Diffuse and spatially variable white matter disruptions are associated with blast-related mild traumatic brain injury

Abstract

Mild traumatic brain injury (mTBI) due to explosive blast is common among military service members and often associated with long term psychological and cognitive disruptions. Little is known about the neurological effects of blast-related mTBI and whether they differ from those of civilian, non-blast mTBI. Given that brain damage from blasts may be diffuse and heterogeneous, we tested the hypothesis that blast mTBI is associated with subtle white matter disruptions in the brain that are spatially inconsistent across individuals. We used diffusion tensor imaging to examine white matter integrity, as quantified by fractional anisotropy (FA), in a group of American military service members with (n = 25) or without (n = 33) blast-related mTBI who had been deployed as part of Operation Iraqi Freedom or Operation Enduring Freedom. History of civilian non-blast mTBI was equally common across groups, which enabled testing of both blast and non-blast mTBI effects on measures sensitive to (1) concentrated, spatially consistent (average FA within a region of interest [ROI]), (2) concentrated, spatially variable (number of ROIs with low average FA), and (3) diffuse (number of voxels with low FA) disruptions of white matter integrity. Blast mTBI was associated with a diffuse, global pattern of lower white matter integrity, and this pattern was not affected by previous civilian mTBI. Neither type of mTBI had an effect on the measures sensitive to more concentrated and spatially consistent white matter disruptions. Additionally, individuals with more than one blast mTBI tended to have a larger number of low FA voxels than individuals with a single blast injury. These results indicate that blast mTBI is associated with disrupted integrity of several white matter tracts, and that these disruptions are diluted by averaging across the large number of voxels within an ROI. The reported pattern of effects supports the conclusion that the neurological effects of blast mTBI are diffuse, widespread, and spatially variable.

Introduction

One of the most common injuries to military service members in recent conflicts is mild traumatic brain injury (mTBI) from explosive blast (Taber et al., 2006, Warden, 2006). Approximately 15–25% of American service members deployed to Iraq or Afghanistan reported mTBI (i.e. concussion), and explosive blast was involved in approximately 75% of these incidents (Hoge et al., 2008, Terrio et al., 2009, Wilk et al., 2010). The brain damage associated with mTBI has traditionally been believed to be minimal and temporary, supported by the relatively rapid reduction of symptoms and lack of gross abnormalities on structural neuroimaging scans like computed tomography (CT) and magnetic resonance imaging (MRI) (Niogi and Mukherjee, 2010). However, evidence of white matter disruptions in moderate and severe forms of TBI (Kasahara et al., 2010, Kinnunen et al., 2010, Levin et al., 2008, Oni et al., 2010, Sidaros et al., 2008), along with reports of persistent post-concussive symptoms in up to 30% of cases (Schneiderman et al., 2008), raises the possibility of long-term neurological effects that may not be evident using traditional clinical and neuropsychological instruments.

Diffusion tensor imaging (DTI), an MRI technique used to assess microstructural properties of white matter, has generally demonstrated lower integrity of white matter tracts in frontal and temporal regions in individuals with mTBI relative to a healthy control group (for full review, see Niogi and Mukherjee, 2010). However, given that the directions of forces involved in the initial injury differ across cases (e.g. the orientation of the head relative to the impact), so too may the locations of injury within the brain. Consistent with multiple and varied areas of white matter being affected in mTBI, two studies have shown that the number of regions with “abnormally” low white matter integrity (i.e. fractional anisotropy [FA] several standard deviations below a control group mean) correlated with measures of trauma severity and cognitive function (Levin et al., 2008, Ptak et al., 2003). Because the specific regions with compromised white matter integrity varied across individuals in these studies it may be the number of areas with affected white matter, rather than the magnitude of damage within any single region, that is the most relevant aspect of the brain damage associated with mTBI (Ptak et al., 2003). Additionally, studies with data at multiple time points have failed to find an effect of time since injury on FA, suggesting that long-term neurological effects of mTBI may be present shortly after the injury (Inglese et al., 2005, Rutgers et al., 2008). Other DTI measures, such as mean diffusivity (MD), have also been used to test effects of mTBI on white matter integrity and have generally demonstrated effects analogous to those of FA (Niogi and Mukherjee, 2010), though some studies have demonstrated an effect of mTBI on MD but not FA (e.g., Cubon et al., 2011) or on FA but not MD (e.g., Smits et al., 2011), suggesting potential differential sensitivity among measures.

Blast and non-blast mTBI are qualitatively different in their origins and may carry different consequences for the structural and functional connectivity of the brain. For instance, most non-blast mTBI is due to impact injuries, such as automobile and sports-related collisions, that involve acceleration-deceleration forces, whereas explosive blast involves a series of pressure waves with compressive and tensile components (Moore and Jaffee, 2010, Taber et al., 2006). The first published comparison of FA between individuals with blast mTBI and healthy controls failed to find effects in any region of interest (ROI) or using voxelwise comparisons (Levin et al., 2010); however, a more recent report found that a subset of service members with blast mTBI had FA abnormalities in a greater number of ROIs than would be expected by chance (MacDonald et al., 2011). Our own previous work has demonstrated that in soldiers who experienced blast mTBI, but not in soldiers without blast mTBI, the FA of frontal tracts correlated with electroencephalography (EEG) measures of functional connectivity between brain regions (Sponheim et al., 2010). Therefore, it is likely that neurological effects of blast injury are present, though their characterization may require different techniques than those used in civilian, non-blast mTBI.

In the current study, we examined United States military service members deployed to Operation Enduring Freedom or Operation Iraqi Freedom to investigate effects of exposure to explosive blasts on the white matter of the brain. We hypothesized that the nature of blast creates a diffuse and widespread pattern of white matter damage characterized by focal reductions in integrity that are diluted when averaged at the level of tracts and that are spatially heterogeneous across individuals. Therefore, we predicted that traditional methods that average measures of white matter integrity within a region or across individuals would be less sensitive to these effects than a method based on voxelwise z-scores that does not have strict spatial constraints. Specifically, we predicted that blast mTBI would be associated with a greater number of voxels with low FA (i.e. more points of compromised white matter integrity) but would not affect average FA within individual regions of interest.