TY - JOUR A1 - Akhrif, Atae A1 - Romanos, Marcel A1 - Domschke, Katharina A1 - Schmitt-Boehrer, Angelika A1 - Neufang, Susanne T1 - Fractal Analysis of BOLD Time Series in a Network Associated With Waiting Impulsivity JF - Frontiers in Physiology N2 - Fractal phenomena can be found in numerous scientific areas including neuroscience. Fractals are structures, in which the whole has the same shape as its parts. A specific structure known as pink noise (also called fractal or 1/f noise) is one key fractal manifestation, exhibits both stability and adaptability, and can be addressed via the Hurst exponent (H). FMRI studies using H on regional fMRI time courses used fractality as an important characteristic to unravel neural networks from artificial noise. In this fMRI-study, we examined 103 healthy male students at rest and while performing the 5-choice serial reaction time task. We addressed fractality in a network associated with waiting impulsivity using the adaptive fractal analysis (AFA) approach to determine H. We revealed the fractal nature of the impulsivity network. Furthermore, fractality was influenced by individual impulsivity in terms of decreasing fractality with higher impulsivity in regions of top-down control (left middle frontal gyrus) as well as reward processing (nucleus accumbens and anterior cingulate cortex). We conclude that fractality as determined via H is a promising marker to quantify deviations in network functions at an early stage and, thus, to be able to inform preventive interventions before the manifestation of a disorder. KW - fMRI KW - Hurst Exponent KW - frontal cortex KW - nucleus accumbens KW - biomarker KW - impulse control disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189191 SN - 1664-042X VL - 9 ER - TY - JOUR A1 - Albrecht, Franziska A1 - Mueller, Karsten A1 - Ballarini, Tommaso A1 - Lampe, Leonie A1 - Diehl-Schmid, Janine A1 - Fassbender, Klaus A1 - Fliessbach, Klaus A1 - Jahn, Holger A1 - Jech, Robert A1 - Kassubek, Jan A1 - Kornhuber, Johannes A1 - Landwehrmeyer, Bernhard A1 - Lauer, Martin A1 - Ludolph, Albert C. A1 - Lyros, Epameinondas A1 - Prudlo, Johannes A1 - Schneider, Anja A1 - Synofzik, Matthis A1 - Wiltfang, Jens A1 - Danek, Adrian A1 - Otto, Markus A1 - Schroeter, Matthias L. T1 - Unraveling corticobasal syndrome and alien limb syndrome with structural brain imaging JF - Cortex N2 - Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure function relationship of alien/anarchic limb was investigated in multi centric structural magnetic resonance imaging (MRI) data. Whole-group and single subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture. (C) 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). KW - Alien limb syndrome KW - Anarchic limb syndrome KW - Corticobasal syndrome KW - Diagnosis prediction KW - Support vector machine Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221040 VL - 117 ER - TY - JOUR A1 - Appel, Patricia A1 - Schuler, Michael A1 - Vogel, Heiner A1 - Oezelsel, Amina A1 - Faller, Hermann T1 - Short Questionnaire for Workplace Analysis (KFZA): factorial validation in physicians and nurses working in hospital settings JF - Journal of Occupational Medicine and Toxicology N2 - Background: In recent years, there has been an increasing interest in psychosocial workplace risk assessments in Germany. One of the questionnaires commonly employed for this purpose is the Short Questionnaire for Workplace Analysis (KFZA). Originally, the KFZA was developed and validated for office workers. The aim of the present study was to examine the factorial validity of the KFZA when applied to hospital settings. Therefore, we examined the factorial structure of a questionnaire that contained all the original items plus an extension adding 11 questions specific to hospital workplaces and analyzed both, the original version and the extended version. Methods: We analyzed questionnaire data of a total of 1731 physicians and nurses obtained over a 10-year period. Listwise exclusion of data sets was applied to account for variations in questionnaire versions and yielded 1163 questionnaires (1095 for the extended version) remaining for factor analysis. To examine the factor structure, we conducted a principal component factor analysis. The number of factors was determined using the Kaiser criterion and scree-plot methods. Factor interpretation was based on orthogonal Varimax rotation as well as oblique rotation. Results: The Kaiser criterion revealed a 7-factor solution for the 26 items of the KFZA, accounting for 62.0% of variance. The seven factors were named: “Social Relationships”, “Job Control”, “Opportunities for Participation and Professional Development”, “Quantitative Work Demands”, “Workplace Environment”, “Variability” and “Qualitative Work Demands”. The factor analysis of the 37 items of the extended version yielded a 9-factor solution. The two additional factors were named “Consequences of Strain” and “Emotional Demands”. Cronbach’s α ranged from 0.63 to 0.87 for these scales. Conclusions: Overall, the KFZA turned out to be applicable to hospital workers, and its content-related structure was replicated well with some limitations. However, instead of the 11 factors originally proposed for office workers, a 7-factor solution appeared to be more suitable when employed in hospitals. In particular, the items of the KFZA factor “Completeness of Task” might need adaptation for the use in hospitals. Our study contributes to the assessment of the validity of this popular instrument and should stimulate further psychometric testing. KW - KFZA KW - mental health KW - work-related stress KW - hospital KW - psychosocial workplace risk assessment KW - validation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157510 VL - 12 IS - 11 ER - TY - THES A1 - Araragi, Naozumi T1 - Electrophysiological investigation of two animal models for emotional disorders - serotonin transporter knockout mice and tryptophan hydroxylase 2 knockout mice T1 - Elektrophysiologische Untersuchung bei zwei Tiermodellen für emotionale Störungen - Serotonin Transporter knockout Mäuse und Tryptophan Hydroxylase 2 knockout Mäuse N2 - Serotonin (5-HT) has been implicated in the regulation of emotions as well as in its pathological states, such as anxiety disorders and depression. Mice with targeted deletion of genes encoding various mediators of central serotonergic neurotransmission therefore provides a powerful tool in understanding contributions of such mediators to homeostatic mechanisms as well as to the development of human emotional disorders. Within this thesis a battery of electrophysiological recordings were conducted in the dorsal raphe nucleus (DRN) and the hippocampus of two murine knockout lines with deficient serotonergic systems. Serotonin transporter knockout mice (5-Htt KO), which lack protein responsible for reuptake of 5-HT from the extracellular space and tryptophan hydroxylase 2 knockout (Tph2 KO) mice, which lack the gene encoding the neuronal 5-HT-synthesising enzyme. First, 5-HT1A receptor-mediated autoinhibition of serotonergic neuron firing in the DRN was assessed using the loose-seal cell-attached configuration. Stimulation of 5-HT1A receptors by a selective agonist, R-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT), showed a mild sensitisation and a marked desensitisation of these receptors in Tph2 KO and 5-Htt KO mice, respectively. While application of tryptophan, a precursor of 5-HT and a substrate of Tph2, did not cause autoinhibition in Tph2 KO mice due to the lack of endogenously produced 5-HT, data from 5-Htt KO mice as well as heterozygous mice of both KO mice lines demonstrated the presence of autoinhibitory mechanisms as normal as seen in wildtype (WT) controls. When the Tph2-dependent step in the 5-HT synthesis pathway was bypassed by application of 5-hydroxytryptophan (5-HTP), serotonergic neurons of both Tph2 KO and 5-Htt KO mice showed decrease in firing rates at lower concentrations of 5-HTP than in WT controls. Elevated responsiveness of serotonergic neurons from Tph2 KO mice correspond to mild sensitisation of 5-HT1A receptors, while responses from 5-Htt KO mice suggest that excess levels of extracellular 5-HT, created by the lack of 5-Htt, stimulates 5-HT1A receptors strong enough to overcome desensitisation of these receptors. Second, the whole-cell patch clamp recording data from serotonergic neurons in the DRN showed no differences in basic electrophysiological properties between Tph2 KO and WT mice, except lower membrane resistances of neurons from KO mice. Moreover, the whole-cell patch clamp recording from CA1 pyramidal neurons in the hippocampus of 5-Htt KO mice showed increased conductance both at a steady state and at action potential generation. Lastly, magnitude of long-term potentiation (LTP) induced by the Schaffer collateral/commissural pathway stimulation in the ventral hippocampus showed no differences among Tph2 KO, 5-Htt KO, and WT counterparts. Taken together, lack and excess of extracellular 5-HT caused sensitisation and desensitisation of autoinhibitory 5-HT1A receptors, respectively. However, this may not directly translate to the level of autoinhibitory regulation of serotonergic neuron firing when these receptors are stimulated by endogenously synthesised 5-HT. In general, KO mice studied here showed an astonishing level of resilience to genetic manipulations of the central serotonergic system, maintaining overall electrophysiological properties and normal LTP inducibility. This may further suggest existence of as-yet-unknown compensatory mechanisms buffering potential alterations induced by genetic manipulations. N2 - Serotonin (5-HT) ist an der Regulation von der Emotionen, sowie ihrer pathologischen Zustände, wie Angststörungen und Depressionen beteiligt. Mäuse denen, mittels einer zielgerichteteten Deletion von Genen, die verschiedenste Proteine involviert in der zentralen serotonergen Nerotransmission fehlen, dienen daher als ein nützliches Tiermodell, um die Rolle dieser Mediatoren bei Homöostasemechanismen und der Entwicklung emotionaler Störungen beim Menschen zu verstehen. Im Rahmen dieser Thesis wurde eine Batterie von elektrophysiologischen Ableitungen im Hippocampus sowie in der dorsalen Raphe Nucleus (DRN) zweier Knockout-Mauslinien mit einem defizienten serotonergen Systems durchgeführt. Serotonintransporter Knockout-Mäuse (5-Htt KO), denen das Protein zur Wiederaufnahme von 5-HT aus dem extrazellulären Raum fehlt und Tryptophanhydroxylase 2 Knockout-Mäuse (Tph2 KO), denen das Gen für das 5-HT-synthetisierende Enzym im Gehirn fehlt. Zunächst wurde mittels der “loose-seal cell-attached” Aufnahmemethode die Eigenhemmung der serotonergen Neuronen untersucht, die durch 5-HT1A Rezeptoren in der DRN vermittelt wird. Stimulierung der 5-HT1A Rezeptoren durch einen selektiven Agonist, R-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT), zeigte eine milde Sensibilisierung und eine deutliche Desensibilisierung dieser Rezeptoren in Tph2 KO bzw. in 5-Htt KO Mäusen. Während die Anwendung von Tryptophan, eine Vorstufe von 5-HT und ein Substrat der Tph2, keine Eigenhemmung, aufgrund des Mangels an endogen produziertem 5-HT, in Tph2 KO Mäusen verursachte, wiesen Daten von 5-Htt KO Mäusen sowie von heterozygoten Mäusen beider KO Mauslinien die Existenz der Eigenhemmungsmechanismen wie in den Wildtypen (WT) nach. Wurde der Tph2-abhängige Schritt im 5-HT Syntheseweg durch Anwendung von 5-Hydroxytryptophan (5-HTP) umgangen, zeigten sowohl Tph2 KO als auch 5-Htt KO Mäuse eine Verminderung der serotonergen neuronalen Feuerungsrate bei niedrigeren Konzentrationen von 5-HTP im Vergleich zu den WT. Die erhöhte Reaktionsfähigkeit der serotonergen Neuronen von Tph2 KO Mäusen entsprechen der milden Sensibilisierung der 5-HT1A Rezeptoren. Stattdessen deuten die Reaktionen der serotonergen Neuronen von 5-Htt KO Mäusen darauf hin, dass das überschüssige Niveau von extrazellularem 5-HT, welches durch den Mangel an 5-Htt verursacht wird, 5-HT1A Rezeptoren stark genug stimuliert, um eine Desensibilisierung dieser Rezeptoren zu überwinden. Zweitens zeigten die Daten der whole-cell Patch Clamp Ableitung von serotonergen Neuronen im DRN keine Unterschiede in grundlegenden elektrophysiologischen Eigenschaften zwischen Tph2 KO und WT, außer niedrigen Membranwiderständen in KO Mäusen. Darüber hinaus zeigte die whole-cell Patch Clamp Ableitungen von CA1 Pyramidenzellen im Hippocampus der 5-Htt KO Mäuse eine erhöhte Leitfähigkeit sowohl bei Ruheständen als auch bei Aktionspotentialerzeugungen. Schließlich zeigte die Stärke der Langzeitpotenzierung (long-term potentiation: LTP) durch die Stimulation der Schaffer-Kollateralen/kommissuralen Fasern im ventralen Hippocampus keine Unterschiede zwischen Tph2 KO, 5-Htt KO, und jeweiligen WT. Zusammengefasst verursachten der Mangel und der Überschuss von extrazellularen 5-HT eine Sensibilisierung bzw. Desensibilisierung der autoinhibitorischen 5-HT1A Rezeptoren. Dies kann jedoch nicht direkt in die Regulierung von serotonergen Neuronen Feuerung umgesetzt werden, wenn die 5-HT1A Rezeptoren durch endogen synthetisiertes 5-HT stimuliert werden. Im Allgemeinen zeigten die hier untersuchten KO Mäuse, ein erstaunliches Maß an Widerstandskraft, die die allgemeinen elektrophysiologischen Eigenschaften und die normale LTP Induzierbarkeit trotz genetischer Manipulationen des zentralen serotonergen Systems aufrechterhielt. Weiterhin deutet dies auf die Existenz noch unbekannter Kompensationsmechanismen hin, die diese potentiellen Veränderungen abzudämpfen scheinen. KW - Serotonin KW - Elektrophysiologie KW - Tryptophan hydroxylase 2 KW - Knockout KW - Serotonin transporter KW - Depression KW - Anxiety KW - Knockout KW - Maus Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-83265 ER - TY - JOUR A1 - Araragi, Naozumi A1 - Mlinar, Boris A1 - Baccini, Gilda A1 - Gutknecht, Lise A1 - Lesch, Klaus-Peter A1 - Corradetti, Renato T1 - Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT) neurons in mice with altered 5-HT homeostasis JF - Frontiers in Neuropharmacology N2 - Firing activity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert-/-) and tryptophan hydroxylase-2 knockout (Tph2-/-) mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+)-8-hydroxy-2-(di-n-propylamino)tetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2-/- mice and Sert-/- mice, respectively. While 5-HT neurons from Tph2-/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert-/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP), neurons from both Tph2-/- and Sert-/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling. KW - serotonin transporter KW - tryptophan hydroxylase-2 KW - knockout KW - dorsal raphe nucleus KW - autoinhibition KW - 5-HT1A receptor Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97098 ER - TY - THES A1 - Asthana, Manish T1 - Associative learning – Genetic modulation of extinction and reconsolidation and the effects of transcranial Direct Current Stimulation (tDCS) T1 - Assoziatives Lernen - Genetische Modulation der Auslöschung und Rück-verfestigung und die Auswirkungen der transkraniellen Gleichstromstimulation (tDCS) N2 - Scientific surveys provide sufficient evidence that anxiety disorders are one of the most common psy-chiatric disorders in the world. The lifetime prevalence rate of anxiety disorder is 28.8% (Kessler, et al., 2005). The most widely studied anxiety disorders are as follows panic disorder (PD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), social phobia (or social anxiety disorder), specific phobias, and generalized anxiety disorder (GAD). (NIMH Article, 2009). Classical conditioning is the stable paradigm used from the last one century to understand the neurobi-ology of fear learning. Neurobiological mechanism of fear learning is well documented with the condi-tioning studies. In the therapy of anxiety disorders, exposure based therapies are known to be the most effective approaches. Flooding is a form of exposure therapy in which a participant is exposed to the fear situation and kept in that situation until their fear dissipates. The exposure therapy is based on the phenomena of extinction; this means that a conditioned response diminishes if the conditioned stimulus (CS) is repeatedly presented without an unconditioned stimulus (UCS). One problem with extinction as well as with exposure-based therapy is the problem of fear return (for e.g. renewal, spontaneous recov-ery and reinstatement) after successful extinction. Therefore, extinction does not delete the fear memory trace. It has been well documented that memory processes can be modulated or disrupted using several sci-entific paradigms such as behavioral (for e.g. exposure therapy), pharmacological (for e.g. drug manipu-lation), non-invasive stimulation (for e.g. non-invasive stimulation such as electroconvulsive shock (ECS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), etc. However, modulation of memory processes after reactivation or via non-invasive stimulation is still not clear, which is the focus of the current study. In addition, study of genetic variant suggests that genetic differences play a vital role in the psychiatric disorder especially in fear learning. Hence, it is also one of the concerns of the current dissertation to investigate the interaction between gene and reconsolidation of memory. With respect to fear-conditioning, there are three findings in the current dissertation, which are as fol-lows: (i) In the first study we investigated that non-invasive weak electrical stimulation interferes with the consolidation process and disrupts the fear consolidation to attain stable form. This might offer an effective treatment in the pathological memories, for e.g. PTSD, PD, etc. (ii) In the second study we demonstrated whether a brief single presentation of the CS will inhibit the fear recovery. Like earlier studies we also found that reactivation followed by reconsolidation douses fear return. Attenuation of fear recovery was observed in the reminder group compared to the no-reminder group. (iii) Finally, in our third study we found a statistically significant role of brain derived neurotrophic factor (BDNF) polymorphism in reconsolidation. Results of the third study affirm the involvement of BDNF variants (Met vs. Val) in the modulation of conditioned fear memory after its reactivation. In summary, we were able to show in the current thesis modulation of associative learning and recon-solidation via transcranial direct current stimulation and genetic polymorphism. N2 - Mit einer lebenslangen Prävalenz von etwa 28% (Kessler Rc, 2005) stellen Angststörungen eine der häufigsten psychischen Störungen weltweit dar. Zu den am besten untersuchten Angststörungen gehö-ren Panikstörungen (PD), posttraumatische Belastungsstörungen (PTSD), Zwangsstörungen (OCD), soziale Phobien (oder soziale Angststörungen), spezifische Phobien und generalisierte Angststörungen (GAD) (NIMH Artikel, 2009). Die klassische Konditionierung ist das seit dem letzten Jahrhundert gültige Paradigma zur Erforschung der neurobiologischen Mechanismen des Angstlernens. Bei der Behandlung von Angststörungen haben sich Konfrontationstherapien als äußerst wirksam herausgestellt. Reizüberflutung (Flooding) ist bei-spielsweise eine Form der Konfrontationstherapie, bei der der Teilnehmer einer furchteinflößenden Situation ausgesetzt und in ihr gehalten wird, bis seine Furcht vergeht. Die Konfrontationstherapie ba-siert auf dem Phänomen der Extinktion, also dem Rückgang eines konditionierten Verhaltens nach wie-derholter Präsentation eines konditionierten Stimulus (CS) ohne einen unkonditionierten Stimulus (UCS). Ein Problem der Extinktion und der Konfrontationstherapien ist, dass das Furchtgefühl nach einer erfolgreichen Extinktion zurückkehren kann, was darauf hinweist, dass eine Extinktion nicht die Spuren des Angstgedächtnisses löscht. Vieles deutet darauf, dass der Erinnerungsprozess mittels verschiedenener wissenschaftlicher Para-digmen moduliert oder unterbrochen werden kann. Hierzu gehören etwa behavioristische (z.B. Kon-frontationstherapie), pharmakologische oder nicht-invasive Interventionen (z.B. Elektrokonvulsions-therapie (ECS), transkranielle Magnetstimulation (TMS) oder transkranielle Gleichstromstimulation (tDCS)). Da die Modulation von Erinnerungsprozessen nach einer Reaktivierung oder durch eine nicht-invasive Stimulation derzeit noch unzureichend erforscht ist, wurde der Schwerpunkt der vorliegenden Studie auf diese Thematik gelegt. Ein weiteres Ziel ist es, die Wechselwirkung bestimmter Gene mit der Rekonsolidierung des Gedächtnisses zu untersuchen, also Prozesse, denen eine entscheidende Rolle für Angststörungen im Allgemeinen und Furcht-Lernen im Speziellen zugeschrieben wird. Die vorliegende Dissertation umfasst drei zentrale Ergebnisse zur konditionierten Angst: (i.) In der ers-ten Studie wurde herausgefunden, dass eine nicht-invasive, schwache Stimulation den Konsolidie-rungsprozess beeinflusst und verhindert, dass die Angstkonsolidierung eine stabile Form erreicht. Dies könnte eine neue Möglichkeit darstellen, pathologische Gedächtnisinhalte, die z.B. bei Störungen wie PTSD oder PD vorkommen, effektiv zu behandeln. (ii.) Die zweite Studie untersuchte, ob eine kurze, einfache Präsentation des CS das Wiederaufkommen von Angst hemmen kann. Ähnlich wie in früheren Studien beschrieben, fanden auch wir, dass eine Reaktivierung gefolgt von einer Rekonsolidierung die Rückkehr der Angst unterbindet. Insbesondere wurde in der Gruppe, deren Teilnehmer erneut kon-frontiert wurden (reminder), im Vergleich zur Kontroll-Gruppe (no-reminder) ein verringertes Wieder-aufkommen von Angst beobachtet. (iii.) Die dritte Studie zeigte, dass ein Polymorphismus im BDNF-Gen (Met vs Val) eine signifikante Rolle für die Rekonsolidierung und die Modulation des konditionierten Angstgedächtnisses nach seiner Reaktivierung spielt. KW - Konditionierung KW - Angststörung KW - Associative learning KW - transcranial Direct Current Stimulation (tDCS) KW - Elektrotherapie KW - Brain-derived neurotrophic factor KW - Assoziatives Lernen KW - transkranielle Gleichstromstimulation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-84158 ER - TY - JOUR A1 - Asthana, Manish Kumar A1 - Brunhuber, Bettina A1 - Mühlberger, Andreas A1 - Reif, Andreas A1 - Schneider, Simone A1 - Herrmann, Martin J. T1 - Preventing the Return of Fear Using Reconsolidation Update Mechanisms Depends on the Met-Allele of the Brain Derived Neurotrophic Factor Val66Met Polymorphism JF - International Journal of Neuropsychopharmacology N2 - Background: Memory reconsolidation is the direct effect of memory reactivation followed by stabilization of newly synthesized proteins. It has been well proven that neural encoding of both newly and reactivated memories requires synaptic plasticity. Brain derived neurotrophic factor (BDNF) has been extensively investigated regarding its role in the formation of synaptic plasticity and in the alteration of fear memories. However, its role in fear reconsolidation is still unclear; hence, the current study has been designed to investigate the role of the BDNF val66met polymorphism (rs6265) in fear memory reconsolidation in humans. Methods: An auditory fear-conditioning paradigm was conducted, which comprised of three stages (acquisition, reactivation, and spontaneous recovery). One day after fear acquisition, the experimental group underwent reactivation of fear memory followed by the extinction training (reminder group), whereas the control group (non-reminder group) underwent only extinction training. On day 3, both groups were subjected to spontaneous recovery of earlier learned fearful memories. The treat-elicited defensive response due to conditioned threat was measured by assessing the skin conductance response to the conditioned stimulus. All participants were genotyped for rs6265. Results: The results indicate a diminishing effect of reminder on the persistence of fear memory only in the Met-allele carriers, suggesting a moderating effect of the BDNF polymorphism in fear memory reconsolidation. Conclusions: Our findings suggest a new role for BDNF gene variation in fear memory reconsolidation in humans. KW - BDNF KW - brain derived neurotrophic factor KW - fear conditioning KW - genetics memory KW - reconsolidation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166217 VL - 19 IS - 6 ER - TY - JOUR A1 - Baader, Anna A1 - Kiani, Behnaz A1 - Brunkhorst-Kanaan, Nathalie A1 - Kittel-Schneider, Sarah A1 - Reif, Andreas A1 - Grimm, Oliver T1 - A within-sample comparison of two innovative neuropsychological tests for assessing ADHD JF - Brain Sciences N2 - New innovative neuropsychological tests in attention deficit hyperactivity disorder ADHD have been proposed as objective measures for diagnosis and therapy. The current study aims to investigate two different commercial continuous performance tests (CPT) in a head-to-head comparison regarding their comparability and their link with clinical parameters. The CPTs were evaluated in a clinical sample of 29 adult patients presenting in an ADHD outpatient clinic. Correlational analyses were performed between neuropsychological data, clinical rating scales, and a personality-based measure. Though inattention was found to positively correlate between the two tests (r = 0.49, p = 0.01), no association with clinical measures and inattention was found for both tests. While hyperactivity did not correlate between both tests, current ADHD symptoms were positively associated with Nesplora Aquarium's motor activity (r = 0.52 to 0.61, p < 0.05) and the Qb-Test's hyperactivity (r = 0.52 to 0.71, p < 0.05). Conclusively, the overall comparability of the tests was limited and correlation with clinical parameters was low. While our study shows some interesting correlation between clinical symptoms and sub-scales of these tests, usage in clinical practice is not recommended. KW - ADHD KW - neuropsychology KW - continuous performance test KW - Qb-Test KW - Nesplora Aquarium KW - attention KW - hyperactivity KW - GHQ-28 KW - UPPS KW - impulsivity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220089 SN - 2076-3425 VL - 11 IS - 1 ER - TY - JOUR A1 - Barteit, Sandra A1 - Hoepffner, Philip A1 - Huwendiek, Sören A1 - Karamagi, Angela A1 - Munthali, Charles A1 - Theurer, Antje A1 - Neuhann, Florian T1 - Self-directed e-learning at a tertiary hospital in Malawi - a qualitative evaluation and lessons learnt JF - GMS Journal for Medical Education N2 - Background: Malawi faces a severe lack of health workers. Despite initiatives to address this problem, a critical shortage of health care staff remains. This lack challenges the education and training of junior medical staff, especially medical interns in their final and crucial training year before they independently work as medical doctors. Project description: We have introduced an e-learning platform in the medical department of the Kamuzu Central Hospital (KCH) in Malawi. With the support of computer-assisted instruction, we aimed to improve the quality of medical training and education, as well as access to current medical materials, in particular for interns. Method: From March to April 2012, we conducted a qualitative evaluation to assess relevance and