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 - THES A1 - Schwitalla [geb. Schmitt], Lisa T1 - Messung niederfrequenter Oszillationen im frontalen und parietalen Kortex mit funktioneller Nahinfrarotspektroskopie in Abhängigkeit vom ApoE-Genotyp T1 - Measurement of low-frequency oscillations in the frontal and parietal cortex with functional near-infrared spectroscopy as a function of the ApoE genotype N2 - Niederfrequenten Oszillationen rücken immer mehr in den Blickpunkt der Forschung um Probanden mit kognitiven Beeinträchtigungen zu untersuchen. Bei an Alzheimer-Demenz erkrankten Patienten konnten bereits Veränderungen niederfrequenter Oszillationsmuster, als Folge pathologischer Umbauprzesse im Gehirn festgestellt werden. Neben zahlreichen prädisponierenden Risikofaktoren für die Entwicklung einer Alzheimer-Demenz existiert eine anerkannte Interaktion zwischen dem erhöhten Erkrankungsrisiko bei Vorliegen des ApoE4-Genotyps. Im Gegensatz zu neutralen ApoE3-Allelträgern weisen Träger der ApoE4-Variante ein erhöhtes Risiko auf, Alzheimer-Demenz zu entwickeln, die ApoE2-Variante gilt hingegen als protektiv. Es war Ziel der Studie, den Einfluss des ApoE-Genotyps auf die Oszillationsmuster unter Ruhebedingungen des Gehirns zu untersuchen. Mögliche frühzeitige Veränderungen niederfrequenter Oszillationen könnten dann als frühdiagnostische Marker auf dementielle Prozesse hinweisen. Insgesamt wurden 277 gesunde Probanden im Alter von 70-75 Jahren mittels funktioneller Nahinfrarotspektroskopie im frontalen und parietalen Kortex untersucht. Dabei konnten ApoE-Genotyp abhängige Veränderungen niederfrequenter Oszillationen im parietalen Kortex nachgewiesen werden. N2 - Low-frequency oscillations are increasingly becoming the focus of research to investigate subjects with cognitive impairment. In patients with Alzheimer's dementia, changes in low-frequency oscillation patterns as a result of pathological remodeling in the brain have already been detected. In addition to numerous predisposing risk factors for the development of Alzheimer's dementia, there is a recognized interaction between the increased risk of disease in the presence of the ApoE4 genotype. In contrast to neutral ApoE3 allele carriers, carriers of the ApoE4 variant have an increased risk of developing Alzheimer's dementia, whereas the ApoE2 variant is regarded as protective. The aim of the study was to investigate the influence of the ApoE genotype on the oscillation pattern under rest conditions of the brain. Possible early changes in low-frequency oscillations could then point to dementia processes as early diagnostic markers. A total of 277 healthy volunteers aged 70-75 years were examined by functional near-infrared spectroscopy in the frontal and parietal cortex. ApoE genotype-dependent changes in low-frequency oscillations in the parietal cortex could be detected. KW - niederfrequente Oszillationen KW - ApoE-Genotyp KW - Demenz vom Alzheimer Typ KW - Ruhebedingungen KW - funktionelle Nahinfrarotspektroskopie Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158832 ER - TY - THES A1 - Kopetschke, Maren T1 - Vagus-somatosensorisch evozierte Potentiale (VSEP) – Testung der Reliabilität und Untersuchungen zu alternativen Stimulations- und Ableitbedingungen T1 - Vagus somatosensory evoked potentials – Testing of reliability and investigation of alternative stimulation and recording sites N2 - Die Ableitung Vagus-somatosensibel evozierter Potentiale (VSEP) ist eine vielversprechende, kostengünstige und nicht-invasive Methode zur Frühdiagnostik von Alzheimer-Demenz. In der vorliegenden Arbeit wurde die Retest-Reliabilität der VSEP untersucht. Des Weiteren wurden alternative Stimulationsbedingungen (Stimulation in der Cymba conchae und im anterioren äußeren Gehörgang) und alternative Ableitbedingungen (referentielle Ableitungen mit Elektroden an Mastoid, Spina scapulae, Vertebra prominens und Handrücken) getestet und mit der herkömmlichen Methode verglichen. Die Reliabilitätsuntersuchungen wurden an 24 gesunden Probanden im Abstand von sechs Monaten durchgeführt. Die alternativen Stimulations- und Ableitbedingungen wurden an je zehn bis zwölf Probanden angewandt und die Ergebnisse mit denen von Messungen mit der herkömmlichen Methode verglichen. Es zeigte sich eine besonders gute Reliabilität in den Ableitungen T3/O1 und T4/O2. Außerdem liegen Hinweise darauf vor, dass das Alter der Probanden die Reliabilität beeinflusst. Als beste alternative Ableitposition erwies sich das Mastoid. Die Messungen mit alternativen Stimulationspositionen ergaben stark von der herkömmlichen Methode abweichende Ergebnisse, deren Ursache die vorliegende Studie nicht sicher klären kann. N2 - The recording of vagus somatosensory evoked potentials (VSEP) is a promising, cheap and non-invasive method for the early diagnosis of Alzheimer´s disease. The present study examined the retest-reliability of VSEP. Furthermore alternative stimulation sites (stimulation at cymba concha and at the anterior side of the external auditory canal) as well as alternative recording sides (recording electrodes at mastoid, spina scapulae, vertebra prominens and dorsum of the hand) were examined and compared to the standard method. For the reliability tests, VSEP-measures were performed on 24 healthy subjects at intervals of at least six months. For the alternative stimulation and recording sites VSEP measures were carried out on ten to twelve subjects for each site and the results were then compared to the ones of measures with the conventional method. The recording positions T3/O1 and T4/O2 showed the highest reliability. Additionally there is evidence for an affection of reliability by the subjects´ age. Among the alternative recording sites, mastoid showed to be the most appropriate one. The VSEP-measures with alternative stimulation sites revealed highly divergent results compared to the results from standard measures. The present study cannot certainly clarify the reasons for these divergences. KW - Vagus KW - Evoziertes Potenzial KW - Evoked potential KW - Alzheimer KW - Reliabilität KW - Vagus-somatosensorisch evozierte Potentiale Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187009 ER - TY - JOUR A1 - Ziegler, C. A1 - Richter, J. A1 - Mahr, M. A1 - Gajewska, A. A1 - Schiele, M.A. A1 - Gehrmann, A. A1 - Schmidt, B. A1 - Lesch, K.-P. A1 - Lang, T. A1 - Helbig-Lang, S. A1 - Pauli, P. A1 - Kircher, T. A1 - Reif, A. A1 - Rief, W. A1 - Vossbeck-Elsebusch, A.N. A1 - Arolt, V. A1 - Wittchen, H.-U. A1 - Hamm, A.O. A1 - Deckert, J. A1 - Domschke, K. T1 - MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy JF - Translational Psychiatry N2 - Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects. KW - Adult KW - Case-Control Studies KW - Cognitive Therapy KW - DNA Methylation KW - Epigenesis KW - Genetic KW - Female KW - Humans KW - Monoamine Oxidase/genetics KW - Panic Disorder/genetics KW - Panic Disorder/therapy KW - Sequence Analysis KW - DNA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164422 IS - 6 ER - TY - THES A1 - Kropp, Anna Marlene T1 - Pharmakotherapie-Epigenetik der Depression – DNA-Methylierung des Serotonin-Transporter-Gens (5-HTT, SLC6A4) T1 - Pharmacotherapy-epigenetics of depression – DNA-methylation of the serotonin transporter gene (5-HTT, SLC6A4) N2 - Die unipolare Depression ist eine der häufigsten psychiatrischen Erkrankungen und geht mit einem hohen Leidensdruck für die Betroffenen einher. Die Symptomatik der Depression besteht v.a. aus gedrückter Stimmung, Interessenverlust und Antriebslosigkeit und führt bei den Betroffenen zu Einbußen in der sozialen und beruflichen Funktionalität. Daneben leiden die Patienten aber auch unter wechselnden Therapieversuchen u.a. aufgrund von fehlendem Ansprechen auf Medikamente. Trotz intensiver Forschung sind die Mechanismen der Krankheitsentstehung und die Wirkweise der antidepressiven Therapie nur teilweise verstanden. Genetische Studien identifizierten einige Suszeptibilitätsgene, die jedoch die Erblichkeit der depressiven Erkrankung nicht ausreichend erklären. Diese „missing heritability“ könnte durch epigenetische Faktoren wie z.B. Veränderungen in der DNA-Methylierung bedingt sein. Neben einer ätiopathogenetischen Rolle kommen epigenetische Modifikationen auch als Marker zur Prädiktion des Therapieerfolgs sowie als Korrelat des biologischen Wirkmechanismus der antidepressiven Therapie infrage. Die vorliegende Arbeit untersuchte daher die Pharmakotherapie-Epigenetik eines Suszeptibilitätsgens (SLC6A4, 5 HTT), das den Serotonin-Transporter kodiert. Hierbei wurde die wechselseitige Beziehung zwischen der antidepressiven Pharmakotherapie und der DNA-Methylierung von neun CpG-Dinukleotiden des Serotonin-Transporter-Gens in Hinblick auf den Therapieerfolg analysiert. Dabei kamen molekularbiologische Methoden wie die Bisulfitsequenzierung zur Ermittlung der DNA-Methylierung sowie psychometrische Diagnostik zur Quantifizierung des Therapieansprechens zum Einsatz. Stationär aufgenommene Patienten mit einer aktuellen depressiven Episode wiesen einen eher geringen durchschnittlichen Methylierungsgrad des Serotonin-Transporter-Gens von 5,5 % auf, wobei die Werte der einzelnen CpG-Dinukleotide von 1,6 % bis 9,8 % reichten. Die mittlere Methylierung zu Studienbeginn sowie die Methylierung der einzelnen CpG-Dinukleotide zeigte dabei keine Korrelation mit dem Therapieerfolg, d.h. der Änderung im Hamilton-Score. Patienten mit hoher und niedriger Methylierung unterschieden sich nicht eindeutig im Wochenverlauf der Hamilton-Scores und auch eine Einteilung der Patienten nach Response bzw. Remission ergab keine Unterschiede der SLC6A4-Methylierung in den jeweiligen Gruppen. Der Methylierungsstatus des 5 HTT-Gens sowie die Methylierungswerte einzelner CpG-Dinukleotide sind demnach diesen Daten zufolge nicht zur Prädiktion des Therapieerfolgs geeignet. Nach sechswöchiger Psychopharmakotherapie lag die mittlere Methylierung bei 6,0 %, wobei keine signifikante Veränderung nachgewiesen werden konnte. Einzelne CpG-Dinukleotide zeigten jedoch einen Trend zu einer Methylierungszunahme. Die mittlere Methylierungänderung korrelierte nicht mit der Änderung des Hamilton-Scores, nur für CpG6 und CpG9 ergaben sich nominell signifikante positive Korrelationen. Gruppiert nach Response bzw. Remission konnte kein signifikanter Unterschied der mittleren Methylierungsänderungen nachgewiesen werden. Bei Therapie-Respondern schien die Methylierung an den meisten CpG-Dinukleotiden zuzunehmen. Lediglich bei CpG6, CpG8 und CpG9 wiesen Non-Responder eine stärkere Methylierungszunahme auf. Auffällig war v.a. CpG1, das bei Non-Respondern eine nominell signifikante Methylierungsabnahme zeigte. Demnach besteht möglicherweise ein Zusammenhang zwischen der Methylierungsänderung einzelner CpG-Dinukleotide des 5 HTT-Gens unter antidepressiver Therapie und dem Therapieerfolg der Patienten. In Bezug auf die Pharmakotherapie hatten ausschließlich SSRI einen signifikanten Einfluss auf die Änderung der SLC6A4-Methylierung. Dabei zeigten Patienten unter SSRI-Therapie eine deutliche Methylierungszunahme, die synergistisch mit der Blockade des Serotonin-Transporters wirken könnte. Epigenetische Modifikationen des 5 HTT-Gens kommen folglich als molekularer Wirkmechanismus dieser Behandlung in Betracht und implizieren neue Ansätze für innovative Pharmakotherapeutika. Die vorliegende Arbeit liefert somit einen Beitrag zum Verständnis der zugrundeliegenden molekularbiologischen Prozesse der antidepressiven Therapie. Zur Sicherung und Replikation der gefundenen Ergebnisse sind jedoch weitere Studien mit größeren und genauestens charakterisierten Stichproben nötig. N2 - Unipolar Depression is one of the most frequent psychiatric diseases and is characterized by an enormous strain for the persons affected. The symptoms of depression are composed of depressed mood, loss of interest and reduced energy and cause deficits in social and professional functionality. Additionally, patients suffer from changing treatment attempts due to non-response to medication. Despite intensive research, mechanisms of disease development and antidepressant action are only partly understood. Genetic studies identified several susceptibility genes which however cannot completely explain the heritability of depressive disorder. This „missing heritability” could be due to epigenetic factors like e.g. changes in DNA methylation. Besides an etiopathogenetic role, epigenetic modifications can also be considered as predictive markers of therapy success as well as biological mechanisms of antidepressant therapy. Thus the present study investigated the pharmacotherapy-epigenetics of a susceptibility gene (SLC6A4, 5 HTT) which codes for the serotonin transporter. The reciprocal relation between antidepressant pharmacotherapy and DNA methylation of nine CpG dinucleotides of the serotonin transporter gene was analysed with regard to therapy success. Therefore molecular biological methods like bisulfite sequencing to determine DNA methylation as well as psychometric diagnostics to quantify therapy response were used. In-patients with acute depressive episode showed a rather low mean methylation level of the serotonin transporter gene of 5,5 % while values of the individual CpG dinucleotides ranged from 1,6 % to 9,8 %. The mean methylation at baseline as well as the methylation of the individual CpG dinucleotides did not show a correlation with therapy success that is the change in Hamilton score. Patients with high and low methylation did not differ in weekly Hamilton scores and a classification of patients by response or remission status did not yield any difference in SLC6A4 methylation between the respective groups. According to this data, the methylation status of the 5-HTT gene as well as the methylation values of the individual CpG dinucleotides are therefore not applicable for the prediction of therapy success. After six weeks of psychopharmacotherapy the mean methylation was 6,0 % whereas no significant change could be detected. However, individual CpG dinucleotides showed a trend towards an increase of methylation. The mean change in methylation did not correlate with the change in Hamilton score, only for CpG6 and CpG9 nominally significant positive correlations were demonstrated. Grouped by response and remission respectively, no significant difference in mean methylation change was detected. The methylation of the most CpG dinucleotides seemed to increase in therapy responders. Only at CpG6, CpG8 and CpG9 non-responder revealed a stronger increase in methylation. Noticeable above all was CpG1, that showed a nominally significant decrease in methylation in non-responders. Therefore a relation possibly might exist between methylation change of individual CpG dinucleotides of the 5-HTT gene under antidepressant therapy and therapy success of the patients. With regard to pharmacotherapy only SSRI had a significant influence of the change in SLC6A4 methylation. Patients under SSRI therapy showed a clear increase in methylation, which could act synergistic with the blockade of the serotonin transporter. Therefore epigenetic modifications of the 5-HTT gene should be considered as molecular mechanism of action of this treatment and implicate new approaches for innovative pharmacotherapeutics. The present work thus provides a contribution