@article{WaiderPoppMlinaretal.2019, author = {Waider, Jonas and Popp, Sandy and Mlinar, Boris and Montalbano, Alberto and Bonfiglio, Francesco and Aboagye, Benjamin and Thuy, Elisabeth and Kern, Raphael and Thiel, Christopher and Araragi, Naozumi and Svirin, Evgeniy and Schmitt-B{\"o}hrer, Angelika G. and Corradetti, Renato and Lowry, Christopher A. and Lesch, Klaus-Peter}, title = {Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, number = {245}, issn = {1662-453X}, doi = {10.3389/fnins.2019.00245}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196077}, year = {2019}, abstract = {Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.}, language = {en} } @article{GenheimerAndreattaAsanetal.2017, author = {Genheimer, Hannah and Andreatta, Marta and Asan, Esther and Pauli, Paul}, title = {Reinstatement of contextual conditioned anxiety in virtual reality and the effects of transcutaneous vagus nerve stimulation in humans}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {17886}, doi = {10.1038/s41598-017-18183-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169892}, year = {2017}, abstract = {Since exposure therapy for anxiety disorders incorporates extinction of contextual anxiety, relapses may be due to reinstatement processes. Animal research demonstrated more stable extinction memory and less anxiety relapse due to vagus nerve stimulation (VNS). We report a valid human three-day context conditioning, extinction and return of anxiety protocol, which we used to examine effects of transcutaneous VNS (tVNS). Seventy-five healthy participants received electric stimuli (unconditioned stimuli, US) during acquisition (Day1) when guided through one virtual office (anxiety context, CTX+) but never in another (safety context, CTX-). During extinction (Day2), participants received tVNS, sham, or no stimulation and revisited both contexts without US delivery. On Day3, participants received three USs for reinstatement followed by a test phase. Successful acquisition, i.e. startle potentiation, lower valence, higher arousal, anxiety and contingency ratings in CTX+ versus CTX-, the disappearance of these effects during extinction, and successful reinstatement indicate validity of this paradigm. Interestingly, we found generalized reinstatement in startle responses and differential reinstatement in valence ratings. Altogether, our protocol serves as valid conditioning paradigm. Reinstatement effects indicate different anxiety networks underlying physiological versus verbal responses. However, tVNS did neither affect extinction nor reinstatement, which asks for validation and improvement of the stimulation protocol.}, language = {en} } @article{SchieleZieglerKollertetal.2018, author = {Schiele, Miriam A. and Ziegler, Christiane and Kollert, Leonie and Katzorke, Andrea and Schartner, Christoph and Busch, Yasmin and Gromer, Daniel and Reif, Andreas and Pauli, Paul and Deckert, J{\"u}rgen and Herrmann, Martin J. and Domschke, Katharina}, title = {Plasticity of Functional MAOA Gene Methylation in Acrophobia}, series = {International Journal of Neuropsychopharmacology}, volume = {21}, journal = {International Journal of Neuropsychopharmacology}, number = {9}, doi = {10.1093/ijnp/pyy050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228571}, pages = {822-827}, year = {2018}, abstract = {Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.}, language = {en} } @article{PoethkeHovestadtMitesser2003, author = {Poethke, Hans-Joachim and Hovestadt, Thomas and Mitesser, Oliver}, title = {Local extinction and the evolution of dispersal rates: Causes and correlations}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-47718}, year = {2003}, abstract = {We present the results of individual-based simulation experiments on the evolution of dispersal rates of organisms living in metapopulations. We find conflicting results regarding the relationship between local extinction rate and evolutionarily stable (ES) dispersal rate depending on which principal mechanism causes extinction: if extinction is caused by environmental catastrophes eradicating local populations, we observe a positive correlation between extinction and ES dispersal rate; if extinction is a consequence of stochastic local dynamics and environmental fluctuations, the correlation becomes ambiguous; and in cases where extinction is caused by dispersal mortality, a negative correlation between local extinction rate and ES dispersal rate emerges. We conclude that extinction rate, which both affects and is affected by dispersal rates, is not an ideal predictor for optimal dispersal rates.}, subject = {Ausbreitung}, language = {en} } @phdthesis{Schwarzmeier2023, author = {Schwarzmeier, Hanna}, title = {From fear extinction to exposure therapy: neural mechanisms and moderators of extinction}, doi = {10.25972/OPUS-22330}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223304}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Emotional-associative learning processes such as fear conditioning and extinction are highly relevant to not only the development and maintenance of anxiety disorders (ADs), but also to their treatment. Extinction, as the laboratory analogue to behavioral exposure, is assumed a core process underlying the treatment of ADs. Although exposure-based treatments are highly effective for the average patient suffering from an AD, there remains a gap in treatment efficacy with over one third of patients failing to achieve clinically significant symptom relief. There is ergo a pressing need for intensified research regarding the underlying neural mechanisms of aberrant emotional-associative learning processes and the neurobiological moderators of treatment (non-)response in ADs. The current thesis focuses on different applications of the fundamental principles of fear conditioning and extinction by using two example cases of ADs from two different multicenter trials. First, we targeted alterations in fear acquisition, extinction, and its recall as a function of psychopathology in panic disorder (PD) patients