Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary.

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p < 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p < 0.039), functional (p < 0.016), and cognitive impairment (p < 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.

White Matter Microstructure Is Associated with Serum Neuroactive Steroids and Psychological Functioning.

Military service members are at increased risk for mental health issues, and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations among white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system. Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FAT) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations. ALLO is associated with whole-brain white matter FAT (ß = 0.24, t = 3.05, p = 0.006). This association is significantly modulated by PTSD+mTBI comorbidity (ß = 0.00, t = 2.50, p = 0.027), although an mTBI diagnosis alone did not significantly impact this association (p = 0.088). There was no significant association between PREGNE and FAT (p = 0.380). Importantly, lower FAT is associated with poor psychological functioning (ß = -0.19, t = -2.35, p = 0.020). This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.

Gene Expression Analysis in Three Posttraumatic Stress Disorder Cohorts Implicates Inflammation and Innate Immunity Pathways and Uncovers Shared Genetic Risk With Major Depressive Disorder.

Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop following exposure to traumatic events. The Psychiatric Genomics Consortium PTSD group (PGC-PTSD) has collected over 20,000 multi-ethnic PTSD cases and controls and has identified both genetic and epigenetic factors associated with PTSD risk. To further investigate biological correlates of PTSD risk, we examined three PGC-PTSD cohorts comprising 977 subjects to identify differentially expressed genes among PTSD cases and controls. Whole blood gene expression was quantified with the HumanHT-12 v4 Expression BeadChip for 726 OEF/OIF veterans from the Veterans Affairs (VA) Mental Illness Research Education and Clinical Center (MIRECC), 155 samples from the Injury and Traumatic Stress (INTRuST) Clinical Consortium, and 96 Australian Vietnam War veterans. Differential gene expression analysis was performed in each cohort separately followed by meta-analysis. In the largest cohort, we performed co-expression analysis to identify modules of genes that are associated with PTSD and MDD. We then conducted expression quantitative trait loci (eQTL) analysis and assessed the presence of eQTL interactions involving PTSD and major depressive disorder (MDD). Finally, we utilized PTSD and MDD GWAS summary statistics to identify regions that colocalize with eQTLs. Although not surpassing correction for multiple testing, the most differentially expressed genes in meta-analysis were interleukin-1 beta (IL1B), a pro-inflammatory cytokine previously associated with PTSD, and integrin-linked kinase (ILK), which is highly expressed in brain and can rescue dysregulated hippocampal neurogenesis and memory deficits. Pathway analysis revealed enrichment of toll-like receptor (TLR) and interleukin-1 receptor genes, which are integral to cellular innate immune response. Co-expression analysis identified four modules of genes associated with PTSD, two of which are also associated with MDD, demonstrating common biological pathways underlying the two conditions. Lastly, we identified four genes (UBA7, HLA-F, HSPA1B, and RERE) with high probability of a shared causal eQTL variant with PTSD and/or MDD GWAS variants, thereby providing a potential mechanism by which the GWAS variant contributes to disease risk. In summary, we provide additional evidence for genes and pathways previously reported and identified plausible novel candidates for PTSD. These data provide further insight into genetic factors and pathways involved in PTSD, as well as potential regions of pleiotropy between PTSD and MDD.

Genetic predictors of hippocampal subfield volume in PTSD cases and trauma-exposed controls.