to the understanding of underlying molecular biological processes of antidepressant therapy. To assure and replicate the detected results further studies with larger and precisely characterized samples are necessary. KW - Depression KW - Epigenetik KW - Serotonin KW - Pharmakoepigenetik KW - Serotonin-Transporter-Gen KW - DNA-Methylierung KW - Antidepressiva Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166064 ER - TY - THES A1 - Schmidt, Brigitte T1 - Veränderungen von Angstsensitivität und allgemeiner Selbstwirksamkeit bei der Therapie der Panikstörung T1 - Changes of anxiety sensitivity and General self-efficacy after therapy of panic disorder N2 - In einer Studie mit 60 Patienten mit Panikstörung und einer aus 60 gesunden Probanden bestehenden Kontrollgruppe wurde eine standardisierte kognitive Verhaltenstherapie mit Psychoedukation und Expositionsübungen durchgeführt. Zu verschiedenen Zeitpunkten wurde mittels Fragebögen die Angstsensitivität (ASI) und allgemeine Selbstwirksamkeitserwartung (GSE) gemessen. Weiterhin wurden Daten zu angstbezogenen Kognitionen (ACQ) und die Anzahl der Panikattacken pro Woche erhoben. Patienten mit Panikstörung wiesen zu Beginn eine niedrigere allgemeine Selbstwirksamkeitserwartung und eine höhere Angstsensitivität auf als gesunde Probanden. Nach der Psychoedukation kam es zu einer Reduktion der Angstsensitivität, nach der Exposition zu einem Anstieg der Selbstwirksamkeitserwartung bei der Patientengruppe. Die Patientengruppe erreichte außerdem einen Rückgang der angstbezogenen Kognitionen. Die Anzahl der Panikattacken veränderte sich nicht signifikant. Die Veränderung von mit der GSE-Skala gemessener Selbstwirksamkeitserwartung durch standardisierte kognitive Verhaltenstherapie bei Panikstörung wurde in der vorliegenden Studie erstmals beschrieben. Es wurde gezeigt, dass durch eine standardisierte kognitive Verhaltenstherapie bei Patienten mit Panikstörung neben einer Reduktion der Angstsensitivität nicht nur, wie bereits bekannt, die panikbezogene Selbstwirksamkeitserwartung gesteigert werden kann, sondern auch die allgemeine Selbstwirksamkeitserwartung. Die Veränderungen wurden außerdem hinsichtlich des Angstsensitivitäts-Responderstatus untersucht. Patienten, die bezüglich der Angstsensitivität mehr als 50 % Verbesserung zeigten (ASI-Responder), zeigten nach der Therapie keinen signifikanten Unterschied mehr zu den Werten von Angstsensitivität, allgemeiner Selbstwirksamkeitserwartung und angstbezogenen Kognitionen der Kontrollgruppe. Bei den ASI-Respondern fanden der signifikante Anstieg des GSE-Werts und der Rückgang des ACQ-Werts bereits nach der Psychoedukation statt. In zukünftigen Studien sollten Unterschiede zwischen ASI-Respondern und ASI-Non-Respondern sowie weitere Maßnahmen zur Reduktion von Angstsensitivität und zur Stärkung der Selbstwirksamkeitserwartung mit dem Ziel der Prävention und Therapie von Angsterkrankungen untersucht werden. N2 - In this study, 60 patients with panic disorder underwent standardized cognitive-behavioral therapy including psychoeducation and exposure exercises and were compared with 60 healthy controls. Anxiety sensitivity (ASI) and general self-efficacy (GSE) were measured at several times, as well as agoraphobic cognitions (ACQ) and the number of panic attacks per week. Compared to controls, patients with panic disorder had a lower self-efficacy and a higher anxiety sensitivity at baseline. After psychoeducation, anxiety sensitivity decreased, after exposure exercises general self-efficacy increased in patients. Agoraphobic cognitions were also reduced. There was no significant effect on the number of panic attacks. Changes in general self-efficacy, measured with the GSE-scale, after cognitive-behavioral therapy in patients with panic disorder were described for the first time in this study. It was shown, that a standardized cognitive-behavioral therapy increases not only, as already known, panic-related self-efficacy, but also general self-efficacy. Changes were further examined considering the response-status in anxiety sensitivity. After therapy, there was no difference in anxiety sensitivity, general self-efficacy and agoraphobic cognitions between patients who reached more than 50 % improvement in anxiety sensitivity (ASI-responders) and controls. ASI-responders already showed a significant improvement in GSE and ACQ after psychoeducation. Future investigation should examine the differences between ASI-responders and ASI-non-responders, as well as further methods to reduce anxiety sensitivity and increase self-efficacy aiming at prevention and therapy of anxiety diseases. KW - Angststörung KW - Selbstwirksamkeit KW - Panikstörung KW - Angstsensitivität Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-163055 ER - TY - JOUR A1 - Klenk, Christoph A1 - Hommers, Leif A1 - Lohse, Martin J. T1 - Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone 1 receptor JF - Frontiers in Endocrinology N2 - Parathyroid hormone 1 receptor (PTH1R) is a member of the class B family of G protein-coupled receptors, which are characterized by a large extracellular domain required for ligand binding. We have previously shown that the extracellular domain of PTH1R is subject to metalloproteinase cleavage in vivo that is regulated by ligand-induced receptor trafficking and leads to impaired stability of PTH1R. In this work, we localize the cleavage site in the first loop of the extracellular domain using amino-terminal protein sequencing of purified receptor and by mutagenesis studies. We further show, that a receptor mutant not susceptible to proteolytic cleavage exhibits reduced signaling to G\(_s\) and increased activation of G\(_q\) compared to wild-type PTH1R. These findings indicate that the extracellular domain modulates PTH1R signaling specificity, and that its cleavage affects receptor signaling. KW - GPCRs KW - parathyroid hormone 1 receptor KW - matrix metalloproteinase KW - ectodomain cleavage KW - biased signaling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262055 SN - 1664-2392 VL - 13 ER - TY - JOUR A1 - Riederer, P. A1 - Monoranu, C. A1 - Strobel, S. A1 - Iordache, T. A1 - Sian-Hülsmann, J. T1 - Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease JF - Journal of Neural Transmission N2 - About 60 years ago, the discovery of a deficiency of dopamine in the nigro-striatal system led to a variety of symptomatic therapeutic strategies to supplement dopamine and to substantially improve the quality of life of patients with Parkinson's disease (PD). Since these seminal developments, neuropathological, neurochemical, molecular biological and genetic discoveries contributed to elucidate the pathology of PD. Oxidative stress, the consequences of reactive oxidative species, reduced antioxidative capacity including loss of glutathione, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, autophagy, suggested to be causal for ɑ-synuclein fibril formation and aggregation and contributing to neuroinflammation and neural cell death underlying this devastating disorder. However, there are no final conclusions about the triggered pathological mechanism(s) and the follow-up of pathological dysfunctions. Nevertheless, it is a fact, that iron, a major component of oxidative reactions, as well as neuromelanin, the major intraneuronal chelator of iron, undergo an age-dependent increase. And ageing is a major risk factor for PD. Iron is significantly increased in the substantia nigra pars compacta (SNpc) of PD. Reasons for this finding include disturbances in iron-related import and export mechanisms across the blood-brain barrier (BBB), localized opening of the BBB at the nigro-striatal tract including brain vessel pathology. Whether this pathology is of primary or secondary importance is not known. We assume that there is a better fit to the top-down hypotheses and pathogens entering the brain via the olfactory system, then to the bottom-up (gut-brain) hypothesis of PD pathology. Triggers for the bottom-up, the dual-hit and the top-down pathologies include chemicals, viruses and bacteria. If so, hepcidin, a regulator of iron absorption and its distribution into tissues, is suggested to play a major role in the pathogenesis of iron dyshomeostasis and risk for initiating and progressing ɑ-synuclein pathology. The role of glial components to the pathology of PD is still unknown. However, the dramatic loss of glutathione (GSH), which is mainly synthesized in glia, suggests dysfunction of this process, or GSH uptake into neurons. Loss of GSH and increase in SNpc iron concentration have been suggested to be early, may be even pre-symptomatic processes in the pathology of PD, despite the fact that they are progression factors. The role of glial ferritin isoforms has not been studied so far in detail in human post-mortem brain tissue and a close insight into their role in PD is called upon. In conclusion, "iron" is a major player in the pathology of PD. Selective chelation of excess iron at the site of the substantia nigra, where a dysfunction of the BBB is suggested, with peripherally acting iron chelators is suggested to contribute to the portfolio and therapeutic armamentarium of anti-Parkinson medications. KW - SARS-CoV-2 KW - iron in parkinsonism KW - parkinson’s disease KW - iiron transporter KW - neuromelanin KW - iron pathology KW - neuroinflammation KW - iron model KW - ferroptosis KW - ɑ-Synuclein and iron KW - virus–iron interaction KW - COVID-19 KW - hepcidin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268539 SN - 1435-1463 VL - 128 IS - 10 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 - Erhardt, Angelika A1 - Meier, Sandra A1 - Deckert, Jürgen T1 - Genetik und Epigenetik von Angsterkrankungen JF - BIOspektrum N2 - Anxiety disorders are the most common mental disorders. The etiology is complex involving genetic and environmental factors. The first genome-wide association studies so far implicate a number of genetic loci, genome-wide epigenetic and therapy response related genetic studies are emerging. Genetic studies of anxiety disorders — as the most recent Psychiatric Genomics Consortium (PGC) group of disorders — are at the threshold of providing findings comparable to other mental disorders. KW - Genetik KW - Epigenetik Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232380 SN - 0947-0867 VL - 26 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 - THES A1 - Zech, Linda T1 - Vitamin-D-Status und depressive Symptome bei gerontopsychiatrischen Patienten T1 - Vitamin d level and depressive symptoms in psychogeriatric patients N2 - In der vorliegenden Studie wurde der Zusammenhang des depressiven Syndroms mit dem Vitamin D-Spiegel an einer Stichprobe gerontopsychiatrischer Patienten (n = 140) der Neurogerontopsychiatrischen Tagesklinik Würzburg untersucht. Die Depressivität der Patienten zu Beginn und im Verlauf der Behandlung wurde zum einen mittels der ICD-10-Klassifikation, zum anderen mittels des Scores auf der GDS- und Hamilton-Skala zu Beginn und Ende des Aufenthalts in der Tagesklinik sowie bei einer poststationären Kontrolle bestimmt. Der Vitamin D-Spiegel wurde bei Behandlungsbeginn bestimmt und im Falle eines Mangels 1000 IU Vitamin D am Tag oral substituiert. Hierbei zeigte sich kein Zusammenhang zwischen der Ausprägung des depressiven Syndroms und dem Vitamin D-Spiegel zu Beginn der Behandlung. Dagegen stellte sich heraus, dass Patienten mit einem höheren Spiegel eine deutlichere Verbesserung der depressiven Symptome auf der GDS im Verlauf der Behandlung erfuhren. Außerdem bestand eine signifikante negative Korrelation zwischen BMI und Vitamin D-Spiegel sowie eine Abhängigkeit der Spiegelhöhe von der Jahreszeit. Vitamin D könnte nach den Ergebnissen dieser Studie möglicherweise eine wirkungssteigernde und nebenwirkungsarme Komedikation in der antidepressiven Therapie von älteren psychisch erkrankten Menschen darstellen. Es bedarf weiterer ausführlicher Forschung über den neurophysiologischen Zusammenhang zwischen Vitamin D und der Schwere einer depressiven Erkrankung. Besonders hinsichtlich der Verwendung von Vitamin D als Komedikation gilt es, weitere intensive Forschung in Form von gut designten, randomisierten Fall-Kontroll-Studien und prospektiven Interventionsstudien zu betreiben, um die Therapie von depressiven Patienten im höheren Lebensalter weiter zu verbessern. N2 - Depression is a common psychiatric disorder among geriatric patients that decreases the quality of life and increases morbidity and mortality. Vitamin D as a neurosteroid hormone might play a role in the onset and treatment of depression. In the present study the association between depressive symptoms and vitamin D concentration in serum was evaluated. 140 patients of a psychogeriatric day-care unit were included. The geriatric depression score (GDS) and the Hamilton depression rating scale (HDRS) were assessed at the beginning and end of treatment, GDS-scores additionally 6 weeks after discharge from the day-care unit. Vitamin D levels were measured at the beginning of the treatment. Patients with levels below 30 mg/l were treated with 1000 IU Vitamin D per day. There was no association between the severity of depression symptoms and the concentration of vitamin D at the beginning of the treatment. Patients with higher vitamin D levels showed a stronger decline of depressive symptoms measured by the GDS during their stay in the day-care unit. Although no association between vitamin D concentration and severity of depression symptoms was found, vitamin D substitution could improve the effectiveness of an antidepressive treatment in geriatric patients. Further investigation is needed to evaluate the neurophysiological association between the serum concentration of vitamin D and symptoms of depression. KW - Altersdepression KW - Depression KW - Vitamin-D-Mangel KW - Geriatrie KW - Alterspsychiatrie KW - depressive Symptome KW - Gerontopsychiatrie KW - Vitamin D KW - Altersmedizin KW - antidepressive Therapie KW - psychogeriatrics KW - old age depression KW - depression KW - depressive symptoms KW - vitamin d Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250745 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 - THES A1 - Eberhardt, Jasmin T1 - Die Entwicklung der psychiatrisch-psychotherapeutischen Versorgung im Bezirk Unterfranken – eine Erhebung der Indexjahre 2004, 2008 und 2012 T1 - The development of psychiatric-psychotherapeutic care in the Lower Franconia district - a survey of the index years 2004, 2008 and 2012 N2 - Ziel der Arbeit war die Beschreibung der Entwicklung der psychiatrisch-psychotherapeutischen Versorgung im Bezirk Unterfranken mit der Ableitung von Erklärungsansätzen und Impulsen für die Versorgungsforschung. Überprüft wurde hierzu einerseits die Hypothese, ob die stationäre psychiatrische Belegung in beiden Bezirkskrankenhäusern zunimmt und andererseits in einer weiteren Hypothese, ob damit eine Verschlechterung der ambulanten und komplementären Versorgungslage (in den unterschiedlichen Sektoren) einhergeht. Dabei wurden folgende Daten vergleichend für die zwei Bezirkskrankenhäuser in Lohr und Werneck und deren regionales Pflichtversorgungsgebiet erhoben: Für die Indexjahre 2004, 2008 und 2012 im stationären Bereich die Fallzahl, die Patientenzahl, die Nutzungsgrade und für die Fälle die durchschnittliche