Publications

OBJECTIVE: This study assessed the strength of military-related concussion-, psychological-, and behavioral-related measures to predict neurobehavioral symptom (NBS) reporting in order to help clarify the extent to which persistent NBS reflect lingering effects of concussion vs other psychological/behavioral factors among veterans. METHODS: Baseline analysis included 351 consecutively enrolled veterans in the Translational Research Center for Traumatic Brain Injury and Stress Disorders longitudinal cohort study. One hundred eighty-six returned for a follow-up evaluation averaging 24 months post baseline. The Neurobehavioral Symptom Inventory (NSI) was used to measure NBS reporting. Predictor variables included diagnosis of military-related mild traumatic brain injury (M-mTBI), psychological measures, including posttraumatic stress disorder, mood, anxiety, and substance abuse disorders, and behavioral measures, including self-reported current pain and sleep impairment. Hierarchical and multivariable regression analyses examined the relationships between the predictor variables and NSI scores. The k-fold cross-validation assessed generalizability and validity of the regressions. RESULTS: Baseline analysis revealed that psychological and behavioral conditions independently accounted for 42.5% of variance in the NSI total score compared to 1.5% for M-mTBI after controlling for psychological and behavioral conditions. Prospective analysis revealed that M-mTBI at baseline did not significantly predict NSI score at follow-up, while psychological and behavioral measures at baseline independently accounted for 24.5% of NSI variance. Posttraumatic stress disorder was the most consistent predictor. Cross-validation analyses supported generalizability of the results. CONCLUSIONS: Psychological and behavioral-related measures are strong predictors of persistent NBS reporting in veterans, while M-mTBI is negligible. NBS more likely reflect influential comorbidities as opposed to brain injury, per se.

OBJECTIVE: To compare the diagnosis of positive versus negative for mild traumatic brain injury (mTBI) using the Boston Assessment of TBI-Lifetime (BAT-L), a validated forensic clinical interview used to identify TBI in research, to the diagnosis of mTBI in the clinical polytrauma service using the Comprehensive TBI Evaluation (CTBIE). PARTICIPANTS: Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn Veterans who were enrolled in the Translational Research Center for TBI and Stress Disorders longitudinal cohort study and received a CTBIE at a Veterans Health Administration healthcare facility (n = 104). MAIN MEASURES: The BAT-L, CTBIE, and Neurobehavioral Symptom Inventory. RESULTS: There was poor correspondence between the BAT-L and CTBIE mTBI diagnoses (κ = 0.283). The CTBIE showed moderate sensitivity but poor specificity relative to the BAT-L. The agreement did not improve after removing individuals who had failed symptom validity measures, as assessed by the Validity-10 scale of the Neurobehavioral Symptom Inventory. CONCLUSIONS: This lack of correspondence highlights the difficulties in diagnosing mTBI in Veterans using retrospective self-report. Future work is needed to establish a reliable and valid method for identifying military mTBI both for the care of our Veterans and for appropriate distribution of benefits.

BACKGROUND: Recent studies have implicated inflammatory processes in the pathophysiology of posttraumatic stress disorder (PTSD). C-reactive protein (CRP) is a widely-used measure of peripheral inflammation, but little is known about the genetic and epigenetic factors that influence blood levels of C-reactive protein (CRP) in individuals with PTSD. METHODS: Participants were 286 U.S. military veterans of post-9/11 conflicts (57% with current PTSD). Analyses focused on single nucleotide polymorphisms (SNPs) in the CRP gene and DNA methylation at cg10636246 in AIM2-a locus recently linked to CRP levels through results from a large-scale epigenome-wide association study. RESULTS: PTSD was positively correlated with serum CRP levels with PTSD cases more likely to have CRP levels in the clinically-elevated range compared to those without a PTSD diagnosis. Multivariate analyses that controlled for white blood cell proportions, genetic principal components, age and sex, showed this association to be mediated by methylation at the AIM2 locus. rs3091244, a functional SNP in the CRP promoter region, moderated the association between lifetime trauma exposure and current PTSD severity. Analyses also revealed that the top SNPs from the largest genome-wide association study of CRP conducted to date (rs1205 and rs2794520) significantly interacted with PTSD to influence CRP levels. CONCLUSIONS: These findings provide new insights into genetic and epigenetic mechanisms of inflammatory processes in the pathophysiology of PTSD and point to new directions for biomarker identification and treatment development for patients with PTSD.

