Chronic Effects of Neurotrauma Consortium

Chronic Effects of Neurotrauma Consortium (CENC)

Founded	2013 (2013)
Type	Research Consortium
Location	Richmond, Virginia, United States
Coordinates	37°32′48″N 77°27′12″W / 37.546615°N 77.453255°W / 37.546615; -77.453255Coordinates: 37°32′48″N 77°27′12″W / 37.546615°N 77.453255°W / 37.546615; -77.453255
Area served	United States
Key people	David X. Cifu (Principal Investigator), COL Sidney Hinds (Co-Principal Investigator), and Rick L. Williams (Co-Principal Investigator)
Website	cenc.rti.org

The Chronic Effects of Neurotrauma Consortium or CENC is a federally funded research project devised to address the long-term effects of mild traumatic brain injury in military service personnel (SMs) and Veterans. Announced by President Barack Obama on August 20, 2013, the CENC was one of two major initiatives developed in response to the injuries incurred by U.S. service personnel during Operation Enduring Freedom and Operation Iraqi Freedom.^[1][2][3] The project is jointly funded in the amount of $62.175 million by the Department of Defense (DoD) and the Department of Veterans Affairs (VA). The CENC is led by Dr. David X. Cifu of the Virginia Commonwealth University.^{[4][5][6][7][8][9][10]}

Background

Nearly 20% of the more than 2.5 million U.S. Service Members (SMs) deployed since 2003 to Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) have sustained at least one traumatic brain injury (TBI), predominantly mild TBI (mTBI),^[11][12] and almost 8% of all OEF/OIF Veterans demonstrate persistent post-TBI symptoms more than six months post-injury.^[13][14] Explosive munitions, predominantly improvised explosive device’ (IEDs), have caused the overwhelming majority of these identified cases. The incidence is likely even significantly higher than reported, as many mTBIs may go unrecognized during and even after deployment because of more visible concomitant injuries capturing greater attention, clinicians’ limited awareness of the often subtle initial findings, and patients’ reduced subjective awareness related to cognitive deficits in the acute period.^[15]

Acute mTBI effects are typically transient, with headache, cognitive, behavioral, balance, and sleep symptoms most often seen in the first one to three months post-injury. However, in a small percentage of individuals, these difficulties persist and even lead to lifelong disability. In these individuals, additional chronic effects, including neuroendocrinologic abnormalities, seizures and seizure-like disorders, fatigue, vision and hearing abnormalities, and numerous other somatic symptoms are more common over time. The long-term effects from these single or repeated TBIs on the persistence of these symptoms, on combat and trauma-related comorbidities, and on long-term brain functioning are unknown. Increasing evidence supports the linkage between both concussions and combat-related trauma with a degenerative neurologic disorder known as chronic traumatic encephalopathy (CTE), which results in progressive cognitive and behavioral decline in sub-populations that are 5 to 50 years out from repeated or cumulative exposures.^[16][17][18] The possibility of a link between mTBI, persistent symptoms, and early dementia has widespread implications for SMs and Veterans; however, these chronic and late-life effects of mTBI are poorly understood. TBIs of mixed severity have been statistically linked to a higher incidence of Alzheimer's disease (AD) and other dementias and a reduced-age of onset of AD, although negative findings have also been reported.^{[19][20][21][22][23]} Although it has long been suspected that repeated concussions can contribute to the development of dementia-like symptoms many years after the injuries, CTE has been almost exclusively studied in boxing. CTE has been reported to occur in retired boxers at higher rates and younger ages compared with dementia in the general population.^[24][25][26] More recently, however, brain autopsies of athletes from a variety of sports (boxing, football, hockey) with confirmed CTE have demonstrated elevated tau proteins, tau-immunoreactive neurofibrillary tangles, and neuropil threads, suggesting that pathological processes similar to those occurring in AD may be involved. The brain structures damaged in CTE are critical for memory and executive function.^[27][28] One cross-sectional study of clinically documented civilian TBI of mixed severity in late-life found impairment compared to controls in many tests, including episodic memory, short-term memory, visuospatial processing, object naming, and semantic processing .^[29] In CTE, neuropsychological deficits have been noted, but appropriate norms do not exist.^[30] A meta-analysis found no cognitive effects in 289 amateur boxers;^[31] however, a more recent large survey study suggested that multiple concussions may increase the risk of late-life cognitive dysfunction.^[32] Specifically, a mild cognitive impairment (MCI) diagnosis and self-reported memory problems were more common among football players who reported three or more concussions than among those who reported none.^[33] Basic science modeling for blast and repetitive injury, chronic sequelae, and neurodegeneration are limited. Additionally, longitudinal research bridging SMs and Veterans with neurotrauma is fragmented and incompletely linked with the strategic needs and vision of the Departments of Defense (DoD) and Veterans Affairs (VA).

