Traumatic Brain Injury, Psychological Trauma Exposure, and Anxious and Depressive Symptoms in a Clinical Population.

BACKGROUND: Approximately 90% of adults endorse psychological trauma exposure. However, barriers to assessment of psychological trauma and sequelae include limited access to care, lack of standardized assessments in nonpsychiatric settings, and comorbid diagnoses, such as traumatic brain injury (TBI), that may mimic psychiatric syndromes. OBJECTIVES: This study aims to assess the prevalence rates of psychological trauma exposure and TBI to understand the relationship of these experiences with current psychiatric symptoms. METHODS: This is a cross-sectional study of a convenience sample of adult patients (age 18 years and older) referred for outpatient evaluation at a neuropsychology clinic in the Western United States between September 2021 and October 2022. Patients completed a clinical interview to assess their history of psychological trauma, TBI, and current psychiatric symptoms. RESULTS: A total of 118 patients met inclusion criteria. Patients in the TBI group (n = 83) endorsed significantly higher rates of childhood trauma and prior physical, emotional, and sexual abuse compared with the No TBI group (n = 35). Psychological trauma exposure and TBI significantly predicted current anxiety and depressive symptoms, but there was no interaction between these experiences in predicting current psychiatric symptoms. CONCLUSIONS: Individuals with prior TBI experienced psychological trauma, particularly childhood trauma, at a significantly higher rate than those without TBI. Psychological trauma exposure and TBI independently predicted anxious and depressive symptoms, suggesting both may be viable treatment targets. Evaluation of prior psychological trauma exposure during evaluation of TBI may provide opportunities for trauma-informed care and may allow for improved outpatient treatment planning.

Striatal reactivity during emotion and reward relates to approach-avoidance conflict behaviour and is altered in adults with anxiety or depression.

BACKGROUND: We have previously reported activation in reward, salience and executive control regions during functional MRI (fMRI) using an approach-avoidance conflict (AAC) decision-making task with healthy adults. Further investigations into how anxiety and depressive disorders relate to differences in neural responses during AAC can inform their understanding and treatment. We tested the hypothesis that people with anxiety or depression have altered neural activation during AAC. METHODS: We compared 118 treatment-seeking adults with anxiety or depression and 58 healthy adults using linear mixed-effects models to examine group-level differences in neural activation (fMRI) during AAC decision-making. Correlational analyses examined relationships between behavioural and neural measures. RESULTS: Adults with anxiety or depression had greater striatal engagement when reacting to affective stimuli (p = 0.008, d = 0.31) regardless of valence, and weaker striatal engagement during reward feedback (p = 0.046, d = -0.27) regardless of the presence of monetary reward. They also had blunted amygdala activity during decision-making (p = 0.023, d = -0.32) regardless of the presence of conflict. Across groups, approach behaviour during conflict decision-making was inversely correlated with striatal activation during affective stimuli (p < 0.001, r = -0.28) and positively related to striatal activation during reward feedback (p < 0.001, r = 0.27). LIMITATIONS: Our transdiagnostic approach did not allow for comparisons between specific anxiety disorders, and our cross-sectional approach did not allow for causal inference. CONCLUSION: Anxiety and depression were associated with altered neural responses to AAC. Findings were consistent with the role of the striatum in action selection and reward responsivity, and they point toward striatal reactivity as a future treatment target. Blunting of amygdala activity in anxiety or depression may indicate a compensatory response to inhibit affective salience and maintain approach.

The role of trauma, social support, and demography on veteran resilience.