appropriateness of the e-learning platform. Data was collected via face-to-face interviews, a guided group discussion and a checklist based observation log. Evaluation data was recorded and coded using content analysis, interviewees were chosen via purposive sampling. Results: E-learning proved to be technically feasible in this setting. Users considered the e-learning platform to be relevant and appropriate. Concerns were raised about sustainability, accessibility and technical infrastructure, as well as limited involvement and responsibilities of Malawian partners. Interest in e-learning was high, yet, awareness of and knowledge about the e-learning platform among potential users was low. Evaluation results indicated that further adaptions to local needs are necessary to increase usage and accessibility. Conclusions: Interview results and our project experiences showed that, in the given setting, e-learning requires commitment from local stakeholders, adequate technical infrastructure, identification and assignation of responsibilities, as well as specific adaption to local needs. T2 - Selbstgesteuertes medizinisches Lernen via E-Learning an einem Lehrkrankenhaus in Malawi: Aufbau,Erkenntnisse und Erfahrungen KW - computer-assisted instruction KW - capacity KW - multimedia, KW - ICT KW - virtual patients KW - medical Education KW - understaffed KW - teaching hospital KW - Sub-saharan Africa Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150208 N1 - Deutschsprachige Version des Artikels ab Seite 8 des Dokuments. VL - 32 IS - 1 ER - TY - JOUR A1 - Bartl, Jasmin A1 - Scholz, Claus-Jürgen A1 - Hinterberger, Margareta A1 - Jungwirth, Susanne A1 - Wichart, Ildiko A1 - Rainer, Michael K. A1 - Kneitz, Susanne A1 - Danielczyk, Walter A1 - Tragl, Karl H. A1 - Fischer, Peter A1 - Riederer, Peter A1 - Grünblatt, Edna T1 - Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzymegene JF - BMC Medical Genetics N2 - Background Insulin-degrading enzyme (IDE) is the ubiquitously expressed enzyme responsible for insulin and amyloid beta (Aβ) degradation. IDE gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with Type 2 diabetes mellitus (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for Alzheimer's disease (AD), however with controversial results. Methods We examined associations of three IDE polymorphisms (IDE2, rs4646953; IDE7, rs2251101 and IDE9, rs1887922) with AD, Aβ42 plasma level and T2DM risk in the longitudinal Vienna Transdanube Aging (VITA) study cohort. Results The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Aβ42 plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9. Conclusions Based on our SNP and haplotype results, we delineate the model that IDE promoter and 3' untranslated region/downstream variation may have different effects on IDE expression, presumably a relevant endophenotype with disorder-specific effects on AD and T2DM susceptibility. KW - Insulin Degrading Enzyme Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137744 VL - 12 IS - 151 ER - TY - JOUR A1 - Bartmann, Catharina A1 - Fischer, Leah-Maria A1 - Hübner, Theresa A1 - Müller-Reiter, Max A1 - Wöckel, Achim A1 - McNeill, Rhiannon V. A1 - Schlaiss, Tanja A1 - Kittel-Schneider, Sarah A1 - Kämmerer, Ulrike A1 - Diessner, Joachim T1 - The effects of the COVID-19 pandemic on psychological stress in breast cancer patients JF - BMC Cancer N2 - Background: The majority of breast cancer patients are severely psychologically affected by breast cancer diagnosis and subsequent therapeutic procedures. The COVID-19 pandemic and associated restrictions on public life have additionally caused significant psychological distress for much of the population. It is therefore plausible that breast cancer patients might be particularly susceptible to the additional psychological stress caused by the pandemic, increasing suffering. In this study we therefore aimed to assess the level of psychological distress currently experienced by a defined group of breast cancer patients in our breast cancer centre, compared to distress levels preCOVID-19 pandemic. Methods: Female breast cancer patients of all ages receiving either adjuvant, neoadjuvant, or palliative therapies were recruited for the study. All patients were screened for current or previous COVID-19 infection. The participants completed a self-designed COVID-19 pandemic questionnaire, the Stress and Coping Inventory (SCI), the National Comprehensive Cancer Network (R) (NCCN (R)) Distress Thermometer (DT), the European Organization for Research and Treatment of Cancer (EORTC) QLQ C30, and the BR23. Results: Eighty-two breast cancer patients were included. Therapy status and social demographic factors did not have a significant effect on the distress caused by the COVID-19 pandemic. The results of the DT pre and during COVID-19 pandemic did not differ significantly. Using the self-designed COVID-19 pandemic questionnaire, we detected three distinct subgroups demonstrating different levels of concerns in relation to SARS-CoV-2. The subgroup with the highest levels of concern reported significantly decreased life quality, related parameters and symptoms. Conclusions: This monocentric study demonstrated that the COVID-19 pandemic significantly affected psychological health in a subpopulation of breast cancer patients. The application of a self-created "COVID-19 pandemic questionnaire"could potentially be used to help identify breast cancer patients who are susceptible to increased psychological distress due to the COVID-19 pandemic, and therefore may need additional intensive psychological support. KW - COVID-19 KW - breast cancer KW - psychological distress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265802 VL - 21 ER - TY - JOUR A1 - Baune, Bernhard T. A1 - Konrad, Carsten A1 - Grotegerd, Dominik A1 - Suslow, Thomas A1 - Birosova, Eva A1 - Ohrmann, Patricia A1 - Bauer, Jochen A1 - Arolt, Volker A1 - Heindel, Walter A1 - Domschke, Katharina A1 - Schöning, Sonja A1 - Rauch, Astrid V. A1 - Uhlmann, Christina A1 - Kugel, Harald A1 - Dannlowski, Udo T1 - Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain JF - Journal of Neuroinflammation N2 - Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e. g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results In a whole-brain analysis, the polymorphism rs1800795 (-174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = -10, z = -15; F(2,286) = 8.54, p(uncorrected) = 0.0002; p(AlphaSim-corrected) = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted. KW - aging brain KW - hippocampal neurogenesis KW - cholinergic neurons KW - neurothrophic factor KW - Alzheimers disease KW - neurite outgrowth KW - inflammatory cytokines KW - major depression KW - nervour system KW - dentate gyrus KW - genetics KW - inflammation KW - interleukin 6 KW - neuroprotection KW - voxel-based morphometry Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130804 VL - 9 IS - 125 ER - TY - JOUR A1 - Beck, Katherina A1 - Ehmann, Nadine A1 - Andlauer, Till F. M. A1 - Ljaschenko, Dmitrij A1 - Strecker, Katrin A1 - Fischer, Matthias A1 - Kittel, Robert J. A1 - Raabe, Thomas T1 - Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons JF - Disease Models & Mechanisms N2 - Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling. KW - mrsk2 KO mouse KW - S6KII RSK KW - transmission KW - neuromuscular junction KW - synapse KW - MAPK signaling KW - axonal transport KW - motoneuron KW - RSK KW - Drosophila KW - mechanisms KW - plasticity KW - protein kinase KW - signal transduction pathway KW - mitochondrial transport KW - glutamate receptor Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145185 VL - 8 ER - TY - JOUR A1 - Beierle, Felix A1 - Schobel, Johannes A1 - Vogel, Carsten A1 - Allgaier, Johannes A1 - Mulansky, Lena A1 - Haug, Fabian A1 - Haug, Julian A1 - Schlee, Winfried A1 - Holfelder, Marc A1 - Stach, Michael A1 - Schickler, Marc A1 - Baumeister, Harald A1 - Cohrdes, Caroline A1 - Deckert, Jürgen A1 - Deserno, Lorenz A1 - Edler, Johanna-Sophie A1 - Eichner, Felizitas A. A1 - Greger, Helmut A1 - Hein, Grit A1 - Heuschmann, Peter A1 - John, Dennis A1 - Kestler, Hans A. A1 - Krefting, Dagmar A1 - Langguth, Berthold A1 - Meybohm, Patrick A1 - Probst, Thomas A1 - Reichert, Manfred A1 - Romanos, Marcel A1 - Störk, Stefan A1 - Terhorst, Yannik A1 - Weiß, Martin A1 - Pryss, Rüdiger T1 - Corona Health — A Study- and Sensor-Based Mobile App Platform Exploring Aspects of the COVID-19 Pandemic JF - International Journal of Environmental Research and Public Health N2 - Physical and mental well-being during the COVID-19 pandemic is typically assessed via surveys, which might make it difficult to conduct longitudinal studies and might lead to data suffering from recall bias. Ecological momentary assessment (EMA) driven smartphone apps can help alleviate such issues, allowing for in situ recordings. Implementing such an app is not trivial, necessitates strict regulatory and legal requirements, and requires short development cycles to appropriately react to abrupt changes in the pandemic. Based on an existing app framework, we developed Corona Health, an app that serves as a platform for deploying questionnaire-based studies in combination with recordings of mobile sensors. In this paper, we present the technical details of Corona Health and provide first insights into the collected data. Through collaborative efforts from experts from public health, medicine, psychology, and computer science, we released Corona Health publicly on Google Play and the Apple App Store (in July 2020) in eight languages and attracted 7290 installations so far. Currently, five studies related to physical and mental well-being are deployed and 17,241 questionnaires have been filled out. Corona Health proves to be a viable tool for conducting research related to the COVID-19 pandemic and can serve as a blueprint for future EMA-based studies. The data we collected will substantially improve our knowledge on mental and physical health states, traits and trajectories as well as its risk and protective factors over the course of the COVID-19 pandemic and its diverse prevention measures. KW - mobile health KW - ecological momentary assessment KW - digital phenotyping KW - longitudinal studies KW - mobile crowdsensing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242658 SN - 1660-4601 VL - 18 IS - 14 ER - TY - JOUR A1 - Bellinger, Daniel A1 - Wehrmann, Kristin A1 - Rohde, Anna A1 - Schuppert, Maria A1 - Störk, Stefan A1 - Flohr-Jost, Michael A1 - Gall, Dominik A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Herrmann, Martin J. A1 - Erhardt-Lehmann, Angelika T1 - The application of virtual reality exposure versus relaxation training in music performance anxiety: a randomized controlled study JF - BMC Psychiatry N2 - Background Performance anxiety is the most frequently reported anxiety disorder among professional musicians. Typical symptoms are - on a physical level - the consequences of an increase in sympathetic tone with cardiac stress, such as acceleration of heartbeat, increase in blood pressure, increased respiratory rate and tremor up to nausea or flush reactions. These symptoms can cause emotional distress, a reduced musical and artistical performance up to an impaired functioning. While anxiety disorders are preferably treated using cognitive-behavioral therapy with exposure, this approach is rather difficult for treating music performance anxiety since the presence of a public or professional jury is required and not easily available. The use of virtual reality (VR) could therefore display an alternative. So far, no therapy studies on music performance anxiety applying virtual reality exposure therapy have investigated the therapy outcome including cardiovascular changes as outcome parameters. Methods This mono-center, prospective, randomized and controlled clinical trial has a pre-post design with a follow-up period of 6 months. 46 professional and semi-professional musicians will be recruited and allocated randomly to an VR exposure group or a control group receiving progressive muscle relaxation training. Both groups will be treated over 4 single sessions. Music performance anxiety will be diagnosed based on a clinical interview using ICD-10 and DSM-5 criteria for specific phobia or social anxiety. A behavioral assessment test is conducted three times (pre, post, follow-up) in VR through an audition in a concert hall. Primary outcomes are the changes in music performance anxiety measured by the German Bühnenangstfragebogen and the cardiovascular reactivity reflected by heart rate variability (HRV). Secondary outcomes are changes in blood pressure, stress parameters such as cortisol in the blood and saliva, neuropeptides, and DNA-methylation. Discussion The trial investigates the effect of VR exposure in musicians with performance anxiety compared to a relaxation technique on anxiety symptoms and corresponding cardiovascular parameters. We expect a reduction of anxiety but also a consecutive improvement of HRV with cardiovascular protective effects. Trial registration This study was registered on clinicaltrials.gov. (ClinicalTrials.gov Number: NCT05735860) KW - music performance anxiety KW - virtual reality exposure therapy KW - progressive muscle relaxation KW - heart rate variability Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357833 VL - 23 ER - TY - JOUR A1 - Biehl, Stefanie C. A1 - Dresler, Thomas A1 - Reif, Andreas A1 - Scheuerpflug, Peter A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Dopamine Transporter (DAT1) and Dopamine Receptor D4 (DRD4) Genotypes Differentially Impact on Electrophysiological Correlates of Error Processing JF - PLoS One N2 - Recent studies as well as theoretical models of error processing assign fundamental importance to the brain's dopaminergic system. Research about how the electrophysiological correlates of error processing—the error-related negativity (ERN) and the error positivity (Pe)—are influenced by variations of common dopaminergic genes, however, is still relatively scarce. In the present study, we therefore investigated whether polymorphisms in the DAT1 gene and in the DRD4 gene, respectively, lead to interindividual differences in these error processing correlates. One hundred sixty participants completed a version of the Eriksen Flanker Task while a 26-channel EEG was recorded. The task was slightly modified in order to increase error rates. During data analysis, participants were split into two groups depending on their DAT1 and their DRD4 genotypes, respectively. ERN and Pe amplitudes after correct responses and after errors as well as difference amplitudes between errors and correct responses were analyzed. We found a differential effect of DAT1 genotype on the Pe difference amplitude but not on the ERN difference amplitude, while the reverse was true for DRD4 genotype. These findings are in line with predictions from theoretical models of dopaminergic transmission in the brain. They furthermore tie results from clinical investigations of disorders impacting on the dopamine system to genetic variations known to be at-risk genotypes. KW - haplotypes KW - electroencephalography KW - basal ganglia KW - reaction time KW - dopaminergics KW - dopamine KW - ADHD KW - research errors Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137930 VL - 6 IS - 12 ER - TY - JOUR A1 - Biehl, Stefanie C. A1 - Ehlis, Ann-Christine A1 - Müller, Laura D. A1 - Niklaus, Andrea A1 - Pauli, Paul A1 - Herrmann, Martin J. T1 - The impact of task relevance and degree of distraction on stimulus processing JF - BMC Neuroscience N2 - Background The impact of task relevance on event-related potential amplitudes of early visual processing was previously demonstrated. Study designs, however, differ greatly, not allowing simultaneous investigation of how both degree of distraction and task relevance influence processing variations. In our study, we combined different features of previous tasks. We used a modified 1-back task in which task relevant and task irrelevant stimuli were alternately presented. The task irrelevant stimuli could be from the same or from a different category as the task relevant stimuli, thereby producing high and low distracting task irrelevant stimuli. In addition, the paradigm comprised a passive viewing condition. Thus, our paradigm enabled us to compare the processing of task relevant stimuli, task irrelevant stimuli with differing degrees of distraction, and passively viewed stimuli. EEG data from twenty participants was collected and mean P100 and N170 amplitudes were analyzed. Furthermore, a potential connection of stimulus processing and symptoms of attention deficit hyperactivity disorder (ADHD) was investigated. Results Our results show a modulation of peak N170 amplitudes by task relevance. N170 amplitudes to task relevant stimuli were significantly higher than to high distracting task irrelevant or passively viewed stimuli. In addition, amplitudes to low distracting task irrelevant stimuli were significantly higher than to high distracting stimuli. N170 amplitudes to passively viewed stimuli were not significantly different from either kind of task irrelevant stimuli. Participants with more symptoms of hyperactivity and impulsivity showed decreased N170 amplitudes across all task conditions. On a behavioral level, lower N170 enhancement efficiency was significantly correlated with false alarm responses. Conclusions Our results point to a processing enhancement of task relevant stimuli. Unlike P100 amplitudes, N170 amplitudes were strongly influenced by enhancement and enhancement efficiency seemed to have direct behavioral consequences. These findings have potential implications for models of clinical disorders affecting selective attention, especially ADHD. KW - Selective attention KW - Working memory KW - Cognitive control KW - P100 KW - N170 KW - ADHD Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97271 UR - http://www.biomedcentral.com/1471-2202/14/107 ER - TY - JOUR A1 - Biehl, Stefanie C. A1 - Merz, Christian J. A1 - Dresler, Thomas A1 - Heupel, Julia A1 - Reichert, Susanne A1 - Jacob, Christian P. A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Increase or Decrease of fMRI Activity in Adult Attention Deficit/ Hyperactivity Disorder: Does It Depend on Task Difficulty? JF - International Journal of Neuropsychopharmacology N2 - 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. KW - working memory KW - clinical trial KW - child memory KW - short-term methylphenidate brain KW - methylphenidate KW - adult attention deficit/hyperactivity disorder KW - fMRI KW - functional magnetic resonance imaging Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147551 VL - 19 IS - 10 ER - TY - JOUR A1 - Biere, Silvia A1 - Kranz, Thorsten M. A1 - Matura, Silke A1 - Petrova, Kristiyana A1 - Streit, Fabian A1 - Chiocchetti, Andreas G. A1 - Grimm, Oliver A1 - Brum, Murielle A1 - Brunkhorst-Kanaan, Natalie A1 - Oertel, Viola A1 - Malyshau, Aliaksandr A1 - Pfennig, Andrea A1 - Bauer, Michael A1 - Schulze, Thomas G. A1 - Kittel-Schneider, Sarah A1 - Reif, Andreas T1 - Risk Stratification for Bipolar Disorder Using Polygenic Risk Scores Among Young High-Risk Adults JF - Frontiers in Psychiatry N2 - Objective: Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD. Methods: A final sample of 185 young, high-risk German adults (aged 18–35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes. Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls. Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification. KW - polygenic risk score KW - bipolar disorder KW - genetic phenotypes KW - depression KW - ADHD KW - early recognition Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214976 VL - 11 ER - TY - JOUR A1 - Biernacka, J. M. A1 - Sangkuhl, K. A1 - Jenkins, G. A1 - Whaley, R. M. A1 - Barman, P. A1 - Batzler, A. A1 - Altman, R. B. A1 - Arolt, V. A1 - Brockmöller, J. A1 - Chen, C. H. A1 - Domschke, K. A1 - Hall-Flavin, D. K. A1 - Hong, C. J. A1 - Illi, A. A1 - Ji, Y. A1 - Kampman, O. A1 - Kinoshita, T. A1 - Leinonen, E. A1 - Liou, Y. J. A1 - Mushiroda, T. A1 - Nonen, S. A1 - Skime, M. K. A1 - Wang, L. A1 - Baune, B. T. A1 - Kato, M. A1 - Liu, Y. L. A1 - Praphanphoj, V. A1 - Stingl, J. C. A1 - Tsai, S. J. A1 - Kubo, M. A1 - Klein, T. E. A1 - Weinshilboum, R. T1 - The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response JF - Translational Psychiatry N2 - Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N = 2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P = 5.03E - 08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted. KW - major depressive disorder KW - genetic variation KW - schizophrenia KW - neuregulin-1 KW - population KW - microcephalin 1 KW - susceptibility KW - metaanalysis KW - MCPH1 KW - loci Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143223 VL - 5 IS - e553 ER - TY - JOUR A1 - Boehme, Stephanie A1 - Ritter, Viktoria A1 - Tefikow, Susan A1 - Stangier, Ulrich A1 - Strauss, Bernhard A1 - Miltner, Wolfgang H. R. A1 - Straube, Thomas T1 - Neural correlates of emotional interference in social anxiety disorder JF - PLoS ONE N2 - Disorder-relevant but task-unrelated stimuli impair cognitive performance in social anxiety disorder (SAD); however, time course and neural correlates of emotional interference are unknown. The present study investigated time course and neural basis of emotional interference in SAD using event-related functional magnetic resonance imaging (fMRI). Patients with SAD and healthy controls performed an emotional stroop task which allowed examining interference effects on the current and the succeeding trial. Reaction time data showed an emotional interference effect in the current trial, but not the succeeding trial, specifically in SAD. FMRI data showed greater activation in the left amygdala, bilateral insula, medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex (ACC), and left opercular part of the inferior frontal gyrus during emotional interference of the current trial in SAD patients. Furthermore, we found a positive correlation between patients' interference scores and activation in the mPFC, dorsal ACC and left angular/supramarginal gyrus. Taken together, results indicate a network of brain regions comprising amygdala, insula, mPFC, ACC, and areas strongly involved in language processing during the processing of task-unrelated threat in SAD. However, specifically the activation in mPFC, dorsal ACC, and left angular/supramarginal gyrus is associated with the strength of the interference effect, suggesting a cognitive network model of attentional bias in SAD. This probably comprises exceeded allocation of attentional resources to disorder-related information of the presented stimuli and increased self-referential and semantic processing of threat words in SAD. KW - threat-related stimuli KW - prefrontal cortex KW - stroop interference KW - processing bias KW - phobia KW - single subject KW - cognitive control KW - amygdala response KW - cytoarchitectonic maps KW - anterior cingulate cortex Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148534 VL - 10 IS - 6 ER - TY - JOUR A1 - Bonn, M. A1 - Schmitt, A. A1 - Lesch, K.-P. A1 - Van Bockstaele, E. J. A1 - Asan, E. T1 - Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei JF - Brain Structure and Function N2 - Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30–40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala. KW - NPY KW - serotonergic system KW - amygdala KW - anxiety Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132591 VL - 218 IS - 2 ER - TY - JOUR A1 - Bonn, Maria A1 - Schmitt, Angelika A1 - Asan, Esther T1 - Double and triple in situ hybridization for coexpression studies: combined fluorescent and chromogenic detection of neuropeptide Y (NPY) and serotonin receptor subtype mRNAs expressed at different abundance levels JF - Histochemistry and Cell Biology N2 - Multiple fluorescence in situ hybridization is the method of choice for studies aimed at determining simultaneous production of signal transduction molecules and neuromodulators in neurons. In our analyses of the monoamine receptor mRNA expression of peptidergic neurons in the rat telencephalon, double tyramide-signal-amplified fluorescence in situ hybridization delivered satisfactory results for coexpression analysis of neuropeptide Y (NPY) and serotonin receptor 2C (5-HT2C) mRNA, a receptor subtype expressed at high-to-moderate abundance in the regions analyzed. However, expression of 5-HT1A mRNA, which is expressed at comparatively low abundance in many telencephalic areas, could not be unequivocally identified in NPY mRNA-reactive neurons due to high background and poor signal-to-noise ratio in fluorescent receptor mRNA detections. Parallel chromogenic in situ hybridization provided clear labeling for 5-HT1A mRNA and additionally offered the possibility to monitor the chromogen deposition at regular time intervals to determine the optimal signal-to-noise ratio. We first developed a double labeling protocol combining fluorescence and chromogenic in situ hybridization and subsequently expanded this variation to combine double fluorescence and chromogenic in situ hybridization for triple labelings. With this method, we documented expression of 5-HT2C and/or 5-HT1A in subpopulations of telencephalic NPY-producing neurons. The method developed in the present study appears suitable for conventional light and fluorescence microscopy, combines advantages of fluorescence and chromogenic in situ hybridization protocols and thus provides a reliable non-radioactive alternative to previously published multiple labeling methods for coexpression analyses in which one mRNA species requires highly sensitive detection. KW - triple in situ hybridization KW - Coexpression KW - NPY KW - 5-HT1A KW - 5-HT2C Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126720 VL - 137 IS - 1 ER - TY - JOUR A1 - Bonn, Maria A1 - Schmitt, Angelika A1 - Asan, Esther T1 - Double and triple in situ hybridization for coexpression studies: combined fluorescent and chromogenic detection of neuropeptide Y (NPY) and serotonin receptor subtype mRNAs expressed at different abundance levels JF - Histochemistry and Cell Biology N2 - Multiple fluorescence in situ hybridization is the method of choice for studies aimed at determining simultaneous production of signal transduction molecules and neuromodulators in neurons. In our analyses of the monoamine receptor mRNA expression of peptidergic neurons in the rat telencephalon, double tyramide-signal-amplified fluorescence in situ hybridization delivered satisfactory results for coexpression analysis of neuropeptide Y (NPY) and serotonin receptor 2C (5-HT2C) mRNA, a receptor subtype expressed at high-to-moderate abundance in the regions analyzed. However, expression of 5-HT1A mRNA, which is expressed at comparatively low abundance in many telencephalic areas, could not be unequivocally identified in NPY mRNA-reactive neurons due to high background and poor signal-to-noise ratio in fluorescent receptor mRNA detections. Parallel chromogenic in situ hybridization provided clear labeling for 5-HT1A mRNA and additionally offered the possibility to monitor the chromogen deposition at regular time intervals to determine the optimal signal-to-noise