Discriminating Mild Traumatic Brain Injury and Posttraumatic Stress Disorder Using Latent Neuroimaging and Neuropsychological Profiles in Active-Duty Military Service Members.

OBJECTIVE: Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) commonly occur among military Service Members and Veterans and have heterogenous, but also overlapping symptom presentations, which often complicate the diagnoses of underlying impairments and development of effective treatment plans. Thus, we sought to examine whether the combination of whole brain gray matter (GM) and white matter (WM) structural measures with neuropsychological performance can aid in the classification of military personnel with mTBI and PTSD. METHODS: Active-Duty US Service Members ( n = 156; 87.8% male) with a history of mTBI, PTSD, combined mTBI+PTSD, or orthopedic injury completed a neuropsychological battery and T1- and diffusion-weighted structural neuroimaging. Cortical, subcortical, ventricular, and WM volumes and whole brain fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were calculated. Latent profile analyses were performed to determine how the GM and WM indicators, together with neuropsychological indicators, classified individuals. RESULTS: For both GM and WM, respectively, a 4-profile model was the best fit. The GM model identified greater ventricular volumes in Service Members with cognitive symptoms, including those with a diagnosis of mTBI, either alone or with PTSD. The WM model identified reduced FA and elevated RD in those with psychological symptoms, including those with PTSD or mTBI and comorbid PTSD. However, contrary to expectation, a global neural signature unique to those with comorbid mTBI and PTSD was not identified. CONCLUSIONS: The findings demonstrate that neuropsychological performance alone is more robust in differentiating Active-Duty Service Members with mTBI and PTSD, whereas global neuroimaging measures do not reliably differentiate between these groups.

Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age-dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.

Latent Neuropsychological Profiles to Discriminate Mild Traumatic Brain Injury and Posttraumatic Stress Disorder in Active-Duty Service Members.

OBJECTIVE: To determine whether cognitive and psychological symptom profiles differentiate clinical diagnostic classifications (eg, history of mild traumatic brain injury [mTBI] and posttraumatic stress disorder [PTSD]) in military personnel. METHODS: US Active-Duty Service Members ( N = 209, 89% male) with a history of mTBI ( n = 56), current PTSD ( n = 23), combined mTBI + PTSD ( n = 70), or orthopedic injury controls ( n = 60) completed a neuropsychological battery assessing cognitive and psychological functioning. Latent profile analysis was performed to determine how neuropsychological outcomes of individuals clustered together. Diagnostic classifications (ie, mTBI, PTSD, mTBI + PTSD, and orthopedic injury controls) within each symptom profile were examined. RESULTS: A 5-profile model had the best fit. The profiles differentiated subgroups with high (34.0%) or normal (21.5%) cognitive and psychological functioning, cognitive symptoms (19.1%), psychological symptoms (15.3%), and combined cognitive and psychological symptoms (10.0%). The symptom profiles differentiated participants as would generally be expected. Participants with PTSD were mainly represented in the psychological symptom subgroup, while orthopedic injury controls were mainly represented in the high-functioning subgroup. Further, approximately 79% of participants with comorbid mTBI and PTSD were represented in a symptomatic group (∼24% = cognitive symptoms, ∼29% = psychological symptoms, and 26% = combined cognitive/psychological symptoms). Our results also showed that approximately 70% of military personnel with a history of mTBI were represented in the high- and normal-functioning groups. CONCLUSIONS: These results demonstrate both overlapping and heterogeneous symptom and performance profiles in military personnel with a history of mTBI, PTSD, and/or mTBI + PTSD. The overlapping profiles may underscore why these diagnoses are often difficult to diagnose and treat, but suggest that advanced statistical models may aid in identifying profiles representing symptom and cognitive performance impairments within patient groups and enable identification of more effective treatment targets.

Neuropsychological Performance and Subjective Symptom Reporting in Military Service Members With a History of Multiple Concussions: Comparison With a Single Concussion, Posttraumatic Stress Disorder, and Orthopedic Trauma.

