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Stressful life events (SLEs) in adulthood are a risk factor for various disorders such as depression, cancer or infections. Part of this risk is mediated through pathways altering brain physiology and structure. There is a lack of longitudinal studies examining associations between SLEs and brain structural changes. High-resolution structural magnetic resonance imaging data of 212 healthy subjects were acquired at baseline and after 2 years. Voxel-based morphometry was used to identify associations between SLEs using the Life Events Questionnaire and grey matter volume (GMV) changes during the 2-year period in an ROI approach. Furthermore, we assessed adverse childhood experiences as a possible moderator of SLEs-GMV change associations. SLEs were negatively associated with GMV changes in the left medial prefrontal cortex. This association was stronger when subjects had experienced adverse childhood experiences. The medial prefrontal cortex has previously been associated with stress-related disorders. The present findings represent a potential neural basis of the diathesis-stress model of various disorders.

Contains fulltext : 288062.pdf (Publisher’s version ) (Closed access) 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 d effect 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

BACKGROUND: Altered brain structural connectivity has been implicated in the pathophysiology of psychiatric disorders including schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). However, it is unknown which part of these connectivity abnormalities are disorder specific and which are shared across the spectrum of psychotic and affective disorders. We investigated common and distinct brain connectivity alterations in a large sample (N = 1743) of patients with SZ, BD, or MDD and healthy control (HC) subjects.METHODS: This study examined diffusion-weighted imaging-based structural connectome topology in 720 patients with MDD, 112 patients with BD, 69 patients with SZ, and 842 HC subjects (mean age of all subjects: 35.7 years). Graph theory-based network analysis was used to investigate connectome organization. Machine learning algorithms were trained to classify groups based on their structural connectivity matrices.RESULTS: Groups differed significantly in the network metrics global efficiency, clustering, present edges, and global connectivity strength with a converging pattern of alterations between diagnoses (e.g., efficiency: HC > MDD > BD > SZ, false discovery rate-corrected p = .028). Subnetwork analysis revealed a common core of edges that were affected across all 3 disorders, but also revealed differences between disorders. Machine learning algorithms could not discriminate between disorders but could discriminate each diagnosis from HC. Furthermore, dysconnectivity patterns were found most pronounced in patients with an early disease onset irrespective of diagnosis.CONCLUSIONS: We found shared and specific signatures of structural white matter dysconnectivity in SZ, BD, and MDD, leading to commonly reduced network efficiency. These results showed a compromised brain communication across a spectrum of major psychiatric disorders.

In the field of face processing, the so-called "core network" has been intensively researched. Its neural activity can be reliably detected in children and adults using functional magnetic resonance imaging (fMRI). However, the core network's counterpart, the so-called "extended network," has been less researched. In the present study, we compared children's and adults' brain activity in the extended system, in particular in the amygdala, the insula, and the inferior frontal gyrus (IFG). Using fMRI, we compared the brain activation pattern between children aged 7-9 years and adults during an emotional face processing task. On the one hand, children showed increased activity in the extended face processing system in relation to adults, particularly in the left amygdala, the right insula, and the left IFG. On the other hand, lateralization indices revealed a "leftward bias" in children's IFG compared to adults. These results suggest that brain activity associated with face processing is characterized by a developmental decrease in activity. They further show that the development is associated with a rightward migration of face-related IFG activation, possibly due to the competition for neural space between several developing brain functions ("developmental competition hypothesis").

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 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).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging 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 predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

While the hippocampus remains a region of high interest for neuropsychiatric research, the precise contributors to hippocampal morphometry are still not well understood. We and others previously reported a hippocampus specific effect of a tescalcin gene (TESC) regulating single nucleotide polymorphism (rs7294919) on gray matter volume. Here we aimed to replicate and extend these findings. Two complementary morphometric approaches (voxel based morphometry (VBM) and automated volumetric segmentation) were applied in a well-powered cohort from the Marburg-Münster Affective Disorder Cohort Study (MACS) including N=1137 participants (n=636 healthy controls, n=501 depressed patients). rs7294919 homozygous T-allele genotype was significantly associated with lower hippocampal gray matter density as well as with reduced hippocampal volume. Exploratory whole brain VBM analyses revealed no further associations with gray matter volume outside the hippocampus. No interaction effects of rs7294919 with depression nor with childhood trauma on hippocampal morphometry could be detected. Hippocampal subfield analyses revealed similar effects of rs7294919 in all hippocampal subfields. In sum, our results replicate a hippocampus specific effect of rs7294919 on brain structure. Due to the robust evidence for a pronounced association between the reported polymorphism and hippocampal morphometry, future research should consider investigating the potential clinical and functional relevance of the reported association.

The diathesis-stress model of major depressive disorder (MDD) predicts interactions of recent stressful life events (SLEs) in adulthood and early developmental risk factors. We tested, for the first time, the diathesis stress model on brain structure in a large group of MDD patients.Structural magnetic resonance imaging data of 1465 participants (656 with lifetime diagnosis MDD; 809 healthy controls) were analyzed using voxel-based morphometry to identify clusters associated with recent SLEs (Life Events Questionnaire). Those clusters were then examined for group (healthy/MDD) × early developmental risk (operationalized as childhood abuse [Childhood Trauma Questionnaire] and a major psychiatric disorder [i.e., MDD, bipolar disorder, schizophrenia, and schizoaffective disorder] in a first-degree relative) × recent SLEs three-way interactions on grey matter volume.There was a group × childhood abuse × recent SLEs interaction on left medial orbitofrontal cortex grey matter volume. This three-way interaction arose because childhood abuse and recent SLEs interacted in MDD subjects but not in healthy subjects.We are not able to draw conclusions about the cause and effect relationship due to our cross-sectional study design.Our data provides evidence for an interplay between orbitofrontal cortex structure, childhood abuse and recent SLEs. These factors have previously been linked to MDD and their complex interaction contributes to the pathogenesis of MDD.

