@article{EversVeehMcNeilletal.2019, author = {Evers, Ann-Kristin and Veeh, Julia and McNeill, Rhiannon and Reif, Andreas and Kittel-Schneider, Sarah}, title = {C-reactive protein concentration in bipolar disorder: association with genetic variants}, series = {International Journal of Bipolar Disorders}, volume = {7}, journal = {International Journal of Bipolar Disorders}, doi = {10.1186/s40345-019-0162-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202289}, pages = {26}, year = {2019}, abstract = {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.}, language = {en} } @phdthesis{SchwitallagebSchmitt2018, author = {Schwitalla [geb. Schmitt], Lisa}, title = {Messung niederfrequenter Oszillationen im frontalen und parietalen Kortex mit funktioneller Nahinfrarotspektroskopie in Abh{\"a}ngigkeit vom ApoE-Genotyp}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158832}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {Niederfrequenten Oszillationen r{\"u}cken immer mehr in den Blickpunkt der Forschung um Probanden mit kognitiven Beeintr{\"a}chtigungen zu untersuchen. Bei an Alzheimer-Demenz erkrankten Patienten konnten bereits Ver{\"a}nderungen niederfrequenter Oszillationsmuster, als Folge pathologischer Umbauprzesse im Gehirn festgestellt werden. Neben zahlreichen pr{\"a}disponierenden Risikofaktoren f{\"u}r die Entwicklung einer Alzheimer-Demenz existiert eine anerkannte Interaktion zwischen dem erh{\"o}hten Erkrankungsrisiko bei Vorliegen des ApoE4-Genotyps. Im Gegensatz zu neutralen ApoE3-Alleltr{\"a}gern weisen Tr{\"a}ger der ApoE4-Variante ein erh{\"o}htes 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. M{\"o}gliche fr{\"u}hzeitige Ver{\"a}nderungen niederfrequenter Oszillationen k{\"o}nnten dann als fr{\"u}hdiagnostische 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 abh{\"a}ngige Ver{\"a}nderungen niederfrequenter Oszillationen im parietalen Kortex nachgewiesen werden.}, language = {de} } @phdthesis{Kopetschke2019, author = {Kopetschke, Maren}, title = {Vagus-somatosensorisch evozierte Potentiale (VSEP) - Testung der Reliabilit{\"a}t und Untersuchungen zu alternativen Stimulations- und Ableitbedingungen}, doi = {10.25972/OPUS-18700}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187009}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Die Ableitung Vagus-somatosensibel evozierter Potentiale (VSEP) ist eine vielversprechende, kosteng{\"u}nstige und nicht-invasive Methode zur Fr{\"u}hdiagnostik von Alzheimer-Demenz. In der vorliegenden Arbeit wurde die Retest-Reliabilit{\"a}t der VSEP untersucht. Des Weiteren wurden alternative Stimulationsbedingungen (Stimulation in der Cymba conchae und im anterioren {\"a}ußeren Geh{\"o}rgang) und alternative Ableitbedingungen (referentielle Ableitungen mit Elektroden an Mastoid, Spina scapulae, Vertebra prominens und Handr{\"u}cken) getestet und mit der herk{\"o}mmlichen Methode verglichen. Die Reliabilit{\"a}tsuntersuchungen wurden an 24 gesunden Probanden im Abstand von sechs Monaten durchgef{\"u}hrt. Die alternativen Stimulations- und Ableitbedingungen wurden an je zehn bis zw{\"o}lf Probanden angewandt und die Ergebnisse mit denen von Messungen mit der herk{\"o}mmlichen Methode verglichen. Es zeigte sich eine besonders gute Reliabilit{\"a}t in den Ableitungen T3/O1 und T4/O2. Außerdem liegen Hinweise darauf vor, dass das Alter der Probanden die Reliabilit{\"a}t beeinflusst. Als beste alternative Ableitposition erwies sich das Mastoid. Die Messungen mit alternativen Stimulationspositionen ergaben stark von der herk{\"o}mmlichen Methode abweichende Ergebnisse, deren Ursache die vorliegende Studie nicht sicher kl{\"a}ren kann.}, subject = {Vagus}, language = {de} } @article{ZieglerRichterMahretal.2016, author = {Ziegler, C. and Richter, J. and Mahr, M. and Gajewska, A. and Schiele, M.A. and Gehrmann, A. and Schmidt, B. and Lesch, K.-P. and Lang, T. and Helbig-Lang, S. and Pauli, P. and Kircher, T. and Reif, A. and Rief, W. and Vossbeck-Elsebusch, A.N. and Arolt, V. and Wittchen, H.-U. and Hamm, A.O. and Deckert, J. and Domschke, K.}, title = {MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy}, series = {Translational Psychiatry}, journal = {Translational Psychiatry}, number = {6}, doi = {10.1038/tp.2016.41}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164422}, pages = {e773}, year = {2016}, abstract = {Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17\%), while non-responders further decreased in methylation (-2.00±1.28\%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.}, language = {en} } @phdthesis{Kropp2018, author = {Kropp, Anna Marlene}, title = {Pharmakotherapie-Epigenetik der Depression - DNA-Methylierung des Serotonin-Transporter-Gens (5-HTT, SLC6A4)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166064}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {Die unipolare Depression ist eine der h{\"a}ufigsten psychiatrischen Erkrankungen und geht mit einem hohen Leidensdruck f{\"u}r die Betroffenen einher. Die Symptomatik der Depression besteht v.a. aus gedr{\"u}ckter Stimmung, Interessenverlust und Antriebslosigkeit und f{\"u}hrt bei den Betroffenen zu Einbußen in der sozialen und beruflichen Funktionalit{\"a}t. 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 Suszeptibilit{\"a}tsgene, die jedoch die Erblichkeit der depressiven Erkrankung nicht ausreichend erkl{\"a}ren. Diese „missing heritability" k{\"o}nnte durch epigenetische Faktoren wie z.B. Ver{\"a}nderungen in der DNA-Methylierung bedingt sein. Neben einer {\"a}tiopathogenetischen Rolle kommen epigenetische Modifikationen auch als Marker zur Pr{\"a}diktion des Therapieerfolgs sowie als Korrelat des biologischen Wirkmechanismus der antidepressiven Therapie infrage. Die vorliegende Arbeit untersuchte daher die Pharmakotherapie-Epigenetik eines Suszeptibilit{\"a}tsgens (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. Station{\"a}r 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 {\"A}nderung 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 Pr{\"a}diktion des Therapieerfolgs geeignet. Nach sechsw{\"o}chiger Psychopharmakotherapie lag die mittlere Methylierung bei 6,0 \%, wobei keine signifikante Ver{\"a}nderung nachgewiesen werden konnte. Einzelne CpG-Dinukleotide zeigten jedoch einen Trend zu einer Methylierungszunahme. Die mittlere Methylierung{\"a}nderung korrelierte nicht mit der {\"A}nderung des Hamilton-Scores, nur f{\"u}r CpG6 und CpG9 ergaben sich nominell signifikante positive Korrelationen. Gruppiert nach Response bzw. Remission konnte kein signifikanter Unterschied der mittleren Methylierungs{\"a}nderungen nachgewiesen werden. Bei Therapie-Respondern schien die Methylierung an den meisten CpG-Dinukleotiden zuzunehmen. Lediglich bei CpG6, CpG8 und CpG9 wiesen Non-Responder eine st{\"a}rkere Methylierungszunahme auf. Auff{\"a}llig war v.a. CpG1, das bei Non-Respondern eine nominell signifikante Methylierungsabnahme zeigte. Demnach besteht m{\"o}glicherweise ein Zusammenhang zwischen der Methylierungs{\"a}nderung 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 {\"A}nderung der SLC6A4-Methylierung. Dabei zeigten Patienten unter SSRI-Therapie eine deutliche Methylierungszunahme, die synergistisch mit der Blockade des Serotonin-Transporters wirken k{\"o}nnte. Epigenetische Modifikationen des 5 HTT-Gens kommen folglich als molekularer Wirkmechanismus dieser Behandlung in Betracht und implizieren neue Ans{\"a}tze f{\"u}r innovative Pharmakotherapeutika. Die vorliegende Arbeit liefert somit einen Beitrag zum Verst{\"a}ndnis der zugrundeliegenden molekularbiologischen Prozesse der antidepressiven Therapie. Zur Sicherung und Replikation der gefundenen Ergebnisse sind jedoch weitere Studien mit gr{\"o}ßeren und genauestens charakterisierten Stichproben n{\"o}tig.