Background: Historically, resilience has often been conceptualized as the sustained lack of symptoms following trauma exposure. In line with a novel conceptualization of resilience as being dynamic over lifespan, determined by interacting biological and environmental factors, we examined the VA Mid-Atlantic Post Deployment Mental Health Repository (PDMH) comprised of 3876 US Military Veterans with and without PTSD diagnoses. Methods: We performed regression modelling to study the relationship between resilience (measured with Connor Davidson Resilience Scale; CD-RISC), posttraumatic stress disorder (PTSD) severity (Davidson Trauma Scale; DTS), social support (Medical Outcome Study Social Support Survey; MOSSS), combat exposure (Combat Exposure Scale; CES), childhood trauma (Trauma Life Events Questionnaire; TLEQ), and demographic factors. CD-RISC was positively correlated with years of education and negatively correlated with DTS, CES and TLEQ scores. Results: We found an interaction between CD-RISC and CES in predicting PTSD severity (Davidson Trauma Scale). Specifically, high resilience predicted lower PTSD symptom severity than low resilience, this relationship was amplified with increasing levels of combat exposure. Structural equation modelling (SEM) identified an optimal latent variable that represents resilience and relationships between latent variables for resilience, trauma, and illness. We derived a resilience latent variable composed of age, education level, MOSSS and race. Conclusions: Our results support a conceptualization of resilience as a multifactorial determinant that coexists with PTSD, a state rather than trait variable, and can be quantified by biological and behavioural metrics. HIGHLIGHTS: • Historically, resilience has often been conceptualized as the sustained lack of symptoms following trauma exposure.• We examined the VA Mid-Atlantic Post Deployment Mental Health Repository (PDMH) comprised of 3876 US Military Veterans.• We found an interaction effect between CD-RISC and CES in predicting PTSD severity (Davidson Trauma Scale).

Antecedentes: Históricamente, la resiliencia a menudo se ha conceptualizado como la ausencia sostenida de síntomas después de la exposición al trauma. En línea con una novedosa conceptualización de la resiliencia como un fenómeno dinámico a lo largo de la vida, determinada por la interacción de factores biológicos y ambientales, examinamos el Repositorio de salud mental post-despliegue VA Mid-Atlantic (PDMH por sus siglas en ingles) compuesto por 3.876 veteranos militares de EE.UU. con y sin diagnósticos de TEPT.Métodos: Realizamos modelos de regresión para estudiar la relación entre resiliencia (medida con la Escala de resiliencia de Connor Davidson; CD-RISC por sus siglas en ingles), gravedad del trastorno de estrés postraumático (TEPT) (con Escala de Trauma de Davidson; DTS por sus siglas en ingles), apoyo social (Encuesta de Estudio de Resultados Médicos - Apoyo Social; MOSSS por sus siglas en ingles), exposición al combate (Escala de exposición al combate; CES por sus siglas en ingles), trauma infantil (Cuestionario de Eventos de vida traumáticos; TLEQ por sus siglas en ingles), y factores demográficos. CD-RISC se correlacionó positivamente con años de educación y se correlacionó negativamente con los puntajes de DTS, CES y TLEQ.Resultados: Encontramos una interacción entre CD-RISC y CES en la predicción de la gravedad del TEPT (Escala de trauma de Davidson). Específicamente, una alta resiliencia predijo menor gravedad de los síntomas de TEPT que una baja resiliencia, esta relación fue amplificada con niveles crecientes de exposición al combate. El modelo de ecuaciones estructurales (SEM por sus siglas en ingles) identificó una variable latente óptima que representa la resiliencia y las relaciones entre las variables latentes de resiliencia, trauma y enfermedad. Derivamos una variable latente de resiliencia compuesta por edad, nivel educativo, MOSSS y raza.Conclusiones: Nuestros resultados apoyan una conceptualización de la resiliencia como un determinante multifactorial que coexiste con el TEPT, una variable de estado más que de rasgo, y puede ser cuantificada con mediciones biológicas y conductuales.

Behavioral activation therapy for depression is associated with a reduction in the concentration of circulating quinolinic acid.

BACKGROUND: An inflammation-induced imbalance in the kynurenine pathway (KP) has been reported in major depressive disorder but the utility of these metabolites as predictive or therapeutic biomarkers of behavioral activation (BA) therapy is unknown. METHODS: Serum samples were provided by 56 depressed individuals before BA therapy and 29 of these individuals also provided samples after 10 weeks of therapy to measure cytokines and KP metabolites. The PROMIS Depression Scale (PROMIS-D) and the Sheehan Disability Scale were administered weekly and the Beck depression inventory was administered pre- and post-therapy. Data were analyzed with linear mixed-effect, general linear, and logistic regression models. The primary outcome for the biomarker analyses was the ratio of kynurenic acid to quinolinic acid (KynA/QA). RESULTS: BA decreased depression and disability scores (p's < 0.001, Cohen's d's > 0.5). KynA/QA significantly increased at post-therapy relative to baseline (p < 0.001, d = 2.2), an effect driven by a decrease in QA post-therapy (p < 0.001, uncorrected, d = 3.39). A trend towards a decrease in the ratio of kynurenine to tryptophan (KYN/TRP) was also observed (p = 0.054, uncorrected, d = 0.78). Neither the change in KynA/QA, nor baseline KynA/QA were associated with response to BA therapy. CONCLUSION: The current findings together with previous research show that electronconvulsive therapy, escitalopram, and ketamine decrease concentrations of the neurotoxin, QA, raise the possibility that a common therapeutic mechanism underlies diverse forms of anti-depressant treatment but future controlled studies are needed to test this hypothesis.

Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. METHOD: Adult subjects (N = 2229; 56.2% male) aged 18-69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age - chronological age) controlling for chronological age, sex, and scan site. RESULTS: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. DISCUSSION: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.

Assessment of Neuropsychological Function in Veterans With Blast-Related Mild Traumatic Brain Injury and Subconcussive Blast Exposure.

Objective: The majority of combat-related head injuries are associated with blast exposure. While Veterans with mild traumatic brain injury (mTBI) report cognitive complaints and exhibit poorer neuropsychological performance, there is little evidence examining the effects of subconcussive blast exposure, which does not meet clinical symptom criteria for mTBI during the acute period following exposure. We compared chronic effects of combat-related blast mTBI and combat-related subconcussive blast exposure on neuropsychological performance in Veterans. Methods: Post-9/11 Veterans with combat-related subconcussive blast exposure (n = 33), combat-related blast mTBI (n = 26), and controls (n = 33) without combat-related blast exposure, completed neuropsychological assessments of intellectual and executive functioning, processing speed, and working memory via NIH toolbox, assessment of clinical psychopathology, a retrospective account of blast exposures and non-blast-related head injuries, and self-reported current medication. Huber Robust Regressions were employed to compare neuropsychological performance across groups. Results: Veterans with combat-related blast mTBI and subconcussive blast exposure displayed significantly slower processing speed compared with controls. After adjusting for post-traumatic stress disorder and depressive symptoms, those with combat-related mTBI exhibited slower processing speed than controls. Conclusion: Veterans in the combat-related blast mTBI group exhibited slower processing speed relative to controls even when controlling for PTSD and depression. Cognition did not significantly differ between subconcussive and control groups or subconcussive and combat-related blast mTBI groups. Results suggest neurocognitive assessment may not be sensitive enough to detect long-term effects of subconcussive blast exposure, or that psychiatric symptoms may better account for cognitive sequelae following combat-related subconcussive blast exposure or combat-related blast mTBI.

Volumetric trajectories of hippocampal subfields and amygdala nuclei influenced by adolescent alcohol use and lifetime trauma.

