Intrusive Traumatic Re-Experiencing Domain: Functional Connectivity Feature Classification by the ENIGMA PTSD Consortium.

Background: Intrusive traumatic re-experiencing domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective. Methods: Data were collected from 9 sites taking part in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) PTSD Consortium (n= 584) and included itemized PTSD symptom scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and trauma-exposed (TE)-only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. A random forest classification model was built on a training set using cross-validation, and the averaged cross-validation model performance for classification was evaluated using the area under the curve. The model was tested using a fully independent portion of the data (test dataset), and the test area under the curve was evaluated. Results: rsFC signatures differentiated TE-only participants from PTSD and ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and ITRED-only participants mainly involved default mode network-related pathways. Some unique features, such as connectivity within the frontoparietal network, differentiated TE-only participants from one group (PTSD or ITRED-only) but to a lesser extent from the other group. Conclusions: Neural network connectivity supports ITRED as a novel neurobiologically based approach to classifying posttrauma psychopathology.

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Examining the association between posttraumatic stress disorder and disruptions in cortical networks identified using data-driven methods.

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.

How does it feel? An exploration of neurobiological and clinical correlates of alexithymia in trauma-exposed police-officers with and without PTSD.

Background: Alexithymia, an inability to recognise one's emotions, has been associated with trauma-exposure and posttraumatic stress disorder (PTSD). Previous research suggests involvement of the oxytocin system, and socio-emotional neural processes. However, the paucity of neurobiological research on alexithymia, particularly in trauma-exposed populations, warrants further investigation.Objective: Explore associations between alexithymia, endogenous oxytocin levels, and socio-emotional brain function and morphometry in a trauma-exposed sample.Method: Dutch trauma-exposed police officers with (n = 38; 18 females) and without PTSD (n = 40; 20 females) were included. Alexithymia was assessed with the Toronto Alexithymia Scale (TAS-20). Endogenous salivary oxytocin was assessed during rest, using radioimmunoassay. Amygdala and insula reactivity to socio-emotional stimuli were assessed with functional MRI, amygdala and insula grey matter volume were derived using Freesurfer.Results: Alexithymia was higher in PTSD patients compared to trauma-exposed controls (F(1,70) = 54.031, p < .001). Within PTSD patients, alexithymia was positively associated with PTSD severity (ρ(36) = 0.497, p = .002). Alexithymia was not associated with childhood trauma exposure (ß = 0.076, p = .509), police work-related trauma exposure (ß = -0.107, p = .355), oxytocin levels (ß = -0.164, p = .161), insula (ß = -0.170, p = .158) or amygdala (ß = -0.175, p = .135) reactivity, or amygdala volume (ß = 0.146, p = .209). Insula volume was positively associated with alexithymia (ß = 0.222, p = .016), though not significant after multiple testing corrections. Bayesian analyses supported a lack of associations.Conclusions: No convincing neurobiological correlates of alexithymia were observed with any of the markers included in the current study. Yet, the current study confirmed high levels of alexithymia in PTSD patients, independent of trauma-exposure, substantiating alexithymia's relevance in the clinical phenotype of PTSD.

Little is known about neurobiological correlates of alexithymia in trauma-exposed and posttraumatic stress disorder (PTSD) populations.In this highly trauma-exposed sample, alexithymia was associated with PTSD symptoms, but not with childhood or adult trauma exposure, suggesting alexithymia is not a direct consequence of trauma.Alexithymia was not convincingly associated with salivary oxytocin, amygdala and insula reactivity to socio-emotional stimuli, amygdala or insula grey matter volume.

Effects of prenatal exposure to the 1944-45 Dutch famine and glucocorticoid receptor polymorphisms on later life PTSD susceptibility.

Background: Exposure to adversity in utero is thought to increase susceptibility to develop posttraumatic stress disorder (PTSD) following later life trauma, due to neurobiological programming effects during critical developmental periods. It remains unknown whether effects of prenatal adversity on PTSD susceptibility are modulated by genetic variations in neurobiological pathways implicated in PTSD susceptibility.Objective: We investigated whether genetic variation in the glucocorticoid receptor (GR) modulated effects of prenatal famine exposure on late adulthood PTSD symptom severity after trauma exposure in childhood and mid-to-late adulthood.Method: We included N = 439 term-born singleton adults (mean age: 72 years, 54.2% women) from the Dutch Famine Birth Cohort, born around the time of the Dutch Famine of 1944/1945, divided into exposure and control groups based on timing of the famine during gestation. Participants filled out self-report questionnaires on childhood (Childhood Trauma Questionnaire) and mid-to-late adulthood (Life Events Checklist for DSM-5) trauma, and current PTSD symptom severity (PTSD Checklist for DSM-5). GR haplotypes were determined from four functional GR single nucleotide polymorphisms (ER22/23EK, N363S, BclI and exon 9ß) in previously collected DNA. Linear regression analyses were performed to investigate associations of GR haplotype and prenatal famine exposure in conjunction with later life trauma on PTSD symptom severity.Results: We observed a significant three-way interaction between the GR Bcll haplotype, famine exposure during early gestation, and adulthood trauma exposure on PTSD symptom severity in late adulthood. Only participants exposed to famine during early gestation without the GR Bcll haplotype showed a significantly stronger positive association between adulthood trauma and PTSD symptom severity than non-exposed participants, indicating increased PTSD susceptibility.Conclusions: Our results illustrate the importance of integrated approaches considering genetics and environmental contexts throughout various life periods, including the rarely investigated prenatal environment, to elucidate how PTSD susceptibility evolves throughout life.HIGHLIGHTS Adversity during pregnancy is thought to increase offspring's PTSD risk following later life trauma, but exact neurobiological mechanisms underlying this process remain unknown.We found that effects of prenatal famine exposure on PTSD symptom severity were influenced by genetic variation in the glucocorticoid receptor, which signals effects of the stress hormone cortisol.Integrated approaches considering genetics and environmental contexts throughout both early and later life are important to understand how PTSD risk evolves throughout life.