OBJECTIVES: To determine the prevalence of comorbid mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and depression, termed the deployment trauma phenotype (DTP), and its constituent diagnoses' impact on unemployment status in a national cohort of veterans. SETTING: Retrospective analysis of the comprehensive TBI evaluation, a Veterans Affairs-wide protocol for assessing TBI, employment status, and psychiatric impressions. PARTICIPANTS: The final data set consisted of 48 821 veterans. MAIN OUTCOMES AND MEASURES: Frequency of mTBI, PTSD, and depression in isolation and combinations and their association with unemployment status. RESULTS: Age- and education-adjusted risk ratios (RRs) showed that the mTBI-only group was the least likely to be unemployed, RR = 0.65 (0.59-0.71). By contrast, the greatest likelihood of unemployment was associated with membership in the DTP group, RR = 1.45 (1.36-1.56), and the comorbid PTSD and depression group, RR = 1.39 (1.27-1.52). Furthermore, the DTP was nearly 3 times more prevalent (16.4%) in this sample compared with comorbid PTSD and depression (5.7%), indicating that the DTP conveys risk for unemployment to a significantly greater number of individuals. CONCLUSIONS AND RELEVANCE: The comorbid and interactive conditions of PTSD, depression, and mTBI, rather than mTBI in isolation, were linked to significant risk for unemployment in this veteran cohort. These findings suggest that multifaceted assessments and interventions to improve postdeployment reintegration are needed.

Objective Metabolic syndrome (MetS) refers to a cluster of risk factors for cardiovascular disease, including obesity, hypertension, dyslipidemia, and hyperglycemia. While sizable prior literature has examined associations between individual risk factors and quantitative measures of cortical thickness (CT), only very limited research has investigated such measures in MetS. Furthermore, the relative contributions of these risk factors to MetS-related effects on brain morphology have not yet been studied. The primary goal of this investigation was to examine how MetS may affect CT. A secondary goal was to explore the relative contributions of individual risk factors to regional alterations in CT, with the potential to identify risk factor combinations that may underlie structural changes. Methods Eighteen participants with MetS (mean age=59.78years) were age-matched with 18 healthy control participants (mean age=60.50years). CT measures were generated from T1-weighted images and groups were contrasted using whole-brain general linear modeling. A follow-up multivariate partial least squares correlation (PLS) analysis, including the full study sample with complete risk factor measurements (N=53), was employed to examine which risk factors account for variance in group structural differences. Results Participants with MetS demonstrated significantly reduced CT in left hemisphere inferior parietal, rostral middle frontal, and lateral occipital clusters and in a right hemisphere precentral cluster. The PLS analysis revealed that waist circumference, high-density lipoprotein cholesterol (HDL-C), triglycerides, and glucose were significant contributors to reduced CT in these clusters. In contrast, diastolic blood pressure showed a significantly positive association with CT while systolic blood pressure did not emerge as a significant contributor. Age was not associated with CT. Conclusion These results indicate that MetS can be associated with regionally specific reductions in CT. Importantly, a novel link between a risk factor profile comprising indices of obesity, hyperglycemia, dyslipidemia and diastolic BP and localized alterations in CT emerged. While the pathophysiological mechanisms underlying these associations remain incompletely understood, these findings may be relevant for future investigations of MetS and might have implications for treatment approaches that focus on specific risk factor profiles with the aim to reduce negative consequences on the structural integrity of the brain.

