Igor Nenadic

Friedrich Schiller University Jena, Jena, Thuringia, Germany

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Publications (112)559.35 Total impact

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    ABSTRACT: Schizotypal traits are phenotypic risk factors for schizophrenia, associated with biological changes across a putative schizophrenia spectrum. In this study, we tested the hypothesis that brain structural changes in key brain areas relevant to this spectrum (esp. medial and lateral prefrontal cortex) would vary across different degrees of schizotypal trait expression and/or phenotypic markers of psychosis proneness in healthy non-clinical volunteers. We analysed high-resolution 3Tesla magnetic resonance images (MRI) of 59 healthy volunteers using voxel-based morphometry (VBM), correlating grey matter values to the positive and negative symptom factors of the schizotypal personality questionnaire (SPQ, German version) and a measure of psychosis proneness (community assessment of psychic experiences, CAPE). We found positive correlations between positive SPQ dimension and bilateral inferior and right superior frontal cortices, and positive CAPE dimension and left inferior frontal cortex, as well as CAPE negative dimension and right supplementary motor area (SMA) and left inferior parietal cortex. However, only the positive correlation of the right precuneus with negative schizotypy scores was significant after FWE correction for multiple comparisons. Our findings confirm an effect of schizotypal traits and psychosis proneness on brain structure in healthy subjects, providing further support to a biological continuum model. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 07/2015; DOI:10.1016/j.schres.2015.06.017 · 4.43 Impact Factor
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    ABSTRACT: Bipolar disorder and schizophrenia share phenotypic and genotypic features, but might differ in aspects of abnormal neurodevelopmental trajectories. We studied gyrification, a marker of early developmental pathology, in high-resolution MRI scans of 34 patients with schizophrenia, 17 euthymic bipolar I disorder patients with previous psychotic symptoms, and 34 matched healthy controls in order to test the hypothesis of overlapping and diverging prefrontal gyrification abnormalities. We applied a novel, validated method for measuring local gyrification in each vertex point of the reconstructed cortical surface. Psychotic bipolar I patients had higher gyrification in dorsal anterior and infragenual cingulate cortex compared to either schizophrenia or healthy controls, while schizophrenia patients had higher gyrification than controls in anterior medial (BA 10) and orbitofrontal areas, altogether indicating disease-specific alterations in the prefrontal cortex. Our findings indicate gyrification changes in a specific subgroup of bipolar I disorder to affect an area relevant to emotion regulation, and distinct from changes seen in schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 06/2015; 185:104-107. DOI:10.1016/j.jad.2015.06.014 · 3.71 Impact Factor
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    ABSTRACT: Recent findings indicate that alterations of the amygdalar resting-state fMRI connectivity play an important role in the etiology of depression. While both depression and resting-state brain activity are shaped by genes and environment, the relative contribution of genetic and environmental factors mediating the relationship between amygdalar resting-state connectivity and depression remain largely unexplored. Likewise, novel neuroimaging research indicates that different mathematical representations of resting-state fMRI activity patterns are able to embed distinct information relevant to brain health and disease. The present study analyzed the influence of genes and environment on amygdalar resting-state fMRI connectivity, in relation to depression risk. High-resolution resting-state fMRI scans were analyzed to estimate functional connectivity patterns in a sample of 48 twins (24 monozygotic pairs) informative for depressive psychopathology (6 concordant, 8 discordant and 10 healthy control pairs). A graph-theoretical framework was employed to construct brain networks using two methods: (i) the conventional approach of filtered BOLD fMRI time-series and (ii) analytic components of this fMRI activity. Results using both methods indicate that depression risk is increased by environmental factors altering amygdalar connectivity. When analyzing the analytic components of the BOLD fMRI time-series, genetic factors altering the amygdala neural activity at rest show an important contribution to depression risk. Overall, these findings show that both genes and environment modify different patterns the amygdala resting-state connectivity to increase depression risk. The genetic relationship between amygdalar connectivity and depression may be better elicited by examining analytic components of the brain resting-state BOLD fMRI signals. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 06/2015; DOI:10.1002/hbm.22876 · 6.92 Impact Factor
