This project has identified core psychological and behavioral findings and their underlying neural mechanisms related to anxiety and anxiety disorders. Using a high-resolution 7 Tesla scanner, we have mapped the functional connectivity of small structures that are key nodes of the brain circuits underlying fear and anxiety, including the central nucleus of the amygdala (CeA), the bed nucleus of the stria terminalis (BNST), and the habenula. We have also characterized the effects of normal anxiety and pathological anxiety on neurocognitive and neurobehavioral processes. This work provides clues as to the boundary between normal and abnormal mechanisms. It also helps identify clinical biomarkers, i.e., processes that distinguish normal from abnormal anxiety. Our approach is to elucidate normative psychological and neurobiological mechanisms of fear and anxiety in healthy subjects to identify perturbations of these mechanisms in anxious people (i.e., individuals with an anxiety disorder). Fear is an adaptive response to threat that enables organisms to efficiently confront an imminent threat via emergency flight or fight responses. Anxiety, which develops when the threat becomes more durable and uncertain, is a sustained state of apprehension. Anxiety is a state of worries, hypervigilance, and behavioral inhibition. Our Section studies anxiety as a normal emotion and as a pathological state (i.e., anxiety disorders). The normal state of emotion is induced by having subjects anticipating mildly unpleasant shock delivered on one wrist. Before the experiment begins, the subjects set the shock at a level that is uncomfortable but tolerable. Although much progress has been made in understanding the mechanisms underlying fear and anxiety, both from animal and human literature, how these circuitries differ from one another, and, particularly how they are uniquely modulated, is still unclear, especially in humans. The advent of new powerful neuroimaging scanners has enabled us to gain better insights into small brain structures that mediate fear and anxiety, the CeA and the BNST. The main result is that the amygdala and the BNST are connected to many of the same structures that have been identified in animals, suggesting close anatomical conservation across mammalian species (Gorka et al., in press). However, we also found new connections with the BNST, especially in cortical regions, which have not been described in animals. These include the ventromedial, ventrolateral, and dorsolateral prefrontal cortex, and the precuneus, regions that are involved in cognition, emotion regulation, and cognitive control. Finally, we found that the amygdala is preferentially connected to structures processing the internal state of the body and sensory information and the BNST with cortical regions involved in threat appraisal and self-referential processing (Gorka et al., in press). This better understanding of the connectivity of the CeA and BNST will help gain insights into the functional role of these structures. In general, to make a diagnosis, clinicians rely on signs, which can be observed and quantified (e.g., thermometer to measure temperature), and symptoms, which are subjective information gathered via patients self-report and clinicians observation of patients. One of the main impediments to progress in anxiety research is that, unlike for many medical conditions, where a blood or urine test can help identify signs of disorders, there are no objective signs associated with anxiety disorders. The discovery of new treatments for anxiety disorders will depend on discovering objective signs of anxiety disorders. To this end, our Section attempts to identify objective signs of the attentional and behavioral symptoms of anxiety using cognitive tasks that probe basic mechanisms associated with anxiety such as hypervigilance and behavioral inhibition. Our findings show that normal anxiety facilitates the detection of environmental threat and novelty, and promotes a cautious behavioral stance combined with a better ability to stop prepotent (ongoing) responses. We have started to identify the brain circuits responsible for these adaptive behaviors. For example, threat detection is improved via increased connectivity between the dorsomedial prefrontal cortex and the amygdala, novelty detection by suppressing the normal feedback in a circuit that includes the auditory cortex, the superior temporal gyrus, and the inferior frontal gyrus, and the facilitation of response inhibition is associated with greater activation of a right-lateralized frontoparietal group of regions previously implicated in sustained attention and motor inhibition. The next step will be to establish whether anxiety disorders are associated with perturbation in these circuits. Critically, this work has the potential to dramatically change our approach to classification and treatment of anxiety disorders, and hopefully to improve the life of people suffering from anxiety.
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