BACKGROUND: Posttraumatic stress disorder is associated with impairments in sustained attention, a fundamental cognitive process important for a variety of social and occupational tasks. To date, however, the precise nature of these impairments and the posttraumatic stress disorder symptoms associated with them have not been well understood. METHODS: Using a well-characterized sample of returning United States military OEF/OIF/OND Veterans who varied in posttraumatic stress disorder symptoms, we employed a validated sustained attention paradigm designed to probe fluctuations across two attentional states characterized by prior research, including a peak state termed "in the zone" and a less efficient, more error-prone state termed "out of the zone." Rewarded and nonrewarded conditions were employed to examine whether motivating strong task performance could ameliorate sustained attention deficits. Analyses examined associations between attentional state, availability of reward, and posttraumatic stress disorder symptoms. RESULTS: Results indicated that, consistent with prior findings, higher levels of posttraumatic stress disorder symptoms were broadly associated with impaired task performance. This impairment was driven largely by performance deficits during individuals' optimal ("in the zone") attentional state, and follow-up analyses indicated that the performance deficit was primarily associated with anhedonia and emotional numbing symptoms. However, the deficit was partially ameliorated when better performance was rewarded. CONCLUSION: Our results provide a more complex understanding of the sustained attention deficits associated with posttraumatic stress disorder and suggest that external incentives may help to enhance sustained attention performance for affected individuals.

Sustained attention is critical for tasks where perceptual information must be continuously processed, like reading or driving; however, the cognitive processes underlying sustained attention remain incompletely characterized. In the experiments that follow, we explore the relationship between sustaining attention and the contents and maintenance of task-relevant features in an attentional template. Specifically, we administered the gradual onset continuous performance task (gradCPT), a sensitive measure of sustained attention, to a large web-based sample (N>20,000) and a smaller laboratory sample for validation and extension. The gradCPT requires participants to respond to most stimuli (city scenes – 90 %) and withhold to rare target images (mountain scenes – 10 %). By using stimulus similarity to probe the representational content of task-relevant features—assuming either exemplar- or category-based feature matching—we predicted that RTs for city stimuli that were more “mountain-like” would be slower and “city-like” mountain stimuli would elicit more erroneous presses. We found that exemplar-based target-nontarget (T-N) similarity predicted both RTs and erroneous button presses, suggesting a stimulus-specific feature matching process was adopted. Importantly, individual differences in the degree of sensitivity to these similarity measures correlated with conventional measures of attentional ability on the gradCPT as well as another CPT that is perceptually less demanding. In other words, individuals with greater sustained attention ability (assessed by two tasks) were more likely to be influenced by stimulus similarity on the gradCPT. These results suggest that sustained attention facilitates the construction and maintenance of an attentional template that is optimal for a given task.

BACKGROUND: Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)-Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS: We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS: In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = -0.17, p = .00054), and smaller amygdalae (d = -0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). CONCLUSIONS: Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma.

Novel paradigms have allowed for more precise measurements of sustained attention ability and fluctuations in sustained attention over time, as well as the neural basis of fluctuations and lapses in performance. However, in recent years, concerns have arisen over the replicability of neuroimaging studies and psychology more broadly, particularly given the typically small sample sizes. One recently developed paradigm, the gradual-onset continuous performance task (gradCPT) has been validated behaviorally in large samples of participants. Yet neuroimaging studies investigating the neural basis of performance on this task have only been collected in small samples. The present study completed both a robust replication of the original neuroimaging findings and extended previous results from the gradCPT task using a large sample of 140 Veteran participants. Results replicate findings that fluctuations in attentional stability are tracked over time by BOLD activity in task positive (e.g., dorsal and ventral attention networks) and task negative (e.g., default network) regions. Extending prior results, we relate this coupling between attentional stability and on-going brain activity to overall sustained attention ability and demonstrate that this coupling strength, along with across-network coupling, could be used to predict individual differences in performance. Additionally, the results extend previous findings by demonstrating that temporal dynamics across the default and dorsal attention networks are associated with lapse-likelihood on subsequent trials. This study demonstrates the reliability of the gradCPT, and underscores the utility of this paradigm in understanding attentional fluctuations, as well as individual variation and deficits in sustained attention.