ratio. We first developed a double labeling protocol combining fluorescence and chromogenic in situ hybridization and subsequently expanded this variation to combine double fluorescence and chromogenic in situ hybridization for triple labelings. With this method, we documented expression of 5-HT2C and/or 5-HT1A in subpopulations of telencephalic NPY-producing neurons. The method developed in the present study appears suitable for conventional light and fluorescence microscopy, combines advantages of fluorescence and chromogenic in situ hybridization protocols and thus provides a reliable non-radioactive alternative to previously published multiple labeling methods for coexpression analyses in which one mRNA species requires highly sensitive detection. KW - 5-HT1A KW - NPY KW - coexpression KW - triple in situ hybridization KW - 5-HT2C Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127080 VL - 137 IS - 1 ER - TY - JOUR A1 - Bonn, Maria A1 - Schmitt, Angelika A1 - Asan, Esther T1 - Double and triple in situ hybridization for coexpression studies: combined fluorescent and chromogenic detection of neuropeptide Y (NPY) and serotonin receptor subtype mRNAs expressed at different abundance levels JF - Histochemistry and Cell Biology N2 - Multiple fluorescence in situ hybridization is the method of choice for studies aimed at determining simultaneous production of signal transduction molecules and neuromodulators in neurons. In our analyses of the monoamine receptor mRNA expression of peptidergic neurons in the rat telencephalon, double tyramide-signal-amplified fluorescence in situ hybridization delivered satisfactory results for coexpression analysis of neuropeptide Y (NPY) and serotonin receptor 2C (5-HT2C) mRNA, a receptor subtype expressed at high-to-moderate abundance in the regions analyzed. However, expression of 5-HT1A mRNA, which is expressed at comparatively low abundance in many telencephalic areas, could not be unequivocally identified in NPY mRNA-reactive neurons due to high background and poor signal-to-noise ratio in fluorescent receptor mRNA detections. Parallel chromogenic in situ hybridization provided clear labeling for 5-HT1A mRNA and additionally offered the possibility to monitor the chromogen deposition at regular time intervals to determine the optimal signal-to-noise ratio. We first developed a double labeling protocol combining fluorescence and chromogenic in situ hybridization and subsequently expanded this variation to combine double fluorescence and chromogenic in situ hybridization for triple labelings. With this method, we documented expression of 5-HT2C and/or 5-HT1A in subpopulations of telencephalic NPY-producing neurons. The method developed in the present study appears suitable for conventional light and fluorescence microscopy, combines advantages of fluorescence and chromogenic in situ hybridization protocols and thus provides a reliable non-radioactive alternative to previously published multiple labeling methods for coexpression analyses in which one mRNA species requires highly sensitive detection. KW - Triple in situ hybridization KW - Coexpression KW - NPY KW - 5-HT1A KW - 5-HT2C Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135229 VL - 137 IS - 1 ER - TY - JOUR A1 - Borchers, Svenja A1 - Müller, Laura A1 - Synofzik, Matthis A1 - Himmelbach, Marc T1 - Guidelines and quality measures for the diagnosis of optic ataxia JF - Frontiers in Human Neuroscience N2 - Since the first description of a systematic mis-reaching by Balint in 1909, a reasonable number of patients showing a similar phenomenology, later termed optic ataxia (OA), has been described. However, there is surprising inconsistency regarding the behavioral measures that are used to detect OA in experimental and clinical reports, if the respective measures are reported at all. A typical screening method that was presumably used by most researchers and clinicians, reaching for a target object in the peripheral visual space, has never been evaluated. We developed a set of instructions and evaluation criteria for the scoring of a semi-standardized version of this reaching task. We tested 36 healthy participants, a group of 52 acute and chronic stroke patients, and 24 patients suffering from cerebellar ataxia. We found a high interrater reliability and a moderate test-retest reliability comparable to other clinical instruments in the stroke sample. The calculation of cut-off thresholds based on healthy control and cerebellar patient data showed an unexpected high number of false positives in these samples due to individual outliers that made a considerable number of errors in peripheral reaching. This study provides first empirical data from large control and patient groups for a screening procedure that seems to be widely used but rarely explicitly reported and prepares the grounds for its use as a standard tool for the description of patients who are included in single case or group studies addressing optic ataxia similar to the use of neglect, extinction, or apraxia screening tools. KW - systems KW - deficit KW - target KW - damage KW - delay KW - posterior cortical atrophy KW - Balints-Syndrome KW - hand KW - impairments KW - reliability KW - cerebellar atrophy KW - cerebellar ataxia KW - cerebellum KW - parietal lobe KW - optic ataxia KW - beside test Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122439 SN - 1662-5161 VL - 7 IS - 324 ER - TY - JOUR A1 - Braun, Alexandra A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Pauli, Paul A1 - Wabel, Thomas A1 - Üçeyler, Nurcan A1 - Sommer, Claudia T1 - Relevance of Religiosity for Coping Strategies and Disability in Patients with Fibromyalgia Syndrome JF - Journal of Religion and Health N2 - Coping strategies are essential for the outcome of chronic pain. This study evaluated religiosity in a cohort of patients with fibromyalgia syndrome (FMS), its effect on pain and other symptoms, on coping and FMS-related disability. A total of 102 FMS patients were recruited who filled in questionnaires, a subgroup of 42 patients participated in a face-to-face interview, and data were evaluated by correlation and regression analyses. Few patients were traditionally religious, but the majority believed in a higher existence and described their spirituality as "transcendence conviction". The coping strategy "praying-hoping" and the ASP dimension "religious orientation" (r = 0.5, P < 0.05) showed a significant relationship independent of the grade of religiosity (P < 0.05). A high grade of belief in a higher existence was negatively associated with the choice of ignoring as coping strategy (r = - 0.4, P < 0.05). Mood and affect-related variables had the highest impact on disability (b = 0.5, P < 0.05). In this cohort, the grade of religiosity played a role in the choice of coping strategies, but had no effects on health and mood outcome. KW - Fibromyalgia syndrome KW - religiosity KW - coping KW - disability Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269135 SN - 1573-6571 VL - 61 IS - 1 ER - TY - JOUR A1 - Brem, Silvia A1 - Grünblatt, Edna A1 - Drechsler, Renate A1 - Riederer, Peter A1 - Walitza, Susanne T1 - The neurobiological link between OCD and ADHD JF - Attention Deficit and Hyperactivity Disorders N2 - Obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) are two of the most common neuropsychiatric diseases in paediatric populations. The high comorbidity of ADHD and OCD with each other, especially of ADHD in paediatric OCD, is well described. OCD and ADHD often follow a chronic course with persistent rates of at least 40–50 %. Family studies showed high heritability in ADHD and OCD, and some genetic findings showed similar variants for both disorders of the same pathogenetic mechanisms, whereas other genetic findings may differentiate between ADHD and OCD. Neuropsychological and neuroimaging studies suggest that partly similar executive functions are affected in both disorders. The deficits in the corresponding brain networks may be responsible for the perseverative, compulsive symptoms in OCD but also for the disinhibited and impulsive symptoms characterizing ADHD. This article reviews the current literature of neuroimaging, neurochemical circuitry, neuropsychological and genetic findings considering similarities as well as differences between OCD and ADHD. KW - OCD KW - ADHD KW - neuroimaging KW - genetics KW - neuropsychology KW - fMRI KW - MRI KW - EEG KW - neurobiology Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121312 VL - 6 IS - 3 ER - TY - JOUR A1 - Breuer, René A1 - Mattheisen, Manuel A1 - Frank, Josef A1 - Krumm, Bertram A1 - Treutlein, Jens A1 - Kassem, Layla A1 - Strohmaier, Jana A1 - Herms, Stefan A1 - Mühleisen, Thomas W. A1 - Degenhardt, Franziska A1 - Cichon, Sven A1 - Nöthen, Markus M. A1 - Karypis, George A1 - Kelsoe, John A1 - Greenwood, Tiffany A1 - Nievergelt, Caroline A1 - Shilling, Paul A1 - Shekhtman, Tatyana A1 - Edenberg, Howard A1 - Craig, David A1 - Szelinger, Szabolcs A1 - Nurnberger, John A1 - Gershon, Elliot A1 - Alliey-Rodriguez, Ney A1 - Zandi, Peter A1 - Goes, Fernando A1 - Schork, Nicholas A1 - Smith, Erin A1 - Koller, Daniel A1 - Zhang, Peng A1 - Badner, Judith A1 - Berrettini, Wade A1 - Bloss, Cinnamon A1 - Byerley, William A1 - Coryell, William A1 - Foroud, Tatiana A1 - Guo, Yirin A1 - Hipolito, Maria A1 - Keating, Brendan A1 - Lawson, William A1 - Liu, Chunyu A1 - Mahon, Pamela A1 - McInnis, Melvin A1 - Murray, Sarah A1 - Nwulia, Evaristus A1 - Potash, James A1 - Rice, John A1 - Scheftner, William A1 - Zöllner, Sebastian A1 - McMahon, Francis J. A1 - Rietschel, Marcella A1 - Schulze, Thomas G. T1 - Detecting significant genotype–phenotype association rules in bipolar disorder: market research meets complex genetics JF - International Journal of Bipolar Disorders N2 - Background Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype–phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. Results Two of these rules—one associated with eating disorder and the other with anxiety—remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. Conclusion Our approach detected novel specific genotype–phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype–phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts. KW - bipolar disorder KW - subphenotypes KW - rule discovery KW - data mining KW - genotype-phenotype patterns Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220509 VL - 6 ER - TY - JOUR A1 - Brunkhorst-Kanaan, Nathalie A1 - Trautmann, Sandra A1 - Schreiber, Yannick A1 - Thomas, Dominique A1 - Kittel-Schneider, Sarah A1 - Gurke, Robert A1 - Geisslinger, Gerd A1 - Reif, Andreas A1 - Tegeder, Irmgard T1 - Sphingolipid and endocannabinoid profiles in adult attention deficit hyperactivity disorder JF - Biomedicines N2 - Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool. KW - attention deficit hyperactivity disorder KW - endocannabinoids KW - ceramides KW - bipolar disorder KW - major depression KW - tandem mass spectrometry Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246080 SN - 2227-9059 VL - 9 IS - 9 ER - TY - JOUR A1 - Buff, Christine A1 - Brinkmann, Leonie A1 - Bruchmann, Maximilian A1 - Becker, Michael P.I. A1 - Tupak, Sara A1 - Herrmann, Martin J. A1 - Straube, Thomas T1 - Activity alterations in the bed nucleus of the stria terminalis and amygdala during threat anticipation in generalized anxiety disorder JF - Social Cognitive and Affective Neuroscience N2 - Sustained anticipatory anxiety is central to Generalized Anxiety Disorder (GAD). During anticipatory anxiety, phasic threat responding appears to be mediated by the amygdala, while sustained threat responding seems related to the bed nucleus of the stria terminalis (BNST). Although sustained anticipatory anxiety in GAD patients was proposed to be associated with BNST activity alterations, firm evidence is lacking. We aimed to explore temporal characteristics of BNST and amygdala activity during threat anticipation in GAD patients. Nineteen GAD patients and nineteen healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during a temporally unpredictable threat anticipation paradigm. We defined phasic and a systematic variation of sustained response models for blood oxygen level-dependent responses during threat anticipation, to disentangle temporally dissociable involvement of the BNST and the amygdala. GAD patients relative to HC responded with increased phasic amygdala activity to onset of threat anticipation and with elevated sustained BNST activity that was delayed relative to the onset of threat anticipation. Both the amygdala and the BNST displayed altered responses during threat anticipation in GAD patients, albeit with different time courses. The results for the BNST activation hint towards its role in sustained threat responding, and contribute to a deeper understanding of pathological sustained anticipatory anxiety in GAD. KW - medicine KW - anticipatory anxiety KW - anxiety KW - fMRI KW - sustained threat responding KW - phasic threat responding Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173298 VL - 12 IS - 11 ER - TY - JOUR A1 - Bürger, Arne A1 - Schoenfeld, Cornelia von A1 - Scheiner, Christin A1 - Seidel, Alexandra A1 - Wasserscheid, Antonia A1 - Gad, Doreya A1 - Kittel-Schneider, Sarah A1 - Romanos, Marcel A1 - Reiter, Andrea M. F. T1 - Universal prevention for non-suicidal self-injury in adolescents is scarce - A systematic review JF - Frontiers in Psychiatry N2 - Non-suicidal self-injury (NSSI) during adolescence is a high-risk marker for the development and persistence of mental health problems and has been recognized as a significant public health problem. Whereas targeted prevention has indeed shown to be effective in reducing NSSI and improve mental health problems, access to such programs is limited. By face validity, universal prevention of NSSI seems an ideal starting point for a stepped-care model to circumvent a lack of resources in the medical care system. However, it is yet unclear how effective such approaches are. Here, we provide a summary of existing work on universal prevention of NSSI in adolescents younger than 21 years based on a systematic literature search. We found that only seven studies are available. None of the programs evaluated was found to be effective in reducing the incidence or frequency of NSSI. After providing a comprehensive summary of the existing work, we evaluate the fact that existing work primarily focusses on selected/targeted prevention and on psychoeducational methods. We derive implications for future directions in the field of universal prevention of NSSI. KW - non-suicidal self-injury KW - NSSI KW - emotion regulation KW - prevention KW - universal prevention KW - adolescence KW - mental health Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357490 VL - 14 ER - TY - THES A1 - Cabello González, Victoria T1 - From behavioral to neurobiological characterization of Rsk2 knockout mice as an animal model for Coffin-Lowry syndrome T1 - Vom Verhalten bis zur neurobiologischen Charakterisierung von Rsk2-defizienten Mäusen, einem Tiermodell für das Coffin-Lowry Syndrom N2 - Coffin-Lowry syndrome is a rare syndromic form of X-linked mental retardation caused by heterogeneous loss-of-function mutations in the gene RPS6KA3 that encodes the RSK2 protein. Clinical features are delayed motor development, small height, progressive skeletal malformations and mental retardation. Rsk2 deficiency affects behavioral, cellular and molecular functions. To characterize and investigate how this deficiency affects these functions, we made a series of experiments using Rsk2-deficient mice as the animal model for Coffin-Lowry syndrome. We applied a battery of behavioral tests and included the use of the IntelliCage for the first time as a behavioral paradigm to study anxiety-like behavior and depression-like behavior in Rsk2-deficient mice. Results from the conventional behavioral tests and from the IntelliCage indicate that Rsk2-deficient mice may have an anti-anxiety and anti-depressive phenotype. We evaluated in Rsk2 deficient mice the relative gene expression of a set of genes coding for proteins related to RSK2 which are involved in fear memory, synaptic plasticity, neurogenesis, learning, emotional behavior and stress. We found gene expression alterations in the prefrontal cortex and striatum. These results suggest that RSK2 may be involved in the expression of the genes. RSK2 is known to be related to monoamine neurotransmitter function. We measured the levels of dopamine, serotonin and noradrenaline/norepinephrine and their metabolites in different brain regions of Rsk2-deficient mice. We found differences in the dopaminergic and noradrenergic systems suggesting an increased or decreased activity of these neurotransmission systems as a result of Rsk2 deficiency. Adult neurogenesis is a form of neuronal plasticity and a multi-step process of cell development. We explored if this form of neuronal plasticity was affected by Rsk2-deficiency. Our results indicate that adult hippocampal neurogenesis is not influenced by lifelong Rsk2 deficiency. It would be worth to analyze in the future other aspects of neuroplasticity. We have confirmed, that behavioral characteristics of Rsk2-deficient mice make them an interesting model to study the Coffin-Lowry syndrome by extending the behavioral characterization on the emotional level. Furthermore, we have extended the characterization of the model on a molecular level, opening new opportunities to study and understand the pathophysiological basis of the Coffin-Lowry syndrome. N2 - Das Coffin-Lowry Syndrom ist eine seltene syndromale Form X-gebunden vererbter geistiger Behinderung, verursacht durch heterogene loss of function Mutationen im RPS6KA3-Gen, welches für das RSK2-Protein kodiert. Klinische Charakteristika sind eine verzögerte motorische Entwicklung, eine geringe Körpergröße, fortschreitende Skelett- Malformationen und geistige Behinderung. Die Rsk2-Mutation hat einen Einfluss auf das Verhalten, auf zelluläre und molekulare Funktionen. Um zu charakterisieren und zu untersuchen, wie diese Defizienz diese Funktionen beeinflusst, führten wir eine Reihe von Experimenten durch und verwendeten Rsk2-defiziente Mäuse als Tiermodell für das Coffin-Lowry Syndrom. Wir wandten eine Reihe von Verhaltens-Tests an, einschließlich erstmals den IntelliCage als ein Verhaltensparadigma, um Angst-ähnliches und Depressions-ähnliches Verhalten in Rsk2-defizienten Mäusen zu untersuchen. Ergebnisse konventioneller Verhaltenstests und aus dem IntelliCage sprechen dafür, dass Rsk2-defiziente Mäuse einen „anti-ängstlichen“ und „anti-depressiven“ Phänotyp haben. Wir haben bei Rsk2-defizienten Mäusen die Expression einer Reihe von Genen untersucht, die für Proteine kodieren, die mit RSK2 in Zusammenhang stehen und darüber hinaus eine Bedeutung für das Angst-Gedächtnis, synaptische Plastizität, Neurogenese, Lernen, emotionales Verhalten und Stress haben. Im präfrontalen Kortex und Striatum konnten wir Genexpressionsunterschiede zwischen Rsk2-Wildtyp- und Knockout-Mäusen detektieren. Diese Ergebnisse sprechen dafür, dass RSK2 eine Rolle bei der Expression dieser Gene spielt. Es ist bekannt, dass RSK2 eine Rolle für die monoaminerge Neurotransmitter-Funktion spielt. Deshalb haben wir die Konzentration von Dopamin, Serotonin und Noradrenalin/Norepinephrin und ihrer Metaboliten in verschiedenen Gehirnregionen von Rsk2-defizienten Mäuse untersucht. Wir haben Unterschiede im dopaminergen und noradrenergen System gefunden, was auf eine gesteigerte oder verminderte Aktivität dieser Neurotransmittersysteme als Folge der Rsk2-Defizienz hinweist. Adulte Neurogenese ist eine Form neuronaler Plastizität und ein mehr-stufiger Prozess zellulärer Entwicklung. Unsere Untersuchungen der adulten Neurogenese im Hippocampus zeigten, dass sie nicht durch eine lebenslange Rsk2-Defizienz beeinflusst wird. In Zukunft wäre es jedoch sinnvoll, andere Aspekte der Neuroplastizität zu analysieren. Durch unsere Verhaltensstudien wurde die Charakterisierung der Rsk2-defizienten Mäuse vor allem im emotionalen Bereich stark erweitert, wodurch wir bestätigen konnten, dass diese Mauslinie ein interessantes Modell zur Untersuchung des Coffein-Lowry Syndroms ist. Darüber hinaus haben wir die Charakterisierung des Modells auf der molekularen Ebene erweitert und damit neue Möglichkeiten eröffnet, die pathophysiologische Grundlage des Coffin-Lowry Syndroms zu studieren. KW - Knockout KW - Maus KW - Coffin-Lowry syndrome KW - Animal behavior IntelliCage system KW - RSK2 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171275 ER - TY - JOUR A1 - Cadar, Dániel A1 - Jellinger, Kurt A. A1 - Riederer, Peter A1 - Strobel, Sabrina A1 - Monoranu, Camelia-Maria A1 - Tappe, Dennis T1 - No metagenomic evidence of causative viral pathogens in postencephalitic parkinsonism following encephalitis lethargica JF - Microorganisms N2 - Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP. KW - postencephalitic parkinsonism KW - encephalitis lethargica KW - von Economo KW - metagenomics KW - neuropathology KW - tauopathy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245074 SN - 2076-2607 VL - 9 IS - 8 ER - TY - JOUR A1 - Conzelmann, Annette A1 - Reif, Andreas A1 - Jacob, Christian A1 - Weyers, Peter A1 - Lesch, Klaus-Peter A1 - Lutz, Beat A1 - Pauli, Paul T1 - A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity JF - Psychopharmacology N2 - RATIONALE: The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. OBJECTIVES: Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. METHODS: We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. RESULTS: Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. CONCLUSIONS: Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders. KW - startle reflex KW - endocannabinoid KW - FAAH KW - genetics KW - emotion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126845 VL - 224 IS - 4 ER - TY - JOUR A1 - Conzelmann, Annette A1 - Reif, Andreas A1 - Jacob, Christian A1 - Weyers, Peter A1 - Lesch, Klaus-Peter A1 - Lutz, Beat A1 - Pauli, Paul T1 - A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional–motivational reactivity JF - Psychopharmacology N2 - Rationale The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional–motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional–motivational reactivity is complex and bidirectional due to upcoming compensatory processes. Objectives Therefore, we further investigated the relationship of the FAAH polymorphism and emotional–motivational reactivity in humans. Methods We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. Results Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. Conclusions Our findings emphasize the bidirectionality and thorough examination of the eCB system’s impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders. KW - startle reflex KW - FAAH KW - genetics KW - endocannabinoid KW - emotion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129936 VL - 224 IS - 4 ER - TY - JOUR A1 - Couch, Yvonne A1 - Trofimov, Alexander A1 - Markova, Natalyia A1 - Nikolenko, Vladimir A1 - Steinbusch, Harry W. A1 - Chekhonin, Vladimir A1 - Schroeter, Careen A1 - Lesch, Klaus-Peter A1 - Anthony, Daniel C. A1 - Strekalova, Tatyana T1 - Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice JF - Journal of Neuroinflammation N2 - Background Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive. Methods Changes in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress. Results When combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels. Conclusions It is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours. KW - SERT KW - Chronic stress KW - LPS KW - Aggressive behaviour KW - S-HT KW - Cytokines Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165676 VL - 13 IS - 108 ER - TY - JOUR A1 - Cox-Limpens, Kimberly E. M. A1 - Vles, Johan S. H. A1 - van den Hove, Daniel L. A. A1 - Zimmermann, Luc Ji A1 - Gavilanes, Antonio W. D. T1 - Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia JF - BMC Neuroscience N2 - Background: Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates. Therefore, we investigated whole-genome transcriptional changes in the brain of rats which underwent perinatal asphyxia (PA), and rats where PA was preceded by fetal asphyctic preconditioning (FAPA). Offspring were sacrificed 6 h and 96 h after birth, and whole-genome transcription was investigated using the Affymetrix Gene1.0ST chip. Microarray data were analyzed with the Bioconductor Limma package. In addition to univariate analysis, we performed Gene Set Enrichment Analysis (GSEA) in order to derive results with maximum biological relevance. Results: We observed minimal, 25% or less, overlap of differentially regulated transcripts across different experimental groups which leads us to conclude that the transcriptional phenotype of these groups is largely unique. In both the PA and FAPA group we observe an upregulation of transcripts involved in cellular stress. Contrastingly, transcripts with a function in the cell nucleus were mostly downregulated in PA animals, while we see considerable upregulation in the FAPA group. Furthermore, we observed that histone deacetylases (HDACs) are exclusively regulated in FAPA animals. Conclusions: This study is the first to investigate whole-genome transcription in the neonatal brain after PA alone, and after perinatal asphyxia preceded by preconditioning (FAPA). We describe several genes/pathways, such as ubiquitination and proteolysis, which were not previously linked to preconditioning-induced neuroprotection. Furthermore, we observed that the majority of upregulated genes in preconditioned animals have a function in the cell nucleus, including several epigenetic players such as HDACs, which suggests that epigenetic mechanisms are likely to play a role in preconditioning-induced neuroprotection. KW - Perinatal Asphyxia KW - oxidative stress KW - microarray KW - cerebral artery occlusion KW - ischemic brain injury KW - genomic response KW - protein aggregation KW - immediate early genes KW - neuroprotection KW - tolerance KW - rat KW - expression KW - transient global ischemia KW - ubiquitination KW - epigenetics KW - fetal preconditioning KW - neonatal brain Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116185 VL - 15 ER - TY - JOUR A1 - Dannhäuser, Sven A1 - Mrestani, Achmed A1 - Gundelach, Florian A1 - Pauli, Martin A1 - Komma, Fabian A1 - Kollmannsberger, Philip A1 - Sauer, Markus A1 - Heckmann, Manfred A1 - Paul, Mila M. T1 - Endogenous tagging of Unc-13 reveals nanoscale reorganization at active zones during presynaptic homeostatic potentiation JF - Frontiers in Cellular Neuroscience N2 - Introduction Neurotransmitter release at presynaptic active zones (AZs) requires concerted protein interactions within a dense 3D nano-hemisphere. Among the complex protein meshwork the (M)unc-13 family member Unc-13 of Drosophila melanogaster is essential for docking of synaptic vesicles and transmitter release. Methods We employ minos-mediated integration cassette (MiMIC)-based gene editing using GFSTF (EGFP-FlAsH-StrepII-TEV-3xFlag) to endogenously tag all annotated Drosophila Unc-13 isoforms enabling visualization of endogenous Unc-13 expression within the central and peripheral nervous