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    ABSTRACT: Previous research suggests that low birth weight (BW) induces reduced brain cortical surface area (SA) which would persist until at least early adulthood. Moreover, low BW has been linked to psychiatric disorders such as depression and psychological distress, and to altered neurocognitive profiles. We present novel findings obtained by analysing high-resolution structural MRI scans of 48 twins; specifically, we aimed: i) to test the BW-SA association in a middle-aged adult sample; and ii) to assess whether either depression/anxiety disorders or intellectual quotient (IQ) influence the BW-SA link, using a monozygotic (MZ) twin design to separate environmental and genetic effects. Both lower BW and decreased IQ were associated with smaller total and regional cortical SA in adulthood. Within a twin pair, lower BW was related to smaller total cortical and regional SA. In contrast, MZ twin differences in SA were not related to differences in either IQ or depression/anxiety disorders. The present study supports findings indicating that i) BW has a long-lasting effect on cortical SA, where some familial and environmental influences alter both foetal growth and brain morphology; ii) uniquely environmental factors affecting BW also alter SA; iii) higher IQ correlates with larger SA; and iv) these effects are not modified by internalizing psychopathology.
    PLoS ONE 06/2015; 10(6):e0129616. DOI:10.1371/journal.pone.0129616 · 3.23 Impact Factor
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    ABSTRACT: Hippocampal pathology has been shown to be central to the pathophysiology of schizophrenia and a putative risk marker for developing psychosis. We applied both (1)H MRS (proton magnetic resonance spectroscopy) at 3Tesla and voxel-based morphometry (VBM) of high-resolution brain structural images in order to study the association of the metabolites glutamate (Glu) and N-acetyl-aspartate (NAA) in the hippocampus with whole-brain morphometry in 31 persons at ultra-high-risk for psychosis (UHR), 18 first-episode schizophrenia patients (Sz), and 42 healthy controls (all subjects being neuroleptic-naïve). Significantly diverging associations emerged for UHR subjects hippocampal glutamate showed positive correlation with the left superior frontal cortex, not seen in Sz or controls, while in first-episode schizophrenia patients a negative correlation was significant between glutamate and a left prefrontal area. For NAA, we observed different associations for left prefrontal and caudate clusters bilaterally for both high-risk and first-episode schizophrenia subjects, diverging from the pattern seen in healthy subjects. Our results suggest that associations of hippocampal metabolites in key areas of schizophrenia might vary due to liability to or onset of the disorder. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2015; DOI:10.1016/j.euroneuro.2015.05.005 · 5.40 Impact Factor
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    ABSTRACT: While schizophrenia and bipolar disorder have been assumed to share phenotypic and genotypic features, there is also evidence for overlapping brain structural correlates, although it is unclear whether these relate to shared psychotic features. In this study, we used voxel-based morphometry (VBM8) in 34 schizophrenia patients, 17 euthymic bipolar I disorder patients (with a history of psychotic symptoms), and 34 healthy controls. Our results indicate that compared to healthy controls schizophrenia patients show grey matter deficits (p<0.05, FDR corrected) in medial and right dorsolateral prefrontal, as well as bilaterally in ventrolateral prefrontal and insular cortical areas, thalamus (bilaterally), left superior temporal cortex, and minor medial parietal and parietooccipital areas. Comparing schizophrenia vs. bipolar I patients (p<0.05, FDR corrected) yielded a similar pattern, however, there was an additional significant reduction in schizophrenia patients in the (posterior) hippocampus bilaterally, left dorsolateral prefrontal cortex, and left cerebellum. Compared to healthy controls, the deficits in bipolar I patients only reached significance at p<0.001 (uncorr.) for a minor parietal cluster, but not for prefrontal areas. Our results suggest that the more extensive prefrontal, thalamic, and hippocampal deficits that might set apart schizophrenia and bipolar disorder might not be related to mere appearance of psychotic symptoms at some stage of the disorders. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 04/2015; 165(2-3). DOI:10.1016/j.schres.2015.04.007 · 4.43 Impact Factor
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    ABSTRACT: Background Alterations of cortical thickness have been shown in imaging studies of schizophrenia but it is unclear to what extent they are related to disease phenotype (including symptom profile) or other aspects such as genetic liability, disease onset and disease progression. Aims To test the hypothesis that cortical thinning would vary across different subgroups of patients with chronic schizophrenia, delineated according to their symptom profiles. Method We compared high-resolution magnetic resonance imaging data of 87 patients with DSM-IV schizophrenia with 108 controls to detect changes in cortical thickness across the entire brain (P<0.05, false discovery rate-adjusted). The patient group was divided into three subgroups, consisting of patients with predominantly negative, disorganised or paranoid symptoms. Results The negative symptoms subgroup showed the most extensive cortical thinning, whereas thinning in the other subgroups was focused in prefrontal and temporal cortical subregions. Conclusions Our findings support growing evidence of potential subtypes of schizophrenia that have different brain structural deficit profiles. Royal College of Psychiatrists.
