cores have been provided in the study documentation module.

The study profile in FITBIR can be found here.

Summary Information

*Clinical, Outcome and Biomarker forms shared.

Dr. Mona Hicks and COL Dallas Hack recognized for their outstanding leadership to the development of the FITBIR Informatics System at FITBIR's 2nd Stakeholders Meeting in April 2015. NINDS Director Walter Koroshetz, MD presented the awards.

The Biomedical Research Informatics Computing System (BRICS), the platform used to support the FITBIR Informatics System, won the Best Overall Federal Health IT Award at the 2015 Digital Health Xchange & Innovation Event held in Washington, DC on March 4, 2015.

On July 15, 2015, NIH's Center for Technology awarded the 2015 Scientific Award of Merit for the development of the Biomedical Research Informatics Computing System (BRICS) to accelerate biomedical discovery through data sharing.

On August 7, 2015, it was announced that BRICS was selected as one of ten finalists, out of 130 nominations, for the 2015 GCN Award for Outstanding Information Technology Advancement in Government award. The awards ceremony will be held on October 14, 2015.

TBI Investigators funded by the National Institute of Health (NIH) and The Department of Defense (DOD) have contributed over 200,000 patient clinical records from over 4500 patients to the FITBIR Informatics System. Over fifteen funded researchers have contributed as of July 1, 2015.

RFA-HD-16-001 - Secondary Analysis of Existing Database in Traumatic Brain Injury to Explore Outcomes Relevant to Medical Rehabilitation (R21) announced; application due date is October 31, 2015. Announcement

ANTMAN RELEASE: OCTOBER 2016

QUERY TOOL REDESIGN FOR USABILITY 

The Query Tool has been redesigned with a sleek and elegant interface and improved         performance. New features include helpful tips about Query Tool functionality, and a clear display for searching and viewing the data results. Additionally, users will be able to lock columns, adjust column width and retract filter panes for maximized data table size. 

UPDATED SYSTEM TO TRACK UNIQUE IDENTIFIERS

Users are now able to view their registered PseudoGUIDs in the My GUIDs Section of the GUID Module. The system has linked the PseudoGUIDs to the converted GUIDs so users can keep track of their unique identifiers for each subject.

NETWORK ENHANCEMENTS FOR INCREASE SPEED AND IMPROVED PERFORMANCE

Upgrades to the system have increased the speed of the user interface, and improved performance of data upload and download. Network enhancements will maximize user experience and user workflow within the system.

BATMAN RELEASE: JANUARY 2017

EFORMS AVAILABLE IN DATA DICTIONARY

eForms are now accessible and can be viewed by all users in the Data Dictionary. Users will be able to add eForms when using ProFoRMS to manage protocols to electronically collect data.

SCHEMA MAPPING OF FITBIR DATA ELEMENTS

A schema mapping file is now part of the data elements reports of a Form Structure. The schema mapping file maps FITBIR’s Permissible Values to other systems’ data collecting standards for metadata such as the Clinical Data Interchange Standards Consortium (CDISC).

UPDATES

TBI NINDS Recommended Standard Data Collection Forms Now Available for Use: 421 TBI NINDS Standard recommended data collection forms are now ready to be used by the FITBIR User Community. This list can be viewed in the TBI Forms page.

Sports Related Concussion Common Data Element (CDE) Working Group: FITBIR has been working with the Sports-Related Concussion Common Data Element (CDE) Working Group classifying case report forms for sports-related concussions as they pertain to different timeframes in a subject’s injury history. FITBIR has been assisting in this process by providing current TBI unique data elements that have already been curated, which will be reviewed and converted for sports-related concussions CDEs.

