The nature of white matter abnormalities in blast-related mild traumatic brain injury.
ABSTRACT: Blast-related traumatic brain injury (TBI) has been a common injury among returning troops due to the widespread use of improvised explosive devices in the Iraq and Afghanistan Wars. As most of the TBIs sustained are in the mild range, brain changes may not be detected by standard clinical imaging techniques such as CT. Furthermore, the functional significance of these types of injuries is currently being debated. However, accumulating evidence suggests that diffusion tensor imaging (DTI) is sensitive to subtle white matter abnormalities and may be especially useful in detecting mild TBI (mTBI). The primary aim of this study was to use DTI to characterize the nature of white matter abnormalities following blast-related mTBI, and in particular, examine the extent to which mTBI-related white matter abnormalities are region-specific or spatially heterogeneous. In addition, we examined whether mTBI with loss of consciousness (LOC) was associated with more extensive white matter abnormality than mTBI without LOC, as well as the potential moderating effect of number of blast exposures. A second aim was to examine the relationship between white matter integrity and neurocognitive function. Finally, a third aim was to examine the contribution of PTSD symptom severity to observed white matter alterations. One hundred fourteen OEF/OIF veterans underwent DTI and neuropsychological examination and were divided into three groups including a control group, blast-related mTBI without LOC (mTBI - LOC) group, and blast-related mTBI with LOC (mTBI + LOC) group. Hierarchical regression models were used to examine the extent to which mTBI and PTSD predicted white matter abnormalities using two approaches: 1) a region-specific analysis and 2) a measure of spatial heterogeneity. Neurocognitive composite scores were calculated for executive functions, attention, memory, and psychomotor speed. Results showed that blast-related mTBI + LOC was associated with greater odds of having spatially heterogeneous white matter abnormalities. Region-specific reduction in fractional anisotropy (FA) in the left retrolenticular part of the internal capsule was observed in the mTBI + LOC group as the number of blast exposures increased. A mediation analysis revealed that mTBI + LOC indirectly influenced verbal memory performance through its effect on white matter integrity. PTSD was not associated with spatially heterogeneous white matter abnormalities. However, there was a suggestion that at higher levels of PTSD symptom severity, LOC was associated with reduced FA in the left retrolenticular part of the internal capsule. These results support postmortem reports of diffuse axonal injury following mTBI and suggest that injuries with LOC involvement may be particularly detrimental to white matter integrity. Furthermore, these results suggest that LOC-associated white matter abnormalities in turn influence neurocognitive function.
Project description:To evaluate whether diffusion tensor imaging (DTI) will noninvasively reveal white matter changes not present on conventional MRI in acute blast-related mild traumatic brain injury (mTBI) and to determine correlations with clinical measures and recovery.Prospective observational study of 95 US military service members with mTBI enrolled within 7 days from injury in Afghanistan and 101 healthy controls. Assessments included Rivermead Post-Concussion Symptoms Questionnaire (RPCSQ), Post-Traumatic Stress Disorder Checklist Military (PCLM), Beck Depression Inventory (BDI), Balance Error Scoring System (BESS), Automated Neuropsychological Assessment Metrics (ANAM), conventional MRI, and DTI.Significantly greater impairment was observed in participants with mTBI vs controls: RPCSQ (19.7 ± 12.9 vs 3.6 ± 7.1, p < 0.001), PCLM (32 ± 13.2 vs 20.9 ± 7.1, p < 0.001), BDI (7.4 ± 6.8 vs 2.5 ± 4.9, p < 0.001), and BESS (18.2 ± 8.4 vs 15.1 ± 8.3, p = 0.01). The largest effect size in ANAM performance decline was in simple reaction time (mTBI 74.5 ± 148.4 vs control -11 ± 46.6 milliseconds, p < 0.001). Fractional anisotropy was significantly reduced in mTBI compared with controls in the right superior longitudinal fasciculus (0.393 ± 0.022 vs 0.405 ± 0.023, p < 0.001). No abnormalities were detected with conventional MRI. Time to return to duty correlated with RPCSQ (r = 0.53, p < 0.001), ANAM simple reaction time decline (r = 0.49, p < 0.0001), PCLM (r = 0.47, p < 0.0001), and BDI (r = 0.36 p = 0.0005).Somatic, behavioral, and cognitive symptoms and performance deficits are substantially elevated in acute blast-related mTBI. Postconcussive symptoms and performance on measures of posttraumatic stress disorder, depression, and neurocognitive performance at initial presentation correlate with return-to-duty time. Although changes in fractional anisotropy are uncommon and subtle, DTI is more sensitive than conventional MRI in imaging white matter integrity in blast-related mTBI acutely.