In short, critical gaps exist in the literature, with a paucity of prospective, controlled studies on late-life outcomes and neurodegeneration after mTBI and related basic science research. These research gaps are particularly prominent in the injuries and difficulties seen in combat-exposed populations. The existing research, although suggestive, is not rigorous or robust enough to allow for a clear understanding of the relationships, risks, and potential effective interventions for mTBI, chronic symptoms, and neurodegeneration. To date, no controlled prospective longitudinal study has examined the late-life cognitive, behavioral, systemic, and functional effects of TBI of any severity. Given the absence of prospective studies, the association between TBI and early neurodegeneration is merely theoretical, and the actual risk factors and rate/extent of physiologic and clinical decline over time are unknown. It is also unclear whether a single TBI may be enough to begin a degenerative cascade in select individuals or whether a critical number (dose threshold) of TBIs is needed to “prime” the central nervous system for degeneration. As the majority of TBIs in the military are mild, prospective studies of cognitive outcomes from mild injury are necessary to determine the long-term risks posed to SMs and Veterans. The potential link between mTBI and the development of early dementia is a significant concern for not only at-risk SMs, Veterans, and their families, but also for DoD and VA resource planning, given the high service utilization in the DoD and VA health systems associated with dementia.^[34]

Given these gaps in scientific research and knowledge, the military- and Veteran-specific issues involved, and the importance of a uniform approach to this critical set of problems, the Department of Defense and the Department of Veterans Affairs jointly issued a request for proposals to fund a 5-year, $62.175 million project to address these concerns. After a competitive application process, a consortium led by Virginia Commonwealth University prevailed and was announced as the recipient of the award by President Obama on August 20, 2013.^{[4][5][6][8][9][10]} At the time of the award, this was the single largest grant ever awarded to Virginia Commonwealth University.^[6]

The Consortium

The mission of the CENC is to fill the gaps in knowledge about the basic science of mild TBI (also termed concussion), to determine its effects on late-life outcomes and neurodegeneration, to identify service members most susceptible to these effects, and to identify the most effective treatment strategies.^{[4][5][6][35]} The CENC is a multi-center collaboration linking premiere basic science, translational, and clinical neuroscience researchers from the DoD, VA, academic universities, and private research institutes to effectively address the scientific, diagnostic, and therapeutic ramifications of mild TBI and its long-term effects.^{[6][7][10][8][9]}

The CENC serves as the comprehensive research network for DoD and VA that focuses on the long-term effects of combat-related and military-relevant TBI.^[10] The CENC is designed to conduct research that provides clinically relevant answers and interventions for current service members and Veterans and to develop the long-term solutions to the chronic effects of TBI. The CENC is identifying and characterizing the anatomic, molecular, and physiological mechanisms of chronic injury from TBI and potential neurodegeneration, investigating the relationship of comorbidities (psychological, neurological, sensory, motor, pain, cognitive, neuroendocrine) of trauma and combat-exposure to TBI with neurodegeneration, and assessing the efficacy of existing and novel treatment and rehabilitation strategies for chronic effects and neurodegeneration following TBI.^[35]

CENC members come from research universities, academic medical centers and medical schools, military/VA medical centers and hospitals, and private research institutions across the United States, along with a coordinating center composed of a research university, a private not-for-profit research institute, and a military medical and nursing school.^[36] The CENC members work together to develop and perform research studies related to SMs and Veterans exposed to combat during their OEF/OIF tours of duty. In this way, studies can be done more quickly than if the individual medical centers were working alone.

