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.

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.

Lifestyle-related risk factors and their cumulative associations with hippocampal and total grey matter volume across the adult lifespan: A pooled analysis in the European Lifebrain consortium.

BACKGROUND: Lifestyle-related risk factors, such as obesity, physical inactivity, short sleep, smoking and alcohol use, have been associated with low hippocampal and total grey matter volumes (GMV). However, these risk factors have mostly been assessed as separate factors, leaving it unknown if variance explained by these factors is overlapping or additive. We investigated associations of five lifestyle-related factors separately and cumulatively with hippocampal and total GMV, pooled across eight European cohorts. METHODS: We included 3838 participants aged 18-90 years from eight cohorts of the European Lifebrain consortium. Using individual person data, we performed cross-sectional meta-analyses on associations of presence of lifestyle-related risk factors separately (overweight/obesity, physical inactivity, short sleep, smoking, high alcohol use) as well as a cumulative unhealthy lifestyle score (counting the number of present lifestyle-related risk factors) with FreeSurfer-derived hippocampal volume and total GMV. Lifestyle-related risk factors were defined according to public health guidelines. RESULTS: High alcohol use was associated with lower hippocampal volume (r = -0.10, p = 0.021), and overweight/obesity with lower total GMV (r = -0.09, p = 0.001). Other lifestyle-related risk factors were not significantly associated with hippocampal volume or GMV. The cumulative unhealthy lifestyle score was negatively associated with total GMV (r = -0.08, p = 0.001), but not hippocampal volume (r = -0.01, p = 0.625). CONCLUSIONS: This large pooled study confirmed the negative association of some lifestyle-related risk factors with hippocampal volume and GMV, although with small effect sizes. Lifestyle factors should not be seen in isolation as there is evidence that having multiple unhealthy lifestyle factors is associated with a linear reduction in overall brain volume.

Stakeholder engagement in European brain research: Experiences of the Lifebrain consortium.

INTRODUCTION: Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain-organized in a separate work package-included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project. METHODS: Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses. RESULTS: Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders. CONCLUSION: Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities. PUBLIC CONTRIBUTION: Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.

People's interest in brain health testing: Findings from an international, online cross-sectional survey.

Brain health entails mental wellbeing and cognitive health in the absence of brain disorders. The past decade has seen an explosion of tests, cognitive and biological, to predict various brain conditions, such as Alzheimer's Disease. In line with these current developments, we investigated people's willingness and reasons to-or not to-take a hypothetical brain health test to learn about risk of developing a brain disease, in a cross-sectional multilanguage online survey. The survey was part of the Global Brain Health Survey, open to the public from 4th June 2019 to 31st August 2020. Respondents were largely recruited via European brain councils and research organizations. 27,590 people responded aged 18 years or older and were predominantly women (71%), middle-aged or older (>40 years; 83%), and highly educated (69%). Responses were analyzed to explore the relationship between demographic variables and responses. Results: We found high public interest in brain health testing: over 91% would definitely or probably take a brain health test and 86% would do so even if it gave information about a disease that cannot be treated or prevented. The main reason for taking a test was the ability to respond if one was found to be at risk of brain disease, such as changing lifestyle, seeking counseling or starting treatment. Higher interest in brain health testing was found in men, respondents with lower education levels and those with poor self-reported cognitive health. Conclusion: High public interest in brain health and brain health testing in certain segments of society, coupled with an increase of commercial tests entering the market, is likely to put pressure on public health systems to inform the public about brain health testing in years to come.

Associations of depression and regional brain structure across the adult lifespan: Pooled analyses of six population-based and two clinical cohort studies in the European Lifebrain consortium.

OBJECTIVE: Major depressive disorder has been associated with lower prefrontal thickness and hippocampal volume, but it is unknown whether this association also holds for depressive symptoms in the general population. We investigated associations of depressive symptoms and depression status with brain structures across population-based and patient-control cohorts, and explored whether these associations are similar over the lifespan and across sexes. METHODS: We included 3,447 participants aged 18-89 years from six population-based and two clinical patient-control cohorts of the European Lifebrain consortium. Cross-sectional meta-analyses using individual person data were performed for associations of depressive symptoms and depression status with FreeSurfer-derived thickness of bilateral rostral anterior cingulate cortex (rACC) and medial orbitofrontal cortex (mOFC), and hippocampal and total grey matter volume (GMV), separately for population-based and clinical cohorts. RESULTS: Across patient-control cohorts, depressive symptoms and presence of mild-to-severe depression were associated with lower mOFC thickness (rsymptoms = -0.15/ rstatus = -0.22), rACC thickness (rsymptoms = -0.20/ rstatus = -0.25), hippocampal volume (rsymptoms = -0.13/ rstatus = 0.13) and total GMV (rsymptoms = -0.21/ rstatus = -0.25). Effect sizes were slightly larger for presence of moderate-to-severe depression. Associations were similar across age groups and sex. Across population-based cohorts, no associations between depression and brain structures were observed. CONCLUSIONS: Fitting with previous meta-analyses, depressive symptoms and depression status were associated with lower mOFC, rACC thickness, and hippocampal and total grey matter volume in clinical patient-control cohorts, although effect sizes were small. The absence of consistent associations in population-based cohorts with mostly mild depressive symptoms, suggests that significantly lower thickness and volume of the studied brain structures are only detectable in clinical populations with more severe depressive symptoms.