system. Results and discussion Electrophysiological characterization using two-electrode voltage clamp (TEVC) reveals that evoked and spontaneous synaptic transmission remain unaffected in unc-13\(^{GFSTF}\) 3rd instar larvae and acute presynaptic homeostatic potentiation (PHP) can be induced at control levels. Furthermore, multi-color structured-illumination shows precise co-localization of Unc-13\(^{GFSTF}\), Bruchpilot, and GluRIIA-receptor subunits within the synaptic mesoscale. Localization microscopy in combination with HDBSCAN algorithms detect Unc-13\(^{GFSTF}\) subclusters that move toward the AZ center during PHP with unaltered Unc-13\(^{GFSTF}\) protein levels. KW - active zone KW - Unc-13 KW - MiMIC KW - presynaptic homeostasis KW - nanoarchitecture KW - localization microscopy KW - STORM KW - HDBSCAN Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299440 SN - 1662-5102 VL - 16 ER - TY - JOUR A1 - Danysz, Wojciech A1 - Dekundy, Andrzej A1 - Scheschonka, Astrid A1 - Riederer, Peter T1 - Amantadine: reappraisal of the timeless diamond—target updates and novel therapeutic potentials JF - Journal of Neural Transmission N2 - The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson’s disease symptoms and viral infections. Considering amantadine’s affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington’s disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine’s therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia. KW - Amantadine Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-330133 VL - 128 IS - 2 ER - TY - JOUR A1 - de Jong, Simone A1 - Diniz, Mateus Jose Abdalla A1 - Saloma, Andiara A1 - Gadelha, Ary A1 - Santoro, Marcos L. A1 - Ota, Vanessa K. A1 - Noto, Cristiano A1 - Curtis, Charles A1 - Newhouse, Stephen J. A1 - Patel, Hamel A1 - Hall, Lynsey S. A1 - O'Reilly, Paul F. A1 - Belangero, Sintia I. A1 - Bressan, Rodrigo A. A1 - Breen, Gerome T1 - Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder JF - Communications Biology N2 - Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders. KW - bipolar disorder KW - depression KW - genetic association study KW - genetic linkage study Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223622 VL - 1 ER - TY - JOUR A1 - de Nijs, Laurence A1 - Choe, Kyonghwan A1 - Steinbusch, Hellen A1 - Schijns, Olaf E. M. G. A1 - Dings, Jim A1 - van den Hove, Daniel L. A. A1 - Rutten, Bart P. F. A1 - Hoogland, Govert T1 - DNA methyltransferase isoforms expression in the temporal lobe of epilepsy patients with a history of febrile seizures JF - Clinical Epigenetics N2 - Background Temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) is a common pharmaco-resistant epilepsy referred for adult epilepsy surgery. Though associated with prolonged febrile seizures (FS) in childhood, the neurobiological basis for this relationship is not fully understood and currently no preventive or curative therapies are available. DNA methylation, an epigenetic mechanism catalyzed by DNA methyltransferases (DNMTs), potentially plays a pivotal role in epileptogenesis associated with FS. In an attempt to start exploring this notion, the present cross-sectional pilot study investigated whether global DNA methylation levels (5-mC and 5-hmC markers) and DNMT isoforms (DNMT1, DNMT3a1, and DNMT3a2) expression would be different in hippocampal and neocortical tissues between controls and TLE patients with or without a history of FS. Results We found that global DNA methylation levels and DNMT3a2 isoform expression were lower in the hippocampus for all TLE groups when compared to control patients, with a more significant decrease amongst the TLE groups with a history of FS. Interestingly, we showed that DNMT3a1 expression was severely diminished in the hippocampus of TLE patients with a history of FS in comparison with control and other TLE groups. In the neocortex, we found a higher expression of DNMT1 and DNMT3a1 as well as increased levels of global DNA methylation for all TLE patients compared to controls. Conclusion Together, the findings of this descriptive cross-sectional pilot study demonstrated brain region-specific changes in DNMT1 and DNMT3a isoform expression as well as global DNA methylation levels in human TLE with or without a history of FS. They highlighted a specific implication of DNMT3a isoforms in TLE after FS. Therefore, longitudinal studies that aim at targeting DNMT3a isoforms to evaluate the potential causal relationship between FS and TLE or treatment of FS-induced epileptogenesis seem warranted. KW - febrile seizures KW - temporal lobe epilepsy KW - epigenetics KW - DNA methylation KW - DNA methyltransferases Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223636 VL - 11 ER - TY - JOUR A1 - Deckert, Jürgen A1 - Ozawa, Hiroki T1 - The joint Nagasaki–Würzburg approach to challenges and perspectives in neuropsychiatric and regenerative research JF - Journal of Neural Transmission N2 - No abstract available. KW - neuropsychiatry KW - regenerative research Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235359 SN - 0300-9564 VL - 127 ER - TY - JOUR A1 - Diehl-Schmid, Janine A1 - Licata, Abigail A1 - Goldhardt, Oliver A1 - Förstl, Hans A1 - Yakushew, Igor A1 - Otto, Markus A1 - Anderl-Straub, Sarah A1 - Beer, Ambros A1 - Ludolph, Albert Christian A1 - Landwehrmeyer, Georg Bernhard A1 - Levin, Johannes A1 - Danek, Adrian A1 - Fliessbach, Klaus A1 - Spottke, Annika A1 - Fassbender, Klaus A1 - Lyros, Epameinondas A1 - Prudlo, Johannes A1 - Krause, Bernd Joachim A1 - Volk, Alexander A1 - Edbauer, Dieter A1 - Schroeter, Matthias Leopold A1 - Drzezga, Alexander A1 - Kornhuber, Johannes A1 - Lauer, Martin A1 - Grimmer, Timo T1 - FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations JF - Translational Psychiatry N2 - C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, 18F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD. KW - diagnostic markers KW - psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225308 VL - 9 ER - TY - JOUR A1 - Dischinger, Ulrich A1 - Heckel, Tobias A1 - Bischler, Thorsten A1 - Hasinger, Julia A1 - Königsrainer, Malina A1 - Schmitt-Böhrer, Angelika A1 - Otto, Christoph A1 - Fassnacht, Martin A1 - Seyfried, Florian A1 - Hankir, Mohammed Khair T1 - Roux-en-Y gastric bypass and caloric restriction but not gut hormone-based treatments profoundly impact the hypothalamic transcriptome in obese rats JF - Nutrients N2 - Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation. KW - obesity KW - Roux-en-Y gastric bypass surgery KW - liraglutide KW - PYY3-36 KW - hypothalamic gene expression Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252392 SN - 2072-6643 VL - 14 IS - 1 ER - TY - JOUR A1 - Dittert, Natalie A1 - Hüttner, Sandrina A1 - Polak, Thomas A1 - Herrmann, Martin J. T1 - Augmentation of fear extinction by transcranial direct current stimulation (tDCS) JF - Frontiers in Behavioral Neuroscience N2 - Although posttraumatic stress disorder (PTSD; DSM-V 309.82) and anxiety disorders (DSM-V 300.xx) are widely spread mental disorders, the effectiveness of their therapy is still unsatisfying. Non-invasive brain-stimulation techniques like transcranial direct current stimulation (tDCS) might be an option to improve extinction learning, which is a main functional factor of exposure-based therapy for anxiety disorders. To examine this hypothesis, we used a fear conditioning paradigm with female faces as conditioned stimuli (CS) and a 95-dB female scream as unconditioned stimulus (UCS). We aimed to perform a tDCS of the ventromedial prefrontal cortex (vmPFC), which is mainly involved in the control of extinction-processes. Therefore, we applied two 4 × 4 cm electrodes approximately at the EEG-positions F7 and F8 and used a direct current of 1.5 mA. The 20-min stimulation was started during a 10-min break between acquisition and extinction and went on overall extinction-trials. The healthy participants were randomly assigned in two double-blinded process into two sham stimulation and two verum stimulation groups with opposite current flow directions. To measure the fear reactions, we used skin conductance responses (SCR) and subjective ratings. We performed a generalized estimating equations model for the SCR to assess the impact of tDCS and current flow direction on extinction processes for all subjects that showed a successful conditioning (N = 84). The results indicate that tDCS accelerates early extinction processes with a significantly faster loss of CS+/CS- discrimination. The discrimination loss was driven by a significant decrease in reaction toward the CS+ as well as an increase in reaction toward the CS- in the tDCS verum groups, whereas the sham groups showed no significant reaction changes during this period. Therefore, we assume that tDCS of the vmPFC can be used to enhance early extinction processes successfully. But before it should be tested in a clinical context further investigation is needed to assess the reason for the reaction increase on CS-. If this negative side effect can be avoided, tDCS may be a tool to improve exposure-based anxiety therapies. KW - brain stimulation KW - fear conditioning KW - skin conduction response KW - tDCS KW - ventromedial prefrontal cortex Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176056 VL - 12 IS - 76 ER - TY - JOUR A1 - Domschke, Katharina A1 - Zwanzger, Peter A1 - Rehbein, Maimu A A1 - Steinberg, Christian A1 - Knoke, Kathrin A1 - Dobel, Christian A1 - Klinkenberg, Isabelle A1 - Kugel, Harald A1 - Kersting, Anette A1 - Arolt, Volker A1 - Pantev, Christo A1 - Junghofer, Markus T1 - Magnetoencephalographic correlates of emotional processing in major depression before and after pharmacological treatment JF - International Journal of Neuropsychopharmacology N2 - Background: In major depressive disorder (MDD), electrophysiological and imaging studies suggest reduced neural activity in the parietal and dorsolateral prefrontal cortex regions. In the present study, neural correlates of emotional processing in MDD were analyzed for the first time in a pre-/post-treatment design by means of magnetoencephalography (MEG), allowing for detecting temporal dynamics of brain activation. Methods: Twenty-five medication-free Caucasian in-patients with MDD and 25 matched controls underwent a baseline MEG session with passive viewing of pleasant, unpleasant, and neutral pictures. Fifteen patients were followed-up with a second MEG session after 4 weeks of antidepressant monopharmacotherapy with mirtazapine. The corresponding controls received no intervention between the measurements. The clinical course of depression was assessed using the Hamilton Depression scale. Results: Prior to treatment, an overall neocortical hypoactivation during emotional processing, particularly at the parietal regions and areas at the right temporoparietal junction, as well as abnormal valence-specific reactions at the right parietal and bilateral dorsolateral prefrontal cortex (dlPFC) regions were observed in patients compared to controls. These effects occurred <150ms, suggesting dysfunctional processing of emotional stimuli at a preconscious level. Successful antidepressant treatment resulted in a normalization of the hypoactivation at the right parietal and right temporoparietal regions. Accordingly, both dlPFC regions revealed an increase of activity after therapy. Conclusions: The present study provides neurophysiological evidence for dysfunctional emotional processing in a fronto-parieto-temporal network, possibly contributing to the pathogenesis of MDD. These activation patterns might have the potential to serve as biomarkers of treatment success. KW - dorsolateral prefrontal cortex KW - temporoparietal junction KW - parietal hypoactivation KW - IAPS KW - EEG KW - MEG KW - MDD Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149873 VL - 19 IS - 2 ER - TY - JOUR A1 - Domschke, Katharina A1 - Zwanzger, Peter A1 - Rehbein, Maimu A. A1 - Steinberg, Christian A1 - Knoke, Kathrin A1 - Dobel, Christian A1 - Klinkenberg, Isabelle A1 - Kugel, Harald A1 - Kersting, Anette A1 - Arolt, Volker A1 - Pantev, Christo A1 - Junghofer, Markus T1 - Magnetoencephalographic Correlates of Emotional Processing in Major Depression Before and After Pharmacological Treatment JF - International Journal of Neuropsychopharmacology N2 - Background: In major depressive disorder (MDD), electrophysiological and imaging studies suggest reduced neural activity in the parietal and dorsolateral prefrontal cortex regions. In the present study, neural correlates of emotional processing in MDD were analyzed for the first time in a pre-/post-treatment design by means of magnetoencephalography (MEG), allowing for detecting temporal dynamics of brain activation. Methods: Twenty-five medication-free Caucasian in-patients with MDD and 25 matched controls underwent a baseline MEG session with passive viewing of pleasant, unpleasant, and neutral pictures. Fifteen patients were followed-up with a second MEG session after 4 weeks of antidepressant monopharmacotherapy with mirtazapine. The corresponding controls received no intervention between the measurements. The clinical course of depression was assessed using the Hamilton Depression scale. Results: Prior to treatment, an overall neocortical hypoactivation during emotional processing, particularly at the parietal regions and areas at the right temporoparietal junction, as well as abnormal valence-specific reactions at the right parietal and bilateral dorsolateral prefrontal cortex (dlPFC) regions were observed in patients compared to controls. These effects occurred <150ms, suggesting dysfunctional processing of emotional stimuli at a preconscious level. Successful antidepressant treatment resulted in a normalization of the hypoactivation at the right parietal and right temporoparietal regions. Accordingly, both dlPFC regions revealed an increase of activity after therapy. Conclusions: The present study provides neurophysiological evidence for dysfunctional emotional processing in a fronto-parieto-temporal network, possibly contributing to the pathogenesis of MDD. These activation patterns might have the potential to serve as biomarkers of treatment success. KW - Dorsolateral prefrontal cortex KW - IAPS KW - MDD KW - EEG KW - MEG KW - parietal hypoactivation KW - temporoparietal junction Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165523 VL - 2016 ER - TY - JOUR A1 - Drgonova, Jana A1 - Walther, Donna A1 - Hartstein, G Luke A1 - Bukhari, Mohammad O A1 - Baumann, Michael H A1 - Katz, Jonathan A1 - Hall, F Scott A1 - Arnold, Elizabeth R A1 - Flax, Shaun A1 - Riley, Anthony A1 - Rivero, Olga A1 - Lesch, Klaus-Peter A1 - Troncoso, Juan A1 - Ranscht, Barbara A1 - Uhl, George R T1 - Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice JF - Molecular Medicine N2 - The Cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD. KW - Cadherin (CDH13) KW - CDH13 mRNA KW - Attention Deficit Hyperactivity Disorder (ADHD) KW - CDH13 Expression KW - Human CDH13 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165842 VL - 22 ER - TY - JOUR A1 - Dürner, Julia A1 - Reinecker, Hans A1 - Csef, Herbert T1 - Individual quality of life in patients with multiple myeloma JF - SpringerPlus N2 - Objective: The situation of patients with multiple myeloma, whose treatment often implies high-dose chemotherapy and stem cell transplantation that can be associated with severe symptoms and psychological distress, has gained attention in recent psychooncological research. This study followed an idiographic approach in order to identify the areas of life most relevant for the interviewed myeloma patients’ quality of life (QoL) as well as their current satisfaction with these. Methods: 64 patients took part in semi-structured interviews according to the SEIQoL-DW Manual (Schedule for the Evaluation of Individual Quality of Life – Direct Weighting). Visual analogue scales (VAS) were used to gain additional information about a general assessment of the present QoL. Qualitative data evaluation preceded quantitative processing. Groups were compared according to the time elapsed since diagnosis regarding specified areas of life, satisfaction with these and their relative weighting. SEIQoL-DW-indices were correlated to the VAS to reflect on an interindividually comparable parameter. Results: Personal social relationships were mentioned significantly more often as important for QoL than healthrelated aspects, and in direct comparison were weighted significantly stronger. Regarding the change of areas relevant for QoL over the time elapsed since diagnosis, there was a significant difference between groups concerning the area of spirituality. Satisfaction differed significantly between groups for the field of leisure. Conclusion: The results for the interviewed patients with multiple myeloma point out the need to take into account the importance of social and individual aspects when reflecting on QoL. Similar findings have been reported for different samples. The relevance of an individualized approach is illustrated by the fact that individually named areas of life were rated comparatively strongly in their importance for the patients’ QoL. An overall assessment for the current QoL by means of VAS is regarded as an adequate supplement to the SEIQoL-Profile and an alternative to the SEIQoL-DW-Index. KW - multiple myeloma KW - individual quality of life KW - cancer KW - psychooncology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130529 VL - 2 IS - 397 ER - TY - JOUR A1 - Egetemeir, Johanna A1 - Stenneken, Prisca A1 - Koehler, Saskia A1 - Fallgatter, Andreas J. A1 - Herrmann, Martin J. T1 - Exploring the neural basis of real-life joint action: measuring brain activation during joint table setting with functional near-infrared spectroscopy JF - FRONTIERS IN HUMAN NEUROSCIENCE N2 - Many every-day life situations require two or more individuals to execute actions together. Assessing brain activation during naturalistic tasks to uncover relevant processes underlying such real-life joint action situations has remained a methodological challenge. In the present study, we introduce a novel joint action paradigm that enables the assessment of brain activation during real-life joint action tasks using functional near-infrared spectroscopy (fNIRS). We monitored brain activation of participants who coordinated complex actions with a partner sitting opposite them. Participants performed table setting tasks, either alone (solo action) or in cooperation with a partner (joint action), or they observed the partner performing the task (action observation). Comparing joint action and solo action revealed stronger activation (higher [oxy-Hb]-concentration) during joint action in a number of areas. Among these were areas in the inferior parietal lobule (IPL) that additionally showed an overlap of activation during action observation and solo action. Areas with such a close link between action observation and action execution have been associated with action simulation processes. The magnitude of activation in these IPL areas also varied according to joint action type and its respective demand on action simulation. The results validate fNIRS as an imaging technique for exploring the functional correlates of interindividual action coordination in real-life settings and suggest that coordinating actions in real-life situations requires simulating the actions of the partner. KW - joint action KW - fNIRS KW - neuroimaging KW - social interaction KW - real-life interaction KW - simulation Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137054 N1 - Copyright © 2011 Egetemeir, Stenneken, Koehler, Fallgatter and Herrmann.This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA,which permits use, distribution and reproduction in other forums, provided the original authors and source are credited andother Frontiers conditions are complied with. VL - 5 IS - 9, Artikel 95 ER - TY - THES A1 - Endres, Ralph Julian T1 - Networks of fear: Functional connectivity of the amygdala, the insula and the anterior cingulate cortex in two subtypes of specific phobia T1 - Netzwerke der Angst: Funktionelle Konnektivität der Amygdala, der Insula und des anterioren cingulären Cortex in zwei Subtypen der spezifischen Phobie N2 - Neuroimaging research has highlighted the relevance of well-balanced functional brain interactions as an essential basis for efficient emotion regulation. In contrast, abnormal coupling of fear-processing regions such as the amygdala, the anterior cingulate cortex (ACC) and the insula could be an important feature of anxiety disorders. Although activity alterations of these regions have been frequently reported in specific phobia, little is known about their functional interactions during phobogenic stimulus processing. To explore these interrelationships in two subtypes of specific phobia – i.e., the blood-injection-injury subtype and the animal subtype – functional connectivity (FC) was analyzed in three fMRI studies. Two studies examined fear processing in a dental phobia group (DP), a snake phobia group (SP) and a healthy control group (HC) during visual phobogenic stimuli presentation while a third study investigated differences between auditory and visual stimuli presentation in DP and HC. Due to a priori hypotheses of impaired interactions between the amygdala, the ACC and the insula, a first analysis was conducted to explore the FC within these three regions of interest. Based on emerging evidence of functionally diverse subregions, the ACC was further divided into a subgenual, pregenual and dorsal ACC and the insula was divided into a ventral-anterior, dorsal-anterior and posterior region. Additionally, an exploratory seed-to-voxel analysis using the amygdala, ACC and insula as seeds was conducted to scan for connectivity patterns across the whole brain. The analyses revealed a negative connectivity of the ACC and the amygdala during phobogenic stimulus processing in controls. This connectivity was predominantly driven by the affective ACC subdivision. By contrast, SP was characterized by an increased mean FC between the examined regions. Interestingly, this phenomenon was specific for auditory, but not visual symptom provocation in DP. During visual stimulus presentation, however, DP exhibited further FC alterations of the ACC and the insula with pre- and orbitofrontal regions. These findings mark the importance of balanced interactions between fear-processing regions in specific phobia, particularly of the inhibitory connectivity between the ACC and the amygdala. Theoretically, this is assumed to reflect top-down inhibition by the ACC during emotion regulation. The findings support the suggestion that SP particularly is characterized by excitatory, or missing inhibitory, (para-) limbic connectivity, reflecting an overshooting fear response based on evolutionary conserved autonomic bottom-up pathways. Some of these characteristics applied to DP as well but only under the auditory stimulation, pointing to stimulus dependency. DP was further marked by altered pre- and orbitofrontal coupling with the ACC and the insula which might represent disturbances of superordinate cognitive control on basal emotion processes. These observations strengthen the assumption that DP is predominantly based on evaluation-based fear responses. In conclusion, the connectivity patterns found may depict an intermediate phenotype that possibly confers risks for inappropriate phobic fear responses. The findings presented could also be of clinical interest. Particularly the ACC – amygdala circuit may be used as a predictive biomarker for treatment response or as a promising target for neuroscience-focused augmentation strategies as neurofeedback or repetitive transcranial magnetic stimulation. N2 - Neurowissenschaftliche Erkenntnisse der letzten Jahre verdeutlichten die Relevanz intakter neuronaler Netzwerke als Grundlage adäquater Emotionsregulationsmechanismen. Funktionelle Dysregulationen zwischen angstverarbeitenden Regionen wie der Amygdala, der Insula oder dem anterioren cingulären Cortex (ACC) könnten hingegen einen wichtigen pathophysiologischen Mechanismus von Angststörungen darstellen. Obwohl Aktivitätsunterschiede dieser Regionen wiederholt für spezifische Phobien beschrieben wurden, sind deren funktionelle Interaktionen während phobischer Stimulusverarbeitung kaum erforscht. Zur Untersuchung dieser Interaktionen in zwei Subtypen der spezifischen Phobie – dem Blut-Spritzen-Verletzungs-Typus und dem Tier-Typus – wurden im Rahmen dieser Arbeit funktionelle Konnektivitäts-Analysen (FK) anhand dreier fMRT- (funktionelle Magnetresonanztomographie) Studien durchgeführt. Zwei Studien untersuchten die neurale Verarbeitung visueller phobischer Stimuli in einer dentalphobischen Gruppe (DP), einer schlangenphobischen Gruppe (SP) sowie einer Kontrollgruppe (KG). Ergänzend verglich eine dritte Studie den Einfluss visueller und akustischer Stimuli für die DP und eine KG. Basierend auf der a priori-Hypothese einer veränderten FK zwischen der Amygdala, der Insula und dem ACC wurden deren spezifische Konnektivitätsmuster untersucht. Aufgrund funktionell unterschiedlicher Subregionen erfolgte eine Untergliederung des ACC in eine subgenuale, perigenuale und dorsalen Region. Analog dazu wurde die Insula in eine ventral-anteriore, dorsal-anteriore und posteriore Region unterteilt. Um darüberhinausgehender Konnektivitätsmuster über das gesamte Gehirn zu ermitteln, wurde eine abschließende Seed-to-Voxel-Analyse mit den Seeds Amygdala, Insula und ACC durchgeführt. In der Auswertung zeigte sich eine negative FK der Amygdala und des ACC während phobischer Stimulusverarbeitung in der KG, die insbesondere auf die ventrale Division des ACC zurückzuführen war. Die phobischen Gruppen hingegen waren im Vergleich zu der Kontrollgruppe durch eine erhöhte Konnektivität der untersuchten Regionen gekennzeichnet. Dieser Effekt war bei der DP spezifisch für die akustische Stimulusmodalität. Bei visueller Stimuluspräsentation zeigten sich hingegen veränderte Konnektivitätsmuster des ACC und der Insula mit prä- und orbitofrontalen Regionen. Insbesondere die negative FK der Amygdala und des ACC, die theoretisch auf einer top-down-Inhibition des ACC über die Amygdala basiert, erscheint einen wichtigen Bestandteil einer effektiven emotionalen Kontrolle darzustellen. In beiden phobischen Gruppen fehlte diese Inhibition. Die erhöhte FK (para-)limbischer Konnektivität der SP könnte hingegen die verstärkte Rekrutierung autonomischer bottom-up-Prozesse als zugrundeliegendem Mechanismus der überschießenden und irrationalen Angstreaktion repräsentieren. Diese Charakteristika konnten in der DP nur für die akustische Stimulusmodalität beobachtet werden. Während der visuellen Stimuluspräsentation war die DP durch Dysregulationen prä- und orbitofrontaler Regionen gekennzeichnet, welche eine beeinträchtigte kognitive Kontrolle über grundlegende Emotionsprozesse widerspiegeln könnte. Dies entspricht der Annahme, dass die DP vor allem durch evaluationsbasierte Furchtreaktionen gekennzeichnet ist, während in der SP als Vertreter des Tier-Typus evolutionär konservierte, limbische Prozesse dominieren. Zusammenfassend bestätigen die Ergebnisse die Bedeutung funktioneller Netzwerke in der spezifischen Phobie, wobei