Publications

2017
Hayes, J. P., Logue, M. W., Sadeh, N., Spielberg, J. M., Verfaellie, M., Hayes, S. M., Reagan, A., et al. (2017). Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer's disease. Brain , 140, 813-825.Abstract
Moderate-to-severe traumatic brain injury is one of the strongest environmental risk factors for the development of neurodegenerative diseases such as late-onset Alzheimer's disease, although it is unclear whether mild traumatic brain injury, or concussion, also confers risk. This study examined mild traumatic brain injury and genetic risk as predictors of reduced cortical thickness in brain regions previously associated with early Alzheimer's disease, and their relationship with episodic memory. Participants were 160 Iraq and Afghanistan War veterans between the ages of 19 and 58, many of whom carried mild traumatic brain injury and post-traumatic stress disorder diagnoses. Whole-genome polygenic risk scores for the development of Alzheimer's disease were calculated using summary statistics from the largest Alzheimer's disease genome-wide association study to date. Results showed that mild traumatic brain injury moderated the relationship between genetic risk for Alzheimer's disease and cortical thickness, such that individuals with mild traumatic brain injury and high genetic risk showed reduced cortical thickness in Alzheimer's disease-vulnerable regions. Among males with mild traumatic brain injury, high genetic risk for Alzheimer's disease was associated with cortical thinning as a function of time since injury. A moderated mediation analysis showed that mild traumatic brain injury and high genetic risk indirectly influenced episodic memory performance through cortical thickness, suggesting that cortical thinning in Alzheimer's disease-vulnerable brain regions is a mechanism for reduced memory performance. Finally, analyses that examined the apolipoprotein E4 allele, post-traumatic stress disorder, and genetic risk for schizophrenia and depression confirmed the specificity of the Alzheimer's disease polygenic risk finding. These results provide evidence that mild traumatic brain injury is associated with greater neurodegeneration and reduced memory performance in individuals at genetic risk for Alzheimer's disease, with the caveat that the order of causal effects cannot be inferred from cross-sectional studies. These results underscore the importance of documenting head injuries even within the mild range as they may interact with genetic risk to produce negative long-term health consequences such as neurodegenerative disease.
Salat, D. H., Robinson, M. E., Miller, D. R., Clark, D. C., & McGlinchey, R. E. (2017). Neuroimaging of deployment-associated traumatic brain injury (TBI) with a focus on mild TBI (mTBI) since 2009. Brain Inj , 31, 1204-1219.Abstract
OBJECTIVES: A substantial body of recent research has aimed to better understand the clinical sequelae of military trauma through the application of advanced brain imaging procedures in Veteran populations. The primary objective of this review was to highlight a portion of these recent studies to demonstrate how imaging tools can be used to understand military-associated brain injury. METHODS: We focus here on the phenomenon of mild traumatic brain injury (mTBI) given its high prevalence in the Veteran population and current recognition of the need to better understand the clinical implications of this trauma. This is intended to provide readers with an initial exposure to the field of neuroimaging of mTBI with a brief introduction to the concept of traumatic brain injury, followed by a summary of the major imaging techniques that have been applied to the study of mTBI. RESULTS: Taken together, the collection of studies reviewed demonstrates a clear role for neuroimaging towards understanding the various neural consequences of mTBI as well as the clinical complications of such brain changes. CONCLUSIONS: This information must be considered in the larger context of research into mTBI, including the potentially unique nature of blast exposure and the long-term consequences of mTBI.
