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.