Verweildauer, die Hauptentlassdiagnosen und die Herkunft nach Meldeort. Im ambulanten Sektor erfolgte die Analyse der Arztsitze und Behandlungsfälle für Nervenärzte und Psychotherapeuten vergleichend für das 4. Quartal 2008 und das 4. Quartal 2012. In den Psychiatrischen Institutsambulanzen am Bezirkskrankenhaus Lohr und am Bezirkskrankenhaus Werneck wurden jeweils die Abrechnungsscheine, die Patienten und die Personalausstattung ausgewertet. Im komplementären Bereich wurden Daten zu Ausgaben, Sozialpsychiatrischen Diensten, Psychosozialen Suchtberatungsstellen, ambulant betreutem Wohnen, Psychiatrischer Familienpflege, Tagesstätten, Werkstätten für psychisch behinderte Menschen, Integrationsfirmen und Zuverdienstmöglichkeiten jeweils für die Jahre 2004, 2008 und 2012 erhoben. Hierbei kam es in beiden Bezirkskrankenhäusern über die Verlaufsjahre zu einer signifikanten Zunahme der Fälle, der Patienten und der Nutzungsgrade bei signifikanter Verkürzung der Verweildauern von 2004 auf 2012. Das Bezirkskrankenhaus Lohr zeigte sich bzgl. Aufnahmen aus dem eigenen Einzugsgebiet selektiver als das Bezirkskrankenhaus Werneck. Über die Beobachtungsjahre veränderte sich das Diagnosespektrum stationärer Fälle signifikant in beiden Kliniken. Im ambulanten Bereich zeigte sich von 2008 auf 2012 eine diskrete Zunahme von Psychotherapeutensitzen bei gleichbleibender Anzahl der Arztsitze für Nervenärzte. Die Behandlungsfälle stiegen in beiden Gruppen merklich an vom 4. Quartal 2008 auf das 4. Quartal 2012. Im komplementären Bereich nahmen Ausgaben und die Kapazitäten im Bereich von Wohnen, Alltagsgestaltung und Arbeit zu. In beiden Bezirkskrankenhäusern ließ sich über die Indexjahre eine Zunahme der stationären Belegung feststellen. Die Belegungszunahme ging allerdings nicht mit einer Verschlechterung der ambulanten oder komplementären Versorgung im regionalen Pflichtversorgungsgebiet der jeweiligen Klinik einher. Es wurde geschlussfolgert, dass die Zuweisung zu den psychiatrischen Fachkliniken als insuffizient und partiell unkontrolliert einzustufen ist und dringender Forschungsbedarf hinsichtlich der Patientenströme vom ambulanten zum stationären Sektor besteht. N2 - The aim of the work was to describe the development of psychiatric-psychotherapeutic care in the Lower Franconia district with the aim to find explanatory approaches and impulses for care research. On the one hand, the hypothesis whether inpatient psychiatric occupancy is increasing in both district hospitals was examined, and on the other hand, wheter this was associated with a deterioration in the outpatient and complementary care (in the different sectors). The following data were collected for the two district hospitals in Lohr and Werneck and their regional compulsory care area: For the index years 2004, 2008 and 2012 in the inpatient area, the no of cases, the number of patients, the degree of utilization and, for the cases, the average length of stay, the main discharge diagnoses and the origin according to reporting location. In the outpatient sector, the doctor's offices and treatment cases for neurologists and psychotherapists were analysed comparatively for the 4th quarter of 2008 and the 4th quarter of 2012. In the psychiatric outpatient departments at the Lohr District Hospital and the Werneck District Hospital, the billing slips, the patients and the staff were evaluated. In the complementary area, data on expenditure, social psychiatric services, psychosocial addiction counselling centers, assisted outpatient housing, psychiatric family care, day care centers, workshops for mentally disabled people, integration companies and additional income opportunities were collected for the years 2004, 2008 and 2012. In both district hospitals, there has been a significant increase in cases, patients and degree of utilization over the years, with a significant reduction in length of stay from 2004 to 2012. The Lohr district hospital was more selective in terms of admissions from its own catchment area than the Werneck district hospital. Over the years of observation, the range of inpatient diagnoses changed significantly in both clinics. In the outpatient area, there was a small increase in psychotherapist offices from 2008 to 2012 while the number of doctors' offices for neurologists remained the same. The treatment cases increased noticeably in both groups from the 4th quarter of 2008 to the 4th quarter of 2012. In the complementary area, expenditure and capacities for living, managing of everyday life and work increased. In both district hospitals, an increase in inpatient occupancy was observed over the index years. However, the increase in occupancy was not accompanied by a deterioration in outpatient or complementary care in the regional compulsory care area of the respective clinic. It was concluded that the referral to the psychiatric specialist clinics seems to be insufficient and partially uncontrolled and that there is an urgent need for research into patient flows from the outpatient to the inpatient sector. KW - Psychiatrische Versorgung KW - Stationäre psychiatrische Versorgung KW - ambulante psychotherapeutische Versorgung KW - Inanspruchnahme KW - Zuweisung KW - psychiatrisch psychotherapeutische Versorgung KW - Belegung KW - psychiatric psychotherapeutic care KW - occupancy KW - use KW - allocation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212323 ER - TY - THES A1 - Kollert, Leonie T1 - Epigenetics of anxiety and depression – a differential role of TGFB-Inducible Early Growth Response Protein 2 gene promoter methylation T1 - Epigenetik von Angst und Depression – Die differentielle Rolle von TGFB-Inducible Early Growth Response Protein 2 Gen Promotor Methylierung N2 - Among mental disorders, panic disorder (PD) is one of the most common anxiety disorders characterized by recurring and unexpected episodes of extreme fear i.e. panic attacks. PD displays lifetime prevalence rates in the general population between 2.1-4.7 % and in about 30 to 40 % occurs comorbid with major depressive disorder (MDD). Differential methylation levels of the monoamine oxidase A (MAOA) gene have previously been associated with the etiology of both PD and MDD. The TGFB-Inducible Early Growth Response Protein 2 (TIEG2; alias KLF11), an activating transcription factor of the MAOA gene, has been reported to be increased in MDD, but has not yet been investigated in PD on any level. Therefore, in an attempt to further define the role of an impaired TIEG2-MAOA pathway in anxiety and affective disorders, in the present thesis TIEG2 promoter DNA methylation was analyzed in two independent samples of I) PD patients with or without comorbid MDD in a case/control design and II) MDD patients with and without anxious depression. Additionally, in PD patients of sample I), TIEG2 methylation was correlated with Beck Depression Inventory (BDI-II) scores. Finally, in a third independent healthy control sample, correlation of TIEG2 promoter methylation levels with Anxiety Sensitivity Index (ASI) scores as a PD-related measure was analyzed. No overall association of TIEG2 promoter methylation with PD was detected. However, PD patients with comorbid MDD showed significant TIEG2 hypomethylation compared to PD patients without comorbid MDD (p=.008) as well as to healthy controls (p=.010). In addition, MDD patients without anxious features displayed a statistical trend in decreased TIEG2 methylation in comparison to MDD patients with anxious depression (p=.052). Furthermore, TIEG2 methylation was negatively correlated with BDI-II scores in PD patients (p=.013) and positively correlated with ASI scores in the healthy control sample (p=.043). In sum, the current study suggests TIEG2 promoter hypomethylation as a potential epigenetic marker of MDD comorbidity in PD or of non-anxious depression, respectively. If replicated and verified in future studies, altered TIEG2 methylation might therefore represent a differential pathomechanism of anxiety and mood disorders. N2 - Die Panikstörung (PD) ist eine der häufigsten Angststörungen, die durch wiederkehrende und unerwartete Episoden extremer Angst gekennzeichnet ist. Die PD tritt in der Allgemeinbevölkerung mit Lebenszeitprävalenzraten zwischen 2,1 und 4,7 % und in etwa 30 bis 40 % der Fälle komorbid mit einer schweren Depression (MDD) auf. Unterschiedliche Methylierungs-Niveaus des Monoaminoxidase A (MAOA) Gens wurden bereits mit der Ätiologie von PD und MDD assoziiert. Das TGFB-Inducible Early Growth Response Protein 2 (TIEG2; alias KLF11) fungiert als ein aktivierender Transkriptionsfaktor des MAOA Gens und wurde bei Patienten mit MDD in seiner Expression erhöht gefunden. Bei der PD wurde TIEG2 bis heute jedoch noch nicht untersucht. Um die Rolle eines gestörten TIEG2-MAOA Signalwegs bei Angst- und affektiven Störungen genauer zu definieren, wurde in der vorliegenden Studie die Methylierung des TIEG2 Promotors in zwei unabhängigen Stichproben bestehend aus I) PD Patienten mit bzw. ohne komorbider MDD, sowie II) MDD Patienten mit bzw. ohne erhöhte Angstsymptomen untersucht. Zusätzlich wurde in der PD Stichprobe die TIEG2 Methylierung mit dem Beck Depression Inventar II (BDI-II) korreliert. Schließlich wurde in einer dritten unabhängigen Stichprobe gesunder Probanden die Korrelation der TIEG2 Methylierung mit den Punktwerten des Angstsensitivitätsindex (ASI) analysiert. Es wurde keine Assoziation von TIEG2 Promotor-Methylierung mit PD beobachtet. Allerdings waren PD Patienten mit komorbider MDD im Vergleich zu PD Patienten ohne komorbide MDD (p=,008) sowie zu gesunden Kontrollprobanden (p=,010) signifikant niedriger methyliert. MDD Patienten ohne ängstliche Symptome zeigten einen statistischen Trend von verringerte TIEG2 Methylierung im Vergleich zu MDD Patienten mit ängstlicher Depression (p=,052). Zusätzlich korrelierte die TIEG2 Methylierung negativ mit den BDI-II Werten bei PD Patienten (p=,013) und positiv mit den ASI Werten in der gesunden Probandenstichprobe (p=,043). KW - Epigenetik KW - Epigenetic Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211268 ER - TY - THES A1 - Wenzel, Martina T1 - Aufmerksamkeitsprozesse und Emotionsregulationsmechanismen in der bipolaren Störung T1 - Attentional bias and emotion regulation strategies in bipolar disorder N2 - Neben Stimmungsschwankungen leiden viele bipolare Patienten unter kognitiven Beeinträchtigungen. Dies ist von hoher Relevanz, da neuropsychologische Defizite zur Aufrechterhaltung der bipolaren Störung beitragen können. Unsere Studie widmete sich zum einen der Untersuchung verzerrter Aufmerksamkeitsprozesse als auch der Erfassung dysfunktionaler Emotionsregulationsstrategien in der bipolaren Störung. Da es uns besonders interessierte, ob diese dysfunktionalen Prozesse im euthymen Intervall bestehen bleiben, rekrutierten wir akut depressive als auch euthyme bipolare Patienten. Weiterhin untersuchten wir, ob der Aspekt der prädominanten Polarität einen Einfluss auf die Informationsverarbeitung und Emotionsregulation haben könnte. Zur Erfassung selektiver Aufmerksamkeitsprozesse verwendeten wir eine Dot-Probe-Aufgabe. In der vorliegenden Arbeit konnte gezeigt werden, dass bei den akut depressiven bipolaren Patienten deutliche Defizite im Reaktionsvermögen vorlagen. Bei den euthymen Patienten mit manischer Polarität fand sich überraschenderweise ein Bias weg von positiven Stimuli, was möglicherweise als Schutzmechanismus vor potentiellen Triggern einer Manie interpretiert werden kann. Um zu testen, ob sich bipolare Patienten in den Emotionsregulationsstrategien von gesunden Kontrollpersonen unterscheiden, wurden zwei verschiedene Fragebögen eingesetzt. In der Auswertung zeigte sich, dass nicht nur akut depressive Patienten, sondern auch remittierte Patienten zu dysfunktionalen Emotionsregulationsstrategien neigten und dass die euthymen Probanden mit depressiver bzw. manischer Polarität in unterschiedlichen Emotionsregulationsstrategien von gesunden Probanden abwichen. Zusammenfassend lässt sich festhalten, dass Defizite in der selektiven Aufmerksamkeit und in der Emotionsregulation nicht nur in der akuten Krankheitsphase, sondern auch im „gesunden Intervall“ vorhanden sind. Darüber hinaus liefert die Studie erste Hinweise darauf, dass sich Patienten mit depressiver und manischer Polarität in der Informationsverarbeitung emotionaler Stimuli als auch in Emotionsregulationsstrategien unterscheiden. N2 - An increasing amount of empirical evidence has documented that many patients with bipolar disorder show significant neurocognitive deficits and that these deficits have been associated with a longer illness duration. This experimental study examined the nature of attentional biases as well as the use of emotion regulation strategies in bipolar disorder. We included patients in the depressive phase of their illness and in remission because we were particularly interested in investigating the presence of dysfunctional processes during euthymic phases. Furthermore, we examined the aspect of predominant polarity regarding information processing and emotion regulation. In the current study we used a dot-probe task to examine attentional biases. We demonstrated that patients in the depressive state of the illness had slower reaction times than healthy controls. Surprisingly, the euthymic patients with manic predominant polarity showed a bias away from positive stimuli, suggesting that there might be a ‘protective bias’ for potential triggers of a relapse into mania. To examine differences in emotion regulation strategies we used two different questionnaires. Findings indicated that not only bipolar depressed patients but also euthymic patients displayed an increased use of maladaptive strategies and that euthymic patients with depressive and manic predominant polarity differed in different emotion regulation strategies from healthy controls. Overall, the study demonstrated that information-processing deficits and dysfunctional emotion regulation strategies are not restricted to bipolar patients in their acute state of the illness, but also persist during remission as vulnerability factors. Furthermore, the results provide some evidence to suggest that patients with depressive and manic predominant polarity differ significantly in information processing and emotion regulation strategies. KW - Manisch-depressive Krankheit KW - Emotionsregulation KW - Aufmerksamkeit KW - bipolar disorder KW - Aufmerksamkeitsverzerrung KW - attentional bias KW - dot-probe Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189638 ER - TY - THES A1 - Trimborn, Anna T1 - Erprobung und Evaluation eines Fragebogeninstruments zum Entlassungsmanagement deutscher Rehabilitationskliniken im Rahmen der Qualitätssicherung der Deutschen Rentenversicherung Nordbayern T1 - Evaluation of a discharge management questionnaire for medical rehabilitation in the context of quality management of the Deutsche Rentenversicherung Nordbayern (German statutory pension insurance in Northern Bavaria) N2 - Mithilfe eines frühzeitigen und umfassenden Entlassungsmanagements sollen Schnittstellen im Behandlungsprozess überwunden und der Übergang des Patienten in die poststationäre Versorgung nach einem Krankenhausaufenthalt optimal vorbereitet werden. Trotz der allgemein anerkannten Bedeutung des Entlassungsmanagements aus der stationären medizinischen Versorgung