Alcohol use and exposure to psychological trauma frequently co-occur in adolescence and share many risk factors. Both exposures have deleterious effects on the brain during this sensitive developmental period, particularly on the hippocampus and amygdala. However, very little is known about the individual and interactive effects of trauma and alcohol exposure and their specific effects on functionally distinct substructures within the adolescent hippocampus and amygdala. Adolescents from a large longitudinal sample (N = 803, 2684 scans, 51% female, and 75% White/Caucasian) ranging in age from 12 to 21 years were interviewed about exposure to traumatic events at their baseline evaluation. Assessments for alcohol use and structural magnetic resonance imaging scans were completed at baseline and repeated annually to examine neurodevelopmental trajectories. Hippocampal and amygdala subregions were segmented using Freesurfer v6.0 tools, followed by volumetric analysis with generalized additive mixed models. Longitudinal statistical models examined the effects of cumulative lifetime trauma measured at baseline and alcohol use measured annually on trajectories of hippocampal and amygdala subregions, while controlling for covariates known to impact brain development. Greater alcohol use, quantified using the Cahalan scale and measured annually, was associated with smaller whole hippocampus (ß = -12.0, pFDR = 0.009) and left hippocampus tail volumes (ß = -1.2, pFDR = 0.048), and larger right CA3 head (ß = 0.4, pFDR = 0.027) and left subiculum (ß = 0.7, pFDR = 0.046) volumes of the hippocampus. In the amygdala, greater alcohol use was associated with larger right basal nucleus volume (ß = 1.3, pFDR = 0.040). The effect of traumatic life events measured at baseline was associated with larger right CA3 head volume (ß = 1.3, pFDR = 0.041) in the hippocampus. We observed an interaction between baseline trauma and within-person age change where younger adolescents with greater trauma exposure at baseline had smaller left hippocampal subfield volumes in the subiculum (ß = 0.3, pFDR = 0.029) and molecular layer HP head (ß = 0.3, pFDR = 0.041). The interaction also revealed that older adolescents with greater trauma exposure at baseline had larger right amygdala nucleus volume in the paralaminar nucleus (ß = 0.1, pFDR = 0.045), yet smaller whole amygdala volume overall (ß = -3.7, pFDR = 0.003). Lastly, we observed an interaction between alcohol use and baseline trauma such that adolescents who reported greater alcohol use with greater baseline trauma showed smaller right hippocampal subfield volumes in the CA1 head (ß = -1.1, pFDR = 0.011) and hippocampal head (ß = -2.6, pFDR = 0.025), yet larger whole hippocampus volume overall (ß = 10.0, pFDR = 0.032). Cumulative lifetime trauma measured at baseline and alcohol use measured annually interact to affect the volume and trajectory of hippocampal and amygdala substructures (measured via structural MRI annually), regions that are essential for emotion regulation and memory. Our findings demonstrate the value of examining these substructures and support the hypothesis that the amygdala and hippocampus are not homogeneous brain regions.

Test-retest reliability of approach-avoidance conflict decision-making during functional magnetic resonance imaging in healthy adults.

Neural and behavioral mechanisms during approach-avoidance conflict decision-making are relevant across various psychiatric disorders, particularly anxiety disorders. Studies using approach-avoidance conflict paradigms in healthy adults have identified preliminary neural mechanisms, but findings must be replicated and demonstrated as reliable before further application. This study sought to replicate previous findings and examine test-retest reliability of behavioral (approach behavior, reaction time) and neural (regions of interest [ROIs]) responses during an approach-avoidance conflict task conducted during functional magnetic resonance imaging (fMRI). Thirty healthy adults completed an approach-avoidance conflict task during fMRI on two occasions (mean interval: 17 days; range: 11-32). Effects of task condition during three task phases (decision-making, affective outcome and monetary reward) and intraclass correlation coefficients (ICCs) were calculated across time points. Results replicated that approach behavior was modulated by conflict during decision-making. ROI activations were replicated such that dorsal anterior cingulate cortex (dACC) was modulated by conflict during decision-making, and dACC, striatum, and anterior insula were modulated by valence during affective outcomes (p's <.0083). Approach behavior during conflict demonstrated excellent reliability (ICCs ≥.77). Activation of dACC during conflict decision-making and anterior insula during negative outcomes demonstrated fair reliability (ICCs = .51 and .54), and dACC and striatum activation demonstrated good reliability during negative outcomes (ICCs = .63 and .69). Two additional ROIs (amygdala, left dorsolateral prefrontal cortex) showed good reliability during negative outcomes (ICCs ≥.60). These results characterize several specific behavioral and neuroimaging responses that are replicable and sufficiently reliable during approach-avoidance conflict decision-making to support future utility.

Cardiac sympathetic denervation and mental health.

BACKGROUND: Bilateral cardiac sympathetic denervation (BCSD) is a surgical treatment for refractory ventricular arrhythmias. Although the procedure has shown efficacy at reducing cardiac arrhythmias, its impact on mental health is unknown. In the current study we examined associations between the BCSD procedure and mental health. METHODS: 10 ventricular arrhythmia patients undergoing BCSD completed assessments of anxiety, depression, and posttraumatic stress symptoms at pre- and post-BCSD time points. Wilcoxon signed rank and Mann-Whitney U tests were used to examine differences in mental health symptoms in the pre- and post-BSCD states. Point biserial correlations were used to explore associations between BCSD response and mental health symptoms. RESULTS: A significant reduction of anxiety symptoms was observed from pre- to post-BCSD. At the post-BCSD assessment, participants who successfully responded to the BCSD procedure exhibited lower anxiety symptoms compared to non-responders. However, no significant relationships were identified for depressive or PTSD symptoms. CONCLUSION: The BCSD procedure is associated with reduced anxiety shortly after successful treatment for refractory ventricular arrhythmias in a small sample. Longitudinal surveillance of mental health symptoms after BCSD may be warranted to monitor the impact of this procedure on mental health.

