@article{KatzorkeZellerMuelleretal.2017, author = {Katzorke, Andrea and Zeller, Julia B. M. and M{\"u}ller, Laura D. and Lauer, Martin and Polak, Thomas and Reif, Andreas and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Reduced activity in the right inferior frontal gyrus in elderly APOE-E4 carriers during a verbal fluency task}, series = {Frontiers in Human Neuroscience}, volume = {11}, journal = {Frontiers in Human Neuroscience}, doi = {10.3389/fnhum.2017.00046}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171892}, year = {2017}, abstract = {Apolipoprotein-E4 (APOE-E4) is a major genetic risk factor for developing Alzheimer's disease (AD). The verbal fluency task (VFT), especially the subtask category fluency, has shown to provide a good discrimination between cognitively normal controls and subjects with AD. Interestingly, APOE-E4 seems to have no effect on the behavioral performance during a VFT in healthy elderly. Thus, the purpose of the present study was to reveal possible compensation mechanisms by investigating the effect of APOE-E4 on the hemodynamic response in non-demented elderly during a VFT by using functional near-infrared spectroscopy (fNIRS). We compared performance and hemodynamic response of high risk APOE-E4/E4, -E3/E4 carriers with neutral APOE-E3/E3 non-demented subjects (N = 288; 70-77 years). No difference in performance was found. APOE-E4/E4, -E3/E4 carriers had a decreased hemodynamic response in the right inferior frontal junction (IFJ) with a corresponding higher response in the left middle frontal gyrus (MFG) during category fluency. Performance was correlated with the hemodynamic response in the MFG. We assume a compensation of decreased IFJ brain activation by utilizing the MFG during category fluency and thus resulting in no behavioral differences between APOE-groups during the performance of a VFT.}, language = {en} } @article{KingslakeDiasDawsonetal.2017, author = {Kingslake, Jonathan and Dias, Rebecca and Dawson, Gerard R. and Simon, Judit and Goodwin, Guy M. and Harmer, Catherine J. and Morriss, Richard and Brown, Susan and Guo, Boliang and Dourish, Colin T. and Ruh{\´e}, Henricus G. and Lever, Anne G. and Veltman, Dick J. and van Schaik, Anneke and Deckert, J{\"u}rgen and Reif, Andreas and St{\"a}blein, Michael and Menke, Andreas and Gorwood, Philip and Voegeli, G{\´e}raldine and Perez, Victor and Browning, Michael}, title = {The effects of using the PReDicT Test to guide the antidepressant treatment of depressed patients: study protocol for a randomised controlled trial}, series = {Trials}, volume = {18}, journal = {Trials}, doi = {10.1186/s13063-017-2247-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173012}, year = {2017}, abstract = {Background Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4-6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen. Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual. Methods/design The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient's antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50\% or greater decrease in baseline scores of depressionmeasured using the Quick Inventory of Depressive Symptoms - Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed. Discussion This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients. Trial registration ClinicalTrials.gov, ID: NCT02790970. Registered on 30 March 2016.}, language = {en} } @article{BiehlMerzDresleretal.2016, author = {Biehl, Stefanie C. and Merz, Christian J. and Dresler, Thomas and Heupel, Julia and Reichert, Susanne and Jacob, Christian P. and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Increase or Decrease of fMRI Activity in Adult Attention Deficit/ Hyperactivity Disorder: Does It Depend on Task Difficulty?}, series = {International Journal of Neuropsychopharmacology}, volume = {19}, journal = {International Journal of Neuropsychopharmacology}, number = {10}, doi = {10.1093/ijnp/pyw049}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147551}, pages = {pyw049}, year = {2016}, abstract = {Background: Attention deficit/hyperactivity disorder has been shown to affect working memory, and fMRI studies in children and adolescents with attention deficit/hyperactivity disorder report hypoactivation in task-related attentional networks. However, studies with adult attention deficit/hyperactivity disorder patients addressing this issue as well as the effects of clinically valid methylphenidate treatment are scarce. This study contributes to closing this gap. Methods: Thirty-five adult patients were randomized to 6 weeks of double-blind