erfolgt die Umsetzung bei den Rehabilitationskliniken sehr unterschiedlich. Im Rahmen dieser Arbeit wird ein kurzes Fragebogeninstrument für Patienten systematisch entwickelt und erprobt, welches im Rahmen einer postalischen Nachbefragung ehemaliger Rehabilitanden eingesetzt werden soll. Es soll die Qualität des Entlassungsmanagements der medizinischen Rehabilitation systematisch erfassen und Impulse für das Qualitätsmanagement der Kliniken bieten. Die Ergebnisse der Erprobung in acht Kliniken mit über 900 auswertbaren Fragebögen weisen darauf hin, dass beides möglich ist. Sie werden mit dem Ziel der Weiterentwicklung des Instruments diskutiert und es werden Vorschläge zur weiteren Nutzung im Alltag der Rehabilitation erarbeitet. N2 - A comprehensive and early discharge management can have positive effects on treatment following acute hospital care. Although the relevance of discharge management in healthcare is widely accepted, its implementation in medical rehabilitation clinics is inconsistent. In this study, a brief questionnaire addressing medical rehabilitation patients after discharge was developed and evaluated. The instrument aims at measuring the quality of discharge management and providing data to be used for quality management in rehabilitation centers. Study results from eight clinics including 900 patients suggest that both goals can be reached. The results are discussed with regard to the further development of the questionnaire. Suggestions for the use of the instrument in daily rehabilitation practice are highlighted. KW - Rehabilitation KW - Entlassungsmanagement KW - Qualitätssicherung Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200362 ER - TY - THES A1 - Logina, Agate T1 - Structural brain alterations in spider phobia : A voxel-based morphometry study T1 - Strukturelle Hirnveränderungen bei Spinnenphobie : Voxel-basierte Morphometrie Studie N2 - In this study, we examined the regional grey matter density in 35 spider phobic patients and 33 age, gender and education matched healthy controls. We used a method called Voxel-Based Morphometry, which allowed us to conduct a voxel- by-voxel analysis of the entire brain. We also tried to determine if there was any relationship between the severity of fear (expressed in BAT and SPQ score) and grey matter density. Based on previous findings, we expected to find structural changes in the following brain regions: - prefrontal cortex; - orbitofrontal cortex; - anterior cingulate cortex; - insula; - visual and associative cortices. Between-group comparison of spider phobic patients and healthy controls yielded no significant results. Additionally, and as expected, we did not find a between- group difference in TIV. Surprisingly, however, we found several brain regions whose GMD was significantly correlated with severity of spider phobia. The score that correlated with several regions GMD and yielded the largest cluster was the SPQ. SPQ was positively correlated with dorsal anterior cingulate, right insula and left inferior parietal lobule. Final distance in centimetres was correlated with left superior frontal gyrus and right paracentral lobule densities. All correlations were observed at a cluster level and no significant results at peak level were found. Interestingly, out of all BAT fear values, only BAT when the spider was taken away had a positive correlation with GMD (vermis). There were no indications of reduced GMD in spider phobic patients. Overall, our regions of significance were in line of those of other structural and functional neuroimaging studies in the field of specific phobia. As expected, we found GMD changes in the prefrontal cortex, ACC, insula and the associative 60 cortices. The functions of these regions such as processing of disgust, attention, autonomous responses, consolidation of memory and regulation of affect support the possible involvement of these structures in SP. We did, however, also yield some unexpected results (vermis, right paracentral lobule). Interestingly and in contrast to other studies, our results were only limited to the phobic group itself- we found no regions of significance in the SP-HC between-group analysis. In the future, more VBM studies with larger size of spider phobic subjects should be conducted, further investigating both the between-group differences and the correlation between spider phobia severity and GMD. Additionally, studies should investigate the relationship between structural changes and activation patterns observed in fMRI, find out whether brain changes precede the clinical symptoms or vice versa and see, if structural changes normalize in response to CBT the same way functional changes do. N2 - In dieser Studie wurde mittels auf MRT-Datensätzen basierender VBM der Frage nachgegangen, ob Patienten mit einer Spinnenphobie Veränderungen der grauen oder weißen Substanz des Gehirns aufweisen. Bei VBM werden regionale Volumenveränderungen der grauen und der weißen Substanz auf dem Boden struktureller MRT-Bilder bestimmt. Wir haben veränderungen in folgenden Regionen erwartet: - präfrontalem Kortex - orbitofrontalem Kortex - anteriorem cingulärem Kortex - Inselkortex - Sehrinde. Der Spinnenphobie-Fragebogen (SPQ) ergab eine positive Korrelation mit dorsalem cingulärem Kortex, rechtem Inselkortex und dem linkem Lobulus parietalis inferior. Auch Vermis, rechter Lobulus paracentralis und der linke Gyrus frontalis superior Dichte zeigte eine positive Korrelation mit Schwergrad der Spinnenphobie. Zusammenfassend sind unsere Ergebnisse übereinstimmend mit den Ergebnissen von anderen Studien. Wie erwartet, haben wir Veränderungen im präfrontalen Kortex, anteriorem cingulärem Kortex und Inselkortex gefunden. Diese Regionen sind für Ekel, Aufmerksamkeit, autonome Reaktionen und Gedächtnis verantwortlich, alle diese Funktionen spielen eine Rolle in spezifischen Phobien. In Zukunft, mehr und größeren VBM-Studien sind notwendig, um die Ergebnisse von unserer Studie zu überprüfen. KW - vbm Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211335 ER - TY - JOUR A1 - Lechermeier, Carina G. A1 - Zimmer, Frederic A1 - Lüffe, Teresa M. A1 - Lesch, Klaus-Peter A1 - Romanos, Marcel A1 - Lillesaar, Christina A1 - Drepper, Carsten T1 - Transcript analysis of zebrafish GLUT3 genes, slc2a3a and slc2a3b, define overlapping as well as distinct expression domains in the zebrafish (Danio rerio) central nervous system JF - Frontiers in Molecular Neuroscience N2 - The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders. KW - glucose transporter KW - nervous system KW - brain disorders KW - psychiatric disorders KW - brain development KW - GABA KW - GAD1 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201797 VL - 12 IS - 199 ER - TY - THES A1 - Eisenhauer, Eva-Lydia T1 - Klinische Charakterisierung katatoner Schizophrenien im Kindesalter; Definition des Krankheitskonzeptes und Implikationen für Therapie und Prophylaxe T1 - Clinical characterisation of catatonic schizophrenia in childhood. Definition of disease-concept and implications for therapy and prophylaxis N2 - In dieser Studie wurden 25 erwachsene Patienten mit den langjährigen Vordiagnosen einer intellektuellen Behinderung, kindlichen Psychosen oder tiefgreifenden Entwicklungsstörungen eingeschlossen. Ziel der Studie war einerseits die Frage ob sich im Spektrum dieser Erkrankungen, die in Karl Leonhards Nosologie beschriebenen (früh)kindlichen Katatonien als eigenständiges Krankheitsbild identifizieren und definieren sowie von den o. b. Krankheitsbildern differentialdiagnostisch abgrenzen lassen. Die Katatonieformen wurden hinsichtlich ihres Beginns und Verlaufs ausgewertet. Ein weiteres Ziel war die diagnostische Definierung des Kranheitsbildes im Sinne einer Herausarbeitung der genauen Symptomatik. Um Betroffene besser fördern und behandeln zu können wurden darüber hinaus familiäre und soziale Einflussfaktoren analysiert. Die Probanden wurden zwischen 2013 und 2015 nachuntersucht, sie stammen sämtlich aus Klinikbeobachtungen vorangegangen stationärer psychiatrischer Aufenthalte. N2 - In this study 25 adult patients with a history of intellectual disability, childhood psychoses or pervasive developmental disorders were included. One aim of this investigation was to determine, whether in these subgroups, the “early childhood catatonias” described in Karl Leonhard´s nosology were identifiable und definable as an independent group of disorders beginning early in life. The catatonic forms were evaluated concerning their beginning and long-term-course. With regard to diagnostic aspects they were distinguished from the above mentioned diseases, furthermore the interrater-reliability was examined. Other aims were the diagnostic definition of early childhood catatonias and its typical symptoms. In order to improve the treatment of affected individuals and promote adequate care possible social and familial factors were also evaluated. The patients were re-examined between 2013 and 2015 after preceding psychiatric inpatient treatment. KW - Chronische Schizophrenie KW - Schizophrenie KW - Katatonie KW - Karl Leonhard KW - ICD-10 KW - Kinder KW - Autismus KW - Geistige Behinderung Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204517 ER - TY - JOUR A1 - Ziegler, Georg C. A1 - Ehlis, Ann-Christine A1 - Weber, Heike A1 - Vitale, Maria Rosaria A1 - Zöller, Johanna E. M. A1 - Ku, Hsing-Ping A1 - Schiele, Miriam A. A1 - Kürbitz, Laura I. A1 - Romanos, Marcel A1 - Pauli, Paul A1 - Kalisch, Raffael A1 - Zwanzger, Peter A1 - Domschke, Katharina A1 - Fallgatter, Andreas J. A1 - Reif, Andreas A1 - Lesch, Klaus-Peter T1 - A Common CDH13 Variant is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD JF - Genes N2 - The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD. KW - ADHD KW - CDH13 KW - neurodevelopment KW - executive functions KW - working memory KW - Big Five KW - agreeableness Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245220 SN - 2073-4425 VL - 12 IS - 9 ER - TY - JOUR A1 - Schaefer, Natascha A1 - Signoret-Genest, Jérémy A1 - von Collenberg, Cora R. A1 - Wachter, Britta A1 - Deckert, Jürgen A1 - Tovote, Philip A1 - Blum, Robert A1 - Villmann, Carmen T1 - Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants JF - Frontiers in Molecular Neuroscience N2 - A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the human GLRB gene of individuals with a prevalence for agoraphobia. GLRB encodes the glycine receptor (GlyRs) β subunit. The identified SNPs are localized within the gene flanking regions (3′ and 5′ UTRs) and intronic regions. It was suggested that these nucleotide polymorphisms modify GlyRs expression and phenotypic behavior in humans contributing to an anxiety phenotype as a mild form of hyperekplexia. Hyperekplexia is a human neuromotor disorder with massive startle phenotypes due to mutations in genes encoding GlyRs subunits. GLRA1 mutations have been more commonly observed than GLRB mutations. If an anxiety phenotype contributes to the hyperekplexia disease pattern has not been investigated yet. Here, we compared two mouse models harboring either a mutation in the murine Glra1 or Glrb gene with regard to anxiety and startle phenotypes. Homozygous spasmodic animals carrying a Glra1 point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover, spasmodic mice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context. Spastic mice exhibit reduced expression levels of the full-length GlyRs β subunit due to aberrant splicing of the Glrb gene. Heterozygous animals appear normal without an obvious behavioral phenotype and thus might reflect the human situation analyzed in the GWAS study on agoraphobia and startle. In contrast to spasmodic mice, heterozygous spastic animals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs β subunit within glycinergic circuits in neuronal networks important for fear and fear-related behavior may exist. Possibly, in human additional changes in fear and fear-related circuits either due to gene-gene interactions e.g., with GLRA1 genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype. KW - glycine receptor KW - spastic KW - fear KW - anxiety KW - startle reaction Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-210041 SN - 1662-5099 VL - 13 IS - 152 ER - TY - THES A1 - Saulin, Anne Christin T1 - Sustainability of empathy as driver for prosocial behavior and social closeness: insights from computational modelling and functional magnetic resonance imaging T1 - Nachhaltigkeit von Empathie als Motiv für prosoziales Verhalten und soziale Nähe: Erkenntnisse auf Grundlage von computational modelling und funktioneller Magnetresonanztomographie N2 - Empathy, the act of sharing another person’s affective state, is a ubiquitous driver for helping others and feeling close to them. These experiences are integral parts of human behavior and society. The studies presented in this dissertation aimed to investigate the sustainability and stability of social closeness and prosocial decision-making driven by empathy and other social motives. In this vein, four studies were conducted in which behavioral and neural indicators of empathy sustainability were identified using model-based functional magnetic resonance imaging (fMRI). Applying reinforcement learning, drift-diffusion modelling (DDM), and fMRI, the first two studies were designed to investigate the formation and sustainability of empathy-related social closeness (study 1) and examined how sustainably empathy led to prosocial behavior (study 2). Using DDM and fMRI, the last two studies investigated how empathy combined with reciprocity, the social norm to return a favor, on the one hand and empathy combined with the motive of outcome maximization on the other hand altered the behavioral and neural social decision process. The results showed that empathy-related social closeness and prosocial decision tendencies persisted even if empathy was rarely reinforced. The sustainability of these empathy effects was related to recalibration of the empathy-related social closeness learning signal (study 1) and the maintenance of a prosocial decision bias (study 2). The findings of study 3 showed that empathy boosted the processing of reciprocity-based social decisions, but not vice versa. Study 4 revealed that empathy-related decisions were modulated by the motive of outcome maximization, depending on individual differences in state empathy. Together, the studies strongly support the concept of empathy as a sustainable driver of social closeness and prosocial behavior. N2 - Empathie, das Teilen des Affekts einer anderen Person, ist eine allgegenwärtige Motivation, anderen Menschen zu helfen und sich ihnen nahe zu fühlen. Diese Erfahrungen sind wesentliche Bestandteile menschlichen Verhaltens und zentral für unsere Gesellschaft. Die vorliegende Dissertation setzte sich zum Ziel, die Nachhaltigkeit und Stabilität sozialer Nähe sowie prosozialem Entscheidungsverhalten basierend auf Empathie und anderen sozialen Motiven zu beleuchten. In den vier Studien wurden das Verhalten und neuronale Indikatoren für die Nachhaltigkeit von Empathie mit modellbasierter funktioneller Magnetresonanztomographie (fMRT) untersucht. Unter Verwendung von Verstärkungslernmodellen, Drift-Diffusionsmodellen (DDM) und fMRT untersuchten die ersten zwei Studien den zeitlichen Verlauf von empathiebasierter