With the use of DTI, we found abnormalities consistent with traumatic axonal injury in U.S. military personnel with blast-related mild traumatic brain injury. Substantial numbers of abnormalities were found in regions of the brain not known to be commonly injured in civilian cases of mild traumatic brain injury but predicted to be vulnerable to blast on the basis of computational simulations.10
Abnormalities were also found in some brain regions that are commonly affected in civilian cases of mild traumatic brain injury.15,20–26
Other regions, such as the corpus callosum,5,15,20,23,25–27
were generally spared. Overall, the distribution of abnormalities can best be accounted for as a combination of traumatic axonal injuries in brain regions vulnerable to primary blast and in regions of the brain vulnerable to other mechanisms of injury. This explanation fits well with the clinical descriptions of the injuries, which in all cases included both primary blast exposure and another mechanism of injury, such as a fall, a motor-vehicle crash, or a blow to the head by a blunt object. However, it is also possible that injuries to the orbitofrontal white matter and cerebellar peduncles are more common in civilian cases of mild traumatic brain injury than currently recognized. Certainly, these and adjacent regions can be affected in more severe instances of civilian traumatic brain injury.28–31
Likewise, primary blast injury could sensitize these regions to subsequent insults. Thus, the exact contributions of primary blast exposure and other types of injury cannot be determined with certainty.
The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning in a fashion that was consistent with the evolution of relatively acute injuries. The pattern of abnormalities on the initial scans was most consistent with axonal injury plus a cellular inflammatory response and edema (, and Fig. S8 in the Supplementary Appendix
). Axial diffusivity has been shown to be decreased with axonal injury but concomitantly increased with edema and cellular inflammation. Thus, axial diffusivity can be pseudonormalized in complex injuries.16
On the follow-up scans, the pattern of abnormalities was most consistent with persistent axonal injury plus resolution of the edema and cellular inflammation (, and Fig. S8 in the Supplementary Appendix
). This evolution over time also confirms that the DTI abnormalities were unlikely to have been preexisting.
The limitations of this study include a moderate sample size, an all-male study population, a finite number of prespecified regions of interest for DTI analysis, and the lack of a direct comparison with identically assessed subjects who had traumatic brain injury that was not blast-related. Another limitation, despite our best efforts at circumvention, is the possibility that some uncharacterized differences between the subjects and the controls, in addition to that of brain injury, affected the DTI signals in such as way as to produce the observed results. Additional research with independent cohorts will be required to validate these findings.
We have not been able to address questions regarding isolated primary blast-related traumatic brain injury. All our subjects had primary blast exposure plus another blast-related mechanism of injury, indicating that the incidence of isolated primary blast-related traumatic brain injury may be low (see the Discussion section in the Supplementary Appendix
Our cohort consisted of active-duty U.S. military personnel with injuries or medical conditions severe enough to prompt commanding officers and medical personnel to at least temporarily remove them from duty. It is not known whether these subjects are representative of all U.S. military personnel with mild traumatic brain injury sustained in Iraq or Afghanistan. Military personnel were brought to the LRMC for a variety of reasons, the most common of which was to obtain specific types of medical care that were not available in Iraq or Afghanistan. Examples include consultations with specialists, certain surgical procedures, and radiologic studies such as MRI. It is possible that many of the subjects with the most mild injuries were returned to duty without being sent to the LRMC.32
Thus, there is a possibility of selection bias toward more seriously injured patients in our cohort. The LRMC serves as a central triage point for the wars in Iraq and Afghanistan; it is not yet possible to perform MRI-based studies in Iraq and Afghanistan because functioning scanners are not currently available to the U.S. military medical system in those countries.
Because DTI can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals, DTI-based assessments may be useful in diagnosis, triage, and treatment planning in clinical practice. The analytic methods used here allowed assessment of individual patients with traumatic brain injury, just as it would in a clinical setting. However, it must be emphasized that only 18 of the 63 subjects with traumatic brain injury had definitively abnormal scans when the scans were analyzed individually. For now, mild traumatic brain injury remains primarily a clinical diagnosis. Normal findings on a DTI scan do not rule out traumatic brain injury, nor are DTI findings in isolation sufficient to make this diagnosis with certainty (see the Discussion section in the Supplementary Appendix
The relationship between DTI abnormalities and clinical outcomes in U.S. military personnel has yet to be determined. A great deal of research along these lines has been conducted in civilians with traumatic brain injury.20,21,31,33–38
However, unique aspects of traumatic brain injury sustained by military personnel include blast injuries and the high rate of post-traumatic stress disorder.3,39–43
The relationships among blast-related traumatic brain injury, axonal injury, and outcomes that include post-traumatic stress disorder are topics of active research. DTI and other advanced MRI techniques are tools that may be useful in probing these relationships.