Miller, D. R., Logue, M. W., Wolf, E. J., Maniates, H., Robinson, M. E., Hayes, J. P., Stone, A., et al. (2017). Posttraumatic stress disorder symptom severity is associated with reduced default mode network connectivity in individuals with elevated genetic risk for psychopathology. Depress Anxiety , 34, 632-640.Abstract
BACKGROUND: Accumulating evidence suggests that posttraumatic stress disorder (PTSD) is associated with disrupted default mode network (DMN) connectivity, but findings across studies have not been uniform. Individual differences in relevant genes may account for some of the reported variability in the relationship between DMN connectivity and PTSD. In this study, we investigated this possibility using genome-wide association study (GWAS) derived polygenic risk scores (PRSs) for relevant psychiatric traits. We hypothesized that the association between PTSD and DMN connectivity would be moderated by genetic risk for one or more psychiatric traits such that individuals with elevated polygenic risk for psychopathology and severe PTSD would exhibit disrupted DMN connectivity. METHODS: Participants were 156 white, non-Hispanic veterans of the wars in Iraq and Afghanistan who were genotyped and underwent resting state functional magnetic resonance imaging and clinical assessment. PRSs for neuroticism, anxiety, major depressive disorder, and cross-disorder risk (based on five psychiatric disorders) were calculated using summary statistics from published large-scale consortia-based GWASs. RESULTS: Cross-disorder polygenic risk influenced the relationship between DMN connectivity and PTSD symptom severity such that individuals at greater genetic risk showed a significant negative association between PTSD symptom severity and connectivity between the posterior cingulate cortex and right middle temporal gyrus. Polygenic risk for neuroticism, anxiety, and major depressive disorder did not influence DMN connectivity directly or through an interaction with PTSD. CONCLUSIONS: Findings illustrate the potential power of genome-wide PRSs to advance understanding of the relationship between PTSD and DMN connectivity, a putative neural endophenotype of the disorder.
Jackson, C. E., Nordstrom, L., Fonda, J. R., Fortier, C. B., Milberg, W. P., & McGlinchey, R. E. (2017). Reporting of symptoms associated with concussion by OEF/OIF/OND Veterans: Comparison between research and clinical contexts. Brain Injury , 31, 485-492 . Taylor & Francis.Abstract
ABSTRACTObjective: Veterans from recent military conflicts frequently report persisting symptoms associated with concussion well beyond the expected period of recovery following mild traumatic brain injury. This study examined differences in the reporting of symptoms associated with concussion between clinical and research contexts. Methods: This naturalistic comparison included 91 Veterans from Operations Enduring Freedom (OEF), Iraqi Freedom (OIF) and New Dawn (OND). All participants were enrolled in a longitudinal study focused on traumatic brain injury and stress-related disorders and had also completed a VHA Comprehensive TBI Evaluation. Individuals completed the Neurobehavioral Symptom Inventory (NSI) during their research and clinical evaluations; additional measures of performance and symptom validity were also available for a subset of participants. Results: NSI mean total and subscale scores were significantly higher when assessed in the clinical compared to the research setting, irrespective of the order and duration of time between evaluations. Rates of over-reporting on the NSI and performance validity test failure were also higher during the clinical evaluation. Conclusion: Clinicians and researchers must appreciate the possible effects of context on the reporting of symptoms commonly associated with concussion. Future research identifying and mitigating factors influencing the effect of context on symptom reporting is needed.
LaMotte, A. D., Taft, C. T., Weatherill, R. P., Casement, M. D., Creech, S. K., Milberg, W. P., Fortier, C. B., et al. (2017). Sleep problems and physical pain as moderators of the relationship between PTSD symptoms and aggression in returning veterans. Psychol Trauma , 9 113-116.Abstract
OBJECTIVE: This study investigated sleep problems and physical pain as moderators of the relationship between PTSD symptoms and aggression among returning veterans. Prior research has demonstrated associations between PTSD symptoms and aggression, but little work has sought to identify moderators of this relationship. Sleep problems and physical pain are both common clinical problems among veterans and have theoretical links to aggression. METHOD: Participants were 103 returning service members and veterans recruited from the greater Boston area and enrolled in the VA Translational Research Center for Traumatic Brain Injury (TBI) and Stress Disorders (TRACTS). Aggression outcomes included physical and psychological intimate partner aggression (IPA), as well as physical and psychological general aggression (GA). Variables were measured via self-report questionnaires, with the exception of PTSD symptoms, which were assessed via clinician interview. RESULTS: Bivariate correlations revealed significant associations between PTSD symptoms, sleep problems, physical pain, and aggression outcomes. Both sleep problems and physical pain significantly moderated the relationship between PTSD symptoms and physical GA, such that this relationship became stronger at higher levels of these moderator variables. However, moderation was not found for the other aggression outcomes. CONCLUSIONS: Findings suggest that sleep problems and physical pain strengthen the relationship between veterans' PTSD symptoms and physical aggression toward others. Although further replication and elucidation is needed, these factors may disinhibit aggression among those at higher risk due to their PTSD symptoms. (PsycINFO Database Record
2016
Miller, M. W., Sperbeck, E., Robinson, M. E., Sadeh, N., Wolf, E. J., Hayes, J. P., Logue, M., et al. (2016). 5-HT2A Gene Variants Moderate the Association between PTSD and Reduced Default Mode Network Connectivity. Frontiers in Neuroscience , 10.Abstract
The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study (STAR*D; McMahon et al., 2006), interacted with PTSD to predict reduced connectivity between the posterior cingulate cortex (PCC) and the right medial prefrontal cortex and right middle temporal gyrus (MTG). rs130058 (HTR1B) was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP × PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT2A receptors in the neurobiology of PTSD.