Behavioural, structural, and functional neuroimaging have implicated the hippocampus as a critical brain region in posttraumatic stress disorder (PTSD) pathogenesis. Recent work in a normative, primarily European, sample identified 15 unique genetic loci contributing to structural variability in six hippocampal subfield volumes. We explored the relevance of these loci in two samples (Mental Illness Research Education and Clinical Centre [MIRECC] and Grady; n = 290) of trauma-exposed individuals enriched for PTSD and of diverse ancestry. Four of the previous loci demonstrated nominal evidence of replication in the MIRECC dataset, primarily within non-Hispanic whites (NHW). One locus replicated in the Grady cohort, which was composed exclusively of non-Hispanic blacks (NHB). Our data supported genetic interactions with diagnosis of lifetime PTSD and genetic interactions with childhood trauma in the MIRECC sample, but not the Grady sample. Given the racial, diagnostic, and trauma-exposure differences with the original genome-wide association study (GWAS) report, we conducted a full GWAS in the MIRECC and Grady datasets. Interactions between genetic variants and lifetime PTSD or childhood trauma were interrogated for single nucleotide polymorphisms (SNPs) with evidence of main effects. Genetic associations surpassed false discovery rate (FDR)-correction within hippocampal subfields in fimbria, subiculum, cornu ammonis-1 (CA1), and hippocampal amygdala transition area (HATA). One association was replicated in the Grady cohort (rs12880795 in TUNAR with left (L)-HATA volume). The most significant association in the MIRECC dataset was between rs6906714 in LINC02571 and right (R)-fimbria volume (p = 5.99×10-8, q = 0.0056). Interestingly, the effect of rs6906714 on R-fimbria volume increased with exposure to childhood trauma (gene*environment [G*E] interaction p = 0.022). These preliminary results argue for G*E interactions between genetic loci with PTSD and childhood trauma on hippocampal phenotypes. Our results underscore the need for larger neuroimaging-genetic studies in PTSD, trauma, and ancestrally diverse populations.

Las neuroimagenologia, conductual, estructural y funcional ha implicado que el hipocampo se constituye como una región cerebral critica en la patogénesis del trastorno de estrés postraumático (TEPT). Un trabajo reciente, realizado en una muestra normativa, principalmente europea, identifico 15 loci genéticos únicos que contribuyen a la variabilidad estructural de seis volúmenes de subcampos hipocampales. Exploramos la relevancia de estos loci en dos muestras enriquecidas para TEPT (del Centro de Educación y Clínica Investigación sobre Enfermedades Mentales, MIRECC por sus siglas en inglés y Grady; n=290) de individuos expuestos a trauma y de ascendencia diversa. Cuatro de los loci previos demostraron evidencia nominal de replicación en la base de datos MIRECC, principalmente en personas de raza blanca no hispánicos (NHW). Se replicó un locus en la cohorte Grady, que estaba compuesta exclusivamente por personas de raza negra no hispánicos (NHB). Nuestros datos respaldaron las interacciones genéticas con el diagnostico de TEPT a lo largo de la vida e interacciones genéticas con trauma infantil en la muestra MIRECC, pero no en la de Grady. Debido a las diferencias raciales, diagnósticas y de exposición a trauma con el reporte original del estudio de asociación del genoma completo (GWAS por sus siglas en ingles), realizamos un GWAS completo con la base de datos MIRECC y Grady. Se exploraron polimorfismos de nucleótido único (SNPs por sus siglas en ingles) en las interacciones de variantes genéticas del TEPT a lo largo de la vida y del trauma infantil, con evidencia de un efecto genético principal. Las asociaciones genéticas sobrepasaron a la corrección de tasa de falso descubrimiento (FDR) dentro de los subcampos hipocampales de la fimbria, subículo, asta de Amon-1 (CA1), y el área de transición hipocampo-amigdaliana (HATA). Una asociación se replicó en la cohorte de Grady (rs 12880795 en TUNAR con volumen izquierdo del HATA). La asociación más significativa en la base de datos de MIRECC estuvo entre rs6906714 en LINC02571 y el volumen de la fimbria derecha (p=5.99×10-8, q=0.0056). Interesantemente, el efecto rs6906714 sobre el volumen de la fimbria derecha se incrementaba con la exposición al trauma infantil (interacción gen* ambiente [G*A] p=0.022). Estos resultados preliminares orientarían a la presencia de interacciones G*A de loci genéticos con el TEPT y trauma infantil en fenotipos del hipocampo. Nuestro resultados destacan la necesidad de estudios más grandes que vinculen neuroimagenes y genética en poblaciones con TEPT, trauma, y genealogía diversa.