Project description:Many brain imaging studies have demonstrated reductions in gray and white matter volumes in alcoholism, with fewer investigators using diffusion tensor imaging (DTI) to examine the integrity of white matter pathways. Among various medical conditions, alcoholism and post-traumatic stress disorder (PTSD) are two comorbid diseases that have similar degenerative effects on the white matter integrity. Therefore, understanding and differentiating these effects would be very important in characterizing alcoholism and PTSD. Alcoholics are known to have neurocognitive deficits in decision-making, particularly in decisions related to emotionally-motivated behavior, while individuals with PTSD have deficits in emotional regulation and enhanced fear response. It is widely believed that these types of abnormalities in both alcoholism and PTSD are related to fronto-limbic dysfunction. In addition, previous studies have shown cortico-limbic fiber degradation through fiber tracking in alcoholism. DTI was used to measure white matter fractional anisotropy (FA), which provides information about tissue microstructure, possibly indicating white matter integrity. We quantitatively investigated the microstructure of white matter through whole brain DTI analysis in healthy volunteers (HV) and alcohol dependent subjects without PTSD (ALC) and with PTSD (ALC+PTSD). These data show significant differences in FA between alcoholics and non-alcoholic HVs, with no significant differences in FA between ALC and ALC+PTSD in any white matter structure. We performed a post-hoc region of interest analysis that allowed us to incorporate multiple covariates into the analysis and found similar results. HV had higher FA in several areas implicated in the reward circuit, emotion, and executive functioning, suggesting that there may be microstructural abnormalities in white matter pathways that contribute to neurocognitive and executive functioning deficits observed in alcoholics. Furthermore, our data do not reveal any differences between ALC and ALC+PTSD, suggesting that the effect of alcohol on white matter microstructure may be more significant than any effect caused by PTSD.
Project description:Mild traumatic brain injuries (mTBIs) are often associated with posttraumatic stress disorder (PTSD). In cases of chronic mTBI, accurate diagnosis can be challenging due to the overlapping symptoms this condition shares with PTSD. Furthermore, mTBIs are heterogeneous and not easily observed using conventional neuroimaging tools, despite the fact that diffuse axonal injuries are the most common injury. Diffusion tensor imaging (DTI) is sensitive to diffuse axonal injuries and is thus more likely to detect mTBIs, especially when analyses account for the inter-individual variability of these injuries. Using a subject-specific approach, we compared fractional anisotropy (FA) abnormalities between groups with a history of mTBI (n = 35), comorbid mTBI and PTSD (mTBI + PTSD; n = 22), and healthy controls (n = 37). We compared all three groups on the number of abnormal FA clusters derived from subject-specific injury profiles (i.e., individual z-score maps) along a common white matter skeleton. The mTBI + PTSD group evinced a greater number of abnormally low FA clusters relative to both the healthy controls and the mTBI group without PTSD (p < .05). Across the groups with a history of mTBI, increased numbers of abnormally low FA clusters were significantly associated with PTSD symptom severity, depression, post-concussion symptoms, and reduced information processing speed (p < .05). These findings highlight the utility of subject-specific microstructural analyses when searching for mTBI-related brain abnormalities, particularly in patients with PTSD. This study also suggests that patients with a history of mTBI and comorbid PTSD, relative to those without PTSD, are at increased risk of FA abnormalities.