Wolf, E. J., Logue, M. W., Hayes, J. P., Sadeh, N., Schichman, S. A., Stone, A., Salat, D. H., et al. (2016). Accelerated DNA methylation age: Associations with PTSD and neural integrity. Psychoneuroendocrinology , 63, 155-62.Abstract
BACKGROUND: Accumulating evidence suggests that posttraumatic stress disorder (PTSD) may accelerate cellular aging and lead to premature morbidity and neurocognitive decline. METHODS: This study evaluated associations between PTSD and DNA methylation (DNAm) age using recently developed algorithms of cellular age by Horvath (2013) and Hannum et al. (2013). These estimates reflect accelerated aging when they exceed chronological age. We also examined if accelerated cellular age manifested in degraded neural integrity, indexed via diffusion tensor imaging. RESULTS: Among 281 male and female veterans of the conflicts in Iraq and Afghanistan, DNAm age was strongly related to chronological age (rs ∼.88). Lifetime PTSD severity was associated with Hannum DNAm age estimates residualized for chronological age (β=.13, p=.032). Advanced DNAm age was associated with reduced integrity in the genu of the corpus callosum (β=-.17, p=.009) and indirectly linked to poorer working memory performance via this region (indirect β=-.05, p=.029). Horvath DNAm age estimates were not associated with PTSD or neural integrity. CONCLUSIONS: Results provide novel support for PTSD-related accelerated aging in DNAm and extend the evidence base of known DNAm age correlates to the domains of neural integrity and cognition.
Corbo, V., Salat, D. H., Powell, M. A., Milberg, W. P., & McGlinchey, R. E. (2016). Combat exposure is associated with cortical thickness in Veterans with a history of chronic pain. Psychiatry Res Neuroimaging , 249, 38-44.Abstract
Chronic Pain (CP) has been associated with changes in gray matter integrity in the cingulate and insular cortex. However, these changes have not been studied in Veterans, despite high prevalence rates of CP and interactions with combat-derived disorders. In the current study, 54 Veterans with a history of CP and 103 Veterans without CP were recruited from the Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS). Cortical thickness from structural MRI scans was determined using the FreeSurfer software package. Results showed that Veterans with CP showed a negative association between cortical thickness and levels of combat exposure in the left inferior frontal gyrus and superior parietal cortex, as well as the right rostral middle frontal gyrus, precentral and postcentral gyri and the superior temporal cortex. These findings suggest that CP may alter the relationship between cortical thickness and exposure to the stress of combat.