Contributions of posttraumatic stress disorder (PTSD) and mild TBI (mTBI) history to suicidality in the INTRuST consortium.

OBJECTIVE: Mild TBI (mTBI) and posttraumatic stress disorder (PTSD) are independent risk factors for suicidal behaviour (SB). Further, co-occurring mTBI and PTSD increase one's risk for negative health and psychiatric outcomes. However, little research has examined the role of comorbid mTBI and PTSD on suicide risk. METHODS: The present study utilized data from the Injury and TRaUmatic STress (INTRuST) Consortium to examine the prevalence of suicidal ideation (SI) and behaviours among four groups: 1) comorbid mTBI+PTSD, 2) PTSD only, 3) mTBI only, and 4) healthy controls. RESULTS: Prevalence of lifetime SI, current SI, and lifetime SB for individuals with mTBI+PTSD was 40%, 25%, and 19%, respectively. Prevalence of lifetime SI, current SI, and lifetime SB for individuals with PTSD only was 29%, 11%, and 11%, respectively. Prevalence of lifetime SI, current SI, and lifetime SB for individuals with mTBI only was 14%, 1%, and 2%, respectively. Group comparisons showed that individuals with mTBI alone experienced elevated rates of lifetime SI compared to healthy controls. History of mTBI did not add significantly to risk for suicidal ideation and behaviour beyond what is accounted for by PTSD. CONCLUSION: Findings suggest that PTSD seems to be driving risk for suicidal behaviour.

Neuroendocrine biomarkers of prolonged exposure treatment response in military-related PTSD.

Posttraumatic stress disorder (PTSD) is associated with dysregulation of the neuroendocrine system, including cortisol, allopregnanolone, and pregnanolone. Preliminary evidence from animal models suggests that baseline levels of these biomarkers may predict response to PTSD treatment. We report the change in biomarkers over the course of PTSD treatment. Biomarkers were sampled from individuals participating in (1) a randomized controlled trial comparing a web-version of Prolonged Exposure (Web-PE) therapy to in-person Present-Centered Therapy (PCT) and (2) from individuals participating in a nonrandomized effectiveness study testing PE delivered in-person as part of an intensive outpatient PTSD program. We found that higher cortisol reactivity during script-driven imagery was associated with higher baseline PTSD severity and that baseline allopregnanolone, pregnanolone, and cortisol reactivity were associated with PTSD treatment responder status over the course of intensive outpatient treatment. These findings demonstrate that peripherally assessed biomarkers are associated with PTSD severity and likelihood of successful treatment outcome of PE delivered daily over two weeks. These assessments could be used to determine which patients are likely to respond to treatment and which patients require augmentation to increase the likelihood of optimal response to PTSD treatment.

Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial.

