Health symptoms after war zone deployment-related mild traumatic brain injury: contributions of mental disorders and lifetime brain injuries.

PRIMARY OBJECTIVE: To gain a better understanding of the complex relationship between combat deployment-related mild traumatic brain injury (mTBI) and persistent post-concussive symptoms (PPCSs), taking into consideration a wide range of potentially mediating and confounding factors. RESEARCH DESIGN: Cross-sectional. METHODS AND PROCEDURES: Subjects were 613 U. S. military Veterans and Service Members who served during operations Enduring Freedom, Iraqi Freedom, or New Dawn (OEF/OIF/OND) and completed a structured interview of mental disorders and a battery of questionnaires. Hierarchical binary logistic regression analyses were used to test the hypotheses. MAIN OUTCOMES AND RESULTS: After accounting for mental disorders, lifetime mTBIs outside of OEF/OIF/OND deployment, medical conditions, and injury/demographic characteristics, deployment-related mTBI continued to be associated with several PPCSs (headaches, sleep disturbance, and difficulty making decisions). Deployment-related mTBI was also associated with two symptoms not normally associated with mTBI (nausea/upset stomach and numbness/tingling). CONCLUSIONS: After adjusting for a wide range of factors, OEF/OIF/OND deployment-related mTBI was still associated with PPCSs on average 10 years after the injury. These findings suggest that mTBI sustained during OEF/OIF/OND deployment may have enduring negative health effects. More studies are needed that prospectively and longitudinally track health and mental health outcomes after TBI.

Alcohol-Related Blackouts, Negative Alcohol-Related Consequences, and Motivations for Drinking Reported by Newly Matriculating Transgender College Students.

BACKGROUND: Many transgender college students struggle with identity formation and other emotional, social, and developmental challenges associated with emerging adulthood. A potential maladaptive coping strategy employed by such students is heavy drinking. Prior literature has suggested greater consumption and negative alcohol-related consequences (ARCs) in transgender students compared with their cisgender peers, but little is known about their differing experiences with alcohol-related blackouts (ARBs). We examined the level of alcohol consumption, the frequency of ARBs and other ARCs, and motivations for drinking reported by the largest sample of transgender college students to date. METHODS: A Web survey from an alcohol-prevention program, AlcoholEdu for College™, assessed student demographics and drinking-related behaviors, experiences, and motivations of newly matriculating first-year college students. A self-reported drinking calendar was used to examine each of the following measures over the previous 14 days: number of drinking days, total number of drinks, and maximum number of drinks on any single day. A 7-point Likert scale was used to measure ARCs, ARBs, and drinking motivations. Transgender students of both sexes were compared with their cisgender peers. RESULTS: A total of 989 of 422,906 students (0.2%) identified as transgender. Over a 14-day period, transgender compared with cisgender students were more likely to consume alcohol over more days, more total drinks, and a greater number of maximum drinks on a single day. Transgender students (36%) were more likely to report an ARB than cisgender students (25%) as well as more negative academic, confrontation-related, social, and sexual ARCs. Transgender respondents more often cited stress reduction, social anxiety, self-esteem issues, and the inherent properties of alcohol as motivations for drinking. For nearly all measures, higher values were yielded by male-to-female than female-to-male transgender students. CONCLUSIONS: Transgender compared with cisgender first-year students engage in higher-risk drinking patterns and experience more ARBs and other negative ARCs. Broad institutional efforts are required to address the unique circumstances of transgender men and women and to reduce negative ARCs in college students, regardless of their sex or gender identity.

Allopregnanolone Levels Are Inversely Associated with Self-Reported Pain Symptoms in U.S. Iraq and Afghanistan-Era Veterans: Implications for Biomarkers and Therapeutics.

