Comparing resting-state connectivity of working memory networks in U.S. Service members with mild traumatic brain injury and posttraumatic stress disorder.

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are prevalent among military populations, and both have been associated with working memory (WM) impairments. Previous resting-state functional connectivity (rsFC) research conducted separately in PTSD and mTBI populations suggests that there may be similar and distinct abnormalities in WM-related networks. However, no studies have compared rsFC of WM brain regions in participants with mTBI versus PTSD. We used resting-state fMRI to investigate rsFC of WM networks in U.S. Service Members (n = 127; ages 18-59) with mTBI only (n = 46), PTSD only (n = 24), and an orthopedically injured (OI) control group (n = 57). We conducted voxelwise rsFC analyses with WM brain regions to test for differences in WM network connectivity in mTBI versus PTSD. Results revealed reduced rsFC between ventrolateral prefrontal cortex (vlPFC), lateral premotor cortex, and dorsolateral prefrontal cortex (dlPFC) WM regions and brain regions in the dorsal attention and somatomotor networks in both mTBI and PTSD groups versus controls. When compared to those with mTBI, individuals with PTSD had lower rsFC between both the lateral premotor WM seed region and middle occipital gyrus as well as between the dlPFC WM seed region and paracentral lobule. Interestingly, only vlPFC connectivity was significantly associated with WM performance across the samples. In conclusion, we found primarily overlapping patterns of reduced rsFC in WM brain regions in both mTBI and PTSD groups. Our finding of decreased vlPFC connectivity associated with WM is consistent with previous clinical and neuroimaging studies. Overall, these results provide support for shared neural substrates of WM in individuals with either mTBI or PTSD.

Distinct patterns of resting-state connectivity in U.S. service members with mild traumatic brain injury versus posttraumatic stress disorder.

Mild traumatic brain injury (mTBI) is highly prevalent in military populations, with many service members suffering from long-term symptoms. Posttraumatic stress disorder (PTSD) often co-occurs with mTBI and predicts worse clinical outcomes. Functional neuroimaging research suggests there are both overlapping and distinct patterns of resting-state functional connectivity (rsFC) in mTBI versus PTSD. However, few studies have directly compared rsFC of cortical networks in military service members with these two conditions. In the present study, U.S. service members (n = 137; ages 19-59; 120 male) underwent resting-state fMRI scans. Participants were divided into three study groups: mTBI only, PTSD only, and orthopedically injured (OI) controls. Analyses investigated group differences in rsFC for cortical networks: default mode (DMN), frontoparietal (FPN), salience, somatosensory, motor, auditory, and visual. Analyses were family-wise error (FWE) cluster-corrected and Bonferroni-corrected for number of network seeds regions at the whole brain level (pFWE < 0.002). Both mTBI and PTSD groups had reduced rsFC for DMN and FPN regions compared with OI controls. These group differences were largely driven by diminished connectivity in the PTSD group. rsFC with the middle frontal gyrus of the FPN was increased in mTBI, but decreased in PTSD. Overall, these results suggest that PTSD symptoms may have a more consistent signal than mTBI. Our novel findings of opposite patterns of connectivity with lateral prefrontal cortex highlight a potential biomarker that could be used to differentiate between these conditions.

Adverse Childhood Experience, Genes, and PTSD Risk in Soldiers: A Methylation Study.