Visual cortical regions show sufficient test-retest reliability while salience regions are unreliable during emotional face processing.

Functional magnetic resonance imaging studies frequently use emotional face processing tasks to probe neural circuitry related to psychiatric disorders and treatments with an emphasis on regions within the salience network (e.g., amygdala). Findings across previous test-retest reliability studies of emotional face processing have shown high variability, potentially due to differences in data analytic approaches. The present study comprehensively examined the test-retest reliability of an emotional faces task utilizing multiple approaches to region of interest (ROI) analysis and by examining voxel-wise reliability across the entire brain for both neural activation and functional connectivity. Analyses included 42 healthy adult participants who completed an fMRI scan concurrent with an emotional faces task on two separate days with an average of 25.52 days between scans. Intraclass correlation coefficients (ICCs) were calculated for the 'FACES-SHAPES' and 'FACES' (compared to implicit baseline) contrasts across the following: anatomical ROIs identified from a publicly available brain atlas (i.e., Brainnetome), functional ROIs consisting of 5-mm spheres centered on peak voxels from a publicly available meta-analytic database (i.e., Neurosynth), and whole-brain, voxel-wise analysis. Whole-brain, voxel-wise analyses of functional connectivity were also conducted using both anatomical and functional seed ROIs. While group-averaged neural activation maps were consistent across time, only one anatomical ROI and two functional ROIs showed good or excellent individual-level reliability for neural activation. The anatomical ROI was the right medioventral fusiform gyrus for the FACES contrast (ICC â€‹= â€‹0.60). The functional ROIs were the left and the right fusiform face area (FFA) for both FACES-SHAPES and FACES (Left FFA ICCs â€‹= â€‹0.69 & 0.79; Right FFA ICCs â€‹= â€‹0.68 & 0.66). Poor reliability (ICCs â€‹< â€‹0.4) was identified for almost all other anatomical and functional ROIs, with some exceptions showing fair reliability (ICCs â€‹= â€‹0.4-0.59). Whole-brain voxel-wise analysis of neural activation identified voxels with good (ICCs â€‹= â€‹0.6-0.74) to excellent reliability (ICCs â€‹> â€‹0.75) that were primarily located in visual cortex, with several clusters in bilateral dorsal lateral prefrontal cortex (DLPFC). Whole-brain voxel-wise analyses of functional connectivity for amygdala and fusiform gyrus identified very few voxels with good to excellent reliability using both anatomical and functional seed ROIs. Exceptions included clusters in right cerebellum and right DLPFC that showed reliable connectivity with left amygdala (ICCs â€‹> â€‹0.6). In conclusion, results indicate that visual cortical regions demonstrate good reliability at the individual level for neural activation, but reliability is generally poor for salience regions often focused on within psychiatric research (e.g., amygdala). Given these findings, future clinical neuroimaging studies using emotional faces tasks to examine individual differences might instead focus on visual regions and their role in psychiatric disorders.

Amygdala Nuclei Volume and Shape in Military Veterans With Posttraumatic Stress Disorder.

BACKGROUND: The amygdala is a subcortical structure involved in socioemotional and associative fear learning processes relevant for understanding the mechanisms of posttraumatic stress disorder (PTSD). Research in animals indicates that the amygdala is a heterogeneous structure in which the basolateral and centromedial divisions are susceptible to stress. While the amygdala complex is implicated in the pathophysiology of PTSD, little is known about the specific contributions of the individual nuclei that constitute the amygdala complex. METHODS: Military veterans (n = 355), including military veterans with PTSD (n = 149) and trauma-exposed control subjects without PTSD (n = 206), underwent high-resolution T1-weighted anatomical scans. Automated FreeSurfer segmentation of the amygdala yielded 9 structures: basal, lateral, accessory basal, anterior amygdaloid, and central, medial, cortical, and paralaminar nuclei, along with the corticoamygdaloid transition zone. Subregional volumes were compared between groups using ordinary-least-squares regression with relevant demographic and clinical regressors followed by 3-dimensional shape analysis of whole amygdala. RESULTS: PTSD was associated with smaller left and right lateral and paralaminar nuclei, but with larger left and right central, medial, and cortical nuclei (p < .05, false discovery rate corrected). Shape analyses revealed lower radial distance in anterior bilateral amygdala and lower Jacobian determinant in posterior bilateral amygdala in PTSD compared with control subjects. CONCLUSIONS: Alterations in select amygdala subnuclear volumes and regional shape distortions are associated with PTSD in military veterans. Volume differences of the lateral nucleus and the centromedial complex associated with PTSD demonstrate a subregion-specific pattern that is consistent with their functional roles in fear learning and fear expression behaviors.