}, subject = {Depression}, language = {de} } @phdthesis{Schmidt2018, author = {Schmidt, Brigitte}, title = {Ver{\"a}nderungen von Angstsensitivit{\"a}t und allgemeiner Selbstwirksamkeit bei der Therapie der Panikst{\"o}rung}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-163055}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {In einer Studie mit 60 Patienten mit Panikst{\"o}rung und einer aus 60 gesunden Probanden bestehenden Kontrollgruppe wurde eine standardisierte kognitive Verhaltenstherapie mit Psychoedukation und Expositions{\"u}bungen durchgef{\"u}hrt. Zu verschiedenen Zeitpunkten wurde mittels Frageb{\"o}gen die Angstsensitivit{\"a}t (ASI) und allgemeine Selbstwirksamkeitserwartung (GSE) gemessen. Weiterhin wurden Daten zu angstbezogenen Kognitionen (ACQ) und die Anzahl der Panikattacken pro Woche erhoben. Patienten mit Panikst{\"o}rung wiesen zu Beginn eine niedrigere allgemeine Selbstwirksamkeitserwartung und eine h{\"o}here Angstsensitivit{\"a}t auf als gesunde Probanden. Nach der Psychoedukation kam es zu einer Reduktion der Angstsensitivit{\"a}t, nach der Exposition zu einem Anstieg der Selbstwirksamkeitserwartung bei der Patientengruppe. Die Patientengruppe erreichte außerdem einen R{\"u}ckgang der angstbezogenen Kognitionen. Die Anzahl der Panikattacken ver{\"a}nderte sich nicht signifikant. Die Ver{\"a}nderung von mit der GSE-Skala gemessener Selbstwirksamkeitserwartung durch standardisierte kognitive Verhaltenstherapie bei Panikst{\"o}rung wurde in der vorliegenden Studie erstmals beschrieben. Es wurde gezeigt, dass durch eine standardisierte kognitive Verhaltenstherapie bei Patienten mit Panikst{\"o}rung neben einer Reduktion der Angstsensitivit{\"a}t nicht nur, wie bereits bekannt, die panikbezogene Selbstwirksamkeitserwartung gesteigert werden kann, sondern auch die allgemeine Selbstwirksamkeitserwartung. Die Ver{\"a}nderungen wurden außerdem hinsichtlich des Angstsensitivit{\"a}ts-Responderstatus untersucht. Patienten, die bez{\"u}glich der Angstsensitivit{\"a}t mehr als 50 \% Verbesserung zeigten (ASI-Responder), zeigten nach der Therapie keinen signifikanten Unterschied mehr zu den Werten von Angstsensitivit{\"a}t, allgemeiner Selbstwirksamkeitserwartung und angstbezogenen Kognitionen der Kontrollgruppe. Bei den ASI-Respondern fanden der signifikante Anstieg des GSE-Werts und der R{\"u}ckgang des ACQ-Werts bereits nach der Psychoedukation statt. In zuk{\"u}nftigen Studien sollten Unterschiede zwischen ASI-Respondern und ASI-Non-Respondern sowie weitere Maßnahmen zur Reduktion von Angstsensitivit{\"a}t und zur St{\"a}rkung der Selbstwirksamkeitserwartung mit dem Ziel der Pr{\"a}vention und Therapie von Angsterkrankungen untersucht werden.}, subject = {Angstst{\"o}rung}, language = {de} } @article{KlenkHommersLohse2022, author = {Klenk, Christoph and Hommers, Leif and Lohse, Martin J.}, title = {Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone 1 receptor}, series = {Frontiers in Endocrinology}, volume = {13}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2022.839351}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262055}, year = {2022}, abstract = {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.}, language = {en} } @article{RiedererMonoranuStrobeletal.2021, author = {Riederer, P. and Monoranu, C. and Strobel, S. and Iordache, T. and Sian-H{\"u}lsmann, J.}, title = {Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease}, series = {Journal of Neural Transmission}, volume = {128}, journal = {Journal of Neural Transmission}, number = {10}, issn = {1435-1463}, doi = {10.1007/s00702-021-02414-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268539}, pages = {1577-1598}, year = {2021}, abstract = {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.}, language = {en} } @article{AsthanaBrunhuberMuehlbergeretal.2016, author = {Asthana, Manish Kumar and Brunhuber, Bettina and M{\"u}hlberger, Andreas and Reif, Andreas and Schneider, Simone and Herrmann, Martin J.}, title = {Preventing the Return of Fear Using Reconsolidation Update Mechanisms Depends on the Met-Allele of the Brain Derived Neurotrophic Factor Val66Met Polymorphism}, series = {International Journal of Neuropsychopharmacology}, volume = {19}, journal = {International Journal of Neuropsychopharmacology}, number = {6}, doi = {10.1093/ijnp/pyv137}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166217}, year = {2016}, abstract = {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.}, language = {en} } @article{ErhardtMeierDeckert2020, author = {Erhardt, Angelika and Meier, Sandra and Deckert, J{\"u}rgen}, title = {Genetik und Epigenetik von Angsterkrankungen}, series = {BIOspektrum}, volume = {26}, journal = {BIOspektrum}, issn = {0947-0867}, doi = {10.1007/s12268-020-1366-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232380}, pages = {252-254}, year = {2020}, abstract = {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.}, language = {de} } @article{DittertHuettnerPolaketal.2018, author = {Dittert, Natalie and H{\"u}ttner, Sandrina and Polak, Thomas and Herrmann, Martin J.}, title = {Augmentation of fear extinction by transcranial direct current stimulation (tDCS)}, series = {Frontiers in Behavioral Neuroscience}, volume = {12}, journal = {Frontiers in Behavioral Neuroscience}, number = {76}, doi = {10.3389/fnbeh.2018.00076}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176056}, year = {2018}, abstract = {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.