FITBIR would like to welcome the following prospective studies:

• Approaches and Decision in Acute Pediatric TBI Trial (ADAPT) is an international study that includes institutions from the United States, United Kingdom, Australia, Spain, Netherlands, New Zealand, South Africa and India. This study will enroll 1,000 children with severe traumatic brain injury and require the placement of an ICP monitor.
• Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) is a NINDS funded study that includes 11 U.S. sites that are collecting and analyzing data on 3000 subjects. As of February 28th, 2017, TRACK TBI has enrolled 1,979 subjects.
• Chronic Effects of Neurotrauma Consortium (CENC) is a multi-center collaboration of researchers from the DoD, VA, academic and private research institutions. This study focuses on mTBI among OEF/OIF/OND Service Members and Veterans.
• Concussion Assessment, Research and Education (CARE) Consortium is a multi-site study that aims that at better understanding the natural progression of sports-related concussions in athletes.

The following is a complete list of FITBIR Studies that have shared datasets available for download:

1. The Center for Neurological and Regenerative Medicine (CNRM) own Diane Damiano , MD has successfully submitted data for her study Effects of Rapid-Resisted Exercise on Ambulatory Adults with Traumatic Brain Injury. The shared data includes 46 subjects who participated in the clinical trial that assessed the effects of exercise on brain function on ambulatory individuals with TBI.
2. The National Institutes of Health Clinical Center (NIHCC) Leighton Chan, Ph. D has successful submitted data for his study Effect of Aerobic Exercise Training on Cardiorespiratory Function in Patients with TBI. The shared data includes 12 subjects and 9 data collection forms.
3. The Uniformed Services University of Health Sciences (USUHS) own Michael Roy, MD, MPH, has successfully submitted data for his study Predictors of PTSD and Post Concussive Syndrome in OIF/OEF Veterans. The shared data includes 85 subjects and 18 data collection forms.
4. Corinna E Lathan, Ph.D., from AnthroTronix, Inc, has successfully submitted data for her study An Independent, Prospective, Head-to-Head Study of the Reliability and Validity of Neurocognitive Test Batteries for the Assessment of Mild Traumatic Brain Injury. The shared data includes 233 subjects and 13 data collection forms.
5. George Manley, MD, Ph. D, from the University of California, San Francisco, has successfully submitted data for his pilot study, Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot. The shared data includes 599 subjects and 26 data collection forms.
6. Emory University’s David Wright, MD and his collaborators at the Medical University of South Carolina (MUSC) for successfully and completely submitting legacy data from the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (PROTECT III) trial to FITBIR. A special thanks to Cassidy Connor, MS and Yuko Palesch, Ph. D from MUSC for all of their support. The shared data includes 882 subjects and 39 data collection forms.
7. The University of Maryland TBI researchers, Rao Gullapalli, MD and Chandler Sours, PhD for successfully and completely submitting data for the retrospective study, as well as, the prospective study for Maryland Magnetic Resonance Imaging of Neurotrauma Study (MagNeTS) to FITBIR. The shared data includes 332 subjects and 28 data collection forms.
8. Boston University’s Anne McKee, MD and Lauren Murphy for successfully and completely submitting the Chronic Traumatic Encephalopathy (CTE) Consensus Slides images in FITBIR for their study Tauopathy Consensus Study of Pathology Images. These slides were discussed in the 2016 article in the Acta Neuropathologica Journal. The images are in a format that can be viewed using the freeware Aperio's ImageScope software. The shared data includes 25 subjects and the Imaging Digital Pathology data collection form.
9. The University of Washington TBI researcher, Frederick Rivara, MD, successfully and completely submitted legacy data for the study Disability Form Pediatric Traumatic Brain Injury as part of the Child Health After Injury (CHAI) Study. The shared data includes to FITBIR 927 subjects and 49 data collection forms.
10. Harvard Medical School and RTI International with Principal Investigators Ross Zafonte, DO and Helen Pan, PhD for successfully and completely submitting legacy data from the Citicoline Brain Injury Treatment Trial (COBRIT) to FITBIR. The shared data includes 1213 subjects and 56 data collection forms.

NATIONAL NEUROTRAUMA SOCIETY 2017 (NNS) - COME MEET US!

July 9-12th
FITBIR will have a booth at the NNS 2017 conference. Our staff will be available to answer questions and for 1-on-1 sessions.