Combat exposure, posttraumatic stress disorder, and head injuries differentially relate to alterations in cortical thickness in military Veterans.

Combat-exposed Veterans are at increased risk for developing psychological distress, mood disorders, and trauma and stressor-related disorders. Trauma and mood disorders have been linked to alterations in brain volume, function, and connectivity. However, far less is known about the effects of combat exposure on brain health. The present study examined the relationship between severity of combat exposure and cortical thickness. Post-9/11 Veterans (N = 337; 80% male) were assessed with structural neuroimaging and clinically for combat exposure, depressive symptoms, prior head injury, and posttraumatic stress disorder (PTSD). Vertex-wide cortical thickness was estimated using FreeSurfer autosegmentation. FreeSurfer's Qdec was used to examine relationship between combat exposure, PTSD, and prior head injuries on cortical thickness (Monte Carlo corrected for multiple comparisons, vertex-wise cluster threshold of 1.3, p < 0.01). Covariates included age, sex, education, depressive symptoms, nonmilitary trauma, alcohol use, and prior head injury. Higher combat exposure uniquely related to lower cortical thickness in the left prefrontal lobe and increased cortical thickness in the left middle and inferior temporal lobe; whereas PTSD negatively related to cortical thickness in the right fusiform. Head injuries related to increased cortical thickness in the bilateral medial prefrontal cortex. Combat exposure uniquely contributes to lower cortical thickness in regions implicated in executive functioning, attention, and memory after accounting for the effects of PTSD and prior head injury. Our results highlight the importance of examining effects of stress and trauma exposure on neural health in addition to the circumscribed effects of specific syndromal pathology.

A pragmatic clinical trial examining the impact of a resilience program on college student mental health.

BACKGROUND: One in three college students experience significant depression or anxiety interfering with daily functioning. Resilience programs that can be administered to all students offer an opportunity for addressing this public health problem. The current study objective was to assess the benefit of a brief, universal resilience program for first-year college students. METHOD: First-year students at a private, midwestern university participated. This trial used a pragmatic design, delivering the intervention within university-identified orientation courses and was not randomized. The four-session resilience program included goal-building, mindfulness, and resilience skills. The comparison was orientation-as-usual. Primary outcomes included PROMIS® Depression and Anxiety and Connor-Davidson Resilience Scale. Secondary and exploratory outcomes included the Perceived Stress Scale, Emotion Regulation, and Cognitive Behavioral Therapy (CBT) Skills Questionnaires, and Freiburg Mindfulness Inventory. Time by treatment interactions at post-training and semester-end were examined using linear mixed models. RESULTS: Analysis included 252 students, 126 who completed resilience programming and a matched comparison sample. Resilience programming did not relate to improvements in depression at post-training (CI: -2.53 to 1.02; p = .404, d =-0.08), but did at semester-end (95% CI: -4.27 to -0.72; p = .006, d = -0.25) and improvements in perceived stress were observed at post-training (CI: -3.31 to -0.44; p = .011, d = -0.24) and semester-end (CI: -3.30 to -0.41; p = .013, d = -0.24). Emotion regulation, mindfulness, and CBT skills increased, with CBT skills mediating clinical improvements. CONCLUSIONS: Universal implementation of a brief, resilience intervention may be effective for improving college student mental health.

Machine Learning Analysis of the Relationships Between Gray Matter Volume and Childhood Trauma in a Transdiagnostic Community-Based Sample.