}, language = {en} } @phdthesis{Zech2021, author = {Zech, Linda}, title = {Vitamin-D-Status und depressive Symptome bei gerontopsychiatrischen Patienten}, doi = {10.25972/OPUS-25074}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250745}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {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 W{\"u}rzburg untersucht. Die Depressivit{\"a}t 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 poststation{\"a}ren 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 Auspr{\"a}gung des depressiven Syndroms und dem Vitamin D-Spiegel zu Beginn der Behandlung. Dagegen stellte sich heraus, dass Patienten mit einem h{\"o}heren 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 Abh{\"a}ngigkeit der Spiegelh{\"o}he von der Jahreszeit. Vitamin D k{\"o}nnte nach den Ergebnissen dieser Studie m{\"o}glicherweise eine wirkungssteigernde und nebenwirkungsarme Komedikation in der antidepressiven Therapie von {\"a}lteren psychisch erkrankten Menschen darstellen. Es bedarf weiterer ausf{\"u}hrlicher Forschung {\"u}ber 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 h{\"o}heren Lebensalter weiter zu verbessern.}, subject = {Altersdepression}, language = {de} } @article{EvdokimovFrankKlitschetal.2019, author = {Evdokimov, Dimitar and Frank, Johanna and Klitsch, Alexander and Unterecker, Stefan and Warrings, Bodo and Serra, Jordi and Papagianni, Aikaterini and Saffer, Nadine and Meyer zu Altenschildesche, Caren and Kampik, Daniel and Malik, Rayaz A. and Sommer, Claudia and {\"U}ceyler, Nurcan}, title = {Reduction of skin innervation is associated with a severe fibromyalgia phenotype}, series = {Annals of Neurology}, volume = {86}, journal = {Annals of Neurology}, number = {4}, doi = {10.1002/ana.25565}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206168}, pages = {504-516}, year = {2019}, abstract = {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.}, language = {en} } @phdthesis{Eberhardt2020, author = {Eberhardt, Jasmin}, title = {Die Entwicklung der psychiatrisch-psychotherapeutischen Versorgung im Bezirk Unterfranken - eine Erhebung der Indexjahre 2004, 2008 und 2012}, doi = {10.25972/OPUS-21232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212323}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Ziel der Arbeit war die Beschreibung der Entwicklung der psychiatrisch-psychotherapeutischen Versorgung im Bezirk Unterfranken mit der Ableitung von Erkl{\"a}rungsans{\"a}tzen und Impulsen f{\"u}r die Versorgungsforschung. {\"U}berpr{\"u}ft wurde hierzu einerseits die Hypothese, ob die station{\"a}re psychiatrische Belegung in beiden Bezirkskrankenh{\"a}usern zunimmt und andererseits in einer weiteren Hypothese, ob damit eine Verschlechterung der ambulanten und komplement{\"a}ren Versorgungslage (in den unterschiedlichen Sektoren) einhergeht. Dabei wurden folgende Daten vergleichend f{\"u}r die zwei Bezirkskrankenh{\"a}user in Lohr und Werneck und deren regionales Pflichtversorgungsgebiet erhoben: F{\"u}r die Indexjahre 2004, 2008 und 2012 im station{\"a}ren Bereich die Fallzahl, die Patientenzahl, die Nutzungsgrade und f{\"u}r die F{\"a}lle die durchschnittliche Verweildauer, die Hauptentlassdiagnosen und die Herkunft nach Meldeort. Im ambulanten Sektor erfolgte die Analyse der Arztsitze und Behandlungsf{\"a}lle f{\"u}r Nerven{\"a}rzte und Psychotherapeuten vergleichend f{\"u}r 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 komplement{\"a}ren Bereich wurden Daten zu Ausgaben, Sozialpsychiatrischen Diensten, Psychosozialen Suchtberatungsstellen, ambulant betreutem Wohnen, Psychiatrischer Familienpflege, Tagesst{\"a}tten, Werkst{\"a}tten f{\"u}r psychisch behinderte Menschen, Integrationsfirmen und Zuverdienstm{\"o}glichkeiten jeweils f{\"u}r die Jahre 2004, 2008 und 2012 erhoben. Hierbei kam es in beiden Bezirkskrankenh{\"a}usern {\"u}ber die Verlaufsjahre zu einer signifikanten Zunahme der F{\"a}lle, der Patienten und der Nutzungsgrade bei signifikanter Verk{\"u}rzung der Verweildauern von 2004 auf 2012. Das Bezirkskrankenhaus Lohr zeigte sich bzgl. Aufnahmen aus dem eigenen Einzugsgebiet selektiver als das Bezirkskrankenhaus Werneck. {\"U}ber die Beobachtungsjahre ver{\"a}nderte sich das Diagnosespektrum station{\"a}rer F{\"a}lle signifikant in beiden Kliniken. Im ambulanten Bereich zeigte sich von 2008 auf 2012 eine diskrete Zunahme von Psychotherapeutensitzen bei gleichbleibender Anzahl der Arztsitze f{\"u}r Nerven{\"a}rzte. Die Behandlungsf{\"a}lle stiegen in beiden Gruppen merklich an vom 4. Quartal 2008 auf das 4. Quartal 2012. Im komplement{\"a}ren Bereich nahmen Ausgaben und die Kapazit{\"a}ten im Bereich von Wohnen, Alltagsgestaltung und Arbeit zu. In beiden Bezirkskrankenh{\"a}usern ließ sich {\"u}ber die Indexjahre eine Zunahme der station{\"a}ren Belegung feststellen. Die Belegungszunahme ging allerdings nicht mit einer Verschlechterung der ambulanten oder komplement{\"a}ren 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 Patientenstr{\"o}me vom ambulanten zum station{\"a}ren Sektor besteht.}, subject = {Psychiatrische Versorgung}, language = {de} } @phdthesis{Kollert2021, author = {Kollert, Leonie}, title = {Epigenetics of anxiety and depression - a differential role of TGFB-Inducible Early Growth Response Protein 2 gene promoter methylation}, doi = {10.25972/OPUS-21126}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211268}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {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.}, subject = {Epigenetik}, language = {en} } @phdthesis{Wenzel2019, author = {Wenzel, Martina}, title = {Aufmerksamkeitsprozesse und Emotionsregulationsmechanismen in der bipolaren St{\"o}rung}, doi = {10.25972/OPUS-18963}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189638}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Neben Stimmungsschwankungen leiden viele bipolare Patienten unter kognitiven Beeintr{\"a}chtigungen. Dies ist von hoher Relevanz, da neuropsychologische Defizite zur Aufrechterhaltung der bipolaren St{\"o}rung beitragen k{\"o}nnen. Unsere Studie widmete sich zum einen der Untersuchung verzerrter Aufmerksamkeitsprozesse als auch der Erfassung dysfunktionaler Emotionsregulationsstrategien in der bipolaren St{\"o}rung. 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 pr{\"a}dominanten Polarit{\"a}t einen Einfluss auf die Informationsverarbeitung und Emotionsregulation haben k{\"o}nnte. 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 Reaktionsverm{\"o}gen vorlagen. Bei den euthymen Patienten mit manischer Polarit{\"a}t fand sich {\"u}berraschenderweise ein Bias weg von positiven Stimuli, was m{\"o}glicherweise 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 Frageb{\"o}gen 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 Polarit{\"a}t in unterschiedlichen Emotionsregulationsstrategien von gesunden Probanden abwichen. Zusammenfassend l{\"a}sst 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. Dar{\"u}ber hinaus liefert die Studie erste Hinweise darauf, dass sich Patienten mit depressiver und manischer Polarit{\"a}t in der Informationsverarbeitung emotionaler Stimuli als auch in Emotionsregulationsstrategien unterscheiden.