Aberrant brain structural connectivity in major depressive disorder (MDD) has been repeatedly reported, yet many previous studies lack integration of different features of MDD with structural connectivity in multivariate modeling approaches. In n = 595 MDD patients, we used structural equation modeling (SEM) to test the intercorrelations between anhedonia, anxiety, neuroticism, and cognitive control in one comprehensive model. We then separately analyzed diffusion tensor imaging (DTI) connectivity measures in association with those clinical variables, and finally integrated brain connectivity associations, clinical/cognitive variables into a multivariate SEM. We first confirmed our clinical/cognitive SEM. DTI analyses (FWE-corrected) showed a positive correlation of anhedonia with fractional anisotropy (FA) in the right anterior thalamic radiation (ATR) and forceps minor/corpus callosum, while neuroticism was negatively correlated with axial diffusivity (AD) in the left uncinate fasciculus (UF) and inferior fronto-occipital fasciculus (IFOF). An extended SEM confirmed the associations of ATR FA with anhedonia and UF/IFOF AD with neuroticism impacting on cognitive control. Our findings provide evidence for a differential impact of state and trait variables of MDD on brain connectivity and cognition. The multivariate approach shows feasibility of explaining heterogeneity within MDD and tracks this to specific brain circuits, thus adding to better understanding of heterogeneity on the biological level.

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 (p(FWE) = 0.021), but not in the MACS (p(FWE) = 0.52) before correcting for CTQ. A significant negative correlation of FA with CTQ emerged in both cohorts (MNC: p(FWE) = 0.006, MACS: p(FWE) = 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: p(FWE) = 0.562, MACS: p(FWE) = 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.

Studies on social cognition often use complex visual stimuli to asses neural processes attributed to abilities like "mentalizing" or "Theory of Mind" (ToM). During the processing of these stimuli, eye gaze, however, shapes neural signal patterns. Individual differences in neural operations on social cognition may therefore be obscured if individuals' gaze behavior differs systematically. These obstacles can be overcome by the combined analysis of neural signal and natural viewing behavior. Here, we combined functional magnetic resonance imaging (fMRI) with eye-tracking to examine effects of unconstrained gaze on neural ToM processes in healthy individuals with differing levels of emotional awareness, i.e. alexithymia. First, as previously described for emotional tasks, people with higher alexithymia levels look less at eyes in both ToM and task-free viewing contexts. Further, we find that neural ToM processes are not affected by individual differences in alexithymia per se. Instead, depending on alexithymia levels, gaze on critical stimulus aspects reversely shapes the signal in medial prefrontal cortex (MPFC) and anterior temporoparietal junction (TPJ) as distinct nodes of the ToM system. These results emphasize that natural selective attention affects fMRI patterns well beyond the visual system. Our study implies that, whenever using a task with multiple degrees of freedom in scan paths, ignoring the latter might obscure important conclusions.

An interplay of early environmental and genetic risk factors with recent stressful life events (SLEs) in adulthood increases the risk for adverse mental health outcomes. The interaction of early risk and current SLEs on brain structure has hardly been investigated. Whole brain voxel-based morphometry analysis was performed in N = 786 (64.6% female, mean age = 33.39) healthy subjects to identify correlations of brain clusters with commonplace recent SLEs. Genetic and early environmental risk factors, operationalized as those for severe psychopathology (i.e., polygenic scores for neuroticism, childhood maltreatment, urban upbringing and paternal age) were assessed as modulators of the impact of SLEs on the brain. SLEs were negatively correlated with grey matter volume in the left medial orbitofrontal cortex (mOFC, FWE p = 0.003). This association was present for both, positive and negative, life events. Cognitive-emotional variables, i.e., neuroticism, perceived stress, trait anxiety, intelligence, and current depressive symptoms did not account for the SLE-mOFC association. Further, genetic and environmental risk factors were not correlated with grey matter volume in the left mOFC cluster and did not affect the association between SLEs and left mOFC grey matter volume. The orbitofrontal cortex has been implicated in stress-related psychopathology, particularly major depression in previous studies. We find that SLEs are associated with this area. Important early life risk factors do not interact with current SLEs on brain morphology in healthy subjects.

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.

Apolipoprotein E (APOE) genotype is the strongest single gene predictor of Alzheimer's disease (AD) and has been frequently associated with AD-related brain structural alterations before the onset of dementia. While previous research has primarily focused on hippocampal morphometry in relation to APOE, sporadic recent findings have questioned the specificity of the hippocampus and instead suggested more global effects on the brain. With the present study we aimed to investigate associations between homozygous APOE e4 status and cortical gray matter structure as well as white matter microstructure. In our study, we contrasted n = 31 homozygous APOE e4 carriers (age=34.47 years, including a subsample of n = 12 subjects with depression) with a demographically matched sample without an e4 allele (resulting total sample: N = 62). Morphometry analyses included a) Freesurfer based cortical segmentations of thickness and surface area measures and b) tract based spatial statistics of DTI measures. We found pronounced and widespread reductions in cortical surface area of e4 homozygotes in 57 out of 68 cortical brain regions. In contrast, no differences in cortical thickness were observed. Furthermore, APOE e4 homozygous carriers showed significantly lower fractional anisotropy in the corpus callosum, the right internal and external capsule, the left corona radiata and the right fornix. The present findings support a global rather than regionally specific effect of homozygous APOE e4 allele status on cortical surface area and white matter microstructure. Future studies should aim to delineate the clinical implications of these findings.

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 (η²

Humans integrate information communicated by speech and gestures. Functional magnetic resonance imaging (fMRI) studies suggest that the posterior superior temporal sulcus (STS) and adjacent gyri are relevant for multisensory integration. However, a connectivity model representing this essential combinatory process is still missing. Here, we used dynamic causal modeling for fMRI to analyze the effective connectivity pattern between middle temporal gyrus (MTG), occipital cortex (OC) and STS associated with auditory verbal, visual gesture-related, and integrative processing, respectively, to unveil the neural mechanisms underlying integration of intrinsically meaningful gestures (e.g., "Thumbs-up gesture") and corresponding speech. 20 participants were presented videos of an actor either performing intrinsic meaningful gestures in the context of German or Russian sentences, or speaking a German sentence without gesture, while performing a content judgment task. The connectivity analyses resulted in a winning model that included bidirectional intrinsic connectivity between all areas. Furthermore, the model included modulations of both connections to the STS (OC→STS; MTG→STS), and non-linear modulatory effects of the STS on bidirectional connections between MTG and OC. Coupling strength in the occipital pathway (OC→STS) correlated with gesture related advantages in task performance, whereas the temporal pathway (MTG→STS) correlated with performance in the speech only condition. Coupling between MTG and OC correlated negatively with subsequent memory performance for sentences of the Gesture-German condition. Our model provides a first step towards a better understanding of speech-gesture integration on network level. It corroborates the importance of the STS during audio-visual integration by showing that this region inhibits direct auditory-visual coupling.