die gefundenen Konnektivitätsmuster einen intermediären Phänotyp darstellen könnten, der möglicherweise das Risiko für das Auftreten dysfunktionaler phobischer Angstreaktionen vermittelt. Von klinischem Interesse ist vor allem die Amygdala – ACC-Vernetzung, die als prädiktiver Biomarker für das Therapieansprechen genutzt oder im Rahmen neuromodulatorischer Therapieansätze wie dem Neurofeedback oder der repetitiven transkraniellen Magnetstimulation gezielt angesteuert werden könnte. KW - Kernspintomografie KW - Psychiatrie KW - Phobie KW - fMRT KW - Funktionelle Konnektivität KW - Spezifische Phobien KW - fMRI KW - Functional Connectivity KW - Specific Phobia KW - Neuroimaging KW - Dental Phobia KW - Zahnbehandlungsphobie KW - Angstverarbeitung Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180950 ER - TY - JOUR A1 - Enge, Sören A1 - Fleischhauer, Monika A1 - Gärtner, Anne A1 - Reif, Andreas A1 - Lesch, Klaus-Peter A1 - Kliegel, Matthias A1 - Strobel, Alexander T1 - Brain-Derived Neurotrophic Factor (Val66Met) and Serotonin Transporter (5-HTTLPR) Polymorphisms Modulate Plasticity in Inhibitory Control Performance Over Time but Independent of Inhibitory Control Training JF - Frontiers in Human Neuroscience N2 - Several studies reported training-induced improvements in executive function tasks and also observed transfer to untrained tasks. However, the results are mixed and there is a large interindividual variability within and across studies. Given that training-related performance changes would require modification, growth or differentiation at the cellular and synaptic level in the brain, research on critical moderators of brain plasticity potentially explaining such changes is needed. In the present study, a pre-post-follow-up design (N = 122) and a 3-weeks training of two response inhibition tasks (Go/NoGo and Stop-Signal) was employed and genetic variation (Val66Met) in the brain-derived neurotrophic factor (BDNF) promoting differentiation and activity-dependent synaptic plasticity was examined. Because Serotonin (5-HT) signaling and the interplay of BDNF and 5-HT are known to critically mediate brain plasticity, genetic variation in the 5-HTT gene-linked polymorphic region (5-HTTLPR) was also addressed. The overall results show that the kind of training (i.e., adaptive vs. non-adaptive) did not evoke genotype-dependent differences. However, in the Go/NoGo task, better inhibition performance (lower commission errors) were observed for BDNF Val/Val genotype carriers compared to Met-allele ones supporting similar findings from other cognitive tasks. Additionally, a gene-gene interaction suggests a more impulsive response pattern (faster responses accompanied by higher commission error rates) in homozygous l-allele carriers relative to those with the s-allele of 5-HTTLPR. This, however, is true only in the presence of the Met-allele of BDNF, while the Val/Val genotype seems to compensate for such non-adaptive responding. Intriguingly, similar results were obtained for the Stop-Signal task. Here, differences emerged at post-testing, while no differences were observed at T1. In sum, although no genotype-dependent differences between the relevant training groups emerged suggesting no changes in the trained inhibition function, the observed genotype-dependent performance changes from pre- to post measurement may reflect rapid learning or memory effects linked to BDNF and 5-HTTLPR. In line with ample evidence on BDNF and BDNF-5-HT system interactions to induce (rapid) plasticity especially in hippocampal regions and in response to environmental demands, the findings may reflect genotype-dependent differences in the acquisition and consolidation of task-relevant information, thereby facilitating a more adaptive responding to task-specific requirements. KW - executive function training KW - response inhibition KW - neuronal plasticity KW - BDNF Val66Met KW - 5-HTTLPR Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165176 VL - 10 IS - 370 ER - TY - JOUR A1 - Erhardt, A. A1 - Akula, N. A1 - Schumacher, J. A1 - Czamara, D. A1 - Karbalai, N. A1 - Müller-Myhsok, B. A1 - Mors, O. A1 - Borglum, A. A1 - Kristensen, A. S. A1 - Woldbye, D. P. D. A1 - Koefoed, P. A1 - Eriksson, E. A1 - Maron, E. A1 - Metspalu, A. A1 - Nurnberger, J. A1 - Philibert, R. A. A1 - Kennedy, J. A1 - Domschke, K. A1 - Reif, A. A1 - Deckert, J. A1 - Otowa, T. A1 - Kawamura, Y. A1 - Kaiya, H. A1 - Okazaki, Y. A1 - Tanii, H. A1 - Tokunaga, K. A1 - Sasaki, T. A1 - Ioannidis, J. P. A. A1 - McMahon, F. J. A1 - Binder, E. B. T1 - Replication and meta-analysis of TMEM132D gene variants in panic disorder JF - Translational Psychiatry N2 - 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. KW - candidate gene KW - genome-wide association KW - Japanese population Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133324 VL - 2 IS - e156 ER - TY - THES A1 - Ettlinger [geb. Haberstumpf], Sophia T1 - Pathological cognitive decline in the elderly participants of the Vogel Study T1 - Pathologische kognitive Verschlechterung in den älteren Studienteilnehmern der Vogel Studie N2 - Due to the global aging society and the enormous global incidence and prevalence rates that will result in the coming years, Alzheimer's Dementia (AD) represents a growing challenge for the health care system. The pathogenesis, which is unclear in parts, the chronic progression of AD, which often lasts for years, as well as insufficient diagnostic and therapeutic options complicate an adequate psychotherapeutic and medical approach to the disease. To date, AD is also considered an incurable disease. Therefore, it is essential to gain deeper insights into the early detection or even prevention of AD. Consideration of prodromal syndromes such as Mild Cognitive Impairment (MCI) can provide significant evidence about high-risk groups for AD progression and differentiate cognitively "normal" aging individuals from those with pathological cognitive decline. Thus, for example, functional Near-Infrared Spectroscopy (fNIRS) imaging helps identify early neurodegenerative processes. In contrast, potential risk factors and predictors of later-onset clinical symptoms of MCI and AD can most often be revealed and quantified via the use of neuropsychiatric test batteries. The present thesis consists of four studies and aimed to assess and describe the pathological cognitive decline in a sample of elderly study participants (age: ≥ 70 years; N = 604 at baseline) of the longitudinal, observational, and prospective "Vogel Study" from Würzburg, Germany, who were primarily healthy at baseline, over two measurement time points approximately 3 years apart, to differentiate between healthy and diseased study participants and to define predictors of MCI/AD and longitudinal study dropout. Studies 1 and 2 differentiated healthy study participants from MCI patients based on the baseline hemodynamic response of the parietal cortex recorded by fNIRS during the processing of a paradigm (here: Angle Discrimination Task [ADT]) for visual-spatial processing performance. Neuronal hypoactivity was found in the MCI patients, with both healthy study participants and MCI patients showing higher superior and right hemispheric activation. MCI patients had more difficulty resolving the paradigm. Thus, no evidence of possible compensatory mechanisms was uncovered in the MCI patients. Study 3 first defined the four latent factors declarative memory, working memory, attention, and visual-spatial processing based on structural equation model (SEM) calculations of the sample using adequate measurement (in-)variant confirmatory factor models from the baseline assessment to the first of a total of two follow-up assessments after approximately 3 years. This allowed a dimensional assessment of pathological cognitive decline versus classificatory-categorical assignment (healthy/diseased) of the sample. In addition, the superiority of the latent factor approach over a composite approach was demonstrated. Next, using a mixed-model approach, predictive analyses were calculated for the prediction of latent factors at first follow-up by baseline risk factors. The sex of study participants proved to be the best predictor of cognitive change in all the cognitive domains, with females performing better than men in the memory domains. Specifically, for declarative memory, older age predicted lower performance regardless of sex. Additional predictive evidence emerged for low serum levels of Brain-Derived Neurotrophic Factor (BDNF) on lower attention performance and higher depression symptoms on lower visual-spatial processing performance. Study 4 further reported baseline predictors of study dropout at first follow-up. Cognitive performance, as defined in Study 3 using the four latent cognitive factors, was a predictor of study dropout for cognitive decline in the domains of declarative memory, attention, and visual-spatial processing. Conspicuous dementia screening on the Mini-Mental Status Examination (MMSE) also predicted dropout. Overall, both the use of fNIRS imaging to detect visual-spatial processing performance in the parietal cortex during applying ADT and the dimensional perspective of the neuropsychiatric test battery in the context of prediction and dropout analyses were found to be suitable for early detection research of MCI and AD. Finally, the results will be interpreted in the overall context and implications, limitations, and perspectives will be discussed. N2 - Aufgrund der global alternden Gesellschaft und der damit auch in den nächsten Jahren einhergehenden enormen globalen Inzidenz- und Prävalenzraten stellt die Alzheimer-Demenz (AD) eine wachsende Herausforderung für das Gesundheitswesen dar. Die in Teilen unklare Pathogenese, die oft über Jahre bestehende, chronische Progression der AD sowie bislang unzureichende Diagnose- und Therapiemöglichkeiten erschweren einen adäquaten psychotherapeutischen und medizinischen Umgang mit der Erkrankung. Bis heute gilt die AD außerdem als unheilbare Erkrankung. Umso wichtiger ist es, tiefergehende Erkenntnisse zur Früherkennung oder gar Prävention der AD zu gewinnen. Insbesondere die Berücksichtigung von Prodromalsyndromen wie das Mild Cognitive Impairment (MCI) können wichtige Hinweise über Risikopersonengruppen für eine AD-Progression liefern und kognitiv „normal“ alternde Menschen von Menschen mit pathologischer kognitiver Verschlechterung differenzieren. Zur Identifikation früher neurodegenerativer Prozesse eignet sich z.B. die funktionelle Nahinfrarotspektroskopie (fNIRS), während potenzielle Risikofaktoren und Prädiktoren für später auftretende, klinische Symptome der MCI und AD am häufigsten über die Anwendung neuropsychiatrischer Testbatterien aufgedeckt und quantifiziert werden können. Die vorliegende Dissertation besteht aus vier Studien und verfolgte das Ziel, die pathologische kognitive Verschlechterung in einer zur Baseline-Erhebung größtenteils gesunden, älteren Stichprobe (Alter: ≥ 70 Jahre; N = 604 zur Baseline-Erhebung) der longitudinalen, beobachtenden und prospektiven „Vogel Studie“ aus Würzburg über zwei Messzeitpunkte im Abstand von ca. 3 Jahren zu erfassen und zu beschreiben, zwischen gesunden und erkrankten StudienteilnehmerInnen zu differenzieren und Prädiktoren der MCI/AD sowie des longitudinalen Studien-Dropouts zu definieren. Studien 1 und 2 differenzierten gesunde StudienteilnehmerInnen von MCI-PatientInnen anhand der über die fNIRS zur Baseline-Erhebung erfassten hämodynamischen Antwort des Parietalkortex während der Bearbeitung eines Paradigmas (hier: Winkeldiskriminationsaufgabe [ADT]) zur visuell-räumlichen Verarbeitungsleistung im Rahmen der Baseline-Erhebung. Es konnte eine neuronale Hypoaktivität bei den MCI-PatientInnen festgestellt werden, wobei sowohl gesunde StudienteilnehmerInnen als auch MCI-PatientInnen eine höhere superiore und rechts-hemisphärische Aktivierung zeigten. MCI-PatientInnen hatten mehr Schwierigkeiten, das Paradigma zu lösen. Dennoch konnten keine Hinweise auf Kompensationsmechanismen bei den MCI-PatientInnen aufgedeckt werden. Studie 3 definierte zunächst die vier latenten Faktoren deklaratives Gedächtnis, Arbeitsgedächtnis, Aufmerksamkeit und visuell-räumliche Verarbeitung basierend auf Strukturgleichungsmodell-Berechnungen (SEM) der Stichprobe anhand von adäquat mess(in-)varianten konfirmatorischen Faktormodellen von der Baseline-Erhebung zum ersten von insgesamt zwei Follow-up-Erhebungen nach rund 3 Jahren. Dadurch wurde eine dimensionale Einschätzung pathologischer kognitiver Verschlechterung gegenüber klassifikatorisch-kategorialer Zuweisung (gesund/krank) der Stichprobe ermöglicht. Zusätzlich konnte die Überlegenheit des latenten Faktor-Ansatzes gegenüber eines Composite-Ansatzes gezeigt werden. Anschließend wurden anhand eines Mixed-Model-Ansatzes Prädiktionsanalysen zur Vorhersage der latenten Faktoren zum ersten Follow-up durch Risikofaktoren der Baseline-Erhebung berechnet. Das Geschlecht der StudienteilnehmerInnen erwies sich als bester Prädiktor für die kognitive Veränderung in allen kognitiven Domänen, wobei Frauen in Gedächtnis-Domänen eine bessere Leistung als Männer erzielten. Vor allem für das deklarative Gedächtnis sagte geschlechterunabhängig ein höheres Alter eine geringere Leistung vorher. Zusätzlich zeigten sich prädiktive Effekte eines geringeren Brain-Derived Neurotrophic Factor (BDNF) Serum-Levels auf geringere Aufmerksamkeitsleistung und der erhöhten Depressivität auf geringere visuell-räumliche Verarbeitungskapazitäten. Studie 4 berichtet darüber hinaus von Baseline-Prädiktoren des Studien-Dropouts zum ersten Follow-up. Die kognitive Leistung, wie in Studie 3 anhand der vier latenten kognitiven Faktoren definiert, stellte für eine kognitive Verschlechterung in den Domänen deklaratives Gedächtnis, Aufmerksamkeit und visuell-räumliche Verarbeitung einen Prädiktor für Studien-Dropout dar. Auch ein auffälliges Demenz-Screening im Mini-Mental Status Examination (MMSE) sagte Dropout vorher. Insgesamt erwiesen sich sowohl die Anwendung des fNIRS-Bildgebungsverfahrens zur Erfassung visuell-räumlicher Verarbeitungsleistung im Parietalkortex während Bearbeitung der ADT als auch die dimensionale Betrachtung der neuropsychiatrischen Testbatterie im Rahmen prädiktiver und Dropout-Analysen als für die Früherkennungs-Forschung der MCI und AD geeignet. Die Ergebnisse werden abschließend im Gesamtkontext interpretiert und Implikationen, Limitation und Perspektiven diskutiert. KW - cognitive decline KW - mild cognitive impairment KW - Alzheimer's Dementia KW - early detection Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265582 ER - TY - JOUR A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Klitsch, Alexander A1 - Unterecker, Stefan A1 - Warrings, Bodo A1 - Serra, Jordi A1 - Papagianni, Aikaterini A1 - Saffer, Nadine A1 - Meyer zu Altenschildesche, Caren A1 - Kampik, Daniel A1 - Malik, Rayaz A. A1 - Sommer, Claudia A1 - Üceyler, Nurcan T1 - Reduction of skin innervation is associated with a severe fibromyalgia phenotype JF - Annals of Neurology N2 - Objective: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS). Methods: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women. Results: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63% of FMS patients (MDP: 10%, controls: 18%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05). Interpretation: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS. KW - fibromyalgia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206168 VL - 86 IS - 4 ER - TY - JOUR A1 - Evers, Ann-Kristin A1 - Veeh, Julia A1 - McNeill, Rhiannon A1 - Reif, Andreas A1 - Kittel-Schneider, Sarah T1 - C-reactive protein concentration in bipolar disorder: association with genetic variants JF - International Journal of Bipolar Disorders N2 - Background Several recent studies have investigated the role of C-reactive protein (CRP) in bipolar disorder (BD), but few studies have directly investigated the interaction between CRP genetic variants and peripheral CRP concentration across different phases of BD. In this study, we aimed to replicate previous findings that demonstrated altered CRP levels in BD, and to investigate whether there is an association of peripheral protein expression with genetic variants in the CRP gene. Methods 221 patients were included in the study, of which 183 (all episodes, 46 not medicated, 174 medicated) were genotyped for CRP single-nucleotide polymorphisms (SNPs) shown to influence peripheral CRP protein expression (rs1800947, rs2808630, rs1417938, rs1205). Results There were no differences in CRP levels associated with the genotypes, only regarding the rs1205 SNP there were significantly different CRP protein expression between the genotypes when taking body mass index, age, BD polarity, subtype and leukocyte number into account. However, we could show significantly elevated CRP protein expression in manic patients compared to euthymic and depressed patients, independent from genotype. Medication was found to have no effect on CRP protein expression. Conclusions These results indicate that low grade inflammation might play a role in mania and might be rather a state than a trait marker of bipolar disorder. KW - Bipolar disorder KW - Genotype KW - C-reactive protein KW - Biomarke KW - Inflammatio Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202289 VL - 7 ER - TY - JOUR A1 - Fernàndez-Castillo, Noèlia A1 - Cabana-Domínguez, Judit A1 - Kappel, Djenifer B. A1 - Torrico, Bàrbara A1 - Weber, Heike A1 - Lesch, Klaus-Peter A1 - Lao, Oscar A1 - Reif, Andreas A1 - Cormand, Bru T1 - Exploring the contribution to ADHD of genes involved in Mendelian disorders presenting with hyperactivity and/or inattention JF - Genes N2 - Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders. KW - ADHD KW - rare mendelian disorders KW - genetic variants Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252346 SN - 2073-4425 VL - 13 IS - 1 ER - TY - JOUR A1 - Fischer, Matthias A1 - Raabe, Thomas T1 - Animal models for Coffin-Lowry syndrome: RSK2 and nervous system dysfunction JF - Frontiers in Behavioral Neuroscience N2 - Loss of function mutations in the rsk2 gene cause Coffin-Lowry syndrome (CLS), which is associated with multiple symptoms including severe mental disabilities. Despite the characterization of ribosomal S6 kinase 2 (RSK2) as a protein kinase acting as a downstream effector of the well characterized ERK MAP-kinase signaling pathway, it turns out to be a challenging task to link RSK2 to specific neuronal processes dysregulated in case of mutation. Animal models such as mouse and Drosophila combine advanced genetic manipulation tools with in vivo imaging techniques, high-resolution connectome analysis and a variety of behavioral assays, thereby allowing for an in-depth analysis for gene functions in the nervous system. Although modeling mental disability in animal systems has limitations because of the complexity of phenotypes, the influence of genetic variation and species-specific characteristics at the neural circuit and behavioral level, some common aspects of RSK2 function in the nervous system have emerged, which will be presented. Only with this knowledge our understanding of the pathophysiology of CLS can be improved, which might open the door for development of potential intervention strategies. KW - Coffin-Lowry syndrome KW - RSK2 KW - mental disorders KW - mouse model KW - Drosophila model KW - neuronal dysfunction KW - behavior Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176799 VL - 12 IS - 106 ER - TY - JOUR A1 - Franke, B. A1 - Faraone, S. V. A1 - Asherson, P. A1 - Buitelaar, J. A1 - Bau, C. H. D. A1 - Ramos-Quiroga, J. A. A1 - Mick, E. A1 - Grevet, E. H. A1 - Johansson, S. A1 - Haavik, J. A1 - Lesch, K.-P. A1 - Cormand, B. A1 - Reif, A. T1 - The genetics of attention deficit/hyperactivity disorder in adults, a review JF - Molecular Psychiatry N2 - The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30–40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood. KW - IMpACT KW - persistent ADHD KW - molecular genetics KW - heritability KW - endophenotype Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124677 VL - 17 ER - TY - JOUR A1 - Frey, Anna A1 - Popp, Sandy A1 - Post, Antonia A1 - Langer, Simon A1 - Lehmann, Marc A1 - Hofmann, Ulrich A1 - Siren, Anna-Leena A1 - Hommers, Leif A1 - Schmitt, Angelika A1 - Strekalova, Tatyana A1 - Ertl, Georg A1 - Lesch, Klaus-Peter A1 - Frantz, Stefan T1 - Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain JF - Frontiers in Behavioral Neuroscience N2 - Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression. KW - chronic heart failure KW - myocardial infarction KW - anxiety KW - depression KW - mice Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118234 SN - 1662-5153 VL - 8 ER - TY - JOUR A1 - Fuhrmann, Saskia A1 - Tesch, Falko A1 - Romanos, Marcel A1 - Abraham, Susanne A1 - Schmitt, Jochen T1 - ADHD in school‐age children is related to infant exposure to systemic H1‐antihistamines JF - Allergy KW - atopic dermatitis KW - histamine KW - pediatrics Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215982 VL - 75 IS - 11 SP - 2956 EP - 2957 ER - TY - JOUR A1 - Galimberti, Daniela A1 - Dell'Osso, Bernardo A1 - Fenoglio, Chiara A1 - Villa, Chiara A1 - Cortini, Francesca A1 - Serpente, Maria A1 - Kittel-Schneider, Sarah A1 - Weigl, Johannes A1 - Neuner, Maria A1 - Volkert, Juliane A1 - Leonhard, C. A1 - Olmes, David G. A1 - Kopf, Juliane A1 - Cantoni, Claudia A1 - Ridolfi, Elisa A1 - Palazzo, Carlotta A1 - Ghezzi, Laura A1 - Bresolin, Nereo A1 - Altamura, A.C. A1 - Scarpini, Elio A1 - Reif, Andreas T1 - Progranulin Gene Variability and Plasma Levels in Bipolar Disorder and Schizophrenia JF - PLoS One N2 - Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n=271) or BPD (n=237) as compared with 574 age-, gender-and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls. A significantly decreased allelic frequency of the minor versus the wild-type allele was observed for rs2879096 (23.2 versus 34.2%, P<0.001, OR: 0.63, 95% CI: 0.49-0.80), rs4792938 (30.7 versus 39.7%, P=0.005, OR: 0.70, 95% CI: 0.55-0.89) and rs5848 (30.3 versus 36.8, P=0.007, OR: 0.71, 95% CI: 0.56-0.91). Mean +/- SEM progranulin plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls (89.69 +/- 3.97 and 116.14 +/- 5.80 ng/ml, respectively, versus 180.81 +/- 18.39 ng/ml P<0.001) and were not correlated with age. In conclusion, GRN variability decreases the risk to develop BPD and schizophrenia, and progranulin plasma levels are significantly lower in BPD patients than in controls. Nevertheless, a larger replication analysis would be needed to confirm these preliminary results. KW - people KW - frontotemporal lobar degeneration KW - genome-wide association KW - Alzheimers disease KW - risk genes KW - dementia KW - GRN KW - mutation KW - families KW - linkage Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131910 VL - 7 IS - 4 ER - TY - JOUR A1 - Gawlik, Micha A1 - Wehner, Ingeborg A1 - Mende, Meinhard A1 - Jung, Sven A1 - Pfuhlmann, Bruno A1 - Knapp, Michael A1 - Stoeber, Gerald T1 - The DAOA/G30 locus and affective disorders: haplotype based association study in a polydiagnostic approach N2 - Background: The DAOA/G30 (D-amino acid oxidase activator) gene complex at chromosomal region 13q32-33 is one of the most intriguing susceptibility loci for the major psychiatric disorders, although there is no consensus about the specific risk alleles or haplotypes across studies. Methods: In a case-control sample of German descent (affective psychosis: n = 248; controls: n = 188) we examined seven single nucleotide polymorphisms (SNPs) around DAOA/G30 (rs3916966, rs1935058, rs2391191, rs1935062, rs947267, rs3918342, and rs9558575) for genetic association in a polydiagnostic approach (ICD 10; Leonhard’s classification). Results: No single marker showed evidence of overall association with affective disorder neither in ICD10 nor Leonhard’s classification. Haplotype analysis revealed no association with recurrent unipolar depression or bipolar disorder according to ICD10, within Leonhard’s classification manic-depression was associated with a 3-locus haplotype (rs2391191, rs1935062, and rs3916966; P = 0.022) and monopolar depression with a 5-locus combination at the DAOA/G30 core region (P = 0.036). Conclusion: Our data revealed potential evidence for partially overlapping risk haplotypes at the DAOA/G30 locus in Leonhard’s affective psychoses, but do not support a common genetic contribution of the DAOA/G30 gene complex to the pathogenesis of affective disorders. KW - Psychisch Kranker KW - D-amino acid oxidase activator Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67963 ER - TY - JOUR A1 - Gehrmann, Andrea A1 - Fiedler, Katrin A1 - Leutritz, Anna Linda A1 - Koreny, Carolin A1 - Kittel-Schneider, Sarah T1 - Lithium medication in pregnancy and breastfeeding — a case series JF - Medicina N2 - Lithium salts are the first-line prophylaxis treatment for bipolar disorder in most guidelines. The majority of bipolar women are treated with mood stabilizers at the time they wish to get pregnant. One reason for this is the rising average age at first childbirth, at least in the high-income countries, which increases in general the likelihood of a medication with psychotropic drugs. Previously, lithium exposition during pregnancy was thought to strongly increase the risk of severe cardiac malformation. However, recent studies only point to a low teratogenic risk, so nowadays an increasing number of women are getting pregnant with ongoing lithium treatment. Regarding lithium medication during breastfeeding, there is evidence that lithium transfers to the breastmilk and can also be detected in the infants' serum. The influence on the infant is still a largely understudied topic. Regular monitoring of the infants' renal clearance, thyroid function, and lithium levels is warranted when breastfeeding under lithium exposure. In this case series, we present three case reports of bipolar mothers who were treated with lithium during pregnancy and breastfeeding to add to the scarce literature on this important topic. In short, we strengthen the importance of therapeutic drug monitoring due to fluctuating plasma levels during pregnancy and after birth, and we can report the birth and development of three healthy infants despite lithium medication during pregnancy and breastfeeding. KW - lithium KW - pregnancy KW - lactation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285640 SN - 1648-9144 VL - 57 IS - 6 ER - TY - JOUR A1 - Gella, Alejandro A1 - Segura, Monica A1 - Durany, Nuria A1 - Pfuhlmann, Bruno A1 - Stoeber, Gerald A1 - Gawlik, Micha T1 - Is Ankyrin a specific genetic risk factor for psychiatric phenotypes? N2 - Background: Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. Methods: We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard’s classification featuring disease entities with specific combination of bipolar and psychotic syndromes. Results: We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard’s classification. Conclusion: Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases. KW - Schizophrenie Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68732 ER - TY - JOUR A1 - Gella, Alejandro A1 - Segura, Mònica