Detection of blast-related traumatic brain injury in U.S. military personnel

Abstract

Background: Blast-related traumatic brain injuries have been common in the Iraq and Afghanistan wars, but fundamental questions about the nature of these injuries remain unanswered.

Methods: We tested the hypothesis that blast-related traumatic brain injury causes traumatic axonal injury, using diffusion tensor imaging (DTI), an advanced form of magnetic resonance imaging that is sensitive to axonal injury. The subjects were 63 U.S. military personnel who had a clinical diagnosis of mild, uncomplicated traumatic brain injury. They were evacuated from the field to the Landstuhl Regional Medical Center in Landstuhl, Germany, where they underwent DTI scanning within 90 days after the injury. All the subjects had primary blast exposure plus another, blast-related mechanism of injury (e.g., being struck by a blunt object or injured in a fall or motor vehicle crash). Controls consisted of 21 military personnel who had blast exposure and other injuries but no clinical diagnosis of traumatic brain injury.

Results: Abnormalities revealed on DTI were consistent with traumatic axonal injury in many of the subjects with traumatic brain injury. None had detectable intracranial injury on computed tomography. As compared with DTI scans in controls, the scans in the subjects with traumatic brain injury showed marked abnormalities in the middle cerebellar peduncles (P<0.001), in cingulum bundles (P=0.002), and in the right orbitofrontal white matter (P=0.007). In 18 of the 63 subjects with traumatic brain injury, a significantly greater number of abnormalities were found on DTI than would be expected by chance (P<0.001). Follow-up DTI scans in 47 subjects with traumatic brain injury 6 to 12 months after enrollment showed persistent abnormalities that were consistent with evolving injuries.

Conclusions: DTI findings in U.S. military personnel support the hypothesis that blast-related mild traumatic brain injury can involve axonal injury. However, the contribution of primary blast exposure as compared with that of other types of injury could not be determined directly, since none of the subjects with traumatic brain injury had isolated primary blast injury. Furthermore, many of these subjects did not have abnormalities on DTI. Thus, traumatic brain injury remains a clinical diagnosis. (Funded by the Congressionally Directed Medical Research Program and the National Institutes of Health; ClinicalTrials.gov number, NCT00785304.).

Figure 1. Brain Regions of Interest for Diffusion Tensor Imaging

The scans in the left and center columns were obtained with conventional (T₁-weighted) MRI and are shown for the purpose of anatomical localization. The scans in the right column are relative anisotropy maps obtained with diffusion tensor imaging (DTI). The vertical and horizontal red bars indicate the anatomical localization of the images in the right column. The white bars indicate the locations and orientation of the slices analyzed for multislice regions of interest. Red, green, and blue indicate the principal directions of diffusion, with red denoting right to left, green anterior to posterior, and blue dorsal to ventral. Panel A shows a sagittal section through the cingulum bundle, anterior– posterior, dorsal to the corpus callosum, and Panel B shows a coronal section through the middle cerebellar peduncle, anterior–posterior, in the dorsal brain stem and cerebellum. Panels C through F are sagittal sections, with Panel C showing orbitofrontal white matter, anterior–posterior, in the ventral frontal lobe, Panel D showing the body of the corpus callosum, right–left, between the lateral ventricles, Panel E showing the genu of the corpus callosum, right–left, anterior to the lateral ventricles, and Panel F showing the splenium of the corpus callosum, right–left, posterior to the lateral ventricles. Panels G and H are coronal sections, with Panel G showing the anterior limb of the internal capsule, anterior–posterior and right–left, between the caudate and putamen, and Panel H showing the posterior limb of the internal capsule, dorsal–ventral and right–left, between the putamen and thalamus. Panel I shows a sagittal section of the uncinate fasciculus, anterior–posterior, in the anterior frontal lobe, and dorsal and anterior to the orbitofrontal white-matter region of interest. Panel J shows a coronal section through the cerebral peduncle, dorsal–ventral in the midbrain and pons, medial to the middle cerebellar peduncle.

Figure 2. Screening and Enrollment of Study Subjects

TBI denotes traumatic brain injury.

Figure 3. Abnormalities Detected on Diffusion Tensor Imaging in Subjects with Blast-Related Traumatic Brain Injury

Panel A shows scatter plots of relative anisotropy in four regions of interest. P values were calculated with the use of one-sided Student’s t-tests, since the prespecified hypothesis was that relative anisotropy would be lower in subjects with traumatic brain injury (TBI) than in controls. The solid horizontal lines indicate means, and the I bars indicate standard deviations; the dashed horizontal lines are positioned 2 SD below the mean for the control group (solid triangles represent values in subjects with TBIs that are 2 SD below this level); the numbers in parentheses indicate the number of subjects with TBI for whom relative anisotropy was below this cut-off point. The formula for calculating relative anisotropy is available in Figure S1 in the Supplementary Appendix. Panel B shows the number of abnormalities detected on DTI as compared with the number that would be expected by chance in the 63 subjects with TBI. The dotted box indicates the group of subjects with two or more abnormal regions of interest. The P value was calculated with the use of the chi-square test.

Figure 4. Evolution of Abnormalities over Time as Assessed with Diffusion Tensor Imaging

All data in Panels A through D are from the 18 controls and 47 subjects with traumatic brain injury (TBI) who underwent both initial and follow-up diffusion tensor imaging (DTI). The formulas for calculating relative anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity are available in Figure S1 and S8 in the Supplementary Appendix. In Panels A and B, the longer horizontal lines indicate the means and the I bars indicate standard deviations. Panel A shows the results of the initial scans (obtained within 90 days after injury) in the cingulum bundles, with reduced relative anisotropy, increased radial diffusivity, and increased mean diffusivity in the subjects with TBI as compared with the controls. Panel B shows the follow-up scans (obtained 6 to 12 months after study enrollment) in the cingulum bundles, with reduced relative anisotropy and reduced axial diffusivity. Panel C shows the changes in DTI parameters between initial and follow-up scanning in subjects with TBI as compared with controls and the interpretation of these changes (see also Fig. S4 in the Supplementary Appendix). The double arrows indicate more extensive reduction in relative anisotropy; the ≈ symbol indicates that there was no significant difference between subjects with TBI and controls. Panel D shows differences in observed versus expected DTI abnormalities on initial and follow-up scans in the 47 subjects with TBI. The dotted box indicates the group of subjects with two or more abnormal regions of interest.