The relationship between tonic immobility and the development, severity, and course of posttraumatic stress disorder: Systematic and meta-analytic literature review.

BACKGROUND: Tonic immobility (TI) is a reflexive, involuntary response that causes motor inhibition, vocal suppression, and analgesia. TI is elicited by extreme fear and perception of entrapment in a life-threatening situation. Research suggests that TI is a frequent peritraumatic response and may be related to subsequent posttraumatic stress disorder (PTSD). However, findings are mixed and, as of yet, no systematic or meta-analytic review examining associations between TI and PTSD has been published. OBJECTIVE: We systematically and meta-analytically reviewed the literature and investigated whether TI is associated with the development, severity, and course of PTSD. Additionally, we evaluated whether different types of traumatic events are differentially associated with TI, and whether TI severity differs according to sex. METHODS: A systematic literature search was conducted using Embase, PubMed, PsycINFO, and Scopus. Meta-analyses were performed on the included articles. RESULTS: We identified 27 eligible articles. We found a significant association between TI and PTSD symptom severity (r = 0.39, 95% CI: 0.34-0.44; p < .0001). TI was more severe among females (Cohen's d=0.37, 95% CI: 0.25-0.48; p < .0001) and was more often elicited in situations involving interpersonal violence. We found limited longitudinal data to perform a meta-analysis of the association between TI and the development and/or course of PTSD. However, the literature available seems to support the role of TI in both the development and course of PTSD. CONCLUSIONS: Peritraumatic TI is associated with PTSD symptom severity, occurs more often during interpersonal violence, and is more severe among females. More longitudinal research is needed to investigate the role of TI in psychopathology development and course.

Moral injury and mental health among health-care workers during the COVID-19 pandemic: meta-analysis.

Background: During the COVID-19 pandemic, health-care workers (HCWs) may have been confronted with situations that may culminate in moral injury (MI). MI is the psychological distress that may result from perpetrating or witnessing actions that violate one's moral codes. Literature suggests that MI can be associated with mental health problems.Objective: We aimed to meta-analytically review the literature to investigate whether MI is associated with symptoms of posttraumatic stress disorder (PTSD), anxiety, depression, burnout, and suicidal ideation among active HCWs during the COVID-19 pandemic.Method: We searched eight databases for studies conducted after the onset of the COVID-19 pandemic up to 18 July 2023, and performed random-effects meta-analyses to examine the relationship between MI and various mental health outcomes.Results: We retrieved 33 studies from 13 countries, representing 31,849 individuals, and pooled 79 effect sizes. We found a positive association between MI and all investigated mental health problems (rs = .30-.41, all ps < .0001). Between-studies heterogeneity was significant. A higher percentage of nurses in the samples was associated with a stronger relationship between MI and depressive and anxiety symptoms. Samples with a higher percentage of HCWs providing direct care to patients with COVID-19 exhibited a smaller effect between MI and depressive and anxiety symptoms. We observed a stronger effect between MI and PTSD symptoms in US samples compared to non-US samples.Conclusion: We found that higher MI is moderately associated with symptoms of PTSD, anxiety, depression, burnout, and suicidal ideation among HCWs during the COVID-19 pandemic. Our findings carry limitations due to the array of MI scales employed, several of which were not specifically designed for HCWs, but underscore the need to mitigate the effect of potentially morally injurious events on the mental health of HCWs.

We conducted the first meta-analysis of moral injury and mental health among healthcare workers.Moral injury is moderately associated with symptoms of PTSD, depression, anxiety, burnout, and suicidal ideation.There was a stronger association between MI and anxiety and depressive symptoms for samples with more nurses.

Associations Between Child Maltreatment, Inflammation, and Comorbid Metabolic Syndrome to Depressed Mood in a Multiethnic Urban Population: The HELIUS Study.

