Our objective is to determine the extent to which fear and anxiety are relevant to features of particular forms of normal and abnormal anxiety in humans and to qualify how these aversive states interfere with ongoing goals and activity. Past work focused mainly on mechanisms of fear/anxiety learning and expression during anticipation of unpleasant stimuli (shocks). More recent investigations explores the interaction between anxiety and cognitive/attention processes. This research has major public health implications. Identifying the psychological and neurobiological substrate of anxiety evoked by different types of threat and defining key aspects of anxietycognition interactions may provide important links between brain dysfunction and clinical phenomenology and may help design better psychological and psychopharmacological treatments. There are three major research areas. 1) We examine pathways by which normative mechanisms malfunction in anxiety disorders. Here we are seeking evidence that the brain circuit responsible for adaptive, healthy threat-processing is hyperactive in anxiety disorders. In past investigations, we found that anxiety evoked by shock anticipation (induced-anxiety) promotes attentional bias for threat in healthy individuals. Attentional bias plays a key role in the etiology and maintenance of anxiety disorders. While it is adaptive to pay attention to threat to react effectively to danger, a chronic state of attentional bias for threat is maladaptive. Our prior work showed that increased positive coupling between the dorsal-medial prefrontal cortex (dmPFC) and the amygdala is critical for the instigation and maintenance of a bias towards threat. We now have confirmed this finding utilizing a different technique;enhanced positive intrinsic connectivity is seen between the dmPFC and the amygdala during prolonged periods of shock anticipation in an adapted, resting state paradigm (Vytal et al, submitted).We also showed that mimicking a pharmacological symptom of anxiety in healthy individuals - reduced serotonergic function - engages functional connectivity within this circuit during the processing of fearful faces (Robinson et al 2013). This study provides a putative psychological and neural mechanism by which, one of the leading psychopharmacological treatment for anxiety disorders, the selective serotonergic reuptake inhibitor medications (e.g., Prozac), which increases serotonin levels, alleviates anxiety. Our results suggest that such a treatment may lessen anxiety by suppressing chronic attentional bias via a reduction in dmPFC-amygdala connectivity. The above hypotheses provide a strong rationale to examine dmPFC-amygdala connectivity in anxiety disorders, a study that is currently ongoing. Showing that dmPFC-amygdala connectivity is increased in anxiety disorders would confirm that a neural mechanism of attentional bias is constantly switched on in these conditions. A second approach investigates the interaction between anxiety and task performance. On the one hand, it is clear that along with the emotional facets of the disorder, anxiety patients have difficulty concentrating and report feeling distracted, which in turn can negatively impact their job performance and interpersonal relationships. On the other hand, it is also clear that humans possess the capacity to actively disengage from anticipation of a potential threat in order to focus on a challenging task, thereby reducing their anxiety. This resource shift is adaptive because it allows for individuals to perform necessary procedures in order to survive in an environment with imminent threat (e.g., war). We have examined these interactive processes using induced-anxiety during performance of working memory (WM) tasks. WM is central to healthy functioning because it supports online maintenance and manipulation of information (e.g., tallying the cost of a grocery bill while shopping). We showed that that the impact of anxiety on verbal WM performance and, reciprocally, of task demand, on anxiety is based on the cognitive demand of a given task. Specifically, when a WM task is easy, anxiety remains relatively high and performance is disrupted (Vytal et al 2013). However, when a task places greater demand on cognitive resources, anxiety is reduced, but not fully suppressed, and performance normalizes. Recently, we identified the dmPFC as a key structure where competition for resources to process threat-related and WM-related information takes place (Vytal et al submitted). Further insight into these mechanisms reveals that anticipatory anxiety and task demand increase communication between dmPFC and amygdala and dorsolateral PFC (dlPFC), respectively. Under low-load (easy tasks), anxiety engages the dmPFC, and dmPFC-amygdala coupling increases to promote an anxious