Leadership and Participating Organizations

Leadership

The project principal investigator for the CENC is Dr. David X. Cifu, Chairman and Herman J. Flax M.D. professor^[37] of the Department of Physical Medicine and Rehabilitation (PM&R) at Virginia Commonwealth University (VCU) in Richmond, Virginia, Staff Physiatrist at the Hunter Holmes McGuire Veterans Administration Medical Center (HHM-VAMC),^[38] Founding Director of the VCU-Center for Rehabilitation Science and Engineering^[39] and National Director of PM&R Services in the Department of Veterans Affairs' Veterans Health Administration.^{[40][41][5][6][8]} Project co-principal investigators are COL Sid Hinds, Brain Health Research Program Coordinator and Medical Advisor, Principle Assistant Research & Technology, United States Army Medical Research and Materiel Command^[42] and Dr. Rick L. Williams, statistician at RTI International and a Fellow of the American Statistical Association.^[7]

Participating Organizations

As of May 2016 the CENC is a collaboration between 27 organizations including nine universities, four non-profit research organizations, 13 VA medical centers, and a military medical center. Sites continue to change as new studies are added, or other studies become completed.^[36]

Consortium Structure

The CENC maintains research cores, principal studies, and an independent granting mechanism to foster additional research in the area of chronic effects post-TBI.^{[43][44][45][46]}

Research Cores

The CENC currently operates the following research cores.

Biorepository Core: The Biorepository Core, located at Uniformed Services University of the Health Sciences (USUHS), manages the storage and processing of blood and saliva samples collected through all CENC protocols. Blood samples consist of plasma, serum, and cells, which will be processed to extract DNA. These biological fluids will be catalogued, tracked, and stored at −80 °C in a dedicated Biorepository Facility maintained by Center for Neuroscience and Regenerative Medicine (CNRM) at USUHS. The core will administer requests for use of these biological samples from investigators inside or outside the CENC, according to the data and sample sharing policies of the Consortium.^[43] The Biorepository Core is led by Dr. Brian Cox of USUHS.

Biostatistics: The Biostatistics Core, located at RTI International, provides analytic expertise and statistical programming support for CENC supported studies. This support includes study design and protocol development, ongoing study monitoring, data analysis, reporting, and manuscript development of basic science, pre-clinical, translational, and observational studies, as well as randomized clinical trials.^[43] The core is led by Dr. Rick Williams.

Data Management and Study Management Core: The Data Management, and Study Management Core, located at RTI International, centrally and securely maintains all CENC-collected data, oversees the clinical monitoring of research sites, and provides a Consortium Research Manager who interacts with the Clinical Research Coordinators from the Research Study Sites to expedite and guide clinical protocols through regulatory approval processes and coordinates patient accrual and study activities across sites.^[43] The core is led by Dr. Rick Williams.

Neuroimaging Core: The Neuroimaging Core, located at Baylor College of Medicine (BCM), is composed of experts from the fields of neuroradiology, neuropsychology, magnetic resonance imaging (MRI) physics, information technology and computer programming, and statistics. The core will facilitate sequence development and pulse programming, training and supervision of technologists and support personnel, acquisition of imaging data, quality assurance (QA), conventional and advanced imaging analysis, transfer, and storage of imaging data, and assistance in the interpretation of neuroimaging data.^[43] The Neuroimaging Core is led by Dr. Lisa Wilde.

Neuropathology Core : The Neuropathology Core, located at Boston University, manages the collection of brain specimens from participants using an existing national network of dieners and neuropathologists. The Core also catalogs and stores these tissues for use by qualified investigators from within or outside the CENC. The Core administers requests for use of these tissues according to sample sharing policies of the Consortium, and tracks the results of these collaborative studies.^[43]

Principal Studies

As of May 2015 the CENC oversees the following principal studies.

Longitudinal Cohort Study

There are many effects of traumatic brain injury that occur immediately after the injury, including cognitive and behavioral changes. These changes in function may be related to changes in brain structure that can be seen on MRI scans. There may also be impairments in fine motor skills, coordination and balance, visual perception, and language. All of these acute effects get better over time unless an injury is very severe, in which case the impairments persist indefinitely.

