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Cognitive deficits are a key source of disability in individuals with major depressive disorder (MDD) and worsen with disease progression. Despite their clinical relevance, the underlying mechanisms of cognitive deficits remain poorly elucidated, hampering effective treatment strategies. Emerging evidence suggests that alterations in white matter microstructure might contribute to cognitive dysfunction in MDD. We aimed to investigate the complex association between changes in white matter integrity, cognitive decline, and disease course in MDD in a comprehensive longitudinal dataset.

Recurrences of depressive episodes in major depressive disorder (MDD) can be explained by the diathesis-stress model, suggesting that stressful life events (SLEs) can trigger MDD episodes in individuals with pre-existing vulnerabilities. However, the longitudinal neurobiological impact of SLEs on gray matter volume (GMV) in MDD and its interaction with early-life adversity remains unresolved. In 754 participants aged 18–65 years (362 MDD patients; 392 healthy controls; HCs), we assessed longitudinal associations between SLEs (Life Events Questionnaire) and whole-brain GMV changes (3 Tesla MRI) during a 2-year interval, using voxel-based morphometry in SPM12/CAT12. We also explored the potential moderating role of childhood maltreatment (Childhood Trauma Questionnaire) on these associations. Over the 2-year interval, HCs demonstrated significant GMV reductions in the middle frontal, precentral, and postcentral gyri in response to higher levels of SLEs, while MDD patients showed no such GMV changes. Childhood maltreatment did not moderate these associations in either group. However, MDD patients who had at least one depressive episode during the 2-year interval, compared to those who did not, or HCs, showed GMV increases in the middle frontal, precentral, and postcentral gyri associated with an increase in SLEs and childhood maltreatment. Our findings indicate distinct GMV changes in response to SLEs between MDD patients and HCs. GMV decreases in HCs may represent adaptive responses to stress, whereas GMV increases in MDD patients with both childhood maltreatment and a depressive episode during the 2-year interval may indicate maladaptive changes, suggesting a neural foundation for the diathesis-stress model in MDD recurrences.

Patients with bipolar disorder (BD) show alterations in both gray matter volume (GMV) and white matter (WM) integrity compared with healthy controls (HC). However, it remains unclear whether the phenotypically distinct BD subtypes (BD-I and BD-II) also exhibit brain structural differences. This study investigated GMV and WM differences between HC, BD-I, and BD-II, along with clinical and genetic associations. N= 73 BD-I, n= 63 BD-II patients and n= 136 matched HC were included. Using voxel-based morphometry and tract-based spatial statistics, main effects of group in GMV and fractional anisotropy (FA) were analyzed. Associations between clinical and genetic features and GMV or FA were calculated using regression models. For FA but not GMV, we found significant differences between groups. BD-I patients showed lower FA compared with BD-II patients (ptfce-FWE= 0.006), primarily in the anterior corpus callosum. Compared with HC, BD-I patients exhibited lower FA in widespread clusters (ptfce-FWE< 0.001), including almost all major projection, association, and commissural fiber tracts. BD-II patients also demonstrated lower FA compared with HC, although less pronounced (ptfce-FWE= 0.049). The results remained unchanged after controlling for clinical and genetic features, for which no independent associations with FA or GMV emerged. Our findings suggest that, at a neurobiological level, BD subtypes may reflect distinct degrees of disease expression, with increasing WM microstructure disruption from BD-II to BD-I. This differential magnitude of microstructural alterations was not clearly linked to clinical and genetic variables. These findings should be considered when discussing the classification of BD subtypes within the spectrum of affective disorders.

Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n= 284 acutely depressed, n= 177 partially and n= 198 fully remitted patients, and n= 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.