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.

The association between clinical and biological characteristics of depression and structural brain alterations.

BACKGROUND: Structural brain alterations are observed in major depressive disorder (MDD). However, MDD is a highly heterogeneous disorder and specific clinical or biological characteristics of depression might relate to specific structural brain alterations. Clinical symptom subtypes of depression, as well as immuno-metabolic dysregulation associated with subtypes of depression, have been associated with brain alterations. Therefore, we examined if specific clinical and biological characteristics of depression show different brain alterations compared to overall depression. METHOD: Individuals with and without depressive and/or anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA) (328 participants from three timepoints leading to 541 observations) and the Mood Treatment with Antidepressants or Running (MOTAR) study (123 baseline participants) were included. Symptom profiles (atypical energy-related profile, melancholic profile and depression severity) and biological indices (inflammatory, metabolic syndrome, and immuno-metabolic indices) were created. The associations of the clinical and biological profiles with depression-related structural brain measures (anterior cingulate cortex [ACC], orbitofrontal cortex, insula, and nucleus accumbens) were examined dimensionally in both studies and meta-analysed. RESULTS: Depression severity was negatively associated with rostral ACC thickness (B = -0.55, pFDR = 0.03), and melancholic symptoms were negatively associated with caudal ACC thickness (B = -0.42, pFDR = 0.03). The atypical energy-related symptom profile and immuno-metabolic indices did not show a consistent association with structural brain measures across studies. CONCLUSION: Overall depression- and melancholic symptom severity showed a dose-response relationship with reduced ACC thickness. No associations between immuno-metabolic dysregulation and structural brain alterations were found, suggesting that although both are associated with depression, distinct mechanisms may be involved.

Neural correlates of anxious distress in depression: A neuroimaging study of reactivity to emotional faces and resting-state functional connectivity.

BACKGROUND: Comorbid anxiety disorders and anxious distress are highly prevalent in major depressive disorder (MDD). The presence of the DSM-5 anxious distress specifier (ADS) has been associated with worse treatment outcomes and chronic disease course. However, little is known about the neurobiological correlates of anxious distress in MDD. METHODS: We probed the relation between the DSM-5 ADS and task-related reactivity to emotional faces, as well as resting-state functional connectivity patterns of intrinsic salience and basal ganglia networks in unmedicated MDD patients with (MDD/ADS+, N = 24) and without ADS (MDD/ADS-, N = 48) and healthy controls (HC, N = 59). Both categorical and dimensional measures of ADS were investigated. RESULTS: MDD/ADS+ patients had higher left amygdala responses to emotional faces compared to MDD/ADS- patients (p = .015)-part of a larger striato-limbic cluster. MDD/ADS+ did not differ from MDD/ADS- or controls in resting-state functional connectivity of the salience or basal ganglia networks. CONCLUSIONS: Current findings suggest that amygdala and striato-limbic hyperactivity to emotional faces may be a neurobiological hallmark specific to MDD with anxious distress, relative to MDD without anxious distress. This may provide preliminary indications of the underlying mechanisms of anxious distress in depression, and underline the importance to account for heterogeneity in depression research.

Public perceptions of brain health: an international, online cross-sectional survey.

OBJECTIVES: To investigate public perspectives on brain health. DESIGN: Cross-sectional multilanguage online survey. SETTING: Lifebrain posted the survey on its website and social media and shared it with stakeholders. The survey was open from 4 June 2019 to 31 August 2020. PARTICIPANTS: n=27 590 aged ≥18 years from 81 countries in five continents completed the survey. The respondents were predominantly women (71%), middle aged (41-60 years; 37%) or above (>60 years; 46%), highly educated (69%) and resided in Europe (98%). MAIN OUTCOME MEASURES: Respondents' views were assessed regarding factors that may influence brain health, life periods considered important to look after the brain and diseases and disorders associated with the brain. We run exploratory linear models at a 99% level of significance to assess correlates of the outcome variables, adjusting for likely confounders in a targeted fashion. RESULTS: Of all significant effects, the respondents recognised the impact of lifestyle factors on brain health but had relatively less awareness of the role socioeconomic factors might play. Most respondents rated all life periods as important for the brain (95%-96%), although the prenatal period was ranked significantly lower (84%). Equally, women and highly educated respondents more often rated factors and life periods to be important for brain health. Ninety-nine per cent of respondents associated Alzheimer's disease and dementia with the brain. The respondents made a connection between mental health and the brain, and mental disorders such as schizophrenia and depression were significantly more often considered to be associated with the brain than neurological disorders such as stroke and Parkinson's disease. Few respondents (<32%) associated cancer, hypertension, diabetes and arthritis with the brain. CONCLUSIONS: Differences in perceptions of brain health were noted among specific segments of the population. Policies providing information about brain-friendly health behaviours and targeting people less likely to have relevant experience may be needed.

