Our objective is to determine the extent to which various aspects of defense mechanisms and conditioned fear are relevant to features of particular forms of normal and abnormal anxiety in humans. Our previous work focused mainly on the mechanisms underlying the expression of fear and anxiety (acquisition, extinction, generalization) (1, 2, 4, 6, 7, 9). We recently initiated studies to examine how anxiety interferes with our thoughts, feelings, and actions (3, 5, 8). Defining cognitive-attentional interactions that are central to anxiety may provide important links between brain dysfunction and clinical phenomenology, and may provide target for psychological and psychopharmacological treatments. Experimental models: Our experiments focus on mechanisms underlying the expression of fear/anxiety. One approach to clarifying the role of a given symptom in the overall pathology of a psychiatric disorder is to reproduce that symptom in healthy individuals (or animal models) and to examine its effect on task performance. For anxiety disorders, we use threat of shock (induced-anxiety) . One of the challenges of such an experimental model is to establish that it can inform on maladaptive responses. We have initiated experiments to identify which cognitive impairments associated with anxiety disorders can be replicated in healthy subjects anticipating shocks. Our first study examined two cognitive impairment found in anxiety disorders, attentional bias threat and conflict adaptation (8). We showed that induced-anxiety does not affect conflict adaptation but increases vigilance to threat. An ongoing study suggests that this latter effect is caused by increased amygdala-rostral dorsomedial prefrontal cortex coupling. Anxiety disorders are believed to be developmental conditions. We recently designed a developmentally-appropriate procedure - derived from our studies in adults - to study fear and anxiety in children (9). In addition, we replicated in children and adolescents the finding that while males and females show equivalent level of fear to a discrete threat, females show increased anxiety than males when anticipating unpredictable aversive events. We also used a virtual reality analogue of the Morris water maze - a task in which subjects navigate to a hidden platform to examine behavior as opposed to emotional responses. An ongoing study examines the role of the hippocampus in spatial navigation and anxiety. Psychopharmacology: While the association between stress and cortisol is wellknown, the specific role of cortisol in fear and anxiety remains to be clarified. We recently reported that while 60 mg of cortisol given acutely does not affect baseline levels of fear and anxiety, it was anxiogenic on anxiety evoked by unpredictable shocks but not on fear to predictable shocks (6). Cortisol may potentiate the effect of the stress hormone corticotrophin releasing factor at extra hypothalamic sites, that is, in limbic structures such as the bed nucleus of the stria terminalis. These results are significant because following findings that low doses of cortisol reduce anxiety (cortisol blocks the retrieval of aversive memories and attentional bias for threat), it has been proposed that it could be used to treat PTSD and phobic symptoms. Because cortisol anxiolytic and anxiogenic effects may depend on drug doses, caution should be taken in using cortisol as an anxiolytic. Affective neuroscience/neuroimaging: We have initiated a series of studies to examine the interaction between cognition and emotion (1,2,5). Results showing that amygdala reactivity to discrete threat stimuli (e.g., fearful faces) is dependent on available attentional resources has shed doubt as to the automaticity of amygdala reactivity. While blocking threat-related distractors from interfering with ongoing activity may be adaptive in a safe context, it may not be advantageous to do so in a dangerous context. We investigated whether anxiety may moderate the interplay between goal-directed behavior and perception of threat. Results showed that induced-anxiety overrides the blocking effects of high perceptual load on amygdala reactivity to threat, probably because anxiety promote neurocognitive processes that enhance sensitivity to danger cues (3). This effect was associated with greater dorsal lateral and ventral prefrontal cortical regions, consistent with attentional control theory that predicts enhanced recruitment of prefrontal attentional mechanisms in anxiety to limit distraction. Hence, distraction by emotional distractors when anxious may result from an inability to enhance dlPFC and VPFC activity sufficiently. Neuroimaging: Anatomically related but distinct neural circuits mediate fear and anxiety in rodents. We explored this issue in humans by examining threat predictability in three virtual reality contexts, one in which electric shocks were predictably signaled by a cue, a second in which shocks occurred unpredictably, and a third safe context. Both predictable and unpredictable shocks evoked transient activity in the dorsal amygdala, but only unpredictable shocks elicited sustained activity in a forebrain region corresponding to the bed nucleus of the stria terminalis complex. Sustained anxiety was also associated with increased activity in anterior insula and a frontoparietal cortical network associated with hypervigilance. In addition, unpredictable shock led to transient activity in the ventral amygdalahippocampal area and pregenual anterior cingulate cortex, as well as transient activation and subsequent deactivation of subgenual anterior cingulate cortex, limbic structures that have been implicated in the regulation of emotional behavior and stress responses. Consistent with basic findings in rodents, these results provide evidence that phasic and sustained fear in humans may manifest similar signs of distress, but appear to be associated with different patterns of neural activity in the human basal forebrain. Clinical studies: We conducted a study of public speaking using virtual reality (VR) to evoke social anxiety in healthy individuals and individuals with social anxiety disorder (SAD). The study had two objectives. The first was to validate a standardized method to study emotional reactivity in a social-evaluative context. The results confirmed the expectation that VR was a powerful tool to study social anxiety. The second objective was to identify specific components of psychophysiological reactivity that discriminate among SAD and non SAD subjects. Two components discriminated SAD from non-SAD subjects. SAD subjects exhibited an overall increased distress reflected in increased subjective anxiety and physiological reactivity (anxiety-potentiated startle) during speech anticipation. This distressed response lasted throughout the study. SAD subjects also showed a more specific fear response when they perceived themselves as being the focus of attention. One practical implication of this study is that startle can be used to track changes in ongoing emotional changed during public speaking before and after treatment. Self-report measures have been criticized for being influenced by social desirability. Startle provides a more objective index of underlying defense mechanisms.

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Hantsoo, Liisa; Golden, Carla E M; Kornfield, Sara et al. (2018) Startling Differences: Using the Acoustic Startle Response to Study Sex Differences and Neurosteroids in Affective Disorders. Curr Psychiatry Rep 20:40
Cooper, Samuel E; Grillon, Christian; Lissek, Shmuel (2018) Impaired discriminative fear conditioning during later training trials differentiates generalized anxiety disorder, but not panic disorder, from healthy control participants. Compr Psychiatry 85:84-93
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Lago, Tiffany R; Hsiung, Abigail; Leitner, Brooks P et al. (2018) Exercise modulates the interaction between cognition and anxiety in humans. Cogn Emot :1-8
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Patel, Nilam; Stoodley, Catherine; Pine, Daniel S et al. (2017) Interaction of induced anxiety and verbal working memory: influence of trait anxiety. Learn Mem 24:407-413

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