INTRODUCTION: Epigenetics can serve as a marker of susceptibility to many known psychiatric diseases. DNA methylation patterns of multiple genes have been studied in both civilian populations and military personnel with post-traumatic stress disorder (PTSD). Many of these genes serve various functions that span the hypothalamic-pituitary-adrenal axis, immune system, and central nervous system (CNS) growth factors and neurotransmission. It is thought that the methylation levels of such genes may be able to identify individuals who are at higher risk of developing PTSD. Our study seeks to establish whether previously reported PTSD genes possess a particular methylation pattern that is predictive of PTSD in active duty military members with combat exposure. MATERIALS AND METHODS: This is an institutional review board (IRB)-approved, cross-sectional, case control, gene-environment interaction study. About 170 active military members with and without PTSD were recruited. Patients with a history of structural brain damage, traumatic brain injury (TBI) resulting in loss of consciousness, predeployment diagnosis of PTSD or anxiety disorder, and predeployment prescription of an antidepressant or psychoactive medication were excluded. Validated measures of childhood trauma and adversity (adverse childhood experience [ACE] score), PTSD symptoms (PTSD check-list military version [PCL-M]), and combat exposure scales (CES) were measured via validated questionnaires for all subjects. After extracting DNA from peripheral blood provided by the 170 subjects, we determined methylation percentages, via pyrosequencing assays, for nine target areas within the following seven genes: BDNF, NR3C1, MAN2C1, TLR8, SLC6A4, IL-18, and SKA2. These genes are commonly reported in the literature as being highly correlated with PTSD and early-life traumatic experiences.Methylation levels were measured as a percentage at specific sites within the previously mentioned genes. Data were examined with SPSS v 22.0 Statistics and JMP v13.1 software using a general linear model for methylation × trauma (CES scores) split by diagnosis of PTSD or not, methylation versus childhood trauma (ACE scores), and methylation versus PTSD severity (PCL-M score). Two-way ANOVA was performed to control for antidepressant use. A two-tailed Student t-test was performed for PTSD analyses and was correlated with PTSD diagnosis, demographic information as well as ACE score, PCL-M score, and CES scores. RESULTS: Differentially methylated sites that were highly associated with PTSD diagnosis were found in three of seven candidate genes: BDNF, NR3C1, and MAN2C1. When compared to controls, patients with PTSD diagnosis had significantly lower levels of methylation, even after controlling for antidepressant use. PCL-M, ACE, and CES scores were significantly associated with PTSD diagnosis. CONCLUSION: Our study suggests that methylation of key genes involved in synaptic plasticity and the hypothalamic-pituitary-adrenal axis is associated with lower levels of methylation in military PTSD subjects exposed to combat when compared to their non-PTSD counterparts. Strengths of this study include controlling for antidepressant use and excluding TBI patients. Similar studies in an active duty population of this size are scarce. What is not clear is whether methylation changes are driving PTSD symptomology or whether they are merely a marker of disease. Future areas of research include prospective studies that measure methylation pre- and postcombat exposure in the same individual.

Sleep problems contribute to post-concussive symptoms in service members with a history of mild traumatic brain injury without posttraumatic stress disorder or major depressive disorder.

BACKGROUND: Many with a history of mild traumatic brain injury (TBI) experience sleep problems, which are also common symptoms of stress-related and mood disorders. OBJECTIVE: To determine if sleep problems contributed unique variance to post-concussive symptoms above and beyond symptoms of posttraumatic stress disorder/major depressive disorder (PTSD/MDD) after mild TBI. METHODS: 313 active duty service members with a history of mild TBI completed sleep, PTSD, and mood symptom questionnaires, which were used to determine contributions to the Neurobehavioral Symptom Inventory. RESULTS: 59% of the variance in post-concussive symptoms were due to PTSD symptom severity while depressive symptoms and sleep problems contributed an additional 1% each. This pattern differed between those with and without clinical diagnosis of PTSD/MDD. For those with PTSD/MDD, PTSD and depression symptoms but not sleep contributed to post-concussive symptoms. For those without PTSD/MDD, PTSD symptoms and sleep contributed specifically to somatosensory post-concussive symptoms. Daytime dysfunction and sleep disturbances were associated with post-concussive symptoms after PTSD and depression symptoms were controlled. CONCLUSIONS: PTSD symptom severity explained the most variance for post-concussive symptoms among service members with a history of mild TBI, while depression symptoms, daytime dysfunction, and sleep disturbances independently contributed small amounts of variance.

Factor analysis of the Caregiver Appraisal Scale in military TBI.

