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The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS−) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS− discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT).
The most prominent brain region evaluating the significance of external stimuli immediately after their onset is the amygdala. Stimuli evaluated as being stressful actuate a number of physiological processes as an immediate stress response. Variation in the serotonin transporter gene has been associated with increased anxiety- and depression-like behavior, altered stress reactivity and adaptation, and pathophysiology of stress-related disorders. In this study the instant reactions to an acute stressor were measured in a serotonin transporter knockout mouse model. Mice lacking the serotonin transporter were verified to be more anxious than their wild-type conspecifics. Genome-wide gene expression changes in the amygdala were measured after the mice were subjected to control condition or to an acute stressor of one minute exposure to water. The dissection of amygdalae and stabilization of RNA was conducted within nine minutes after the onset of the stressor. This extremely short protocol allowed for analysis of first wave primary response genes, typically induced within five to ten minutes of stimulation, and was performed using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays. RNA profiling revealed a largely new set of differentially expressed primary response genes between the conditions acute stress and control that differed distinctly between wild-type and knockout mice. Consequently, functional categorization and pathway analysis indicated genes related to neuroplasticity and adaptation in wild-types whereas knockouts were characterized by impaired plasticity and genes more related to chronic stress and pathophysiology. Our study therefore disclosed different coping styles dependent on serotonin transporter genotype even directly after the onset of stress and accentuates the role of the serotonergic system in processing stressors and threat in the amygdala. Moreover, several of the first wave primary response genes that we found might provide promising targets for future therapeutic interventions of stress-related disorders also in humans.
The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers) and NPSR1 rs324981 (T+ vs. AA carriers) polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA) of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality (VR) paradigm. During acquisition, one virtual office room (anxiety context, CXT+) was paired with an unpredictable electric stimulus (unconditioned stimulus, US), whereas another virtual office room was not paired with any US (safety context, CXT−). During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+) exhibited higher startle responses in CXT+ compared to CXT−. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT−. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Enhanced contextual fear conditioning as reflected in potentiated startle responses may be an endophenotype for anxiety disorders.
It has been shown that applying transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) influences declarative memory processes. This study investigates the efficacy of tDCS on emotional memory consolidation, especially experimental fear conditioning. We applied an auditory fear-conditioning paradigm, in which two differently colored squares (blue and yellow) were presented as conditioned stimuli (CS) and an auditory stimulus as unconditioned stimulus (UCS). Sixty-nine participants were randomly assigned into three groups: anodal, cathodal, and sham stimulation. The participants of the two active groups (i.e., anodal and cathodal) received tDCS over the left DLPFC for 12 min after fear conditioning. The effect of fear conditioning and consolidation (24 h later) was measured by assessing the skin conductance response (SCR) to the CS. The results provide evidence that cathodal stimulation of the left DLPFC leads to an inhibitory effect on fear memory consolidation compared to anodal and sham stimulation, as indicated by decreased SCRs to CS+ presentation during extinction training at day 2. In conclusion, current work suggests that cathodal stimulation interferes with processes of fear memory consolidation.
The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system - partly conferred by catechol-O-methyltransferase (COMT) gene variation - for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.
Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype6gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype6gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
Recent studies as well as theoretical models of error processing assign fundamental importance to the brain's dopaminergic system. Research about how the electrophysiological correlates of error processing—the error-related negativity (ERN) and the error positivity (Pe)—are influenced by variations of common dopaminergic genes, however, is still relatively scarce. In the present study, we therefore investigated whether polymorphisms in the DAT1 gene and in the DRD4 gene, respectively, lead to interindividual differences in these error processing correlates. One hundred sixty participants completed a version of the Eriksen Flanker Task while a 26-channel EEG was recorded. The task was slightly modified in order to increase error rates. During data analysis, participants were split into two groups depending on their DAT1 and their DRD4 genotypes, respectively. ERN and Pe amplitudes after correct responses and after errors as well as difference amplitudes between errors and correct responses were analyzed. We found a differential effect of DAT1 genotype on the Pe difference amplitude but not on the ERN difference amplitude, while the reverse was true for DRD4 genotype. These findings are in line with predictions from theoretical models of dopaminergic transmission in the brain. They furthermore tie results from clinical investigations of disorders impacting on the dopamine system to genetic variations known to be at-risk genotypes.