sozialer Nähe und prosozialem Verhalten. Mit Hilfe von DDM und fMRT wurde in den abschließenden Studien untersucht, wie Empathie in Kombination mit Reziprozität, der sozialen Norm, Gefallen zurückzuzahlen, und Empathie in Kombination mit dem Motiv der Gewinnmaximierung den verhaltensbezogenen und neuronalen sozialen Entscheidungsprozess verändert. Die Ergebnisse zeigten, dass empathiebasierte soziale Nähe und prosoziale Entscheidungstendenzen selbst dann fortbestanden wenn Empathie nur noch selten verstärkt wurde. Die Nachhaltigkeit dieser Effekte hing mit der Rekalibrierung des empathiebasierten Lernsignals für soziale Nähe (Studie 1) und dem Aufrechterhalten eines prosozialen Entscheidungsbias zusammen (Studie 2). Die Ergebnisse von Studie 3 zeigten, dass Empathie reziprozitätsbasierte soziale Entscheidungen stärkt, aber nicht umgekehrt. Studie 4 zeigte, dass empathiebasierte soziale Entscheidungen durch das Motiv der Gewinnmaximierung vereinfacht werden können. Zusammengefasst unterstützen die Ergebnisse der vorliegenden Dissertation nachdrücklich das Konzept von Empathie als nachhaltige Triebkraft für soziale Nähe und prosoziales Verhalten. KW - Einfühlung KW - Bestärkendes Lernen KW - Modellierung KW - Funktionelle Kernspintomografie KW - Prosoziales Verhalten KW - drift-diffusion model KW - reciprocity KW - anterior insula KW - temporo-parietal junction KW - inferior frontal gyrus Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305550 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 - Üçeyler, Nurcan A1 - Schließer, Mira A1 - Evdokimov, Dimitar A1 - Radziwon, Jakub A1 - Feulner, Betty A1 - Unterecker, Stefan A1 - Rimmele, Florian A1 - Walter, Uwe T1 - Reduced midbrain raphe echogenicity in patients with fibromyalgia syndrome JF - PloS One N2 - Objectives The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS. Methods Sixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis. Results Quantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (p<0.05), but not different from that of patients with depression and accompanying physical pain. Pain and FMS symptom burden did not correlate with midbrain raphe echogenicity as well as the presence and severity of depressive symptoms. Conclusion We found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression. KW - midbrain KW - fibromyalgia KW - depression KW - pain KW - ultrasound imaging KW - neuropathic pain KW - diagnostic medicine KW - migraine Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300639 VL - 17 IS - 11 ER - TY - JOUR A1 - Schiele, Miriam A. A1 - Reinhard, Julia A1 - Reif, Andreas A1 - Domschke, Katharina A1 - Romanos, Marcel A1 - Deckert, Jürgen A1 - Pauli, Paul T1 - Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults JF - Developmental Psychobiology N2 - Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues. KW - fear conditioning KW - fear generalization KW - development KW - skin conductance KW - maturation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189488 VL - 58 IS - 4 ER - TY - THES A1 - Müller, Annika Wiebke T1 - Funktionalität eines \(Stathmin\)-Promotor-Polymorphismus T1 - Functionality of a \(stathmin\) promoter polymorphism N2 - Bereits in vorausgegangenen Studien konnte nachgewiesen werden, dass das Stathmin-Gen eine entscheidende Rolle im Hinblick auf erlernte und angeborene Angstreaktionen spielt. So konnte Frau Dr. Julia Katharina Heupel in ihrer Arbeit aus dem Jahr 2013 eine Assoziation eines (TAA)n-Polymorphismus, welcher sich ca. 2 kb upstream des ersten Exons des Stathmin-Gens und ca. 4 kb upstream des Translationsstarts befindet, mit Cluster-C-Persönlichkeitsstörungen belegen. Sie vermutete, dass eine Hochregulation der Expression des Stathmin-Gens ein Risikofaktor für die Entstehung von Cluster C Persönlichkeitsstörungen darstellen könnte. Da sich der beschriebene Polymorphismus in der Promotor-Region des Stathmin-Gens befindet, ist eine allelspezifische Auswirkung auf die Genexpression vorstellbar. Um diese Vermutung zu stützen, wurde in dieser Arbeit die Auswirkung zweier Allele des STR-Polymorphismus im Bereich der Promotorregion des Stathmin-Gens im Hinblick auf die Promotoraktivität untersucht. Hierzu wurde die zu untersuchende Sequenz zunächst mittels Polymerase-Ketten-Reaktion vervielfältigt und anschließend in einen pGL4.23.Vektor kloniert. Im Anschluss daran erfolgte die Untersuchung der Promotoraktivität mittels eines Luciferase-Assays in der humanen Neuroblastomzelllinie SH-SY5Y. Nach statischer Auswertung der Messreihen zeigte sich eine signifikant höhere Luciferase-Aktivität des STR-Polymorphismus (TAA)12 im Vergleich zu dem STR-Polymorphismus (TAA)13. Hierdurch kann von einer höheren Promotoraktivität bei dem Genotyp (TAA)12 gegenüber dem Genotyp (TAA)13 ausgegangen werden. Zusammenfassend unterstützen die Ergebnisse dieser Arbeit die These, dass es sich bei dem Stathmin-Gen um ein Suszeptibilitätsgen für die Entstehung von Cluster C Persönlichkeitsstörungen handeln könnte. N2 - Previous studies have shown that the stathmin gene plays a crucial role in both learned and innate fear. In 2013 Dr. Julia Katharina Heupel suggested an association between a (TAA)n-polymorphism - which is located around 2 kb upstream of the first exon of the stathmin gene and around 4 kb upstream of the translation start site – with Cluster C personality disorders. She assumed that the upregulation of the stathmin gene expression constitutes a risk factor for the development of Cluster C personality disorders. Since the polymorphism described is located in the promoter region of the stathmin gene, an allele-specific effect on gene expression is conceivable. To support this premise, the impact on promoter activity of two alleles of the STR polymorphism located in the promoter region of the stathmin gene was investigated. First the sequence was amplified using polymerase chain reaction and then cloned into a pGL4.23 vector. Subsequently, the promoter activity was analyzed using a luciferase assay in the human neuroblastoma cell line SH-SY5Y. After statistical evaluation a significantly higher luciferase activity of the STR polymorphism (TAA)12 was shown in comparison to the STR polymorphism (TAA)13. As a result, it can be assumed that the genotype (TAA)12 has a higher promoter activity than the genotype (TAA)13. In summary, the results of this work support the thesis that the stathmin gene could be a susceptibility gene for the development of Cluster C personality disorders. KW - Persönlichkeitsstörung KW - Stathmin KW - Cluster C Persönlichkeitsstörungen KW - Promotorpolymorphismus KW - Cluster C personality disorders KW - promoter polymorphism Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318120 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 - 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 - 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 - Hommers, L. G. A1 - Richter, J. A1 - Yang, Y. A1 - Raab, A. A1 - Baumann, C. A1 - Lang, K. A1 - Schiele, M. A. A1 - Weber, H. A1 - Wittmann, A. A1 - Wolf, C. A1 - Alpers, G. W. A1 - Arolt, V. A1 - Domschke, K. A1 - Fehm, L. A1 - Fydrich, T. A1 - Gerlach, A. A1 - Gloster, A. T. A1 - Hamm, A. O. A1 - Helbig-Lang, S. A1 - Kircher, T. A1 - Lang, T. A1 - Pané-Farré, C. A. A1 - Pauli, P. A1 - Pfleiderer, B. A1 - Reif, A. A1 - Romanos, M. A1 - Straube, B. A1 - Ströhle, A. A1 - Wittchen, H.-U. A1 - Frantz, S. A1 - Ertl, G. A1 - Lohse, M. J. A1 - Lueken, U. A1 - Deckert, J. T1 - A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety JF - Translational Psychiatry N2 - Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities. KW - clinical genetics KW - psychiatric disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322497 VL - 8 ER - TY - JOUR A1 - Gál, Bernadett I. A1 - Kilencz, Tünde A1 - Albert, Anita A1 - Demeter, Ildikó A1 - Hegedűs, Klára Mária A1 - Janka, Zoltán A1 - Csifcsák, Gábor A1 - Álmos, Péter Z. T1 - Mild Effect of Nalmefene on Alcoholic Cue-Induced Response Invigoration in Alcohol Use Disorder Without Accompanying Changes in Electrophysiological Signatures of Early Visual Processing and Executive Control JF - Frontiers in Pharmacology N2 - Nalmefene is approved for as-needed pharmacological treatment in alcohol use disorder (AUD) by the European Medicines Agency. While the cellular effects of nalmefene have been thoroughly investigated, data are very limited on how this agent influences neural signals associated with inhibitory control and the visual analysis of environmental cues. This double-blind crossover study assessed the behavioral and neural effects of acute nalmefene administration in patients diagnosed with AUD. In experiment 1, we validated our experimental paradigm (electroencephalography combined with a modified Go/NoGo task using images of alcoholic and nonalcoholic drinks as prime stimuli) in 20 healthy adults to ensure that our protocol is suitable for assessing the behavioral and neural aspects of executive control. In experiment 2, we recruited 19 patients with AUD, and in a double-blind crossover design, we investigated the effects of nalmefene versus placebo on task performance (response accuracy, the sensitivity index, and reaction times), visual responses to appetitive cues (occipital P1, N1, and P2 components), and electrophysiological markers of conflict detection and response inhibition (frontal N2 and P3 waveforms). Under placebo, patients produced faster reaction times to alcohol-primed Go stimuli, an effect that was weak despite being statistically significant. However, the effect of alcoholic cues on the speed of response initiation disappeared after receiving nalmefene. We found no placebo versus nalmefene difference regarding our patients’ ability to accurately inhibit responses to NoGo stimuli or for occipital and frontal event-related potentials. Our results suggest that nalmefene might be potent in reducing the vigor to act upon alcoholic cues in AUD patients, but this effect is most probably mediated via subcortical (rather than cortical) neural circuits. KW - nalmefene KW - alcohol use disorder KW - response inhibition KW - incentive salience KW - event-related potentials KW - Go/NoGo task Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369182 VL - 10 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 - THES A1 - Blickle, Marc Manuel T1 - Das Zusammenspiel von Herz und Gehirn: Interozeptive Genauigkeit, Herzratenvariabilität und funktionelle Konnektivität kortikaler Netzwerke bei depressiven Patientinnen und Patienten T1 - The interplay of heart and brain: Interoceptive accuracy, heart rate variability, and functional connectivity of cortical networks in patients with depression N2 - Hintergrund: Depressionen zählen zu den häufigsten psychischen Erkrankungen. Depressive Symptome umfassen beeinträchtigte kognitive Funktionen, vegetative Beschwerden und ein verändertes emotionales Erleben. Die defizitäre Wahrnehmung interner körperlicher Signale wird sowohl mit der Pathogenese der Depression als auch mit Angststörungen in Verbindung gebracht. Interozeptive Genauigkeit (IAc) beschreibt dabei die Fähigkeit, körperliche Empfindungen wie den eigenen Herzschlag akkurat wahrzunehmen und wird mit einer Herzwahrnehmungsaufgabe erfasst. In bildgebenden Verfahren wie der funktionellen Magnetresonanztomografie (fMRT) war eine niedrigere IAc mit einer verringerten Inselaktivität assoziiert. Während der Ruhezustandsmessung des Gehirns (resting-state fMRT) kann in Abwesenheit einer Aufgabe die intrinsische Aktivität des Gehirns gemessen werden. Dies ermöglicht die Identifizierung von kortikalen Netzwerken. Depressive Patienten weisen eine veränderte funktionelle Konnektivität innerhalb und zwischen einzelnen Netzwerken wie dem Salience Network (SN), welchem die Insel zugerechnet wird, und dem Default Mode Network (DMN) auf. Bisherige Studien, in denen überwiegend jüngere depressive Patienten untersucht wurden, kamen jedoch hinsichtlich der IAc und den kortikalen Netzwerken zu inkonsistenten Ergebnissen. Insbesondere ist unklar, inwieweit sich die IAc nach einem Therapieansprechen verändert, von der Herzratenvariabilität (HRV) moduliert wird und welche Auswirkungen dies auf die funktionelle Konnektivität kortikaler Netzwerke hat. Ziele: Eine veränderte IAc und HRV wie auch funktionelle Konnektivitätsunterschiede im DMN und SN könnten Biomarker der Depression darstellen. Im Rahmen einer Längsschnittuntersuchung wurde getestet, ob ältere depressive Patienten über eine verringerte IAc, eine geringere HRV und über eine veränderte funktionelle Konnektivität im SN sowie DMN verfügen. Darüber hinaus sollte erforscht werden, in welchem Ausmaß sich Patienten, die auf die Behandlung ansprachen (Responder), von sogenannten Non-Respondern in Bezug auf die IAc, die HRV, das SN und das DMN unterschieden. Methoden: In Studie 1 (Baseline) wurden 30 größtenteils medizierte, schwer depressive Patienten (> 50 Jahre) und 30 gesunde Kontrollprobanden untersucht. Die IAc wurde in einer Herzwahrnehmungsaufgabe ermittelt und die HRV bestimmt. Zusätzlich wurde eine resting-state fMRT durchgeführt. Eine funktionelle Konnektivitätsanalyse für Saatregionen im SN und DMN wurde mit einem saatbasierten Ansatz (seed-to-voxel) durchgeführt. Für eine Subgruppenanalyse wurde die Patientengruppe in ängstlich-depressive und nicht-ängstlich depressive Patienten unterteilt. In Studie 2 (sechs Monate Follow-up) wurde die Studienkohorte nochmals untersucht. Es nahmen 21 Personen der Patientengruppe und 28 Probanden der Kontrollgruppe teil. Wiederum wurden die IAc und die HRV bestimmt. Außerdem fand eine resting-state fMRT-Messung statt. Die Patientengruppe wurde unterteilt in depressive Responder und Non-Responder. Ergebnisse: In Studie 1 zeigten depressive Patienten eine funktionelle Hypokonnektivität zwischen einzelnen Saatregionen der Insel (SN) und Teilen des superioren frontalen Gyrus, des supplementärmotorischen Cortex, des lateralen okzipitalen Cortex sowie des Okzipitalpols. Zudem wiesen depressive Patienten zwischen der Saatregion im anterioren Teil des DMN und der Insel sowie dem Operculum eine erhöhte funktionelle Konnektivität auf. Die Gruppen unterschieden sich nicht in der IAc und der HRV. Ängstlich-depressive Patienten zeigten eine höhere funktionelle Konnektivität innerhalb der Insel als nicht-ängstlich depressive Patienten, jedoch zeigten sich keine Unterschiede in der IAc und der HRV. In Studie 2 wiesen depressive Non-Responder im Vergleich zu Respondern eine Hyperkonnektivität zwischen dem posterioren DMN und dem Frontalpol sowie zwischen dem posterioren DMN und temporalen Arealen im SN auf. Keine funktionellen Konnektivitätsunterschiede zeigten sich für die Saatregionen im SN. Depressive Responder, Non-Responder und die Kontrollprobanden unterschieden sich in ihrer IAc und HRV nicht. Schlussfolgerungen: Die Ergebnisse der Studien unterstreichen, dass bei depressiven Patienten, Respondern und Non-Respondern Unterschiede in der intrinsischen Gehirnaktivität funktioneller Netzwerke bestehen, jedoch nicht in der akkuraten Wahrnehmung des eigenen Herzschlages und der HRV. Therapeutische Interventionen, die auf eine Verbesserung der IAc abzielen, könnten insbesondere für Non-Responder dennoch eine zusätzliche Behandlungsmöglichkeit darstellen. Für eine personalisierte Medizin könnte die weitere Erforschung von kortikalen Netzwerken einen wesentlichen