BACKGROUND AND OBJECTIVES: Pain symptoms are common among Iraq/Afghanistan-era veterans, many of whom continue to experience persistent pain symptoms despite multiple pharmacological interventions. Preclinical data suggest that neurosteroids such as allopregnanolone demonstrate pronounced analgesic properties, and thus represent logical biomarker candidates and therapeutic targets for pain. Allopregnanolone is also a positive GABAA receptor modulator with anxiolytic, anticonvulsant, and neuroprotective actions in rodent models. We previously reported inverse associations between serum allopregnanolone levels and self-reported pain symptom severity in a pilot study of 82 male veterans. METHODS: The current study investigates allopregnanolone levels in a larger cohort of 485 male Iraq/Afghanistan-era veterans to attempt to replicate these initial findings. Pain symptoms were assessed by items from the Symptom Checklist-90-R (SCL-90-R) querying headache, chest pain, muscle soreness, and low back pain over the past 7 days. Allopregnanolone levels were quantified by gas chromatography/mass spectrometry. RESULTS: Associations between pain ratings and allopregnanolone levels were examined with Poisson regression analyses, controlling for age and smoking. Bivariate nonparametric Mann­Whitney analyses examining allopregnanolone levels across high and low levels of pain were also conducted. Allopregnanolone levels were inversely associated with muscle soreness [P = 0.0028], chest pain [P = 0.032], and aggregate total pain (sum of all four pain items) [P = 0.0001]. In the bivariate analyses, allopregnanolone levels were lower in the group reporting high levels of muscle soreness [P = 0.001]. CONCLUSIONS: These findings are generally consistent with our prior pilot study and suggest that allopregnanolone may function as an endogenous analgesic. Thus, exogenous supplementation with allopregnanolone could have therapeutic potential. The characterization of neurosteroid profiles may also have biomarker utility.

Suicidal ideation and sex differences in relation to 18 major psychiatric disorders in college and university students: anonymous web-based assessment.

College/university students are at high risk for psychiatric disorder and suicide secondary to age, campus stressors, and social pressures. We therefore report frequencies of 18 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision disorders and suicidal ideation (SI) acquired anonymously from a Web site receiving 113,181 visits from more than 1,500 predominantly US colleges/universities. Depression was foremost, followed by social phobia and eating disorders. Substance-related disorders were less frequent than expected. SI occurred in 47.1% of students, with women evidencing somewhat stronger findings than men. SI was more associated with substance, bipolar, and panic disorders than depression. Self-reported emotional volatility exceeded thoughts of self-harm for all disorders. The results support two subtypes of suicide risk: dysphoric premeditators and those primarily angry and/or impulsive. Clinicians and researchers should therefore consider suicide as an independent psychopathological phenomenon that includes emotional volatility as a risk factor and thoroughly evaluate psychiatric disorders potentially conferring greater suicidal propensity than depression.

Evaluation of an augmented virtual reality and haptic control interface for psychomotor training.

This study investigated the design of a virtual reality (VR) simulation integrating a haptic control interface for motor skill training. Twenty-four healthy participants were tested and trained in standardized psychomotor control tasks using native and VR forms with their nondominant hands in order to identify VR design features that might serve to accelerate motor learning. The study was also intended to make preliminary observations on the degree of specific motor skill development that can be achieved with a VR-based haptic simulation. Results revealed significant improvements in test performance following training for the VR with augmented haptic features with insignificant findings for the native task and VR with basic haptic features. Although performance during training was consistently better with the native task, a correspondence between the VR training and test task interfaces led to greater improvement in test performance as reported by a difference between baseline and post-test scores. These findings support use of VR-based haptic simulations of standardized psychomotor tests for motor skill training, including visual and haptic enhancements for effective pattern recognition and discrete movement of objects. The results may serve as an applicable guide for design of future haptic VR features.

A case of frontal neuropsychological and neuroimaging signs following multiple primary-blast exposure.

Blast-related traumatic brain injury (TBI) from the Afghanistan and Iraq wars represents a significant medical concern for troops and veterans. To better understand the consequences of primary-blast injury in humans, we present a case of a Marine exposed to multiple primary blasts during his 14-year military career. The neuropsychological profile of this formerly high-functioning veteran suggested primarily executive dysfunction. Diffusion-tensor imaging revealed white-matter pathology in long fiber tracks compared with a composite fractional-anisotropy template derived from a veteran reference control group without TBI. This study supports the existence of primary blast-induced neurotrauma in humans and introduces a neuroimaging technique with potential to discriminate multiple-blast TBI.

Neurosteroids and self-reported pain in veterans who served in the U.S. Military after September 11, 2001.