Importance: In response to the national opioid public health crisis, there is an urgent need to develop nonopioid solutions for effective pain management. Neurosteroids are endogenous molecules with pleotropic actions that show promise for safe and effective treatment of chronic low back pain. Objective: To determine whether adjunctive pregnenolone has therapeutic utility for the treatment of chronic low back pain in Iraq- and Afghanistan-era US military veterans. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled clinical trial that enrolled for 42 months, from September 2013 to April 2017. Participants were Iraq- and Afghanistan-era veterans aged 18 to 65 years with chronic low back pain who received treatment in the Durham VA Health Care System in Durham, North Carolina, over 6 weeks. Data analysis began in 2018 and was finalized in March, 2019. Interventions: Following a 1-week placebo lead-in, participants were randomized to pregnenolone or placebo for 4 weeks. Pregnenolone and placebo were administered at fixed, escalating doses of 100 mg for 1 week, 300 mg for 1 week, and 500 mg for 2 weeks. Main Outcomes and Measures: The primary outcome measure was the change in mean pain intensity ratings from a daily pain diary (numerical rating scale, 0-10) between visit 3 (baseline) and visit 6. Secondary outcomes included pain interference scores (Brief Pain Inventory, Short Form). Preintervention and postintervention neurosteroid levels were quantified by gas chromatography with tandem mass spectrometry. Hypotheses tested were formulated prior to data collection. Results: A total of 94 participants (84 [89.4%] male; mean [SD] age, 37.5 [9.8] years; 53 [56.4%] of self-reported Caucasian race and 31 [33.0%] of self-reported African American race) were included. Forty-eight participants were randomized to pregnenolone and 52 to placebo, of whom 45 and 49, respectively, were included in baseline demographic characteristics secondary to noncompliance with medications as per protocol. Veterans randomized to pregnenolone reported significant reductions in low back pain relative to those randomized to placebo. Baseline unadjusted mean (SE) pain diary ratings were 4.83 (0.23) and 5.24 (0.22) for the placebo- and pregnenolone-treated groups, respectively (baseline unadjusted mean [SE] ratings for pain recall were 4.78 [0.24] and 5.15 [0.23], respectively). Unadjusted mean (SE) ratings following treatment (visit 6) were 4.74 (0.26) in the placebo group and 4.19 (0.30) in the pregnenolone-treated group. Unadjusted mean (SE) ratings for pain recall following treatment were 4.86 (0.27) for placebo and 4.18 (0.29) for pregnenolone. Least-square mean (LSM) analysis showed that pain scores significantly improved in the pregnenolone-treated group compared with placebo (LSM [SE] change in pain diary rating, -0.56 [0.25]; P = .02; LSM [SE] change in pain recall, -0.70 [0.27]; P = .01). Pain interference scores for work (LSM [SE] change, 0.71 [0.12]; P = .04) and activity (LSM [SE] change, 0.71 [0.11]; P = .03) were also improved in veterans randomized to pregnenolone compared with placebo. Pregnenolone was well tolerated. Conclusions and Relevance: Participants receiving pregnenolone reported a clinically meaningful reduction in low back pain and 2 pain interference domains compared with those receiving placebo. Pregnenolone may represent a novel, safe, and potentially efficacious treatment for the alleviation of chronic low back pain in Iraq- and Afghanistan-era veterans. Trial Registration: ClinicalTrials.gov Identifier: NCT01898013.

Serum Neurosteroid Levels Are Associated With Cortical Thickness in Individuals Diagnosed With Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury.

Posttraumatic stress disorder (PTSD) co-occurring with mild traumatic brain injury (mTBI) is common in veterans. Worse clinical outcome in those with PTSD has been associated with decreased serum neurosteroid levels. Furthermore, decreased cortical thickness has been associated with both PTSD and mTBI. However, it is not known whether decreased neurosteroids are associated with decreased cortical thickness in PTSD co-occurring with mTBI. This study included 141 individuals divided into the following groups: (a) mTBI group (n = 32 [10 female, 22 male] veterans with a history of mTBI); (b) PTSD + mTBI group (n = 41 [6 female, 35 male] veterans with current PTSD with a history of mTBI); and (c) control group (n = 68 [35 female, 33 male] control participants), which were acquired through the Injury and Traumatic Stress (INTRuST) Clinical Consortium. Subjects underwent clinical assessment, magnetic resonance imaging at 3 T, and serum neurosteroid quantifications of allopregnanolone (ALLO) and pregnenolone (PREGN). Group differences in cortical thickness and associations between serum neurosteroid levels and cortical thickness were investigated. Cortical thickness was decreased in the PTSD + mTBI group compared with the other groups. In the PTSD + mTBI group, decreased cortical thickness was also associated with lower serum ALLO (right superior frontal cortex) and lower serum PREGN (left middle temporal and right orbitofrontal cortex). Cortical thickness in the middle temporal and orbitofrontal cortex was associated with PTSD symptom severity. There were no significant associations between neurosteroids and cortical thickness in the mTBI or control groups. Decreased cortical thickness in individuals with PTSD + mTBI is associated with decreased serum neurosteroid levels and greater PTSD symptom severity. Causality is unclear. However, future studies might investigate whether treatment with neurosteroids could counteract stress-induced neural atrophy in PTSD + mTBI by potentially preserving cortical thickness.