The successful recovery from affective loss (i.e., bereavement, relationship breakup) has been linked to adult attachment style (AAS), a personality trait. Up to now, the association between AAS, affective loss experiences and brain gray matter volume is unclear. In 192 healthy subjects we investigated the association between MRI brain gray matter volume, applying voxel based morphometry, AAS (Relationship Scales Questionnaire (RSQ), subscales "avoidance" (AV) and "anxiety" (ANX)), and number of affective losses within the last 5 years (AL; List of Threatening Experiences Questionnaire). In a whole-brain analysis (p 0.05 FWE-corrected) ANX compared to AV was significantly more positively associated with brain gray matter volume in the left insula and in the pars opercularis of left inferior frontal gyrus. In additional region-of-interest (ROI) analyses (p 0.05 FWE-corrected), based on previously reported findings, no significant associations were observed. ANX and AV differently correlate with local volumes of the left insula and pars opercularis of the left inferior frontal gyrus, which are implicated in emotion processing, empathy and emotion regulation among other functions. Our results support the notion that individual attachment styles, which develop in the interplay of genes and social environment, differ in their correlation with brain structure.

Patients with major depressive disorder (MDD) exhibit gray matter volume (GMV) reductions in limbic regions. Clinical variables-such as the number of depressive episodes-seem to affect volume alterations. It is unclear whether the observed cross-sectional GMV abnormalities in MDD change over time, and whether there is a longitudinal relationship between GMV changes and the course of disorder. We investigated T1 structural MRI images of 54 healthy control (HC) and 37 MDD patients in a 3-Tesla-MRI with a follow-up interval of 3 years. The Cat12 toolbox was used to analyze longitudinal data (p 0.05, FWE-corrected, whole-brain analysis; flexible factorial design). Interaction effects indicated increasing GMV in MDD in the bilateral amygdala, and decreasing GMV in the right thalamus between T1 and T2. Further analyses comparing patients with a mild course of disorder (MCD; 0-1 depressive episode during the follow-up) to patients with a severe course of disorder (SCD; 1 depressive episode during the follow-up) revealed increasing amygdalar volume in MCD. Our study confirms structural alterations in limbic regions in MDD patients and an association between these impairments and the course of disorder. Thus, we assume that the reported volumetric alterations in the left amygdala (i.e. volumetric normalization) are reversible and apparently driven by the clinical phenotype. Hence, these results support the assumption that the severity and progression of disease influences amygdalar GMV changes in MDD or vice versa.

Large, longitudinal, multi-center MR neuroimaging studies require comprehensive quality assurance (QA) protocols for assessing the general quality of the compiled data, indicating potential malfunctions in the scanning equipment, and evaluating inter-site differences that need to be accounted for in subsequent analyses. We describe the implementation of a QA protocol for functional magnet resonance imaging (fMRI) data based on the regular measurement of an MRI phantom and an extensive variety of currently published QA statistics. The protocol is implemented in the MACS (Marburg-Münster Affective Disorders Cohort Study, http://for2107.de/), a two-center research consortium studying the neurobiological foundations of affective disorders. Between February 2015 and October 2016, 1214 phantom measurements have been acquired using a standard fMRI protocol. Using 444 healthy control subjects which have been measured between 2014 and 2016 in the cohort, we investigate the extent of between-site differences in contrast to the dependence on subject-specific covariates (age and sex) for structural MRI, fMRI, and diffusion tensor imaging (DTI) data. We show that most of the presented QA statistics differ severely not only between the two scanners used for the cohort but also between experimental settings (e.g. hardware and software changes), demonstrate that some of these statistics depend on external variables (e.g. time of day, temperature), highlight their strong dependence on proper handling of the MRI phantom, and show how the use of a phantom holder may balance this dependence. Site effects, however, do not only exist for the phantom data, but also for human MRI data. Using T1-weighted structural images, we show that total intracranial (TIV), grey matter (GMV), and white matter (WMV) volumes significantly differ between the MR scanners, showing large effect sizes. Voxel-based morphometry (VBM) analyses show that these structural differences observed between scanners are most pronounced in the bilateral basal ganglia, thalamus, and posterior regions. Using DTI data, we also show that fractional anisotropy (FA) differs between sites in almost all regions assessed. When pooling data from multiple centers, our data show that it is a necessity to account not only for inter-site differences but also for hardware and software changes of the scanning equipment. Also, the strong dependence of the QA statistics on the reliable placement of the MRI phantom shows that the use of a phantom holder is recommended to reduce the variance of the QA statistics and thus to increase the probability of detecting potential scanner malfunctions.

Objective Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsy syndrome. Neuropsychological, electrophysiological, and neuroimaging studies have led to the hypothesis that JME is related to dysfunction of frontal brain regions and mainly frontal thalamocortical networks. Methods We investigated possible microstructural white matter abnormalities of 20 patients with JME as compared with 20 healthy control subjects using diffusion tensor imaging (DTI). We analyzed whole-head DTI scans without an a-priori hypothesis using Tract-Based Spatial Statistics (TBSS). To analyze associated gray matter changes, we applied voxel-based morphometry (VBM) to a 3D T1 magnetization prepared rapid gradient echo (MPRAGE) sequence. Neuropsychological testing and personality trait tests were performed to bridge the gap between structure and function. Results In patients, DTI revealed microstructural white matter changes in anterior parts of the Corpus callosum, anterior parts of the cingulate gyrus, and widespread frontal white matter bilaterally as well as in anterior parts of the right thalamus, which were not accompanied by gray matter changes in VBM. Microstructural changes in the cingulum correlated with personality traits. Neuropsychological test results showed impaired attention and executive functions and reduced short-term memory in the patient group. Also, there was a tendency toward alexithymia and significantly higher scores on depression. Significance The present study results showed neuropsychological deficits including frontal lobe cognitive performance and a tendency toward alexithymia as well as accompanying microstructural neuroimaging changes in patients with JME, which all point to alterations in frontal brain regions and frontal thalamocortical networks in these patients.

The unfolding of emotions over time (i.e., emotion dynamics) has been characterized by baseline, intraindividual variability and regulatory tendency (return time to baseline after deflection). Mounting evidence suggests that compared to healthy individuals, individuals with schizophrenia are characterized by a more negatively valenced baseline and a higher intraindividual variability. However, the regulatory tendency has not been investigated in schizophrenia so far. We hypothesize that the severity of positive symptoms is linked to increased emotional variability and that the severity of negative symptoms is associated with an increased regulatory tendency. Fifteen individuals diagnosed with schizophrenia took part in this pilot experience sampling study and reported their emotional state ten times a day. The dynamics of valence and arousal and their relationship with symptomatology were estimated with the DynAffect model. Regulatory tendency in valence and arousal was positively associated with negative symptom severity and negatively associated with positive symptom severity. However, the severity of positive symptoms was not credibly associated with the variability of valence. The study only partly corroborates findings on increased stress reactivity in schizophrenia, which might be due to the small sample size. However, results suggest that negative symptoms could stem from over-regulated emotion dynamics, which may impede goal-directed behavior.