A1 - Durany, Núria A1 - Pfuhlmann, Bruno A1 - Stöber, Gerald A1 - Gawlik, Micha T1 - Is Ankyrin a genetic risk factor for psychiatric phenotypes? JF - BMC Psychiatry N2 - Background Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. Methods We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes. Results We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification. Conclusion Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases. KW - Ankyrin KW - genetic risk factor Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137769 VL - 11 IS - 103 ER - TY - JOUR A1 - Gerlach, Manfred A1 - Maetzler, Walter A1 - Broich, Karl A1 - Hampel, Harald A1 - Rems, Lucas A1 - Reum, Torsten A1 - Riederer, Peter A1 - Stäffler, Albrecht A1 - Streffer, Johannes A1 - Berg, Daniela T1 - Biomarker candidates of neurodegeneration in Parkinson's disease for the evaluation of disease-modifying therapeutics JF - Journal of Neural Transmission N2 - Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies. KW - disease progression KW - biomarkers KW - neuroprotection KW - disease-modifying therapies KW - Parkinson’s disease KW - surrogate endpoints KW - drug development Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125375 VL - 119 IS - 1 ER - TY - JOUR A1 - Gerlach, Manfred A1 - Maetzler, Walter A1 - Broich, Karl A1 - Hampel, Harald A1 - Rems, Lucas A1 - Reum, Torsten A1 - Riederer, Peter A1 - Stöffler, Albrecht A1 - Streffer, Johannes A1 - Berg, Daniela T1 - Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics JF - Journal of Neural Transmission N2 - Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies. KW - Parkinson’s disease KW - Disease-modifying therapies KW - Neuroprotection KW - Biomarkers KW - Surrogate endpoints KW - Drug development KW - Disease progression Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133856 VL - 119 IS - 1 ER - TY - JOUR A1 - Gilder, Stuart A. A1 - Wack, Michael A1 - Kaub, Leon A1 - Roud, Sophie C. A1 - Petersen, Nikolai A1 - Heinsen, Helmut A1 - Hillenbrand, Peter A1 - Milz, Stefan A1 - Schmitz, Chistoph T1 - Distribution of magnetic remanence carriers in the human brain JF - Scientific Reports N2 - That the human brain contains magnetite is well established; however, its spatial distribution in the brain has remained unknown. We present room temperature, remanent magnetization measurements on 822 specimens from seven dissected whole human brains in order to systematically map concentrations of magnetic remanence carriers. Median saturation remanent magnetizations from the cerebellum were approximately twice as high as those from the cerebral cortex in all seven cases (statistically significantly distinct, p = 0.016). Brain stems were over two times higher in magnetization on average than the cerebral cortex. The ventral (lowermost) horizontal layer of the cerebral cortex was consistently more magnetic than the average cerebral cortex in each of the seven studied cases. Although exceptions existed, the reproducible magnetization patterns lead us to conclude that magnetite is preferentially partitioned in the human brain, specifically in the cerebellum and brain stem. KW - brain KW - neurophysiology Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233035 VL - 8 ER - TY - JOUR A1 - Glotzbach, Evelyn A1 - Mühlberger, Andreas A1 - Gschwendtner, Kathrin A1 - Fallgatter, Andreas J A1 - Pauli, Paul A1 - Herrmann, Martin J T1 - Prefrontal Brain Activation During Emotional Processing: A Functional Near Infrared Spectroscopy Study (fNIRS) JF - The Open Neuroimaging Journal N2 - The limbic system and especially the amygdala have been identified as key structures in emotion induction and regulation. Recently research has additionally focused on the influence of prefrontal areas on emotion processing in the limbic system and the amygdala. Results from fMRI studies indicate that the prefrontal cortex (PFC) is involved not only in emotion induction but also in emotion regulation. However, studies using fNIRS only report prefrontal brain activation during emotion induction. So far it lacks the attempt to compare emotion induction and emotion regulation with regard to prefrontal activation measured with fNIRS, to exclude the possibility that the reported prefrontal brain activation in fNIRS studies are mainly caused by automatic emotion regulation processes. Therefore this work tried to distinguish emotion induction from regulation via fNIRS of the prefrontal cortex. 20 healthy women viewed neutral pictures as a baseline condition, fearful pictures as induction condition and reappraised fearful pictures as regulation condition in randomized order. As predicted, the view-fearful condition led to higher arousal ratings than the view-neutral condition with the reappraise-fearful condition in between. For the fNIRS results the induction condition showed an activation of the bilateral PFC compared to the baseline condition (viewing neutral). The regulation condition showed an activation only of the left PFC compared to the baseline condition, although the direct comparison between induction and regulation condition revealed no significant difference in brain activation. Therefore our study underscores the results of previous fNIRS studies showing prefrontal brain activation during emotion induction and rejects the hypothesis that this prefrontal brain activation might only be a result of automatic emotion regulation processes. KW - fNIRS KW - Emotional processing KW - emotional regulation Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141714 VL - 5 ER - TY - JOUR A1 - Goepel, Johanna A1 - Biehl, Stefanie C. A1 - Kissler, Johanna A1 - Paul-Jordanov, Isabelle T1 - Pro- and antisaccades in children elicited by visual and acoustic targets - does modality matter? JF - BMC Pediatrics N2 - Background: Children are able to inhibit a prepotent reaction to suddenly arising visual stimuli, although this skill is not yet as pronounced as it is in adulthood. However, up to now the inhibition mechanism to acoustic stimuli has been scarcely investigated Methods: Reflexive (prosaccade) and inhibitory (antisaccade) responses to visual and acoustic targets were examined with an eye tracker system in 31 children between seven and twelve years of age using a gap-overlap task and two target eccentricities. Results: Acoustically cued saccades had longer reaction times than visually cued saccades. A gap effect (i.e., shorter reaction time in the gap than the overlap condition) was only found for visually elicited saccades, whereas an eccentricity effect (i.e., faster saccades to more laterally presented targets - 12 degrees vs. 6 degrees or rather 90 degrees vs. 45 degrees) was only present in the acoustic condition. Longer reaction times of antisaccades compared to prosaccades were found only in the visual task. Across both tasks the typical pattern of elevated error rates in the antisaccade condition was found. Antisaccade errors declined with age, indicating an ongoing development of inhibitory functions. Conclusions: The present results lay the ground for further studies of acoustically triggered saccades in typically as well as atypically developing children and it might thus be possible to upgrade physiological diagnostic tools. KW - Saccadic eye-movements KW - Auditory targets KW - Voluntary control KW - Task-performance KW - Latency KW - Prosaccade KW - Vergence KW - Stimuli KW - GAP Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141807 VL - 11 IS - 116 ER - TY - JOUR A1 - Gorlova, Anna A1 - Svirin, Evgeniy A1 - Pavlov, Dmitrii A1 - Cespuglio, Raymond A1 - Proshin, Andrey A1 - Schroeter, Careen A. A1 - Lesch, Klaus-Peter A1 - Strekalova, Tatyana T1 - Understanding the role of oxidative stress, neuroinflammation and abnormal myelination in excessive aggression associated with depression: recent input from mechanistic studies JF - International Journal of Molecular Sciences N2 - Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions. KW - major depressive disorder (MDD) KW - aggression KW - neuroinflammation KW - oxidative stress KW - insulin receptor KW - myelination Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304917 SN - 1422-0067 VL - 24 IS - 2 ER - TY - JOUR A1 - Gottschalk, Michael G. A1 - Richter, Jan A1 - Ziegler, Christiane A1 - Schiele, Miriam A. A1 - Mann, Julia A1 - Geiger, Maximilian J. A1 - Schartner, Christoph A1 - Homola, György A. A1 - Alpers, Georg W. A1 - Büchel, Christian A1 - Fehm, Lydia A1 - Fydrich, Thomas A1 - Gerlach, Alexander L. A1 - Gloster, Andrew T. A1 - Helbig-Lang, Sylvia A1 - Kalisch, Raffael A1 - Kircher, Tilo A1 - Lang, Thomas A1 - Lonsdorf, Tina B. A1 - Pané-Farré, Christiane A. A1 - Ströhle, Andreas A1 - Weber, Heike A1 - Zwanzger, Peter A1 - Arolt, Volker A1 - Romanos, Marcel A1 - Wittchen, Hans-Ulrich A1 - Hamm, Alfons A1 - Pauli, Paul A1 - Reif, Andreas A1 - Deckert, Jürgen A1 - Neufang, Susanne A1 - Höfler, Michael A1 - Domschke, Katharina T1 - Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes JF - Translational Psychiatry N2 - Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system. KW - human behaviour KW - molecular neuroscience KW - personalized medicine KW - predictive markers KW - psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227479 VL - 9 ER - TY - JOUR A1 - Gram, Maximilian A1 - Albertova, P. A1 - Schirmer, V. A1 - Blaimer, M. A1 - Gamer, M. A1 - Herrmann, M. J. A1 - Nordbeck, P. A1 - Jakob, P. M. T1 - Towards robust in vivo quantification of oscillating biomagnetic fields using Rotary Excitation based MRI JF - Scientific Reports N2 - Spin-lock based functional magnetic resonance imaging (fMRI) has the potential for direct spatially-resolved detection of neuronal activity and thus may represent an important step for basic research in neuroscience. In this work, the corresponding fundamental effect of Rotary EXcitation (REX) is investigated both in simulations as well as in phantom and in vivo experiments. An empirical law for predicting optimal spin-lock pulse durations for maximum magnetic field sensitivity was found. Experimental conditions were established that allow robust detection of ultra-weak magnetic field oscillations with simultaneous compensation of static field inhomogeneities. Furthermore, this work presents a novel concept for the emulation of brain activity utilizing the built-in MRI gradient system, which allows REX sequences to be validated in vivo under controlled and reproducible conditions. Via transmission of Rotary EXcitation (tREX), we successfully detected magnetic field oscillations in the lower nano-Tesla range in brain tissue. Moreover, tREX paves the way for the quantification of biomagnetic fields. KW - functional magnetic resonance imaging KW - Rotary EXcitation (REX) KW - oscillating biomagnetic fields Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300862 VL - 12 IS - 1 ER - TY - JOUR A1 - Grünblatt, Edna A1 - Bartl, Jasmin A1 - Iuhos, Diana-Iulia A1 - Knezovic, Ana A1 - Trkulja, Vladimir A1 - Riederer, Peter A1 - Walitza, Susanne A1 - Salkovic-Petrisic, Melita T1 - Characterization of cognitive deficits in spontaneously hypertensive rats, accompanied by brain insulin receptor dysfunction JF - Journal of Molecular Psychiatry N2 - Background The spontaneously hypertensive rat (SHR) has been used to model changes in the central nervous system associated with cognitive-related disorders. Recent human and animal studies indicate a possible relationship between cognitive deficits, insulin resistance and hypertension. We aimed to investigate whether cognitively impaired SHRs develop central and/or peripheral insulin resistance and how their cognitive performance is influenced by the animal’s sex and age as well as strains used for comparison (Wistar and Wistar-Kyoto/WKY). Methods Three and seven-month-old SHR, Wistar, and WKY rats were studied for their cognitive performance using Morris Water Maze (MWM) and Passive Avoidance tests (PAT). Plasma glucose and insulin were obtained after oral glucose tolerance tests. Cerebral cortex, hippocampus, and striatum status of insulin-receptor (IR) β-subunit and glycogen synthase kinase-3β (GSK3β) and their phosphorylated forms were obtained via ELISA. Results SHRs performed poorly in MWM and PAT in comparison to both control strains but more pronouncedly compared to WKY. Females performed poorer than males and 7-month-old SHRs had poorer MWM performance than 3-month-old ones. Although plasma glucose levels remained unchanged, plasma insulin levels were significantly increased in the glucose tolerance test in 7-month-old SHRs. SHRs demonstrated reduced expression and increased activity of IRβ-subunit in cerebral cortex, hippocampus, and striatum with different regional changes in phospho/total GSK3β ratio, as compared to WKYs. Conclusion Results indicate that cognitive deficits in SHRs are accompanied by both central and peripheral insulin dysfunction, thus allowing for the speculation that SHRs might additionally be considered as a model of insulin resistance-induced type of dementia. KW - spontaneously hypertensive rat KW - age KW - control strain KW - gender KW - glycogen synthase kinase-3β KW - insulin resistance KW - learning and memory Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149593 VL - 3 IS - 6 ER - TY - JOUR A1 - Grünblatt, Edna A1 - Oneda, Beatrice A1 - Ekici, Arif B. A1 - Ball, Juliane A1 - Geissler, Julia A1 - Uebe, Steffen A1 - Romanos, Marcel A1 - Rauch, Anita A1 - Walitza, Susanne T1 - High resolution chromosomal microarray analysis in paediatric obsessive-compulsive disorder JF - BMC Medical Genomics N2 - Background Obsessive-Compulsive Disorder (OCD) is a common and chronic disorder in which a person has uncontrollable, reoccurring thoughts and behaviours. It is a complex genetic condition and, in case of early onset (EO), the patients manifest a more severe phenotype, and an increased heritability. Large (>500 kb) copy number variations (CNVs) previously associated with autism and schizophrenia have been reported in OCD. Recently, rare CNVs smaller than 500 kb overlapping risk loci for other neurodevelopmental conditions have also been reported in OCD, stressing the importance of examining CNVs of any size range. The aim of this study was to further investigate the role of rare and small CNVs in the aetiology of EO-OCD. Methods We performed high-resolution chromosomal microarray analysis in 121 paediatric OCD patients and in 124 random controls to identify rare CNVs (>50 kb) which might contribute to EO-OCD. Results The frequencies and the size of the observed rare CNVs in the patients did not differ from the controls. However, we observed a significantly higher frequency of rare CNVs affecting brain related genes, especially deletions, in the patients (OR = 1.98, 95% CI 1.02–3.84; OR = 3.61, 95% CI 1.14–11.41, respectively). Similarly, enrichment-analysis of CNVs gene content, performed with three independent methods, confirmed significant clustering of predefined genes involved in synaptic/brain related functional pathways in the patients but not in the controls. In two patients we detected \(de-novo\) CNVs encompassing genes previously associated with different neurodevelopmental disorders \(\textit{NRXN1, ANKS1B, UHRF1BP1}\)). Conclusions Our results further strengthen the role of small rare CNVs, particularly deletions, as susceptibility factors for paediatric OCD. KW - Medicine KW - OCD KW - CNV KW - Enrichment analysis KW - De-novo KW - Early-onset Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172791 VL - 10 IS - 68 ER - TY - THES A1 - Gründahl, Marthe Erda T1 - From Lab to Life: Investigating the Role of Social Contact for Anxiety and Related Autonomic Responses T1 - Vom Labor ins Leben: Die Erforschung der Rolle von sozialem Kontakt für Angst und damit verbundene autonome Reaktionen N2 - Social contact is an integral part of daily life. Its health-enhancing effects include reduced negative affective experiences of fear and anxiety, a phenomenon called social buffering. This dissertation studied different forms of social contact and their anxiety-buffering effects with diverse methodologies. The laboratory-based first study investigated minimal social contact in the context of pain relief learning. Results showed that the observed decreased autonomic and increased subjective fear responses following pain relief learning were independent of social influence. The minimalistic and controlled social setting may have prevented social buffering. Study 2 targeted social buffering in daily life using Ecological Momentary Assessment. We repeatedly assessed individuals’ state anxiety, related cardiovascular responses, and aspects of social interactions with smartphones and portable sensors on five days. Analyses of over 1,500 social contacts revealed gender-specific effects, e.g., heart rate-reducing effects of familiarity in women, but not men. Study 3 examined anxiety, loneliness, and related social factors in the absence of social contact due to social distancing. We constructed and validated a scale measuring state and trait loneliness and isolation, and analysed its link to mental health. Results include a social buffering-like relation of lower anxiety with more trait sociability and sense of belonging. In sum, the studies showed no fear reduction by minimal social contact, but buffering effects relating to social and personal factors in more complex social situations. Anxiety responses during daily social contacts were lower with more familiar or opposite-gender interaction partners. During limited social contact, lower anxiety related to inter-individual differences in sociability, social belonging, and loneliness. By taking research from lab to life, this dissertation underlined the diverse nature of social contact and its relevance to mental health. N2 - Sozialer Kontakt ist ein wesentlicher Teil des Alltags. Zu seinen Effekten gehört die Minderung negativer affektiver Erfahrungen von Angst und Furcht („Social Buffering“). Diese Dissertation untersucht verschiedene Formen sozialen Kontakts und ihre angstmindernde Wirkung mit diversen Methoden. Studie 1 untersuchte minimalen sozialen Kontakt im Kontext von Pain Relief Learning im Labor. Die verringerten autonomen und erhöhten subjektiven Furchtreaktionen nach dem Pain Relief Learning waren unabhängig vom sozialen Einfluss. Das minimalistische und kontrollierte soziale Setting könnte Social Buffering verhindert haben. Studie 2 erfasste Social Buffering im Alltag mit Ecological Momentary Assessment. An fünf Tagen wurden wiederholt State Angst und kardiovaskuläre Reaktionen der ProbandInnen sowie Merkmale ihrer sozialen Interaktionen mit Smartphones und tragbaren Sensoren gemessen. Die Analyse der über 1500 sozialen Kontakte ergab geschlechtsspezifische Effekte, z. B. eine herzratenmindernde Wirkung von Vertrautheit bei Frauen, aber nicht bei Männern. Studie 3 untersuchte Angst, Einsamkeit und weitere soziale Faktoren bei abwesendem sozialen Kontakt durch Social Distancing. Wir konstruierten und validierten eine Skala zur Messung von State- und Trait-Einsamkeit und Isolation und prüften ihren Zusammenhang mit psychischer Gesundheit. Weniger Angst ging mit mehr Trait-Geselligkeit und Zugehörigkeitsgefühl einher. Somit zeigte sich keine Furchtminderung bei minimalem sozialen Kontakt, aber Social Buffering in komplexeren sozialen Situationen bedingt durch soziale und persönliche Faktoren. Angstreaktionen waren in Alltagsinteraktionen mit vertrauteren oder gegengeschlechtlichen Personen geringer. Bei begrenztem sozialen Kontakt ging geringere Angst mit Unterschieden in Geselligkeit, sozialer Zugehörigkeit und Einsamkeit einher. Durch Forschung in Labor und Leben unterstreicht diese Dissertation die Vielfältigkeit sozialer Kontakte und ihre Relevanz für psychische Gesundheit. KW - Angst KW - Sozialer Kontakt KW - Herzfrequenz KW - Angst als Zustand KW - Einsamkeit KW - Social Buffering KW - Ecological Momentary Assessment KW - Hautleitfähigkeit KW - Social Distancing Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-316859 ER - TY - JOUR A1 - Gründahl, Marthe A1 - Weiß, Martin A1 - Maier, Lisa A1 - Hewig, Johannes A1 - Deckert, Jürgen A1 - Hein, Grit T1 - Construction and validation of a scale to measure loneliness and isolation during social distancing and its effect on mental health JF - Frontiers in Psychiatry N2 - A variety of factors contribute to the degree to which a person feels lonely and socially isolated. These factors may be particularly relevant in contexts requiring social distancing, e.g., during the COVID-19 pandemic or in states of immunodeficiency. We present the Loneliness and Isolation during Social Distancing (LISD) Scale. Extending existing measures, the LISD scale measures both state and trait aspects of loneliness and isolation, including indicators of social connectedness and support. In addition, it reliably predicts individual differences in anxiety and depression. Data were collected online from two independent samples in a social distancing context (the COVID-19 pandemic). Factorial validation was based on exploratory factor analysis (EFA; Sample 1, N = 244) and confirmatory factor analysis (CFA; Sample 2, N = 304). Multiple regression analyses were used to assess how the LISD scale predicts state anxiety and depression. The LISD scale showed satisfactory fit in both samples. Its two state factors indicate being lonely and isolated as well as connected and supported, while its three trait factors reflect general loneliness and isolation, sociability and sense of belonging, and social closeness and support. Our results imply strong predictive power of the LISD scale for state anxiety and depression, explaining 33 and 51% of variance, respectively. Anxiety and depression scores were particularly predicted by low dispositional sociability and sense of belonging and by currently being more lonely and isolated. In turn, being lonely and isolated was related to being less connected and supported (state) as well as having lower social closeness and support in general (trait). We provide a novel scale which distinguishes between acute and general dimensions of loneliness and social isolation while also predicting mental health. The LISD scale could be a valuable and economic addition to the assessment of mental health factors impacted by social distancing. KW - loneliness KW - social isolation KW - social distancing KW - depression KW - anxiety Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269446 SN - 1664-0640 VL - 13 ER - TY - JOUR A1 - Gründahl, Marthe A1 - Weiß, Martin A1 - Stenzel, Kilian A1 - Deckert, Jürgen A1 - Hein, Grit T1 - The effects of everyday-life social interactions on anxiety-related autonomic responses differ between men and women JF - Scientific Reports N2 - Social buffering, a phenomenon where social presence can reduce anxiety and fear-related autonomic responses, has been studied in numerous laboratory settings. The results suggest that the familiarity of the interaction partner influences social buffering while also providing some evidence for gender effects. In the laboratory, however, it is difficult to mimic the complexity of real-life social interactions. Consequently, the social modulation of anxiety and related autonomic responses in everyday life remains poorly understood. We used smartphone-based Ecological Momentary Assessment (EMA) combined with wearable electrocardiogram sensors to investigate how everyday-life social interactions affect state anxiety and related cardiac changes in women and men. On five consecutive days, 96 healthy young participants (53% women) answered up to six EMA surveys per day, indicating characteristics of their most recent social interaction and the respective interaction partner(s). In women, our results showed lower heart rate in the presence of a male interaction partner. Men showed the same effect with female interaction partners. Moreover, only women showed decreased heart rate and increased heart rate variability with increasing interaction partner familiarity. These findings specify the conditions under which social interactions reduce anxiety-related responses in women and men. KW - physiology KW - psychology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357840 VL - 13 ER - TY - JOUR A1 - Grünewald, Benedikt A1 - Lange, Maren D A1 - Werner, Christian A1 - O'Leary, Aet A1 - Weishaupt, Andreas A1 - Popp, Sandy A1 - Pearce, David A A1 - Wiendl, Heinz A1 - Reif, Andreas A1 - Pape, Hans C A1 - Toyka, Klaus V A1 - Sommer, Claudia A1 - Geis, Christian T1 - Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis JF - eLife N2 - Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition. KW - CLN3 KW - mutation KW - mouse model KW - synaptic transmission KW - amygdala KW - hippocampus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170004 VL - 6 IS - e28685 ER - TY - THES A1 - Guhn, Anne T1 - Modulating the Fear Network: Preclinical Studies on Prefrontal Cortex Stimulation T1 - Modulation des Furchtnetzwerkes: Vorklinische Studien zur Stimulation des Präfrontalkortex N2 - Pavlovian fear conditioning describes a form of associative learning in which a previously neutral stimulus elicits a conditioned fear response after it has been temporally paired with an aversive consequence. Once acquired, the fear response can be extinguished by repeatedly presenting the former neutral stimulus in the absence of the aversive consequence. Although most patients suffering from anxiety disorders cannot recall a specific conditioned association between a formerly neutral stimulus and the feeling of anxiety, the produced behavioral symptoms, such as avoidance or safety behavior to prevent the anticipated aversive consequence are commonly exhibited in all anxiety disorders. Moreover, there is considerable similarity between the neural structures involved in fear and extinction in the rodent and in the human. Translational research thus contributes to the understanding of neural circuitries involved in the development and maintenance of anxiety disorders, and further provides hypotheses for improvements in treatment strategies aiming at inhibiting the fear response. Since the failure to appropriately inhibit or extinguish a fear response is a key feature of pathological anxiety, the present preclinical research focuses on the interplay between the amygdala and the medial prefrontal cortex (mPFC) during fear learning with particular regard to the prefrontal recruitment during fear extinction and its recall. By firstly demonstrating an increased mPFC activity over the time course of extinction learning with functional near-infrared spectroscopy, the main study of this dissertation focused on repetitive transcranial magnetic stimulation (rTMS) as brain stimulation technique suitable to enhance extinction learning. Since hypofrontality is assumed to underlie the maintenance of pathological anxiety, rTMS application revealed an increased mPFC activity, which resulted in a decreased fear response on the behavioral level both during extinction learning as well as during the recall of extinction 24 hours later and in the absence of another stimulation. The following attempt to improve the generalization of extinction with rTMS from an extinguished stimulus to a second stimulus which was reinforced but not extinguished was at