PURPOSE/OBJECTIVE: To (a) examine the factor structure of the original 47-item Caregiver Appraisal Scale (CAS) in caregivers of service members/veterans (SMVs) following traumatic brain injury (TBI) and (b) assess whether the CAS yields a similar factor structure in this population compared to caregivers of civilian adults following TBI. Research Method/Design: Participants were 287 caregivers (female = 96.2%; spouse = 87.8%; mean age = 38.6 years) of SMVs who sustained a mild, moderate, severe, or penetrating TBI, recruited from Walter Reed National Military Medical Center and via caregiver community outreach. Caregivers completed the CAS, Caregiver Questionnaire, and Mayo-Portland Adaptability Inventory-4 upon enrollment in the study. RESULTS: Principal component analysis (PCA) revealed four factors that explained 43.2% of the variance in CAS scores: Perceived Burden, Caregiving Relationship Satisfaction, Caregiving Ideology, and Caregiving Mastery. Thirty-seven of the 47 CAS items loaded significantly onto only one of the four factors (≥ .40). A secondary PCA was performed on these 37 items, resulting in a four-factor solution very similar to that of the 47-item solution, which explained 46.8% of the variance in the 37-item measure. All but one item loaded significantly on a factor corresponding to a conceptually similar construct. CONCLUSIONS/IMPLICATIONS: Military and civilian caregivers have overlapping and differing concerns. The findings support a 37-item four-factor model of caregiving stress appraisal that has the potential for use as an outcome measure for developing caregiver interventions. It may be as useful to administer a reduced 37-item measure of the CAS to caregivers as the original 47-item measure, but further development is required. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Correlates of Depression in U.S. Military Service Members With a History of Mild Traumatic Brain Injury.

OBJECTIVES: Post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) are identified as signature injuries of the Wars in Iraq and Afghanistan. Statistics have confirmed a high incidence of PTSD among military personnel with mild TBI (mTBI) who served in these conflicts. Although receiving less attention, individuals with a history of mTBI are also at increased risk for depressive disorders. This study examines the incidence and correlates of depression in service members with a history of mTBI received an average of 4-1/2 years prior to evaluation. METHODS: Retrospective analysis of 184 service members with a history of mTBI extracted from a data repository maintained at a military medical center. RESULTS: One-third of the sample (34.2%) was clinically diagnosed with a depressive disorder in the month preceding evaluation. Of those with depression, 81% (51 of 63) were also diagnosed with PTSD. Proportionately more women than men had depression. Depression was more common among those who were undergoing a Military Evaluation Board and those who served in more than three combat deployments. CONCLUSIONS: Results confirm chronically elevated the rates of depressive disorders and PTSD comorbidity among service members with a history of mTBI. Depression screening and treatment within the Military Health System should remain a priority for service members reporting a remote history of mTBI. Individuals with chronic PTSD, women, service members undergoing MEB and those who served in greater than three combat deployments are at particular risk.

Subcortical shape and neuropsychological function among U.S. service members with mild traumatic brain injury.

In a recent manuscript, our group demonstrated shape differences in the thalamus, nucleus accumbens, and amygdala in a cohort of U.S. Service Members with mild traumatic brain injury (mTBI). Given the significant role these structures play in cognitive function, this study directly examined the relationship between shape metrics and neuropsychological performance. The imaging and neuropsychological data from 135 post-deployed United States Service Members from two groups (mTBI and orthopedic injured) were examined. Two shape features modeling local deformations in thickness (RD) and surface area (JD) were defined vertex-wise on parametric mesh-representations of 7 bilateral subcortical gray matter structures. Linear regression was used to model associations between subcortical morphometry and neuropsychological performance as a function of either TBI status or, among TBI patients, subjective reporting of initial concussion severity (CS). Results demonstrated several significant group-by-cognition relationships with shape metrics across multiple cognitive domains including processing speed, memory, and executive function. Higher processing speed was robustly associated with more dilation of caudate surface area among patients with mTBI who reported more than one CS variables (loss of consciousness (LOC), alteration of consciousness (AOC), and/or post-traumatic amnesia (PTA)). These significant patterns indicate the importance of subcortical structures in cognitive performance and support a growing functional neuroanatomical literature in TBI and other neurologic disorders. However, prospective research will be required before exact directional evolution and progression of shape can be understood and utilized in predicting or tracking cognitive outcomes in this patient population.

Symptom Reporting Patterns of US Military Service Members with a History of Concussion According to Duty Status.