Beitrag leisten, um ein individuelles Therapieansprechen zu prädizieren. N2 - Background: Major depressive disorder (MDD) is among the most prevalent psychiatric disorders. Symptoms include impaired cognitive functions, vegetative complaints, and altered emotional experience. The deficient perception of internal body signals is associated with the pathogenesis of depression and anxiety disorders. Interoceptive accuracy (IAc) refers to the ability to accurately perceive bodily sensations (e.g., own heartbeat) and is assessed via a heartbeat perception task. In neuroimaging studies using functional magnetic resonance imaging (fMRI) lower IAc was associated with reduced insula activity. Resting-state fMRI allows to measure intrinsic brain activity without performing a task. This enables the identification of cortical networks. Patients with depression exhibit altered functional connectivity within and between various networks: the salience network (SN), which comprises the insula, and the default mode network (DMN). Previous studies investigating IAc and cortical networks in predominantly younger patients with depression yielded inconsistent results. In particular it remains unclear to what extent IAc alters after treatment response and how it is modulated by heart rate variability (HRV). The impact of changed IAc on the functional connectivity of cortical networks is insufficiently understood. Objectives: Altered IAc and HRV as well as functional connectivity differences in DMN and SN could serve as biomarkers of MDD. In a longitudinal study it was investigated, whether middle-aged and older patients with depression exhibit lower IAc, reduced HRV, and altered functional connectivity in SN and DMN. Furthermore, differences between depressed responders and non-responders with regard to IAc, HRV, SN, and DMN were investigated. Methods: In Study 1 (baseline) 30 mostly medicated patients with depression (> 50 years) and 30 healthy controls were examined. IAc was measured by the heartbeat perception task and HRV was assessed. Additionally, all participants underwent resting-state fMRI. Seed-to-voxel resting-state functional connectivity analysis with seeds in the SN and the DMN was conducted. The patient group was divided into anxious and non-anxious depressed patients for a subgroup analysis. In Study 2 (six-month follow-up) participants were invited again. 21 persons from the former patient group and 28 healthy controls participated. IAc was measured, HRV assessed, and resting-state fMRI acquired. The former depressed patient group was split into responders and non-responders. Results: In Study 1 patients with depression showed functional hypoconnectivity between several seeds in the insula (SN) and parts of the superior frontal gyrus, the supplementary motor cortex, the lateral occipital cortex, and the occipital pole. Patients with depression exhibited higher functional connectivity between the seed region in the anterior DMN and the insula together with the operculum. Groups did not differ with regard to IAc and HRV. Patients with anxious depression showed higher functional connectivity within the insula than patients with non-anxious depression without alterations in IAc and HRV. In Study 2 non-responders exhibited hyperconnectivity between the posterior DMN and the frontal pole as well as between the posterior DMN and temporal areas in the SN compared to responders. No functional connectivity differences were found for seed regions in the SN. There were no group differences between responders, non-responders, and healthy controls with regard to IAc and HRV. Conclusions: The findings underscore differences in intrinsic functional connectivity between patients with depression, responders, and non-responders. However, patients with depression showed normal IAc and HRV. Yet, therapeutical interventions enhancing IAc could be a useful additional treatment option especially for non-responders. In terms of personal medicine, further research of functional connectivity of cortical networks might contribute to a prediction of treatment response. KW - Depression KW - Interozeption KW - Funktionelle Kernspintomografie KW - Interozeptive Genauigkeit KW - Herzratenvariabilität KW - resting-state fMRT KW - Herzfrequenzvariabilität Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-316762 ER - TY - JOUR A1 - Morimoto, Yoshiro A1 - Shimada-Sugimoto, Mihoko A1 - Otowa, Takeshi A1 - Yoshida, Shintaro A1 - Kinoshita, Akira A1 - Mishima, Hiroyuki A1 - Yamaguchi, Naohiro A1 - Mori, Takatoshi A1 - Imamura, Akira A1 - Ozawa, Hiroki A1 - Kurotaki, Naohiro A1 - Ziegler, Christiane A1 - Domschke, Katharina A1 - Deckert, Jürgen A1 - Umekage, Tadashi A1 - Tochigi, Mamoru A1 - Kaiya, Hisanobu A1 - Okazaki, Yuji A1 - Tokunaga, Katsushi A1 - Sasaki, Tsukasa A1 - Yoshiura, Koh-ichiro A1 - Ono, Shinji T1 - Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder JF - Translational Psychiatry N2 - Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein-altering variants. We then screened these genes in a Japanese PD case–control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case–control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene. KW - clinical genetics KW - medical genetics Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224192 VL - 8 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 - 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 - Schroeter, Matthias L. A1 - Pawelke, Sarah A1 - Bisenius, Sandrine A1 - Kynast, Jana A1 - Schuemberg, Katharina A1 - Polyakova, Maryna A1 - Anderl-Straub, Sarah A1 - Danek, Adrian A1 - Fassbender, Klaus A1 - Jahn, Holger A1 - Jessen, Frank A1 - Kornhuber, Johannes A1 - Lauer, Martin A1 - Prudlo, Johannes A1 - Schneider, Anja A1 - Uttner, Ingo A1 - Thöne-Otto, Angelika A1 - Otto, Markus A1 - Diehl-Schmid, Janine T1 - A Modified Reading the Mind in the Eyes Test Predicts Behavioral Variant Frontotemporal Dementia Better Than Executive Function Tests JF - Frontiers in Aging Neuroscience N2 - Behavioral variant frontotemporal dementia (bvFTD) is characterized by deep alterations in behavior and personality. Although revised diagnostic criteria agree for executive dysfunction as most characteristic, impairments in social cognition are also suggested. The study aimed at identifying those neuropsychological and behavioral parameters best discriminating between bvFTD and healthy controls. Eighty six patients were diagnosed with possible or probable bvFTD according to Rascovsky et al. (2011) and compared with 43 healthy age-matched controls. Neuropsychological performance was assessed with a modified Reading the Mind in the Eyes Test (RMET), Stroop task, Trail Making Test (TMT), Hamasch-Five-Point Test (H5PT), and semantic and phonemic verbal fluency tasks. Behavior was assessed with the Apathy Evaluation Scale, Frontal Systems Behavioral Scale, and Bayer Activities of Daily Living Scale. Each test’s discriminatory power was investigated by Receiver Operating Characteristic curves calculating the area under the curve (AUC). bvFTD patients performed significantly worse than healthy controls in all neuropsychological tests. Discriminatory power (AUC) was highest in behavioral questionnaires, high in verbal fluency tasks and the RMET, and lower in executive function tests such as the Stroop task, TMT and H5PT. As fluency tasks depend on several cognitive functions, not only executive functions, results suggest that the RMET discriminated better between bvFTD and control subjects than other executive tests. Social cognition should be incorporated into diagnostic criteria for bvFTD in the future, such as in the International Classification of Diseases (ICD)-11, as already suggested in the Diagnostic and Statistical Manual for Mental Disorders (DSM)-5. KW - behavioral variant frontotemporal dementia KW - diagnostic criteria KW - executive function KW - social cognition KW - theory of mind Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234254 VL - 10 ER - TY - JOUR A1 - Ullrich, M A1 - Weber, M A1 - Post, A M A1 - Popp, S A1 - Grein, J A1 - Zechner, M A1 - González, H Guerrero A1 - Kreis, A A1 - Schmitt, A G A1 - Üҫeyler, N A1 - Lesch, K-P A1 - Schuh, K T1 - OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency JF - Molecular Psychiatry N2 - Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD. KW - molecular biology KW - neuroscience KW - physiology KW - psychiatric disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232096 VL - 23 ER - TY - JOUR A1 - Levy, Marion J. F. A1 - Boulle, Fabien A1 - Emerit, Michel Boris A1 - Poilbout, Corinne A1 - Steinbusch, Harry W. M. A1 - Van den Hove, Daniel L. A. A1 - Kenis, Gunter A1 - Lanfumey, Laurence T1 - 5-HTT independent effects of fluoxetine on neuroplasticity JF - Scientific Reports N2 - Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB. KW - depression KW - neurotrophic factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236759 VL - 9 ER - TY - JOUR A1 - Gerber, Bertram A1 - König, Christian A1 - Fendt, Markus A1 - Andreatta, Marta A1 - Romanos, Marcel A1 - Pauli, Paul A1 - Yarali, Ayse T1 - Timing-dependent valence reversal: a principle of reinforcement processing and its possible implications JF - Current Opinion in Behavioral Sciences N2 - Punishment feels bad, but relief upon its termination feels good. As a consequence of such timing-dependent valence reversal, memories of opposite valence can result from associating stimulus A with, for example, the occurrence of punishment (A-) versus punishment termination (-A): A- training results in aversive memory, but -A training in appetitive memory (corresponding effects exist for reward occurrence and termination). Whereas learning through the occurrence of punishment is well studied, much less is known about learning through its termination. Current research investigates how dopaminergic system function contributes to these processes in Drosophila, rats and humans. We argue that dopamine-related psychopathology may entail distortions in learning through punishment termination, and that this may contribute, for example, to non-suicidal self-injury or post-traumatic stress disorder. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232933 VL - 26 ER - TY - THES A1 - Das [geb. Nitschke], Felix Marcel T1 - DNA-Methylierung und Genexpression von FKPB5 als Teil des Stresshormonsystems bei von Depressionen und Herzinsuffizienz Betroffenen sowie gesunden Kontrollen T1 - DNA methylation and gene expression of FKPB5 as part of the stress hormone system in people affected by depression and heart failure as well as healthy controls N2 - FKBP5 stellt im Stresssystem der HPA-Achse ein zentrales Gen bei der Regulation der Sensitivität des Glukokortikoidrezeptors und somit der Reaktion auf Stress dar. Zur Adaptation an Umwelteinflüsse ist es selbst in ein komplexes System von Regulationsmechanismen eingebettet, die unter anderem epigenetische Modifikationen in Form von DNA-Methylierung umfassen. Bisherige Studien legen eine starke Assoziation von FKBP5 zu stressinduzierten psychischen Erkrankungen nahe und weisen auf eine Dysregulation der HPA-Achse als möglichen Pathomechanismus hin. Für die enge klinische Interaktion von Depression und Herzinsuffizienz sowie eine ebenfalls vermutete Rolle der HPA-Achse in der Pathogenese letzterer, könnte FKBP5 daher ein entscheidendes Bindeglied darstellen. Gleichzeitig bietet die Identifikation einer über FKBP5 ausgedrückten Dysregulation der HPA-Achse einen biologischen Befund, der als Marker für das Ansprechen einer antidepressiven Therapie herangezogen werden könnte. Ziel dieser Arbeit war daher die Untersuchung eines möglichen Einflusses regulatorischer Parameter von FKBP5 auf die Herzinsuffizienz sowie eine Prüfung dieser als mögliche Biomarker für einen Erfolg der antidepressiven Therapie. Dazu wurden Blutproben von ProbandInnen der GEParD- bzw. DaCFail-Studie mit Depression, Herzinsuffizienz sowie gesunde Kontrollen untersucht. Durch Pyrosequenzierung bisulfitkonvertierter DNA erfolgte die Bestimmung der Methylierung regulatorischer CpGs. Die Messung der relativen mRNA-Expression erfolgte durch den Einsatz einer qPCR. In der Auswertung fand sich keine differentielle mRNA-Expression oder Methylierung zwischen den vier Untersuchungsgruppen. Allerdings reagierten depressive PatientInnen verglichen mit der Kontrollgruppe mit einer geringeren Zunahme der mRNA-Expression als Reaktion auf den mDST. Das Therapieansprechen in der Depressionsgruppe wiederum war mit einer niedrigeren Methylierung auf CpG7 sowie einer höheren mRNA-Expression zu Therapiebeginn assoziiert. Im Behandlungsverlauf führte eine Abnahme der mRNA-Expression bei den Respondern zu einer Annäherung beider Gruppen. Diese Arbeit konnte keine Hinweise für eine Rolle von FKBP5 in der Pathogenese der Herzinsuffizienz finden. Allerdings zeigten die Befunde zur Regulation des Gens bei Glukokortikoidstimulation eine hohe Konstanz zu vorherigen Ergebnissen. In diesen Kontext reihen sich auch die Ergebnisse für das Therapieansprechen ein, die aufgrund einer Herabregulation der HPA-Achse im Therapieverlauf die Idee einer ursächlichen HPA-Dysregulation in der Gruppe der Responder bekräftigen. Für sich allein genommen lassen sich mRNA-Expression und Methylierung aufgrund mangelnder Sensitivität und Spezifität nicht als Biomarker für das Therapieansprechen einsetzen. Die bisherigen Befunde bestärken aber eine mögliche Rolle in einer Batterie unterschiedlicher Biomarker auf verschiedenen Ebenen, wie Klinik, Psychometrie und Physiologie. N2 - FKBP5 represents a central gene in the stress system of the HPA axis in the regulation of the sensitivity of the glucocorticoid receptor and thus the reaction to stress. To adapt to environmental influences, it is itself embedded in a complex system of regulatory mechanisms, including epigenetic modifications in the form of DNA -Methylation. Previous studies suggest a strong association of FKBP5 with stress-induced mental illnesses and point to a dysregulation of the HPA axis as a possible pathomechanism. FKBP5 could therefore represent a crucial link for the close clinical interaction between depression and heart failure as well as a suspected role of the HPA axis in the pathogenesis of the latter. At the same time, the identification of HPA axis dysregulation expressed via FKBP5 provides a biological finding that could be used as a marker for the response to antidepressant therapy. The aim of this work was therefore to investigate a possible influence of regulatory parameters of FKBP5 on heart failure and to examine these as possible biomarkers for the success of the antidepressive therapy. For this purpose, blood samples from subjects of the GEParD or DaCFail study with depression, heart failure and healthy controls were examined. Pyrosequencing of bisulfite-converted DNA was used to determine the methylation of regulatory CpGs. The relative mRNA expression was measured using qPCR. The analysis found no differential mRNA expression or methylation between the four study groups. However, depressed patients responded with a smaller increase in mRNA expression in response to the mDST compared to the control group. The treatment response in the depression group was associated with lower methylation on CpG7 and higher mRNA expression at the start of therapy. Over the course of treatment, a