Up to 70% of patients with major depressive disorder present with psychomotor disturbance (PmD), but at the present time understanding of its pathophysiology is limited. In this study, we capitalized on a large sample of patients to examine the neural correlates of PmD in depression. This study included 820 healthy participants and 699 patients with remitted (n= 402) or current (n= 297) depression. Patients were further categorized as having psychomotor retardation, agitation, or no PmD. We compared resting-state functional connectivity (ROI-to-ROI) between nodes of the cerebral motor network between the groups, including primary motor cortex, supplementary motor area, sensory cortex, superior parietal lobe, caudate, putamen, pallidum, thalamus, and cerebellum. Additionally, we examined network topology of the motor network using graph theory. Among the currently depressed 55% had PmD (15% agitation, 29% retardation, and 11% concurrent agitation and retardation), while 16% of the remitted patients had PmD (8% retardation and 8% agitation). When compared with controls, currently depressed patients with PmD showed higher thalamo-cortical and pallido-cortical connectivity, but no network topology alterations. Currently depressed patients with retardation only had higher thalamo-cortical connectivity, while those with agitation had predominant higher pallido-cortical connectivity. Currently depressed patients without PmD showed higher thalamo-cortical, pallido-cortical, and cortico-cortical connectivity, as well as altered network topology compared to healthy controls. Remitted patients with PmD showed no differences in single connections but altered network topology, while remitted patients without PmD did not differ from healthy controls in any measure. We found evidence for compensatory increased cortico-cortical resting-state functional connectivity that may prevent psychomotor disturbance in current depression, but may perturb network topology. Agitation and retardation show specific connectivity signatures. Motor network topology is slightly altered in remitted patients arguing for persistent changes in depression. These alterations in functional connectivity may be addressed with non-invasive brain stimulation.

Childhood maltreatment (CM) has been associated with changes in structural brain connectivity even in the absence of mental illness. Social support, an important protective factor in the presence of childhood maltreatment, has been positively linked to white matter integrity. However, the shared effects of current social support and CM and their association with structural connectivity remain to be investigated. They might shed new light on the neurobiological basis of the protective mechanism of social support. Using connectome-based predictive modeling (CPM), we analyzed structural connectomes of N= 904 healthy adults derived from diffusion-weighted imaging. CPM predicts phenotypes from structural connectivity through a cross-validation scheme. Distinct and shared networks of white matter tracts predicting childhood trauma questionnaire scores and the social support questionnaire were identified. Additional analyses were applied to assess the stability of the results. CM and social support were predicted significantly from structural connectome data (all rs ≥ 0.119, all ps≤ 0.016). Edges predicting CM and social support were inversely correlated, i.e., positively correlated with CM and negatively with social support, and vice versa, with a focus on frontal and temporal regions including the insula and superior temporal lobe. CPM reveals the predictive value of the structural connectome for CM and current social support. Both constructs are inversely associated with connectivity strength in several brain tracts. While this underlines the interconnectedness of these experiences, it suggests social support acts as a protective factor following adverse childhood experiences, compensating for brain network alterations. Future longitudinal studies should focus on putative moderating mechanisms buffering these adverse experiences.

In bipolar disorder (BD), the alternation of extreme mood states indicates deficits in emotion processing, accompanied by aberrant neural function of the emotion network. The present study investigated the effects of an emotion-centered psychotherapeutic intervention on amygdala responsivity and connectivity during emotional face processing in BD.

The promise of machine learning has fueled the hope for developing diagnostic tools for psychiatry. Initial studies showed high accuracy for the identification of major depressive disorder (MDD) with resting-state connectivity, but progress has been hampered by the absence of large datasets. Here we used regular machine learning and advanced deep learning algorithms to differentiate patients with MDD from healthy controls and identify neurophysiological signatures of depression in two of the largest resting-state datasets for MDD. We obtained resting-state functional magnetic resonance imaging data from the REST-meta-MDD (N= 2338) and PsyMRI (N= 1039) consortia. Classification of functional connectivity matrices was done using support vector machines (SVM) and graph convolutional neural networks (GCN), and performance was evaluated using 5-fold cross-validation. Features were visualized using GCN-Explainer, an ablation study and univariate t-testing. The results showed a mean classification accuracy of 61% for MDD versus controls. Mean accuracy for classifying (non-)medicated subgroups was 62%. Sex classification accuracy was substantially better across datasets (73–81%). Visualization of the results showed that classifications were driven by stronger thalamic connections in both datasets, while nearly all other connections were weaker with small univariate effect sizes. These results suggest that whole brain resting-state connectivity is a reliable though poor biomarker for MDD, presumably due to disease heterogeneity as further supported by the higher accuracy for sex classification using the same methods. Deep learning revealed thalamic hyperconnectivity as a prominent neurophysiological signature of depression in both multicenter studies, which may guide the development of biomarkers in future studies.