Background: Child maltreatment is a common negative experience and has potential long-lasting adverse consequences for mental and physical health, including increased risk for major depressive disorder (MDD) and metabolic syndrome. In addition, child maltreatment may increase the risk for comorbid physical health conditions to psychiatric conditions, with inflammation as an important mediator linking child maltreatment to poor adult health. However, it remains unresolved whether experiencing child maltreatment increases the risk for the development of comorbid metabolic syndrome to MDD. Therefore, we investigated whether child maltreatment increased the risk for comorbid metabolic syndrome to depressed mood. Subsequently, we examined whether C-reactive protein (CRP), as an inflammatory marker, mediated this association. In addition, we investigated whether effects differed between men and women. Methods: Associations were examined within cross-sectional data from the multiethnic HELIUS study (N = 21,617). Adult residents of Amsterdam, Netherlands, self-reported on child maltreatment (distinct and total number of types experienced before the age of 16 years) as well as current depressed mood (PHQ-9 score ≥ 10), and underwent physical examination to assess metabolic syndrome. The CRP levels were assessed in N = 5,998 participants. Logistic and linear regressions were applied for binary and continuous outcomes, respectively. All analyses were adjusted for relevant demographic, socioeconomic, and lifestyle characteristics, including ethnicity. Results: A higher number of maltreatment types as well as distinct types of emotional neglect, emotional abuse, and sexual abuse were significantly associated with a higher risk for current depressed mood. Child maltreatment was not significantly associated with the risk for metabolic syndrome in the whole cohort, nor within individuals with depressed mood. As child maltreatment was not significantly associated with the CRP levels, subsequent mediation analyses were not performed. No significant moderating effects by sex were observed. Conclusion: In this multiethnic urban cohort, child maltreatment was associated with a higher risk for depressed mood. Contrary to our expectations, child maltreatment was not significantly associated with an increased risk for metabolic syndrome, neither in the whole cohort nor as a comorbid condition in individuals with depressed mood. As the data were cross-sectional and came from a non-clinical adult population, longitudinal perspectives in relation to various stages of the investigated conditions were needed with more comprehensive assessments of inflammatory markers.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium.

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Sex-differential PTSD symptom trajectories across one year following suspected serious injury.

Background: Recent years have shown an increased application of prospective trajectory-oriented approaches to posttraumatic stress disorder (PTSD). Although women are generally considered at increased PTSD risk, sex and gender differences in PTSD symptom trajectories have not yet been extensively studied. Objective: To perform an in-depth investigation of differences in PTSD symptom trajectories across one-year post-trauma between men and women, by interpreting the general trends of trajectories observed in sex-disaggregated samples, and comparing within-trajectory symptom course and prevalence rates. Method: We included N = 554 participants (62.5% men, 37.5% women) from a multi-centre prospective cohort of emergency department patients with suspected severe injury. PTSD symptom severity was assessed at 1, 3, 6, and 12 months post-trauma, using the Clinician-Administered PTSD Scale for DSM-IV. Latent growth mixture modelling on longitudinal PTSD symptoms was performed within the sex-disaggregated whole samples. Bayesian modelling with informative priors was applied for reliable model estimation, considering the imbalanced prevalence of the expected latent trajectories. Results: In terms of general trends, the same trajectories were observed for men and women, i.e. resilient, recovery, chronic symptoms and delayed onset. Within-trajectory symptom courses were largely comparable, but resilient women had higher symptoms than resilient men. Sex differences in prevalence rates were observed for the recovery (higher in women) and delayed onset (higher in men) trajectories. Model fit for the sex-disaggregated samples was better than for the whole sample, indicating preferred application of sex-disaggregation. Analyses within the whole sample led to biased estimates of overall and sex-specific trajectory prevalence rates. Conclusions: Sex-disaggregated trajectory analyses revealed limited sex differences in PTSD symptom trajectories within one-year post-trauma in terms of general trends, courses and prevalence rates. The observed biased trajectory prevalence rates in the whole sample emphasize the necessity to apply appropriate statistical techniques when conducting sex-sensitive research.