An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.

BACKGROUND: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). METHODS: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). RESULTS: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10-7, padj = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10-6), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10-5, padj = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10-6, padj = 0.042). CONCLUSIONS: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.

Widespread Cortical Thickness Is Associated With Neuroactive Steroid Levels.

BACKGROUND: Neuroactive steroids are endogenous molecules with regenerative and neuroprotective actions. Both cortical thickness and many neuroactive steroid levels decline with age and are decreased in several neuropsychiatric disorders. However, a systematic examination of the relationship between serum neuroactive steroid levels and in vivo measures of cortical thickness in humans is lacking. METHODS: Peripheral serum levels of seven neuroactive steroids were assayed in United States military veterans. All (n = 143) subsequently underwent high-resolution structural MRI, followed by parcellelation of the cortical surface into 148 anatomically defined regions. Regression modeling was applied to test the association between neuroactive steroid levels and hemispheric total gray matter volume as well as region-specific cortical thickness. False discovery rate (FDR) correction was used to control for Type 1 error from multiple testing. RESULTS: Neuroactive steroid levels of allopregnanolone and pregnenolone were positively correlated with gray matter thickness in multiple regions of cingulate, parietal, and occipital association cortices (r = 0.20-0.47; p < 0.05; FDR-corrected). CONCLUSION: Positive associations between serum neuroactive steroid levels and gray matter cortical thickness are found in multiple brain regions. If these results are confirmed, neuroactive steroid levels and cortical thickness may help in monitoring the clinical response in future intervention studies of neuroregenerative therapies.

Neurosteroid Levels in the Orbital Frontal Cortex of Subjects with PTSD and Controls: A Preliminary Report.

Background: Neurosteroids mediate stress signaling and have been implicated in the pathogenesis of post-traumatic stress disorder (PTSD) in both preclinical and clinical studies. Compared to controls, subjects with PTSD exhibit altered neurosteroid levels in peripheral blood and cerebrospinal fluid as well as hypoactivity in the medial orbital frontal cortex (mOFC). Therefore, the aim of this study was to compare neurosteroid levels in the mOFC of subjects with PTSD (n = 18) and controls (n = 35). Methods: Gray matter was dissected from fresh-frozen mOFC, and levels of the neurosteroids pregnenolone, allopregnanolone, pregnanolone, epiallopregnanolone, epipregnanolone, tetrahydrodeoxycorticosterone, and androsterone were determined by gas chromatography - tandem mass spectrometry (GC/MS/MS). Results: Analyses of unadjusted levels revealed that males with PTSD had significantly decreased levels of allopregnanolone (p = 0.03) compared to control males and females with PTSD had significantly increased levels of pregnenolone (p = 0.03) relative to control females. After controlling for age, postmortem interval, and smoking status, results showed that males with PTSD had significantly decreased levels of androsterone (t46 = 2.37, p = 0.02) compared to control males and females with PTSD had significantly increased levels of pregnanolone (t46 = -2.25, p = 0.03) relative to control females. Conclusions: To our knowledge, this is the first report of neurosteroid levels in postmortem brain tissue of subjects with PTSD. Although replication is required in other brain regions and in a larger cohort of subjects, the results suggest a dysregulation of allopregnanolone and androsterone in males with PTSD and pregnanolone in females with PTSD in the mOFC.

Pain Intensity and Pain Interference in Male and Female Iraq/Afghanistan-era Veterans.