OBJECTIVE: To compare symptom reporting patterns of service members with a history of concussion based on work status: full duty, limited duty, or in the Medical Evaluation Board (MEB)/disability process. METHODS: Retrospective analysis of 181 service members with a history of concussion (MEB n = 56; limited duty n = 62; full duty n = 63). Neurobehavioral Symptom Inventory (NSI) Validity-10 cutoff (>22) and Mild Brain Injury Atypical Symptoms Scale (mBIAS) cutoffs (≥10 and ≥8) were used to evaluate potential over-reporting of symptoms. RESULTS: The MEB group displayed significantly higher NSI scores and significantly higher proportion scored above the mBIAS ≥10 cutoff (MEB = 15%; limited duty = 3%; full duty = 5%). Validity-10 cutoff did not distinguish between groups. CONCLUSIONS: MEB but not limited duty status was associated with increased risk of over-reporting symptoms in service members with a history of concussion. Results support the use of screening measures for over-reporting in the MEB/disability samples.

Relationships Between Subcortical Shape Measures and Subjective Symptom Reporting in US Service Members With Mild Traumatic Brain Injury.

OBJECTIVE: To assess interactions of subcortical structure with subjective symptom reporting associated with mild traumatic brain injury (mTBI), using advanced shape analysis derived from volumetric MRI. PARTICIPANTS: Seventy-six cognitively symptomatic individuals with mTBI and 59 service members sustaining only orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Self-report symptom measures included the PTSD Checklist-Military, Neurobehavioral Symptom Inventory, and Symptom Checklist-90-Revised. High-dimensional measures of shape characteristics were generated from volumetric MRI for 7 subcortical structures in addition to standard volume measures. RESULTS: Several significant interactions between group status and symptom measures were observed across the various shape measures. These interactions were revealed in the right thalamus and globus pallidus for each of the shape measures, indicating differences in structure thickness and expansion/contraction for these regions. No relationships with volume were observed. CONCLUSION: Results provide evidence for the sensitivity of shape measures in differentiating symptomatic mTBI individuals from controls, while volumetric measures did not exhibit this same sensitivity. Disruptions to thalamic nuclei identified here highlight the role of the thalamus in the spectrum of symptoms associated with mTBI. Additional work is needed to prospectively, and longitudinally, assess these measures along with cognitive performance and advanced multimodal imaging methods to extend the utility of shape analysis in relation to functional outcomes in this population.

Diffusion Imaging Findings in US Service Members With Mild Traumatic Brain Injury and Posttraumatic Stress Disorder.

OBJECTIVE: Use diffusion tensor imaging to investigate white matter microstructure attributable to mild TBI (mTBI) and/or posttraumatic stress disorder (PTSD). PARTICIPANTS: Twenty-seven individuals with mTBI only, 16 with PTSD only, 42 with mTBI + PTSD, and 43 service members who sustained orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Clinical diffusion tensor imaging sequence to assess fractional anisotropy, mean, axial, and radial diffusivity within selected regions of interest. RESULTS: Corrected analyses revealed a pattern of lower white matter integrity in the PTSD group for several scalar metrics. Regions affected included primarily right hemisphere areas of the internal capsule. These differences associated with the PTSD only cohort were observed in relation to all 3 comparison groups, while the mTBI + PTSD group did not exhibit any notable pattern of white matter abnormalities. CONCLUSION: Results suggest that lower resolution scan sequences are sensitive to post-acute abnormalities associated with PTSD, particularly in the right hemisphere. In addition, these findings suggest that ongoing PTSD symptoms are associated with differences in white matter diffusion that are more readily detected in a clinical scan sequence than mTBI abnormalities. Future studies are needed to prospectively assess service members prior to onset of injury to verify this pattern of results.

Adversity and Resilience Are Associated with Outcome after Mild Traumatic Brain Injury in Military Service Members.