Impaired emotion regulation mediates partly the effect of insomnia on paranoia ideation. -Insomnia might be a valuable treatment target for patients with psychosis. -Impaired emotion regulation is closely linked to paranoid ideation.

There are only few data on the persistence and transmission of methicillin resistant Staphylococcus aureus (MRSA) of the clonal complex (CC) 398 among veterinarians and their household members. We therefore investigated the long-term colonisation with MRSA CC398 among participants of veterinary conferences in Germany in 2008/2009 and their household members. Forty-five initially MRSA CC398 positive and 180 initially MRSA CC398 negative conference participants were included in a longitudinal study. These persons and their household members were tested for nasal colonisation in 2011, 2012 and 2014. Of 31 continuously tested and initially MRSA CC398 positive participants only 8 (26%) were colonized with MRSA CC398 at all 4 time points, 4 (13%) of them consistently with the same spa type. Among initially MRSA CC398 negative participants, 13 (7%) were tested MRSA CC398 positive at least once during the follow-up period. Data for household members at least at one time point were available for 185 households. Of these 21 (11%) households had one or more household member who tested positive for MRSA CC398 at least once. The odds of household members to be MRSA CC398 positive was 12 times higher (95% confidence interval 4–37) when the conference participant tested MRSA CC398 positive in 2008/2009. This association remained strong when household members working in veterinary medicine or livestock farms were excluded. In summary, these data suggest that colonisation with MRSA CC398 is partially transient and that household members of MRSA CC398 colonized persons are at an increased risk of colonisation with MRSA CC398.

Altres ajuts: The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PMT) and NIH grant R01 MH116147 (PMT). LS is supported by an NHMRC MRFF Career Development Fellowship (APP1140764). We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. M-JvT was supported by a VENI grant (NWO grant number 016.156.077). UCSF: This work was supported by the Brain and Behavior Research Foundation (formerly NARSAD) to TTY; the National Institute of Mental Health (R01MH085734 to TTY; K01MH117442 to TCH) and by the American Foundation for Suicide Prevention (PDF-1-064-13) to TCH. Stanford: This work was supported by NIMH Grants R01MH59259 and R37101495 to IHG. MS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. Muenster: This work was funded by the German Research Foundation (SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). Marburg: This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; KI 588/ 14-1, KI 588/14-2 to TK; KR 3822/7-1, KR 3822/7-2 to AK; JA 1890/ 7-1, JA 1890/7-2 to AJ). IMH-MDD: This work was supported by the National Healthcare Group Research Grant (SIG/15012) awarded to KS. Barcelona: This study was funded by two grants of the Fondo de Investigación Sanitaria from the Instituto de Salud Carlos III, by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). The author is funded through 'Miguel Servet' research contract (CP16-0020), co-financed by the European Regional Development Fund (ERDF) (2016-2019). QTIM: We thank the twins and singleton siblings who gave generously of their time to participate in the QTIM study. We also thank the many research assistants, radiographers, and IT support staff for data acquisition and DNA sample preparation. This study was funded by White matter disturbances in major depressive disorder: a coordinated analysis across 20 international. . . 1521 the National Institute of Child Health & Human Development (RO1 HD050735); National Institute of Biomedical Imaging and Bioengineering (Award 1U54EB020403-01, Subaward 56929223); National Health and Medical Research Council, Australia (Project Grants 496682, 1009064). NIH ENIGMA-BD2K U54 EB020403 (Thompson); R01 MH117601 (Jahanshad/Schmaal). Magdeburg: M.L. and M.W. are funded by SFB 779. Bipolar Family Study: This study has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013). This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. This work was also supported by a Wellcome Trust Strategic Award (104036/Z/14/Z). Minnesota Adolescent Depression Study: The study was funded by the National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Women's Health Seed Grant, University of Minnesota. Dublin: This study was supported by Science Foundation Ireland through a Stokes Professorhip grant to TF. MPIP: The MPIP Sample comprises patients included in the Recurrent Unipolar Depression (RUD) Case-Control study at the clinic of the Max Planck Institute of Psychiatry, Munich, German. The RUD study was supported by GlaxoSmithKline. 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 d between 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 d between 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.

Schizotypy is a multidimensional risk phenotype distributed in the general population, constituting of subclinical, psychotic-like symptoms. It is associated with psychosis proneness, and several risk genes for psychosis are associated with schizotypy in non-clinical populations. Schizotypy might also modulate cognitive abilities as it is associated with attentional deficits in healthy subjects. In this study, we tested the hypothesis that established genetic risk variants ZNF804A rs1344706 and CACNA1C rs1006737 are associated with psychometric schizotypy and that schizotypy mediates their effect on attention or vice versa. In 615 healthy subjects from the FOR2107 cohort study, we analysed the genetic risk variants ZNF804A rs1344706 and CACNA1C rs1006737, psychometric schizotypy (schizotypal personality questionnaire-brief SPQ B), and a neuropsychological measure of sustained and selective attention (d2 test). ZNF804A rs1344706 C (non-risk) alleles were significantly associated with higher SPQ-B Cognitive-Perceptual subscores in women and with attention deficits in both sexes. This schizotypy dimension also mediated the effect of ZNF804A on attention in women, but not in men. CACNA1C rs1006737-A showed a significant sex-modulated negative association with Interpersonal schizotypy only in men, and no effect on attention. Our multivariate model demonstrates differential genetic contributions of two psychosis risk genes to dimensions of schizotypy and, partly, to attention. This supports a model of shared genetic influence between schizotypy and cognitive functions impaired in schizophrenia.

