Discovering Diagnostics, Subtypes, and Natural History of Traumatic Brain Injury (TBI) vs. Non-TBI Recovery to Gain Military Advantage: The D2ISENTANGLE Focused Program Award

DISENTANGLE OVERALL PROGRAM

A big problem that has challenged the ability of researchers to understand and develop better treatments for traumatic brain injury (TBI) is that it is difficult to know who has experienced a TBI. That is because the great majority of people who are civilians or in the military and experience a TBI are not knocked out for many hours, like individuals with a severe brain injury. They may be knocked out for a very short time or have a brief period where they aren't sure they remember what happened. Most often, people with TBI have symptoms like dizziness, lightheadness, taking longer to think, nausea, and different types of anxiety or bodily (somatic) symptoms. The problem is that a lot of people who don't have TBI also have these same kinds of symptoms because being exposed to a very stressful situation can also commonly cause these types of symptoms. Most past studies of TBI have used symptoms to diagnose the presence of TBI, and the people who have been put in the 'TBI' group have really been a mix of people with and without TBI. This has caused lots of problems, and it has been very difficult to make progress with understanding TBI and developing better treatments.

Fortunately, very recently a new blood test has been developed that identifies individuals with TBI on the basis of molecules that are released from the brain into the blood when it is injured. This is very exciting because it finally allows us to separate out the people with symptoms after trauma exposure who have symptoms due to TBI from people who have symptoms due to activation of brain systems involved in the response to stress. The proposed study will use this new blood test it to identify people with brain injury who participated in a recent large-scale study of trauma survivors. This study, the AURORA study, cost more than $30 million dollars and enrolled nearly 3,000 trauma survivors in the emergency department after a trauma exposure (3/4 had experienced a car accident). These individuals had blood sample collected in the emergency department and then had a great many different types of testing over the coming days and weeks. A huge amount of data was collected regarding what these people's symptoms were over time, they wore a fitbit-type watch to collect physiologic data, they had an app placed on their smartphone that assessed how quickly they typed on their phone, and other characteristics from their phone, hundreds of them had a magnetic resonance imaging (MRI) scan 2 weeks after the trauma and had other testing to assess brain function, and blood collected for molecular analyses.

The DISENTANGLE will use this blood test to identify people in the study who had a TBI at the time of their trauma, and then will use all of the different kinds of data to learn a lot more about TBI and separate out ('DISENTANGLE') the effects of TBI from the stressful experience itself. For example, Project 1 will use information obtained in the emergency department and via surveys to identify risk factors for developing acute and chronic symptoms after trauma, both among people with TBI and those without TBI. This information can be used to identify individuals for preventive interventions or identify people with symptoms in the early aftermath of trauma whose symptoms are likely to persistent, so that they can get early treatment. Project 2 will examine the neuroimaging characteristics that distinguish TBI vs. non-TBI-related posttraumatic symptoms, using advanced MRI imaging-type data. Project 3 will use the > 90,000 serial neurocognitive assessments obtained in AURORA from study participants to distinguish the acute and persistent neurocognitive effects of TBI from stress exposure, and Project 4 will use the testing performed at 2 weeks to learn a lot more about how TBI affects emotional health. Project 5 will use >537,000 minutes of watch wear data and 1,375,000 cumulative days of continuous digital phenotyping data – keystroke, GPS, text, and movement data – to see if we can identify people with TBI from 'fitbit' type information and information that can be collected without effort from them. This is important because it could be used to identify Service men and women who have had a TBI who might not even know they had had one, so that they can get early intervention. Finally, Project 6 will use molecular data collected from blood to learn a lot more about the biology of TBI and of acute and chronic PTSD-type symptoms. The work across all of these different projects will yield a huge amount of new discoveries that can be used to improve the lives of Service men and women, and of civilians, who experience TBI or posttraumatic stress.

DISENTANGLE PROJECT 1

A big problem that has challenged the ability of researchers to understand and develop better treatments for traumatic brain injury (TBI) is that it is difficult to know who has experienced damage to the brain after a head injury. That is because the great majority of people who are civilians or in the military and experience a TBI are not knocked out for many hours, like individuals with a severe brain injury. They may be knocked out for a very short time or have a brief period where they aren't sure they remember what happened. Most often, people with TBI have symptoms like dizziness, lightheadness, taking longer to think, nausea, and different types of anxiety or bodily (somatic) symptoms. The problem is, a lot of people who don't have TBI also have these same kinds of symptoms because upsetting circumstances often associated with experiencing a head injury can also lead to symptoms related to stress. Most past studies of TBI have used symptoms to diagnose the presence of TBI, and the people who have been put in the 'TBI' group are a mix of people with stress symptoms and those with mild mechanical brain injury. This has caused lots of problems with diagnosis, and it has been very difficult to make progress with understanding TBI and developing better treatments.