Project description:Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are common among recent military veterans and involve substantial symptom overlap, making clinical distinction and effective intervention difficult. Emerging evidence of cerebral white matter abnormalities associated with mTBI may provide a biological measure to inform diagnosis and treatment, but the potentially confounding effects between PTSD and mTBI have largely gone unexamined. We collected diffusion imaging data from 133 recently-deployed American service members who developed PTSD and/or sustained mTBI, or had neither condition. Effects of PTSD and mTBI on traditional tensor-based measures of cerebral white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD]) were compared in anatomical regions of interest and individual voxels throughout the brain. Generalized FA (GFA), which allows for multiple fiber orientations per voxel, was also included to improve sensitivity in white matter areas containing crossing or diverging axon bundles. PTSD was consistently associated with high GFA in select brain regions, greater likelihood of regions and voxels with abnormally low MD, and a greater number of voxels with abnormally high FA, while mTBI was associated with fewer high MD regions. Overall, PTSD was associated with more restricted diffusion (low MD) and greater anisotropy (high GFA) in regions of crossing/diverging fibers poorly characterized by a single tensor (FA), suggesting that interstitial fibers may be involved. Contrary to earlier results in a sample without PTSD, mTBI was not associated with anisotropy abnormalities, perhaps indicating the cooccurrence of PTSD and mTBI requires special consideration with regard to structural brain connectivity.
Project description:Only a handful of studies have investigated the nature, functional significance, and course of white matter abnormalities associated with mild traumatic brain injury (mTBI) during the semi-acute stage of injury. The present study used diffusion tensor imaging (DTI) to investigate white matter integrity and compared the accuracy of traditional anatomic scans, neuropsychological testing, and DTI for objectively classifying mTBI patients from controls.Twenty-two patients with semi-acute mTBI (mean = 12 days postinjury), 21 matched healthy controls, and a larger sample (n = 32) of healthy controls were studied with an extensive imaging and clinical battery. A subset of participants was examined longitudinally 3-5 months after their initial visit.mTBI patients did not differ from controls on clinical imaging scans or neuropsychological performance, although effect sizes were consistent with literature values. In contrast, mTBI patients demonstrated significantly greater fractional anisotropy as a result of reduced radial diffusivity in the corpus callosum and several left hemisphere tracts. DTI measures were more accurate than traditional clinical measures in classifying patients from controls. Longitudinal data provided preliminary evidence of partial normalization of DTI values in several white matter tracts.Current findings of white matter abnormalities suggest that cytotoxic edema may be present during the semi-acute phase of mild traumatic brain injury (mTBI). Initial mechanical damage to axons disrupts ionic homeostasis and the ratio of intracellular and extracellular water, primarily affecting diffusion perpendicular to axons. Diffusion tensor imaging measurement may have utility for objectively classifying mTBI, and may serve as a potential biomarker of recovery.
Project description:<h4>Background</h4>Mild traumatic brain injury (mTBI) is a common injury among military personnel serving in Iraq or Afghanistan. The impact of repeated episodes of combat mTBI is unknown.<h4>Objective</h4>To evaluate relationships among mTBI, post-traumatic stress disorder (PTSD) and neurological deficits (NDs) in US veterans who served in Iraq or Afghanistan.<h4>Methods</h4>This was a case-control study. From 2091 veterans screened for traumatic brain injury, the authors studied 126 who sustained mTBI with one or more episodes of loss of consciousness (LOC) in combat. Comparison groups: 21 combat veterans who had definite or possible episodes of mTBI without LOC and 21 veterans who sustained mTBI with LOC as civilians.<h4>Results</h4>Among combat veterans with mTBI, 52% had NDs, 66% had PTSD and 50% had PTSD and an ND. Impaired olfaction was the most common ND, found in 65 veterans. The prevalence of an ND or PTSD correlated with the number of mTBI exposures with LOC. The prevalence of an ND or PTSD was >90% for more than five episodes of LOC. Severity of PTSD and impairment of olfaction increased with number of LOC episodes. The prevalence of an ND for the 34 combat veterans with one episode of LOC (4/34=11.8%) was similar to that of the 21 veterans of similar age and educational background who sustained civilian mTBI with one episode of LOC (2/21=9.5%, p-NS).<h4>Conclusions</h4>Impaired olfaction was the most frequently recognised ND. Repeated episodes of combat mTBI were associated with increased likelihood of PTSD and an ND. Combat setting may not increase the likelihood of an ND. Two possible connections between mTBI and PTSD are (1) that circumstances leading to combat mTBI likely involve severe psychological trauma and (2) that altered cerebral functioning following mTBI may increase the likelihood that a traumatic event results in PTSD.