Introduction The oxytocin system is involved in human social behavior and social cognition such as attachment, emotion recognition and mentalizing (i.e. the ability to represent mental states of oneself and others). It is shaped by social experiences in early life, especially by parent–infant interactions. The single nucleotid polymorphism rs53576 in the oxytocin receptor (OXTR) gene has been linked to social behavioral phenotypes. Method In 195 adult healthy subjects we investigated the interaction of OXTR rs53576 and childhood attachment security (CAS) on the personality traits “adult attachment style” and “alexithymia” (i.e. emotional self-awareness), on brain structure (voxel-based morphometry) and neural activation (fMRI) during an interactive mentalizing paradigm (prisoner's dilemma game; subgroup: n = 163). Results We found that in GG-homozygotes, but not in A-allele carriers, insecure childhood attachment is - in adulthood - associated with a) higher attachment-related anxiety and alexithymia, b) higher brain gray matter volume of left amygdala and lower volumes in right superior parietal lobule (SPL), left temporal pole (TP), and bilateral frontal regions, and c) higher mentalizing-related neural activity in bilateral TP and precunei, and right middle and superior frontal gyri. Interaction effects of genotype and CAS on brain volume and/or function were associated with individual differences in alexithymia and attachment-related anxiety. Interactive effects were in part sexually dimorphic. Conclusion The interaction of OXTR genotype and CAS modulates adult personality as well as brain structure and function of areas implicated in salience processing and mentalizing. Rs53576 GG-homozygotes are partially more susceptible to childhood attachment experiences than A-allele carriers.

Individuals with high anxiety sensitivity (AS) have an increased risk of developing anxiety disorders and are more biased in how they process fear-related stimuli. This study investigates the neural correlates of fear-related words and word associations in high- and low-AS individuals. We used a semantic priming paradigm during functional magnetic resonance imaging in which three types of target words (fear symptoms, e.g. 'dizziness'; neutral, e.g. 'drink'; and pseudowords, e.g. 'salkom') were preceded by two types of prime words (fear-triggers, e.g. 'elevator'; and neutral, e.g. 'bottle'). Subjects with high AS rated fear-symptom words (vs neutral words) as more unpleasant than low-AS individuals; they also related these words more strongly to fear-triggers and showed prolonged reaction times. During the processing of fear-symptom words, greater activation in the left anterior insula was observed in high-AS subjects than in low-AS subjects. Lower activation in the left inferior frontal gyrus, angular gyrus, fusiform gyrus and bilateral amygdalae was found in high-AS subjects when fear-symptom words were preceded by fear-trigger words. The findings suggest that cognitive biases and the anterior insula play a crucial role in high-AS individuals. Furthermore, semantic processes may contribute to high AS and the risk of developing anxiety disorders.

Showing empathy is crucial for social functioning and empathy is related to group membership. The aim of the current study was to investigate the influence of experimentally generated groups on empathy for pain in a functional magnetic resonance imaging (fMRI) paradigm. Thirty healthy participants underwent a minimal group paradigm to create two groups. While BOLD contrast was measured using fMRI, subjects were instructed to empathize with ingroup and outgroup members, who were depicted in a picture paradigm of painful and neutral situations. Behavioral measure of state empathy was measured using a visual analog scale. Furthermore, self-reported trait empathy measures were obtained. Repeated-measures ANOVAs were conducted for fMRI and behavioral data. In addition to a main effect of pain in pain-related areas, a main effect of group in areas belonging to the visual cortex was found. Although there was no ingroup bias for empathy ratings, subjects showed altered neural activation in regions of the right fusiform gyrus, the cerebellum, the hippocampal and amygdala region during the pain×group interaction. Activation in the preceding structures, revealed by the interaction of pain by group, suggests that activation in the pallidum might reflect specific empathy for pain-related regulation processes.

While being in the center of attention and exposed to other's evaluations humans are prone to experience embarrassment. To characterize the neural underpinnings of such aversive moments, we induced genuine experiences of embarrassment during person-group interactions in a functional neuroimaging study. Using a mock-up scenario with three confederates, we examined how the presence of an audience affected physiological and neural responses and the reported emotional experiences of failures and achievements. The results indicated that publicity induced activations in mentalizing areas and failures led to activations in arousal processing systems. Mentalizing activity as well as attention towards the audience were increased in socially anxious participants. The converging integration of information from mentalizing areas and arousal processing systems within the ventral anterior insula and amygdala forms the neural pathways of embarrassment. Targeting these neural markers of embarrassment in the (para-)limbic system provides new perspectives for developing treatment strategies for social anxiety disorders. (C) 2015 Elsevier Inc. All rights reserved.

This work is part of the German multicenter trial ‘Mechanisms of Action in CBT (MAC)’. The MAC study is funded by the German Federal Ministry of Education and Research (BMBF; project no. 01GV0615) as part of the BMBF Psychotherapy Research Funding Initiative. The study was further supported by the DFG (Grant RE1632/5-1 and KFO 125 to AR; SFB TRR 58 Z02 to JD, PP and AR; C02 to JD and KD; DE357/4-1 to JD, AR, JR and AH; RTG 1256 to AR, JD and PP; IZKF-Würzburg Z-6 to HW). Corticotropin releasing hormone (CRH) is a major regulator of the hypothalamicpituitary-adrenal (HPA) axis. Binding to its receptor CRHR1 triggers the downstream release of cortisol, a hormone needed for regulation of stress responses. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here, we aimed to evaluate CRHR1 as a candidate molecule in panic disorder (PD). Allelic variation throughout the CRHR1 gene was captured by 9 selected single nucleotide polymorphisms (SNPs); these were genotyped in 531 matched case/control pairs (discovery sample (n=239); replication sample (n=292)). Four SNPs were found to be associated with PD, in at least one sub-sample. The minor alleles of rs17689918 and rs17689966 were found to significantly increase risk for PD in females of the discovery, the replication and the combined sample, both withstanding correction for multiple testing (prs17689918=1.3*10-4; prs17689966=0.042). Expressional analysis demonstrated that both minor alleles of rs17689918 and rs17689966 significantly decreased CRHR1 mRNA in the forebrain and amygdala. Bioinformatical analysis revealed a high proportion of differential neuro-relevant transcription factor binding possibly underlying expression changes. When investigating the neural correlates underlying this association, risk allele carriers of rs17689918 and rs17689966 showed aberrant differential conditioning and safety signal processing arguing for predominant generalization of fear and hence anxious apprehension. Furthermore, the minor risk (A) allele of rs17689918 led to less flight behavior during fear provoking situations, but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus, reduced CRHR1 expression driven by CRHR1 risk allele leads to a phenotype characterized by a fear bias and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder. Postprint