Fortunately, a new blood test has been developed that identifies individuals with TBI on the basis of molecules that are released from the brain into the blood when it is injured. This is very exciting because it finally allows us to separate out the people with symptoms after trauma exposure who have symptoms due to TBI from people who have symptoms due to activation of brain systems involved in the response to stress. The proposed study will use this new blood test to identify people with brain injury who participated in a recent large-scale study of trauma survivors. This study, the AURORA study, cost more than $30 million dollars and enrolled nearly 3,000 trauma survivors in the emergency department after a trauma exposure (3/4 of the same had experienced a car accident).

DISENTANGLE Project 1 will use data from nearly 3,000 individuals to identify individual risk factors for the development of substantial symptoms in the hours after trauma (posttraumatic stress disorder [PTSD]-like symptoms, or bodily symptoms like dizziness, headache, concentration difficulty) and will examine how the influence of each of these risk factors differs in people who had a TBI vs. those who did not have a TBI. We will also look at risk factors/predictors for having persistence of those symptoms for weeks and how those risk factors are affected by the presence or absence of TBI. This is important because this information about who is high risk to have their symptoms stay for weeks, and not go away in a few hours, will help us to know who would benefit from early treatment interventions.

DISENTANGLE PROJECT 2

A big problem that has challenged the ability of researchers to understand and develop better treatments for traumatic brain injury (TBI) is that it is difficult to know who has experienced a TBI. That is because the great majority of people who are civilians or in the military and experience a TBI may be knocked out for a very short time or have a brief period where they aren't sure they remember what happened. Most often, people with TBI have symptoms like dizziness, lightheadness, taking longer to think, nausea, and different types of anxiety or bodily (somatic) symptoms. The problem is that a lot of people who don't have TBI also have these same kinds of symptoms because being exposed to a very stressful situation can also commonly cause these types of symptoms. Most past studies of TBI have used symptoms to diagnose the presence of TBI, and the people who have been put in the 'TBI' group are a mix of people with stress symptoms and those with mild mechanical brain injury. This has caused lots of problems with diagnosis, and it has been very difficult to make progress with understanding TBI and developing better treatments.

Fortunately, a new blood test has been developed that identifies individuals with TBI on the basis of molecules that are released from the brain into the blood when it is injured. This is very exciting because it finally allows us to separate out the people with symptoms after trauma exposure who have symptoms due to TBI from people who have symptoms due to activation of brain systems involved in the response to stress. The proposed project will use this new blood test it to identify people with brain injury who participated in two recent large-scale studies of trauma survivors. These studies, AURORA and TRACK-TBI, cost more than $50 million dollars and enrolled >4,000 trauma survivors in the emergency department after a trauma exposure and obtained more than 900 magnetic resonance imaging (MRI) brain scans 2 weeks after trauma.

DISENTANGLE Project 2 will use the new blood test to identify patients who had a head injury and were scanned with MRI scans from these two large studies and determine brain findings in TBI in comparison of brain findings who do not have TBI, but who have acute symptoms, or no symptoms. This will clear up a lot of confusion about the different types of brain problems that are caused by head injury. Importantly, these brain scans do not just have information on the structure of the brain, but also were functional scans that evaluated how the brain was functioning after trauma. The results of this study will provide a lot of new important information regarding what happens to the brain after TBI. Gaining this type of accurate information is critical to developing new treatments and interventions for individuals with TBI.

DISENTANGLE PROJECT 3

A big problem that has challenged the ability of researchers to understand and develop better treatments for, traumatic brain injury (TBI) is that it is difficult to know who has experienced a TBI. That is because the great majority of people who are civilians or in the military and experience a TBI may be knocked out for a very short time or have a brief period where they aren't sure they remember what happened. Most often, people with TBI have symptoms like dizziness, lightheadness, taking longer to think, nausea, and different types of anxiety or bodily (somatic) symptoms. The problem is that a lot of people who don't have TBI also have these same kinds of symptoms because being exposed to a very stressful situation can also commonly cause these types of symptoms. Most past studies of TBI have used symptoms to diagnose the presence of TBI, and the people who have been put in the 'TBI' group are a mix of people with stress symptoms and those with mild mechanical brain injury. This has caused lots of problems with diagnosis, and it has been very difficult to make progress with understanding TBI and developing better treatments.