For less severe head injuries, known as mild TBI (mTBI) or concussion, the effects later in life are understudied and less understood. This lack of research needed to understand the long-term outlook, including the potential risk of worsening problems, specifically chronic traumatic encephalopathy (CTE), creates a critical problem for the care of the mTBI patient. Awareness of this problem has increased as more reports and retrospective case series suggest mid- and late-life risks from mTBI, especially multiple concussions. The potential for early dementia after mTBI(s) is a frightening prospect for service members (SMs) and Veterans who have sustained mTBI(s) during their service to our country.

The purpose of this study is to address this critical research gap by identifying and characterizing the late effects of mTBI and assessing the influence and interaction of the many potential risk factors for early dementia. To achieve these goals, the CENC relies on the expertise and knowledge of multiple civilian and military research groups, including the National Institute on Disability and Rehabilitation Research (NIDRR) TBI Model System (TBIMS) program, which has studied the long-term outcomes of more than 10,000 people with moderate to severe TBI for the past 20 years. The CENC study will extend the work of the TBIMS program to the population of Veterans with mTBI using a mixed-methods approach of combining patient-reported outcomes with assessments of cognitive and neurologic functioning. The study will also look at biological measures including laboratory, neuroimaging, and electrophysiological testing to sort out the role of mTBI in late outcomes including CTE and other illnesses. This study’s goal is to establish a large cohort (880) of former U.S. OEF/OIF combatants who have had at least one mild Traumatic Brain Injury (mTBI), and follow the members of the cohort long-term to assess specific areas of their physical and mental health. Given the unclear role of mTBI(s) on long-term health and the frequent co-occurrence of posttraumatic stress disorder (PTSD) in warfighters, the study will include a group of participants (220) who have experienced combat but have not had an mTBI.^[44]

All study participants will first have a detailed assessment to determine whether or not they have had an mTBI in the past and to assess the type, if any, of mental and physical health problems they are currently experiencing. After the first assessment, participants will have yearly re-assessments either over the phone or in person to follow up on the first set of measures.^[44] The Longitudinal Cohort Study is led by Dr. Wililam Walker of the Virginia Commonwealth University.^[8]

Epidemiology of mild Traumatic Brain Injury and Neurosensory Outcomes

The primary objective of this project is to integrate and analyze existing VA healthcare data to study the chronic effects of mild traumatic brain injury (mTBI) on neurodegenerative disease and other comorbidities, and the methods to treat and rehabilitate adverse effects of mTBI, in Veterans over time. Although prior studies have found that moderate and severe TBI are associated with a variety of adverse clinical outcomes, the effects of mTBI are less well understood. This study aims to address this gap in knowledge through four complimentary specific aims: (1) To evaluate the association between mTBI and important shorter-term clinical outcomes such as accidents and injuries in Veterans from recent conflicts in Iraq and Afghanistan, focusing on identifying factors associated with resilience and the potential benefits of adequate treatment. (2) To expand Aim 1 to include Veterans from all eras and to study longer-term clinical outcomes including neurosensory disorders and mortality, focusing on the potential confounding effects of comorbid medical conditions and the impact of their treatment. (3) To identify different trajectories of mTBI-related comorbid burden, with the goal of identifying factors associated with being in low and high distress trajectories. (4) To lay the groundwork for future analyses using more detailed and unified mTBI data by developing the groundwork to create a National CENC Data Repository (NCDR). Together, these Aims will advance our knowledge of the effects of mTBI on important clinical outcomes in Veterans of all ages and eras in a highly efficient manner and will provide insight into potential strategies for prevention and intervention.^[47]

Tau Modification and Aggregation in Traumatic Brain Injury

The continued increase in the use of improvised explosive devices (IEDs) and the protection provided by modern body armor places mild traumatic brain injury (mTBI, also referred to as concussion) as the “signature injury” of modern warfare. The consequences of mTBI may persist indefinitely in Veterans, causing progressive neurological degeneration similar to Alzheimer's disease (AD). Unfortunately, little is known about its acute effects on the brain or its long-term behavioral consequences, particularly in individuals who have suffered multiple mTBIs. With the current practice of repeated redeployment, the opportunities for Service Members to experience multiple mTBIs increase dramatically. A single mTBI is usually perceived as relatively benign because most people recover quickly and fully without any lingering symptoms; however, in those affected, some symptoms appear right away, while others progress over days or months. Indeed, mTBI can silently affect a subject without inducing obvious behavioral changes. Although there are many procedures to assist the physician in the detection of mTBI, very little is known about the underlying pathobiology of neuronal degeneration in patients with mTBI.