In bipolar disorder, impaired affective theory of mind (aToM) performance and aberrant neural activation in the ToM brain network partly explain social functioning impairments. However, it is not yet known whether psychotherapy of bipolar disorder influences neuroimaging markers of aToM.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects deffect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d= −0.077, pFWE= 0.037; right: d= −0.104, pFWE= 0.001), and a significant interaction between SAD and age was found for the left putamen (r= −0.034, pFWE= 0.045). Smaller bilateral putamen volumes (left: d= −0.141, pFWE< 0.001; right: d= −0.158, pFWE< 0.001) and larger bilateral pallidum volumes (left: d= 0.129, pFWE= 0.006; right: d= 0.099, pFWE= 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

Many therapeutic interventions in psychiatry can be viewed as attempts to influence the brain’s large-scale, dynamic network state transitions. Building on connectome-based graph analysis and control theory, Network Control Theory is emerging as a powerful tool to quantify network controllability—i.e., the influence of one brain region over others regarding dynamic network state transitions. If and how network controllability is related to mental health remains elusive. Here, from Diffusion Tensor Imaging data, we inferred structural connectivity and inferred calculated network controllability parameters to investigate their association with genetic and familial risk in patients diagnosed with major depressive disorder (MDD, n= 692) and healthy controls (n= 820). First, we establish that controllability measures differ between healthy controls and MDD patients while not varying with current symptom severity or remission status. Second, we show that controllability in MDD patients is associated with polygenic scores for MDD and psychiatric cross-disorder risk. Finally, we provide evidence that controllability varies with familial risk of MDD and bipolar disorder as well as with body mass index. In summary, we show that network controllability is related to genetic, individual, and familial risk in MDD patients. We discuss how these insights into individual variation of network controllability may inform mechanistic models of treatment response prediction and personalized intervention-design in mental health.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD, schizophrenia, and schizoaffective disorder) overlap in symptomatology, risk factors, genetics, and other biological measures. Based on previous findings, it remains unclear what transdiagnostic regional gray matter volume (GMV) alterations exist across these disorders, and with which factors they are associated. GMV (3-T magnetic resonance imaging) was compared between healthy controls (HC; n= 110), DSM-IV-TR diagnosed MDD (n= 110), BD (n= 110), and SSD patients (n= 110), matched for age and sex. We applied a conjunction analysis to identify shared GMV alterations across the disorders. To identify potential origins of identified GMV clusters, we associated them with early and current risk and protective factors, psychopathology, and neuropsychology, applying multiple regression models. Common to all diagnoses (vs. HC), we identified GMV reductions in the left hippocampus. This cluster was associated with the neuropsychology factor working memory/executive functioning, stressful life events, and with global assessment of functioning. Differential effects between groups were present in the left and right frontal operculae and left insula, with volume variances across groups highly overlapping. Our study is the first with a large, matched, transdiagnostic sample to yield shared GMV alterations in the left hippocampus across major mental disorders. The hippocampus is a major network hub, orchestrating a range of mental functions. Our findings underscore the need for a novel stratification of mental disorders, other than categorical diagnoses.

Background: Whipple disease, which is caused by infection with Tropheryma whipplei, can be treated effectively with antimicrobials. Occasionally, inflammation reappears after initial improvement; this is often interpreted as refractory or recurrent disease. However, polymerase chain reaction for T. whipplei in tissue is sometimes negative during reinflammation, indicating absence of vital bacteria, and this reinflammation does not respond to antimicrobials but does respond to steroids. Objective: To demonstrate that the immune reconstitution inflammatory syndrome (IRIS) occurs in patients treated for Whipple disease. Design: Cohort study. (International Standard Randomised Controlled Trial Number Register registration number: ISRCTN45658456) Setting: 2 academic medical centers in Germany. Methods: 142 patients treated for Whipple disease out of a cohort of 187 were observed for reappearance of inflammatory signs after effective antibiotic therapy. Definitions of IRIS in HIV infection, tuberculosis, and leprosy were adapted for application to Whipple disease. Results: On the basis of study definitions, IRIS was diagnosed in 15 of 142 patients. Symptoms included fever, arthritis, pleurisy, erythema nodosum, inflammatory orbitopathy, small-bowel perforation, and a hypothalamic syndrome. Two patients died. There was a positive correlation with previous immunosuppressive treatment and a negative correlation with previous diarrhea and weight loss. Limitations: The study was observational and thus has inherent weaknesses, such as incomplete and potentially selective data recording. Conclusion: The immune reconstitution inflammatory syndrome was diagnosed in about 10% of patients with Whipple disease in the study cohort; the outcome varied from mild to fatal. Patients who had had previous immunosuppressive therapy were at particular risk. An immune reconstitution syndrome should be considered in patients with Whipple disease in whom inflammatory symptoms recur after effective treatment. Early diagnosis and treatment with steroids may be beneficial; prospective studies are needed. Primary Funding Source: European Commission and Deutsche Forschungsgemeinschaft.