Corbo, V., Amick, M. A., Milberg, W. P., McGlinchey, R. E., & Salat, D. H. (2016). Early life trauma is associated with altered white matter integrity and affective control. J Psychiatr Res , 79, 70-77.Abstract
Early life trauma (ELT) has been shown to impair affective control and attention well into adulthood. Neuroimaging studies have further shown that ELT was associated with decreased white matter integrity in the prefrontal areas in children and adults. However, no study to date has looked at the relationship between white matter integrity and affective control in individuals with and without a history of ELT. To examine this, we tested 240 Veterans with (ELT N = 80) and without (NoELT N = 160) a history of childhood sexual abuse, physical abuse or family violence. Affective control was measured with the Affective Go/No-Go (AGN) and attention was indexed with the Test of Variable Attention (TOVA). White matter integrity was measured using fractional anisotropy (FA). Results showed greater number of errors on the AGN in ELT compared to NoELT. There was no difference on the TOVA. While there were no mean differences in FA, there was an interaction between FA and reaction time to positive stimuli on the AGN where the ELT group showed a positive relationship between FA and reaction time in right frontal and prefrontal areas, whereas the NoELT group showed a negative or no association between FA and reaction time. This suggests that ELT may be associated with a distinct brain-behavior relationship that could be related to other determinants of FA than those present in healthy adults.
Leritz, E. C., McGlinchey, R. E., Salat, D. H., & Milberg, W. P. (2016). Elevated levels of serum cholesterol are associated with better performance on tasks of episodic memory. Metab Brain Dis , 31, 465-73.Abstract
We examined how serum cholesterol, an established risk factor for cerebrovascular disease (CVD), relates to cognitive function in healthy middle-older aged individuals with no neurologic or CVD history. A complete lipid panel was obtained from a cohort of one hundred twenty individuals, ages 43-85, who also underwent a comprehensive neuropsychological examination. In order to reduce the number of variables and empirically identify broad cognitive domains, scores from neuropsychological tests were submitted into a factor analysis. This analysis revealed three explainable factors: Memory, Executive Function and Memory/Language. Three separate hierarchical multiple regression analyses were conducted using individual cholesterol metrics (total cholesterol, low density lipoprotein; LDL, high density lipoprotein; HDL, and triglycerides), as well as age, education, medication status (lipid lowering agents), ApoE status, and additional risk factors for CVD to predict neuropsychological function. The Memory Factor was predicted by a combination of age, LDL, and triglyceride levels; both age and triglycerides were negatively associated with factor score, while LDL levels revealed a positive relationship. Both the Executive and Memory/Language factor were only explained by education, whereby more years were associated with better performance. These results provide evidence that individual cholesterol lipoproteins and triglycerides may differentially impact cognitive function, over and above other common CVD risk factors and ApoE status. Our findings demonstrate the importance of consideration of vascular risk factors, such as cholesterol, in studies of cognitive aging.
Stojanovic, M. P., Fonda, J., Fortier, C. B., Higgins, D. M., Rudolph, J. L., Milberg, W. P., & McGlinchey, R. E. (2016). Influence of Mild Traumatic Brain Injury (TBI) and Posttraumatic Stress Disorder (PTSD) on Pain Intensity Levels in OEF/OIF/OND Veterans. Pain Med , 17, 2017-2025.Abstract
OBJECTIVE: Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are common among US veterans of Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND). We postulated that these injuries may modulate pain processing in these individuals and affect their subjective pain levels. DESIGN: Cross-sectional. SUBJECTS: 310 deployed service members of OEF/OIF/OND without a lifetime history of moderate or severe TBI were included in this study. METHODS: All participants completed a comprehensive evaluation for Blast Exposure, mTBI, PTSD, and Pain Levels. The Boston Assessment of TBI-Lifetime Version (BAT-L) was used to assess blast exposure and potential brain injury during military service. The Clinician-Administered PTSD Scale (CAPS) characterized presence and severity of PTSD. The Visual Analog Scale (VAS) was used to assess pain intensity over the previous month before the interview, with higher scores indicative of worse pain. Statistical analysis was performed by ANOVA and results were adjusted for co-morbidities, clinical characteristics and demographic data. RESULTS: In comparison to control participants (veterans without mTBI or current PTSD), veterans with both current PTSD and mTBI reported the highest pain intensity levels, followed by veterans with PTSD only (P < 0.0001 and P = 0.0005, respectively). Pain levels in veterans with mTBI only were comparable to control participants. CONCLUSIONS: Comorbid PTSD and mTBI is associated with increased self-reported pain intensity. mTBI alone was not associated with increased pain.