Antecedentes: Los últimos años han demostrado una mayor aplicación de enfoques prospectivos orientados a la trayectoria para el trastorno de estrés postraumático (TEPT). Aunque generalmente se considera que las mujeres tienen un mayor riesgo de TEPT, las diferencias de sexo y género en las trayectorias de los síntomas del TEPT aún no se han estudiado ampliamente.Objetivo: Realizar una investigación en profundidad de las diferencias en las trayectorias de los síntomas del TEPT a lo largo de un año después de un trauma entre hombres y mujeres, interpretando las tendencias generales de las trayectorias observadas en muestras desagregadas por sexo, así como comparar el curso y la evolución de los síntomas dentro de la trayectoria y las tasas de prevalencia.Método: Incluimos N = 554 participantes (62.5% hombres, 37.5% mujeres) de una cohorte prospectiva multicéntrica de pacientes del servicio de urgencias con sospecha de lesión grave. La gravedad de los síntomas del TEPT se evaluó 1, 3, 6 y 12 meses después del trauma, utilizando la Escala de TEPT administrada por un médico para el DSM-IV. Se realizó un modelo de mezcla de crecimiento latente sobre los síntomas longitudinales de TEPT en las muestras desagregadas por sexo y en la muestra completa. Se aplicó un modelo bayesiano con antecedentes informativos para una estimación confiable del modelo, considerando la prevalencia desequilibrada de las trayectorias latentes esperadas.Resultados: En términos de tendencias generales, se observaron las mismas trayectorias para hombres y mujeres, es decir, resiliente, recuperación, síntomas crónicos y aparición tardía. Los cursos de síntomas dentro de la trayectoria fueron en gran medida comparables, pero las mujeres resilientes tenían más síntomas másque los hombres resilientes. Se observaron diferencias por sexo en las tasas de prevalencia para las trayectorias de recuperación (mayor en mujeres) y de inicio tardío (mayor en hombres). El ajuste del modelo para las muestras desagregadas por sexo fue mejor que para la muestra completa, lo que indica la aplicación preferida de la desagregación por sexo. Los análisis de la muestra completa llevaron a estimaciones sesgadas de las tasas de prevalencia de trayectorias generales y específicas por sexo.Conclusiones: Los análisis de trayectoria desagregados por sexo revelaron diferencias limitadas entre los sexos en las trayectorias de los síntomas del TEPT durante el año posterior al trauma en términos de tendencias generales, cursos y tasas de prevalencia. Las tasas de prevalencia de trayectoria sesgada observadas en el conjunto de la muestra enfatizan la necesidad de aplicar técnicas estadísticas apropiadas al realizar investigaciones que tengan en cuenta el sexo.

The impact of neighborhood context on telomere length: A systematic review.

A growing body of research demonstrates the association between neighborhood context and health. The underlying biological mechanisms of this association are not fully understood. We conducted a systematic review of studies that investigated the association between neighborhood context and telomere length (TL), a DNA-protein complex that shortens after cell division. Short TL is linked to age-related diseases and may be impacted by chronic stress. Nineteen eligible articles identified through PubMed and Scopus met inclusion criteria. Results demonstrated inconsistent support for the relationship between neighborhood disadvantage and short TL. However, findings across several studies provide evidence for an inverse association between perceived neighborhood problems and TL, suggesting that TL may be an important factor in understanding health vulnerabilities associated specifically with negative perceptions of the neighborhood context.

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.

Ethnic discrimination and depressed mood: The role of autonomic regulation.

Perceived ethnic discrimination (PED) is thought to underlie increased prevalence of depressed mood in ethnic minorities. Depression is associated with increased sympathetic and decreased parasympathetic activity. We investigated a biopsychosocial model linking PED, disrupted sympathovagal balance and depressed mood. Baseline data of HELIUS, a cohort study on health among a multi-ethnic population, was used. Heart rate variability (HRV), baroreflex sensitivity (BRS), PED (evaluated with the Everyday Discrimination Scale) and presence of depressed mood (evaluated with the Patient Health Questionnaire-9) were assessed. Associations of PED, HRV/BRS and depressed mood were analyzed with linear and logistic regression analyses. Mediation of the association of PED and depressed mood by HRV/BRS was assessed in a potential outcomes model and four steps mediation analysis. Of 9492 included participants, 14.7% fulfilled criteria for depressed mood. Higher PED was associated with depressed mood (P < .001). Lower autonomic regulation indexes were associated with depressed mood (deltaR2 = 0.4-1.1%, P < .001) and at most weakly with PED (deltaR2 = 0.2-0.3%, P < .001). A very modest mediating effect by HRV/BRS in the association between PED and depressed mood was attenuated after adjustment for socioeconomic status. To conclude, we found no support for the hypothesis that autonomic regulation relevantly mediates the association between PED and depression.

Dysregulated functional brain connectivity in response to acute social-evaluative stress in adolescents with PTSD symptoms.

Background: Posttraumatic stress disorder (PTSD) is associated with dysregulated neural, cortisol, and cardiac stress reactivity and recovery. This understanding is predominantly based on studies in adults applying emotional-cognitive and trauma-related stimuli inducing negative emotions or perceived threat. Despite large numbers of adolescents with PTSD, few studies are available on neurobiological stress reactivity in this population. Moreover, no previous studies investigated neural reactivity to social-evaluative stress. Objective: To investigate functional brain connectivity, cortisol and cardiac reactivity to acute social-evaluative stress, and additional cortisol measures in trauma-exposed adolescents with and without high PTSD symptoms. Method: A speech preparation task to induce acute social-evaluative stress elicited by anticipatory threat, was used in a subsample of the Amsterdam Born Child and their Development (ABCD) birth cohort, consisting of trauma-exposed adolescents with (n = 20) and without (n = 29) high PTSD symptoms. Psychophysiological interaction analyses were performed to assess group differences in functional connectivity of the hippocampus, mPFC and amygdala during social-evaluative stress and recovery, measured by fMRI. Additionally, perceived stress, heart rate and cortisol stress reactivity and recovery, cortisol awakening response and day curve were compared. Results: The stressor evoked significant changes in heart rate and perceived stress, but not cortisol. The PTSD symptom and control groups differed in functional connectivity between the hippocampus and cerebellum, middle and inferior frontal gyrus, and the mPFC and inferior frontal gyrus during social-evaluative stress versus baseline. Mostly, the same patterns were found during recovery versus baseline. We observed no significant group differences in amygdala connectivity, and cortisol and cardiac measures. Conclusions: Our findings suggest threat processing in response to social-evaluative stress is disrupted in adolescents with PTSD symptoms. Our findings are mainly but not entirely in line with findings in adults with PTSD, which denotes the importance to investigate adolescents with PTSD as a separate population.