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N= 519), clinical controls with a mood disorder but without STBs (CC; N= 246) and young people with current suicidal ideation (N= 223). In separate analyses, MRI metrics were compared among HCs (N= 253), CCs (N= 217), and suicide attempters (N= 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N= 163) than those without a lifetime suicide attempt (N= 323; FDR-p= 0.035, Cohen’s d= 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1and APOEare associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18–75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen’s d= 0.14, 95% CI: 0.08–0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Childhood maltreatment is associated with cognitive deficits that in turn have been predictive for therapeutic outcome in psychiatric patients. However, previous studies have either investigated maltreatment associations with single cognitive domains or failed to adequately control for confounders such as depression, socioeconomic environment, and genetic predisposition. We aimed to isolate the relationship between childhood maltreatment and dysfunction in diverse cognitive domains, while estimating the contribution of potential confounders to this relationship, and to investigate gene–environment interactions. We included 547 depressive disorder and 670 healthy control participants (mean age: 34.7 years, SD = 13.2). Cognitive functioning was assessed for the domains of working memory, executive functioning, processing speed, attention, memory, and verbal intelligence using neuropsychological tests. Childhood maltreatment and parental education were assessed using self-reports, and psychiatric diagnosis was based on DSM-IV criteria. Polygenic scores for depression and for educational attainment were calculated. Multivariate analysis of cognitive domains yielded significant associations with childhood maltreatment (η²p= 0.083, P< 0.001), depression (η²p= 0.097, P< 0.001), parental education (η²p= 0.085, P< 0.001), and polygenic scores for depression (η²p= 0.021, P= 0.005) and educational attainment (η²p= 0.031, P< 0.001). Each of these associations remained significant when including all of the predictors in one model. Univariate tests revealed that maltreatment was associated with poorer performance in all cognitive domains. Thus, environmental, psychopathological, and genetic risk factors each independently affect cognition. The insights of the current study may aid in estimating the potential impact of different loci of interventions for cognitive dysfunction. Future research should investigate if customized interventions, informed by individual risk profiles and related cognitive preconditions, might enhance response to therapeutic treatments.

Neuroticism has been shown to act as an important risk factor for major depressive disorder (MDD). Genetic and neuroimaging research has independently revealed biological correlates of neurotic personality including cortical alterations in brain regions of high relevance for affective disorders. Here we investigated the influence of a polygenic score for neuroticism (PGS) on cortical brain structure in a joint discovery sample of n?=?746 healthy controls (HC) and n?=?268 MDD patients. Findings were validated in an independent replication sample (n?=?341 HC and n?=?263 MDD). Subgroup analyses stratified for case-control status and analyses of associations between neurotic phenotype and cortical measures were carried out. PGS for neuroticism was significantly associated with a decreased cortical surface area of the inferior parietal cortex, the precuneus, the rostral cingulate cortex and the inferior frontal gyrus in the discovery sample. Similar associations between PGS and surface area of the inferior parietal cortex and the precuneus were demonstrated in the replication sample. Subgroup analyses revealed negative associations in the latter regions between PGS and surface area in both HC and MDD subjects. Neurotic phenotype was negatively correlated with surface area in similar cortical regions including the inferior parietal cortex and the precuneus. No significant associations between PGS and cortical thickness were detected. The morphometric overlap of associations between both PGS and neurotic phenotype in similar cortical regions closely related to internally focused cognition points to the potential relevance of genetically shaped cortical alterations in the development of neuroticism.

Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12–88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen’s dbetween 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen’s dbetween 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Major depressive disorder (MDD) is associated to affected brain wiring. Little is known whether these changes are stable over time and hence might represent a biological predisposition, or whether these are state markers of current disease severity and recovery after a depressive episode. Human white matter network (“connectome”) analysis via network science is a suitable tool to investigate the association between affected brain connectivity and MDD. This study examines structural connectome topology in 464 MDD patients (mean age: 36.6 years) and 432 healthy controls (35.6 years). MDD patients were stratified categorially by current disease status (acute vs. partial remission vs. full remission) based on DSM-IV criteria. Current symptom severity was assessed continuously via the Hamilton Depression Rating Scale (HAMD). Connectome matrices were created via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging. Global tract-based metrics were not found to show significant differences between disease status groups, suggesting conserved global brain connectivity in MDD. In contrast, reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with HAMD, an effect remaining when correcting for lifetime disease severity. Therefore, our findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode.

Reduced fractional anisotropy (FA) associated with Major Depressive Disorder (MDD) overlaps anatomically with effects of childhood maltreatment experiences. The aim of this study was, therefore, to replicate the negative effect of childhood maltreatment on white matter fiber structure and to demonstrate, that alterations in MDD might be partially attributed to the higher occurrence of childhood maltreatment in MDD. Two independent cohorts (total N= 1 256) were investigated in a diffusion tensor imaging study: The Münster Neuroimaging Cohort (MNC, N= 186 MDD, N= 210 healthy controls, HC) as discovery sample and the Marburg-Münster Affective Disorders Cohort Study (MACS, N= 397 MDD, N= 462 HC) as replication sample. The effects of diagnosis (HC vs. MDD) and Childhood Trauma Questionnaire (CTQ) scores on FA were analyzed. A main effect of diagnosis with higher FA in MDD patients compared with HC was found in the MNC (pFWE= 0.021), but not in the MACS (pFWE= 0.52) before correcting for CTQ. A significant negative correlation of FA with CTQ emerged in both cohorts (MNC: pFWE= 0.006, MACS: pFWE= 0.012) in several tracts previously described in the literature. No CTQ × diagnosis interaction could be detected. Any main effect of diagnosis was abolished after correcting for CTQ (MNC: pFWE= 0.562, MACS: pFWE= 0.115). No differences in FA between MDD and HC could be found after correcting for childhood maltreatment, suggesting that previously reported group differences might be attributed partially to higher levels of maltreatment experiences in MDD rather than diagnosis itself. Furthermore, a well-established finding of reduced FA following childhood maltreatment experiences was replicated.

It has been shown, using functional magnetic resonance imaging (fMRI), that hemispheric lateralization of brain activity depends on the requirements of the cognitive task performed during the processing of a sensory stimulus rather than on the intrinsic characteristics of that stimulus [Stephan et al., 2003, Science 301 (5631): 384–6]. Task-dependent increase in the coupling of the anterior cingulate cortex (ACC), a region involved in cognitive control, and brain areas in the left prefrontal and right parietal cortex, respectively, regions involved in task execution, was proposed as the mechanism underlying this task-dependency of hemispheric lateralization. The aim of the present study was two-fold: First, we aimed for a conceptual replication of these findings in an independent sample of subjects. Second, we investigated the test–retest reliability of the imaging paradigm to assess whether the task can be used to capture reliable measures of inter-individual differences in hemispheric lateralization. We were able to confirm previous findings showing that hemispheric lateralization depends on the nature of the cognitive task rather than on the nature of the processed stimuli. The task-related brain activation patterns were highly reliable across sessions (as indicated by intra-class correlation coefficients – ICCs, ≥.51). We could, however, not replicate previous results proposing task-dependent changes in the coupling between ACC and brain regions for task execution as the mechanism underlying hemispheric lateralization. This re-opens the question which mechanisms could determine the task-dependent functional asymmetries that were observed previously and replicated in this study.