Stricker, N. H., Salat, D. H., Kuhn, T. P., Foley, J. M., Price, J. S., Westlye, L. T., Esterman, M. S., et al. (2016). Mild Cognitive Impairment is Associated With White Matter Integrity Changes in Late-Myelinating Regions Within the Corpus Callosum. Am J Alzheimers Dis Other Demen , 31, 68-75.Abstract
Degenerative brain changes in Alzheimer's disease may occur in reverse order of normal brain development based on the retrogenesis model. This study tested whether evidence of reverse myelination was observed in mild cognitive impairment (MCI) using a data-driven analytic approach based on life span developmental data. Whole-brain high-resolution diffusion tensor imaging scans were obtained for 31 patients with MCI and 79 demographically matched healthy older adults. Comparisons across corpus callosum (CC) regions of interest (ROIs) showed decreased fractional anisotropy (FA) in the body but not in the genu or splenium; early-, middle-, and late-myelinating ROIs restricted to the CC revealed decreased FA in late- but not early- or middle-myelinating ROIs. Voxelwise group differences revealed areas of lower FA in MCI, but whole-brain differences were equally distributed across early-, middle-, and late-myelinating regions. Overall, results within the CC support the retrogenesis model, although caution is needed when generalizing these results beyond the CC.
Sadeh, N., Wolf, E. J., Logue, M. W., Lusk, J., Hayes, J. P., McGlinchey, R. E., Milberg, W. P., et al. (2016). Polygenic Risk for Externalizing Psychopathology and Executive Dysfunction in Trauma-Exposed Veterans. Clin Psychol Sci , 4 545-558.Abstract
The frequent co-occurrence of antisocial behavior and other disinhibited phenotypes reflects a highly heritable externalizing spectrum. We examined the molecular genetic basis of this spectrum by testing polygenic associations with psychopathology symptoms, impulsive traits, and cognitive functions in two samples of primarily military veterans (n =537, n =194). We also investigated whether polygenic risk for externalizing moderated the effects of trauma on these phenotypes. As hypothesized, polygenic risk positively predicted externalizing psychopathology and negatively predicted performance on inhibitory control tasks. Gene-by-environment effects were also evident, with trauma exposure predicting greater impulsivity and less working memory capacity, but only at high levels of genetic liability. As expected, polygenic risk was not associated with internalizing psychopathology or episodic memory performance. This is the first independent replication of the polygenic score as a measure of genetic predispositions for externalizing and provides preliminary evidence that executive dysfunction is a heritable vulnerability for externalizing psychopathology.
Wolf, E. J., Sadeh, N., Leritz, E. C., Logue, M. W., Stoop, T. B., McGlinchey, R., Milberg, W., et al. (2016). Posttraumatic Stress Disorder as a Catalyst for the Association Between Metabolic Syndrome and Reduced Cortical Thickness. Biol Psychiatry , 80, 363-71.Abstract
BACKGROUND: Metabolic syndrome (MetS), defined by a constellation of cardiometabolic pathologies, is highly prevalent among veterans, especially veterans with posttraumatic stress disorder (PTSD), and poses a major risk for adverse health outcomes, including neurodegeneration and mortality. Given this, we evaluated 1) the association between MetS and neural integrity, indexed by cortical thickness; 2) the relationship between PTSD and MetS; and 3) whether PTSD was associated with cortical thickness indirectly through MetS. METHODS: The sample consisted of 346 U.S. military veterans (89.3% male; 71.4% white) who deployed to Iraq, Afghanistan, or both. Neuroimaging data were available for 274 participants. RESULTS: In whole-brain analyses, MetS was negatively associated with cortical thickness in two left and four right hemisphere regions, as follows: bilateral temporal lobe, including temporal pole, fusiform gyrus, and insula, and extending into occipital cortex (left hemisphere) and orbitofrontal cortex (right hemisphere); bilateral precuneus, posterior cingulate, calcarine, and occipital-parietal cortex; and right rostral anterior cingulate cortex and central sulcus/postcentral gyrus. Path models showed that PTSD predicted MetS (β = .19, p < .001), which was associated with reduced cortical thickness (β = -.29 to -.43, all p < .001). CONCLUSIONS: Results from this young veteran sample provide evidence that PTSD confers risk for cardiometabolic pathology and neurodegeneration and raise concern that this cohort may be aging prematurely and at risk for substantial medical and cognitive decline. This study highlights the need to identify the molecular mechanisms linking PTSD to MetS and effective interventions to reduce PTSD-related health comorbidities.