Antecedentes: El trastorno de estrés postraumático (TEPT) está asociado con la recuperación. Esta comprensión se basa predominantemente en estudios con adultos, que aplican estímulos emocional-cognitivos y relacionados con el trauma que inducen emociones negativas, o percepción de amenaza. A pesar del gran número de adolescentes con TEPT, hay pocos estudios disponibles sobre la reactividad neurobiológica al estrés en esta población. Además, ningún estudio previo ha investigado la reactividad neuronal al estrés socio-evaluativo.Objetivos: Investigar la conectividad cerebral funcional, el cortisol y la reactividad cardíaca al estrés socio-evaluativo, y medidas adicionales de cortisol en adolescentes expuestos a trauma con y sin síntomas elevados de TEPT.Método: Se utilizó una tarea de preparación de discurso para inducir un estrés socio-evaluativo agudo, provocado por la amenaza anticipatoria, en una submuestra del cohorte de nacimiento del Niño nacido en Amsterdam y su Desarrollo (Amsterdam Born Child and their Development, ABCD), que consta de adolescentes expuestos a traumas con (n = 20) y sin (n = 29) síntomas elevados de TEPT. Se realizaron análisis de interacción psicofisiológica para evaluar las diferencias de grupo en la conectividad funcional del hipocampo, mPFC y amígdala durante el estrés socio-evaluativo y la recuperación, medido por fMRI. Además, se compararon el estrés percibido, la frecuencia cardíaca y la reactividad y recuperación del estrés por cortisol, la respuesta del cortisol al despertar, y la curva diurna.Resultados: El estresor provocó cambios significativos en la frecuencia cardíaca y el estrés percibido, pero no del cortisol. Los grupos con síntomas de TEPT y control difirieron en la conectividad funcional entre el hipocampo y el cerebelo, la circunvolución frontal media e inferior, y la mPFC y la circunvolución frontal inferior durante el estrés socio-evaluativo frente al valor inicial. En su mayoría, se encontraron los mismos patrones durante la recuperación frente a la línea de base. No observamos diferencias significativas entre grupos respecto de la conectividad de la amígdala, ni en las medidas de cortisol y cardíacas.Conclusiones: Nuestros hallazgos sugieren que el procesamiento de amenazas en respuesta al estrés socio-evaluativo se encuentra alterado en adolescentes con síntomas de TEPT. Nuestros hallazgos están principalmente, pero no completamente, en línea con los hallazgos en adultos con TEPT, lo que denota la importancia de investigar a adolescentes con TEPT como una población aparte.

Forecasting individual risk for long-term Posttraumatic Stress Disorder in emergency medical settings using biomedical data: A machine learning multicenter cohort study.

The necessary requirement of a traumatic event preceding the development of Posttraumatic Stress Disorder, theoretically allows for administering preventive and early interventions in the early aftermath of such events. Machine learning models including biomedical data to forecast PTSD outcome after trauma are highly promising for detection of individuals most in need of such interventions. In the current study, machine learning was applied on biomedical data collected within 48 h post-trauma to forecast individual risk for long-term PTSD, using a multinominal approach including the full spectrum of common PTSD symptom courses within one prognostic model for the first time. N = 417 patients (37.2% females; mean age 46.09 ± 15.88) admitted with (suspected) serious injury to two urban Academic Level-1 Trauma Centers were included. Routinely collected biomedical information (endocrine measures, vital signs, pharmacotherapy, demographics, injury and trauma characteristics) upon ED admission and subsequent 48 h was used. Cross-validated multi-nominal classification of longitudinal self-reported symptom severity (IES-R) over 12 months and bimodal classification of clinician-rated PTSD diagnosis (CAPS-IV) at 12 months post-trauma was performed using extreme Gradient Boosting and evaluated on hold-out sets. SHapley Additive exPlanations (SHAP) values were used to explain the derived models in human-interpretable form. Good prediction of longitudinal PTSD symptom trajectories (multiclass AUC = 0.89) and clinician-rated PTSD at 12 months (AUC = 0.89) was achieved. Most relevant prognostic variables to forecast both multinominal and dichotomous PTSD outcomes included acute endocrine and psychophysiological measures and hospital-prescribed pharmacotherapy. Thus, individual risk for long-term PTSD was accurately forecasted from biomedical information routinely collected within 48 h post-trauma. These results facilitate future targeted preventive interventions by enabling future early risk detection and provide further insights into the complex etiology of PTSD.