}, subject = {Manisch-depressive Krankheit}, language = {de} } @phdthesis{Trimborn2020, author = {Trimborn, Anna}, title = {Erprobung und Evaluation eines Fragebogeninstruments zum Entlassungsmanagement deutscher Rehabilitationskliniken im Rahmen der Qualit{\"a}tssicherung der Deutschen Rentenversicherung Nordbayern}, doi = {10.25972/OPUS-20036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200362}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Mithilfe eines fr{\"u}hzeitigen und umfassenden Entlassungsmanagements sollen Schnittstellen im Behandlungsprozess {\"u}berwunden und der {\"U}bergang des Patienten in die poststation{\"a}re Versorgung nach einem Krankenhausaufenthalt optimal vorbereitet werden. Trotz der allgemein anerkannten Bedeutung des Entlassungsmanagements aus der station{\"a}ren medizinischen Versorgung erfolgt die Umsetzung bei den Rehabilitationskliniken sehr unterschiedlich. Im Rahmen dieser Arbeit wird ein kurzes Fragebogeninstrument f{\"u}r Patienten systematisch entwickelt und erprobt, welches im Rahmen einer postalischen Nachbefragung ehemaliger Rehabilitanden eingesetzt werden soll. Es soll die Qualit{\"a}t des Entlassungsmanagements der medizinischen Rehabilitation systematisch erfassen und Impulse f{\"u}r das Qualit{\"a}tsmanagement der Kliniken bieten. Die Ergebnisse der Erprobung in acht Kliniken mit {\"u}ber 900 auswertbaren Frageb{\"o}gen weisen darauf hin, dass beides m{\"o}glich ist. Sie werden mit dem Ziel der Weiterentwicklung des Instruments diskutiert und es werden Vorschl{\"a}ge zur weiteren Nutzung im Alltag der Rehabilitation erarbeitet.}, subject = {Rehabilitation}, language = {de} } @phdthesis{Logina2020, author = {Logina, Agate}, title = {Structural brain alterations in spider phobia : A voxel-based morphometry study}, doi = {10.25972/OPUS-21133}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211335}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {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.}, language = {en} } @article{LechermeierZimmerLueffeetal.2019, author = {Lechermeier, Carina G. and Zimmer, Frederic and L{\"u}ffe, Teresa M. and Lesch, Klaus-Peter and Romanos, Marcel and Lillesaar, Christina and Drepper, Carsten}, title = {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}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, number = {199}, doi = {10.3389/fnmol.2019.00199}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201797}, year = {2019}, abstract = {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.}, language = {en} } @phdthesis{Eisenhauer2020, author = {Eisenhauer, Eva-Lydia}, title = {Klinische Charakterisierung katatoner Schizophrenien im Kindesalter; Definition des Krankheitskonzeptes und Implikationen f{\"u}r Therapie und Prophylaxe}, doi = {10.25972/OPUS-20451}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204517}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {In dieser Studie wurden 25 erwachsene Patienten mit den langj{\"a}hrigen Vordiagnosen einer intellektuellen Behinderung, kindlichen Psychosen oder tiefgreifenden Entwicklungsst{\"o}rungen eingeschlossen. Ziel der Studie war einerseits die Frage ob sich im Spektrum dieser Erkrankungen, die in Karl Leonhards Nosologie beschriebenen (fr{\"u}h)kindlichen Katatonien als eigenst{\"a}ndiges 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 f{\"o}rdern und behandeln zu k{\"o}nnen wurden dar{\"u}ber hinaus famili{\"a}re und soziale Einflussfaktoren analysiert. Die Probanden wurden zwischen 2013 und 2015 nachuntersucht, sie stammen s{\"a}mtlich aus Klinikbeobachtungen vorangegangen station{\"a}rer psychiatrischer Aufenthalte.}, subject = {Chronische Schizophrenie}, language = {de} } @article{ZieglerEhlisWeberetal.2021, author = {Ziegler, Georg C. and Ehlis, Ann-Christine and Weber, Heike and Vitale, Maria Rosaria and Z{\"o}ller, Johanna E. M. and Ku, Hsing-Ping and Schiele, Miriam A. and K{\"u}rbitz, Laura I. and Romanos, Marcel and Pauli, Paul and Kalisch, Raffael and Zwanzger, Peter and Domschke, Katharina and Fallgatter, Andreas J. and Reif, Andreas and Lesch, Klaus-Peter}, title = {A Common CDH13 Variant is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD}, series = {Genes}, volume = {12}, journal = {Genes}, number = {9}, issn = {2073-4425}, doi = {10.3390/genes12091356}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245220}, year = {2021}, abstract = {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.}, language = {en} } @article{SchaeferSignoretGenestvonCollenbergetal.2020, author = {Schaefer, Natascha and Signoret-Genest, J{\´e}r{\´e}my and von Collenberg, Cora R. and Wachter, Britta and Deckert, J{\"u}rgen and Tovote, Philip and Blum, Robert and Villmann, Carmen}, title = {Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants}, series = {Frontiers in Molecular Neuroscience}, volume = {13}, journal = {Frontiers in Molecular Neuroscience}, number = {152}, issn = {1662-5099}, doi = {10.3389/fnmol.2020.00152}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-210041}, year = {2020}, abstract = {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.}, language = {en} } @phdthesis{Saulin2023, author = {Saulin, Anne Christin}, title = {Sustainability of empathy as driver for prosocial behavior and social closeness: insights from computational modelling and functional magnetic resonance imaging}, doi = {10.25972/OPUS-30555}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305550}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {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.}, subject = {Einf{\"u}hlung }, language = {en} } @phdthesis{Hamann2023, author = {Hamann, Catharina Sophia}, title = {Fear and anxiety disorders - interaction of AVP and OXT brain systems with the serotonergic system}, doi = {10.25972/OPUS-30333}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303338}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {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.}, subject = {Serotonin}, language = {en} } @article{UeceylerSchliesserEvdokimovetal.2022, author = {{\"U}{\c{c}}eyler, Nurcan and Schließer, Mira and Evdokimov, Dimitar and Radziwon, Jakub and Feulner, Betty and Unterecker, Stefan and Rimmele, Florian and Walter, Uwe}, title = {Reduced midbrain raphe echogenicity in patients with fibromyalgia syndrome}, series = {PloS One}, volume = {17}, journal = {PloS One}, number = {11}, doi = {10.1371/journal.pone.0277316}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300639}, year = {2022}, abstract = {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.}, language = {en} } @article{SchieleReinhardReifetal.2016, author = {Schiele, Miriam A. and Reinhard, Julia and Reif, Andreas and Domschke, Katharina and Romanos, Marcel and Deckert, J{\"u}rgen and Pauli, Paul}, title = {Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults}, series = {Developmental Psychobiology}, volume = {58}, journal = {Developmental Psychobiology}, number = {4}, doi = {10.1002/dev.21393}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189488}, pages = {471-481}, year = {2016}, abstract = {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.