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Veterans who deployed in support of Operation Enduring Freedom (OEF), Iraqi Freedom (OIF), and New Dawn (OND) commonly experience severe psychological trauma, often accompanied by physical brain trauma resulting in mild traumatic brain injury (mTBI). Prior studies of individuals with posttraumatic stress disorder (PTSD) have revealed alterations in brain structure, accelerated cellular aging, and impacts on cognition following exposure to severe psychological trauma and potential interactive effects of military-related mTBI. To date, however, little is known how such deployment-related trauma changes with time and age of injury of the affected veteran. In this study, we explored changes in cortical thickness, volume, and surface area after an average interval of approximately 2 years in a cohort of 254 OEF/OIF/OND Veterans ranging in age from 19 to 67 years. Whole-brain vertex-wise analyses revealed that veterans who met criteria for severe PTSD (Clinician-Administered PTSD Scale ≥60) at baseline showed greater negative longitudinal changes in cortical thickness, volume, and area over time. Analyses also revealed a significant severe-PTSD by age interaction on cortical measures with severe-PTSD individuals exhibiting accelerated cortical degeneration with increasing age. Interaction effects of comorbid military-related mTBI within the severe-PTSD group were also observed in several cortical regions. These results suggest that those exhibiting severe PTSD symptomatology have accelerated atrophy that is exacerbated with increasing age and history of mTBI., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Human Brain Mapping published by Wiley Periodicals LLC.)

Mounting evidence indicates that serum cholesterol and other risk factors for cardiovascular disease intensify normative trajectories of age-related cognitive decline. However, the neural mechanisms by which this occurs remain largely unknown. To understand the impact of cholesterol on brain networks, we applied graph theory to resting-state fMRI in a large sample of early- to mid-life Veterans (N = 206, Mean age  = 32). A network emerged (centered on the banks of the superior temporal sulcus) that evidenced age-related decoupling (i.e., decreased network connectivity with age), but only in participants with clinically-elevated total cholesterol (≥180 mg/dL). Crucially, decoupling in this network corresponded to greater day-to-day disability and mediated age-related declines in psychomotor speed. Finally, examination of network organization revealed a pattern of age-related dedifferentiation for the banks of the superior temporal sulcus, again present only with higher cholesterol. More specifically, age was related to decreasing within-module communication (indexed by Within-Module Degree Z-Score) and increasing between-module communication (indexed by Participation Coefficient), but only in participants with clinically-elevated cholesterol. Follow-up analyses indicated that all findings were driven by low-density lipoprotein (LDL) levels, rather than high-density lipoprotein (HDL) or triglycerides, which is interesting as LDL levels have been linked to increased risk for cardiovascular disease, whereas HDL levels appear inversely related to such disease. These findings provide novel insight into the deleterious effects of cholesterol on brain health and suggest that cholesterol accelerates the impact of age on neural trajectories by disrupting connectivity in circuits implicated in integrative processes and behavioral control. Hum Brain Mapp 38:3249-3261, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Deficits in impulse control are increasingly recognized in association with posttraumatic stress disorder (PTSD). To our further understanding of the neurobiology of PTSD-related disinhibition, we examined alterations in brain morphology and network connectivity associated with response inhibition failures and PTSD severity. The sample consisted of 189 trauma-exposed Operation Enduring Freedom/Operation Iraqi Freedom veterans (89% male, ages 19-62) presenting with a range of current PTSD severity. Disinhibition was measured using commission errors on a Go/No-Go (GNG) task with emotional stimuli, and PTSD was assessed using a measure of current symptom severity. Whole-brain vertex-wise analyses of cortical thickness revealed two clusters associated with PTSD-related disinhibition (Monte Carlo cluster corrected P < 0.05). The first cluster included portions of right inferior and middle frontal gyri and frontal pole. The second cluster spanned portions of left medial orbital frontal, rostral anterior cingulate, and superior frontal gyrus. In both clusters, commission errors were associated with reduced cortical thickness at higher (but not lower) levels of PTSD symptoms. Resting-state functional magnetic resonance imaging analyses revealed alterations in the functional connectivity of the right frontal cluster. Together, study findings suggest that reductions in cortical thickness in regions involved in flexible decision-making, emotion regulation, and response inhibition contribute to impulse control deficits in PTSD. Furthermore, aberrant coupling between frontal regions and networks involved in selective attention, memory/learning, and response preparation suggest disruptions in functional connectivity may also play a role., (© 2015 Wiley Periodicals, Inc.)