The objective of this study was to assess the associations between resilience, adversity, post-concussion symptoms, and post-traumatic stress symptom reporting after mild traumatic brain injury (mTBI). We hypothesized that resilience would be associated with less symptom reporting, and adversity would be associated with greater symptom reporting. This was a cross-sectional study of retrospective data collected for an ongoing TBI repository. United States military service members who screened positive for mTBI during a primary care visit completed the Trauma History Screen (THS), Connor-Davidson Resilience Scale (CD-RISC), Neurobehavioral Symptom Inventory (NSI), and post-traumatic stress disorder (PTSD) Checklist-Civilian Version (PCL-C). Data collected from February 2015 to August 2016 were used for the present study. Only participants with complete data for the above measures were included, yielding a sample size of 165 participants. Adversity (THS) and resilience (CD-RISC) scores were each correlated significantly with post-concussion (NSI) and traumatic stress (PCL-C) total and subscale scores in the hypothesized direction. Interactions between adversity and resilience were absent for all measures except the NSI sensory subscale. Four traumatic event types were significantly associated positively with most NSI and PCL-C total and subscale scores, but the age at which traumatic events were first experienced showed few and mixed significant associations. In conclusion, resilience and adversity were significantly associated with symptom endorsement after mTBI. Screening for cumulative adversity may identify individuals at greater risk of developing persistent post-concussion symptoms and/or PTSD, and interventions that increase resilience may reduce symptom severity.

Comparing Two Processing Pipelines to Measure Subcortical and Cortical Volumes in Patients with and without Mild Traumatic Brain Injury.

PURPOSE: To compare volumetric results from NeuroQuant® and FreeSurfer in a service member setting. Since the advent of medical imaging, quantification of brain anatomy has been a major research and clinical effort. Rapid advancement of methods to automate quantification and to deploy this information into clinical practice has surfaced in recent years. NeuroQuant® is one such tool that has recently been used in clinical settings. Accurate volumetric data are useful in many clinical indications; therefore, it is important to assess the intermethod reliability and concurrent validity of similar volume quantifying tools. METHODS: Volumetric data from 148 U.S. service members across three different experimental groups participating in a study of mild traumatic brain injury (mTBI) were examined. Groups included mTBI (n = 71), posttraumatic stress disorder (n = 22), or a noncranial orthopedic injury (n = 55). Correlation coefficients and nonparametric group mean comparisons were used to assess reliability and concurrent validity, respectively. RESULTS: Comparison of these methods across our entire sample demonstrates generally fair to excellent reliability as evidenced by large intraclass correlation coefficients (ICC = .4 to .99), but little concurrent validity as evidenced by significantly different Mann-Whitney U comparisons for 26 of 30 brain structures measured. CONCLUSION: While reliability between the two segmenting tools is fair to excellent, volumetric outcomes are statistically different between the two methods. As suggested by both developers, structure segmentation should be visually verified prior to clinical use and rigor should be used when interpreting results generated by either method.

Profile Analysis of the Neurobehavioral and Psychiatric Symptoms Following Combat-Related Mild Traumatic Brain Injury: Identification of Subtypes.

OBJECTIVE: To explore the taxonomy of combat-related mild traumatic brain injury (mTBI) based on symptom patterns. PARTICIPANTS: Up to 1341 military personnel who experienced a combat-related mTBI within 2 years of evaluation. MEASURES: Neurobehavioral Symptom Inventory and PTSD Checklist-Civilian Version (PCL-C). RESULTS: Cluster analysis revealed the following 4 subtypes: primarily psychiatric (posttraumatic stress disorder) group, a cognitive group, a mixed symptom group, and a good recovery group. The posttraumatic stress disorder cluster (21.9% of the sample) reported symptoms related to hyperarousal and dissociation/depression with few complaints related to cognition or headaches. The cognitive group (21.5% of the sample) had primarily cognitive and headache complaints with few mood symptoms. The mixed profile cluster included 18.6% of the sample and was characterized by a combination of mood complaints (hyperarousal and dissociation/depression), cognitive complaints, and headaches. The largest cluster (37.8% of the sample) had an overall low symptom profile and was labeled the "good recovery" group. CONCLUSIONS: The results support a unique taxonomy for combat-related mTBI. The clinical differences among these subtypes indicate a need for unique treatment resources and programs.

Profile analyses of the Personality Assessment Inventory following military-related traumatic brain injury.