}, language = {en} } @phdthesis{Mueller2023, author = {M{\"u}ller, Annika Wiebke}, title = {Funktionalit{\"a}t eines \(Stathmin\)-Promotor-Polymorphismus}, doi = {10.25972/OPUS-31812}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318120}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {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-Pers{\"o}nlichkeitsst{\"o}rungen belegen. Sie vermutete, dass eine Hochregulation der Expression des Stathmin-Gens ein Risikofaktor f{\"u}r die Entstehung von Cluster C Pers{\"o}nlichkeitsst{\"o}rungen darstellen k{\"o}nnte. 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 st{\"u}tzen, wurde in dieser Arbeit die Auswirkung zweier Allele des STR-Polymorphismus im Bereich der Promotorregion des Stathmin-Gens im Hinblick auf die Promotoraktivit{\"a}t untersucht. Hierzu wurde die zu untersuchende Sequenz zun{\"a}chst mittels Polymerase-Ketten-Reaktion vervielf{\"a}ltigt und anschließend in einen pGL4.23.Vektor kloniert. Im Anschluss daran erfolgte die Untersuchung der Promotoraktivit{\"a}t mittels eines Luciferase-Assays in der humanen Neuroblastomzelllinie SH-SY5Y. Nach statischer Auswertung der Messreihen zeigte sich eine signifikant h{\"o}here Luciferase-Aktivit{\"a}t des STR-Polymorphismus (TAA)12 im Vergleich zu dem STR-Polymorphismus (TAA)13. Hierdurch kann von einer h{\"o}heren Promotoraktivit{\"a}t bei dem Genotyp (TAA)12 gegen{\"u}ber dem Genotyp (TAA)13 ausgegangen werden. Zusammenfassend unterst{\"u}tzen die Ergebnisse dieser Arbeit die These, dass es sich bei dem Stathmin-Gen um ein Suszeptibilit{\"a}tsgen f{\"u}r die Entstehung von Cluster C Pers{\"o}nlichkeitsst{\"o}rungen handeln k{\"o}nnte.}, subject = {Pers{\"o}nlichkeitsst{\"o}rung}, language = {de} } @phdthesis{Gruendahl2023, author = {Gr{\"u}ndahl, Marthe Erda}, title = {From Lab to Life: Investigating the Role of Social Contact for Anxiety and Related Autonomic Responses}, doi = {10.25972/OPUS-31685}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316859}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {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.}, subject = {Angst}, language = {en} } @article{BraunEvdokimovFranketal.2022, author = {Braun, Alexandra and Evdokimov, Dimitar and Frank, Johanna and Pauli, Paul and Wabel, Thomas and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Relevance of Religiosity for Coping Strategies and Disability in Patients with Fibromyalgia Syndrome}, series = {Journal of Religion and Health}, volume = {61}, journal = {Journal of Religion and Health}, number = {1}, issn = {1573-6571}, doi = {10.1007/s10943-020-01177-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269135}, pages = {524-539}, year = {2022}, abstract = {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.}, language = {en} } @article{GottschalkRichterZiegleretal.2019, author = {Gottschalk, Michael G. and Richter, Jan and Ziegler, Christiane and Schiele, Miriam A. and Mann, Julia and Geiger, Maximilian J. and Schartner, Christoph and Homola, Gy{\"o}rgy A. and Alpers, Georg W. and B{\"u}chel, Christian and Fehm, Lydia and Fydrich, Thomas and Gerlach, Alexander L. and Gloster, Andrew T. and Helbig-Lang, Sylvia and Kalisch, Raffael and Kircher, Tilo and Lang, Thomas and Lonsdorf, Tina B. and Pan{\´e}-Farr{\´e}, Christiane A. and Str{\"o}hle, Andreas and Weber, Heike and Zwanzger, Peter and Arolt, Volker and Romanos, Marcel and Wittchen, Hans-Ulrich and Hamm, Alfons and Pauli, Paul and Reif, Andreas and Deckert, J{\"u}rgen and Neufang, Susanne and H{\"o}fler, Michael and Domschke, Katharina}, title = {Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-019-0415-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227479}, year = {2019}, abstract = {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.}, language = {en} } @article{HommersRichterYangetal.2018, author = {Hommers, L. G. and Richter, J. and Yang, Y. and Raab, A. and Baumann, C. and Lang, K. and Schiele, M. A. and Weber, H. and Wittmann, A. and Wolf, C. and Alpers, G. W. and Arolt, V. and Domschke, K. and Fehm, L. and Fydrich, T. and Gerlach, A. and Gloster, A. T. and Hamm, A. O. and Helbig-Lang, S. and Kircher, T. and Lang, T. and Pan{\´e}-Farr{\´e}, C. A. and Pauli, P. and Pfleiderer, B. and Reif, A. and Romanos, M. and Straube, B. and Str{\"o}hle, A. and Wittchen, H.-U. and Frantz, S. and Ertl, G. and Lohse, M. J. and Lueken, U. and Deckert, J.}, title = {A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety}, series = {Translational Psychiatry}, volume = {8}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-018-0278-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322497}, year = {2018}, abstract = {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.}, language = {en} } @article{GalKilenczAlbertetal.2019, author = {G{\´a}l, Bernadett I. and Kilencz, T{\"u}nde and Albert, Anita and Demeter, Ildik{\´o} and Hegedűs, Kl{\´a}ra M{\´a}ria and Janka, Zolt{\´a}n and Csifcs{\´a}k, G{\´a}bor and {\´A}lmos, P{\´e}ter Z.}, title = {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}, series = {Frontiers in Pharmacology}, volume = {10}, journal = {Frontiers in Pharmacology}, doi = {10.3389/fphar.2019.01087}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369182}, year = {2019}, abstract = {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.}, language = {en} } @article{GilderWackKaubetal.2018, author = {Gilder, Stuart A. and Wack, Michael and Kaub, Leon and Roud, Sophie C. and Petersen, Nikolai and Heinsen, Helmut and Hillenbrand, Peter and Milz, Stefan and Schmitz, Chistoph}, title = {Distribution of magnetic remanence carriers in the human brain}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-29766-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233035}, year = {2018}, abstract = {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.}, language = {en} } @phdthesis{Blickle2024, author = {Blickle, Marc Manuel}, title = {Das Zusammenspiel von Herz und Gehirn: Interozeptive Genauigkeit, Herzratenvariabilit{\"a}t und funktionelle Konnektivit{\"a}t kortikaler Netzwerke bei depressiven Patientinnen und Patienten}, doi = {10.25972/OPUS-31676}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316762}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Hintergrund: Depressionen z{\"a}hlen zu den h{\"a}ufigsten psychischen Erkrankungen. Depressive Symptome umfassen beeintr{\"a}chtigte kognitive Funktionen, vegetative Beschwerden und ein ver{\"a}ndertes emotionales Erleben. Die defizit{\"a}re Wahrnehmung interner k{\"o}rperlicher Signale wird sowohl mit der Pathogenese der Depression als auch mit Angstst{\"o}rungen in Verbindung gebracht. Interozeptive Genauigkeit (IAc) beschreibt dabei die F{\"a}higkeit, k{\"o}rperliche 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 Inselaktivit{\"a}t assoziiert. W{\"a}hrend der Ruhezustandsmessung des Gehirns (resting-state fMRT) kann in Abwesenheit einer Aufgabe die intrinsische Aktivit{\"a}t des Gehirns