ABSTRACTClinical manifestations of leptospirosis are highly variable: from asymptomatic to severe and potentially fatal. The outcome of the disease is usually determined in the immunological phase, beginning in the second week of symptoms. The underlying mechanisms, predictive factors, and individual immune responses that contribute to clinical variations are not well understood. The aim of this study was to determine the specifics of CD4+T-cell reactivity and cytokine release after stimulation with leptospiral antigens in patients with leptospirosis of different disease severities (patients with mild and severe symptoms) and in control subjects (with and without proven exposure to Leptospira). Whole-blood specimens were stimulated with Leptospiraantigens in vitro. Subsequently, intracellular staining of cytokines was performed, and flow cytometry was used to assess the expression of CD40 ligand (CD40L) and the production of gamma interferon (IFN-?), interleukin-10 (IL-10), IL-2, and tumor necrosis factor alpha (TNF-a) by CD4+T cells. The production of inflammatory cytokines such as TNF-a by CD4+T cells after stimulation with leptospiral antigens was highest in patients with severe disease. In contrast, the ratio of IL-10 production to TNF-a production was higher in exposed subjects than in patients with mild and severe disease. Levels of proinflammatory cytokines such as TNF-a may be useful markers of the severity of the immunological phase of leptospirosis. IL-10 production by T cells after antigen-specific stimulation may indicate a more successful downregulation of the inflammatory response and may contribute to an asymptomatic course of the disease.

Emotional instability, difficulties in social adjustment, and disinhibited behavior are the most common symptoms of the psychiatric comorbidities in juvenile myoclonic epilepsy (JME). This psychopathology has been associated with dysfunctions of mesial-frontal brain circuits. The present work is a first direct test of this link and adapted a paradigm for probing frontal circuits during empathy for pain. Neural and psychophysiological parameters of pain empathy were assessed by combining functional magnetic resonance imaging (fMRI) with simultaneous pupillometry in 15 JME patients and 15 matched healthy controls. In JME patients, we observed reduced neural activation of the anterior cingulate cortex (ACC), the anterior insula (AI), and the ventrolateral prefrontal cortex (VLPFC). This modulation was paralleled by reduced pupil dilation during empathy for pain in patients. At the same time, pupil dilation was positively related to neural activity of the ACC, AI, and VLPFC. In JME patients, the ACC additionally showed reduced functional connectivity with the primary and secondary somatosensory cortex, areas fundamentally implicated in processing the somatic cause of another's pain. Our results provide first evidence that alterations of mesial-frontal circuits directly affect psychosocial functioning in JME patients and draw a link of pupil dynamics with brain activity during emotional processing. The findings of reduced pain empathy related activation of the ACC and AI and aberrant functional integration of the ACC with somatosensory cortex areas provide further evidence for this network's role in social behavior and helps explaining the JME psychopathology and patients' difficulties in social adjustment.

Der vorliegende Beitrag befasst sich mit der Frage nach dem Einfluss kulturell geprägter Normen und kultureller Werte hinsichtlich der idealen Ausgestaltung des Altersübergangs auf die Erwerbsbeteiligung älterer Menschen zwischen 55 und 64 Jahren in Europa. Im Anschluss an die inhaltliche Konkretisierung des Begriffes der Altersübergangskultur, wird auf Basis des Modells der soziologischen Erklärung ein erweitertes Altersübergangsmodell entwickelt, in dem die Altersübergangskultur einer Gesellschaft explizite Berücksichtigung findet. Im Rahmen einer quantitativen Datenanalyse wird dann ein erster Versuch unternommen, das theoretische Modell empirisch zu plausibilisieren. Als Datengrundlage dient die dritte Runde des European Social Survey (ESS) aus dem Jahre 2006. Im Ergebnis zeigt sich, dass der Einfluss kultureller Normen und Werte auf die Altersübergangsentscheidung der Individuen sowohl theoretisch modellierbar, als auch empirisch belegbar ist. Theoretisch besitzt die Kultur eine doppelte Bedeutung für die Altersübergangsentscheidung, da sie sowohl handlungsbedingend als auch handlungsstrukturierend wirkt. In den empirischen Analysen zeigt sich ein positiver Zusammenhang zwischen den Einstellungen zur idealen Ausgestaltung des Altersübergangs und der individuellen Erwerbswahrscheinlichkeit im höheren Alter. In Hinblick auf spezifische Muster von Altersübergangskulturen weisen überdies Länder mit einer geringen Erwerbstätigenquote Älterer auch eine tendenziell ausstiegsorientierte Altersübergangskultur auf und umgekehrt. The article examines the impact of culturally influenced norms and cultural values towards the ideal arrangement due to the transition to retirement on the labor market participation of older people aged 55 to 64 in Europe. Subsequent to a basic definition of retirement cultures, an extended explanatory model for the transition to retirement is developed, which takes cultural norms and values or rather the country-specific-retirement culture explicitly into account. Secondly, the model is empirically validated. The underlying dataset is the third round of the European Social Survey (ESS) which was conducted in 2006. Overall it is found that the impact of societal norms and values on the participation decision of older individuals can be both, theoretically modeled and empirically verified. Within the explanatory model the importance of cultural norms and values for explaining the retirement decisions of older people is twofold. Firstly, like the nation-specific institutional framework of the transition to retirement as well as the material resources of the individuals, this specific transition-to-retirement-culture belongs to the conditional part of the model and limits the number of alternative courses of action. Secondly, as an internalized social norm, the transition-to-retirement-culture is an integral part of the definition of the situation and structures the preference order of the individuals. The theoretical influence can also be validated in the empirical model. Firstly, there is a highly significant (positive) correlation between the attitudes towards the ideal retirement transition on the one hand and the participation decision on the individual level. On the societal level, a significant correlation between the country-specific transition-to-retirement-culture and the employment rate of older people can be seen. In this context, a low labor market participation of older people goes along with a comparatively exit-oriented transition-to-retirement-culture and vice versa.