One of the few known biological changes seen in mTBI is the massive intraneuronal accumulation of a protein called Tau in very specific and recognizable patterns in the human brain. The consequences of repeated mTBI (r-mTBI) over a prolonged period have not been well studied, and the factors and mechanisms that contribute to the long-term consequences of r-mTBI are still poorly understood.

Thus the goal of this study is to develop an animal model of r-mTBI model that will allow the tracking of progressive intraneuronal tau alterations that can be correlated with behavioral dysfunction, fluorescent in situ hybridization, and gene expression signatures. The model could then be used to assess the effects of interventions. The observations made in the animal model will be tested for agreement in soldiers who have died after sustaining r-mTBI. Exploitation of such a model will have great translational significance by providing seminal data needed to develop new and better treatments for our military personnel with mTBI.^[45] The Tau Modification Study is jointly led by Dr. Fiona Crawford of the Roskamp Institute, and Dr. Elliott Mufson of the Barrow Neurological Institute.

Otolith Dysfunction

This research study is part of a long-term goal to establish a unique treatment platform to diagnose, localize, and treat dizziness and imbalance related to inner ear balance issues associated with mTBI. In the recent wars in Iraq and Afghanistan, many soldiers have been exposed to blasts from IEDs or roadside bombs, and TBI has been called the signature condition of Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) combat Veterans.^[48]

The objective of the study is to determine the effect of inner ear balance (vestibular) dysfunction on balance, gait and quality of life. The primary function of the inner ear balance function is to keep vision steady when the head is in motion and to maintain balance. Loss of inner ear balance function can result in dizziness and/or imbalance, and individuals with these symptoms are at risk of falling. The incidence of dizziness and imbalance increases in two populations relevant to VA and military healthcare: older individuals and individuals who have suffered a head injury or blast exposure.

Until recently, inner ear balance assessment was limited to measuring only one part of the inner ear balance system, the horizontal semicircular canal and its connections to the eyes (called vestibulo-ocular reflex). In addition, treatment for inner ear balance problems has been based on the principles of vestibulo-ocular reflex recovery from injury. Recently though, clinical tests have been developed that provide information about otolith organ function – two inner ear balance organs that sense gravity and contribute to maintaining upright posture or balance. Although new otolith organ tests are available, they are used less widely than horizontal canal tests, and one reason may be that it is unclear if abnormal otolith organ function impacts a person negatively in terms of maintaining balance and participating in activities of everyday living. Thus, determining the impact of abnormal otolith organ function is important in developing clinical recommendations for evaluating patients suffering from dizziness and imbalance.

There is recent evidence to suggest that otolith organ dysfunction can occur in patients with mild traumatic brain injury (TBI) or blast exposure. This is important because symptoms of dizziness and imbalance resulting from mTBI or blast exposure can last six months or longer which is often longer than recovery from other types of inner ear balance disturbances. If the dizziness and imbalance symptoms that occur following head injury or blast exposure are related to injury to the otolith organs rather the horizontal semicircular canal, than new treatment approaches may be necessary to focus on otolith organ pathway recovery rather than horizontal canal recovery.

The main purpose of this study is to determine the impact of abnormal otolith function on a person’s ability to maintain balance while standing and walking and on their quality of life. In addition, we hope to determine the further impact of head injury/blast exposure and older age on postural stability and quality of life. To address these objectives, we will compare performance on balance tasks while standing and walking and questionnaires on the impact on quality of life in several groups of people with and without head injury/blast exposure and across a wide range of ages. The groups will include individuals with otolith organ dysfunction, horizontal canal dysfunction, both otolith and horizontal canal dysfunction, and healthy individuals.

This study is the first step toward novel therapeutic approaches to reduce the negative impact of dizziness and imbalance on individuals with otolith organ dysfunction. In addition, our research findings may direct the development of new clinical protocols to better assess individuals with dizziness and balance problems particularly.

