Effects of context preexposure and delay until anxiety retrieval on generalization of contextual anxiety.

Animal studies suggest that time delay between acquisition and retrieval of contextual anxiety increases generalization. Moreover, such generalization is prevented by preexposure to the context (CTX), presumably due to an improved representation of such context. We investigated whether preexposure and time-passing modulate generalization of contextual anxiety, in humans.

Converging evidence for an impact of a functional NOS gene variation on anxiety-related processes.

Being a complex phenotype with substantial heritability, anxiety and related phenotypes are characterized by a complex polygenic basis. Thereby, one candidate pathway is neuronal nitric oxide (NO) signaling, and accordingly, rodent studies have identified NO synthase (NOS-I), encoded by NOS1, as a strong molecular candidate for modulating anxiety and hippocampus-dependent learning processes. Using a multi-dimensional and -methodological replication approach, we investigated the impact of a functional promoter polymorphism (NOS1-ex1f-VNTR) on human anxiety-related phenotypes in a total of 1019 healthy controls in five different studies.

Generalization of Contextual Fear in Humans.

Enhanced fear responses to cues, which were not associated with the threat but share perceptual characteristics with the threat signal, indicate generalization of conditioned fear. Here, we investigated for the first time generalization processes in contextual fear conditioning. Thirty-two participants were guided through two virtual offices (acquisition phases).

Reinstatement of contextual anxiety in humans: Effects of state anxiety.

After successful extinction of conditioned fear, the presentation of an unsignaled unconditioned stimulus (US) leads to return of fear, thus, the previously extinguished conditioned stimulus (CS) triggers fear responses again. Human studies on such reinstatement processes are still inconclusive. Some revealed a general increase of fear reactions, both to the fear (CS+) and the safety stimulus (CS-), whereas other studies discovered a differential return of fear with enhanced fear responses to the CS+ only.

Initial and sustained brain responses to contextual conditioned anxiety in humans.

Contextual fear conditioning takes place if the occurrence of threat cannot be predicted by specific cues. As a consequence the context becomes the best predictor of the threat and later induces anxiety (sustained fear response). Previous studies suggest that both the amygdala and the hippocampus are crucial for contextual fear conditioning.

Brain activity associated with illusory correlations in animal phobia.

Anxiety disorder patients were repeatedly found to overestimate the association between disorder-relevant stimuli and aversive outcomes despite random contingencies. Such an illusory correlation (IC) might play an important role in the return of fear after extinction learning; yet, little is known about how this cognitive bias emerges in the brain. In a functional magnetic resonance imaging study, 18 female patients with spider phobia and 18 healthy controls were exposed to pictures of spiders, mushrooms and puppies followed randomly by either a painful electrical shock or nothing.

Delay and trace fear conditioning in a complex virtual learning environment-neural substrates of extinction.

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.

The BDNF Val66Met polymorphism modulates the generalization of cued fear responses to a novel context.

Brain-derived neurotrophic factor (BDNF) has a crucial role in activity-dependent synaptic plasticity and learning and memory. The human functional single-nucleotide BDNF rs6265 (Val66Met) polymorphism has been found to be associated with alteration in neural BDNF release and function correlating with altered emotional behavior. Here, we investigated for the first time the hypothesis that this polymorphism in humans modulates the context dependency of conditioned fear responses.

Pain predictability reverses valence ratings of a relief-associated stimulus.

Relief from pain is positively valenced and entails reward-like properties. Notably, stimuli that became associated with pain relief elicit reward-like implicit responses too, but are explicitly evaluated by humans as aversive. Since the unpredictability of pain makes pain more aversive, this study examined the hypotheses that the predictability of pain also modulates the valence of relief-associated stimuli.

Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle.

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.

Enhanced discrimination between threatening and safe contexts in high-anxious individuals.

Trait anxiety, a stable personality trait associated with increased fear responses to threat, is regarded as a risk factor for the development and maintenance of anxiety disorders. Although the effect of trait anxiety has been examined with regard to explicit threat cues, little is known about the effect of trait anxiety on contextual threat learning. To assess this issue, extreme groups of low and high trait anxiety underwent a contextual fear conditioning protocol using virtual reality.