placebo or methylphenidate treatment. Patients completed an fMRI n-back working memory task both before and after the assigned treatment, and matched healthy controls were tested and compared to the untreated patients. Results: There were no whole-brain differences between any of the groups. However, when specified regions of interest were investigated, the patient group showed enhanced BOLD responses in dorsal and ventral areas before treatment. This increase was correlated with performance across all participants and with attention deficit/hyperactivity disorder symptoms in the patient group. Furthermore, we found an effect of treatment in the right superior frontal gyrus, with methylphenidate-treated patients exhibiting increased activation, which was absent in the placebo-treated patients. Conclusions: Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes.}, language = {en} } @article{PetersHempAppelhansetal.2016, author = {Peters, Marcell K. and Hemp, Andreas and Appelhans, Tim and Behler, Christina and Classen, Alice and Detsch, Florian and Ensslin, Andreas and Ferger, Stefan W. and Frederiksen, Sara B. and Gebert, Frederike and Haas, Michael and Helbig-Bonitz, Maria and Hemp, Claudia and Kindeketa, William J. and Mwangomo, Ephraim and Ngereza, Christine and Otte, Insa and R{\"o}der, Juliane and Rutten, Gemma and Costa, David Schellenberger and Tardanico, Joseph and Zancolli, Giulia and Deckert, J{\"u}rgen and Eardley, Connal D. and Peters, Ralph S. and R{\"o}del, Mark-Oliver and Schleuning, Matthias and Ssymank, Axel and Kakengi, Victor and Zhang, Jie and B{\"o}hning-Gaese, Katrin and Brandl, Roland and Kalko, Elisabeth K.V. and Kleyer, Michael and Nauss, Thomas and Tschapka, Marco and Fischer, Markus and Steffan-Dewenter, Ingolf}, title = {Predictors of elevational biodiversity gradients change from single taxa to the multi-taxa community level}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms13736}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169374}, year = {2016}, abstract = {The factors determining gradients of biodiversity are a fundamental yet unresolved topic in ecology. While diversity gradients have been analysed for numerous single taxa, progress towards general explanatory models has been hampered by limitations in the phylogenetic coverage of past studies. By parallel sampling of 25 major plant and animal taxa along a 3.7 km elevational gradient on Mt. Kilimanjaro, we quantify cross-taxon consensus in diversity gradients and evaluate predictors of diversity from single taxa to a multi-taxa community level. While single taxa show complex distribution patterns and respond to different environmental factors, scaling up diversity to the community level leads to an unambiguous support for temperature as the main predictor of species richness in both plants and animals. Our findings illuminate the influence of taxonomic coverage for models of diversity gradients and point to the importance of temperature for diversification and species coexistence in plant and animal communities.}, language = {en} } @article{ZieglerRichterMahretal.2016, author = {Ziegler, C. and Richter, J. and Mahr, M. and Gajewska, A. and Schiele, M.A. and Gehrmann, A. and Schmidt, B. and Lesch, K.-P. and Lang, T. and Helbig-Lang, S. and Pauli, P. and Kircher, T. and Reif, A. and Rief, W. and Vossbeck-Elsebusch, A.N. and Arolt, V. and Wittchen, H.-U. and Hamm, A.O. and Deckert, J. and Domschke, K.}, title = {MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy}, series = {Translational Psychiatry}, journal = {Translational Psychiatry}, number = {6}, doi = {10.1038/tp.2016.41}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164422}, pages = {e773}, year = {2016}, abstract = {Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17\%), while non-responders further decreased in methylation (-2.00±1.28\%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.}, language = {en} } @article{StraubeReifRichteretal.2014, author = {Straube, B. and Reif, A. and Richter, J. and Lueken, U. and Weber, H. and Arolt, V. and Jansen, A. and Zwanzger, P. and Domschke, K. and Pauli, P. and Konrad, C. and Gerlach, A. L. and Lang, T. and Fydrich, T. and Alpers, G. W. and Stroehle, A. and Wittmann, A. and Pfleiderer, B. and Wittchen, H.-U. and Hamm, A. and Deckert, J. and Kircher, T.