decrease in mRNA expression in responders led to a convergence of both groups. This work did not find any evidence for a role for FKBP5 in the pathogenesis of heart failure. However, the findings on the regulation of the gene during glucocorticoid stimulation showed a high degree of consistency with previous results. The results for the treatment response also fit into this context, which strengthen the idea of a causal HPA dysregulation in the group of responders due to a downregulation of the HPA axis during the course of therapy. Taken alone, mRNA expression and methylation cannot be used as biomarkers of treatment response due to a lack of sensitivity and specificity. However, the findings so far support a possible role in a battery of different biomarkers at different levels, such as clinical, psychometrics and physiology. KW - Gen FKBP5 KW - Methylierung KW - Genexpression KW - Depression KW - Herzinsuffizienz KW - FKBP5 Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369730 ER - TY - JOUR A1 - Figel, Benedikt A1 - Brinkmann, Leonie A1 - Buff, Christine A1 - Heitmann, Carina Y. A1 - Hofmann, David A1 - Bruchmann, Maximilian A1 - Becker, Michael P. I. A1 - Herrmann, Martin J. A1 - Straube, Thomas T1 - Phasic amygdala and BNST activation during the anticipation of temporally unpredictable social observation in social anxiety disorder patients JF - NeuroImage: Clinical N2 - Anticipation of potentially threatening social situations is a key process in social anxiety disorder (SAD). In other anxiety disorders, recent research of neural correlates of anticipation of temporally unpredictable threat suggests a temporally dissociable involvement of amygdala and bed nucleus of the stria terminalis (BNST) with phasic amygdala responses and sustained BNST activation. However, the temporal profile of amygdala and BNST responses during temporal unpredictability of threat has not been investigated in patients suffering from SAD. We used functional magnetic resonance imaging (fMRI) to investigate neural activation in the central nucleus of the amygdala (CeA) and the BNST during anticipation of temporally unpredictable aversive (video camera observation) relative to neutral (no camera observation) events in SAD patients compared to healthy controls (HC). For the analysis of fMRI data, we applied two regressors (phasic/sustained) within the same model to detect temporally dissociable brain responses. The aversive condition induced increased anxiety in patients compared to HC. SAD patients compared to HC showed increased phasic activation in the CeA and the BNST for anticipation of aversive relative to neutral events. SAD patients as well as HC showed sustained activity alterations in the BNST for aversive relative to neutral anticipation. No differential activity during sustained threat anticipation in SAD patients compared to HC was found. Taken together, our study reveals both CeA and BNST involvement during threat anticipation in SAD patients. The present results point towards potentially SAD-specific threat processing marked by elevated phasic but not sustained CeA and BNST responses when compared to HC. KW - FMRI KW - threat anticipation KW - social anxiety disorder KW - bed nucleus of stria terminalis KW - amygdala Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228071 VL - 22 ER - TY - JOUR A1 - Kiser, Dominik P. A1 - Popp, Sandy A1 - Schmitt-Böhrer, Angelika G. A1 - Strekalova, Tatyana A1 - van den Hove, Daniel L. A1 - Lesch, Klaus-Peter A1 - Rivero, Olga T1 - Early-life stress impairs developmental programming in Cadherin 13 (CDH13)-deficient mice JF - Progress in Neuropsychopharmacology & Biological Psychiatry N2 - Objective Cadherin-13 (CDH13), a member of the calcium-dependent cell adhesion molecule family, has been linked to neurodevelopmental disorders, including autism spectrum (ASD) and attention-deficit/hyperactivity (ADHD) disorders, but also to depression. In the adult brain, CDH13 expression is restricted e.g. to the presynaptic compartment of inhibitory GABAergic synapses in the hippocampus and Cdh13 knockout mice show an increased inhibitory drive onto hippocampal CA1 pyramidal neurons, leading to a shift in excitatory/inhibitory balance. CDH13 is also moderating migration of serotonergic neurons in the dorsal raphe nucleus, establishing projections preferentially to the thalamus and cerebellum during brain development. Furthermore, CDH13 is upregulated by chronic stress as well as in depression, suggesting a role in early-life adaptation to stressful experience. Here, we therefore investigated the interaction between Cdh13 variation and neonatal maternal separation (MS) in mice. Methods Male and female wild-type (Cdh13+/+), heterozygous (Cdh13+/−) and homozygous (Cdh13−/−) knockout mice exposed to MS, or daily handling as control, were subjected to a battery of behavioural tests to assess motor activity, learning and memory as well as anxiety-like behaviour. A transcriptome analysis of the hippocampus was performed in an independent cohort of mice which was exposed to MS or handling, but remained naïve for behavioural testing. Results MS lead to increased anxiety-like behaviour in Cdh13−/− mice compared to the other two MS groups. Cdh13−/− mice showed a context-dependent effect on stress- and anxiety-related behaviour, impaired extinction learning following contextual fear conditioning and decreased impulsivity, as well as a mild decrease in errors in the Barnes maze and reduced risk-taking in the light-dark transition test after MS. We also show sex differences, with increased locomotor activity in female Cdh13−/− mice, but unaltered impulsivity and activity in male Cdh13−/− mice. Transcriptome analysis revealed several pathways associated with cell surface/adhesion molecules to be altered following Cdh13 deficiency, together with an influence on endoplasmic reticulum function. Conclusion MS resulted in increased stress resilience, increased exploration and an overall anxiolytic behavioural phenotype in male Cdh13+/+ and Cdh13+/− mice. Cdh13 deficiency, however, obliterated most of the effects caused by early-life stress, with Cdh13−/− mice exhibiting delayed habituation, no reduction of anxiety-like behaviour and decreased fear extinction. Our behavioural findings indicate a role of CDH13 in the programming of and adaptation to early-life stress. Finally, our transcriptomic data support the view of CDH13 as a neuroprotective factor as well as a mediator in cell-cell interactions, with an impact on synaptic plasticity. KW - Cadherin-13 (CDH13) KW - T-cadherin KW - neurodevelopment KW - autism KW - ADHD KW - depression KW - psychiatric disorders KW - early-life stress KW - mouse KW - RNA sequencing KW - endoplasmic reticulum stress KW - adhesion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325859 VL - 89 ER - TY - JOUR A1 - Argyrousi, Elentina K. A1 - de Nijs, Laurence A1 - Lagatta, Davi C. A1 - Schlütter, Anna A1 - Weidner, Magdalena T. A1 - Zöller, Johanna A1 - van Goethem, Nick P. A1 - Joca, Sâmia R. L. A1 - van den Hove, Daniel L. A. A1 - Prickaerts, Jos T1 - Effects of DNA methyltransferase inhibition on pattern separation performance in mice JF - Neurobiology of Learning and Memory N2 - Enhancement of synaptic plasticity through changes in neuronal gene expression is a prerequisite for improved cognitive performance. Moreover, several studies have shown that DNA methylation is able to affect the expression of (e.g. plasticity) genes that are important for several cognitive functions. In this study, the effect of the DNA methyltransferase (DNMT) inhibitor RG108 was assessed on object pattern separation (OPS) task in mice. In addition, its effect on the expression of target genes was monitored. Administration of RG108 before the test led to a short-lasting, dose-dependent increase in pattern separation memory that was not present anymore after 48 h. Furthermore, treatment with RG108 did not enhance long-term memory of the animals when tested after a 24 h inter-trial interval in the same task. At the transcriptomic level, acute treatment with RG108 was accompanied by increased expression of Bdnf1, while expression of Bdnf4, Bdnf9, Gria1 and Hdac2 was not altered within 1 h after treatment. Methylation analysis of 14 loci in the promoter region of Bdnf1 revealed a counterintuitive increase in the levels of DNA methylation at three CpG sites. Taken together, these results indicate that acute administration of RG108 has a short-lasting pro-cognitive effect on object pattern separation that could be explained by increased Bdnf1 expression. The observed increase in Bdnf1 methylation suggests a complex interplay between Bdnf methylation-demethylation that promotes Bdnf1 expression and associated cognitive performance. Considering that impaired pattern separation could constitute the underlying problem of a wide range of mental and cognitive disorders, pharmacological agents including DNA methylation inhibitors that improve pattern separation could be compelling targets for the treatment of these disorders. In that respect, future studies are needed in order to determine the effect of chronic administration of such agents. KW - object pattern separation KW - DNA methyltransferase inhibitors KW - BDNF KW - CpG islands KW - epigenetics KW - hippocampal plasticity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221226 VL - 159 ER - TY - JOUR A1 - Barkhuizen, Melinda A1 - van Mechelen, Ralph A1 - Vermeer, Marijne A1 - Chedraui, Peter A1 - Paes, Dean A1 - van den Hove, Daniel L. A. A1 - Vaes, Bart A1 - Mays, Robert W. A1 - Steinbusch, Harry W. M. A1 - Robertson, Nicola J. A1 - Kramer, Boris W. A1 - Gavilanes, Antonio W. D. T1 - Systemic multipotent adult progenitor cells improve long-term neurodevelopmental outcomes after preterm hypoxic-ischemic encephalopathy JF - Behavioural Brain Research N2 - There is an urgent need for therapies that could reduce the disease burden of preterm hypoxic-ischemic encephalopathy. Here, we evaluate the long-term effects of multipotent adult progenitor cells (MAPC) on long-term behavioral outcomes in a preterm rat model of perinatal asphyxia. Rats of both sexes were treated with two doses of MAPCs within 24 h after the insult. Locomotor, cognitive and psychiatric impairments were evaluated starting at 1.5 (juvenile) and 6 months (adult). Hypoxia-ischemia affected locomotion, cognition, and anxiety in a sex-dependent manner, with higher vulnerability observed in males. The MAPC therapy partially attenuated deficits in object recognition memory in females of all tested ages, and in the adult males. The hypoxic insult caused delayed hyperactivity in adult males, which was corrected by MAPC therapy. These results suggest that MAPCs may have long-term benefits for neurodevelopmental outcome after preterm birth and global hypoxia-ischemia, which warrants further preclinical exploration. KW - hypoxic-ischemic encephalopathy KW - preterm brain KW - stem cell therapy KW - neurodevelopment Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221506 VL - 362 ER - TY - JOUR A1 - Gorlova, Anna A1 - Pavlov, Dmitrii A1 - Anthony, Daniel C. A1 - Ponomarev, Eugene D. A1 - Sambon, Margaux A1 - Proshin, Andrey A1 - Shafarevich, Igor A1 - Babaevskaya, Diana A1 - Lesch, Klaus-Peter A1 - Bettendorff, Lucien A1 - Strekalova, Tatyana T1 - Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice JF - Neuropharmacology N2 - The negative societal impacts associated with the increasing prevalence of violence and aggression is increasing, and, with this rise, is the need to understand the molecular and cellular changes that underpin ultrasound-induced aggressive behavior. In mice, stress-induced aggression is known to alter AMPA receptor subunit expression, plasticity markers, and oxidative stress within the brain. Here, we induced aggression in BALB/c mice using chronic ultrasound exposure and examined the impact of the psychoactive anti-oxidant compounds thiamine (vitamin B1), and its derivative benfotiamine, on AMPA receptor subunit expression, established plasticity markers, and oxidative stress. The administration of thiamine or benfotiamine (200 mg/kg/day) in drinking water decreased aggressive behavior following 3-weeks of ultrasound exposure and benfotiamine, reduced floating behavior in the swim test. The vehicle-treated ultrasound-exposed mice exhibited increases in protein carbonyl and total glutathione, altered AMPA receptor subunits expression, and decreased expression of plasticity markers. These ultrasound-induced effects were ameliorated by thiamine and benfotiamine treatment; in particular both antioxidants were able to reverse ultrasound-induced changes in GluA1 and GluA2 subunit expression, and, within the prefrontal cortex, significantly reversed the changes in protein carbonyl and polysialylated form of neural cell adhesion molecule (PSA-NCAM) expression levels. Benfotiamine was usually more efficacious than thiamine. Thus, the thiamine compounds were able to counteract ultrasound-induced aggression, which was accompanied by the normalization of markers that have been showed to be associated with ultrasound-induced aggression. These commonly used, orally-active compounds may have considerable potential for use in the control of aggression within the community. This article is part of the Special Issue entitled ‘Current status of the neurobiology of aggression and impulsivity’. KW - aggression KW - emotional stress KW - brain oxidative stress KW - plasticity KW - thiamine KW - mice Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227439 VL - 156 ER - TY - JOUR A1 - Verheijen, Bert M. A1 - Stevens, Jo A. A. A1 - Gentier, Romina J. G. A1 - van't Hekke, Christian D. A1 - van den Hove, Daniel L. A. A1 - Hermes, Denise J. H. P. A1 - Steinbusch, Harry W. M. A1 - Ruijter, Jan M. A1 - Grimm, Marcus O. W. A1 - Haupenthal, Viola J. A1 - Annaert, Wim A1 - Hartmann, Tobias A1 - van Leeuwen, Fred W. T1 - Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model JF - Neurobiology of Aging N2 - Amyloid-β (Aβ) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated Aβ peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several Aβ-associated factors. Efficient clearance of Aβ from the brain is thought to be important to prevent the development and progression of AD. The ubiquitin-proteasome system (UPS) is one of the major pathways for protein breakdown in cells and it has been suggested that impaired UPS-mediated removal of protein aggregates could play an important role in the pathogenesis of AD. To study the effects of an impaired UPS on Aβ pathology in vivo, transgenic APPSwe/PS1ΔE9 mice (APPPS1) were crossed with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based inhibitor of the UPS. Surprisingly, the APPPS1/UBB+1 crossbreed showed a remarkable decrease in Aβ plaque load during aging. Further analysis showed that UBB+1 expression transiently restored PS1-NTF expression and γ-secretase activity in APPPS1 mice. Concurrently, UBB+1 decreased levels of β-APP-CTF, which is a γ-secretase substrate. Although UBB+1 reduced Aβ pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals. KW - mutant ubiquitin KW - ubiquitin-proteasome system KW - γ-secretase KW - amyloid-β KW - behavior KW - Alzheimer's disease Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233185 VL - 72 ER - TY - THES