OBJECTIVE: Nearly half of Operation Enduring Freedom/Operation Iraqi Freedom veterans experience continued pain post-deployment. Several investigations report analgesic effects of allopregnanolone and other neurosteroids in animal models, but few data are currently available focusing on neurosteroids in clinical populations. Allopregnanolone positively modulates GABA(A) receptors and demonstrates pronounced analgesic and anxiolytic effects in rodents, yet studies examining the relationship between pain and allopregnanolone in humans are limited. We thus hypothesized that endogenous allopregnanolone and other neurosteroid levels may be negatively correlated with self-reported pain symptoms in humans. DESIGN: We determined serum neurosteroid levels by gas chromatography/mass spectrometry (allopregnanolone, pregnenolone) or radioimmunoassay (dehydroepiandrosterone [DHEA], progesterone, DHEA sulfate [DHEAS]) in 90 male veterans who served in the U.S. military after September 11, 2001. Self-reported pain symptoms were assessed in four areas (low back pain, chest pain, muscle soreness, headache). Stepwise linear regression analyses were conducted to investigate the relationship between pain assessments and neurosteroids, with the inclusion of smoking, alcohol use, age, and history of traumatic brain injury as covariates. SETTING: Durham VA Medical Center. RESULTS: Allopregnanolone levels were inversely associated with low back pain (P=0.044) and chest pain (P=0.013), and DHEA levels were inversely associated with muscle soreness (P=0.024). DHEAS levels were positively associated with chest pain (P=0.001). Additionally, there was a positive association between traumatic brain injury and muscle soreness (P=0.002). CONCLUSIONS: Neurosteroids may be relevant to the pathophysiology of self-reported pain symptoms in this veteran cohort, and could represent future pharmacological targets for pain disorders.

Cognitive sequelae of blast-related versus other mechanisms of brain trauma.

The use of improvised explosive devices has become the hallmark of modern warfare and has resulted in an ever-increasing number of blast-related traumatic brain injuries (TBIs). Despite this fact, very little is actually known about the cognitive sequelae of blast-related TBIs. The purpose of the current study was to compare patterns of performance on neuropsychological measures in subjects who have sustained TBIs as a result of blast (or explosion) with those who have sustained TBIs from non-blast or blunt force trauma (motor vehicle accident, fall, assault, etc.). Participants were categorized as blast-related TBI or non-blast-related TBI and according to severity of injury (mild or moderate-to-severe). No main effects were observed in analysis of covariance between blast-related TBI participants and non-blast-related TBI participants across any of the neuropsychological variables, although an interaction was observed on a visual memory test showing stronger performance for mild blast-related and poorer performance for moderate-to-severe blast-related participants compared with both non-blast groups. Overall, the results do not provide any strong evidence that blast is categorically different from other TBI mechanisms, at least with regard to cognitive sequelae on select measures. Additional findings included a marginally increased incidence of reported posttraumatic stress disorder symptoms among blast-injured participants. (JINS, 2009, 15, 1-8.).

An effect-size analysis of pharmacologic treatments for generalized anxiety disorder.

Generalized anxiety disorder (GAD) is a prevalent and impairing disorder, associated with extensive psychiatric and medical comorbidity and usually characterized by a chronic course. Different drugs have been investigated in GAD; among them are the following: 1) SSRIs: paroxetine, sertraline, fluvoxamine and escitalopram; 2) SNRI1s: venlafaxine; 3) benzodiazepines (BZs): alprazolam, diazepam and lorazepam; 4) azapirones (AZAs): buspirone; 5) antihistamines (AHs): hydroxyzine; 6) pregabalin (PGB); and 7) complementary/alternative medicine (CAM): kava-kava and homeopathic preparation. We conducted an effect size (ES) analysis of 21 double-blind placebo-controlled trials of medications treating DSM-III-R, DSM-IV or ICD-10 GAD using HAM-A change in score from baseline or endpoint score as the main efficacy measure. Literature search was performed using MEDLINE and PsycINFO databases including articles published between 1987 and 2003 and personal communications with investigators and sponsors. comparing all drugs versus placebo, the ES was 0.39. Mean ESs, excluding children, were PGB: 0.50, AH: 0.45, SNRI: 0.42, BZ: 0.38, SSRI: 0.36, AZA: 0.17 and CAM: -0.31. Comparing ES for adults versus children/adolescents (excluding CAM) and conventional drugs versus CAM (excluding children/adolescents) we found significantly higher ES for children/adolescents and for conventional drugs (p < 0.001 and p < 0.01, respectively). No significant differences were found when comparing date of publication, location of site (i.e. US versus other), fixed versus flexible dosing, number of study arms, or number of outcome measures used. Medications varied in the magnitude of their ES, ranging from moderate to poor. Adolescents and children showed a much greater ES compared with adults. Subjects taking CAM had worse outcomes than placebo.