Sadeh, N., Spielberg, J. M., Logue, M. W., Wolf, E. J., Smith, A. K., Lusk, J., Hayes, J. P., et al. (2016). SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans. Mol Psychiatry , 21, 357-63.Abstract
Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness and psychiatric phenotypes linked to suicide in trauma-exposed veterans. About 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine-guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD) and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylation(adj)). Specifically, DNA methylation(adj) was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation(adj) and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylation(adj) of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.
2015
Spielberg, J. M., McGlinchey, R. E., Milberg, W. P., & Salat, D. H. (2015). Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans. Biol Psychiatry , 78, 210-6.Abstract
BACKGROUND: Understanding the neural causes and consequences of posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) is a high research priority, given the high rates of associated disability and suicide. Despite remarkable progress in elucidating the brain mechanisms of PTSD and mTBI, a comprehensive understanding of these conditions at the level of brain networks has yet to be achieved. The present study sought to identify functional brain networks and topological properties (measures of network organization and function) related to current PTSD severity and mTBI. METHODS: Graph theoretic tools were used to analyze resting-state functional magnetic resonance imaging data from 208 veterans of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn, all of whom had experienced a traumatic event qualifying for PTSD criterion A. Analyses identified brain networks and topological network properties linked to current PTSD symptom severity, mTBI, and the interaction between PTSD and mTBI. RESULTS: Two brain networks were identified in which weaker connectivity was linked to higher PTSD re-experiencing symptoms, one of which was present only in veterans with comorbid mTBI. Re-experiencing was also linked to worse functional segregation (necessary for specialized processing) and diminished influence of key regions on the network, including the hippocampus. CONCLUSIONS: Findings of this study demonstrate that PTSD re-experiencing symptoms are linked to weakened connectivity in a network involved in providing contextual information. A similar relationship was found in a separate network typically engaged in the gating of working memory, but only in veterans with mTBI.
Robinson, M. E., Lindemer, E. R., Fonda, J. R., Milberg, W. P., McGlinchey, R. E., & Salat, D. H. (2015). Close-range blast exposure is associated with altered functional connectivity in Veterans independent of concussion symptoms at time of exposure. Hum Brain Mapp , 36, 911-22.Abstract
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.
Fortier, C. B., Amick, M. M., Kenna, A., Milberg, W. P., & McGlinchey, R. E. (2015). Correspondence of the Boston Assessment of Traumatic Brain Injury-Lifetime (BAT-L) clinical interview and the VA TBI screen. J Head Trauma Rehabil , 30, E1-7.Abstract
OBJECTIVE: Mild traumatic brain injury is the signature injury of Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND), yet its identification and diagnosis is controversial and fraught with challenges. SETTING: In 2007, the Department of Veterans Affairs (VA) implemented a policy requiring traumatic brain injury (TBI) screening on all individuals returning from deployment in the OEF/OIF/OND theaters of operation that lead to the rapid and widespread use of the VA TBI screen. The Boston Assessment of TBI-Lifetime (BAT-L) is the first validated, postcombat semistructured clinical interview to characterize head injuries and diagnose TBIs throughout the life span, including prior to, during, and post-military service. PARTICIPANTS: Community-dwelling convenience sample of 179 OEF/OIF/OND veterans. MAIN MEASURES: BAT-L, VA TBI screen. RESULTS: Based on BAT-L diagnosis of military TBI, the VA TBI screen demonstrated similar sensitivity (0.85) and specificity (0.82) when administered by research staff. When BAT-L diagnosis was compared with historical clinician-administered VA TBI screen in a subset of participants, sensitivity was reduced. CONCLUSIONS: The specificity of the research-administered VA TBI screen was more than adequate. The sensitivity of the VA TBI screen, although relatively high, suggests that it does not oversample or "catch all" possible military TBIs. Traumatic brain injuries identified by the BAT-L, but not identified by the VA TBI screen, were predominantly noncombat military injuries. There is potential concern regarding the validity and reliability of the clinician administered VA TBI screen, as we found poor correspondence between it and the BAT-L, as well as low interrater reliability between the clinician-administered and research-administered screen.