OBJECTIVE: To examine differences in objective neurocognitive performance and subjective cognitive symptoms in individuals with a history of a single concussion, multiple concussions, orthopedic injuries, and posttraumatic stress disorder (PTSD). METHOD: Participants included 116 military service members who sustained a mild traumatic brain injury (mTBI) during combat deployment. Subjects were subdivided into groups based on concussion frequency: a single concussion (n = 42), 2 concussions (n = 21), and 3 or more concussions (n = 53). Eighty-one subjects sustained an orthopedic injury (n = 60) during deployment or were diagnosed with PTSD (n = 21), but had no history of mTBI. Subjects completed a battery of neuropsychological tests and self-report measures of postconcussive symptoms, PTSD symptoms, and psychopathology. RESULTS: No differences were found among the concussion groups on a composite neuropsychological measure. The PTSD group had the highest number of symptom complaints, with the 2-concussion and 3-plus-concussion groups being most similar to the PTSD group. The concussion groups showed a nonsignificant pattern of increasing distress with increasing number of concussions. CONCLUSIONS: The current findings are consistent with meta-analytic results showing no differential effect on neuropsychological functioning due to multiple concussions. Results also support the burden of adversity hypothesis suggesting increasing symptom levels with increasing psychological or physically traumatic exposures.

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.

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'.

Persistent MRI Findings Unique to Blast and Repetitive Mild TBI: Analysis of the CENC/LIMBIC Cohort Injury Characteristics.

INTRODUCTION: MRI represents one of the clinical tools at the forefront of research efforts aimed at identifying diagnostic and prognostic biomarkers following traumatic brain injury (TBI). Both volumetric and diffusion MRI findings in mild TBI (mTBI) are mixed, making the findings difficult to interpret. As such, additional research is needed to continue to elucidate the relationship between the clinical features of mTBI and quantitative MRI measurements. MATERIAL AND METHODS: Volumetric and diffusion imaging data in a sample of 976 veterans and service members from the Chronic Effects of Neurotrauma Consortium and now the Long-Term Impact of Military-Relevant Brain Injury Consortium observational study of the late effects of mTBI in combat with and without a history of mTBI were examined. A series of regression models with link functions appropriate for the model outcome were used to evaluate the relationships among imaging measures and clinical features of mTBI. Each model included acquisition site, participant sex, and age as covariates. Separate regression models were fit for each region of interest where said region was a predictor. RESULTS: After controlling for multiple comparisons, no significant main effect was noted for comparisons between veterans and service members with and without a history of mTBI. However, blast-related mTBI were associated with volumetric reductions of several subregions of the corpus callosum compared to non-blast-related mTBI. Several volumetric (i.e., hippocampal subfields, etc.) and diffusion (i.e., corona radiata, superior longitudinal fasciculus, etc.) MRI findings were noted to be associated with an increased number of repetitive mTBIs versus. CONCLUSIONS: In deployment-related mTBI, significant findings in this cohort were only observed when considering mTBI sub-groups (blast mechanism and total number/dose). Simply comparing healthy controls and those with a positive mTBI history is likely an oversimplification that may lead to non-significant findings, even in consortium analyses.

The Effect of Intranasal Plus Transcranial Photobiomodulation on Neuromuscular Control in Individuals with Repetitive Head Acceleration Events.

Objective: This proof-of-concept study was to investigate the relationship between photobiomodulation (PBM) and neuromuscular control. Background: The effects of concussion and repetitive head acceleration events (RHAEs) are associated with decreased motor control and balance. Simultaneous intranasal and transcranial PBM (itPBM) is emerging as a possible treatment for cognitive and psychological sequelae of brain injury with evidence of remote effects on other body systems. Methods: In total, 43 (39 male) participants, age 18-69 years (mean, 49.5; SD, 14.45), with a self-reported history of concussive and/or RHAE and complaints of their related effects (e.g., mood dysregulation, impaired cognition, and poor sleep quality), completed baseline and posttreatment motor assessments including clinical reaction time, grip strength, grooved pegboard, and the Mini Balance Evaluation Systems Test (MiniBEST). In the 8-week interim, participants self-administered itPBM treatments by wearing a headset comprising four near-infrared light-emitting diodes (LED) and a near-infrared LED nasal clip. Results: Posttreatment group averages in reaction time, MiniBEST reactive control subscores, and bilateral grip strength significantly improved with effect sizes of g = 0.75, g = 0.63, g = 0.22 (dominant hand), and g = 0.34 (nondominant hand), respectively. Conclusion: This study provides a framework for more robust studies and suggests that itPBM may serve as a noninvasive solution for improved neuromuscular health.

ENIGMA's simple seven: Recommendations to enhance the reproducibility of resting-state fMRI in traumatic brain injury.