While the associations between psychological distress (e.g., posttraumatic stress disorder [PTSD], depression) and sleep dysfunction have been demonstrated in trauma-exposed populations, studies have not fully explored the associations between sleep dysfunction and the wide range of common physical and physiological changes that can occur after trauma exposure (e.g., pain, cardiometabolic risk factors). We aimed to clarify the unique associations of psychological and physical trauma sequelae with different aspects of self-reported sleep dysfunction. A comprehensive psychological and physical examination was administered to 283 combat-deployed trauma-exposed Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veterans. The Pittsburgh Sleep Quality Index (PSQI) and PSQI Addendum for PSTD (PSQI-A) were administered along with measures of PTSD, depression, anxiety, pain, traumatic brain injury, alcohol use, nicotine dependence, and cardiometabolic symptoms. We first performed a confirmatory factor analysis of the PSQI and then conducted regressions with the separate PSQI factors as well as the PSQI-A to identify unique associations between trauma-related measures and the separate aspects of sleep. We found that the PSQI global score was composed of three factors: Sleep Efficiency (sleep efficiency/sleep duration), Perceived Sleep Quality (sleep quality/sleep latency/sleep medication) and Daily Disturbances (sleep disturbances/daytime dysfunction). Linear regressions demonstrated that PTSD symptoms were uniquely associated with the PSQI global score and all three factors, as well as the PSQI-A. For the other psychological distress variables, anxiety was independently associated with PSQI global as well as Sleep Efficiency, Perceived Sleep Quality, and PSQI-A, whereas depression was uniquely associated with Daily Disturbances and PSQI-A. Notably, cardiometabolic symptoms explained independent variance in PSQI global and Sleep Efficiency. These findings help lay the groundwork for further investigations of the mechanisms of sleep dysfunction in trauma-exposed individuals and may help in the development of more effective, individualized treatments.

OBJECTIVES: This study investigated the relationship between close proximity to detonated blast munitions and cognitive functioning in OEF/OIF/OND Veterans. METHODS: A total of 333 participants completed a comprehensive evaluation that included assessment of neuropsychological functions, psychiatric diagnoses and history of military and non-military brain injury. Participants were assigned to a Close-Range Blast Exposure (CBE) or Non-Close-Range Blast Exposure (nonCBE) group based on whether they had reported being exposed to at least one blast within 10 meters. RESULTS: Groups were compared on principal component scores representing the domains of memory, verbal fluency, and complex attention (empirically derived from a battery of standardized cognitive tests), after adjusting for age, education, PTSD diagnosis, sleep quality, substance abuse disorder, and pain. The CBE group showed poorer performance on the memory component. Rates of clinical impairment were significantly higher in the CBE group on select CVLT-II indices. Exploratory analyses examined the effects of concussion and multiple blasts on test performance and revealed that number of lifetime concussions did not contribute to memory performance. However, accumulating blast exposures at distances greater than 10 meters did contribute to poorer performance. CONCLUSIONS: Close proximity to detonated blast munitions may impact memory, and Veterans exposed to close-range blast are more likely to demonstrate clinically meaningful deficits. These findings were observed after statistically adjusting for comorbid factors. Results suggest that proximity to blast should be considered when assessing for memory deficits in returning Veterans. Comorbid psychiatric factors may not entirely account for cognitive difficulties. (JINS, 2018, 24, 466-475).

The majority of research examining affective attentional bias in posttraumatic stress disorder (PTSD) has not examined the influence of co-occurring psychiatric disorders. This study examined the individual and interactive effects of PTSD symptoms and substance use disorders (SUDs) on affective attentional processing among 323 veterans deployed to Iraq or Afghanistan. Participants were divided into those with SUD (SUD+, n = 46) and those without (SUD-, n = 277). Substance use disorder was determined using the Structured Clinical Interview for DSM-IV. Posttraumatic stress disorder was measured using the Clinician Administered PTSD Scale. A computerized go/no-go task (Robbins et al., 1994, Robbins et al.,1998) assessed affective attentional processing. Relative to those without SUD, those with SUD showed a significant association between PTSD symptoms and increased omission and commission accuracy rates and decreased d prime. No effects of valence were found. Findings suggest the need to consider co-occurring SUD when investigating the effects of PTSD on attentional control.