Early posttraumatic autonomic and endocrine markers to predict posttraumatic stress symptoms after a preventive intervention with oxytocin.

BACKGROUND: Efficient prevention of posttraumatic stress disorder (PTSD) needs to target individuals with an increased risk for adverse outcome after trauma. Prognostic or prescriptive biological markers assessed early posttrauma may inform personalized treatment recommendations. OBJECTIVE: To test prognostic and prescriptive effects of early (posttraumatic) autonomic and endocrine markers on PTSD symptom development. METHOD: Autonomic and endocrine markers were assessed within 12 days posttrauma and before treatment initiation within a randomized placebo-controlled trial investigating repeated oxytocin administration as preventive intervention for PTSD. Linear mixed effects models were used to test the effects of heart rate (variability), resting cortisol, morning cortisol and cortisol awakening response (CAR), cortisol suppression by dexamethasone and resting oxytocin on PTSD symptoms 1.5, 3 and 6 months posttrauma in men (n = 54), women using hormonal contraception (n = 27) and cycling women (n = 19). RESULTS: We found significant prognostic effects of resting oxytocin and cortisol suppression. In women using hormonal contraception, higher oxytocin was associated with higher PTSD symptoms across follow-up. Stronger cortisol suppression by dexamethasone, reflecting increased glucocorticoid receptor feedback sensitivity, was associated with lower PTSD symptoms across follow-up in men, but with higher symptoms at 1.5 months in women using hormonal contraception. These effects were independent of treatment condition. No further significant prognostic or prescriptive effects were detected. CONCLUSION: Our exploratory study indicates that resting oxytocin and glucocorticoid receptor feedback sensitivity early posttrauma are associated with subsequent PTSD symptom severity. Notably, prognostic effects depended on sex and hormonal contraception use, emphasizing the necessity to consider these factors in biomedical PTSD research.

Antecedentes: La prevención eficiente del trastorno de estrés postraumático (TEPT) necesita dirigirse a personas con un mayor riesgo de consecuencias adversas después de un trauma. Los marcadores biológicos pronósticos o preceptivos evaluados tempranamente luego del trauma pueden informar recomendaciones de tratamiento personalizadas.Objetivo: Evaluar los efectos pronósticos y preceptivos de los marcadores tempranos (postraumáticos) autonómicos y endocrinos sobre el desarrollo de síntomas de TEPT.Método: Fueron evaluados marcadores autonómicos y endocrinos dentro de los 12 días postrauma y antes de la iniciación del tratamiento dentro de un estudio aleatorio placebo-control, investigando la administración repetida de oxitocina como intervención preventiva para TEPT. Se utilizaron modelos lineales de efectos mixtos para evaluar los efectos de la frecuencia cardiaca (variabilidad), cortisol en reposo, cortisol matutino y respuesta al despertar de cortisol (CAR por sus siglas en inglés), supresión del cortisol por dexametasona y oxitocina en reposo sobre los síntomas de TEPT a los 1.5, 3 y 6 meses postrauma en hombres (N=54), mujeres que usaban contracepción hormonal (N=27) y mujeres ciclantes (N=19).Resultados: Encontramos efectos pronósticos significativos de la oxitocina en reposo y de la supresión de cortisol. En las mujeres que usaban contracepción hormonal, los niveles de oxitocina más altos se asociaron con más síntomas de TEPT a lo largo del seguimiento. La supresión mayor del cortisol por dexametasona, que refleja una mayor sensibilidad a la retroalimentación del receptor de glucocorticoides, se asoció con menos síntomas de TEPT a lo largo del seguimiento en los hombres, pero con mayores síntomas a los 1.5 meses en las mujeres que usaban contracepción hormonal. Estos efectos fueron independientes de la condición de tratamiento. No se detectaron más efectos pronósticos o preceptivos significativos.Conclusión: Nuestro estudio exploratorio indica que la oxitocina en reposo y la sensibilidad a la retroalimentación del receptor de glucocorticoides tempranamente luego del trauma se asocian con la subsecuente severidad de los síntomas de TEPT. Notablemente, los efectos pronósticos dependen del sexo y del uso de contracepción hormonal, lo que enfatiza la necesidad de considerar estos factores en la investigación biomédica en TEPT.

Help in hand after traumatic events: a randomized controlled trial in health care professionals on the efficacy, usability, and user satisfaction of a self-help app to reduce trauma-related symptoms.