Resting state functional magnetic resonance imaging (rsfMRI) provides researchers and clinicians with a powerful tool to examine functional connectivity across large-scale brain networks, with ever-increasing applications to the study of neurological disorders, such as traumatic brain injury (TBI). While rsfMRI holds unparalleled promise in systems neurosciences, its acquisition and analytical methodology across research groups is variable, resulting in a literature that is challenging to integrate and interpret. The focus of this narrative review is to address the primary methodological issues including investigator decision points in the application of rsfMRI to study the consequences of TBI. As part of the ENIGMA Brain Injury working group, we have collaborated to identify a minimum set of recommendations that are designed to produce results that are reliable, harmonizable, and reproducible for the TBI imaging research community. Part one of this review provides the results of a literature search of current rsfMRI studies of TBI, highlighting key design considerations and data processing pipelines. Part two outlines seven data acquisition, processing, and analysis recommendations with the goal of maximizing study reliability and between-site comparability, while preserving investigator autonomy. Part three summarizes new directions and opportunities for future rsfMRI studies in TBI patients. The goal is to galvanize the TBI community to gain consensus for a set of rigorous and reproducible methods, and to increase analytical transparency and data sharing to address the reproducibility crisis in the field.

Chemistry at the alkyne-carbene intersection: a metallacyclobutene-η3-vinylcarbene equilibration.

Synthesis of a sterically congested metallacyclobutene complex has led to the first observation of metallacyclobutene-η(3)-vinylcarbene equilibration. The structure of the η(3)-vinylcarbene complex was elucidated by spectroscopy, HRMS, and ab initio computations. The vinylcarbene complex was trapped by reactions with ethyl diazoacetate and (C5H5)Co(PPh3)2 to give cobalt-diene and dicobalt complexes, respectively.

Levels of felt stigma among a group of people with HIV in Puerto Rico.

OBJECTIVE: HIV felt stigma is a major problem needing to be addressed because of its association with poor treatment adherence, decreases in help-seeking behaviors, high-risk sexual conduct, emotional discomfort, and the reduction of well-being in people with HIV/AIDS (PWHA). The aim of this study was to identify the frequency of felt stigma among PWHA in Puerto Rico. METHODS: A cross-sectional study was conducted with 249 subjects (59% men, 41% women). Participants completed the Puerto Rico Comprehensive Center for HIV Disparities (PR-CCHD) Sociodemographic Questionnaire and the HIV Felt Sigma Scale. RESULTS: 80% of the subjects showed some level of felt stigma. Women showed significantly higher levels of HIV-related felt stigma than did men. Disclosure, negative self-image, and public attitude scores were also higher in women than in men. Sociodemographic variables such as age, marital status, employment status, income, and educational level showed significant associations with felt stigma and its dimensions. CONCLUSION: Results of this study evidence the need to develop culturally sensitive intervention models to reduce the felt-stigma burden in PWHA.

Biomarkers of Exposure to Phthalate Mixtures and Adverse Birth Outcomes in a Puerto Rico Birth Cohort.

BACKGROUND: Humans are exposed to complex mixtures of phthalate chemicals from a range of consumer products. Previous studies have reported significant associations between individual phthalate metabolites and pregnancy outcomes, but mixtures research is limited. OBJECTIVES: We used the Puerto Rico Testsite for Exploring Contamination Threats longitudinal pregnancy cohort to investigate associations between phthalate metabolite mixtures and pregnancy outcomes. METHODS: Women (n=462 carrying females, n=540 carrying males) provided up to three urine samples throughout gestation (median 18, 22, and 26 wk), which were analyzed for 13 phthalate metabolites. Pregnancy outcomes including preterm birth (PTB), spontaneous PTB, small and large for gestational age (SGA, LGA), birth weight z-score, and gestational age at delivery were abstracted from medical records. Environmental risk scores (ERS) were calculated as a weighted linear combination of the phthalates from ridge regression and adaptive elastic net, which are variable selection methods to handle correlated predictors. Birth outcomes were regressed on continuous ERS. We assessed gestational average and visit-specific ERS and stratified all analyses by fetal sex. Finally, we used Bayesian kernel machine regression (BKMR) to explore nonlinear associations and interactions between metabolites. RESULTS: Differences in metabolite weights from ridge and elastic net were apparent between birth outcomes and between fetal sexes. An interquartile range increase in gestational average phthalate ERS was associated with increased odds of PTB [male odds ratio (OR)=1.56; 95% confidence interval (CI): 1.08, 2.27; female OR=1.91; 95% CI: 1.23, 2.98], spontaneous PTB (male OR=2.32; 95% CI: 1.46, 3.68; female OR=2.00; 95% CI: 1.04, 3.82), and reduced gestational age at birth (male ß=-0.39 wk, 95% CI: -0.62, -0.15; female ß=-0.29 wk, 95% CI: -0.52, -0.05). Analyses by study visit suggested that exposure at ∼22 wk (range 20-24 wk) was driving those associations. Bivariate plots from BKMR analysis revealed some nonlinear associations and metabolite interactions that were different between fetal sexes. DISCUSSION: These results suggest that exposure to phthalate mixtures was associated with increased risk of early delivery and highlight the need to study mixtures by fetal sex. We also identified various metabolites displaying nonlinear relationships with measures of birth weight. https://doi.org/10.1289/EHP8990.