least partially evidenced. By revealing an increased prefrontal activity to the non-extinguished stimulus, the active and the placebo rTMS condition, however, did not differ on behavioral parameters. These preclinical findings were discussed in the light of genetic and environmental risk factors with special regard to the combination of a risk variant of the neuropeptide S receptor 1 gene polymorphism (NPSR1 rs324981) and anxiety sensitivity. While the protective homozygous AA genotype group showed no correlation with anxiety sensitivity, the NPSR1 T genotype group exhibited an inverse correlation with anxiety sensitivity in the presence of emotionally negative stimuli. In light of other findings assuming a role of the NPSR1 T allele in panic disorder, the revealed hypofrontality was discussed to define a risk group of patients who might particularly benefit from an augmentation of exposure therapy with rTMS. Taken together, the presented studies support the central role of the prefrontal cortex in fear extinction and suggest the usefulness of rTMS as an augmentation strategy to exposure therapy in order to decrease therapy relapse rates. The combination of rTMS and extinction has been herein evidenced to modulate fear processes in a preclinical approach thereby establishing important implications for the design of future clinical studies. N2 - Die Furchtkonditionierung nach Pavlov beschreibt einen assoziativen Lernmechanismus bei dem ein ursprünglich neutraler Stimulus nach wiederholter kontingenter Darbietung mit einem aversiven Stimulus zu einer konditionierten Furchtreaktion führt, die darauffolgend allein durch den nun konditionierten Reiz ausgelöst werden kann. Obwohl die meisten Angstpatienten keine initiale Reiz-Reaktionsverbindung erinnern können, gelten die Mechanismen der Furchtkonditionierung als Erklärungsmodelle für die Entstehung und Aufrechterhaltung von Angststörungen. Evidenz erhalten sie zudem durch den Einsatz und die Wirksamkeit expositionsbasierter Methoden in der Behandlung von Angststörungen. Ihnen liegt die Extinktion einer erworbenen konditionierten Reaktion zugrunde, bei der der konditionierte Reiz wiederholt ohne seine erwartete aversive Konsequenz dargeboten wird. Dies führt in der Folge zu einer abnehmenden Furchtreaktion. Da die neuronalen Strukturen, die in den Erwerb und die Extinktion einer konditionierten Furchtreaktion involviert sind, weitgehend speziesübergreifend sind, lassen sich aus Tiermodellen wertvolle Hypothesen zur Verbesserung bestehender Behandlungsstrategien mit dem Ziel der Reduktion der erworbenen Furchtreaktion generieren. Eine unzureichende Inhibition bzw. Extinktion der Furchtreaktion gilt als Charakteristikum von pathologischer Angst. Die im Rahmen dieser Dissertation vorgestellten Studien beschäftigen sich mit dem zugrundliegenden neurobiologischen Ungleichgewicht zwischen der Amygdala und dem Präfrontalkortex, das als ursächlich für die Aufrechterhaltung pathologischer Angst vermutet wird. Zunächst wird hierbei eine Untersuchung vorgestellt, bei der die zunehmende Beteiligung des Präfrontalkortex' über den Verlauf eines Extinktionstrainings erstmals mit der funktionellen Nahinfrarot- Spektroskopie dargestellt werden konnte. Da zunehmende Evidenz auf eine unzureichende präfrontale Kortexaktivierung bei pathologischer Angst hindeutet, beschäftigt sich die Hauptstudie dieser Dissertation mit der Fragestellung, ob die Aktivität des Präfrontalkortex' mit Hilfe der repetitiven transkraniellen Magnetstimulation (rTMS) gesteigert werden kann. In Analogie zu tierexperimentellen Untersuchungen konnte in einer Gruppe gesunder Probanden nach einer Stimulation mit rTMS verglichen mit einer Placebobedingung eine verringerte Furchtreaktion gezeigt werden, die auch während des Abrufs des Extinktionsgedächtnis nach 24 Stunden und unabhängig von einer erneuten Stimulation noch nachweisbar war. In einem nächsten Schritt wurde, wiederum in Anlehnung an tierexperimentelle Studien, die Generalisierung eines Extinktionstrainings auf einen ebenfalls konditionierten, aber nicht extingierten Stimulus untersucht. Hierbei zeigte sich eine partielle Bestätigung der Hypothesen. So konnten zwar auf behavioraler Ebene keine Gruppenunterschiede zwischen einer aktiven und einer Placebobedingung detektiert werden, in der aktiven Gruppe ließ sich 24 Stunden nach der Stimulation jedoch eine erhöhte präfrontale Kortexaktivierung auf den nicht-extingierten Stimulus zeigen. Diese Studienergebnisse werden auf Basis einer weiteren Arbeit zu Gen-Umwelt-Einflüssen diskutiert. Hierbei konnte eine Konstellation bestehend aus der Risikovariante (T Allel) des Neuropeptid S Rezeptor Gens (NPSR1 rs324981) und einer erhöhten Angstsensitivität im Unterschied zu einer homozygoten AA Genotyp-Gruppe mit einer verringerten präfrontalen Kortexaktivierung auf negative emotionale Stimuli assoziiert werden. Unter Einbezug des literarischen Kontexts zu NPSR1 und dem Auftreten der Panikstörung legen diese Ergebnisse nahe, dass insbesondere solche und ähnliche Risikogruppen von einer Augmentationsstrategie mit rTMS profitieren könnten. Zusammenfassend bestätigen die vorliegenden Studien die Rolle des Präfrontalkortex bei der Furchtextinktion und legen den Einsatz der rTMS für die Verbesserung der Expositionstherapie nahe. Aus diesen präklinischen Arbeiten werden Hinweise für die Umsetzung von klinischen Studien generiert, die über die Augmentation von Exposition mit rTMS zu einer Rückfallreduktion bei der Therapie von Angststörungen beitragen könnten. KW - Angststörung KW - Fear Conditioning KW - Fear Extinction KW - Transcranial Magnetic Stimulation KW - Anxiety Disorders KW - Prefrontalt Cortex KW - Konditionierung KW - Präfrontaler Cortex KW - Fear Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133403 ER - TY - JOUR A1 - Guhn, Anne A1 - Dresler, Thomas A1 - Andreatta, Marta A1 - Müller, Laura D. A1 - Hahn, Tim A1 - Tupak, Sara V. A1 - Polak, Thomas A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Medial prefrontal cortex stimulation modulates the processing of conditioned fear N2 - 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). KW - fear conditioning KW - memory consolidation and extinction KW - learning KW - transcranial magnetic stimulation (TMS) KW - medial prefrontal cortex (mPFC) Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111309 ER - TY - JOUR A1 - Gutknecht, Lise A1 - Araragi, Naozumi A1 - Merker, Sören A1 - Waider, Jonas A1 - Sommerlandt, Frank M. J. A1 - Mlinar, Boris A1 - Baccini, Gilda A1 - Mayer, Ute A1 - Proft, Florian A1 - Hamon, Michel A1 - Schmitt, Angelika G. A1 - Corradetti, Renato A1 - Lanfumey, Laurence A1 - Lesch, Klaus-Peter T1 - Impacts of Brain Serotonin Deficiency following Tph2 Inactivation on Development and Raphe Neuron Serotonergic Specification JF - PLoS One N2 - Brain serotonin (5-HT) is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2). Tph2 inactivation (Tph2-/-) resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT) demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT\(_{1A}\) and 5-HT\(_{1B}\) receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis. KW - lacking KW - knock-out mice KW - energy expenditure KW - locomotor activity KW - 5-HT transporter KW - anxiety like KW - receptors KW - behavior KW - tryptophan KW - nucleus Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133728 VL - 7 IS - 8 ER - TY - JOUR A1 - Gutknecht, Lise A1 - Popp, Sandy A1 - Waider, Jonas A1 - Sommerlandt, Frank M. J. A1 - Göppner, Corinna A1 - Post, Antonia A1 - Reif, Andreas A1 - van den Hove, Daniel A1 - Strekalova, Tatyana A1 - Schmitt, Angelika A1 - Colaςo, Maria B. N. A1 - Sommer, Claudia A1 - Palme, Rupert A1 - Lesch, Klaus-Peter T1 - Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice JF - Psychopharmacology N2 - Rationale While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation. Objective Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene. Results Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2\(^{−/−}\)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2\(^{−/−}\) males displayed increased impulsivity and high aggressiveness. Tph2\(^{−/−}\) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2\(^{−/−}\) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner. Conclusions Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality. KW - Serotonin KW - Tryptophan hydroxylase-2 (Tph2) KW - chronic stress KW - gene-by-environment interaction KW - anxiety KW - fear KW - depression KW - aggression Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154586 VL - 232 SP - 2429 EP - 2441 ER - TY - JOUR A1 - Göpfert, Dennis A1 - Traub, Jan A1 - Sell, Roxane A1 - Homola, György A. A1 - Vogt, Marius A1 - Pham, Mirko A1 - Frantz, Stefan A1 - Störk, Stefan A1 - Stoll, Guido A1 - Frey, Anna T1 - Profiles of cognitive impairment in chronic heart failure—A cluster analytic approach JF - Frontiers in Human Neuroscience N2 - Background Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. Methods The prospective cohort study “Cognition.Matters-HF” recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Results Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the “global deficits” cluster and the “no deficits” group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Conclusion Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition. KW - chronic heart failure KW - cluster analysis KW - cognitive impairment KW - intensity of attention KW - glial fibrillary acidic protein Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313429 VL - 17 ER - TY - JOUR A1 - Haberstumpf, Sophia A1 - Forster, André A1 - Leinweber, Jonas A1 - Rauskolb, Stefanie A1 - Hewig, Johannes A1 - Sendtner, Michael A1 - Lauer, Martin A1 - Polak, Thomas A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Measurement invariance testing of longitudinal neuropsychiatric test scores distinguishes pathological from normative cognitive decline and highlights its potential in early detection research JF - Journal of Neuropsychology N2 - Objective Alzheimer’s disease (AD) is a growing challenge worldwide, which is why the search for early-onset predictors must be focused as soon as possible. Longitudinal studies that investigate courses of neuropsychological and other variables screen for such predictors correlated to mild cognitive impairment (MCI). However, one often neglected issue in analyses of such studies is measurement invariance (MI), which is often assumed but not tested for. This study uses the absence of MI (non-MI) and latent factor scores instead of composite variables to assess properties of cognitive domains, compensation mechanisms, and their predictability to establish a method for a more comprehensive understanding of pathological cognitive decline. Methods An exploratory factor analysis (EFA) and a set of increasingly restricted confirmatory factor analyses (CFAs) were conducted to find latent factors, compared them with the composite approach, and to test for longitudinal (partial-)MI in a neuropsychiatric test battery, consisting of 14 test variables. A total of 330 elderly (mean age: 73.78 ± 1.52 years at baseline) were analyzed two times (3 years apart). Results EFA revealed a four-factor model representing declarative memory, attention, working memory, and visual–spatial processing. Based on CFA, an accurate model was estimated across both measurement timepoints. Partial non-MI was found for parameters such as loadings, test- and latent factor intercepts as well as latent factor variances. The latent factor approach was preferable to the composite approach. Conclusion The overall assessment of non-MI latent factors may pose a possible target for this field of research. Hence, the non-MI of variances indicated variables that are especially suited for the prediction of pathological cognitive decline, while non-MI of intercepts indicated general aging-related decline. As a result, the sole assessment of MI may help distinguish pathological from normative aging processes and additionally may reveal compensatory neuropsychological mechanisms. KW - Alzheimer’s disease KW - early-onset predictors KW - mild cognitive impairment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318932 VL - 16 IS - 2 SP - 324 EP - 352 ER - TY - JOUR A1 - Haberstumpf, Sophia A1 - Leinweber, Jonas A1 - Lauer, Martin A1 - Polak, Thomas A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Factors associated with dropout in the longitudinal Vogel study of cognitive decline JF - The European Journal of Neuroscience N2 - Dementia, including Alzheimer's disease, is a growing problem worldwide. Prevention or early detection of the disease or a prodromal cognitive decline is necessary. By means of our long-term follow-up ‘Vogel study’, we aim to predict the pathological cognitive decline of a German cohort (mean age was 73.9 ± 1.55 years at first visit) with three measurement time points within 6 years per participant. Especially in samples of the elderly and subjects with chronic or co-morbid diseases, dropouts are one of the biggest problems of long-term studies. In contrast to the large number of research articles conducted on the course of dementia, little research has been done on the completion of treatment. To ensure unbiased and reliable predictors of cognitive decline from study completers, our objective was to determine predictors of dropout. We conducted multivariate analyses of covariance and multinomial logistic regression analyses to compare and predict the subject's dropout behaviour at the second visit 3 years after baseline (full participation, partial participation and no participation/dropout) with neuropsychiatric, cognitive, blood and lifestyle variables. Lower performance in declarative memory, attention and visual–spatial processing predicted dropout rather than full participation. Lower performance in visual–spatial processing predicted partial participation as opposed to full participation. Furthermore, lower performance in mini-mental status examination predicted whether subjects dropped out or participated partially instead of full participation. Baseline cognitive parameters are associated with dropouts at follow-up with a loss of impaired participants. We expect a bias into a healthier sample over time. KW - dementia KW - prevention KW - cognitive decline Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318945 VL - 56 IS - 9 SP - 5587 EP - 5600 ER - TY - JOUR A1 - Haeussinger, Florian B. A1 - Heinzel, Sebastian A1 - Hahn, Tim A1 - Schecklmann, Martin A1 - Ehlis, Ann-Christine A1 - Fallgatter, Andreas J. T1 - Simulation of Near-Infrared Light Absorption Considering Individual Head and Prefrontal Cortex Anatomy: Implications for Optical Neuroimaging JF - PLoS ONE N2 - Functional near-infrared spectroscopy (fNIRS) is an established optical neuroimaging method for measuring functional hemodynamic responses to infer neural activation. However, the impact of individual anatomy on the sensitivity of fNIRS measuring hemodynamics within cortical gray matter is still unknown. By means of Monte Carlo simulations and structural MRI of 23 healthy subjects (mean age: (25.0 +/- 2.8) years), we characterized the individual distribution of tissue-specific NIR-light absorption underneath 24 prefrontal fNIRS channels. We, thereby, investigated the impact of scalp-cortex distance (SCD), frontal sinus volume as well as sulcal morphology on gray matter volumes (V(gray)) traversed by NIR-light, i.e. anatomy-dependent fNIRS sensitivity. The NIR-light absorption between optodes was distributed describing a rotational ellipsoid with a mean penetration depth of (23.6 +/- 0.7) mm considering the deepest 5% of light. Of the detected photon packages scalp and bone absorbed (96.4 +/- 9: 7)% and V(gray) absorbed (3.1 +/- 1.8)% of the energy. The mean V(gray) volume (1.1 +/- 0.4)cm(3) was negatively correlated (r = - .76) with the SCD and frontal sinus volume (r = - .57) and was reduced by 41.5% in subjects with relatively large compared to small frontal sinus. Head circumference was significantly positively correlated with the mean SCD (r = .46) and the traversed frontal sinus volume (r = .43). Sulcal morphology had no significant impact on V(gray). Our findings suggest to consider individual SCD and frontal sinus volume as anatomical factors impacting fNIRS sensitivity. Head circumference may represent a practical measure to partly control for these sources of error variance. KW - Beer-lambert law KW - Adult head KW - Human brain KW - Spectroscopy fnirs KW - Photon migration KW - Propagation KW - Scattering KW - Model KW - Tissues KW - Media Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142311 VL - 6 IS - 10 ER - TY - THES A1 - Hahn, Tim T1 - Integrating neurobiological markers of depression: an fMRI-based pattern classification approach T1 - Integration neurobiologischer Marker depressiver Erkrankungen mittels fMRT-basierter Musterklassifikation N2 - While depressive disorders are, to date, diagnosed based on behavioral symptoms and course of illness, the interest in neurobiological markers of psychiatric disorders has grown substantially in recent years. However, current classification approaches are mainly based on data from a single biomarker, making it difficult to predict diseases such as depression which are characterized by a complex pattern of symptoms. Accordingly, none of the previously investigated single biomarkers has shown sufficient predictive power for practical application. In this work, we therefore propose an algorithm which integrates neuroimaging data associated with multiple, symptom-related neural processes relevant in depression to improve classification accuracy. First, we identified the core-symptoms of depression from standard classification systems. Then, we designed and conducted three experimental paradigms probing psychological processes known to be related to these symptoms using functional Magnetic Resonance Imaging. In order to integrate the resulting 12 high-dimensional biomarkers, we developed a multi-source pattern recognition algorithm based on a combination of Gaussian Process Classifiers and decision trees. Applying this approach to a group of 30 healthy controls and 30 depressive in-patients who were on a variety of medications and displayed varying degrees of symptom-severity allowed for high-accuracy single-subject classification. Specifically, integrating biomarkers yielded an accuracy of 83% while the best of the 12 single biomarkers alone classified a significantly lower number of subjects (72%) correctly. Thus, integrated biomarker-based classification of a heterogeneous, real-life sample resulted in accuracy comparable to the highest ever achieved in previous single biomarker research. Furthermore, investigation of the final prediction model revealed that neural activation during the processing of neutral facial expressions, large rewards, and safety cues is most relevant for over-all classification. We conclude that combining brain activation related to the core-symptoms of depression using the multi-source pattern classification approach developed in this work substantially increases classification accuracy while providing a sparse relational biomarker-model for future prediction. N2 - Während depressive Erkrankungen bislang größtenteils auf der Basis von Symptomen auf der Verhaltensebene und den jeweiligen Krankheitsverläufen diagnostiziert werden, hat das Interesse an der Verwendung neurobiologischer Marker bei psychischen Erkrankungen in den letzten Jahren stark zugenommen. Da jedoch die momentan verfügbaren Klassifikationsansätze zumeist auf Informationen eines einzelnen Biomarkers beruhen, ist die Vorhersage von auf der Symptomebene so komplexen Erkrankungen wie Depressionen in der Praxis deutlich erschwert. Dementsprechend konnte keiner der einzelnen bisher untersuchten Biomarker eine Vorhersagegüte erreichen, die für die praktische Anwendung eines solchen Ansatzes im klinischen Alltag ausreichend wäre. Vor diesem Hintergrund schlagen wir deshalb zur Verbesserung der Klassifikationsgüte einen Algorithmus vor, der Messdaten vielfältiger depressionsrelevanter neuronaler Prozesse integriert. Zunächst wurden hierzu die Kernsymptome depressiver Erkrankungen aus standardisierten Klassifikationssystemen ermittelt. Anschließend entwickelten wir drei experimentelle Paradigmen, welche die Messung neuronaler Korrelate der mit den depressiven Kernsymptomen assoziierten psychologischen Prozesse mittels funktioneller Kernspintomographie ermöglichen. Um die resultierenden 12 hochdimensionalen Biomarker zu integrieren, entwickelten wir basierend auf der Kombination von Gauß-Prozess Klassifikatoren und Entscheidungsbäumen einen zweistufigen Mustererkennungsalgorithmus für multiple, hochdimensionale Datenquellen. Dieser Ansatz wurde an einer Gruppe von 30 gesunden Probanden und 30 unterschiedlich schwer betroffenen und unterschiedlich medizierten stationären depressiven Patienten evaluiert. Insgesamt ermöglicht der Ansatz eine hohe Klassifikationsgüte auf Einzelfallebene. Insbesondere die Integration der verschiedenen Biomarker führte zu einer Klassifikationsgüte von 83%, wohingegen die alleinige Klassifikationsgüte der 12 einzelnen Biomarker mit bestenfalls 72% deutlich geringer ausfiel. Somit konnte der entwickelte Klassifikationsansatz in einer heterogenen, im Alltag aber typisch anzutreffenden depressiven Patientenstichprobe, eine Klassifikationsgüte erreichen, die mit der bislang bestmöglichen durch einzelne Biomarker erreichten Klassifikationsgüte in selektiven Einzelstichproben vergleichbar ist. Darüber hinaus zeigte die Analyse des empirischen Prädiktionsmodells, dass die Kombination der neuronalen Aktivität während der Verarbeitung von neutralen Gesichtern, großen monetären Belohnungen und Sicherheitssignalen zur optimalen Gesamtklassifikation führt. Zusammenfassend lässt sich schlussfolgern, dass der im Rahmen dieser Arbeit entwickelte, zweistufige Mustererkennungsalgorithmus für multiple, hochdimensionale Datenquellen die Klassifikationsgüte substantiell verbessert und erstmals die Konstruktion eines effizienten relationalen Biomarker-Modells für zukünftige Vorhersagen ermöglicht. KW - Patientenklassifikation KW - Depression KW - Biomarker KW - Neurobiologie KW - Algorithmus KW - Gauss Prozess Klassifikation KW - Klassifikations- und Regressionsbaum KW - Systematik KW - Automatische Klassifikation KW - Magnetische Resonanz KW - Gaussian Process Classification Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-49962 ER - TY - JOUR A1 - Hahn, Tim A1 - Dresler, Thomas A1 - Pyka, Martin A1 - Notebaert, Karolien A1 - Fallgatter, Andreas J. T1 - Local Synchronization of Resting-State Dynamics Encodes Gray's Trait Anxiety JF - PLoS ONE N2 - The Behavioral Inhibition System (BIS) as defined within the Reinforcement Sensitivity Theory (RST) modulates reactions to stimuli indicating aversive events. Gray's trait Anxiety determines the extent to which stimuli activate the BIS. While studies have identified the amygdala-septo-hippocampal circuit as the key-neural substrate of this system in recent years and measures of resting-state dynamics such as randomness and local synchronization of spontaneous BOLD fluctuations have recently been linked to personality traits, the relation between resting-state dynamics and the BIS remains unexplored. In the present study, we thus examined the local synchronization of spontaneous fMRI BOLD fluctuations as measured by Regional Homogeneity (ReHo) in the hippocampus and the amygdala in twenty-seven healthy subjects. Correlation analyses showed that Gray's trait Anxiety was significantly associated with mean ReHo in both the amygdala and the hippocampus. Specifically, Gray's trait Anxiety explained 23% and 17% of resting-state ReHo variance in the left amygdala and the left hippocampus, respectively. In summary, we found individual differences in Gray's trait Anxiety to be associated with ReHo in areas previously associated with BIS functioning. Specifically, higher ReHo in resting-state neural dynamics corresponded to lower sensitivity to punishment scores both in the amygdala and the hippocampus. These findings corroborate and extend recent findings relating resting-state dynamics and personality while providing first evidence linking properties of resting-state fluctuations to Gray's BIS. KW - reward KW - bold activity KW - amygdala KW - brain KW - personality KW - sensitivity KW - punishment KW - dimensions KW - modulation KW - predict Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131057 VL - 8 IS - 3 ER - TY - JOUR A1 - Hahn, Tim A1 - Karolien, Hilde A1 - Dresler, Thomas A1 - Kowarsch, Linda A1 - Reif, Andreas A1 - Fallgatter, Andreas J. T1 - Linking online gaming and addictive behavior: converging evidence for a general reward deficiency in frequent online garners JF - Frontiers in Behavioral Neuroscience N2 - Millions of people regularly play so-called massively multiplayer online role playing games (MMORPGs). Recently, it has been argued that MMORPG overuse is becoming a significant health problem worldwide. Symptoms such as tolerance, withdrawal, and craving have been described. Based on behavioral, resting state, and task-related neuroimaging data, we test whether frequent players of the MMORPG "World of VVarcraft" (WoW) similar to drug addicts and individuals with an increased risk for addictions show a generally deficient reward system. In frequent players of the MMORPG "World of VVarcraft" (WoW-players) and in a control group of non-gamers we assessed (1) trait sensitivity to reward (SR), (2) BOLD responses during monetary reward processing in the ventral striatum, and (3) ventral-striatal resting-state dynamics. We found a decreased neural activation in the ventral striatum during the anticipation of both small and large monetary rewards. Additionally, we show generally altered neurodynamics in this region independent of any specific task for WoW players (resting state). On the behavioral level, we found differences in trait SR, suggesting that the reward processing deficiencies found in this study are not a consequence of gaming, but predisposed to it. These findings empirically support a direct link between frequent online gaming and the broad field of behavioral and drug addiction research, thus opening new avenues for clinical interventions in addicted gamers and potentially improving the assessment of addiction-risk in the vast population of frequent gamers. KW - behavioral activation system KW - video-game KW - drug-addiction KW - sensitivity KW - dopamine KW - anticipation KW - massively multiplayer online role playing games KW - world of warcraft KW - resting-state fMRI KW - monetary incentive delay task KW - reward deficiency syndrome Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114737 SN - 1662-5153 VL - 14 IS - 8 ER - TY - JOUR A1 - Hamann, Catharina S. A1 - Bankmann, Julian A1 - Mora Maza, Hanna A1 - Kornhuber, Johannes A1 - Zoicas, Iulia A1 - Schmitt-Böhrer, Angelika T1 - Social fear affects limbic system neuronal activity and gene expression JF - International Journal of Molecular Sciences N2 - Social anxiety disorder (SAD) is a highly prevalent and comorbid anxiety disorder with rather unclear underlying mechanisms. Here, we aimed to characterize neurobiological changes occurring in