Adapt/Evolve

Traumatic brain injury (TBI) affects approximately 3.5 million individuals annually in the United States and approximately 75% are due to 'mild' or concussive events. In the US military, it is estimated that roughly 20% of the deployed force suffered a head injury in the wars in Iraq and Afghanistan; 83.3% of whom endured a mild, uncomplicated TBI or concussion, the long-term impact of which is just beginning to be appreciated. Many of these service members are young males, 20–30 years old who have decades of life to live with the complex and often debilitating impact of war-time brain injury. Although much effort has been placed on trying to better understand this type of injury, many of these studies have been forced to rely largely on self-reporting, retrospective medical records review or evaluations of only later stages of injury No study to date has prospectively followed active-duty US military from concussive brain injury to long-term outcome with advanced Magnetic Resonance Imaging (MRI) and clinical evaluation.^[49]

The overall goal of this study is to investigate advanced MR imaging and clinical outcome measures of concussive traumatic brain injury (TBI) in US military personnel injured during deployment. As part of previous collaborative efforts, we completed early prospective, longitudinal studies enrolling active-duty US military at 0–7 days, 0–30 days, and 0–90 days post-injury. All subjects met the DoD definition for mild uncomplicated traumatic brain injury . Non-brain injured control (CTL) subjects were also enrolled at each time point for comparison. Early advanced MR imaging and clinical information was collected before these subjects were followed to 6–12 months. At 6– 12 months, advanced MR imaging was repeated and a battery of neurological, neuropsychological and psychiatric evaluations were completed. In total, 591 subjects were enrolled through these efforts;54% TBI,46% control. This study will re-examine these subjects now 3–5 years post-injury and compare their current clinical and imaging presentation with the previously acquired longitudinal data.

Four groups of subjects will be studied: 1) subjects who sustained a concussive brain injury from blast during deployment,2) subjects who sustained a concussive brain injury from mechanisms other than blast during deployment,3) subjects with prior blast exposure but no diagnosis of brain injury from deployment, 4) subjects without history of blast exposure and no diagnosis of brain injury from deployment. Groups 3 and 4 serve as control populations for the blast-related and non-blast-related concussive brain injury groups. Group 3 also allows for the investigation of a blast-exposed control group to explore whether blast exposures not resulting in a diagnosis of TBI, could also contribute to long-term outcomes.

We hypothesize that early clinical and imaging measures will correlate with 3-5 year late stage clinical outcome. This will offer predictive insight into the long-term impact of war-time concussive TBI thereby guiding new recommendations for clinical management and therapeutic intervention.

Novel White Matter Imaging to Improve Diagnosis of Mild TBI

Mild traumatic brain injury (mTBI), also known as a concussion, is prevalent in military personnel and has been deemed the ‘signature injury’ of the conflicts in Iraq and Afghanistan. Cognitive complaints, headaches, nausea, and dizziness, among others, are common and expected symptoms following mTBI. These symptoms resolve within 7–10 days in most individuals, though 90 days is often referenced as the duration of ‘normal’ recovery after a mild TBI. However, 15-30% of individuals do not recover along this timeline and experience persistent post-concussive symptoms. Psychological factors have been shown to play a substantial role in the persistence of post-concussive symptoms beyond 90 days. Because post-traumatic stress disorder (PTSD) is also highly prevalent in combat Veterans and highly comorbid with mTBI in this population, it has been difficult to tease apart the etiology of persistent cognitive symptoms in the comorbid group and determine if remote history of concussion is contributing to current behavioral symptoms or if the presentation is driven by mental health factors. Traditional structural neuroimaging techniques are largely insensitive to the subtle damage resulting from mTBI. Newer magnetic resonance imaging (MRI) acquisition methods such as Diffusion Tensor Imaging (DTI) have shown more promise in identifying changes in white matter integrity following mTBI. However, even this advanced technology produces equivocal results, and lacks the sensitivity or specificity to identify the underlying cause of any white matter changes. Therefore we will utilize a new approach for assessment specifically of myelin abnormalities, multicomponent-driven equilibrium single-pulse observation of T1 and T2 (mcDESPOT), to calculate myelin volume on Veterans with a history of mTBI, PTSD, or both.