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.

White matter integrity, suicidal ideation, and cognitive dysfunction in combat-exposed Iraq and Afghanistan Veterans.

White matter alterations in frontolimbic circuits and poorer cognitive functioning have been observed in individuals endorsing suicidality across numerous psychiatric conditions. However, relationships between white matter integrity, cognition, and suicidality in Veterans are poorly understood, particularly for those at increased risk for suicide due to mental health conditions (e.g., posttraumatic stress disorder, depression) and traumatic brain injury history. We (1) examined white matter alterations in combat-exposed Iraq/Afghanistan Veterans with and without suicidal ideation (SI) and (2) investigated relationships between white matter integrity and neuropsychological functioning in regions that differed between SI groups. No group differences were found regarding psychiatric diagnoses. Participants with SI had lower fractional anisotropy (FA) in the posterior corona radiata, superior corona radiata, and superior longitudinal fasciculus relative to those without SI. Worse processing speed/attention performance was associated with lower FA in the superior longitudinal fasciculus, while worse executive functioning performance was associated with lower FA in the superior corona radiata and superior longitudinal fasciculus. Memory performance was not associated with FA. These findings suggest that white matter integrity may be involved in cognitive dysfunction and increased risk for SI. Interventions that target cognitive dysfunction may ameliorate SI, and in turn, reduce risk for suicide among Veterans.

Association between white matter organization and cognitive performance in athletes with a history of sport-related concussion.

INTRODUCTION: Impairments in cognitive performance after sport-related concussion (SRC) typically resolve within weeks of the injury, whereas alterations to white matter (WM) organization have been found to persist longer into the chronic injury stage. However, longer-term associations between cognition and WM organization following SRC have not been studied. The objective of this study was to compare WM organization and cognitive performance in collegiate athletes an average of almost 4 years post-SRC to athletes with no history of SRC. METHOD: National Collegiate Athletic Association Division III athletes (n = 71, age = 19.3 ± 1.2; 14 with self-reported SRC) completed a neurocognitive assessment and diffusion tensor imaging (DTI). WM organization was assessed by extracting measures of fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) from 20 WM regions of interest (ROIs). Multivariate partial least squares analyses were used to compare athletes with and without a history of SRC and assess relationships between DTI-derived metrics of WM organization and cognitive measures. RESULTS: Cognitive performance and ROI metrics did not differ between athletes with and without prior SRC. However, among athletes with a history of SRC, better executive function, processing speed, and memory but worse choice reaction time were associated with higher FA and lower MD and RD in several WM tracts. CONCLUSION: Athletes with a history of SRC demonstrated greater associations between cognitive performance and WM organization, but also variability in the domains showing associations. Taken together, the findings demonstrate the importance of examining brain-behavior relationships several years after SRC to better gauge how WM organization supports cognition.

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.

Coordinating Global Multi-Site Studies of Military-Relevant Traumatic Brain Injury: Opportunities, Challenges, and Harmonization Guidelines.