    The British journal of psychiatry: the journal of mental science 02/2015; 206(6). DOI:10.1192/bjp.bp.114.148510 · 7.34 Impact Factor
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    ABSTRACT: Early intervention research in schizophrenia has suggested that brain structural alterations might be present in subjects at high risk of developing psychosis. The heterogeneity of regional effects of these changes, which is established in schizophrenia, however, has not been explored in prodromal or high-risk populations. We used high-resolution MRI and voxel-based morphometry (VBM8) to analyze grey matter differences in 43 ultra high-risk subjects for psychosis (meeting ARMS criteria, identified through CAARMS interviews), 24 antipsychotic-naïve first-episode schizophrenia patients and 49 healthy controls (groups matched for age and gender). Compared to healthy controls, resp., first-episode schizophrenia patients had reduced regional grey matter in left prefrontal, insula, right parietal and left temporal cortices, while the high-risk group showed reductions in right middle temporal and left anterior frontal cortices. When dividing the ultra-high-risk group in those with a genetic risk vs. those with attenuated psychotic symptoms, the former showed left anterior frontal, right caudate, as well as a smaller right hippocampus, and amygdala reduction, while the latter subgroup showed right middle temporal cortical reductions (each compared to healthy controls). Our findings in a clinical psychosis high-risk cohort demonstrate variability of brain structural changes according to subgroup and background of elevated risk, suggesting frontal and possibly also hippocampal/amygdala changes in individuals with genetic susceptibility. Heterogeneity of structural brain changes (as seen in schizophrenia) appears evident even at high-risk stage, prior to potential onset of psychosis. Copyright © 2014 Elsevier B.V. All rights reserved.
    Schizophrenia Research 12/2014; 161(2-3). DOI:10.1016/j.schres.2014.10.041 · 4.43 Impact Factor
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    ABSTRACT: In aetiologically complex illnesses such as schizophrenia, there is no direct link between genotype and phenotype. Intermediate phenotypes could help clarify the underlying biology and assist in the hunt for genetic vulnerability variants. We have previously shown that cognition shares substantial genetic variance with schizophrenia; however, it is unknown if this reflects pleiotropic effects, direct causality or some shared third factor that links both, for example, brain volume (BV) changes. We quantified the degree of net genetic overlap and tested the direction of causation between schizophrenia liability, brain structure and cognition in a pan-European schizophrenia twin cohort consisting of 1243 members from 626 pairs. Cognitive deficits lie upstream of the liability for schizophrenia with about a quarter of the variance in liability to schizophrenia explained by variation in cognitive function. BV changes lay downstream of schizophrenia liability, with 4% of BV variation explained directly by variation in liability. However, our power to determine the nature of the relationship between BV deviation and schizophrenia liability was more limited. Thus, while there was strong evidence that cognitive impairment is causal to schizophrenia liability, we are not in a position to make a similar statement about the relationship between liability and BV. This is the first study to demonstrate that schizophrenia liability is expressed partially through cognitive deficits. One prediction of the finding that BV changes lie downstream of the disease liability is that the risk loci that influence schizophrenia liability will thereafter influence BV and to a lesser extent. By way of contrast, cognitive function lies upstream of schizophrenia, thus the relevant loci will actually have a larger effect size on cognitive function than on schizophrenia. These are testable predictions.Molecular Psychiatry advance online publication, 2 December 2014; doi:10.1038/mp.2014.152.
    Molecular Psychiatry 12/2014; DOI:10.1038/mp.2014.152 · 15.15 Impact Factor
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    ABSTRACT: First combined grey and white matter analysis in narcissistic personality disorder•Narcissistic personality disorder is associated with frontal grey matter loss•NaPD is also associated with right frontal white matter alterations
    Psychiatry Research: Neuroimaging 11/2014; 231(2). DOI:10.1016/j.pscychresns.2014.11.001 · 2.83 Impact Factor
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    ABSTRACT: Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2) and IGF2BP1-3 (IGF2-binding proteins 1-3) were examined in a sample consisting of 34 adult monozygotic (MZ) twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW) and adult working memory (WM) performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.