Clinical and neuroimaging correlates of neurodegeneration in military mild TBI

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. In particular, to identify veterans demonstrating evidence of worsening cognitive disruption and/or neural degeneration. Improved characterization of long-term, ongoing damage associated with mTBI among active duty service members and veterans may improve the diagnostic and monitoring procedures used in these populations, reduce clinical costs, and improve long-term veteran health outcomes. We aim to test several psychological and biological measures for utility as markers of mTBI-related neurodegeneration, and characterize the utility and limitations of self-report measures in the context of mTBI and comorbid psychopathology. The results of this research may have implications for the assessment and documentation of mTBI during deployment, education of soldiers and military medical providers, long-term monitoring of service members who sustain mTBI, and enable more efficient provision of long-term care. Therefore, there are clear potential benefits for active duty military as well as for veteran care.

Visual Sensory Impairments and Progression Following Mild TBI

Traumatic brain injury (TBI) is one of the invisible wounds of war, and one of the signature injuries of troops wounded in Afghanistan and Iraq. It is estimated that between 10-20% of Iraqi veterans, or 150,000 - 300,000 persons have some level of TBI. Visual symptoms are a common sequelae of TBI. Very little is known about the chronic visual consequences of mild TBI, its progression, and its correlation with central nervous system (CNS) deficits. Currently, it is not known if neuronal loss in the retina and brain after mTBI continues to progress over time. Closing this knowledge gap is important for understanding and treating TBI-related visual symptoms and for establishing whether ocular biomarkers can be used to predict risk of CNS dysfunction and its progression over time. The purpose of this study is to identify the spectrum of visual sensory disturbances after mTBI by utilizing more detailed tests of visual function and ocular motility, as well as newer structural analyses of optical coherence tomography (OCT) combined with functional MRI imaging of visual pathways in the brain and volume analysis of corresponding grey and white matter locations. 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 thousand 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. This study will provide important information about the extent and progression of visual dysfunction present in mTBI and to what extent there are also deficits present in brain networks. Our long-term goal is to design and test rehabilitative therapies aimed at strengthening impaired connections, through focal therapies. Potential therapeutic modalities include focal transcranial magnetic stimulation, visual behavioral tasks that may strengthen synaptic connections, chemical neuromodulation, and peripheral and central nerve stimulation.

Structural and Functional Neurobiology of Veterans Exposed to Primary Blast Forces

The goal of the current study is to more fully characterize the neurobiological sequelae of exposure to primary blast forces, extending our previous findings of white matter injury in primary blast exposed Veterans both with and without acute symptoms of concussion at the time of exposure. Department of Defense (DoD) surveillance data reported 287,861 total diagnosed traumatic brain injuries (TBI) from 2000 through November, 2013, 82.5% of which were mild in severity. It is estimated that 75% of mild TBI sustained during deployment are blast-related. It is likely that many more individuals are exposed to blast during deployment but do not display symptoms consistent with mild TBI. Most combat-related TBIs are classified as mild on the basis of symptoms at the time of injury. Preliminary evidence suggests that early evolution of blast-related mild TBI may differ from other injury mechanisms. Differences in injury mechanism(s) and/or injury evolution make it essential to determine the effects in the human brain of exposure to primary blast. Adding to the complexity of the situation, a growing body of evidence demonstrates the potential of sub-concussive events to injure the brain. Recently, our group demonstrated the use of diffusion tensor imaging (DTI) to identify spatially heterogeneous areas of white matter injury on an individual basis that were due to primary blast alone, with no other possible mechanisms of head injury present. This project will investigate the microstructural nature and functional effect of diffuse heterogeneous white matter abnormalities present in post-deployment Veterans exposed only to primary blast, without exposure to other mechanisms likely to injure the brain. We hypothesize that post-deployment Veterans exposed to primary blast will display a greater number of white matter abnormalities than healthy unexposed post-deployment Veterans. We expect the extent of white matter abnormalities to be directly related to increased blast exposure history. Specific Aims: 1) We will characterize white matter abnormalities present in Veterans exposed to primary blast using multimodal neuroimaging. 2) We will investigate how history of primary blast exposure and mild TBI are related to the presence of white matter abnormalities. 3) We will characterize the sequelae of white matter abnormalities present in Veterans exposed to primary blast, including effects on brain function, cognitive processes, and symptom presentation. There is growing evidence that repetitive sub-concussive events can injure the brain. Our recent findings suggest that subconcussive exposure only to primary blast forces also has the potential to injure the brain. The proposed study will provide a better understanding of the microstructural nature of white matter abnormalities present following primary blast exposure, as well as insights into the relationship between severity of blast exposure history and presence of white matter abnormalities. Further, the effect on brain networks, cognitive function, and symptom presentation will be investigated. These results will provide vital information to better understand the effect of blast exposure on the brain at all levels, possibly improving identification of at risk active duty service members and diagnosis of affected Veterans.

