Advanced MRI in Blast-related TBI
Advanced MRI in Blast-related TBI
Thousands of soldiers, marines, and other military personnel have had injuries to the brain
 due the wars in Iraq and Afghanistan. In addition, 1.5 million civilians per year in the
 United States have traumatic brain injuries caused by car accidents, falls, sports-related
 injuries or assaults. There are important advances in technology that we think will help us
 learn a lot more about these injuries. One such advance involves new types of MRI scans that
 we think will be able to show what has happened to the brain after trauma more clearly that
 regular scans can. These first new scan is called diffusion tensor imaging, which shows
 injury to the axons (the wiring of the brain). The second new scan is called resting-state
 functional MRI correlation analysis, which shows how well various parts of the brain are
 connected to each other. Importantly, the new types of scans can be done using regular
 scanners that we already have in every major hospital. The innovation is entirely in how the
 scanners are used and how the resulting pictures are analyzed on a computer after they have
 been taken.

 Our overall goal is to see whether these new MRI scans will be useful for people who have had
 traumatic brain injuries. We have already tested them on some civilian brain injury patients
 and found them to be very helpful. For this study, we will test them on military personnel
 who have had traumatic brain injuries caused by explosions. The specific goal will be to see
 if the amount of injury we see can be used to predict how well the patients will do overall
 over the next 6-12 months. We think with the new scans we will be able to predict overall
 outcomes better than with regular scans and other information. A related goal will be to see
 whether injuries to specific parts of the brain seen by these new scans can be used to
 predict whether patients will be likely to have specific problems like memory loss, attention
 deficit, depression, or post-traumatic stress disorder. A final goal will be to repeat the
 scans 6-12 months later to see whether the new MRI scans can show whether the injuries to the
 brain have healed, gotten worse, or stayed the same.

 If the study is successful, it will show that these new MRI techniques can to be used to make
 earlier and more accurate diagnoses of traumatic brain injury, predictions of the sorts of
 problems that are likely to occur after brain injury, and assessments of how severe the
 injuries are.

 This study will help traumatic brain injury patients. It will be most useful for military
 personnel who have had brain injuries due to explosions. It is highly likely that it will
 also be useful for younger adults who have had brain injuries due to other causes like car
 accidents, sports-related concussions, falls, or assaults. It is possible that but not known
 for sure whether it will help young children or older adults with traumatic brain injuries.

 These new scans could help with decisions about whether military personnel can return to
 duty, what sort of rehabilitation would benefit them most, and what family members should
 watch for and expect. This could become used in some hospitals within 2 years, and could
 become standard in every major hospital within 5 years.

 The new scans could also be helpful in developing new treatments. For example, if a new drug
 works by blocking injury to the axons, it would be a good idea to test on people who have
 injury to their axons. Right now we have no good way to tell who these people are, and so a
 new drug like this would get tested on lots of people who don't have injured axons, along
 with those who do. This would make it harder to tell if the new drug is working. With the new
 scans we should be able to tell who has injured axons, tell how severe the injury is, and
 figure out whom to test the drugs on. It will likely take 10 years or more to develop new
 drugs like this.

 Further in the future, the new scans could be used to help guide surgery to implant computer
 chips to help rewire the brain. We don't know how long this will take, but estimate 15-20
 years or more.

 Overall MRI scanning is very safe and has no known major risks. Because the scanner uses
 strong magnets, anyone with metal objects in their bodies can't be scanned, as this could be
 dangerous. We will make sure that no one with metal objects in their bodies is included in
 the study. There can be some psychological risks involved in taking tests and answering
 questions, but these are usually mild and can be managed. There is always a risk that
 important confidential information will be made public and that this could have consequences.
 We will do everything possible to maintain confidentiality. Nearly all of the information
 will only be identified using a code number and not by the name of the person, and all of it
 will be kept securely.
Background: In traumatic brain injury, axonal damage is a major pathophysiological process
 and may be a primary cause of adverse neurological outcomes. However, traumatic axonal injury
 and its effects on brain functional connectivity are very difficult to directly detect and
 quantify in living patients. Diffusion tensor imaging (DTI) appears to have great promise
 with regard to detecting axonal injury. Resting-state fMRI correlation analysis likewise may
 be a powerful and broadly applicable method for investigating brain functional connectivity.
 In our preliminary studies, these two techniques have been successfully used together in
 several civilian TBI patients. They appear to synergistically cross validate each other;
 disrupted functional connectivity underlying focal neurological deficits were revealed using
 resting-state fMRI correlation analysis while DTI demonstrated the axonal injury responsible
 for the disruptions. Conventional MRI and CT entirely failed to explain many of these
 deficits. This cross validation is important as it adds confidence to the interpretation of
 the results. Without resting-state fMRI correlation analysis, the consequences of apparent
 axonal injury on DTI for the functional connectivity of the brain may not be clear; the
 axonal injury could be in white matter tracts that are redundant, or not severe enough to be
 functionally important. Without DTI, the cause of a disruption in connectivity seen using
 resting-state fMRI correlation analysis will likewise not always be known; processes other
 than traumatic axonal injury could be responsible. Both of these advanced techniques along
 with a full conventional MRI can be performed on standard clinical MRI scanners in
 approximately 45 minutes per patient. Apart from in our preliminary studies, resting-state
 fMRI and DTI have not been used together to investigate traumatic brain injury.