BACKGROUND: Childhood trauma is a significant risk factor for adult psychopathology. Previous investigations have implicated childhood trauma-related structural changes in anterior cingulate, dorsolateral prefrontal and orbitofrontal cortex, and hippocampus. Using a large transdiagnostic community sample, the goal of this investigation was to differentially associate regional gray matter (GM) volume with childhood trauma severity specifically, distinct from adult psychopathology. METHODS: A total of 577 non-treatment-seeking adults (n = 207 men) completed diagnostic, childhood trauma, and structural magnetic resonance imaging assessments with regional GM volume estimated using FreeSurfer. Elastic net analysis was conducted in a nested cross-validation framework, with GM volumes, adult psychopathology, age, education, sex, and magnetic resonance imaging coil type as potential predictors for childhood trauma severity. RESULTS: Elastic net identified age, education, sex, medical condition, adult psychopathology, and 13 GM regions as predictors of childhood trauma severity. GM regions identified included right caudate; left pallidum; bilateral insula and cingulate sulcus; left superior, inferior, and orbital frontal regions; and regions within temporal and parietal lobes and cerebellum. CONCLUSIONS: Results from this large, transdiagnostic sample implicate GM volume in regions central to current neurobiological theories of trauma (e.g., prefrontal cortex) as well as additional regions involved in reward, interoceptive, attentional, and sensory processing (e.g., striatal, insula, and parietal/occipital cortices). Future longitudinal studies examining the functional impact of structural changes in this broader network of regions are needed to clarify the role each may play in longer-term outcomes following trauma.

Computer-Based Executive Function Training for Combat Veterans With PTSD: A Pilot Clinical Trial Assessing Feasibility and Predictors of Dropout.

Background: While evidence-based PTSD treatments are often efficacious, 20-50% of individuals continue to experience significant symptoms following treatment. Further, these treatments do not directly target associated neuropsychological deficits. Here, we describe the methods and feasibility for computer-based executive function training (EFT), a potential alternative or adjunctive PTSD treatment. Methods: Male combat veterans with full or partial PTSD (n = 20) and combat-exposed controls (used for normative comparison; n = 20) completed clinical, neuropsychological and functional neuroimaging assessments. Those with PTSD were assigned to EFT (n = 13) or placebo training (word games; n = 7) at home for 6 weeks, followed by repeat assessment. Baseline predictors of treatment completion were explored using logistic regressions. Individual feedback and changes in clinical symptoms, neuropsychological function, and neural activation patterns are described. Results: Dropout rates for EFT and placebo training were 38.5 and 57.1%, respectively. Baseline clinical severity and brain activation (i.e., prefrontal-insula-amygdala networks) during an emotional anticipation task were predictive of treatment completion. Decreases in clinical symptoms were observed following treatment in both groups. EFT participants improved on training tasks but not on traditional neuropsychological assessments. All training completers indicated liking EFT, and indicated they would engage in EFT (alone or as adjunctive treatment) if offered. Conclusion: Results provide an initial framework to explore the feasibility of placebo-controlled, computerized, home-based executive function training (EFT) on psychological and neuropsychological function and brain activation in combat veterans with PTSD. Clinical severity and neural reactivity to emotional stimuli may indicate which veterans will complete home-based computerized interventions. While EFT may serve as a potential alternative or adjunctive PTSD treatment, further research is warranted to address compliance and determine whether EFT may benefit functioning above and beyond placebo interventions.

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.

PTSD and cognitive symptoms relate to inhibition-related prefrontal activation and functional connectivity.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with reduced executive functioning and verbal memory performance, as well as abnormal task-specific activity in prefrontal cortex (PFC) and anterior cingulate cortices (ACC). The current study examined how PTSD symptoms and neuropsychological performance in combat veterans relates to (1) medial PFC and ACC activity during cognitive inhibition, and (2) task-independent PFC functional connectivity. METHODS: Thirty-nine male combat veterans with varying levels of PTSD symptoms completed the multisource interference task during functional magnetic resonance imaging. Robust regression analyses were used to assess relationships between percent signal change (PSC: incongruent-congruent) and both PTSD severity and neuropsychological performance. Analyses were conducted voxel-wise and for PSC extracted from medial PFC and ACC regions of interest. Resting-state scans were available for veterans with PTSD. Regions identified via task-based analyses were used as seeds for resting-state connectivity analyses. RESULTS: Worse PTSD severity and neuropsychological performance related to less medial PFC and rostral ACC activity during interference processing, driven partly by increased activation to congruent trials. Worse PTSD severity related to reduced functional connectivity between these regions and bilateral, lateral PFC (Brodmann area 10). Worse neuropsychological performance related to reduced functional connectivity between these regions and the inferior frontal gyrus. CONCLUSIONS: PTSD and associated neuropsychological deficits may result from difficulties regulating medial PFC regions associated with "default mode," or self-referential processing. Further clarification of functional coupling deficits between default mode and executive control networks in PTSD may enhance understanding of neuropsychological and emotional symptoms and provide novel treatment targets.