Fortunately, a new blood test has been developed that identifies individuals with TBI on the basis of molecules that are released from the brain into the blood when it is injured. This is very exciting because it finally allows us to separate out the people with symptoms after trauma exposure who have symptoms due to TBI from people who have symptoms due to activation of brain systems involved in the response to stress. The proposed study will use this new blood test to identify people with brain injury who participated in a recent large-scale study of trauma survivors. This study, the AURORA study, cost more than $30 million dollars and enrolled nearly 3,000 trauma survivors in the emergency department after a trauma exposure (3/4 of the sample had experienced a car accident).

DISENTANGLE Project 3 will use neurocognitive data (for example, tests of memory and attention) from nearly 3,000 individuals to identify how TBI affects neurocognitive function and how the influence of TBI on neurocognitive function differs from the effects related to stress. 'Neurocognitive function' also refers to our ability to concentrate, process information, our reaction time, and our ability to know when to react and when not to react. Neurocognitive function is very important for daily life and critically important to our Warfighters to be able to survive and achieve individual and unit success. In addition to learning a lot more about how TBI affects neurocognitive function, we will also look at whether we can predict individuals who will experience a decline in function after trauma exposure, either when they have a TBI or when they do not have a TBI but encounter a stressful event, and which individuals will have persistent reductions in neurocognitive function. This is important to know so that those individuals with a big drop in neurocognitive function after stress/trauma can be given early interventions to enable a better recovery. This is very important both for their survival, for their fellow Warfighter's survival, and for unit/mission success.

DISENTANGLE PROJECT 4

A big problem that has challenged the ability of researchers to understand and develop better treatments for traumatic brain injury (TBI) is that it is difficult to know who has experienced a TBI. That is because the great majority of people who are civilians or in the military and experience a TBI may be knocked out for a very short time or have a brief period where they aren't sure they remember what happened. Most often, people with TBI have symptoms like dizziness, lightheadness, taking longer to think, nausea, and different types of anxiety or bodily (somatic) symptoms. The problem is that a lot of people who don't have TBI also have these same kinds of symptoms because being exposed to a very stressful situation can also commonly cause these types of symptoms. Most past studies of TBI have used symptoms to diagnose the presence of TBI, and the people who have been put in the 'TBI' group are a mix of people with stress symptoms and those with mild mechanical brain injury. This has caused lots of problems with diagnosis, and it has been very difficult to make progress with understanding TBI and developing better treatments.

Fortunately, a new blood test has been developed that identifies individuals with TBI on the basis of molecules that are released from the brain into the blood when it is injured. This is very exciting because it finally allows us to separate out the people with symptoms after trauma exposure who have symptoms due to TBI from people who have symptoms due to activation of brain systems involved in the response to stress. The proposed study will use this new blood test to identify people with brain injury who participated in a recent large-scale study of trauma survivors. This study, the AURORA study, cost more than $30 million dollars and enrolled nearly 3,000 trauma survivors in the emergency department after a trauma exposure (3/4 of the sample had experienced a car accident).

DISENTANGLE Project 4 will analyze data obtained from hundreds of people went to a testing center 2 weeks after the traumatic event and had testing done to measure how their autonomic nervous system was functioning. The autonomic nervous system controls involuntary actions, such as the beating of your heart and the widening or narrowing of your blood vessels, and affects things like ability to sleep, and how 'wired' or on edge you feel. It also has to do with the body's response to stress. Because of problems with the diagnosis of TBI, there is still a lot of confusion about how TBI, compared with stress exposure, or the combination of TBI and stress affects the function of the autonomic nervous system. This is really important to understand because when the autonomic nervous system is excessively activated, it causes a lot of symptoms and suffering. This project group will gain a lot of important new information that has the potential to shed a lot of important light on this issue. This will help us to develop new treatments for TBI and stress-related symptoms and could also help us to monitor treatment progress. For example, we could see if specific changes linked to TBI improve after treatment.

