One main project focuses on identifying core underlying neuromechanisms mediating defensive responses associated with sustained anxiety states with a primary focus on two nodes of the extended amygdala, the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA). Because these structures, especially the BNST, are difficult to image due to their small sizes, we use a powerful neuroimaging scanner, a high-spatial resolution 7 Tesla scanner, to gain better insights into these brain regions. While our past research focused on describing the functional connectivity of the BNST and CeA in control subjects, more recently, we explored the functional connectivity of these structures in individuals with anxiety disorders. Consistent with findings in animals, resting-state functional connectivity for both the BNST and the CeA showed distinct patterns in individuals with anxiety disorders compared with healthy volunteers. Overall, findings are consistent with the proposed functional specialization of these regions, which assumes a primarily role of the BNST in anxiety and the CeA in fear. The CeA acts as the output nucleus of the amygdala, channeling emotional and social information to be processed into phasic fight or flight defensive responses (e.g., fear). The individuals with anxiety disorders show alterations of CeA resting-state functional connectivity with the lateral orbital frontal cortex (which supports emotional valuation and regulation) and the superior temporal sulcus (which mediates social perception and cognition via multisensory integration). These findings might be responsible for the exaggerated automatic responses to emotional/social information displayed in anxiety disorders. The BNST, working in tandem with the amygdala, integrates sensory, social and emotional information into deliberate motivated behaviors (e.g., anxiety) and affects neurocognitive functions. As such, we would expect perturbations of resting-state functional connectivity in the BNST to affect regions involved in higher order cognitive functions. In line with this notion, participants with anxiety show abnormal BNST coupling with the dorsolateral prefrontal cortex, a structure associated with executive functions and emotion-regulation strategies such as reappraisal. Taken together these results support the functional dissociation of these 2 nodes of the extended amygdala, which engage distinct abnormal paths in clinical anxiety. The paths engaged by the BNST might be related more closely to networks involved in cognitive regulation of anxiety (weaker coupling in individuals with anxiety than in healthy volunteers), whereas those engaged by the CeA might preferentially involve automatic value coding and regulation (stronger coupling in individuals with anxiety than in healthy volunteers). These findings are important for guiding future work to extend and better understand the vulnerability mechanisms that underlie excessive anxiety. One key impediment to psychiatric research, including research on anxiety disorders, is the way we diagnose the disorders. Unlike other branches of medicine, psychiatric diagnoses are based on symptoms and not on underlying mechanisms and objective signs that can be quantified (e.g., a diagnosis of cancer is based on measurable characteristics of cells or tissues). Indeed, the diagnosis of an anxiety disorder is based on subjective information gathered via patients self-report and clinicians observation of patients. The discovery of new treatments for anxiety disorders will depend on discovering underlying mechanisms responsible for the pathological state. Our second main project seeks to identify objective signs of the neurocognitive and behavioral symptoms of anxiety using cognitive tasks that probe basic mechanisms associated with anxiety such as hypervigilance, working memory, and behavioral inhibition. One promising avenue of research on the neurocognitive deficits associated with anxiety disorders concerns executive functions, particularly working memory (WM). WM refers to the temporary storage and manipulation of information (e.g., remembering a phone number when dialing the number). WM is not only necessary to maintain and protect a mental representation of information about current goals, but it also gives rise to conscious experience, including the subjective feelings about threat. Because WM has limited capacity, these two mental representations (information about goals and threat) compete for access to awareness, the stronger tending to inhibit the others. Understanding this competition in WM has therefore important practical and theoretical implications for explaining key cognitive symptoms of anxiety such as lack of concentration and distractibility. In a series of studies during the last few years, we have shown that in healthy controls, anxiety experimentally induced by threat of shock can be reduced when participants are involved in a difficult WM task. This is probably because task-related representation weakens threat-related representation, an effect due to increased activation of the dorsolateral prefrontal cortex (dlPFC), a key region that supports WM. We have also shown that individuals with anxiety disorders show poor engagement of the dorsolateral prefrontal cortex during such tasks. The clinical implication of these findings is that boosting WM may facilitate the down-regulation of anxiety. We have recently initiated proof-of-concept studies to investigate this possibility, starting with methylphenidate. Methylphenidate, the firstline medication treatment of attention deficit hyperactivity disorder, increases extracellular dopamine levels and improves attention. Results were contrary to expectation. While we hypothesized that methylphenidate would reduce experimentally-induced anxiety during performance of a WM task, we found an opposite effect (i.e., increased anxiety). In a second study, we examined the effect of acute exercise, which has been shown to improve executive functions. Here again, results were contrary to expectation (i.e., exercise increased rather than decreased anxiety). The interpretation of these results is that as WM improves, fewer resources are required to perform the task, leaving available resources to process threat information, leading to increased anxiety. We are currently testing this hypothesis in a study that compare subjects who are trained in the WM task with subjects who are not trained. The hypothesis is that WM training should lead to increase anxiety because WM training will facilitate task performance, leaving more resources for threat processing. Parallel to these studies, rather than boosting WM per se, we use neurostimulation, to improve the functioning of regions involved in WM using transcranial magnetic stimulation (TMS). Our first study focuses on the dlPFC. Results were largely negative. We are now targeting the parietal cortex.

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18
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2019
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U.S. National Institute of Mental Health
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