Although there is emerging data on the effects of blast-related concussion (or mTBI) on cognition, the effects of blast exposure itself on the brain have only recently been explored. Toward this end, we examine functional connectivity to the posterior cingulate cortex, a primary region within the default mode network (DMN), in a cohort of 134 Iraq and Afghanistan Veterans characterized for a range of common military-associated comorbidities. Exposure to a blast at close range (<10 meters) was associated with decreased connectivity of bilateral primary somatosensory and motor cortices, and these changes were not different from those seen in participants with blast-related mTBI. These results remained significant when clinical factors such as sleep quality, chronic pain, or post traumatic stress disorder were included in the statistical model. In contrast, differences in functional connectivity based on concussion history and blast exposures at greater distances were not apparent. Despite the limitations of a study of this nature (e.g., assessments long removed from injury, self-reported blast history), these data demonstrate that blast exposure per se, which is prevalent among those who served in Iraq and Afghanistan, may be an important consideration in Veterans' health. It further offers a clinical guideline for determining which blasts (namely, those within 10 meters) are likely to lead to long-term health concerns and may be more accurate than using concussion symptoms alone., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

White matter lesions, typically manifesting as regions of signal intensity abnormality (WMSA) on MRI, increase in frequency with age. However, the role of this damage in cognitive decline and disease is still not clear, as lesion volume has only loosely been associated with clinical status. Diffusion tensor imaging (DTI) has been used to examine the quantitative microstructural integrity of white matter, and has applications in the examination of subtle changes to tissue that appear visually normal on conventional imaging. The primary goal of this study was to determine whether major macrostructural white matter damage, (total WMSA volume), is associated with microstructural integrity of normal appearing white matter, and if these macrostructural changes fully account for microstructural changes. Imaging was performed in 126 nondemented individuals, ages 43-85 years, with no history of cerebrovascular disease. Controlling for age, greater WMSA volume was associated with decreased fractional anisotropy (FA) in widespread brain regions. Patterns were similar for FA and radial diffusivity but in contrast, WMSA was associated with axial diffusivity in fewer areas. Age was associated with FA in several regions, and many of these effects remained even when controlling for WMSA volume, suggesting the etiology of WMSAs does not fully account for all age-associated white matter deterioration. These results provide evidence that WMSA volume is associated with the integrity of normal-appearing white matter. In addition, our results suggest that overt lesions may not account for the association of increasing age with decreased white matter tissue integrity., (Copyright © 2013 Wiley Periodicals, Inc.)

Prior research has demonstrated links among vascular health and the occurrence of stroke, mild cognitive decline, and dementia in older adults. However, little is known about whether normal variation in vascular indicators may be related to changes in neural tissue integrity. Even less is known about how the brain is affected by cholesterol levels in the normal to moderate risk range, leading up to overt disease pathology. This study examined associations between serum lipid levels and DTI indicators of white matter (WM) structural integrity in a sample of 125 generally healthy older adults aged 43-87 years. Whole-brain voxelwise analysis, controlling for age and gender, revealed low density lipoprotein levels (LDL) as the most robust correlate of regional WM structural integrity of the measured lipids. Higher LDL was associated with decreased WM integrity in right frontal and temporal regions, the superior longitudinal fasciculus and internal/external capsules. Increasing LDL was associated with increased radial and axial diffusivity; however, more widespread statistical effects were found for radial diffusivity. These findings suggest that normal interindividual variation in lipid levels is associated with compromised regional WM integrity, even in individuals below clinical thresholds for hyperlipidemia. Given the prevalence of cholesterol-associated sequelae in older adults, and mounting evidence suggesting a vascular role in the etiology of dementia, the current data suggest that understanding the relationship between cholesterol and brain tissue microstructure may have important clinical implications for early detection of vascular-related cognitive disorders and optimal regulation of serum lipids to maintain neural health in older adults., (Copyright © 2012 Wiley Periodicals, Inc.)

Cerebral white matter damage is not only a commonly reported consequence of healthy aging, but is also associated with cognitive decline and dementia. The aetiology of this damage is unclear; however, individuals with hypertension have a greater burden of white matter signal abnormalities (WMSA) on MR imaging than those without hypertension. It is therefore possible that elevated blood pressure (BP) impacts white matter tissue structure which in turn has a negative impact on cognition. However, little information exists about whether vascular health indexed by BP mediates the relationship between cognition and white matter tissue structure. We used diffusion tensor imaging to examine the impact of vascular health on regional associations between white matter integrity and cognition in healthy older adults spanning the normotensive to moderate-severe hypertensive BP range (43-87 years; N = 128). We examined how white matter structure was associated with performance on tests of two cognitive domains, executive functioning (EF) and processing speed (PS), and how patterns of regional associations were modified by BP and WMSA. Multiple linear regression and structural equation models demonstrated associations between tissue structure, EF and PS in frontal, temporal, parietal, and occipital white matter regions. Radial diffusivity was more prominently associated with performance than axial diffusivity. BP only minimally influenced the relationship between white matter integrity, EF and PS. However, WMSA volume had a major impact on neurocognitive associations. This suggests that, although BP and WMSA are causally related, these differential metrics of vascular health may act via independent pathways to influence brain structure, EF and PS., (Copyright © 2011 Wiley Periodicals, Inc.)