gemessen werden. Dies erm{\"o}glicht die Identifizierung von kortikalen Netzwerken. Depressive Patienten weisen eine ver{\"a}nderte funktionelle Konnektivit{\"a}t 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 {\"u}berwiegend j{\"u}ngere 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 ver{\"a}ndert, von der Herzratenvariabilit{\"a}t (HRV) moduliert wird und welche Auswirkungen dies auf die funktionelle Konnektivit{\"a}t kortikaler Netzwerke hat. Ziele: Eine ver{\"a}nderte IAc und HRV wie auch funktionelle Konnektivit{\"a}tsunterschiede im DMN und SN k{\"o}nnten Biomarker der Depression darstellen. Im Rahmen einer L{\"a}ngsschnittuntersuchung wurde getestet, ob {\"a}ltere depressive Patienten {\"u}ber eine verringerte IAc, eine geringere HRV und {\"u}ber eine ver{\"a}nderte funktionelle Konnektivit{\"a}t im SN sowie DMN verf{\"u}gen. Dar{\"u}ber 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 gr{\"o}ßtenteils medizierte, schwer depressive Patienten (> 50 Jahre) und 30 gesunde Kontrollprobanden untersucht. Die IAc wurde in einer Herzwahrnehmungsaufgabe ermittelt und die HRV bestimmt. Zus{\"a}tzlich wurde eine resting-state fMRT durchgef{\"u}hrt. Eine funktionelle Konnektivit{\"a}tsanalyse f{\"u}r Saatregionen im SN und DMN wurde mit einem saatbasierten Ansatz (seed-to-voxel) durchgef{\"u}hrt. F{\"u}r eine Subgruppenanalyse wurde die Patientengruppe in {\"a}ngstlich-depressive und nicht-{\"a}ngstlich 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 Hypokonnektivit{\"a}t zwischen einzelnen Saatregionen der Insel (SN) und Teilen des superioren frontalen Gyrus, des supplement{\"a}rmotorischen 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 erh{\"o}hte funktionelle Konnektivit{\"a}t auf. Die Gruppen unterschieden sich nicht in der IAc und der HRV. {\"A}ngstlich-depressive Patienten zeigten eine h{\"o}here funktionelle Konnektivit{\"a}t innerhalb der Insel als nicht-{\"a}ngstlich 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 Hyperkonnektivit{\"a}t zwischen dem posterioren DMN und dem Frontalpol sowie zwischen dem posterioren DMN und temporalen Arealen im SN auf. Keine funktionellen Konnektivit{\"a}tsunterschiede zeigten sich f{\"u}r 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 Gehirnaktivit{\"a}t funktioneller Netzwerke bestehen, jedoch nicht in der akkuraten Wahrnehmung des eigenen Herzschlages und der HRV. Therapeutische Interventionen, die auf eine Verbesserung der IAc abzielen, k{\"o}nnten insbesondere f{\"u}r Non-Responder dennoch eine zus{\"a}tzliche Behandlungsm{\"o}glichkeit darstellen. F{\"u}r eine personalisierte Medizin k{\"o}nnte die weitere Erforschung von kortikalen Netzwerken einen wesentlichen Beitrag leisten, um ein individuelles Therapieansprechen zu pr{\"a}dizieren.}, subject = {Depression}, language = {de} } @article{MorimotoShimadaSugimotoOtowaetal.2018, author = {Morimoto, Yoshiro and Shimada-Sugimoto, Mihoko and Otowa, Takeshi and Yoshida, Shintaro and Kinoshita, Akira and Mishima, Hiroyuki and Yamaguchi, Naohiro and Mori, Takatoshi and Imamura, Akira and Ozawa, Hiroki and Kurotaki, Naohiro and Ziegler, Christiane and Domschke, Katharina and Deckert, J{\"u}rgen and Umekage, Tadashi and Tochigi, Mamoru and Kaiya, Hisanobu and Okazaki, Yuji and Tokunaga, Katsushi and Sasaki, Tsukasa and Yoshiura, Koh-ichiro and Ono, Shinji}, title = {Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder}, series = {Translational Psychiatry}, volume = {8}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-017-0088-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224192}, year = {2018}, abstract = {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.}, language = {en} } @article{deJongDinizSalomaetal.2018, author = {de Jong, Simone and Diniz, Mateus Jose Abdalla and Saloma, Andiara and Gadelha, Ary and Santoro, Marcos L. and Ota, Vanessa K. and Noto, Cristiano and Curtis, Charles and Newhouse, Stephen J. and Patel, Hamel and Hall, Lynsey S. and O'Reilly, Paul F. and Belangero, Sintia I. and Bressan, Rodrigo A. and Breen, Gerome}, title = {Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder}, series = {Communications Biology}, volume = {1}, journal = {Communications Biology}, organization = {Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium}, doi = {10.1038/s42003-018-0155-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223622}, year = {2018}, abstract = {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.}, language = {en} } @article{DiehlSchmidLicataGoldhardtetal.2019, author = {Diehl-Schmid, Janine and Licata, Abigail and Goldhardt, Oliver and F{\"o}rstl, Hans and Yakushew, Igor and Otto, Markus and Anderl-Straub, Sarah and Beer, Ambros and Ludolph, Albert Christian and Landwehrmeyer, Georg Bernhard and Levin, Johannes and Danek, Adrian and Fliessbach, Klaus and Spottke, Annika and Fassbender, Klaus and Lyros, Epameinondas and Prudlo, Johannes and Krause, Bernd Joachim and Volk, Alexander and Edbauer, Dieter and Schroeter, Matthias Leopold and Drzezga, Alexander and Kornhuber, Johannes and Lauer, Martin and Grimmer, Timo}, title = {FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, organization = {FTLDc Study Group}, doi = {10.1038/s41398-019-0381-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225308}, year = {2019}, abstract = {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.}, language = {en} } @article{SchroeterPawelkeBiseniusetal.2018, author = {Schroeter, Matthias L. and Pawelke, Sarah and Bisenius, Sandrine and Kynast, Jana and Schuemberg, Katharina and Polyakova, Maryna and Anderl-Straub, Sarah and Danek, Adrian and Fassbender, Klaus and Jahn, Holger and Jessen, Frank and Kornhuber, Johannes and Lauer, Martin and Prudlo, Johannes and Schneider, Anja and Uttner, Ingo and Th{\"o}ne-Otto, Angelika and Otto, Markus and Diehl-Schmid, Janine}, title = {A Modified Reading the Mind in the Eyes Test Predicts Behavioral Variant Frontotemporal Dementia Better Than Executive Function Tests}, series = {Frontiers in Aging Neuroscience}, volume = {10}, journal = {Frontiers in Aging Neuroscience}, organization = {FTLD Study Group Germany}, doi = {10.3389/fnagi.2018.00011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234254}, year = {2018}, abstract = {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.}, language = {en} } @article{UllrichWeberPostetal.2018, author = {Ullrich, M and Weber, M and Post, A M and Popp, S and Grein, J and Zechner, M and Gonz{\´a}lez, H Guerrero and Kreis, A and Schmitt, A G and {\"U}ҫeyler, N and Lesch, K-P and Schuh, K}, title = {OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency}, series = {Molecular Psychiatry}, volume = {23}, journal = {Molecular Psychiatry}, doi = {10.1038/mp.2016.232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232096}, pages = {444-458}, year = {2018}, abstract = {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.