The Post-Deployment Mental Health (PDMH) study and repository: A multi-site study of US Afghanistan and Iraq era veterans.

The United States (US) Department of Veterans Affairs (VA) Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) Post-Deployment Mental Health (PDMH) multi-site study examines post-deployment mental health in US military Afghanistan/Iraq-era veterans. The study includes the comprehensive behavioral health characterization of over 3600 study participants and the genetic, metabolomic, neurocognitive, and neuroimaging data for many of the participants. The study design also incorporates an infrastructure for a data repository to re-contact participants for follow-up studies. The overwhelming majority (94%) of participants consented to be re-contacted for future studies, and our recently completed feasibility study indicates that 73-83% of these participants could be reached successfully for enrollment into longitudinal follow-up investigations. Longitudinal concurrent cohort follow-up studies will be conducted (5-10+ years post-baseline) to examine predictors of illness chronicity, resilience, recovery, functional outcome, and other variables, and will include neuroimaging, genetic/epigenetic, serum biomarker, and neurocognitive studies, among others. To date, the PDMH study has generated more than 35 publications from the baseline data and the repository has been leveraged in over 20 publications from follow-up studies drawing from this cohort. Limitations that may affect data collection for a longitudinal follow-up study are also presented.

Segmented hippocampal volume in children and adolescents with posttraumatic stress disorder.

BACKGROUND: Although many studies of adults with posttraumatic stress disorder (PTSD) have reported smaller hippocampal volume compared with control subjects, comparable studies of children and adolescents have failed to replicate these findings or have noted opposite trends suggesting a larger hippocampus. We therefore performed a secondary analysis combining data from prior studies to examine the hypothesis that hippocampus would be larger in pediatric subjects with PTSD compared with non-maltreated control subjects. We also hypothesized that differences in PTSD subjects would be observed between boys and girls. METHODS: Sixty-one subjects (31 boys, 30 girls) with maltreatment-related PTSD and 122 control subjects matched on age and gender underwent magnetic resonance imaging. RESULTS: As hypothesized, we observed a significantly larger hippocampus controlling for cerebral volume in PTSD subjects compared with control subjects. Segmented hippocampal white-matter volume was greater in PTSD subjects but not gray-matter volume. Hippocampal volume was positively related to age of trauma onset and level of psychopathology, particularly externalizing behavior. No interactions with group were observed for age or gender. CONCLUSIONS: Future longitudinal studies with trauma control subjects and neuropsychological measures are indicated to further elucidate the relationship between hippocampus and behavioral abnormalities in young PTSD subjects.

Treatment outcome variation between depression symptom combinations in the STAR*D study.

BACKGROUND: In response to recent documentation of symptom and subtype heterogeneity in major depressive disorder, we report on exploratory analyses of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical-trial data to further describe heterogeneity in depression and test the hypothesis that citalopram treatment-outcome patterns differ as a function of depression symptom combinations. METHODS: Combinatorial algorithms, latent profile analysis, and repeated-measures multivariate analysis of variance were employed to characterize heterogeneity and depression outcome-measure profile variability in the most prevalent symptom combinations with full data (26% of baseline and 13% of endpoint total sample). RESULTS: Descriptive results suggest that substantial heterogeneity and moderate coherence characterize major depressive disorder; as in previous analyses, pairs of individuals sharing no symptoms in common were observed. Exploratory latent profile analysis indicated that different patterns of treatment outcome data exist among STAR*D participants. A small but significant interaction effect of symptom combination×outcome measure profile was observed for clinician-rated but not self-reported symptom combinations. LIMITATIONS: Factors moderating the generalizability of these findings include binary symptom measures, a short treatment period, and a smaller number of individuals per combination. CONCLUSIONS: These results provide evidence that citalopram treatment outcomes vary as a function of diagnostic combinations, thereby providing preliminary evidence that the substantial heterogeneity documented in depression symptom presentations may carry implications for prognosis and treatment outcome. At the level of descriptive phenomenology, these results appear to corroborate the claim that depression is not a homogenous syndrome.