BACKGROUND: Chronic pain conditions are common among both male and female Iraq/Afghanistan-era veterans and can have substantial negative impacts on quality of life and function. Although in general women tend to report higher levels of pain intensity than men, findings remain mixed on whether gender differences in pain exist in Iraq/Afghanistan-era veterans. Additionally, the relationships between functional impairment, pain intensity, and gender remain unknown. METHODS: This project examined gender differences in pain intensity and pain interference in 875 male and female Iraq/Afghanistan-era veterans. Nonparametric Wilcoxon rank-tests examined gender differences in pain scores. Multivariable generalized linear regression modeling was used to evaluate the magnitude of pain intensity and interference across levels of chronicity and gender, and to evaluate the role of chronicity in gender effects in measures of pain and function. RESULTS: Pain intensity and interference scores were significantly greater among both male and female veterans reporting chronic pain relative to acute pain. Women veterans endorsed higher levels of pain intensity and pain interference compared with men. Results derived from multivariable analyses implicated pain intensity as a factor underlying gender differences in functional impairment among chronic pain sufferers, indicating that gender differences in functional measures were eliminated after controlling statistically for pain intensity. CONCLUSIONS: Results demonstrate that the effects of functional impairment are impacted by pain intensity, and not by gender.

Resilience as a translational endpoint in the treatment of PTSD.

Resilience is a neurobiological entity that shapes an individual's response to trauma. Resilience has been implicated as the principal mediator in the development of mental illness following exposure to trauma. Although animal models have traditionally defined resilience as molecular and behavioral changes in stress responsive circuits following trauma, this concept needs to be further clarified for both research and clinical use. Here, we analyze the construct of resilience from a translational perspective and review optimal measurement methods and models. We also seek to distinguish between resilience, stress vulnerability, and posttraumatic growth. We propose that resilience can be quantified as a multifactorial determinant of physiological parameters, epigenetic modulators, and neurobiological candidate markers. This multifactorial definition can determine PTSD risk before and after trauma exposure. From this perspective, we propose the use of an 'R Factor' analogous to Spearman's g factor for intelligence to denote these multifactorial determinants. In addition, we also propose a novel concept called 'resilience reserve', analogous to Stern's cognitive reserve, to summarize the sum total of physiological processes that protect and compensate for the effect of trauma. We propose the development and application of challenge tasks to measure 'resilience reserve' and guide the assessment and monitoring of 'R Factor' as a biomarker for PTSD.

Associations between neuropsychiatric and health status outcomes in individuals with probable mTBI.

Mild traumatic brain injury (mTBI) is a common occurrence, and may impact distal outcomes in a subgroup of individuals. Improved characterization of health outcomes and identification of factors associated with poor outcomes is needed to better understand the impact of mTBI, particularly in those with co-occurring posttraumatic stress disorder (PTSD). Participants in a data repository of the Injury and Traumatic Stress (INTRuST) Clinical Consortium (n = 625) completed functional disability [FD] and health-related quality of life [HRQOL] questionnaires, and a subset completed a neuropsychological assessment. FD and HRQOL were compared among participants with probable mTBI (mTBI), probable mTBI with PTSD (mTBI/PTSD), and health comparison participants (HC). Associations between symptoms, neuropsychological performance, and health outcomes were examined in those with probable mTBI with and without PTSD (n = 316). Individuals in the mTBI/PTSD group endorsed poorer health outcomes than those in the mTBI group, who endorsed poorer outcomes than those in the HC group. Individuals in either mTBI group performed worse than those in the HC on verbal learning and memory and psychomotor speed. Health outcomes were correlated with mental health and postconcussive symptoms, as well as neuropsychological variables. mTBI may adversely impact self-reported health, with the greatest effect observed in individuals with co-occurring mTBI/PTSD.

White matter abnormalities in mild traumatic brain injury with and without post-traumatic stress disorder: a subject-specific diffusion tensor imaging study.