 Objective/Hypothesis: The objective of this proposal is to test these two advanced MRI
 methods, DTI and resting-state fMRI, in active-duty military blast-related TBI patients
 acutely after injury and correlate findings with TBI-related clinical outcomes 6-12 months
 later. These methods may add clinically useful predictive information following traumatic
 brain injury that could be of assistance in standardizing diagnostic criteria for TBI, making
 return-to-duty triage decisions, guiding post-injury rehabilitation, and developing novel
 therapeutics. The overarching hypothesis guiding this project is that traumatic axonal injury
 is a principal cause of impaired brain function following blast-related TBI. Specific
 hypotheses to be tested are:

 1. DTI and resting-state fMRI correlation analysis will noninvasively reveal abnormalities
 that are not present on CT or conventional MRI acutely following blast-related TBI.

 2. Specific patterns of acute axonal injury (on DTI) causing disruption of brain functional
 connectivity (on resting-state fMRI correlation analysis) will predict specific
 neurological, neuropsychological, and psychiatric deficits and disorders.

 3. The overall burden of acute axonal injury and disrupted brain functional connectivity
 will strongly predict overall 6-12 month clinical outcome.

 Specific Aims: 1) to obtain DTI, resting-state fMRI and conventional MRI scans acutely after
 blast-related TBI in active-duty military personnel presenting to Landstuhl Regional Medical
 Center (LRMC).

 2) to collect detailed clinical information on TBI-related outcomes 6-12 months after
 injuries.

 3) to extensively analyze the acute imaging predictors and correlates of 6-12 month clinical
 outcomes.

 Study Design: We propose a prospective, observational study of 80 active duty military
 personnel who have sustained blast-related TBI. Initial scans will be performed within 4 days
 of injury at LRMC. Follow-up will occur monthly by telephone and in person at Washington
 University 6-12 months after injury. Clinical information on TBI outcomes collected will
 include global outcome assessments, neuropsychological testing for memory, attention and
 executive function deficits, motor performance measures, and clinician administered rating
 scales for depression and post-traumatic stress disorder. Controls will include 1) an
 additional group of 20 active duty military personnel with other injuries, but who have not
 had TBI, and 2) age, gender and education-based norms for standardized test and assessment
 results. Repeat DTI, resting-state fMRI, and conventional MRI will be performed to track the
 evolution of the injuries. Analysis approaches will include prespecified hypotheses based on
 known brain anatomical-clinical correlations and several exploratory approaches, as the
 structural bases for many post-traumatic neurological and neuropsychological deficits are not
 well understood. Non-parametric correlational statistical methods and rigorous correction for
 multiple comparisons will be employed. Expert collaborators and logistics coordinators will
 be or have already been recruited. Confidentiality and privacy will be tightly controlled.
Inclusion Criteria:

 1. Clinical diagnosis of blast-related TBI of any severity, as made by LRMC staff, based
 on clinical history, examination, and/or standard clinical imaging (CT, conventional
 MRI).

 2. Acute injury or injuries, defined as first occurring 0-90 days prior to enrollment.

 3. Ability to lie still in a supine position for the duration of the scan sessions, e.g.
 no severe claustrophobia or limiting pain from other injuries.

 4. No known metallic implants or metallic foreign objects.

 5. Ability to provide informed consent.

 6. Not known to be HIV positive

 7. Not known to be pregnant

 8. No previous major traumatic brain injury

 9. No contraindication to MRI for medical reasons such as arrhythmias.