Preliminary Evidence for the Impact of Combat Experiences on Gray Matter Volume of the Posterior Insula.

Background: Combat-exposed veteran populations are at an increased risk for developing cardiovascular disease. The anterior cingulate cortex (ACC) and insula have been implicated in both autonomic arousal to emotional stressors and homeostatic processes, which may contribute to cardiovascular dysfunction in combat veteran populations. The aim of the present study was to explore the intersecting relationships of combat experiences, rostral ACC and posterior insula volume, and cardiovascular health in a sample of combat veterans. Method: Twenty-four male combat veterans completed clinical assessment of combat experiences and posttraumatic stress symptoms. Subjects completed a magnetic resonance imaging scan and autosegmentation using FreeSurfer was used to estimate regional gray matter volume (controlling for total gray matter volume) of the rostral ACC and posterior insula. Flow-mediated dilation (FMD) was conducted to assess cardiovascular health. Theil-sen robust regressions and Welch's analysis of variance were used to examine relationships of combat experiences and PTSD symptomology with (1) FMD and (2) regional gray matter volume. Results: Increased combat experiences, deployment duration, and multiple deployments were related to smaller posterior insula volume. Combat experiences were marginally associated with poorer cardiovascular health. However, cardiovascular health was not related to rostral ACC or posterior insula volume. Conclusion: The present study provides initial evidence for the relationships of combat experiences, deployment duration, and multiple deployments with smaller posterior insula volume. Results may suggest that veterans with increased combat experiences may exhibit more dysfunction regulating the autonomic nervous system, a key function of the posterior insula. However, the relationship between combat and cardiovascular health was not mediated by regional brain volume. Future research is warranted to further clarify the cardiovascular or functional impact of smaller posterior insula volume in combat veterans.

Pilot Investigation of PTSD, Autonomic Reactivity, and Cardiovascular Health in Physically Healthy Combat Veterans.

Posttraumatic stress disorder (PTSD), and combat-related PTSD in particular, has been associated with increased rates of cardiovascular disease, and cardiovascular-related death. However, less research has examined possible factors that may link PTSD to poorer cardiovascular health in combat veteran populations. The current pilot study investigated whether psychological symptomology and autonomic reactivity to emotional scripts would relate to poorer cardiovascular health in combat veterans without a current diagnosis of cardiovascular disease. Male veterans (N = 24), who served in combat since Operation Iraqi Freedom, completed a semi-structured interview and self-report measures to assess psychological symptomology. Autonomic reactivity, measured using heart rate variability (HRV; low to high frequency ratio), was obtained during script-driven imagery of emotional memories. Cardiovascular health was assessed using flow-mediated dilation (FMD) of the brachial artery. Correlational analyses and discriminant analysis were used to assess the relationship between psychological symptoms (PTSD, depression, anger, as measured via self-report), autonomic reactivity to emotional scripts (HRV), and FMD. Overall, veterans in the current study showed poor cardiovascular health despite their relatively young age and lack of behavioral risk factors, with 15/24 exhibiting impaired FMD (FMD < 5%). Psychological symptomology was not associated with FMD; whereas autonomic reactivity to emotional (compared to neutral) scripts was found to relate to FMD. Autonomic reactivity to negative scripts correctly classified 76.5% of veterans as having impaired versus normative FMD. Results from this pilot study highlight the importance of cardiovascular screening with combat veterans despite psychological diagnosis. Results also support the need for longitudinal research assessing the use of autonomic reactivity to emotionally valenced stimuli as a potential risk factor for poorer cardiovascular health.