DISENTANGLE PROJECT 5

A big problem that has challenged the ability of researchers to understand and develop better treatments for traumatic brain injury (TBI) is that it is difficult to know who has experienced a TBI. That is because the great majority of people who are civilians or in the military and experience a TBI may be knocked out for a very short time or have a brief period where they aren't sure they remember what happened. Most often, people with TBI have symptoms like dizziness, lightheadness, taking longer to think, nausea, and different types of anxiety or bodily (somatic) symptoms. The problem is that a lot of people who don't have TBI also have these same kinds of symptoms because being exposed to a very stressful situation can also commonly cause these types of symptoms. Most past studies of TBI have used symptoms to diagnose the presence of TBI, and the people who have been put in the 'TBI' group are a mix of people with stress symptoms and those with mild mechanical brain injury. This has caused lots of problems with diagnosis, and it has been very difficult to make progress with understanding TBI and developing better treatments.

Fortunately, a new blood test has been developed that identifies individuals with TBI on the basis of molecules that are released from the brain into the blood when it is injured. This is very exciting because it finally allows us to separate out the people with symptoms after trauma exposure who have symptoms due to TBI from people who have symptoms due to activation of brain systems involved in the response to stress. The proposed study will use this new blood test to identify people with brain injury who participated in a recent large-scale study of trauma survivors. This study, the AURORA study, cost more than $30 million dollars and enrolled nearly 3,000 trauma survivors in the emergency department after a trauma exposure (3/4 had experienced a car accident). The study gave everybody a 'fitbit' type watch to wear in the emergency department, and they wore it for many months. In addition, the study also asked everyone to put an app on their smartphone that collected information about their typing speed and errors, the types of words that they used in text. All together, AURORA collected more than >537,000 minutes of 'fitbit'-type wear data and 1,375,000 cumulative days of smartphone data – a huge treasure trove of data to mine.

DISENTANGLE Project 5 will use these data, and the results of the TBI test obtained from blood samples that people gave in the emergency department, to gain important new understanding regarding the effect of TBI on sleep, daytime activity, and autonomic nervous system function (defined in Project 4), and on 'real-world' psychomotor tasks – speed and errors when typing on your phone, use of the smartphone keypad. The research team will determine how TBI affects these things when compared to stress exposure without TBI. The team will also see whether information from these inexpensive devices alone can identify individuals who have had a TBI. This is important so that people could be given early intervention.

DISENTANGLE PROJECT 6

A big problem that has challenged the ability of researchers to understand, and develop better treatments for, traumatic brain injury (TBI) is that it is difficult to know who has experienced a TBI. That is because the great majority of people who are civilians or in the military and experience a TBI may be knocked out for a very short time or have a brief period where they aren't sure they remember what happened. Most often, people with TBI have symptoms like dizziness, lightheadness, taking longer to think, nausea, and different types of anxiety or bodily (somatic) symptoms. The problem is that a lot of people who don't have TBI also have these same kinds of symptoms because being exposed to a very stressful situation can also commonly cause these types of symptoms. Most past studies of TBI have used symptoms to diagnose the presence of TBI, and the people who have been put in the 'TBI' group are a mix of people with stress symptoms and those with mild mechanical brain injury. This has caused lots of problems with diagnosis, and it has been very difficult to make progress with understanding TBI and developing better treatments.

Fortunately, a new blood test has been developed that identifies individuals with TBI on the basis of molecules that are released from the brain into the blood when it is injured. This is very exciting because it finally allows us to separate out the people with symptoms after trauma exposure who have symptoms due to TBI from people who have symptoms due to activation of brain systems involved in the response to stress. The proposed study will use this new blood test to identify people with brain injury who participated in a recent large-scale study of trauma survivors. This study, the AURORA study, cost more than $30 million dollars and enrolled nearly 3,000 trauma survivors in the emergency department after a trauma exposure (3/4 of the sample had experienced a car accident).

DISENTANGLE Project 6 will use molecular data (RNA, DNA, proteins) in blood samples from a subset of hundreds of AURORA participants to gain new insights into how the body's response to TBI differs from the body's response to stress itself. This information is very important to understand the biological of TBI to inform the development of new treatment interventions. In addition, in the future it is possible that the knowledge gained from this study could help with diagnosis, or with the identification of different subgroups of patients (e.g., subgroups of patients with TBI).