Mild traumatic brain injuries (mTBIs) are often associated with posttraumatic stress disorder (PTSD). In cases of chronic mTBI, accurate diagnosis can be challenging due to the overlapping symptoms this condition shares with PTSD. Furthermore, mTBIs are heterogeneous and not easily observed using conventional neuroimaging tools, despite the fact that diffuse axonal injuries are the most common injury. Diffusion tensor imaging (DTI) is sensitive to diffuse axonal injuries and is thus more likely to detect mTBIs, especially when analyses account for the inter-individual variability of these injuries. Using a subject-specific approach, we compared fractional anisotropy (FA) abnormalities between groups with a history of mTBI (n = 35), comorbid mTBI and PTSD (mTBI + PTSD; n = 22), and healthy controls (n = 37). We compared all three groups on the number of abnormal FA clusters derived from subject-specific injury profiles (i.e., individual z-score maps) along a common white matter skeleton. The mTBI + PTSD group evinced a greater number of abnormally low FA clusters relative to both the healthy controls and the mTBI group without PTSD (p < .05). Across the groups with a history of mTBI, increased numbers of abnormally low FA clusters were significantly associated with PTSD symptom severity, depression, post-concussion symptoms, and reduced information processing speed (p < .05). These findings highlight the utility of subject-specific microstructural analyses when searching for mTBI-related brain abnormalities, particularly in patients with PTSD. This study also suggests that patients with a history of mTBI and comorbid PTSD, relative to those without PTSD, are at increased risk of FA abnormalities.

Multi-site harmonization of diffusion MRI data in a registration framework.

Diffusion MRI (dMRI) data acquired on different scanners varies significantly in its content throughout the brain even if the acquisition parameters are nearly identical. Thus, proper harmonization of such data sets is necessary to increase the sample size and thereby the statistical power of neuroimaging studies. In this paper, we present a novel approach to harmonize dMRI data (the raw signal, instead of dMRI derived measures such as fractional anisotropy) using rotation invariant spherical harmonic (RISH) features embedded within a multi-modal image registration framework. All dMRI data sets from all sites are registered to a common template and voxel-wise differences in RISH features between sites at a group level are used to harmonize the signal in a subject-specific manner. We validate our method on diffusion data acquired from seven different sites (two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across these sites before and after data harmonization. Validation was also done on a group oftest subjects, which were not used to "learn" the harmonization parameters. We also show results using TBSS before and after harmonization for independent validation of the proposed methodology. Using synthetic data, we show that any abnormality in diffusion measures due to disease is preserved during the harmonization process. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences in the signal can be removed using the proposed method in a model independent manner.

Genome-wide association study of subcortical brain volume in PTSD cases and trauma-exposed controls.

Depending on the traumatic event, a significant fraction of trauma survivors subsequently develop PTSD. The additional variability in PTSD risk is expected to arise from genetic susceptibility. Unfortunately, several genome-wide association studies (GWAS) have failed to identify a consistent genetic marker for PTSD. The heritability of intermediate phenotypes such as regional brain volumes is often 80% or higher. We conducted a GWAS of subcortical brain volumes in a sample of recent military veteran trauma survivors (n = 157), grouped into PTSD (n = 66) and non-PTSD controls (n = 91). Covariates included PTSD diagnosis, sex, intracranial volume, ancestry, childhood trauma, SNP×PTSD diagnosis, and SNP×childhood trauma. We identified several genetic markers in high linkage disequilibrium (LD) with rs9373240 (p = 2.0 × 10-7, FDR q = 0.0375) that were associated with caudate volume. We also observed a significant interaction between rs9373240 and childhood trauma (p-values = 0.0007-0.002), whereby increased trauma exposure produced a stronger association between SNPs and increased caudate volume. We identified several SNPs in high LD with rs34043524, which is downstream of the TRAM1L1 gene that were associated with right lateral ventricular volume (p = 1.73 × 10-7; FDR q = 0.032) and were also associated with lifetime alcohol abuse or dependence (p = 2.49 × 10-7; FDR q = 0.0375). Finally, we identified several SNPs in high LD with rs13140180 (p = 2.58 × 10-7; FDR q = .0016), an intergenic region on chromosome 4, and several SNPs in the TMPRSS15 associated with right nucleus accumbens volume (p = 2.58 × 10-7; FDR q = 0.017). Both TRAM1L1 and TMPRSS15 have been previously implicated in neuronal function. Key results survived genome-wide multiple-testing correction in our sample. Leveraging neuroimaging phenotypes may offer a shortcut, relative to clinical phenotypes, in mapping the genetic architecture and neurobiological pathways of PTSD.