Traumatic brain injury (TBI) is common among military personnel and the civilian population and is often followed by a heterogeneous array of clinical, cognitive, behavioral, mood, and neuroimaging changes. Unlike many neurological disorders that have a characteristic abnormal central neurologic area(s) of abnormality pathognomonic to the disorder, a sufficient head impact may cause focal, multifocal, diffuse or combination of injury to the brain. This inconsistent presentation makes it difficult to establish or validate biological and imaging markers that could help improve diagnostic and prognostic accuracy in this patient population. The purpose of this manuscript is to describe both the challenges and opportunities when conducting military-relevant TBI research and introduce the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Military Brain Injury working group. ENIGMA is a worldwide consortium focused on improving replicability and analytical power through data sharing and collaboration. In this paper, we discuss challenges affecting efforts to aggregate data in this patient group. In addition, we highlight how "big data" approaches might be used to understand better the role that each of these variables might play in the imaging and functional phenotypes of TBI in Service member and Veteran populations, and how data may be used to examine important military specific issues such as return to duty, the late effects of combat-related injury, and alteration of the natural aging processes.

A global collaboration to study intimate partner violence-related head trauma: The ENIGMA consortium IPV working group.

Intimate partner violence includes psychological aggression, physical violence, sexual violence, and stalking from a current or former intimate partner. Past research suggests that exposure to intimate partner violence can impact cognitive and psychological functioning, as well as neurological outcomes. These seem to be compounded in those who suffer a brain injury as a result of trauma to the head, neck or body due to physical and/or sexual violence. However, our understanding of the neurobehavioral and neurobiological effects of head trauma in this population is limited due to factors including difficulty in accessing/recruiting participants, heterogeneity of samples, and premorbid and comorbid factors that impact outcomes. Thus, the goal of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium Intimate Partner Violence Working Group is to develop a global collaboration that includes researchers, clinicians, and other key community stakeholders. Participation in the working group can include collecting harmonized data, providing data for meta- and mega-analysis across sites, or stakeholder insight on key clinical research questions, promoting safety, participant recruitment and referral to support services. Further, to facilitate the mega-analysis of data across sites within the working group, we provide suggestions for behavioral surveys, cognitive tests, neuroimaging parameters, and genetics that could be used by investigators in the early stages of study design. We anticipate that the harmonization of measures across sites within the working group prior to data collection could increase the statistical power in characterizing how intimate partner violence-related head trauma impacts long-term physical, cognitive, and psychological health.

Associations of Phthalates and Phthalate Replacements With CRH and Other Hormones Among Pregnant Women in Puerto Rico.

CONTEXT: Phthalates are endocrine-disrupting chemicals that may be associated with adverse birth outcomes. Dysregulation of maternal endocrine homeostasis could be a possible biological pathway between phthalates and birth outcomes. OBJECTIVE: Examine associations between 19 maternal urinary phthalate or phthalate replacement metabolites and 9 serum hormones measured over two time points during pregnancy. DESIGN: Longitudinal study conducted in the PROTECT pregnancy cohort. SETTING: Puerto Rico. PATIENTS: Six hundred seventy-seven women in the first trimester of pregnancy. MAIN OUTCOME MEASURES SERUM: CRH, estriol, SHBG, progesterone, TSH, total T3, free T4, total T4, and testosterone. RESULTS: T3 was significantly associated with most metabolites. CRH was inversely associated with mono carboxyisononyl phthalate [MCNP; percent change (%Δ), -4.08; 95% CI, -7.24, -0.804], mono-3-carboxypropyl phthalate (MCPP; %Δ, -5.25; 95% CI, -8.26, -2.14), mono-2-ethyl-5-carboxypentyl phthalate (MECPP; %Δ, -18.4; 95% CI, -30.4, -4.37), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP; %Δ, -13.4; 95% CI, -22.7, -2.92), and mono-2-ethyl-5-oxohexyl phthalate (MEOHP; %Δ, -12.7; 95% CI, -22.2, -2.20). Positive associations were found between numerous phthalate metabolites and free T4, T4, and the T3/T4 ratio. Testosterone was positively associated with mono hydroxybutyl phthalate (MHBP; %Δ, 4.71; 95% CI, 0.27, 9.35) and inversely associated with monoethyl phthalate (MEP; %Δ, -14.5; 95% CI, -24.3, -3.42), and relationships with MCNP and mono carboxyisooctyl phthalate (MCOP) were significantly modified by study visit. Finally, an inverse association was found between mono-2-ethyl-5-hydrohexyl terephthalate (MEHHTP), a terephthalate metabolite, and progesterone at visit 3 only (%Δ, -13.1; 95% CI, -22.3, -2.75). CONCLUSIONS: These results indicate that exposure to phthalates may differentially impact the maternal endocrine system at different points during pregnancy, and that exposures to phthalate replacement chemicals may be particularly important to consider in future human health studies.