Project description:A history of mild traumatic brain injury (mTBI), particularly repeated mTBI (rmTBI), has been identified as a risk factor for late-onset neurodegenerative conditions. The mild and transient nature of early symptoms often impedes diagnosis in young adults who are disproportionately affected by mTBIs. A proportion of the affected population will incur long-term behavioral and cognitive consequences but the underlying pathomechanism is currently unknown. Diffusion tensor imaging (DTI) provides sensitive and quantitative assessment of TBI-induced structural changes, including white matter injury, and may be used to predict long-term outcome. We used DTI in an animal model of blast rmTBI (rmbTBI) to quantify blast-induced structural changes at 7 and 90?days post-injury, and their evolution between the two time points. Young adult male rats (~P65 at injury) were exposed to repeated mild blast overpressure, or anesthetized as shams, and their fixed brains were imaged using high-field (7?T) MRI. We found that whole brain volumes similarly increased in injured and sham rats from 7 to 90?days. However, we detected localized volume increases in blast-exposed animals 7?days post-injury, mainly ipsilateral to incident blast waves. Affected regions included gray matter of the frontal association, cingulate, and motor cortex, thalamus, substantia nigra, and raphe nuclei (median and dorsal), as well as white matter of the internal capsule and cerebral peduncle. Conversely, we measured volume reductions in these and other regions, including the hippocampus and cerebellum, at 90?days post-injury. DTI also detected both transient and persistent microstructural changes following injury, with some changes showing distinct ipsilateral versus contralateral side differences relative to blast impact. Early changes in fractional anisotropy (FA) were subtle, becoming more prominent at 90?days in the cerebral and inferior cerebellar peduncles, and cerebellar white matter. Widespread increases in radial diffusivity (RD) and axial diffusivity (primary eigenvalue or E1) at 7?days post-injury largely subsided by 90?days, although RD was more sensitive than E1 at detecting white matter changes. E1 effects in gray and white matter, which paralleled increases in apparent diffusion, were likely more indicative of dysregulated water homeostasis than pathologic structural changes. Importantly, we found evidence for a different developmental trajectory following rmbTBI, as indicated by significant injury x age interactions on volume. Our findings demonstrate that rmbTBI initiates dynamic pathobiological processes that may negatively alter the course of late-stage neurodevelopment and adversely affect long-term cognitive and behavioral outcomes.
Project description:We report on the results of a multimodal imaging study involving behavioral assessments, evoked and resting-state BOLD fMRI, and DTI in chronic mTBI subjects. We found that larger task-evoked BOLD activity in the MT+/LO region in extra-striate visual cortex correlated with mTBI and PTSD symptoms, especially light sensitivity. Moreover, higher FA values near the left optic radiation (OR) were associated with both light sensitivity and higher BOLD activity in the MT+/LO region. The MT+/LO region was localized as a region of abnormal functional connectivity with central white matter regions previously found to have abnormal physiological signals during visual eye movement tracking (Astafiev et al., 2015). We conclude that mTBI symptoms and light sensitivity may be related to excessive responsiveness of visual cortex to sensory stimuli. This abnormal sensitivity may be related to chronic remodeling of white matter visual pathways acutely injured.
Project description:Mild traumatic brain injury (mTBI) is an increasing public health concern as repetitive injuries can exacerbate existing neuropathology and result in increased neurologic deficits. In contrast to other models of repeated mTBI (rmTBI), our study focused on long-term white-matter abnormalities after bilateral mTBIs induced 7 days apart. A controlled cortical impact (CCI) was used to induce an initial mTBI to the right cortex of Single and rmTBI Sprague Dawley rats, followed by a second injury to the left cortex of rmTBI animals. Shams received only a craniectomy. Ex vivo diffusion tensor imaging (DTI), transmission electron microscopy (TEM), and histology were performed on the anterior corpus callosum at 60 days after injury. The rmTBI animals showed a significant bilateral increase in radial diffusivity (myelin), while only modest changes in axial diffusivity (axonal) were seen between the groups. Further, the rmTBI group showed an increased g-ratio and axon caliber in addition to myelin sheath abnormalities using TEM. Our DTI results indicate ongoing myelin changes, while the TEM data show continuing axonal changes at 60 days after rmTBI. These data suggest that bilateral rmTBI induced 7 days apart leads to progressive alterations in white matter that are not observed after a single mTBI.