Despite the prevalence of blast injuries in recent overseas conflicts, knowledge of their impact on neural health is lacking. We have recently published work demonstrating differences in functional magnetic resonance imaging (fMRI) connectivity that were specific to close-range blast exposure (CBE), as opposed to other prevalent military-related factors. Here, we replicate this finding in an independent sample of 135 veterans, again finding that CBE, regardless of concussion, is predictive of persistent changes in brain physiology. Although there was weak overlap anatomically, in both samples, the group differences could be described as spreading of anticorrelation. Using the combined sample, we now seek to identify likely mechanisms that could bring about this effect. We compared participants with (n = 116) and without (n = 153) CBE by analyzing two networks through group difference maps and correlation distributions to assess spatially homogenous and heterogeneous effects. As boundaries between positive and negative correlations in fcMRI are determined by noise covariates, we compared analyses with and without global signal regression. We found evidence of widespread altered connectivity that was spatially heterogeneous across participants, and that the role of global signal regression was network dependent. These findings are not consistent with expected results from damaged white matter or impaired neural function. Rather, potential biological interpretations include disrupted cerebral blood flow or impaired neurovascular coupling, which have each been observed in animal models of blast exposure. Further targeted work will be necessary to distinguish the contribution of each of these mechanisms to producing changes in brain function associated with CBE.

BACKGROUND: Memory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume. METHODS: Recent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) × PTSD severity interaction and its association with hippocampal volume. RESULTS: We included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype × PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume. LIMITATIONS: The direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both. CONCLUSION: Our findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD.

BACKGROUND: Research suggests that posttraumatic stress disorder (PTSD) is associated with metabolic syndrome (MetS) and that PTSD-associated MetS is related to decreased cortical thickness. However, the role of genetic factors in these associations is unclear. This study evaluated contributions of polygenic obesity risk and PTSD to MetS and of MetS and polygenic obesity risk to cortical thickness. METHODS: 196 white, non-Hispanic veterans of the wars in Iraq and Afghanistan underwent clinical diagnostic interviews, physiological assessments, and genome-wide genotyping; 168 also completed magnetic resonance imaging scans. Polygenic risk scores (PRSs) for obesity were calculated from results of a prior genome-wide association study (Speliotes et al., 2010) and PTSD and MetS severity factor scores were obtained. RESULTS: Obesity PRS (β=0.15, p=0.009) and PTSD (β=0.17, p=0.005) predicted MetS and interacted such that the association between PTSD and MetS was stronger in individuals with greater polygenic obesity risk (β=0.13, p=0.02). Whole-brain vertex-wise analyses suggested that obesity PRS interacted with MetS to predict decreased cortical thickness in left rostral middle frontal gyrus (β=-0.40, p<0.001). CONCLUSIONS: Results suggest that PTSD, genetic variability, and MetS are related in a transactional fashion wherein obesity genetic risk increases stress-related metabolic pathology, and compounds the ill health effects of MetS on the brain. Genetic proclivity towards MetS should be considered in PTSD patients when prescribing psychotropic medications with adverse metabolic profiles. Results are consistent with a growing literature suggestive of PTSD-related accelerated aging.

AIM: We examined concordance of methylation levels across the Illumina Infinium HumanMethylation450 BeadChip and the Infinium MethylationEPIC BeadChip. METHODS: We computed the correlation for 145 whole blood DNA samples at each of the 422,524 CpG sites measured by both chips. RESULTS: The correlation at some sites was high (up to r = 0.95), but many sites had low correlation (55% had r < 0.20). The low correspondence between 450K and EPIC measured methylation values at many loci was largely due to the low variability in methylation values for the majority of the CpG sites in blood. CONCLUSION: Filtering out probes based on the observed correlation or low variability may increase reproducibility of BeadChip-based epidemiological studies.