Lippa, S. M., Fonda, J. R., Fortier, C. B., Amick, M. A., Kenna, A., Milberg, W. P., & McGlinchey, R. E. (2015). Deployment-related psychiatric and behavioral conditions and their association with functional disability in OEF/OIF/OND veterans. J Trauma Stress , 28, 25-33.Abstract
Understanding the factors that influence veterans' functional outcome after deployment is critical to provide appropriately targeted care. Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) have been related to disability, but other psychiatric and behavioral conditions are not as well examined. We investigated the impact of deployment-related psychiatric and behavioral conditions on disability among 255 OEF/OIF/OND service members and veterans. Structured clinical interviews assessed TBI and the psychiatric conditions of depression, PTSD, anxiety, and substance use. Self-report questionnaires assessed disability and the behavioral conditions of sleep disturbance and pain. Over 90% of participants had a psychiatric and/or behavioral condition, with approximately half presenting with ≥ 3 conditions. Exploratory factor analysis revealed 4 clinically relevant psychiatric and behavioral factors which accounted for 76.9% of the variance: (a) depression, PTSD, and military mTBI (deployment trauma factor); (b) pain and sleep (somatic factor); (c) anxiety disorders, other than PTSD (anxiety factor); and (d) substance abuse or dependence (substance use factor). Individuals with the conditions comprising the deployment trauma factor were more likely to be substantially disabled than individuals with depression and PTSD, but no military mTBI, OR = 3.52; 95% CI [1.09, 11.37]. Depression, PTSD, and a history of military mTBI may comprise an especially harmful combination associated with high risk for substantial disability.
Trotter, B. B., Robinson, M. E., Milberg, W. P., McGlinchey, R. E., & Salat, D. H. (2015). Military blast exposure, ageing and white matter integrity. Brain , 138, 2278-92.Abstract
Mild traumatic brain injury, or concussion, is associated with a range of neural changes including altered white matter structure. There is emerging evidence that blast exposure-one of the most pervasive causes of casualties in the recent overseas conflicts in Iraq and Afghanistan-is accompanied by a range of neurobiological events that may result in pathological changes to brain structure and function that occur independently of overt concussion symptoms. The potential effects of brain injury due to blast exposure are of great concern as a history of mild traumatic brain injury has been identified as a risk factor for age-associated neurodegenerative disease. The present study used diffusion tensor imaging to investigate whether military-associated blast exposure influences the association between age and white matter tissue structure integrity in a large sample of veterans of the recent conflicts (n = 190 blast-exposed; 59 without exposure) between the ages of 19 and 62 years. Tract-based spatial statistics revealed a significant blast exposure × age interaction on diffusion parameters with blast-exposed individuals exhibiting a more rapid cross-sectional age trajectory towards reduced tissue integrity. Both distinct and overlapping voxel clusters demonstrating the interaction were observed among the examined diffusion contrast measures (e.g. fractional anisotropy and radial diffusivity). The regions showing the effect on fractional anisotropy included voxels both within and beyond the boundaries of the regions exhibiting a significant negative association between fractional anisotropy and age in the entire cohort. The regional effect was sensitive to the degree of blast exposure, suggesting a 'dose-response' relationship between the number of blast exposures and white matter integrity. Additionally, there was an age-independent negative association between fractional anisotropy and years since most severe blast exposure in a subset of the blast-exposed group, suggesting a specific influence of time since exposure on tissue structure, and this effect was also independent of post-traumatic stress symptoms. Overall, these data suggest that blast exposure may negatively affect brain-ageing trajectories at the microstructural tissue level. Additional work examining longitudinal changes in brain tissue integrity in individuals exposed to military blast forces will be an important future direction to the initial findings presented here.

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