    PLoS ONE 08/2014; 9(8):e103639. DOI:10.1371/journal.pone.0103639 · 3.23 Impact Factor
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    ABSTRACT: Imaging genetics examines genetic influences on brain structure and function. This preliminary study tested a fundamental assumption of that approach by estimating the heritability of the blood oxygen level dependent (BOLD) signal during antisaccades, a measure of response inhibition impaired in different psychiatric conditions. One hundred thirty-two healthy same-sex reared-together twins (90 monozygotic (MZ; 32 male) and 42 dizygotic (DZ; 24 male)) performed antisaccades in the laboratory. Of these, 96 twins (60 MZ, 28 male; 36 DZ, 22 male) subsequently underwent functional magnetic resonance imaging (fMRI) during antisaccades. Variation in antisaccade direction errors in the laboratory showed significant heritability (47%; 95% confidence interval (CI) 22-65). In fMRI, the contrast of antisaccades with prosaccades yielded BOLD signal in fronto-parietal-subcortical networks. Twin modelling provided tentative evidence of significant heritability (50%, 95% CI: 18-72) of BOLD in the left thalamus only. However, due to the limited power to detect heritability in this study, replications in larger samples are needed.
    Biological Psychology 08/2014; 103. DOI:10.1016/j.biopsycho.2014.07.017 · 3.47 Impact Factor
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    ABSTRACT: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
    Nature 07/2014; 511(7510):421-427. DOI:10.1038/nature13595 · 42.35 Impact Factor
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    ABSTRACT: In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.
    PLoS Genetics 06/2014; DOI:10.1371/journal.pgen.1004345 · 8.17 Impact Factor
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    ABSTRACT: Season of birth has been shown to influence risk for several neuropsychiatric diseases. Furthermore, it has been suggested that season of birth modifies a number of brain morphological traits. Since cortical thickness alterations have been reported across some levels of the psychosis-spectrum, this study was aimed at i) assessing the scarcely explored relationship between cortical thickness and severity of subclinical psychotic experiences (PEs) in healthy subjects, and ii) evaluating the potential impact of season of birth in the preceding thickness-PEs relationship. As both PEs and brain cortical features are heritable, the current work used monozygotic twins to separately evaluate familial and unique environmental factors. High-resolution structural MRI scans of 48 twins (24 monozygotic pairs) were analyzed to estimate cortical thickness using FreeSurfer. They were then examined in relation to PEs, accounting for the effects of birth season; putative differential relationships between PEs and cortical thickness depending on season of birth were also tested. Current results support previous findings indicative of cortical thickening in healthy individuals with high psychometrically assessed psychosis scores, probably in line with theories of compensatory aspects of brain features in non-clinical populations. Additionally, they suggest distinct patterns of cortical thickness-PEs relationships depending on birth seasonality. Familial factors underlying the presence of PEs may drive these effects.
    Journal of Psychiatric Research 05/2014; 56. DOI:10.1016/j.jpsychires.2014.05.014 · 4.09 Impact Factor
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    ABSTRACT: Background Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive.Method We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls.Results We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts.Conclusions Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors.
    Psychological Medicine 05/2014; 45(01):1-10. DOI:10.1017/S0033291714001159 · 5.43 Impact Factor
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    ABSTRACT: To test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding. Perceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population. In the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization. Met carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding.
    European Psychiatry 04/2014; DOI:10.1016/j.eurpsy.2014.03.001 · 3.21 Impact Factor
  • Schizophrenia Research 04/2014; 153:S348-S349. DOI:10.1016/S0920-9964(14)70984-3 · 4.43 Impact Factor
  • Schizophrenia Research 04/2014; 153:S189. DOI:10.1016/S0920-9964(14)70551-1 · 4.43 Impact Factor
  • Schizophrenia Research 04/2014; 153:S111. DOI:10.1016/S0920-9964(14)70341-X · 4.43 Impact Factor

Publication Stats

2k Citations
559.35 Total Impact Points

Institutions

  • 2000–2015
    • Friedrich Schiller University Jena
      • • Clinic of Psychiatry and Psychotherapy
      • • Neuroscience Laboratory
      Jena, Thuringia, Germany
    • Mount Sinai School of Medicine
      • Department of Psychiatry
      Manhattan, New York, United States
  • 2013
    • Ludwig-Maximilian-University of Munich
      • Department of Psychiatry
      München, Bavaria, Germany
  • 2000–2011
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
  • 2001
    • University of California, Irvine
      Irvine, California, United States