Dynamic causal modeling (DCM) is a Bayesian framework for inferring effective connectivity among brain regions from neuroimaging data. While the validity of DCM has been investigated in various previous studies, the reliability of DCM parameter estimates across sessions has been examined less systematically. Here, we report results of a software comparison with regard to test-retest reliability of DCM for fMRI, using a challenging scenario where complex models with many parameters were applied to relatively few data points. Specifically, we examined the reliability of different DCM implementations (in terms of the intra-class correlation coefficient, ICC) based on fMRI data from 35 human subjects performing a simple motor task in two separate sessions, one month apart. We constructed DCMs of motor regions with fair to excellent reliability of conventional activation measures. Using classical DCM (cDCM) in SPM5, we found that the test-retest reliability of DCM results was high, both concerning the model evidence (ICC=0.94) and the model parameter estimates (median ICC=0.47). However, when using a more recent DCM version (DCM10 in SPM8), test-retest reliability was reduced notably. Analyses indicated that, in our particular case, the prior distributions played a crucial role in this change in reliability across software versions. Specifically, when using cDCM priors for model inversion in DCM10, this not only restored reliability but yielded even better results than in cDCM. Analyzing each component of the objective function in DCM, we found a selective change in the reliability of posterior mean estimates. This suggests that tighter regularization afforded by cDCM priors reduces the possibility of local extrema in the objective function. We conclude this paper with an outlook to ongoing developments for overcoming the software-dependency of reliability observed in this study, including global optimization and empirical Bayesian procedures.

Demographic data from South Korean MERS CoV cases are analysed. We show that stratification by age and sex may reveal relevant gender-specific differences.

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.

BackgroundAlthough several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients.MethodThe blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls.ResultsDifferential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation.ConclusionsThe results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

Background Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment. Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia (PD/A). Cognitive-behavioral therapy (CBT) is an effective treatment for PD/A. However, the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown. Methods In a randomized, controlled, multicenter clinical trial in medication-free patients with PD/A who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before and after CBT. Quality-controlled fMRI data from 42 patients and 42 healthy subjects were obtained. Results After CBT, patients compared to control subjects revealed reduced activation for the conditioned response (CS+ > CS–) in the left inferior frontal gyrus (IFG). This activation reduction was correlated with reduction in agoraphobic symptoms from t1 to t2. Patients compared to control subjects also demonstrated increased connectivity between the IFG and regions of the “fear network” (amygdalae, insulae, anterior cingulate cortex) across time. Conclusions This study demonstrates the link between cerebral correlates of cognitive (IFG) and emotional (“fear network”) processing during symptom improvement across time in PD/A. Further research along this line has promising potential to support the development and further optimization of targeted treatments.

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.

While the right-hemispheric lateralization of the face perception network is well established, recent evidence suggests that handedness affects the cerebral lateralization of face processing at the hierarchical level of the fusiform face area (FFA). However, the neural mechanisms underlying differential hemispheric lateralization of face perception in right- and left-handers are largely unknown. Using dynamic causal modeling (DCM) for fMRI, we aimed to unravel the putative processes that mediate handedness-related differences by investigating the effective connectivity in the bilateral core face perception network. Our results reveal an enhanced recruitment of the left FFA in left-handers compared to right-handers, as evidenced by more pronounced face-specific modulatory influences on both intra- and interhemispheric connections. As structural and physiological correlates of handedness-related differences in face processing, right- and left-handers varied with regard to their gray matter volume in the left fusiform gyrus and their pupil responses to face stimuli. Overall, these results describe how handedness is related to the lateralization of the core face perception network, and point to different neural mechanisms underlying face processing in right- and left-handers. In a wider context, this demonstrates the entanglement of structurally and functionally remote brain networks, suggesting a broader underlying process regulating brain lateralization., Scientific Reports, 6, ISSN:2045-2322

Impaired fiber bundle connectivity between brain regions is a key neuropathological finding in schizophrenia. Symptom dimensions in schizophrenia can be clustered into factor models. Single syndromes have been related to grey and white matter brain structure alterations. We associated all core syndromes of schizophrenia in a single patient group with changes in white matter integrity. Diffusion weighted images (3T MRI) and SAPS/SANS scores were measured in 26 male patients and 26 healthy controls. First, group differences in fractional anisotropy (FA) were calculated with TBSS. Second, core symptom dimensions of schizophrenia were correlated with FA within these altered tracts. We found differences between groups in nine white matter tracts. Hallucinations were positively correlated with FA in the left uncinate fasciculus and left corticospinal tract. Ego-disturbances (passivity phenomena) showed a positive correlation with FA in the right anterior thalamic radiation. Positive formal thought disorders (FTD) corresponded negatively with FA in the right cingulum bundle. Negative symptoms were positively associated with the right anterior thalamic radiation and negatively with the right ventral cingulum bundle. For the first time, we analyzed the whole range of psychopathological factors in one schizophrenia patient group. We could validate our novel results for positive FTD and passivity phenomena by replicating findings for hallucinations and negative symptoms. Only those brain circuits which are most vulnerable at a given time during neurodevelopment are affected by a particular pathological impact (genetic, environmental). This scenario could explain the predominance of particular psychopathological syndromes related to specific white matter anomalies.

Q fever is a zoonosis caused by Coxiella burnetii. Infection can result in severe disease. However, little is known about the risk of infection in veterinarians. In a cross-sectional study among German veterinarians, participants provided sera and completed an exposure questionnaire. We investigated predictors for seropositivity using multivariable logistic regression modelling. The 424 participants' median age was 40 (18-74) years, and 276 (65%) were female. Sera of 162 (38%) were positive for Coxiella burnetii phase II IgG antibodies (by ELISA and IFAT). Predictors for seropositivity were occupational exposure to cattle (aOR 2.83, 95% CI 1.64-4.87), occupational exposure to sheep (2.09, 1.22-3.58), male sex (1.9, 1.15-3.13), and increasing age (30-39 years: 4.91, 2.00-12.04; 40-49 years: 5.32, 2.12-13.33; >50 years: 6.70, 2.60-17.25; compared with

Genome‐wide association studies identified the single nucleotide polymorphism rs1344706 in ZNF804A as a common risk‐variant for schizophrenia and bipolar disorder. Whereas the molecular function of ZNF804A is yet unclear, recent imaging genetics studies have started to characterize the neural systems architecture linking rs1344706 genotype to psychosis. Carring rs1344706 risk‐alleles was associated with a decrease in functional connectivity within the dorsolateral prefrontal cortices (DLPFCs) as well as an increase in connectivity between the DLPFC and the hippocampal formation (HF) in the context of a working memory task. The present study aimed at replicating these findings in an independent sample of 94 healthy subjects. Subjects were genotyped for rs1344706 and performed a working memory task during functional magnetic resonance imaging. Results indicate no support for a decrease of functional coupling between the bilateral DLPFCs at higher ZNF804A risk status. However, the current data show the previously described alteration in functional coupling between the right DLPFC and the HFs, albeit with weaker effects. Decoupled by default, the functional connectivity between the right DLPFC and anterior HFs increased with the number of rs1344706 risk alleles. The present data support fronto‐hippocampal dysconnectivity as intermediate phenotype linking rs1344706 genotype to psychosis. We discuss the issues in replicating the interhemispheric DLPFC coupling in light of the effect sizes rs1344706 genotype has on brain function, concluding that further independent replication studies are fundamentally needed to ascertain the role of rs1344706 in the functional integration of neural systems. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.