ABSTRACT“Classical” Whipple's disease (cWD) is caused by Tropheryma whippleiand is characterized by arthropathy, weight loss, and diarrhea. T. whippleiinfectious endocarditis (TWIE) is rarely reported, either in the context of cWD or as isolated TWIE without signs of systemic infection. The frequency of TWIE is unknown, and systematic studies are lacking. Here, we performed an observational cohort study on the incidence of T. whippleiinfection in explanted heart valves in two German university centers. Cardiac valves from 1,135 patients were analyzed for bacterial infection using conventional culture techniques, PCR amplification of the bacterial 16S rRNA gene, and subsequent sequencing. T. whipplei-positive heart valves were confirmed by specific PCR, fluorescence in situhybridization, immunohistochemistry, histological examination, and culture for T. whipplei. Bacterial endocarditis was diagnosed in 255 patients, with streptococci, staphylococci, and enterococci being the main pathogens. T. whippleiwas the fourth most frequent pathogen, found in 16 (6.3%) cases, and clearly outnumbered Bartonella quintana, Coxiella burnetii, and members of the HACEK group (Haemophilusspecies, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). In this cohort, T. whippleiwas the most commonly found pathogen associated with culture-negative infective endocarditis.

"Classical" Whipple's disease (cWD) is caused by Tropheryma whipplei and is characterized by arthropathy, weight loss, and diarrhea. T. whipplei infectious endocarditis (TWIE) is rarely reported, either in the context of cWD or as isolated TWIE without signs of systemic infection. The frequency of TWIE is unknown, and systematic studies are lacking. Here, we performed an observational cohort study on the incidence of T. whipplei infection in explanted heart valves in two German university centers. Cardiac valves from 1,135 patients were analyzed for bacterial infection using conventional culture techniques, PCR amplification of the bacterial 16S rRNA gene, and subsequent sequencing. T. whipplei-positive heart valves were confirmed by specific PCR, fluorescence in situ hybridization, immunohistochemistry, histological examination, and culture for T. whipplei. Bacterial endocarditis was diagnosed in 255 patients, with streptococci, staphylococci, and enterococci being the main pathogens. T. whipplei was the fourth most frequent pathogen, found in 16 (6.3%) cases, and clearly outnumbered Bartonella quintana, Coxiella burnetii, and members of the HACEK group (Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). In this cohort, T. whipplei was the most commonly found pathogen associated with culture-negative infective endocarditis.