mice expressing symptoms of social fear and to identify possible therapeutic targets for SAD. Social fear was induced via social fear conditioning (SFC), a validated animal model of SAD. We assessed the expression levels of the immediate early genes (IEGs) cFos, Fosl2 and Arc as markers of neuronal activity and the expression levels of several genes of the GABAergic, serotoninergic, oxytocinergic, vasopressinergic and neuropeptide Y (NPY)-ergic systems in brain regions involved in social behavior or fear-related behavior in SFC+ and SFC− mice 2 h after exposure to a conspecific. SFC+ mice showed a decreased number and density of cFos-positive cells and decreased expression levels of IEGs in the dorsal hippocampus. SFC+ mice also showed alterations in the expression of NPY and serotonin system-related genes in the paraventricular nucleus of the hypothalamus, basolateral amygdala, septum and dorsal raphe nucleus, but not in the dorsal hippocampus. Our results describe neuronal alterations occurring during the expression of social fear and identify the NPY and serotonergic systems as possible targets in the treatment of SAD. KW - social anxiety KW - fear expression KW - social avoidance KW - gene expression KW - Npy KW - Npyr1 KW - Npyr2 KW - Htr1a KW - Htr2a KW - Htr2c Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284274 SN - 1422-0067 VL - 23 IS - 15 ER - TY - THES A1 - Hamann, Catharina Sophia T1 - Fear and anxiety disorders – interaction of AVP and OXT brain systems with the serotonergic system T1 - Furcht und Angsterkrankungen – Interaktion von AVP und OXT Gehirnsystemen mit dem serotonergen System N2 - Anxiety disorders pose a great burden onto society and economy and can have devastating consequences for affected individuals. Treatment options are still limited to psychopharmacotherapy originally developed for the treatment of depression and behavioral therapy. A combination of genetic traits together with aversive events is most likely the cause of these diseases. Gene x environment studies are trying to find a link between genetic traits and specific negative circumstances. In a first study, we focused on social anxiety disorder (SAD), which is the second most-common anxiety disorder after specific phobias. We used a social fear conditioning (SFC) paradigm, which is able to mimic the disease in a mouse model. We wanted to investigate protein levels, as well as mRNA expression of immediate early genes (IEGs), to determine brain areas affected by the paradigm. We also included genes of the vasopressin (AVP)-, oxytocin (OXT)-, neuropeptide Y (NPY)-, and the serotonin system, to investigate the effects of SFC on neurotransmitter gene expression levels in brain regions related to social as well as fear-related behavior. AVP and OXT regulate a lot of different social and anxiety-related behaviors, both positive and negative. Finding a link between different neurotransmitter systems in the development of anxiety disorders could help to identify potential targets for new treatment approaches, which are desperately needed, because the rate of patients not responding to available treatment is very high. We were able to show altered gene expression of the IEGs cFos and Fosl2, as well as a change in number and density of cFOS-positive cells in the dorsal hippocampus, indicating an influence of SFC on neuronal activity. Our results reveal a possible involvement of anterior dentate gyrus (DG), as well as cornu ammonis area 1 (CA1) and CA3 in the dorsal hippocampus during the expression of social fear. Contrary to our hypothesis, we were not able to see changes in neuronal activity through expression changes of IEGs in the amygdala. Significant higher IEG immunoreactivity and gene expression in the dorsal hippocampus of animals without fear conditioning (SFC-), compared to animals with fear conditioning (SFC+), indicate an involvement of different hippocampal regions in two possible scenarios. Either as elevated gene expression in SFC- animals compared to SFC+ animals or as reduction in SFC+ animals compared to SFC- animals. However, this question cannot be answered without an additional control of basal IEG-activity without social interaction. The NPY system in general and the neuropeptide y receptor type 2 in particular seem to be involved in regulating the response to social fear, mostly through the septum region. In addition to that, a possible role for the induction of social fear response could be identified in the serotonergic system and especially the serotonin receptor 2a of the PVN. In a second study we focused on changes in the serotonergic system. A polymorphism in the human serotonin transporter (5-HTT) gene is associated with higher risks for the development of anxiety disorders. This makes the 5-HTT a widely used target to study possible causes and the development of anxiety disorders. In mice, a genetically induced knockout of the 5-Htt gene is associated with increased anxiety-like behavior. High amounts of stress during pregnancy, also known as prenatal stress, significantly increase the risk to develop psychiatric disorders for the unborn child. We utilized a prenatal stress paradigm in mice heterozygous for the 5-Htt gene. Some of the animals which had been subjected to prenatal stress showed noticeably “unsocial” interaction behavior towards conspecifics. Again, we were searching for links between the serotonergic system and AVP- and OXT systems. Through quantitative gene expression analysis, we were able to show that both AVP and OXT neuromodulator systems are affected through prenatal stress in female mice, but not in male mice. The 5-Htt genotype seems to be only slightly influential to AVP, OXT or any other neurotransmitter system investigated. Gene expression of AVP and OXT brain systems is highly influenced through the estrous cycle stages of female mice. Additionally, we analyzed the AVP and OXT neuropeptide levels of mice with different 5-Htt genotypes and in both sexes, in order to see whether the production of AVP and OXT is influenced by 5-Htt genotype. On neuropeptide level, we were able to identify a sex difference for vasopressin-immunoreactive (ir) cells in the PVN, with male mice harboring significantly more positive cells than female mice. N2 - Angsterkrankungen sind eine große Belastung für Gesellschaft und Wirtschaft und können verheerende Folgen für Betroffene haben. Behandlungsmöglichkeiten sind nach wie vor auf Psychopharmakotherapie, welche ursprünglich für die Behandlung von Depressionen entwickelt wurde, und Verhaltenstherapie beschränkt. Eine Kombination aus bestimmten genetischen Eigenschaften zusammen mit aversiven Lebensereignissen sind die wahrscheinlichste Ursache für die Entstehung dieser Erkrankungen. Gen x Umweltstudien versuchen dabei, Verbindungen zwischen genetischen Merkmalen und spezifischen negativen Ereignissen zu finden. In einer ersten Studie haben wir uns auf die soziale Phobie konzentriert, welche die zweithäufigste Angsterkrankung nach spezifischen Phobien ist. Wir haben ein soziales Furchtkonditionierungs-Paradigma (social fear conditioning, SFC), verwendet, welches in der Lage ist, die soziale Phobie im Tiermodell nachzustellen. Wir haben nach einer Verbindung zwischen dem serotonergen System und den zwei Systemen der Neuromodulatoren Vasopressin (AVP) und Oxytocin (OXT) gesucht. Diese Neuropeptide beeinflussen im Gehirn als Neuromodulatoren das Verhalten, und regulieren sowohl positive als auch negative Aspekte des Sozial- und Angstverhaltens. Eine gegenseitige Beeinflussung dieser Neurotransmittersysteme bei der Entstehung von Angsterkrankungen zu identifizieren könnte dabei helfen, potentielle Ziele für neue Behandlungsansätze zu finden. Diese werden dringend benötigt, da der prozentuale Anteil der Patienten, für die es keine wirksame Behandlung gibt, hoch ist. Wir haben Proteinebene und mRNA Expression von unmittelbar frühen Genen (immediate early genes, IEGs) analysiert, um zu ermitteln, in welchen Hirnregionen die neuronale Aktivität durch das Paradigma beeinflusst wird. Außerdem wurde in dieser Studie eine Untersuchung der Gene von AVP-, OXT-, Neuropeptid Y (NPY)-Systemen, sowie von Genen des serotonergen Transmissionssystems eingeschlossen. Damit sollten die Auswirkungen von SFC auf die Genexpression in Hirnregionen, die mit Sozial- sowie Angstverhalten in Verbindung stehen, ermittelt werden. Wir konnten sowohl eine veränderte Genexpression von verschiedenen IEGs wie cFos und Fosl2, als auch Veränderungen in Zahl und Dichte von cFOS-positiven Zellen feststellen, was einen Einfluss von SFC auf neuronale Aktivität andeutet. Unsere Ergebnisse offenbaren eine mögliche Beteiligung des Gyrus dentatus (DG), sowie der Cornu ammonis area 1 (CA1) und CA3 im dorsalen Hippocampus bei der Expression von sozialer Angst. Entgegen unseren Vermutungen waren in der Amygdala keine Veränderungen der neuronalen Aktivität durch Expressionsänderungen der IEGs nachzuweisen. Signifikant höhere IEG-Immunreaktivität und -Genexpression im dorsalen Hippocampus von Tieren ohne Furchtkonditionierung (SFC-) im Vergleich zu Tieren mit Furchtkonditionierung (SFC+) weisen auf zwei mögliche Szenarien hin. Entweder handelt es sich um eine verstärkte Expression in SFC--Tieren im Vergleich zu SFC+-Tieren, oder die Expression in SFC+-Tieren ist im Vergleich zu SFC--Tieren erniedrigt. Ohne eine zusätzliche Kontrolle der basalen mRNA Konzentration und des Proteinvorkommens der IEGs in einer Kontrollgruppe ohne soziale Interaktionsmöglichkeit kann diese Frage allerdings nicht beantwortet werden. Das NPY-System generell und der NPY-Rezeptor 2 im Speziellen scheinen in die Regulation der Reaktion auf soziale Angst involviert zu sein, und dies hauptsächlich im Septum. Zusätzlich konnte eine mögliche Rolle für das serotonerge System und insbesondere den Serotonin Rezeptor 2a im Nucleus paraventricularis (PVN) bei der Reaktion auf soziale Angst identifiziert werden. In einer zweiten Studie haben wir uns auf Veränderungen des serotonergen Systems konzentriert. Ein Polymorphismus im humanen Serotonintransporter Gen (5-HTT) konnte mit einem höheren Risiko für Angsterkrankungen assoziiert werden. Dies macht den 5-HTT zu einem weit verbreiteten Ziel zur Erforschung von möglichen Ursachen und der Entwicklung von Angsterkrankungen. In Mäusen ist ein gentechnisch induzierter knockout des 5-Htt Gens mit erhöhtem Angstverhalten assoziiert. Ein hohes Stresslevel während der Schwangerschaft, auch als pränataler Stress bekannt, erhöht das Risiko für spätere psychiatrische Erkrankungen des noch ungeborenen Kindes signifikant. In unserer Studie haben wir ein pränatales Stress-Paradigma in Mäusen mit einer Defizienz des 5-Htt Gens verwendet. In einer vorangegangenen Studie hatten sich bereits einige der Tiere, die pränatalem Stress ausgesetzt waren, in der Interaktion mit anderen Tieren auffällig „unsozial“ verhalten, bzw. geringes Sozialverhalten gezeigt. Wir haben erneut mithilfe von Genexpressionsstudien nach einer Verbindung zwischen dem serotonergen System und den AVP- und OXT-Systemen gesucht. Zusätzlich haben wir AVP und OXT in Mäusen mit verschiedenen 5-Htt Genotypen und in beiden Geschlechtern auf Neuropeptidebene analysiert, um zu sehen, ob die Produktion von AVP und OXT durch den 5-Htt Genotyp und das Geschlecht beeinflusst ist. Im Zuge der quantitativen Genexpressionsstudie konnten wir zeigen, dass die AVP- und OXT- Neuropeptidsysteme in weiblichen, aber nicht in männlichen Mäusen, durch Pränatalstress beeinflusst werden. Der 5-Htt Genotyp scheint AVP, OXT und andere untersuchte Neurotransmittersysteme nur geringfügig zu beeinflussen. In Weibchen ist die Genexpression von Oxt und Oxtr teilweise stark durch den Östruszyklus beeinflusst. Auf Neuropeptidebene konnten wir einen Geschlechterunterschied bzgl. der durchschnittlichen Anzahl AVP-positiver Zellen im PVN feststellen; männliche Tiere hatten signifikant mehr positive Zellen als weibliche Tiere. KW - Serotonin KW - Vasopressin KW - Oxytocin KW - Angststörung KW - Angsterkrankung KW - Anxiety disorders Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303338 ER - TY - JOUR A1 - Hampf, Chantal A1 - Scherf-Clavel, Maike A1 - Weiß, Carolin A1 - Klüpfel, Catherina A1 - Stonawski, Saskia A1 - Hommers, Leif A1 - Lichter, Katharina A1 - Erhardt-Lehmann, Angelika A1 - Unterecker, Stefan A1 - Domschke, Katharina A1 - Kittel-Schneider, Sarah A1 - Menke, Andreas A1 - Deckert, Jürgen A1 - Weber, Heike T1 - Effects of anxious depression on antidepressant treatment response JF - International Journal of Molecular Sciences N2 - Anxious depression represents a subtype of major depressive disorder and is associated with increased suicidality, severity, chronicity and lower treatment response. Only a few studies have investigated the differences between anxious depressed (aMDD) and non-anxious depressed (naMDD) patients regarding treatment dosage, serum-concentration and drug-specific treatment response. In our naturalistic and prospective study, we investigated whether the effectiveness of therapy including antidepressants (SSRI, SNRI, NaSSA, tricyclics and combinations) in aMDD patients differs significantly from that in naMDD patients. In a sample of 346 patients, we calculated the anxiety somatization factor (ASF) and defined treatment response as a reduction (≥50%) in the Hamilton Depression Rating Scale (HDRS)-21 score after 7 weeks of pharmacological treatment. We did not observe an association between therapy response and the baseline ASF-scores, or differences in therapy outcomes between aMDD and naMDD patients. However, non-responders had higher ASF-scores, and at week 7 aMDD patients displayed a worse therapy outcome than naMDD patients. In subgroup analyses for different antidepressant drugs, venlafaxine-treated aMDD patients showed a significantly worse outcome at week 7. Future prospective, randomized-controlled studies should address the question of a worse therapy outcome in aMDD patients for different psychopharmaceuticals individually. KW - pharmacotherapy KW - depressive disorder KW - anxious depression KW - anxiety KW - therapy response Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-355801 SN - 1422-0067 VL - 24 IS - 24 ER - TY - JOUR A1 - Harris, Fiona M. A1 - Maxwell, Margaret A1 - O'Connor, Rory C. A1 - Coyne, James A1 - Arensman, Ella A1 - András, Székely A1 - Gusmão, Ricardo A1 - Coffey, Claire A1 - Costa, Susana A1 - Zoltan, Cserháti A1 - Koburger, Nicole A1 - van Audenhove, Chantal A1 - McDaid, David A1 - Maloney, Julia A1 - Värnik, Peeter A1 - Hegerl, Ulrich T1 - Developing social capital in implementing a complex intervention: a process evaluation of the early implementation of a suicide prevention intervention in four European countries JF - BMC Public Health N2 - Background: Variation in the implementation of complex multilevel interventions can impact on their delivery and outcomes. Few suicide prevention interventions, especially multilevel interventions, have included evaluation of both the process of implementation as well as outcomes. Such evaluation is essential for the replication of interventions, for interpreting and understanding outcomes, and for improving implementation science. This paper reports on a process evaluation of the early implementation stage of an optimised suicide prevention programme (OSPI-Europe) implemented in four European countries. Methods: The process analysis was conducted within the framework of a realist evaluation methodology, and involved case studies of the process of implementation in four European countries. Datasets include: repeated questionnaires to track progress of implementation including delivery of individual activities and their intensity; serial interviews and focus groups with stakeholder groups; and detailed observations at OSPI implementation team meetings. Results: Analysis of local contexts in each of the four countries revealed that the advisory group was a key mechanism that had a substantial impact on the ease of implementation of OSPI interventions, particularly on their ability to recruit to training interventions. However, simply recruiting representatives of key organisations into an advisory group is not sufficient to achieve impact on the delivery of interventions. In order to maximise the potential of high level 'gatekeepers', it is necessary to first transform them into OSPI stakeholders. Motivations for OSPI participation as a stakeholder included: personal affinity with the shared goals and target groups within OSPI; the complementary and participatory nature of OSPI that adds value to pre-existing suicide prevention initiatives; and reciprocal reward for participants through access to the extended network capacity that organisations could accrue for themselves and their organisations from participation in OSPI. Conclusions: Exploring the role of advisory groups and the meaning of participation for these participants revealed some key areas for best practice in implementation: careful planning of the composition of the advisory group to access target groups; the importance of establishing common goals; the importance of acknowledging and complementing existing experience and activity; and facilitating an equivalence of benefit from network participation. KW - suicide prevention KW - realist evaluation KW - social capital KW - advisory groups KW - depression KW - strategies KW - alliance KW - complex interventions KW - process evaluation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122117 VL - 13 IS - 158 ER - TY - JOUR A1 - Hautmann, Christopher A1 - Döpfner, Manfred A1 - Katzmann, Josepha A1 - Schürmann, Stephanie A1 - Wolff Metternich-Kaizman, Tanja A1 - Jaite, Charlotte A1 - Kappel, Viola A1 - Geissler, Julia A1 - Warnke, Andreas A1 - Jacob, Christian A1 - Hennighausen, Klaus A1 - Haack-Dees, Barbara A1 - Schneider-Momm, Katja A1 - Philipsen, Alexandra A1 - Matthies, Swantje A1 - Rösler, Michael A1 - Retz, Wolfgang A1 - Gontard, Alexander von A1 - Sobanski, Esther A1 - Alm, Barbara A1 - Hohmann, Sarah A1 - Häge, Alexander A1 - Poustka, Luise A1 - Colla, Michael A1 - Gentschow, Laura A1 - Freitag, Christine M. A1 - Becker, Katja A1 - Jans, Thomas T1 - Sequential treatment of ADHD in mother and child (AIMAC study): importance of the treatment phases for intervention success in a randomized trial JF - BMC Psychiatry N2 - Background The efficacy of parent-child training (PCT) regarding child symptoms may be reduced if the mother has attention-deficit/hyperactivity disorder (ADHD). The AIMAC study (ADHD in Mothers and Children) aimed to compensate for the deteriorating effect of parental psychopathology by treating the mother (Step 1) before the beginning of PCT (Step 2). This secondary analysis was particularly concerned with the additional effect of the Step 2 PCT on child symptoms after the Step 1 treatment. Methods The analysis included 143 mothers and children (aged 6–12 years) both diagnosed with ADHD. The study design was a two-stage, two-arm parallel group trial (Step 1 treatment group [TG]: intensive treatment of the mother including psychotherapy and pharmacotherapy; Step 1 control group [CG]: supportive counseling only for mother; Step 2 TG and CG: PCT). Single- and multi-group analyses with piecewise linear latent growth curve models were applied to test for the effects of group and phase. Child symptoms (e.g., ADHD symptoms, disruptive behavior) were rated by three informants (blinded clinician, mother, teacher). Results Children in the TG showed a stronger improvement of their disruptive behavior as rated by mothers than those in the CG during Step 1 (Step 1: TG vs. CG). In the CG, according to reports of the blinded clinician and the mother, the reduction of children’s disruptive behavior was stronger during Step 2 than during Step 1 (CG: Step 1 vs. Step 2). In the TG, improvement of child outcome did not differ across treatment steps (TG: Step 1 vs. Step 2). Conclusions Intensive treatment of the mother including pharmacotherapy and psychotherapy may have small positive effects on the child’s disruptive behavior. PCT may be a valid treatment option for children with ADHD regarding disruptive behavior, even if mothers are not intensively treated beforehand. Trial registration ISRCTN registry ISRCTN73911400. Registered 29 March 2007. KW - mothers KW - children KW - adult treatment KW - parent training KW - efficacy Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227930 VL - 18 ER - TY - JOUR A1 - Hebestreit, Helge A1 - Zeidler, Cornelia A1 - Schippers, Christopher A1 - de Zwaan, Martina A1 - Deckert, Jürgen A1 - Heuschmann, Peter A1 - Krauth, Christian A1 - Bullinger, Monika A1 - Berger, Alexandra A1 - Berneburg, Mark A1 - Brandstetter, Lilly A1 - Deibele, Anna A1 - Dieris-Hirche, Jan A1 - Graessner, Holm A1 - Gündel, Harald A1 - Herpertz, Stephan A1 - Heuft, Gereon A1 - Lapstich, Anne-Marie A1 - Lücke, Thomas A1 - Maisch, Tim A1 - Mundlos, Christine A1 - Petermann-Meyer, Andrea A1 - Müller, Susanne A1 - Ott, Stephan A1 - Pfister, Lisa A1 - Quitmann, Julia A1 - Romanos, Marcel A1 - Rutsch, Frank A1 - Schaubert, Kristina A1 - Schubert, Katharina A1 - Schulz, Jörg B. A1 - Schweiger, Susann A1 - Tüscher, Oliver A1 - Ungethüm, Kathrin A1 - Wagner, Thomas O. F. A1 - Haas, Kirsten T1 - Dual guidance structure for evaluation of patients with unclear diagnosis in centers for rare diseases (ZSE-DUO): study protocol for a controlled multi-center cohort study JF - Orphanet Journal of Rare Diseases N2 - Background In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design This multi-center, prospective controlled study has a two-phase cohort design. Methods Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach. Conclusions This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease. KW - rare diseases KW - multi‑center cohort study KW - dual guidance Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300440 VL - 17 IS - 1 ER - TY - JOUR A1 - Hefner, Jochen A1 - Berberich, Sara A1 - Lanvers, Elena A1 - Sanning, Maria A1 - Steimer, Ann-Kathrin A1 - Kunzmann, Volker T1 - Patient-doctor relationship and adherence to capecitabine in outpatients of a German comprehensive cancer center JF - Patient Preference and Adherence N2 - Purpose: The prescribing of oral chemotherapy agents has introduced the new challenge of ensuring patients’ adherence to therapy. Aspects of a close patient–doctor relationship are reported to be correlated with adherence to oral anticancer drugs, but data on capecitabine are scarce. Patients and methods: Sixty-four outpatients with a diagnosis of cancer and prescribed capecitabine were recruited from a German Comprehensive Cancer Center. We used the Patient–Doctor Relationship Questionnaire (PDRQ-9), the Medical Adherence Rating Scale (MARS), the Beliefs about Medicines Questionnaire (BMQ), and the Satisfaction with Information about Medicines Scale (SIMS) to assess patients’ perceptions and behavior. Medical data were extracted from the charts. Results: Non-adherence was reported by 20% of the 64 participants. The perceived quality of the patient–doctor relationship was high in general, but it did not emerge as a predictor of adherence in our survey (odds ratio [OR]=0.915, P=0.162, 95% CI=0.808–1.036). However, beliefs about medicine (OR=1.268, P<0.002; 95% CI=1.090–1.475) as well as satisfaction with information about medicine (OR=1.252, P<0.040, 95% CI=1.010–1.551) were predictors of adherence and the quality of the patient–doctor relationship was correlated with both variables (r=0.373, P=0.002 for SIMS sum score; r=0.263, P=0.036 for BMQ necessity/concern difference). Overall, adherence to capecitabine was high with a conviction that the therapy is necessary. However, concerns were expressed regarding the long-term effect of capecitabine use. Patients have unmet information needs regarding interactions of capecitabine with other medicines and the impairment of their intimate life. Conclusions: In order to ensure adherence to capecitabine, our results seem to encourage the default use of modern and perhaps more impersonal means of information brokerage (eg, email, internet). However, the contents of some of patients’ informational needs as well as the associations of patients’ beliefs and satisfaction about the information received suggest a benefit from a trustful patient–doctor relationship. KW - oral anticancer drugs KW - patient-doctor-relationship KW - capecitabine Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177143 VL - 12 ER - TY - JOUR A1 - Hefner, Jochen A1 - Csef, Herbert A1 - Frantz, Stefan A1 - Glatter, Nina A1 - Warrings, Bodo T1 - Recurrent Tako-Tsubo cardiomyopathy (TTC) in a pre-menopausal woman: late sequelae of a traumatic event? JF - BMC Cardiovascular Disorders N2 - Background “Tako-Tsubo cardiomyopathy” (TTC) is a syndrome characterized by left ventricular (LV) wall motion abnormalities, usually without coronary artery disease, mimicking the diagnosis of acute coronary syndrome. It most often affects post-menopausal women and TTC tends to run a benign course with very low rates of recurrence, complications or mortality. The condition is also called “stress-induced cardiomyopathy” because acute physical or emotional stress appears to be frequently related to its onset. The pathogenic role of premorbid or comorbid psychiatric illnesses has been discussed controversially. For the first time, we present a case of fourfold recurrent TTC with severe complications in a pre-menopausal woman. Furthermore, a long history of flaring posttraumatic stress symptoms anteceded the first event. Case presentation A 43-year old, pre-menopausal Caucasian woman was hospitalized with symptoms of acute coronary syndrome. Clinical examination revealed hypokinetic wall motion in the apical ventricular region with no signs of coronary artery disease and diagnosis of TTC was established. She experienced recurrence three times within the following ten months, which led to thrombembolism and myocardial scarring among others. The circumstances of chronic distress were striking. 16 years ago she miscarried after having removed a myoma according to her doctor’s suggestion. Since then, she has suffered from symptoms of posttraumatic distress which peaked annually at the day of abortion. Chronic distress became even more pronounced after the premature birth of a daughter some years later. The first event of TTC occurred after a family dispute about parenting. Conclusion This is the first case report of fourfold TTC in a pre-menopausal woman. From somatic perspectives, the course of the disease with recurrences and complications underlines the fact that TTC is not entirely benign. Furthermore, it is the first case report of long lasting symptoms of traumatic stress anteceding TTC. Close connections between adrenergic signaling and late onset of clinical stress symptoms are well known in the psychopathology of traumatization. Although larger clinical trials are needed to elucidate possible interactions of premorbid psychiatric illnesses and TTC, cardiologists should be vigilant especially in cases of recurrent TTC. KW - recurrent Tako-Tsubo cardiomyopathy KW - chronic distress KW - gene-environment interaction KW - comprehensive psychosomatic assessment Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124949 VL - 15 IS - 3 ER -