BackgroundRecent genetic studies found the A allele of the variant rs1006737 in the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene to be over-represented in patients with psychosis, including schizophrenia, bipolar disorder and major depressive disorder. In these disorders, attention deficits are among the main cognitive symptoms and have been related to altered neural activity in cerebral attention networks. The particular effect of CACNA1C on neural function, such as attention networks, remains to be elucidated.MethodThe current event-related functional magnetic resonance imaging (fMRI) study investigated the effect of the CACNA1C gene on brain activity in 80 subjects while performing a scanner-adapted version of the Attention Network Test (ANT). Three domains of attention were probed simultaneously: alerting, orienting and executive control of attention.ResultsRisk allele carriers showed impaired performance in alerting and orienting in addition to reduced neural activity in the right inferior parietal lobule [Brodmann area (BA) 40] during orienting and in the medial frontal gyrus (BA 8) during executive control of attention. These areas belong to networks that have been related to impaired orienting and executive control mechanisms in neuropsychiatric disorders.ConclusionsOur results suggest that CACNA1C plays a role in the development of specific attention deficits in psychiatric disorders by modulation of neural attention networks.

The purpose of the present study was to establish a short paradigm for the examination of classical aversive conditioning processes for application in patients with anxiety disorders. We measured behavioral, autonomic and neural correlates of the paradigm in healthy subjects, applying functional magnetic resonance imaging (fMRI) and measurement of skin conductance. Therefore, neutral visual stimuli were paired with an unpleasant white noise as unconditioned stimulus. Twenty healthy subjects performed three experimental phases of learning: familiarization, acquisition and extinction. Subjective ratings of valence and arousal after each phase of conditioning as well as skin conductance measurement indicated successful conditioning. During acquisition, fMRI results showed increased activation for the conditioned stimulus (CS+(unpaired)) when compared with the non-conditioned stimulus (CS-) in the right amygdala, the insulae, the anterior cingulate cortex and the parahippocampal gyrus, all regions known to be involved in emotional processing. In addition, a linearly decreasing activation in the right amygdala/hippocampus for the CS- across the acquisition phase was found. There were no significant differences between CS+ and CS- during extinction. In conclusion, the applicability of this paradigm for the evaluation of neural correlates in conditioning and extinction processes has been proven. Thus, we present a promising paradigm for the examination of the fear-circuit in patients with anxiety disorders and additionally effects of cognitive-behavioral interventions.

Body orientation and eye gaze influence how information is conveyed during face-to-face communication. However, the neural pathways underpinning the comprehension of social cues in everyday interaction are not known. In this study we investigated the influence of addressing vs. non-addressing body orientation on the neural processing of speech accompanied by gestures. While in an fMRI scanner, participants viewed short video clips of an actor speaking sentences with object- (O; e.g., shape) or person-related content (P; e.g., saying goodbye) accompanied by iconic (e.g., circle) or emblematic gestures (e.g., waving), respectively. The actor's body was oriented either toward the participant (frontal, F) or toward a third person (lateral, L) not visible. For frontal vs. lateral actor orientation (F>L), we observed activation of bilateral occipital, inferior frontal, medial frontal, right anterior temporal and left parietal brain regions. Additionally, we observed activity in the occipital and anterior temporal lobes due to an interaction effect between actor orientation and content of the communication (PF>PL)>(OF>OL). Our findings indicate that social cues influence the neural processing of speech-gesture utterances. Mentalizing (the process of inferring the mental state of another individual) could be responsible for these effects. In particular, socially relevant cues seem to activate regions of the anterior temporal lobes if abstract person-related content is communicated by speech and gesture. These new findings illustrate the complexity of interpersonal communication, as our data demonstrate that multisensory information pathways interact at both perceptual and semantic levels.

Gestures are an important part of interpersonal communication, for example by illustrating physical properties of speech contents (e.g., “the ball is round”). The meaning of these so‐called iconic gestures is strongly intertwined with speech. We investigated the neural correlates of the semantic integration for verbal and gestural information. Participants watched short videos of five speech and gesture conditions performed by an actor, including variation of language (familiar German vs. unfamiliar Russian), variation of gesture (iconic vs. unrelated), as well as isolated familiar language, while brain activation was measured using functional magnetic resonance imaging. For familiar speech with either of both gesture types contrasted to Russian speech‐gesture pairs, activation increases were observed at the left temporo‐occipital junction. Apart from this shared location, speech with iconic gestures exclusively engaged left occipital areas, whereas speech with unrelated gestures activated bilateral parietal and posterior temporal regions. Our results demonstrate that the processing of speech with speech‐related versus speech‐unrelated gestures occurs in two distinct but partly overlapping networks. The distinct processing streams (visual versus linguistic/spatial) are interpreted in terms of “auxiliary systems” allowing the integration of speech and gesture in the left temporo‐occipital region. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.

Variation in the val(158)met polymorphism of the COMT gene has been found to be associated with cognitive performance. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal areas. Given the complex modulation and functional heterogeneity of frontal lobe systems, further specification of COMT gene-related phenotypes differing in prefrontally mediated cognitive performance are of major interest. Eighty healthy individuals (54 men, 26 women; mean age 23.3 years) performed an overt semantic verbal fluency task while brain activation was measured with functional magnetic resonance imaging (fMRI). COMT val(158)met genotype was determined and correlated with brain activation measured with fMRI during the task. Although there were no differences in performance, brain activation in the left inferior frontal gyrus [Brodmann area 10] was positively correlated with the number of val alleles in the COMT gene. COMT val(158)met status modulates brain activation during the language production on a semantic level in an area related to executive functions.