Brain morphometry, T2-weighted hyperintensities, and IQ in children with neurofibromatosis type 1.

BACKGROUND: Larger gray matter (GM) volume in healthy children is correlated with higher IQ. Children with neurofibromatosis type 1 (NF1) have larger brains, their magnetic resonance images frequently show T2-weighted hyperintensities, and their IQs are lower. OBJECTIVES: To confirm the hypotheses that (1) children with NF1 have larger GM and white matter volumes, (2) the greatest volume differences are in the frontal and parietal regions and in children with NF1 with hyperintensities, and (3) GM volume is inversely related to IQ in children with NF1. DESIGN: Wechsler Intelligence Scale for Children-Third Edition IQ testing and measurement of cerebral volumes and hyperintensities in brain magnetic resonance images were performed on 36 children with NF1 and on 36 matched relatives who served as control subjects. RESULTS: Gray matter and white matter volumes were significantly larger in children with NF1. The greatest difference was observed in cerebral white matter volume, predominantly in the frontal lobes, whereas the greatest difference in GM volume was in the temporal, parietal, and occipital regions. In controls, IQ was significantly related to GM volume, but in children with NF1, IQ was not inversely associated with GM volume, although IQs of children with NF1 were significantly lower. CONCLUSIONS: Children with NF1 do not have the normal relationship between GM volume and IQ. Larger GM volume in the posterior brain regions and larger white matter volumes in the frontal brain regions contribute to the larger brain volume in children with NF1.

Focal and lateralized subcortical abnormalities in unipolar major depressive disorder: an automated multivoxel proton magnetic resonance spectroscopy study.

BACKGROUND: The results of prior proton magnetic resonance spectroscopy ((1)H-MRS) studies in unipolar major depressive disorder (MDD) evaluating choline (Cho)/creatine (Cr) and N-acetyl-L-aspartate (NAA)/Cr ratios are mixed. These single-voxel or one-dimensional chemical-shift imaging (CSI) nonautomated (1)H-MRS studies has been unable to evaluate global or lateralized abnormalities in neuronal or membrane function. Using automated multivoxel two-dimensional CSI (1)H-MRS techniques, we tested the hypothesis that patients with MDD have focal neuronal and membrane abnormalities localized in the subcortical region. METHODS: Whole brain and subcortical measures of Cho, NAA, Cr, and myo-inositol (mI) were obtained in 18 patients with MDD and 20 control subjects using automated two-dimensional CSI (1)H-MRS. RESULTS: Compared with control subjects, MDD patients had a significantly lower mean NAA/Cr amplitude in the caudate and a significantly higher mean Cho/Cr amplitude in the putamen, particularly on the right side. No differences were observed for global whole brain measurements. CONCLUSIONS: The findings support reduced neuronal viability or function in the caudate and altered membrane phospholipid metabolism in the putamen for patients with MDD. Our results are consistent with prior magnetic resonance imaging, positron emission tomography, and postmortem reports of focal and lateralized abnormalities of the basal ganglia in MDD.

Puzzling thoughts for H. M.: can new semantic information be anchored to old semantic memories?

Researchers currently debate whether new semantic knowledge can be learned and retrieved despite extensive damage to medial temporal lobe (MTL) structures. The authors explored whether H. M., a patient with amnesia, could acquire new semantic information in the context of his lifelong hobby of solving crossword puzzles. First, H. M. was tested on a series of word-skills tests believed important in solving crosswords. He also completed 3 new crosswords: 1 puzzle testing pre-1953 knowledge, another testing post-1953 knowledge, and another combining the 2 by giving postoperative semantic clues for preoperative answers. From the results, the authors concluded that H. M. can acquire new semantic knowledge, at least temporarily, when he can anchor it to mental representations established preoperatively.

