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 using a translational approach. Past works focused mainly on the mechanisms underlying the expression of fear and anxiety (acquisition, extinction, generalization) (1,4,8) while subjects anticipate unpleasant shocks. We recently initiated studies to examine how induced anxiety interferes with our thoughts, feelings, and actions (10). 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. Affective neuroscience/neuroimaging: Our experiments focus on mechanisms underlying the expression of fear/anxiety evoked by anticipation of unpleasant shocks. 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 emotional expression and task performance. Anxiety impairs the ability to think and concentrate, but being engaged in a task can also reduce anxiety. We have recently focused on this type of interaction between emotion and cognition as it may help elucidate the debilitating nature of pathological anxiety, but also provide clues about how cognitive mechanisms can help alleviate anxiety. Using a verbal n-back working memory (WM) task that parametrically modulated cognitive load, we explored the effect of experimentally induced anxiety on task performance and the startle reflex (10). Findings suggest there is a crucial inflection point between moderate and high cognitive load, where resources shift from anxious apprehension to focus on task demands. Specifically, we demonstrated that anxiety impairs performance under low load, but is reduced when subjects engage in a difficult task that occupies executive resources. We propose a two-component model of anxiety that describes a cognitive mechanism behind performance impairment and an automatic response that supports sustained anxiety-potentiated startle. We have now initiated a series of fMRI studies to examine the neural underpinning of these effects (i.e., interactions between anxiety and WM load). Preliminary results show that 1) as cognitive load increases, activation in anxiety-related areas (amygdala, insula, dorsal ACC) decreases, 2) dorsal frontal regions are activated by both anxiety and cognition, suggesting that these regions may be clinically important, and 3) the insula is the only anxiety-related area that remain activated at high cognitive load suggesting that this region may play a key role in the maintenance of the physiological symptoms of anxiety. Psychopharmacology: The nonapeptide oxytocin (OT), dubbed by the media as the moral or love molecule, has a variety of pro-social effects across species. A relatively simple explanation for these complex effects is that OT alleviates anxiety, thereby indirectly promoting trust, cooperation and other affiliative behaviors. Indeed, OT can reduce anxiety-like behavior in animals. Surprisingly, OT also promotes territoriality, aggression, and other defensive behaviors toward out-group members, complicating any straightforward interpretation of OTs socio-emotional effects. We recently showed that OT does not reduce but rather increases anxiety evoked by unpredictable shocks. These results are significant because it has been proposed that OT could be used to treat socio-emotional disorders such as autism, schizophrenia, and social anxiety. However, given the present finding of an anxiolytic effect, it may be premature to speculate on the therapeutic effect of OT before we have a better understanding of its non-social effects. Clinical studies: We have begun to study patients with major depression (MDD) as well as the effect of depressed mood (7) because of the high level of comorbidity between anxiety and depression. While dysregulated affect is a hallmark of MDD, the nature of such dysregulation remains to be characterized. It has been suggested that MDD is characterized by blunted emotional response not only to positive stimuli but, perhaps more surprisingly, to negative events, including threatening stimuli. This emotional blunting is seen as an adaptive response signaling the need to disengage from the environment. However, emotional blunting in MDD as been demonstrated only in experiments that use hypothetical threats such as looking at unpleasant pictures. In addition, that MDD shows reduced anxiety in the face of threat is inconsistent with the theoretical conceptualization that depression and anxiety disorders share a common distress factor of heightened affective negativity. Such a distress factor would predict exaggerated not blunted response to aversive stimuli. We have investigated this question using threat of shock. Results do not support the view of emotional blunting in MDD. Rather, MDD patients show increased anxiety compared to healthy volunteers. These results suggest that depression may be associated with blunted emotional responses when confronted with hypothetical and personally-irrelevant threats, probably because of emotional disengagement. However, when confronted with an actual physical threat, MDD patients exhibit enhanced anxiety. Studies in animals and in humans are beginning to identify psychopharmacological and neural mechanisms involved in anxiety. The current experimental paradigm is a valuable translational tool to identify brain dysfunction in mood and anxiety disorders and may help uncover novel pathophysiology-based treatments.

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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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