Background: Despite the fact that many people are affected by trauma and suffer from posttraumatic stress symptoms (PTSS) there is a lack of easy-accessible interventions to self-manage these symptoms. Mobile apps may deliver low-intensity self-help to reduce trauma-related symptoms and empower individuals following trauma, such as high-risk professionals who are regularly exposed to potentially traumatic events. In this randomized controlled trial, we examined the efficacy, and evaluated the usability and user satisfaction of the app 'SUPPORT Coach' as a self-help tool to reduce trauma-related symptoms. Methods: Health care professionals (e.g. nurses, physicians, paramedics and ambulance drivers) completed an online screening on PTSS (T0). They were randomized when at least one PTSS was reported, either to the intervention (1 month unlimited access to SUPPORT Coach) or control condition (no access to SUPPORT Coach). Self-reported PTSS, negative trauma-related cognitions, psychological resilience, and social support were assessed online at baseline (T1), post-condition (T2), and 1 month follow-up (T3). Results: Of the 1175 participants screened, 287 (24.4%) indicated at least one posttraumatic stress symptom and were randomized. The majority of intervention condition participants (83%, n = 103) used SUPPORT Coach; they were slightly to moderately satisfied with the app. There was no significant group difference in change in PTSS and social support after one-month app usage. However, the intervention condition showed a greater decline in negative trauma-related cognitions at T2 and T3, and a larger increase in psychological resilience at T3 than the control condition. Conclusions: SUPPORT Coach without guidance could potentially provide easy-accessible self-help to diminish negative trauma-related cognitions, and strengthen resilience in coping with adversities. However, since the attrition rate was substantially higher in the intervention than in control condition, our findings should be interpreted with caution and warrant replication.

Antecedentes: Pese al hecho de que muchas personas son afectadas por traumas y sufren de síntomas de estrés postraumático (PTSS por sus siglas en inglés) existe una carencia de intervenciones fácilmente accesibles para auto-manejar estos síntomas. Las aplicaciones móviles pueden entregar autoayuda de baja intensidad para reducir los síntomas relacionados con el trauma y empoderar individuos posterior a un trauma, tales como en profesionales de alto riesgo que están regularmente expuestos a eventos potencialmente traumáticos. En este ensayo controlado randomizado examinamos la eficacia, y evaluamos la usabilidad y satisfacción de la aplicación 'SUPPORT Coach' como una herramienta de autoayuda para reducir síntomas relacionados con el trauma.Métodos: Profesionales de atención en salud (como enfermeras, médicos, paramédicos y conductores de ambulancia) completaron un tamizaje online de PTSS (T0). Fueron randomizados cuando al menos un PTSS fue reportado, ya sea a la intervención (un mes de acceso ilimitado a SUPPORT Coach) o a control (sin acceso a la aplicación). Se evaluó el auto-reporte de PTSS, cogniciones negativas relacionadas al trauma, resiliencia psicológica y apoyo social basalmente (T1), post condición (T2) y un seguimiento al mes de la intervención (T3).Resultados: de los 1175 participantes tamizados, 287 (24.4%) indicaron al menos un síntoma de estrés postraumático y fueron randomizados. La mayoría de los participantes del grupo de la intervención usaron SUPPORT Coach (83% n=103), y se encontraron de leve a moderamente satisfechos con la aplicación. No hubo diferencia significativa entre los grupos en PTSS y en apoyo social después de un mes de haber utilizado la aplicación. Sin embargo, el grupo que recibió la intervención mostró una mayor declinación en cogniciones negativas relacionadas con el trauma en T2 y T3, y un mayor aumento de la resiliencia psicológica en T3 que en el grupo control.Conclusiones: El uso de SUPPORT Coach sin guía podría potencialmente proveer autoayuda fácilmente accesible para disminuir cogniciones negativas relacionadas con el trauma, y fortalecer la resiliencia al lidiar con adversidades. Sin embargo, dado que la tasa de deserción fue sustancialmente más alta en el grupo de intervención que en el de control, nuestros hallazgos debiesen ser interpretados con cautela y justifican replicación.

Associations Between Child Maltreatment, Autonomic Regulation, and Adverse Cardiovascular Outcome in an Urban Population: The HELIUS Study.

INTRODUCTION: A mounting body of literature emphasizes the potential negative effects of adverse childhood experiences (ACEs) on both mental and physical health throughout life, including an increased risk for developing cardiovascular disease (CVD). Since CVD is one of the leading causes of mortality and morbidity worldwide, it is of great importance to advance our understanding of the effects of on CVD. This holds both for the actual incidence and for intermediate biological pathways that may convey CVD risk, such as imbalance in autonomic nervous system regulation, resulting in a chronically heightened sympathetic activity and lowered reactivity. In a large urban, multi-ethnic population-based cohort study we investigated whether there is an association between child maltreatment, CVD incidence and autonomic regulation. METHODS: Within the Health in an Urban Setting (HELIUS) study, a large, multi-ethnic population cohort study including n = 22,165 Amsterdam residents, we used logistic regression analyses to investigate the association between the number of self-reported types of child maltreatment (range 0-4), and self-reported adverse cardiovascular outcome (aCVO). Self-reported child maltreatment included emotional neglect, emotional abuse, physical abuse, and sexual abuse. Furthermore, in a subsample (n = 10,260), mean age 44.3, we investigated associations between child maltreatment, autonomic regulation, and aCVO using linear regression analyses. Both baroreflex sensitivity (BRS) and heart rate variability (HRV) were assessed as non-invasive indices of autonomic regulation. RESULTS: The number of endorsed child maltreatment types was significantly associated with a higher aCVO risk. The association remained significant after adjustment for demographic, socioeconomic, health-behavioral, and psychological covariates (p = 0.011, odds ratio: 1.078, confidence interval: 1.018-1.142). The cumulative exposure to child maltreatment was negatively associated with BRS and HRV, but the association was no longer significant after correction for socioeconomic and demographic covariates. CONCLUSION: In a large, multi-ethnic urban-population cohort study we observed a positive association between number of endorsed child maltreatment types and self-reported aCVO but not autonomic regulation, over and above the effect of relevant demographic, health, and psychological factors. Future studies should examine the potential role of the dynamics of autonomic dysregulation as potential underlying biological pathways in the association between ACEs and CVD, as this could eventually facilitate the development of preventive and therapeutic strategies for CVD.

