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. Homozygous carriers of the NOS1-ex1f short-allele displayed enhanced trait anxiety, worrying and depression scores. Furthermore, short-allele carriers were characterized by increased anxious apprehension during contextual fear conditioning. While autonomous measures (fear-potentiated startle) provided only suggestive evidence for a modulatory role of NOS1-ex1f-VNTR on (contextual) fear conditioning processes, neural activation at the amygdala/anterior hippocampus junction was significantly increased in short-allele carriers during context conditioning. Notably, this could not be attributed to morphological differences. In accordance with data from a plethora of rodent studies, we here provide converging evidence from behavioral, subjective, psychophysiological and neuroimaging studies in large human cohorts that NOS-I plays an important role in anxious apprehension but provide only limited evidence for a role in (contextual) fear conditioning.

A test for the implementation-maintenance model of reappraisal.

Reappraisal has been defined as a conscious, deliberate change in the way an emotional stimulus is interpreted, initiated in order to change its emotion-eliciting character (Gross, 2002). Reappraisal can be used to down-regulate negative emotions, including anxiety (reviewed in Kalisch, 2009). There is currently a strong interest in identifying the cognitive processes and neural substrates that mediate reappraisal. We have recently proposed a model (termed implementation-maintenance model or IMMO) that conceptualizes reappraisal as a temporally extended, dynamic, and multi-componential process (Kalisch, 2009). A key tenet of IMMO is that reappraisal episodes are marked by an early phase of implementation that may comprise strategy selection and retrieval of reappraisal material into working memory, and a later phase of maintenance that may comprise working memory and performance monitoring processes. These should be supported by dissociable neural networks. We here show, using a detachment-from-threat paradigm and concurrent functional magnetic resonance imaging, that reappraisal-related brain activity shifts from left posterior to right anterior parts of the lateral frontal cortex during the course of a reappraisal episode. Our data provide first empirical evidence for the existence of two separable reappraisal stages. Implications for further model development are discussed.

A meta-analysis of instructed fear studies: implications for conscious appraisal of threat.

In classical Pavlovian fear conditioning, a neutral stimulus (conditioned stimulus, CS) comes to be evaluated as threatening due to its association with an aversive stimulus (unconditioned stimulus, UCS), and elicits fear. In a subtype of fear conditioning paradigms, called instructed fear or anticipatory anxiety, subjects are made aware of the CS-UCS association prior to actually experiencing it. Initial fear elicitation during this type of conditioning results from the negative evaluation of the CS as a consequence of CS-UCS contingency awareness. Prior reports have suggested that this conscious appraisal process is mediated by a variety of brain regions, including rostral dorsomedial prefrontal/dorsal anterior cingulate cortex (dmPFC/dACC), lateral prefrontal cortex (lPFC), posterior cingulate, hippocampus/parahippocampus, and nucleus accumbens, but there is little overlap between results. We reasoned that a formal meta-analysis of existing instructed fear studies should help narrow down the search for conscious appraisal areas in fear conditioning to those consistently activated across studies. We found consistent activation in rostral dmPFC but not in the other candidate areas. These results allow for maintaining the theory that the rostral dmPFC is involved in conscious threat appraisal. We also report a meta-analysis of uninstructed (classical) fear conditioning studies in which we found notable activation in more posterior parts of the dmPFC/dACC that overlapped with some of the instructed fear activations. These data suggest that mid regions of the dmPFC/dACC are part of a "core" fear network that is activated irrespective of how fear was learnt.