}, title = {The functional - 1019C/G HTR1A polymorphism and mechanisms of fear}, series = {Translational Psychiatry}, volume = {4}, journal = {Translational Psychiatry}, issn = {2158-3188}, doi = {10.1038/tp.2014.130}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114369}, pages = {e490}, year = {2014}, abstract = {Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n = 185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n = 245; after CBT: n = 171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n = 39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders.}, language = {en} } @article{GuhnDreslerAndreattaetal.2014, author = {Guhn, Anne and Dresler, Thomas and Andreatta, Marta and M{\"u}ller, Laura D. and Hahn, Tim and Tupak, Sara V. and Polak, Thomas and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Medial prefrontal cortex stimulation modulates the processing of conditioned fear}, doi = {10.3389/fnbeh.2014.00044}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111309}, year = {2014}, abstract = {The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS-) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS- discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT).}, language = {en} } @article{ManishNueckelMuehlbergeretal.2013, author = {Manish, Asthana and Nueckel, Katharina and M{\"u}hlberger, Andreas and Neueder, Dorothea and Polak, Thomas and Domschke, Katharina and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Effects of transcranial direct current stimulation on consolidation of fear memory}, series = {Frontiers in Neuropsychiatric Imaging and Stimulation}, journal = {Frontiers in Neuropsychiatric Imaging and Stimulation}, doi = {10.3389/fpsyt.2013.00107}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97294}, year = {2013}, abstract = {It has been shown that applying transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) influences declarative memory processes. This study investigates the efficacy of tDCS on emotional memory consolidation, especially experimental fear conditioning. We applied an auditory fear-conditioning paradigm, in which two differently colored squares (blue and yellow) were presented as conditioned stimuli (CS) and an auditory stimulus as unconditioned stimulus (UCS). Sixty-nine participants were randomly assigned into three groups: anodal, cathodal, and sham stimulation. The participants of the two active groups (i.e., anodal and cathodal) received tDCS over the left DLPFC for 12 min after fear conditioning. The effect of fear conditioning and consolidation (24 h later) was measured by assessing the skin conductance response (SCR) to the CS. The results provide evidence that cathodal stimulation of the left DLPFC leads to an inhibitory effect on fear memory consolidation compared to anodal and sham stimulation, as indicated by decreased SCRs to CS+ presentation during extinction training at day 2. In conclusion, current work suggests that cathodal stimulation interferes with processes of fear memory consolidation.}, language = {en} } @article{ErhardtAkulaSchumacheretal.2012, author = {Erhardt, A. and Akula, N. and Schumacher, J. and Czamara, D. and Karbalai, N. and M{\"u}ller-Myhsok, B. and Mors, O. and Borglum, A. and Kristensen, A. S. and Woldbye, D. P. D. and Koefoed, P. and Eriksson, E. and Maron, E. and Metspalu, A. and Nurnberger, J. and Philibert, R. A. and Kennedy, J. and Domschke, K. and Reif, A. and Deckert, J. and Otowa, T. and Kawamura, Y. and Kaiya, H. and Okazaki, Y. and Tanii, H. and Tokunaga, K. and Sasaki, T. and Ioannidis, J. P. A. and McMahon, F. J. and Binder, E. B.}, title = {Replication and meta-analysis of TMEM132D gene variants in panic disorder}, series = {Translational Psychiatry}, volume = {2}, journal = {Translational Psychiatry}, number = {e156}, doi = {10.1038/tp.2012.85}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133324}, year = {2012}, abstract = {A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n 1038 cases and n 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.}, language = {en} } @article{KlaukeWinterGajewskaetal.2012, author = {Klauke, Benedikt and Winter, Bernward and Gajewska, Agnes and Zwanzger, Peter and Reif, Andreas and Herrmann, Martin J. and Dlugos, Andrea and Warrings, Bodo and Jacob, Christian and M{\"u}hlberger, Andreas and Arolt, Volker and Pauli, Paul and Deckert, J{\"u}rgen and Domschke, Katharina}, title = {Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {6}, doi = {10.1371/journal.pone.0039709}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132184}, pages = {e39709}, year = {2012}, abstract = {The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system - partly conferred by catechol-O-methyltransferase (COMT) gene variation - for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.}, language = {en} }