}, language = {en} } @article{LevyBoulleEmeritetal.2019, author = {Levy, Marion J. F. and Boulle, Fabien and Emerit, Michel Boris and Poilbout, Corinne and Steinbusch, Harry W. M. and Van den Hove, Daniel L. A. and Kenis, Gunter and Lanfumey, Laurence}, title = {5-HTT independent effects of fluoxetine on neuroplasticity}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-42775-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236759}, year = {2019}, abstract = {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.}, language = {en} } @article{GerberKoenigFendtetal.2019, author = {Gerber, Bertram and K{\"o}nig, Christian and Fendt, Markus and Andreatta, Marta and Romanos, Marcel and Pauli, Paul and Yarali, Ayse}, title = {Timing-dependent valence reversal: a principle of reinforcement processing and its possible implications}, series = {Current Opinion in Behavioral Sciences}, volume = {26}, journal = {Current Opinion in Behavioral Sciences}, doi = {10.1016/j.cobeha.2018.12.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232933}, pages = {114-120}, year = {2019}, abstract = {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.}, language = {en} } @phdthesis{DasgebNitschke2024, author = {Das [geb. Nitschke], Felix Marcel}, title = {DNA-Methylierung und Genexpression von FKPB5 als Teil des Stresshormonsystems bei von Depressionen und Herzinsuffizienz Betroffenen sowie gesunden Kontrollen}, doi = {10.25972/OPUS-36973}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369730}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {FKBP5 stellt im Stresssystem der HPA-Achse ein zentrales Gen bei der Regulation der Sensitivit{\"a}t des Glukokortikoidrezeptors und somit der Reaktion auf Stress dar. Zur Adaptation an Umwelteinfl{\"u}sse 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 m{\"o}glichen Pathomechanismus hin. F{\"u}r die enge klinische Interaktion von Depression und Herzinsuffizienz sowie eine ebenfalls vermutete Rolle der HPA-Achse in der Pathogenese letzterer, k{\"o}nnte FKBP5 daher ein entscheidendes Bindeglied darstellen. Gleichzeitig bietet die Identifikation einer {\"u}ber FKBP5 ausgedr{\"u}ckten Dysregulation der HPA-Achse einen biologischen Befund, der als Marker f{\"u}r das Ansprechen einer antidepressiven Therapie herangezogen werden k{\"o}nnte. Ziel dieser Arbeit war daher die Untersuchung eines m{\"o}glichen Einflusses regulatorischer Parameter von FKBP5 auf die Herzinsuffizienz sowie eine Pr{\"u}fung dieser als m{\"o}gliche Biomarker f{\"u}r 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 h{\"o}heren mRNA-Expression zu Therapiebeginn assoziiert. Im Behandlungsverlauf f{\"u}hrte eine Abnahme der mRNA-Expression bei den Respondern zu einer Ann{\"a}herung beider Gruppen. Diese Arbeit konnte keine Hinweise f{\"u}r 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 f{\"u}r das Therapieansprechen ein, die aufgrund einer Herabregulation der HPA-Achse im Therapieverlauf die Idee einer urs{\"a}chlichen HPA-Dysregulation in der Gruppe der Responder bekr{\"a}ftigen. F{\"u}r sich allein genommen lassen sich mRNA-Expression und Methylierung aufgrund mangelnder Sensitivit{\"a}t und Spezifit{\"a}t nicht als Biomarker f{\"u}r das Therapieansprechen einsetzen. Die bisherigen Befunde best{\"a}rken aber eine m{\"o}gliche Rolle in einer Batterie unterschiedlicher Biomarker auf verschiedenen Ebenen, wie Klinik, Psychometrie und Physiologie.}, subject = {Gen FKBP5}, language = {de} } @article{FigelBrinkmannBuffetal.2019, author = {Figel, Benedikt and Brinkmann, Leonie and Buff, Christine and Heitmann, Carina Y. and Hofmann, David and Bruchmann, Maximilian and Becker, Michael P. I. and Herrmann, Martin J. and Straube, Thomas}, title = {Phasic amygdala and BNST activation during the anticipation of temporally unpredictable social observation in social anxiety disorder patients}, series = {NeuroImage: Clinical}, volume = {22}, journal = {NeuroImage: Clinical}, doi = {10.1016/j.nicl.2019.101735}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228071}, year = {2019}, abstract = {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.}, language = {en} } @article{KiserPoppSchmittBoehreretal.2019, author = {Kiser, Dominik P. and Popp, Sandy and Schmitt-B{\"o}hrer, Angelika G. and Strekalova, Tatyana and van den Hove, Daniel L. and Lesch, Klaus-Peter and Rivero, Olga}, title = {Early-life stress impairs developmental programming in Cadherin 13 (CDH13)-deficient mice}, series = {Progress in Neuropsychopharmacology \& Biological Psychiatry}, volume = {89}, journal = {Progress in Neuropsychopharmacology \& Biological Psychiatry}, doi = {10.1016/j.pnpbp.2018.08.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325859}, pages = {158-168}, year = {2019}, abstract = {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 na{\"i}ve 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.}, language = {en} } @article{ArgyrousideNijsLagattaetal.2019, author = {Argyrousi, Elentina K. and de Nijs, Laurence and Lagatta, Davi C. and Schl{\"u}tter, Anna and Weidner, Magdalena T. and Z{\"o}ller, Johanna and van Goethem, Nick P. and Joca, S{\^a}mia R. L. and van den Hove, Daniel L. A. and Prickaerts, Jos}, title = {Effects of DNA methyltransferase inhibition on pattern separation performance in mice}, series = {Neurobiology of Learning and Memory}, volume = {159}, journal = {Neurobiology of Learning and Memory}, doi = {https://doi.org/10.1016/j.nlm.2019.02.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221226}, pages = {6-15}, year = {2019}, abstract = {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.}, language = {en} } @article{BarkhuizenvanMechelenVermeeretal.2019, author = {Barkhuizen, Melinda and van Mechelen, Ralph and Vermeer, Marijne and Chedraui, Peter and Paes, Dean and van den Hove, Daniel L. A. and Vaes, Bart and Mays, Robert W. and Steinbusch, Harry W. M. and Robertson, Nicola J. and Kramer, Boris W. and Gavilanes, Antonio W. D.}, title = {Systemic multipotent adult progenitor cells improve long-term neurodevelopmental outcomes after preterm hypoxic-ischemic encephalopathy}, series = {Behavioural Brain Research}, volume = {362}, journal = {Behavioural Brain Research}, doi = {10.1016/j.bbr.2019.01.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221506}, pages = {77-81}, year = {2019}, abstract = {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.}, language = {en} } @article{GorlovaPavlovAnthonyetal.2019, author = {Gorlova, Anna and Pavlov, Dmitrii and Anthony, Daniel C. and Ponomarev, Eugene D. and Sambon, Margaux and Proshin, Andrey and Shafarevich, Igor and Babaevskaya, Diana and Lesch, Klaus-Peter and Bettendorff, Lucien and Strekalova, Tatyana}, title = {Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice}, series = {Neuropharmacology}, volume = {156}, journal = {Neuropharmacology}, doi = {10.1016/j.neuropharm.2019.02.025}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227439}, year = {2019}, abstract = {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'.