Cortisol awakening response over the course of humanitarian aid deployment: a prospective cohort study.

Background: Internationally deployed humanitarian aid (HA) workers are routinely confronted with potentially traumatic stressors. However, it remains unknown whether HA deployment and related traumatic stress are associated with long-term changes in hypothalamic-pituitary-adrenal (HPA) axis function. Therefore, we investigated whether cortisol awakening response (CAR) decreased upon deployment and whether this was moderated by previous and recent trauma exposure and parallel changes in symptom severity and perceived social support. Methods: In this prospective study, n = 86 HA workers (68% females) completed questionnaires regarding trauma exposure, posttraumatic stress disorder (PTSD), anxiety and depressive symptoms and perceived social support, as well as salivary cortisol assessments at awakening and 30 minutes post-awakening at before, early and 3-6 months post-deployment. Results: Linear mixed models showed significantly decreased CAR (b(SE) = -.036(.011), p = .002) and awakening cortisol over time (b(SE) = -.007(.003), p = .014). The extent of awakening cortisol change was significantly moderated by interactions between previous and recent trauma exposure. Also, a steeper awakening cortisol decrease was significantly associated with higher mean anxiety and PTSD symptoms across assessments. No significant effects were found for social support. Conclusions: We observed attenuated CAR and awakening cortisol upon HA deployment, with a dose-response effect between trauma exposure before and during the recent deployment on awakening cortisol. Awakening cortisol change was associated with PTSD and anxiety symptom levels across assessments. Our findings support the need for organizational awareness that work-related exposures may have long-lasting biological effects. Further research assessing symptoms and biological measures in parallel is needed to translate current findings into guidelines on the individual level.

Antecedentes: Los trabajadores de la ayuda humanitaria desplegados internacionalmente (HA) se enfrentan rutinariamente a estresores potencialmente traumáticos. Sin embargo, aún se desconoce si el despliegue de la HA y el estrés traumático relacionado están asociados con cambios a largo plazo en la función del eje hipotalámico-pituitaria-suprarrenal (HPA). Por lo tanto, investigamos si la respuesta del cortisol al despertar (CAR, en sus siglas en inglés) disminuyó en el momento del despliegue y si esto fue moderado por una anterior o reciente exposición a un trauma y los cambios paralelos en la gravedad de los síntomas y el apoyo social percibido.Métodos: En este estudio prospectivo, x = 86 trabajadores de la HA (68% mujeres) completaron cuestionarios sobre la exposición al trauma, el trastorno de estrés postraumático (TEPT), la ansiedad y los síntomas depresivos y el apoyo social percibido, así como evaluaciones del cortisol salival al despertar y 30 minutos después del despertar, antes, durante y 3-6 meses después del despliegue.Resultados: Los modelos lineales mixtos mostraron una disminución significativa de la CAR (b(SE) = −.036(.011), p = .002) y del cortisol al despertar, en el transcurso del tiempo (b(SE) = −.007(.003), p = .014). El grado de cambio en el cortisol al despertar fue significativamente moderado por las interacciones entre la exposición anterior y reciente al trauma. Además, una disminución más pronunciada del cortisol al despertar se asoció significativamente con una mayor media de ansiedad y síntomas de TEPT en todas las evaluaciones. No se encontraron efectos significativos en cuanto al apoyo social.Conclusiones: Observamos CAR atenuado y cortisol al despertar en el despliegue de HA, con un efecto dosis-respuesta en el cortisol al despertar, entre la exposición al trauma antes y durante el reciente despliegue. El cambio de cortisol al despertar se asoció con el TEPT y los niveles de síntomas de ansiedad en todas las evaluaciones. Nuestros hallazgos apoyan la necesidad de la conciencia organizacional de que las exposiciones relacionadas con el trabajo pueden tener efectos biológicos duraderos. Se necesitan más investigaciones que evalúen los síntomas y las medidas biológicas en paralelo para traducir los hallazgos actuales en directrices a nivel individual.