DTI Phantom Study

Diffusion imaging has gained importance in the past decade as a valuable means of depicting white matter injury caused by various disease processes. Diffusion imaging holds particular promise for evaluation of individuals who have experienced traumatic brain injury (TBI) because damage to white matter pathways is considered to be an important component in the causation of the many types of neurocognitive impairment that can result from TBI. Diffusion imaging can be performed using a number of imaging techniques, and no single technique is universally recognized as the single best method. As a result, development of large pools of data is hampered by the fact that combining imaging studies obtained by multiple techniques results in an inhomogeneous data set that is difficult to analyze. If diffusion imaging is to be developed as a means to evaluate Veterans with suspected TBI, a uniform type of image acquisition is needed across the different types of imaging systems available within the VA hospital network. To construct such a system, a means is needed to establish exactly how one scanner differs from another (or from itself over the course of time). Then, modification of imaging sequences and, as needed, hardware and software components, can be performed to allow more uniform data acquisition across scanners. This study uses diffusion imaging phantoms to evaluate differences between scanners with the goal of providing acquisition techniques that will allow data to be compared across different patient groups and combined into large data collections. The objective is to provide a means for the many scanners across the VA hospital system to provide the same imaging answers in a suspected TBI patient. Inter-scanner differences in diffusion values will be evaluated using two types of novel diffusion phantoms. The first type of phantom will be provided by Michael Boss, PhD at the National Institute of Standards and Technology. These phantoms are composed of various forms of aqueous polymer solutions, which each provide a ground truth value of random microscopic water motion (termed the apparent diffusion coefficient, or ADC) value. The second type of phantom, which will be provided by Walter Schneider, PhD at the University of Pittsburgh, will provide ground truth for other important diffusion imaging parameters, including fractional anisotropy and radial diffusivity. This second type of phantom is composed of micron-scale hollow fiber textiles in various arrays of controlled packing and crossing patterns, which are designed to provide ground truth for axonal patterns similar to those found in the human brain. In addition, the study team will perform diffusion imaging on one to two human volunteers at each of four sites, in conjunction with phantom imaging. Both phantoms and the individual will be scanned multiple times at each site during the study period. Intra- and inter-scanner differences will be measured and, based on these findings, an imaging protocol that will provide optimal uniformity of diffusion results across the sites will be designed.

CENC Grant Program

As part of its mission, the CENC has an integrated grant program. Over the duration of the project, numerous requests for applications have been promulgated and opened to the greater scientific community. The review and approval of studies to be implemented through the CENC were conducted under the CENC Peer Review Program (PRP). The studies that were considered for development must have addressed focused questions, developed preliminary data, or provided an avenue for new researchers and novel research approaches to contribute to the Consortium mission to advance the science of brain injury treatment and prevention. The PRP was designed to provide support for mild traumatic brain injury (mTBI) / chronic traumatic encephalopathy (CTE) research with an active duty service member (ADSM) and/or veteran foci of exceptional scientific merit. The CENC grant program is administered by Dr. Steven West, Associate Director of the Virginia Commonwealth University Center for Rehabilitation Science and Engineering.^[46][8]

Oversight

The CENC has oversight from a Government Steering Committee (GSC). Members of the GSC are DoD/VA appointed and is composed of both government representatives and non-government subject matter experts. The GSC approves all studies to be conducted, recommends new studies, and identifies existing and new requirements as they arise. The GSC is the overall main governing and management committee for the project and the committee through which the DoD and VA interact and collaborate with the CENC. The GSC determines all major scientific decisions, and clinical studies proposed by the Consortium Committee proceed into the implementation stage only with the approval of the GSC. ^[50][51]

References