INTRODUCTION: Studies investigating the neurocognitive effects of posttraumatic stress disorder (PTSD) routinely find "deficits" in various cognitive domains. However, the rate of cognitive impairment in individuals with PTSD remains unclear, as studies have focused on null hypothesis testing (NHT) and inferring patterns of impairment rather than empirically determining the rate of cognitive impairment in this sample. METHOD: This study examined rates of cognitive impairment using a domain-specific approach in non-treatment-seeking Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn service members and veterans with (n = 92) and without (n = 79) PTSD and without substance abuse/dependence who passed a performance validity measure and were matched on age, education, estimated IQ, and ethnicity. Chi-square analyses were used to compare the rate of cognitive impairment across groups based on normative scores using three cutoffs (-1, -1.5, and -2 SDs). NHT was also used to compare performances across groups. RESULTS: Individuals with PTSD showed higher rates of impairment in memory (-1-SD cutoff) than controls, but equivalent rates of impairment in attention, processing speed, and executive functioning; no significant differences were found on NHT. Impairment in any domain was also more prevalent in PTSD (-1-, -1.5-, and -2-SD cutoffs). No differences were found on NHT or rates of impairment in individuals with PTSD with (n = 34) and without (n = 58) depression. CONCLUSIONS: Patients with PTSD were more likely to meet criteria for memory impairment and to show impairment in any domain than controls. Patients with PTSD and comorbid depression were no more likely to be impaired in any cognitive domain or to have lower scores on individual cognitive tasks than patients with PTSD alone. Clinicians noting cognitive impairment in individuals with PTSD should exercise caution before ascribing that impairment to another etiology if deficits are limited to memory.

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.

INTRODUCTION: Interpersonal early life trauma (I-ELT) is associated with a myriad of functional impairments in adulthood, increased risk of drug addiction, and neuropsychiatric disorders. While deficits in emotional regulation and amygdala functioning are well characterized, deficits in general cognitive functioning have also been documented. However, the neural underpinnings of cognitive dysfunction in adults with a history of I-ELT and the potential relationship between amygdala-based functional connectivity and behavioral performance are currently poorly understood. This study examined how I-ELT affects the cognitive and neural mechanisms supporting sustained attention. METHODS: A total of 66 Veterans (18 with and 48 without a history of I-ELT) completed a nonemotional sustained attention task during functional MRI. RESULTS: The individuals with I-ELT showed significant impairments in sustained attention (i.e., higher error rates, greater response variability). This cohort exhibited increased amygdala functional connectivity with the prefrontal cortex and decreased functional connectivity with the parahippocampal gyrus when compared to those without I-ELT. These connections were significantly correlated with individual differences in sustained attention performance. Notably, classification analyses revealed that the pattern of amygdala connectivity across the whole brain was able to classify I-ELT status with 70% accuracy. CONCLUSION: These results provide evidence of a lasting negative impact for those with a history of I-ELT on sustained attention ability. They also highlight a critical role for amygdala functioning in cognitive control and sustained attention for those with a history of I-ELT, which may underlie the observed attention deficits in clinical assessments and cognitive tests involving both emotional and nonemotional stimuli.

Many US veterans of Afghanistan and Iraq have multiple physical and psychiatric problems. A major focus of research has been on determining the effects of mild Traumatic Brain Injury (mTBI), but mTBI is rarely diagnosed in the absence of co-occurring conditions such as blast exposure, post-traumatic stress disorder (PTSD), depression, substance abuse, etc. These potentially interactive psychological and physical conditions produce complex patterns of cognitive, psychological, and physical symptoms that impede civilian reintegration and complicate efficient and effective treatment planning. The Translational Research Center for TBI and Stress Disorders (TRACTS) has developed a multidisciplinary approach to the assessment of deployment trauma and its consequences in veterans of these wars. The prospective TRACTS longitudinal cohort study conducts state-of-the-art assessments in the domains of biomedical function, lifetime head trauma, psychological function encompassing deployment experience and lifetime exposure to traumatic events, neuropsychological function, and structural and functional neuroimaging. The TRACTS longitudinal cohort study is the first of its kind to comprehensively evaluate lifetime incidence of TBI and PTSD in these veterans, in addition to those incurred during military deployment. The protocol has begun to reveal information that will help improve understanding of the complex pathophysiology associated with co-occurring mTBI and related stress disorders.