response. Under high-load (difficult task) WM engages dmPFC and dmPFC-dlPFC coupling increases to promote increased focus on task demands. By describing the neural underpinnings of anxiety/cognition interaction we are one step closer to identifying biomarkers of vulnerability to anxious pathology, and discrete neural site for novel treatments that target both emotional and cognitive disruption associated with anxiety. We are currently extending this research into three areas, 1) exploring the interaction between anxiety and other types of tasks, 2) examining these processes in individuals with anxiety disorders, and 3) investigating whether the interaction between anxiety and WM can be manipulated pharmacologically. The third approach focuses on basic mechanisms that help maintain sustained anxiety responses. One such mechanism is prediction error, which is a fundamental neural learning process that reflects the difference between an actual outcome and an expected outcome. We have reported that prediction error is increased by induced-anxiety, which may explain the propensity for threat-related associations under stress (Robinson et al 2013). Another basic mechanism is stimulus generalization. It is adaptive for a neutral stimulus that has been associated with an aversive event to evoke a conditioned fear response because it may predict danger in the future. Stimulus generalization is the propensity to also react with fear to stimuli that resemble or share features with the conditioned stimulus (e.g., a person who survived an explosion reacts with fear to any loud sound). It has been proposed that overgeneralization of fear to many safe stimuli could contribute importantly to anxiety disorders. Our past studies reported results consistent with this view. We showed that stimulus generalization is increased in individuals with panic disorder. We have now extended these findings to another anxiety disorder, generalized anxiety disorder (Lissek et al in press). In a recent study, we also identified neural mechanisms underlying various aspects of stimulus generalization. The dmPFC and insula show increased activity as stimuli increasingly resemble the conditioned fear stimulus (Lissek et al 2013). Conversely, the hippocampus and the ventromedial PFC, a structure that mediates the inhibition of fear, show increased activity as stimuli less resemble the conditioned fear stimulus. In addition, these two structures showed positive coupling, suggesting that stimuli that less resembled the conditioned fear stimulus were associated with greater safety values and with more fear inhibition. These results have potential treatment implications. Future studies: We are planning to pursue this line of research by examining a basic mechanism of over-generalization, pattern separation, which is mechanism that helps differentiate stimuli that are perceptually similar.

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Cornwell, B R; Overstreet, C; Grillon, C (2014) Spontaneous fast gamma activity in the septal hippocampal region correlates with spatial learning in humans. Behav Brain Res 261:258-64
Schmitz, Anja; Grillon, Christian; Avenevoli, Shelli et al. (2014) Developmental investigation of fear-potentiated startle across puberty. Biol Psychol 97:15-21
Vytal, Katherine E; Overstreet, Cassie; Charney, Danielle R et al. (2014) Sustained anxiety increases amygdala-dorsomedial prefrontal coupling: a mechanism for maintaining an anxious state in healthy adults. J Psychiatry Neurosci 39:321-9
Colloca, Luana; Grillon, Christian (2014) Understanding placebo and nocebo responses for pain management. Curr Pain Headache Rep 18:419
Ballard, Elizabeth D; Ionescu, Dawn F; Vande Voort, Jennifer L et al. (2014) Increased fear-potentiated startle in major depressive disorder patients with lifetime history of suicide attempt. J Affect Disord 162:34-8
Mueller, Sven C; Cornwell, Brian R; Grillon, Christian et al. (2014) Evidence of MAOA genotype involvement in spatial ability in males. Behav Brain Res 267:106-10
Lissek, Shmuel; Bradford, Daniel E; Alvarez, Ruben P et al. (2014) Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study. Soc Cogn Affect Neurosci 9:1134-42
Robinson, Oliver J; Krimsky, Marissa; Grillon, Christian (2013) The impact of induced anxiety on response inhibition. Front Hum Neurosci 7:69
Robinson, Oliver J; Vytal, Katherine; Cornwell, Brian R et al. (2013) The impact of anxiety upon cognition: perspectives from human threat of shock studies. Front Hum Neurosci 7:203
Robinson, Oliver J; Overstreet, Cassie; Allen, Philip S et al. (2013) The role of serotonin in the neurocircuitry of negative affective bias: serotonergic modulation of the dorsal medial prefrontal-amygdala 'aversive amplification' circuit. Neuroimage 78:217-23

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