Personality Assessment Inventory (PAI) profiles were examined in 160 U.S. service members (SMs) following mild-severe traumatic brain injury (TBI). Participants who sustained a mild TBI had significantly higher PAI scores than those with moderate-severe TBI on eight of the nine clinical scales examined. A two-step cluster analysis identified four PAI profiles, heuristically labeled "High Distress", "Moderate Distress", "Somatic Distress," and "No Distress". Postconcussive and posttraumatic stress symptom severity was highest for the High Distress group, followed by the Somatic and Moderate Distress groups, and the No Distress group. Profile groups differed in age, ethnicity, rank, and TBI severity. Findings indicate that meaningful patterns of behavioral and personality characteristics can be detected in active duty military SMs following TBI, which may prove useful in selecting the most efficacious rehabilitation strategies.

Discriminating military and civilian traumatic brain injuries.

Traumatic brain injury (TBI) occurs at higher rates among service members than civilians. Explosions from improvised explosive devices and mines are the leading cause of TBI in the military. As such, TBI is frequently accompanied by other injuries, which makes its diagnosis and treatment difficult. In addition to postconcussion symptoms, those who sustain a TBI commonly report chronic pain and posttraumatic stress symptoms. This combination of symptoms is so typical they have been referred to as the "polytrauma clinical triad" among injured service members. We explore whether these symptoms discriminate civilian occurrences of TBI from those of service members, as well as the possibility that repeated blast exposure contributes to the development of chronic traumatic encephalopathy (CTE). This article is part of a Special Issue entitled 'Traumatic Brain Injury'.

A multisite study of the relationships between blast exposures and symptom reporting in a post-deployment active duty military population with mild traumatic brain injury.

Explosive devices have been the most frequent cause of traumatic brain injury (TBI) among deployed contemporary U.S. service members. The purpose of this study was to examine the influence of previous cumulative blast exposures (that did or did not result in TBI) on later post-concussion and post-traumatic symptom reporting after sustaining a mild TBI (MTBI). Participants were 573 service members who sustained MTBI divided into four groups by number of blast exposures (1, 2, 3, and 4-10) and a nonblast control group. Post-concussion symptoms were measured using the Neurobehavioral Symptom Inventory (NSI) and post-traumatic stress disorder (PTSD) symptoms using the Post-traumatic Checklist-Civilian version (PCL-C). Results show groups significantly differed on total NSI scores (p<0.001), where symptom endorsement increased as number of reported blast exposures increased. Total NSI scores were significantly higher for the 3- and 4-10 blast groups compared with the 1- and 2-blast groups with effect sizes ranging from small to moderate (d=0.31 to 0.63). After controlling for PTSD symptoms using the PCL-C total score, NSI total score differences remained between the 4-10-blast group and the 1- and 2-blast groups, but were less pronounced (d=0.35 and d=0.24, respectively). Analyses of NSI subscale scores using PCL-C scores as a covariate revealed significant between-blast group differences on cognitive, sensory, and somatic, but not affective symptoms. Regression analyses revealed that cumulative blast exposures accounted for a small but significant amount of the variance in total NSI scores (4.8%; p=0.009) and total PCL-C scores (2.3%; p<0.001). Among service members exposed to blast, post-concussion symptom reporting increased as a function of cumulative blast exposures. Future research will need to determine the relationship between cumulative blast exposures, symptom reporting, and neuropathological changes.

The social environment and IL-6 in rats and humans.

Inflammatory cytokine levels predict a wide range of human diseases including depression, cardiovascular disease, type 2 diabetes, autoimmune disease, general morbidity, and mortality. Stress and social experiences throughout the lifecourse have been associated with inflammatory processes. We conducted studies in humans and laboratory rats to examine the effect of early life experience and adult social position in predicting IL-6 levels. Human participants reported family homeownership during their childhood and current subjective social status. Interleukin-6 (IL-6) was measured from oral mucosal transudate. Rats were housed in groups of three, matched for quality of maternal care received. Social status was assessed via competition for resources, and plasma IL-6 was assessed in adulthood. In both humans and rats, we identified an interaction effect; early social experience moderated the effect of adult social status on IL-6 levels. Rats that experienced low levels of maternal care and people with low childhood socioeconomic status represented both the highest and lowest levels of IL-6 in adulthood, depending on their social status as young adults. The predicted interaction held for non-Hispanic people, but did not occur among Hispanic individuals. Adversity early in life may not have a monotonically negative effect on adult health, but may alter biological sensitivity to later social experiences.