Anatomic location and laterality of MRI signal hyperintensities in late-life depression.

OBJECTIVES: Evidence is mounting linking cerebrovascular disease with the development of major depression in the elderly. Lesions in both white and gray matter have been associated with geriatric depression. In addition, the literature on poststroke depression suggests that left-sided lesions are associated with depression. We sought to examine the severity and location of white- and gray-matter lesions in a group of elderly depressives and nondepressed control subjects. METHOD: 115 depressed patients (69 with late onset, 46 with early onset) and 37 controls, all over age 45, received magnetic resonance imaging (MRI). Semiquantitative severity ratings and quantitative measurements of number and size of MRI hyperintensities were obtained, and groups were compared using Cochran-Mantel-Haenszel (CMH) analyses and repeated-measures analyses of covariance adjusting for age. RESULTS: Late-onset depressed patients had more severe hyperintensity ratings in deep white matter than early-onset patients and controls. Late- and early-onset patients had more severe subcortical gray-matter hyperintensities (particularly in the putamen) compared with controls. Left-sided white-matter lesions were significantly associated with older age of depression onset, whereas right-anterior white matter and left-subcortical lesions (particularly in the putamen) were associated with melancholia in the depressed group. CONCLUSION: These findings extend previous reports of an association between cerebrovascular disease and depression, as well as recent studies showing lateralized lesion involvement in geriatric depression. Such vascular pathology may disrupt neural pathways involved in affective processing and the maintenance of a normal mood and psychomotor state.

MR signal intensity of gray matter/white matter contrast and intracranial fat: effects of age and sex.

Signal intensity (SI) values of gray- and white-matter brain regions of interest (ROIs) were obtained from T(2)- and proton density-weighted magnetic resonance (MR) images of 58 normal subjects aged 22-82 years (31 females, 52.3+/-18.8 years; 27 males, 54.1+/-18.1 years). Sampled ROIs included the caudate, putamen, thalamus, orbitofrontal gyrus, gyrus rectus, uncus, frontal white matter, anterior and posterior corpus callosum, cranial-cervical junction fat, and retroorbital fat. Effects of age and sex on SI were examined using repeated-measures analysis of covariance. For both T(2)- and proton density-weighted acquisitions, a significant inverse relationship between age and SI was observed for the ratio of all summed gray-matter ROIs divided by summed white-matter ROIs. This relationship was additionally observed for ratios of both subcortical gray/white matter and cortical gray/white matter. Females compared with males had significantly lower cortical gray/white matter ratios on T(2)-weighted scans. Differences in SI were observed between cranial-cervical junction fat and retroorbital fat on both acquisitions, with females showing significantly higher values for cranial-cervical junction fat and males showing higher values for retroorbital fat. Implications for brain morphometry, the use of fat as a reference standard, and other issues in neuroimaging are discussed.

Quantifying heterogeneity attributable to polythetic diagnostic criteria: theoretical framework and empirical application.

Heterogeneity within psychiatric disorders is both theoretically and practically problematic: For many disorders, it is possible for 2 individuals to share very few or even no symptoms in common yet share the same diagnosis. Polythetic diagnostic criteria have long been recognized to contribute to this heterogeneity, yet no unified theoretical understanding of the coherence of symptom criteria sets currently exists. A general framework for analyzing the logical and mathematical structure, coherence, and diversity of Diagnostic and Statistical Manual diagnostic categories (DSM-5 and DSM-IV-TR) is proposed, drawing from combinatorial mathematics, set theory, and information theory. Theoretical application of this framework to 18 diagnostic categories indicates that in most categories, 2 individuals with the same diagnosis may share no symptoms in common, and that any 2 theoretically possible symptom combinations will share on average less than half their symptoms. Application of this framework to 2 large empirical datasets indicates that patients who meet symptom criteria for major depressive disorder and posttraumatic stress disorder tend to share approximately three-fifths of symptoms in common. For both disorders in each of the datasets, pairs of individuals who shared no common symptoms were observed. Any 2 individuals with either diagnosis were unlikely to exhibit identical symptomatology. The theoretical and empirical results stemming from this approach have substantive implications for etiological research into, and measurement of, psychiatric disorders.