Our work focuses on two major research themes. One theme attempts to elucidate normative psychological and neurobiological mechanisms of fear and anxiety in healthy individuals in order to identify which of these mechanisms are perturbed in anxiety disorders. Anxiety is an adaptive response to threat that enables organisms to efficiently confront challenges either via rapid flight or fight responses (fear) or via sustained increased vigilance and behavioral inhibition (anxiety). When anxiety is evoked by anticipation of an unpleasant stimulus such as a mild electric shock (induced-anxiety), our sensorimotor system becomes primed to detect and react quickly to any threat. Our past work shows that this effect is mediated by increased communication between an aversive amplification circuit that includes the dorsal-medial prefrontal cortex (dmPFC) and the amygdala. Phasic increased dmPFC-amygdala communication is responsible for our ability to rapidly detect and react to threat, but when switched on chronically it is also responsible for the crippling attentional bias for threat that characterizes anxious individuals. Additionally, we have identified a potential vulnerability marker for panic attack. Our past studies showed that patients with panic disorder and posttraumatic stress disorder have a propensity to show elevated sustained anxiety to unpredictable threat. Initial results from a collaborative family study of mood and anxiety disorders with Dr. Merikangas suggested that such increased anxiety response to unpredictable threat was also found in individuals with a history of panic attack, regardless of their disorders. Ongoing studies in our lab confirm this link between panic attack and heightened response to unpredictable threat. Current results show that among patients with social phobia or/and generalized anxiety disorder, a history of panic attack is associated with increased response to unpredictable threat. Because we also found that such anxiety response is heritable, our results suggest that an exaggerated response to unpredictable threat constitutes a risk factor for panic attack and, by extension, anxiety disorders given that individuals with a history of panic attack are at increased risk for these conditions. Because of our interest in responses to unpredictable threat, we have initiated a series of neuroimaging studies focusing on the BNST, a structure implicated in sustained anxiety in animal models, but which has been much less investigated than the amygdala, a structure critically involved in fear. One study examined BNST resting-state functional connectivity using ultra-high field 7 Tesla MRI scan. We identified strong BNST functional connectivity in the amygdala, hippocampus, thalamic subregions, caudate, periaqueductal gray, hypothalamus, and cortical areas such as the medial PFC and precuneus. While connectivity with many of these regions has previously been described in rodents and nonhuman primate studies, connectivity with other regions such as the dorsolateral PFC, precuneus, caudate, medial PFC, and nucleus accumbens has not been reported previously. We are currently analyzing changes in BNST functional connectivity during the anticipation of unpredictable shock. Improving our understanding of the anatomy of anxiety should facilitate identification of pathophysiological mechanisms and provide targets for better treatments. According to data from animal models, corticotropin releasing factor (CRF) receptors are involved in fear and anxiety. However, the specific nature of this role remains to be determined and the degree to which CRF effects in animals apply to humans is poorly understood. CRF receptors differentially affect fear and anxiety responses in animals. In rodents, sustained anxiety is maintained by activation of CRF1 receptors in the BNST. Because the BNST has inhibitory connections with the medial portion of the central nucleus of the amygdala, which mediates fear, activation of BNST receptors can inhibit fear. Indeed, in rodents CRF1 receptor antagonists reduce anxiety, but have no effect or even can enhance fear. We recently tested the effect of the CRF antagonist GSK561679 developed by GlaxoSmithKline (GSK) on fear to predictable shock and anxiety to unpredictable shock in healthy individuals. Results showed that while anxiety was reduced by a classic anxiolytic, the benzodiazepine alprazolam, it was not affected by GSK561679. Conversely, fear was not affected by alprazolam but it was enhanced by GSK561679. Taken together studies in animals and our study confirm that CRH has inhibitory and excitatory roles on aversive responses. A second theme focuses on the interactions between anxiety and cognition. Anxiety influences cognition, positively or negatively, and conversely, cognitive processes can foster or reduce anxiety. Clarifying the mechanisms underlying anxiety x cognitive interactions is critical to understand the factors that lead to and/or maintain anxiety, particularly maladaptive anxiety, and to formulate treatment approaches. Recently, we examined behavioral inhibition. Humans and animals show avoidance and freezing responses when threatened. These behaviors are adaptive; they minimize the likelihood of capture or detection by a predator. However, we recently showed that patients with anxiety disorders exhibit a chronic enhancement of behavioral inhibition, even in the absence of threat, leading to maladaptive cautious behaviors. Using a task that tests vigilance and behavioral inhibition, the sustained attention to response task (SART), we have started to map neural mechanisms by which anxiety affects behavioral inhibition. In healthy individuals, anxiety, induced by shock threat, facilitates behavioral inhibition. This facilitation is mediated by activating a right lateralized frontoparietal group of regions. Because these regions are also involved in sustained attention, our next study will explore whether activation of these regions reflects improved behavioral inhibition per se or enhanced sustained attention. In a related study, we investigated mechanisms by which anxiety interferes with day-to-day activity. Indeed, anxiety patients report difficulty concentrating, together with feeling distracted, which in turn can negatively impact their job performance and interpersonal relationships. We have examined individuals' ability to focus attention when anxious during performance of working memory (WM) tasks. WM is central to healthy functioning because it supports maintenance and manipulation of information (e.g., keeping in mind a phone number). One key question is whether underlying deficits in patients with anxiety disorders is the same as that due to elevated anxiety state. We examined neural activity during WM performance in patients with anxiety disorders and in controls during anticipation shocks. We focused on two brain regions, the dorsolateral prefrontal (dlPFC), which is activated by cognitively demanding tasks, and regions of the default mode network (DMN), such as the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), which are typically activated during self-referential processes but deactivated during demanding tasks. We showed that clinical anxiety was associated with under-engagement of the dlPFC, suggesting poor cognitive control. This effect was independent of state anxiety. Conversely, clinical anxiety and state anxiety were associated with reduced DMN activation, probably reflecting difficulty to disengage from self-referential thoughts. By describing the neural underpinnings of anxiety/cognition interactions we are one step closer to identifying biomarkers of vulnerability to anxious pathology, and discrete neural sites for novel treatments that target both emotional and cognitive disruptions associated with anxiety.