Neurosteroid Levels in Patients With Bipolar Disorder and a History of Cannabis Use Disorders.

PURPOSE/BACKGROUND: In animal models, levels of the neurosteroid pregnenolone increase after tetrahydrocannabinol (THC) administration and pregnenolone appears to attenuate the brain effects of THC. Given these interactions between pregnenolone and THC, we evaluated baseline neurosteroid levels in participants with a history of a cannabis use disorders (CUDs). METHODS/PROCEDURES: Bipolar depressed participants were enrolled in a randomized placebo-controlled clinical trial to evaluate the efficacy of add-on pregnenolone for depression and before receiving pregnenolone or placebo. Baseline serum levels of neurosteroids (pregnenolone, allopregnanolone, pregnanolone, and androsterone) were analyzed in 53 participants with highly sensitive and specific gas chromatography/mass spectrometry. Current, active substance use disorders, or a positive baseline urine drug screen, were exclusionary. Participants were classified by past cannabis abuse or dependence diagnosis using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Data were analyzed by independent t tests for separate neurosteroids. FINDINGS/RESULTS: Participants with a history of CUD had higher serum pregnanolone, lower allopregnanolone, a higher pregnanolone to allopregnanolone ratio, and a lower pregnenolone to pregnanolone ratio compared with those without a history of cannabis use. Similar findings were not observed based on a history of other substance use disorders with the exception of lower allopregnanolone in those with opioid use disorders. Notably, the majority of those with an opioid use disorder also had a CUD (75%). IMPLICATIONS/CONCLUSIONS: These findings potentially suggest either enduring changes in neurosteroids in people with past CUDs or represent a vulnerability marker for a CUD.

Stress-Related Mental Health Symptoms in Coast Guard: Incidence, Vulnerability, and Neurocognitive Performance.

U.S. Coast Guard (CG) personnel face occupational stressors (e.g., search and rescue) which compound daily life stressors encountered by civilians. However, the degree CG personnel express stress-related mental health symptoms of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) is understudied as a military branch, and little is known concerning the interplay of vulnerabilities and neurocognitive outcomes in CG personnel. The current study addressed this knowledge gap, recruiting 241 active duty CG personnel (22% female) to assess mental health, personality, and neurocognitive function. Participants completed a battery of scales: PTSD Checklist with military and non-military prompts to screen for PTSD, Psychological Health Questionnaire 8 for MDD, and scales for behaviorally inhibited (BI) temperament, and distressed (Type D) personality. Neurocognitive performance was assessed with the Defense Automated Neurobehavioral Assessment (DANA) battery. Cluster scoring yielded an overall rate of PTSD of 15% (95% CI: 11-20%) and 8% (95% CI: 3-9%) for MDD. Non-military trauma was endorsed twice that of military trauma in those meeting criteria for PTSD. Individual vulnerabilities were predictive of stress-related mental health symptoms in active duty military personnel; specifically, BI temperament predicted PTSD whereas gender and Type D personality predicted MDD. Stress-related mental health symptoms were also associated with poorer reaction time and response inhibition. These results suggest rates of PTSD and MDD are comparable among CG personnel serving Boat Stations to those of larger military services after combat deployment. Further, vulnerabilities distinguished between PTSD and MDD, which have a high degree of co-occurrence in military samples. To what degree stress-related mental healthy symptoms and attendant neurocognitive deficits affect operational effectiveness remains unknown and warrant future study.