compared to healthy subjects using fMRI. Second, exposure-based therapy and pre-treatment patient characteristics exerting a moderating influence on this essential learning process later on (i.e. treatment outcome) were examined using multimodal functional and structural neuroimaging in spider phobia. We observed aberrations in emotional-associative learning processes in PD patients compared to healthy subjects indicated by an accelerated fear acquisition and an attenuated extinction recall. Furthermore, pre-treatment differences related to defensive, regulatory, attentional, and perceptual processes may exert a moderating influence on treatment outcome to behavioral exposure in spider phobia. Although the current results need further replication, on an integrative meta level, results point to a hyperactive defensive network system and deficient emotion regulation processes (including extinction processes) and top-down control in ADs. This speaks in favor of transdiagnostic deficits in important functional domains in ADs. Deficits in transdiagnostic domains such as emotion regulation processes could be targeted by enhancing extinction learning or by means of promising tools like neurofeedback. The detection of pre-treatment clinical response moderators, for instance via machine learning frameworks, may help in supporting clinical decision making on individually tailored treatment approaches or, respectively, to avoid ineffective treatment and its related financial costs. In the long run, the identification of neurobiological markers which are capable of detecting non-responders a priori represents an ultimate goal.}, subject = {Extinktion}, language = {en} } @article{EwaldGlotzbachSchoonGerdesetal.2014, author = {Ewald, Heike and Glotzbach-Schoon, Evelyn and Gerdes, Antje B. M. and Andreatta, Marta and M{\"u}ller, Mathias and M{\"u}hlberger, Andreas and Pauli, Paul}, title = {Delay and trace fear conditioning in a complex virtual learning environment - neural substrates of extinction}, series = {Frontiers in Human Neuroscience}, volume = {8}, journal = {Frontiers in Human Neuroscience}, number = {323}, issn = {1662-5161}, doi = {10.3389/fnhum.2014.00323}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116230}, year = {2014}, abstract = {Extinction is an important mechanism to inhibit initially acquired fear responses. There is growing evidence that the ventromedial prefrontal cortex (vmPFC) inhibits the amygdala and therefore plays an important role in the extinction of delay fear conditioning. To our knowledge, there is no evidence on the role of the prefrontal cortex in the extinction of trace conditioning up to now. Thus, we compared brain structures involved in the extinction of human delay and trace fear conditioning in a between-subjects-design in an fMRI study. Participants were passively guided through a virtual environment during learning and extinction of conditioned fear. Two different lights served as conditioned stimuli (CS); as unconditioned stimulus (US) a mildly painful electric stimulus was delivered. In the delay conditioning group (DCG) the US was administered with offset of one light (CS+), whereas in the trace conditioning group (TCG) the US was presented 4s after CS+ offset. Both groups showed insular and striatal activation during early extinction, but differed in their prefrontal activation. The vmPFC was mainly activated in the DCG, whereas the TCG showed activation of the dorsolateral prefrontal cortex (dlPFC) during extinction. These results point to different extinction processes in delay and trace conditioning. VmPFC activation during extinction of delay conditioning might reflect the inhibition of the fear response. In contrast, dlPFC activation during extinction of trace conditioning may reflect modulation of working memory processes which are involved in bridging the trace interval and hold information in short term memory.}, language = {en} } @article{AndreattaPauli2015, author = {Andreatta, Marta and Pauli, Paul}, title = {Appetitive vs. aversive conditioning in humans}, series = {Frontiers in Behavioral Neuroscience}, volume = {9}, journal = {Frontiers in Behavioral Neuroscience}, number = {128}, doi = {10.3389/fnbeh.2015.00128}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148614}, year = {2015}, abstract = {In classical conditioning, an initially neutral stimulus (conditioned stimulus, CS) becomes associated with a biologically salient event (unconditioned stimulus, US), which might be pain (aversive conditioning) or food (appetitive conditioning). After a few associations, the CS is able to initiate either defensive or consummatory responses, respectively. Contrary to aversive conditioning, appetitive conditioning is rarely investigated in humans, although its importance for normal and pathological behaviors (e.g., obesity, addiction) is undeniable. The present study intents to translate animal findings on appetitive conditioning to humans using food as an US. Thirty-three participants were investigated between 8 and 10 am without breakfast in order to assure that they felt hungry. During two acquisition phases, one geometrical shape (avCS+) predicted an aversive US (painful electric shock), another shape (appCS+) predicted an appetitive US (chocolate or salty pretzel according to the participants' preference), and a third shape (CS) predicted neither US. In a extinction phase, these three shapes plus a novel shape (NEW) were presented again without US delivery. Valence and arousal ratings as well as startle and skin conductance (SCR) responses were collected as learning indices. We found successful aversive and appetitive conditioning. On the one hand, the avCS+ was rated as more negative and more arousing than the CS and induced startle potentiation and enhanced SCR. On the other hand, the appCS+ was rated more positive than the CS and induced startle attenuation and larger SCR. In summary, we successfully confirmed animal findings in (hungry) humans by demonstrating appetitive learning and normal aversive learning.}, language = {en} }