}, language = {en} } @article{VerheijenStevensGentieretal.2018, author = {Verheijen, Bert M. and Stevens, Jo A. A. and Gentier, Romina J. G. and van't Hekke, Christian D. and van den Hove, Daniel L. A. and Hermes, Denise J. H. P. and Steinbusch, Harry W. M. and Ruijter, Jan M. and Grimm, Marcus O. W. and Haupenthal, Viola J. and Annaert, Wim and Hartmann, Tobias and van Leeuwen, Fred W.}, title = {Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model}, series = {Neurobiology of Aging}, volume = {72}, journal = {Neurobiology of Aging}, doi = {10.1016/j.neurobiolaging.2018.08.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233185}, pages = {62-71}, year = {2018}, abstract = {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.}, language = {en} } @phdthesis{Adolf2024, author = {Adolf, Jonas Michael}, title = {Die Zusammenarbeit zwischen der station{\"a}ren beziehungsweise teilstation{\"a}ren psychotherapeutischen Behandlung und niedergelassenen Psychotherapeut:innen}, doi = {10.25972/OPUS-37109}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371098}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das Ziel der vorliegenden Arbeit war es die aktuelle Versorgungskontinuit{\"a}t in der psychotherapeutischen Versorgung hinsichtlich der Zusammenarbeit des (teil-)station{\"a}ren und des ambulanten Sektors aus Sicht der niedergelassenen Psychotherapeut:innen zu untersuchen, diese in den wissenschaftlichen Kontext einzuordnen und - falls m{\"o}glich - erste M{\"o}glichkeiten zur Verbesserung der derzeitigen Versorgungskontinuit{\"a}t aufzuzeigen. In Zusammenarbeit mit dem Arbeitsbereich f{\"u}r Medizinische Psychologie und Psychotherapie im Zentrum f{\"u}r psychische Gesundheit des Universit{\"a}tsklinikums W{\"u}rzburg wurde hierzu ein Fragebogen entwickelt und acht ausgew{\"a}hlten 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 poststation{\"a}ren 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 f{\"u}r L{\"o}sungen auf. Aufgrund der besonderen Relevanz der aufgezeigten Ergebnisse, gilt es - zur Erm{\"o}glichung einer ad{\"a}quaten kontinuierlichen psychotherapeutischen Versorgung - eine weitergehende Betrach-tung der aufgezeigten Defizite vorzunehmen. F{\"u}r ein umfassendes Bild sind zudem kongruente Folgearbeiten mit dem Augenmerk auf der Sichtweise der (teil-)station{\"a}ren Behandlungseinrichtungen und der Patient:innen notwendig. Insbesondere vor dem Hintergrund der limitierten M{\"o}glichkeiten der vorliegenden Arbeit gilt es große repr{\"a}sentative und nationale Studien anzustreben. Hierzu w{\"a}re die Etablierung zentral verwalteter Register zur B{\"u}ndelung der bisherigen und zuk{\"u}nftigen Forschungsarbeiten im Bereich der Psychotherapie w{\"u}nschenswert. Vor allem vor dem Hintergrund zahlreicher Modellprojekte erscheint dies sinnvoll und k{\"o}nnte einen wichtigen Beitrag zur Optimierung der derzeitigen psychotherapeutischen Forschungs- und Versorgungslage beitragen.}, subject = {Psychotherapie}, language = {de} } @phdthesis{RuppertgebRapp2024, author = {Ruppert [geb. Rapp], Elisabeth Marlene}, title = {Einfluss von sozialem Stress und 5-Htt-Genotyp: Quantitative Untersuchung der Morphologie von Neuronen der lateralen Amygdala und der CA3-Region des Hippocampus von M{\"a}usen der Serotonintransporter-Knockout-Linie}, doi = {10.25972/OPUS-36948}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369488}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {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 gef{\"a}rbten Gehirnen der 5-HTT-KO-Linie in der lateralen Amygdala (LA) die Apikal- und Basaldendriten pyramidenzell{\"a}hnlicher 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 k{\"o}nnen (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 Komplexit{\"a}t der Dendritenb{\"a}ume durch l{\"a}ngere und auch st{\"a}rker verzweigte Dendriten vor allem in der Gruppe der WT-M{\"a}use f{\"u}hrt. HET- und KO-M{\"a}use zeigten keinen entsprechenden Stress-Effekt. Dar{\"u}ber hinaus zeigten sich deutliche Genotypeffekte. Unabh{\"a}ngig vom Stresserleben besitzen HET-M{\"a}use l{\"a}ngere Dendriten als WT-M{\"a}use sowie eine h{\"o}here Spinedichte als WT- und KO-M{\"a}use. Die Hypothese, die in der Arbeit von Nietzer et al. aufgestellt wurde, dass eine vollst{\"a}ndige 5-HTT-Defizienz zu mehr Spines f{\"u}hrt, 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 ausgel{\"o}sten Ver{\"a}nderungen ein im Vergleich zu den LA-Neuronen entgegengesetzten Effekt. Der soziale Stress f{\"u}hrt hier zu einer Dendritenatrophie in der WT-Gruppe mit k{\"u}rzeren und weniger komplexen Dendriten. Außerdem f{\"u}hrte er zu einer geringeren Spinedichte bei den HET-M{\"a}usen. Es zeigten sich klare Genotypeffekte, unabh{\"a}ngig von der Stresserfahrung, mit einer reduzierten Spinedichte der KO-M{\"a}use gegen{\"u}ber den WT-M{\"a}usen und einer nur in den Kontrollen detektierten, reduzierten Spinedichte der KO-M{\"a}use im Vergleich zu den WT- und HET-M{\"a}usen. Sowohl in der LA als auch in der CA3-Region lassen sich Kompensationsmechanismen des 5-HTT-Defizits der HET-Tiere vermuten, {\"u}ber die die KO-Tiere nicht verf{\"u}gen. Die in LA und CA3 gezeigten gegens{\"a}tzlichen Auswirkungen des sozialen Stresses weisen auf die unterschiedlichen Funktionen dieser beiden Regionen im Furchtkreislauf und/oder bei der Verarbeitung von Stress hin. Dar{\"u}ber hinaus deutet diese Arbeit darauf hin, dass Arbeiten mit {\"a}hnlichen Untersuchungsmethoden und sogar gleichem Untersuchungsmaterial unterschiedliche Ergebnisse liefern k{\"o}nnen.}, subject = {Serotoninstoffwechsel}, language = {de} } @phdthesis{Kussberger2024, author = {Kußberger, Julia Bettina}, title = {Protein - Biomarker zur Unterscheidung zwischen unipolarer und bipolarer Depression}, doi = {10.25972/OPUS-37110}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371109}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {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 verf{\"u}gbar. Da sich die beide Krankheitsbilder vor allem in der depressiven Episode stark {\"a}hneln, ist eine Unterscheidung in diesem Krankheitsstadium h{\"a}ufig nicht eindeutig m{\"o}glich. Dies kann zu Fehldiagnosen, einer Verschlechterung des Krankheitsverlaufs, einer erh{\"o}hten Krankheitslast und h{\"o}heren Gesundheitskosten f{\"u}hren. Periphere Biomarker w{\"a}ren daher wertvoll, um die klinische Diagnosestellung zu unterst{\"u}tzen und eine ad{\"a}quate Behandlung fr{\"u}hzeitige zu erm{\"o}glichen. 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 k{\"o}nnten. 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 w{\"a}hrend 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 f{\"u}r die Unterscheidung zwischen unipolarer und bipolarer Depression zu dienen, w{\"a}hrend 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.  }, subject = {Differentialdiagnose}, language = {de} }