A1 - Adolf, Jonas Michael T1 - Die Zusammenarbeit zwischen der stationären beziehungsweise teilstationären psychotherapeutischen Behandlung und niedergelassenen Psychotherapeut:innen T1 - The Collaboration between inpatient and semi-inpatient psychotherapeutic treatment and outpatient psychotherapists N2 - Das Ziel der vorliegenden Arbeit war es die aktuelle Versorgungskontinuität in der psychotherapeutischen Versorgung hinsichtlich der Zusammenarbeit des (teil-)stationären und des ambulanten Sektors aus Sicht der niedergelassenen Psychotherapeut:innen zu untersuchen, diese in den wissenschaftlichen Kontext einzuordnen und – falls möglich – erste Möglichkeiten zur Verbesserung der derzeitigen Versorgungskontinuität aufzuzeigen. In Zusammenarbeit mit dem Arbeitsbereich für Medizinische Psychologie und Psychotherapie im Zentrum für psychische Gesundheit des Universitätsklinikums Würzburg wurde hierzu ein Fragebogen entwickelt und acht ausgewählten psychotherapeutischen Fachgesellschaften beziehungsweise Psychotherapeutenkammern mit der Bitte um Weiterleitung an deren Mitglieder zugesandt. In der vorliegenden Studie wurden – neben einer Globalbeurteilung – im Speziellen die Teil-aspekte des Austauschs, der entsprechenden Rahmenbedingungen und die Bereitstellung des poststationären ambulanten Psychotherapieplatzes betrachtet. Die Studienergebnisse bilden den derzeitigen Status Quo der psychotherapeutischen Versorgungslage aus Sicht der niedergelassenen Psychotherapeut:innen ab und weisen im Zuge dessen auf einige Defizite in den untersuchten Teilaspekten hin. Die aufgestellten Nebenfragestellungen zeigen gleichsam aber auch Ansatzunkte für Lösungen auf. Aufgrund der besonderen Relevanz der aufgezeigten Ergebnisse, gilt es – zur Ermöglichung einer adäquaten kontinuierlichen psychotherapeutischen Versorgung – eine weitergehende Betrach-tung der aufgezeigten Defizite vorzunehmen. Für ein umfassendes Bild sind zudem kongruente Folgearbeiten mit dem Augenmerk auf der Sichtweise der (teil-)stationären Behandlungseinrichtungen und der Patient:innen notwendig. Insbesondere vor dem Hintergrund der limitierten Möglichkeiten der vorliegenden Arbeit gilt es große repräsentative und nationale Studien anzustreben. Hierzu wäre die Etablierung zentral verwalteter Register zur Bündelung der bisherigen und zukünftigen Forschungsarbeiten im Bereich der Psychotherapie wünschenswert. Vor allem vor dem Hintergrund zahlreicher Modellprojekte erscheint dies sinnvoll und könnte einen wichtigen Beitrag zur Optimierung der derzeitigen psychotherapeutischen Forschungs- und Versorgungslage beitragen. N2 - The aim of the study was to identify the current continuity of care regarding psychotherapeutic care and the collaboration of the (semi-)inpatient and outpatient field from point of view of the outpatient psychotherapists. Furthermore, the study wants to integrate the findings in the recent scientific context and wants to reveal improvements regarding the continuity of care in the field of psychotherapy. An explorative survey was created in collaboration with the working group of medical psychology and psychotherapy at the centre for mental health of the university hospital of Würzburg. Eight selected psychotherapeutic organisations (psychotherapy chambers and societies) were invited to conduct the survey to their members. Apart from a general assessment the study took a closer look at the framework conditions, the field of exchange and the care of outpatient psychotherapy to patients after (semi-)inpatient care. The study results describe the current situation of the psychotherapy care in Germany from the point of view of the outpatient psychotherapists and demonstrate on the one hand deficits regarding the analysed aspects and – as part of the side questions – on the other hand possible approaches for improvements. To facilitate a better continuity of psychotherapeutic care, it is important to take a closer look at the demonstrated deficits reported by the study. Moreover further studies are necessary treating the point of view of (semi-)inpatient psychotherapists as well as to conduct large national-wide representative studies, especially against the backdrop of the limited possibilities of the present study. For this purpose, it is helpful to establish a central-managed register to collect all studies in the field of psychotherapy. That could contribute to improve the current situation of research and care in the field of psychotherapy, in particular against the backdrop of the numerous pilot projects. KW - Psychotherapie KW - Medizinische Versorgung KW - Versorgungskontinuität KW - Sektoren KW - Versorgung KW - Psychiatrie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371098 ER - TY - THES A1 - Ruppert [geb. Rapp], Elisabeth Marlene T1 - Einfluss von sozialem Stress und 5-Htt-Genotyp: Quantitative Untersuchung der Morphologie von Neuronen der lateralen Amygdala und der CA3-Region des Hippocampus von Mäusen der Serotonintransporter-Knockout-Linie T1 - Influence of social stress and 5-Htt genotype: Quantitative investigation of the morphology of neurons of the lateral amygdala and the CA3 region of the hippocampus of mice of the serotonin transporter knockout line N2 - In dieser Arbeit wurde der Einfluss sozialer Stresserfahrung sowie des 5-Htt-Genotyps auf die neuronale Morphologie bestimmter Hirnregionen anhand eines Mausmodells untersucht. Es wurde in mit Golgi-Cox gefärbten Gehirnen der 5-HTT-KO-Linie in der lateralen Amygdala (LA) die Apikal- und Basaldendriten pyramidenzellähnlicher Neurone und die Apikaldendriten der Pyramidenzellen der Cornu ammonis (CA)3-Region des Hippocampus mithilfe des Neurolucidasystems rekonstruiert und die so gewonnenen Daten anschließend statistisch ausgewertet. Die erzielten Ergebnisse belegen, dass vor allem die Erfahrung von sozialem Verteidigungsstress aber auch der 5-Htt-Genotyp (WT, HET, KO) im Mausmodell signifikanten Einfluss auf die Morphologie der Neurone der LA und der CA3-Region besitzen. Um die in dieser Arbeit mit allen drei 5-Htt-Genotypen erzielten Ergebnisse der LA-Neurone besser mit den Ergebnissen von Nietzer und Bonn (nur WT, KO) vergleichen zu können (Nietzer et al., 2011), wurden die von mir erhobenen Daten nicht nur in einem 3er-Vergleich, sondern auch einem 2er-Vergleich (WT vs. KO) statistisch analysiert. Untersuchungen der LA-Neurone aller drei 5-Htt-Genotypen zeigen, dass sozialer Stress zu einer Zunahme der Komplexität der Dendritenbäume durch längere und auch stärker verzweigte Dendriten vor allem in der Gruppe der WT-Mäuse führt. HET- und KO-Mäuse zeigten keinen entsprechenden Stress-Effekt. Darüber hinaus zeigten sich deutliche Genotypeffekte. Unabhängig vom Stresserleben besitzen HET-Mäuse längere Dendriten als WT-Mäuse sowie eine höhere Spinedichte als WT- und KO-Mäuse. Die Hypothese, die in der Arbeit von Nietzer et al. aufgestellt wurde, dass eine vollständige 5-HTT-Defizienz zu mehr Spines führt, ließ sich hier weder durch den 3er- noch durch den 2er-Vergleich replizieren. Die Pyramidenzellen der CA3-Region, die in dieser Studie zum ersten Mal analysiert wurden, zeigen in Bezug auf die durch den Stress ausgelösten Veränderungen ein im Vergleich zu den LA-Neuronen entgegengesetzten Effekt. Der soziale Stress führt hier zu einer Dendritenatrophie in der WT-Gruppe mit kürzeren und weniger komplexen Dendriten. Außerdem führte er zu einer geringeren Spinedichte bei den HET-Mäusen. Es zeigten sich klare Genotypeffekte, unabhängig von der Stresserfahrung, mit einer reduzierten Spinedichte der KO-Mäuse gegenüber den WT-Mäusen und einer nur in den Kontrollen detektierten, reduzierten Spinedichte der KO-Mäuse im Vergleich zu den WT- und HET-Mäusen. Sowohl in der LA als auch in der CA3-Region lassen sich Kompensationsmechanismen des 5-HTT-Defizits der HET-Tiere vermuten, über die die KO-Tiere nicht verfügen. Die in LA und CA3 gezeigten gegensätzlichen Auswirkungen des sozialen Stresses weisen auf die unterschiedlichen Funktionen dieser beiden Regionen im Furchtkreislauf und/oder bei der Verarbeitung von Stress hin. Darüber hinaus deutet diese Arbeit darauf hin, dass Arbeiten mit ähnlichen Untersuchungsmethoden und sogar gleichem Untersuchungsmaterial unterschiedliche Ergebnisse liefern können. N2 - In this study, the influence of social stress experience and the 5-Htt genotype on the neuronal morphology of certain brain regions was investigated using a mouse model. The apical and basal dendrites of pyramidal cell-like neurons and the apical dendrites of the pyramidal cells of the cornu ammonis (CA)3 region of the hippocampus were reconstructed in Golgi-Cox-stained brains of the 5-HTT-KO line in the lateral amygdala (LA) using the neurolucida system and the data obtained was then statistically analyzed. The results obtained show that especially the experience of social defense stress but also the 5-Htt genotype (WT, HET, KO) have a significant influence on the morphology of the neurons of the LA and the CA3 region in the mouse model. In order to better compare the results of the LA neurons obtained in this study with all three 5-Htt genotypes with the results of Nietzer and Bonn (WT, KO only) (Nietzer et al., 2011), the data collected by me were statistically analyzed not only in a 3-way comparison, but also in a 2-way comparison (WT vs. KO). Investigations of the LA neurons of all three 5-Htt genotypes show that social stress leads to an increase in the complexity of the dendrite trees due to longer and also more branched dendrites, especially in the group of WT mice. HET and KO mice showed no corresponding stress effect. In addition, there were clear genotype effects. Regardless of the stress experience, HET mice have longer dendrites than WT mice and a higher spin density than WT and KO mice. The hypothesis put forward in the work of Nietzer et al. that complete 5-HTT deficiency leads to more spines could not be replicated here by either the 3-way or 2-way comparison. The pyramidal cells of the CA3 region, which were analyzed for the first time in this study, show an opposite effect compared to the LA neurons with regard to the changes triggered by stress. Here, social stress leads to dendrite atrophy in the WT group with shorter and less complex dendrites. It also led to a lower spin density in the HET mice. There were clear genotype effects, independent of the stress experience, with a reduced spin density in the KO mice compared to the WT mice and a reduced spin density in the KO mice compared to the WT and HET mice, which was only detected in the controls. Compensatory mechanisms for the 5-HTT deficit in the HET animals, which the KO animals do not have, can be assumed in both the LA and the CA3 region. The contrasting effects of social stress shown in LA and CA3 indicate the different functions of these two regions in the fear circuit and/or in the processing of stress. Furthermore, this work suggests that studies using similar research methods and even the same research material may yield different results. KW - Serotoninstoffwechsel KW - Hippocampus KW - Stress KW - Corpus amygdaloideum KW - Ammonshorn KW - CA3-Region KW - laterale Amygdala KW - sozialer Stress KW - Serotonintransporter-Knockout-Linie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369488 ER - TY - THES A1 - Kußberger, Julia Bettina T1 - Protein - Biomarker zur Unterscheidung zwischen unipolarer und bipolarer Depression T1 - Protein - Biomarkers for Differentiating Between Unipolar and Bipolar Depression N2 - Die Diagnosestellung von unipolarer und bipolarer Depression basiert bis heute ausschließlich auf der Bewertung klinischer Symptome. Objektive biochemische Marker, wie sie bei zahlreichen somatischen Krankheiten zur Diagnosestellung angewendet werden, sind bisher nicht verfügbar. Da sich die beide Krankheitsbilder vor allem in der depressiven Episode stark ähneln, ist eine Unterscheidung in diesem Krankheitsstadium häufig nicht eindeutig möglich. Dies kann zu Fehldiagnosen, einer Verschlechterung des Krankheitsverlaufs, einer erhöhten Krankheitslast und höheren Gesundheitskosten führen. Periphere Biomarker wären daher wertvoll, um die klinische Diagnosestellung zu unterstützen und eine adäquate Behandlung frühzeitige zu ermöglichen. In einer vorherigen Studie der Arbeitsgruppe haben Proteom-Analysen bestimmte Proteine wie den Wachstumsfaktor PDGF-BB und das Thrombospondin TSP-1 identifiziert, die potenziell als Biomarker fungieren könnten. In der vorliegenden Studie wurde untersucht, ob sich die Konzentration von PDGF-BB und TSP-1 im Blut zwischen Patient*innen mit unipolarer bzw. bipolarer Depression signifikant unterscheidet. Es konnte gezeigt werden, dass PDGF-BB bei unipolaren Patientinnen signifikant niedriger ist als bei bipolaren Patientinnen und gesunden Kontrollpersonen. Zudem sank die PDGF-BB-Konzentration bei bipolaren Patientinnen während einer remittierten Episode im Vergleich zu einer depressiven Episode signifikant ab. Im Gegensatz dazu zeigte TSP-1 keine signifikanten Unterschiede zwischen den Patient*innengruppen und Kontrollpersonen. Die Arbeit konnte zeigen, dass PDGF-BB das Potenzial hat, als diagnostischer Biomarker für die Unterscheidung zwischen unipolarer und bipolarer Depression zu dienen, während TSP-1 in dieser Hinsicht nicht geeignet erscheint. Weitere Forschung ist jedoch notwendig, um die Rolle von PDGF-BB in der Pathogenese affektiver Erkrankungen besser zu verstehen und seinen Einsatz als Biomarker im klinischen Alltag zu validieren.   N2 - The diagnosis of unipolar and bipolar depression is still based on clinical symptoms. Objective biochemical markers, which are commonly used for diagnosing somatic diseases, are not yet available. Since both conditions, particularly during the depressive phase, exhibit very similar symptoms, distinguishing between them in this stage is often complicated. This can lead to misdiagnosis, a worsening of the disease course, increased disease burden, and higher healthcare costs. Peripheral biomarkers would therefore be of great value in supporting clinical diagnosis and enabling early and appropriate treatment. A previous study by our research group identified proteins such as the growth factor PDGF-BB and thrombospondin TSP-1 through proteomic analysis, which could potentially serve as biomarkers. In the present study, the concentrations of PDGF-BB and TSP-1 in the blood of patients with unipolar and bipolar depression were examined to determine if there were significant differences. The results showed that PDGF-BB levels were significantly lower in unipolar patients compared to bipolar patients and healthy controls. Additionally, PDGF-BB concentrations decreased significantly in bipolar patients during a remitted episode compared to a depressive episode. In contrast, TSP-1 did not show significant differences between the groups studied. The study suggests that PDGF-BB has the potential to serve as a diagnostic biomarker for differentiating between unipolar and bipolar depression, whereas TSP-1 appears less suitable in this context. However, further research is needed to better understand the role of PDGF-BB in the pathogenesis of affective disorders and to validate its clinical utility as a biomarker. KW - Differentialdiagnose KW - Depression KW - Biomarker KW - Affektive Erkrankungen Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371109 ER -