The classical core system of face perception consists of the occipital face area (OFA), fusiform face area (FFA), and posterior superior temporal sulcus (STS). The functional interaction within this network, more specifically the effective connectivity, was first described by Fairhall and Ishai (2007) using functional magnetic resonance imaging and dynamic causal modeling. They proposed that the core system is hierarchically organized; information is processed in a parallel and predominantly feed-forward fashion from the OFA to downstream regions such as the FFA and STS, with no lateral connectivity, i.e., no connectivity between the two downstream regions (FFA and STS). Over a decade later, we conducted a conceptual replication of their model using four different functional magnetic resonance imaging data sets. The effective connectivity within the core system was assessed with contemporary versions of dynamic causal modeling.

Human brucellosis is a multiple organ disease that presents with fever and is most often transmitted via contaminated, unpasteurized goat milk and cheese. In chronic cases, focal complications (eg, spondylitis, neurobrucellosis and endocarditis) are frequently seen. Although the disease may be severely debilitating, the mortality rate is low. Fatal cases are often due to endocarditis. Because Brucellaendocarditis is a rare complication (2% to 5%), therapeutic considerations are based on single-case experiences only. Therapy includes long-term antibiotic treatment using combinations of various antimicrobial drugs and surgical valve replacement when required. A case of Brucellaendocarditis complicated by the infection of two valvular prostheses implanted after involvement of the mitral and aortic valve due to rheumatic fever is described. The patient was successfully treated by a medical and surgical approach. Therapeutic strategies in Brucellaendocarditis are discussed in light of the current literature.

In der Bundesrepublik Deutschland muss ein Niedriglohnsektor nicht erst noch geschaffen werden - er existiert bereits. Unterstellt man einen nach West- (8,49 €) und Ostdeutschland (6,30 €) differenzierten gesetzlichen Mindestlohn, so hätten etwa 13% der abhängig Erwerbstätigen einen Anspruch darauf. Eine detaillierte Analyse des Niedriglohnsektors zeigt deutlich, dass sowohl persönliche als auch strukturelle Merkmale den Niedriglohnbezug beeinflussen. Neben der individuellen Merkmalsstruktur der Niedriglohnempfänger sind die rückläufige Tarifbindung sowie die abnehmende Tarifverbindlichkeit mögliche Gründe für die Entstehung bzw. Ausweitung des Niedriglohnsektors. Da auch die vorhandenen rechtlichen Instrumente zur Flankierung des Tarifsystems Niedriglöhne nur unzureichend regulieren können, stellt ein gesetzlicher Mindestlohn eine durchaus realistische Option für die BRD dar.

Using functional magnetic resonance imaging during word generation and spatial judgement (Landmark task), we investigated how hemispheric specializations for language and spatial processing interact in healthy individuals. We found individuals with atypical, right-hemispheric dominance for language to have more bilateral activation during spatial judgement than individuals with typical, disjunct hemispheric specialization, that is, left dominance for language and right dominance for spatial tasks. These findings suggest that hemispheric specializations for language and spatial functions interfere to some extent and favour additional recruitment of the opposite hemispheres for spatial functions.

Using a variety of methods phenol water clusters phenol(H₂O)_n, n7, are investigated with a focus on phenol(H₂O)_5,6. A comprehensive search for low-energy isomers is conducted on a polarizable intermolecular potential energy surface. Zero-point energy contributions are calculated rigorously with the rigid-body quantum Monte Carlo method. The OH stretch vibrational spectra of the isomers are calculated using a local-mode model and compared with experimental isomer-selective IR–UV spectral hole burning (SHB) spectra. The topology of the clusters phenol(H₂O)_5,6 is shown in deviate from the corresponding pure water clusters.

Major depressive disorder (MDD) and type 2 diabetes (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if so, how these effects could contribute to the disease course of MDD.

Brain functional alterations during emotion processing in patients with major depressive disorder (MDD) compared to healthy controls (HC) are frequently reported. However, evidence for functional correlates of emotion processing with regard to MDD trajectories is scarce. The present study investigated the role of lifetime disease course for limbic brain activation during negative emotional face processing in patients with MDD.

In 2007, Clostridium difficilepolymerase chain reaction (PCR) ribotype 027 emerged in Germany. We conducted a hospital-based case-control study to identify specific risk factors for infection with this strain. Logistic regression analysis involving 15 case patients and 31 control patients revealed that exposure to fluoroquinolones (matched odds ratio, 36.2; P< .01) or cephalosporins (matched odds ratio, 19.1; P< .01) was independently related to C. difficilePCR ribotype 027 infection.