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.

Education and Income Show Heterogeneous Relationships to Lifespan Brain and Cognitive Differences Across European and US Cohorts.

Higher socio-economic status (SES) has been proposed to have facilitating and protective effects on brain and cognition. We ask whether relationships between SES, brain volumes and cognitive ability differ across cohorts, by age and national origin. European and US cohorts covering the lifespan were studied (4-97 years, N = 500 000; 54 000 w/brain imaging). There was substantial heterogeneity across cohorts for all associations. Education was positively related to intracranial (ICV) and total gray matter (GM) volume. Income was related to ICV, but not GM. We did not observe reliable differences in associations as a function of age. SES was more strongly related to brain and cognition in US than European cohorts. Sample representativity varies, and this study cannot identify mechanisms underlying differences in associations across cohorts. Differences in neuroanatomical volumes partially explained SES-cognition relationships. SES was more strongly related to ICV than to GM, implying that SES-cognition relations in adulthood are less likely grounded in neuroprotective effects on GM volume in aging. The relatively stronger SES-ICV associations rather are compatible with SES-brain volume relationships being established early in life, as ICV stabilizes in childhood. The findings underscore that SES has no uniform association with, or impact on, brain and cognition.

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.

Associations between depression, lifestyle and brain structure: A longitudinal MRI study.

BACKGROUND: Depression has been associated with decreased regional grey matter volume, which might partly be explained by an unhealthier lifestyle in depressed individuals which has been ignored by most earlier studies. Also, the longitudinal nature of depression, lifestyle and brain structure associations is largely unknown. This study investigates the relationship of depression and lifestyle with brain structure cross-sectionally and longitudinally over up to 9 years. METHODS: We used longitudinal structural MRI data of persons with depression and/or anxiety disorders and controls (Nunique participants = 347, Nobservations = 609). Cortical thickness of medial orbitofrontal cortex (mOFC), rostral anterior cingulate cortex (rACC) and hippocampal volume were derived using FreeSurfer. Using Generalized Estimating Equations, we investigated associations of depression and lifestyle (Body mass index (BMI), smoking, alcohol consumption, physical activity and sleep duration) with brain structure and change in brain structure over 2 (n = 179) and 9 years (n = 82). RESULTS: Depression status (B = -.053, p = .002) and severity (B = -.002, p = .002) were negatively associated with rACC thickness. mOFC thickness was negatively associated with BMI (B = -.004, p < .001) and positively with moderate alcohol consumption (B = .030, p = .009). All associations were independent of each other. No associations were observed between (change in) depression, disease burden or lifestyle factors with brain change over time. CONCLUSIONS: Depressive symptoms and diagnosis were independently associated with thinner rACC, BMI with thinner mOFC, and moderate alcohol consumption with thicker mOFC. No longitudinal associations were observed, suggesting that regional grey matter alterations are a long-term consequence or vulnerability indicator for depression but not dynamically or progressively related to depression course trajectory.

How childhood trauma and recent adverse events are related to hair cortisol levels in a large adult cohort.

BACKGROUND: Exposure to adversity is a risk factor for many mental and somatic health problems. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is a potential mechanism linking adversity exposure and negative health outcomes. However, associations between adversity exposure and HPA-axis activity have been inconsistent. To understand the impact of adversity on the HPA-axis, we examined associations between early-life and recent adversity with hair cortisol concentration, an indicator of long-term systemic cortisol levels. METHODS: We included 1166 adult participants of the Netherlands Study of Depression and Anxiety (NESDA). Hair cortisol was measured in 3 cm of proximal hair, representing cortisol exposure during the previous 3 months. Childhood maltreatment, childhood negative life events, and recent negative life events were retrospectively assessed using interview and self-report questionnaires. Linear regression analyses were performed to assess the associations between childhood maltreatment, childhood life events and recent life events with hair cortisol. Associations with cumulative adversity exposure and with subtypes of childhood maltreatment, childhood and recent negative life events were also investigated, as were interaction effects between adversity and sex, age and psychopathology. RESULTS: Childhood maltreatment (ß = 0.034, p = 0.243), childhood life events (ß = - 0.017, p = 0.544), and recent life events (ß = - 0.021, p = 0.456) were not significantly associated with hair cortisol levels. Subtypes of childhood maltreatment and specific childhood and recent life events were not significantly associated with hair cortisol (pFDR>0.05). There were no significant interaction effects between adversity exposure and sex, age or depression/anxiety diagnostic status on hair cortisol. CONCLUSIONS: There were no significant associations between childhood and recent adversity with systemic cortisol levels in adults. Effects of early-life and adult adversity are complex and may not directly impact on long-term systemic cortisol levels as measured in hair.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders : Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = -0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

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.