G72 is a vulnerability gene for schizophrenia and affective psychosis, disorders that are characterized by deficits in working memory. In the present study we investigated whether the G72 genotype influences verbal and spatial working memory functions in healthy individuals. Working memory was assessed at the behavioural level in 423 subjects using the spatial span of the Wechsler Memory Scale (spatial working memory) and the letter–number-span test (verbal working memory). In a sub-sample of 83 subjects, we assessed working memory functions also at the neural level using functional magnetic resonance imaging during a classical letter variant of the n -back task. Unexpectedly the high risk allele carriers performed better in the verbal working memory task than the other subjects. These behavioural differences were accompanied by brain activation differences in the right parahippocampus, a brain region that plays a major role in schizophrenia and affective disorders. The high risk variant of a vulnerability gene therefore does not necessarily have to negatively affect cognitive abilities per se, but may even have beneficial effects on cognitive functions in the non-affected population.

The changing epidemiology of vector-borne diseases represents a growing threat to human health. Contemporary surveillance systems have to adapt to these changes. We describe temporal trends and geographic origins of vector-borne diseases in Germany with regard to strengths of existing disease surveillance and to areas marked for improvement. We focused on hantavirus infection (endemic in Germany), chikungunya fever (recently emerging in Europe) and dengue fever (imported from tropical regions), representing important subgroups of vector-borne infections. Routine surveillance data on demographics, origin of infection and the date of reporting were analysed. From 2001 through 2007, 3,005 symptomatic hantavirus infections, and 85 cases of chikungunya fever were reported, similarly 1,048 cases of dengue fever in 2002 through 2007. The geographic origin of hantavirus infection was reported for 95.5% of all cases (dengue virus, 98.4%; chikungunya virus, 100%). Hantavirus infections were acquired in Germany in 97.6% of cases (n = 2800). In 2007, there was a marked increase of hantavirus cases, mainly in areas known to be endemic for hantavirus. In 2006, imported cases of chikungunya fever primarily returned from several islands of the Indian Ocean, while the majority of imported cases in 2007 came from India. The reported number of dengue fever cases have increased since 2004. Thailand contributed the largest proportion of cases (17-43% in individual years), followed by India, Brazil and Indonesia. Surveillance of notifiable vector-borne diseases in Germany is able to timely detect spatial and temporal changes of autochthonous an imported infections. Geographic and temporal data obtained by routine surveillance served as a basis for public health recommendations. In addition to surveillance of vector-borne infections in humans, nationwide monitoring programs and inventory techniques for emerging and reemerging vectors and for wildlife disease are warranted.

Speech may have evolved from earlier modes of communication based on gestures. Consistent with such a motor theory of speech, cortical orofacial and hand motor areas are activated by both speech production and speech perception. However, the extent of speech-related activation of the motor cortex remains unclear. Therefore, we examined if reading and listening to continuous prose also activates non-brachiofacial motor representations like the leg motor cortex. We found corticospinal excitability of bilateral leg muscle representations to be enhanced by speech production and silent reading. Control experiments showed that speech production yielded stronger facilitation of the leg motor system than non-verbal tongue-mouth mobilization and silent reading more than a visuo-attentional task thus indicating speech-specificity of the effect. In the frame of the motor theory of speech this finding suggests that the system of gestural communication, from which speech may have evolved, is not confined to the hand but includes gestural movements of other body parts as well.

Huntington's Disease (HD) is a neurogenetic disorder accompanied by an atrophy of the striatum and hence of the dopaminergic (DA) system. Neural processes subserving error processing presumably depend on the DA system. We assessed error processing in manifest HD and in presymptomatic HD‐gene‐mutation‐carriers (pHD) with event‐related potentials reflecting error processing (the error negativity or error‐related negativity and the error positivity derived from a flanker‐task. We found a reduction of the Ne in the case of HD compared to pHD reflecting dopamine system pathology. Despite the Ne being reduced in HD, behavioral adaptation was possible. In addition, the error‐rates did not differ between the groups. Optimized voxel‐based morphometry revealed that grey matter volume in the medial frontal gyrus is correlated with the Ne amplitude in symptomatic patients. In addition, the effect of a Ne‐reduction was related to the grey matter underneath the medial frontal gyrus, which is in line with two theories of the Ne. In contrast, the Pe did not differ between the groups, suggesting that the Pe is decoupled from the DA system. Interestingly we found a reduction of a late slow negativity on correct responses, which possibly reflects decreased preparatory processes in HD compared to pHD as induced by the DA alterations in HD. In conclusion a deterioration in error processing in HD compared to pHD is mainly reflected by the Ne. The deterioration might rely on two factors: a neurofunctional and a neuroanatomical. Hum Brain Mapp 2008. © 2007 Wiley‐Liss, Inc.

Clinical 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 toLeptospira). Whole-blood specimens were stimulated withLeptospiraantigensin 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-γ), interleukin-10 (IL-10), IL-2, and tumor necrosis factor alpha (TNF-α) by CD4+T cells. The production of inflammatory cytokines such as TNF-α 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-α production was higher in exposed subjects than in patients with mild and severe disease. Levels of proinflammatory cytokines such as TNF-α 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.

Background: Oxytocin has received much attention as a prosocial and anxiolytic neuropeptide. In human studies, the G-allele of a common variant ( rs53576 ) in the oxytocin receptor gene ( OXTR ) has been associated with protective properties such as reduced stress response and higher receptiveness for social support. In contrast, recent studies suggest a detrimental role of the rs53576 G-allele in the context of childhood maltreatment. To further elucidate the role of OXTR, gene by maltreatment interactions on brain structure and function were investigated. Methods: Three hundred nine healthy participants genotyped for OXTR rs53576 underwent structural as well as functional magnetic resonance imaging during a common emotional face-matching task. Childhood maltreatment was assessed with the Childhood Trauma Questionnaire ( CTQ ). Gray matter volumes were investigated by means of voxel-based morphometry across the entire brain. Results: Structural magnetic resonance imaging data revealed a strong interaction of rs53576 genotype and CTQ scores, mapping specifically to the bilateral ventral striatum. GG homozygotes but not A-allele carriers showed strong gray matter reduction with increasing CTQ scores. In turn, lower ventral striatum gray matter volumes were associated with lower reward dependence, a prosocial trait. Furthermore, the G-allele was associated with increased amygdala responsiveness to emotional facial expressions. Conclusions: The findings suggest that the G-allele constitutes a vulnerability factor for specific alterations of limbic brain structure in individuals with adverse childhood experiences, complemented by increased limbic responsiveness to emotional interpersonal stimuli. While oxytocinergic signaling facilitates attachment and bonding in supportive social environments, this attunement for social cues may turn disadvantageous under early adverse conditions.