Einleitung: Medizinische Trainingsfälle sind in der studentischen Ausbildung inzwischen weit verbreitet. In den meisten Publikationen wird über die Entwicklung und die Erfahrungen in einem Kurs mit Trainingsfällen berichtet. In diesem Beitrag vergleichen wir die Akzeptanz von verschiedenen Trainingsfallkursen, die als Ergänzung zu zahlreichen Vorlesungen der Medizinischen Fakultät der Universität Würzburg mit sehr unterschiedlichen Nutzungsraten eingesetzt wurden, über einen Zeitraum von drei Semestern.
Methoden: Die Trainingsfälle wurden mit dem Autoren- und Ablaufsystem CaseTrain erstellt und über die Moodle-basierte Würzburger Lernplattform WueCampus den Studierenden verfügbar gemacht. Dabei wurden umfangreiche Daten über die Nutzung und Akzeptanz erhoben.
Ergebnisse: Im Zeitraum vom WS 08/09 bis zum WS 09/10 waren 19 Kurse mit insgesamt ca. 200 Fällen für die Studierenden verfügbar, die pro Semester von ca. 550 verschiedenen Medizinstudenten der Universität Würzburg und weiteren 50 Studierenden anderer bayerischer Universitäten genutzt wurden. Insgesamt wurden pro Semester ca. 12000 Mal Trainingsfälle vollständig durchgespielt zu denen ca. 2000 Evaluationen von den Studierenden ausgefüllt wurden. In den verschiedenen Kursen variiert die Nutzung zwischen unter 50 Bearbeitungen in wenig frequentierten Fallsammlungen und über 5000 Bearbeitungen in stark frequentierten Fallsammlungen.
Diskussion: Auch wenn Studierende wünschen, dass zu allen Vorlesungen Trainingsfälle angeboten werden, zeigen die Daten, dass der Umfang der Nutzung nicht primär von der Qualität der verfügbaren Trainingsfälle abhängt. Dagegen werden die Trainingsfälle in fast allen Fallsammlungen kurz vor den Klausuren extrem häufig bearbeitet. Dies zeigt, dass die Nutzung von Trainingsfällen im Wesentlichen von der wahrgenommenen Klausurrelevanz der Fälle abhängt.
Einleitung:
Multiple-Choice-Klausuren spielen immer noch eine herausragende Rolle für fakultätsinterne medizinische Prüfungen. Neben inhaltlichen Arbeiten stellt sich die Frage, wie die technische Abwicklung optimiert werden kann. Für Dozenten in der Medizin gibt es zunehmend drei Optionen zur Durchführung von MC-Klausuren: Papierklausuren mit oder ohne Computerunterstützung oder vollständig elektronische Klausuren. Kritische Faktoren sind der Aufwand für die Formatierung der Klausur, der logistische Aufwand bei der Klausurdurchführung, die Qualität, Schnelligkeit und der Aufwand der Klausurkorrektur, die Bereitstellung der Dokumente für die Einsichtnahme, und die statistische Analyse der Klausurergebnisse.
Methoden:
An der Universität Würzburg wird seit drei Semestern ein Computerprogramm zur Eingabe und Formatierung der MC-Fragen in medizinischen und anderen Papierklausuren verwendet und optimiert, mit dem im Wintersemester (WS) 2009/2010 elf, im Sommersemester (SS) 2010 zwölf und im WS 2010/11 dreizehn medizinische Klausuren erstellt und anschließend die eingescannten Antwortblätter automatisch ausgewertet wurden. In den letzten beiden Semestern wurden die Aufwände protokolliert.
Ergebnisse:
Der Aufwand der Formatierung und der Auswertung einschl. nachträglicher Anpassung der Auswertung einer Durchschnittsklausur mit ca. 140 Teilnehmern und ca. 35 Fragen ist von 5-7 Stunden für Klausuren ohne Komplikation im WS 2009/2010 über ca. 2 Stunden im SS 2010 auf ca. 1,5 Stunden im WS 2010/11 gefallen. Einschließlich der Klausuren mit Komplikationen bei der Auswertung betrug die durchschnittliche Zeit im SS 2010 ca. 3 Stunden und im WS 10/11 ca. 2,67 Stunden pro Klausur.
Diskussion:
Für konventionelle Multiple-Choice-Klausuren bietet die computergestützte Formatierung und Auswertung von Papierklausuren einen beträchtlichen Zeitvorteil für die Dozenten im Vergleich zur manuellen Korrektur von Papierklausuren und benötigt im Vergleich zu rein elektronischen Klausuren eine deutlich einfachere technische Infrastruktur und weniger Personal bei der Klausurdurchführung.