Our approach is to elucidate normative psychological and neurobiological mechanisms of fear and anxiety in non-anxious individuals to identify which of these mechanisms are perturbed 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 accompanied by worries, hypervigilance, and behavioral inhibition. Our Section studies two type of anxiety, induced-anxiety, which is evoked by the anticipation of mildly unpleasant stimuli such as shock, and clinical anxiety, especially patients diagnosed with social phobia and generalized anxiety disorder. 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. A critical obstacle to addressing this question has been the difficulty of imaging small structures, e.g., those identified as key nodes in the coding of fear (amygdala sub-nuclei) and anxiety (bed nucleus of the stria terminalis BNST). The advent of ultra-high field 7T-fMRI can help circumvent this limitation. Accordingly, we recently used 7T fMRI to examine the way the BNST communicates with other brain structures using intrinsic functional connectivity (iFC) (Torrisi et al., 2015) and found a strong connectivity between the BNST and the central nucleus of the amygdala (CeA) at rest. We are currently using 7T-fMRI to compare the iFC of the BNST with the iFC of the CeA as well as to explore how these iFC are perturbed when subjects are made anxious experimentally. 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 is no objective signs associated with anxiety disorders. Clinicians have to rely only on symptoms. Progresses will depend on discovering objective signs of anxiety disorders. To this end, our Section has identified a potential sign or marker for panic attack. Unexpected surges of fear called panic attacks are the hallmark of panic disorder, but individuals with other disorders can also experience unexpected panic attacks. Our past studies showed that patients with panic disorder have a propensity to show elevated sustained anxiety to unpredictable threat. More recent studies showed that 1) among patients with various types of anxiety disorders, a history of panic attack was also associated with increased response to unpredictable threat and that such anxiety response was heritable, suggesting that an exaggerated response to unpredictable threat constitutes a risk factor for panic attack and, by extension, anxiety disorders (because individuals with a history of panic attack are at increased risk for these conditions). Panic attacks or panic-like symptoms can be evoked in healthy individuals by exposing them to panicogenic challenges such as CO2. To explore further the association between panic attack and reactivity to unpredictable threat, we are currently examining whether non-anxious people who show excessive reactivity to unpredictable threat also tend to have increased panic-like symptoms when exposed to CO2. Another research theme focuses on the interactions between anxiety and both cognition and behavior. While much is known about the effect of anxiety on physiological arousal (i.e., when anxious our heart beat accelerates, our muscles tense), we are only beginning to understand how anxiety affects cognition and behavior. We have all experienced being distracted when anxious. However, being involved in a task can also help us reduce our anxiety. Our work attempts to better understand the mechanisms underlying this interaction between anxiety and cognition. In a recent study, we examined the role of working memory (WM) in anxiety. WM is an executive function that supports maintenance and manipulation of information (e.g., keeping in mind a phone number). We previously showed induced-anxiety was reduced during a WM n-back task. During an n-back task, stimuli are presented sequentially one at a time and subjects need to indicate whether the current stimulus matches the stimulus that was presented n steps earlier. Because, the n-bask task is complex, requiring the simultaneous encoding, maintenance, manipulation, and protection of information from interference, it was not clear which cognitive processes could be responsible for reducing induced-anxiety. Using a Sternberg WM task to activate encoding, maintenance, and retrieval separately, we recently showed that WM maintenance was sufficient to reduce induced-anxiety, probably because engaging WM fully leaves little room to process distracting anxious thoughts. Clinically anxious individuals exhibit a bias toward negative or threatening information, which they process preferentially. This bias is adaptive when we are actually threatened, but anxious individuals are stuck in this attention bias mode of functioning. One key aim of our work is to understand the underlying neural mechanisms of adaptive and maladaptive attention bias in order to provide target for treatment. Our past studies showed that when healthy individuals are made anxious in the laboratory (induced-anxiety), they display attentional bias for threat. We have further identified that this bias is mediated by increased communication between the amygdala and the dorso-medial prefrontal cortex (dmPFC). At the same time, this mechanism is engaged chronically in patients with anxiety disorders. Recently, we showed that this mechanism is under volitional control. When healthy subjects are asked to disengage from threat stimuli, their amygdala-dmPFC coupling is reduced. This raises the possibility that psychological instructions may reduce engagement of this circuitry in anxious patients, leading to a down-regulation of their attentional bias. Humans and animals show motor inhibition, i.e., avoidance and freezing, when threatened. Motor inhibition is adaptive; it minimizes the likelihood of capture or detection by a predator. The Sustained Attention to Response Task (SART), where participants respond to frequent target stimuli whilst withholding a response to infrequent distractor stimuli, can explore the interaction between stress and inhibitory control. We have shown that in non-anxious subjects, induced-anxiety increases motor inhibition. This facilitation is mediated by activating a right lateralized fronto-parietal group of regions. Failure to inhibit a motor response is also associated with reduced activation of the same regions. We are currently examining detailed communication between small regions implicated in motor inhibition with 7T fMRI. Uncovering the mechanisms associated with motor inhibition may prove useful for investigating excessive motor inhibition in anxious patients.

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15
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2016
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U.S. National Institute of Mental Health
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Grillon, C; Robinson, O J; O'Connell, K et al. (2017) Clinical anxiety promotes excessive response inhibition. Psychol Med 47:484-494
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
Balderston, Nicholas L; Mathur, Ambika; Adu-Brimpong, Joel et al. (2017) Effect of anxiety on behavioural pattern separation in humans. Cogn Emot 31:238-248
Balderston, Nicholas L; Hsiung, Abigail; Liu, Jeffrey et al. (2017) Reducing State Anxiety Using Working Memory Maintenance. J Vis Exp :
Balderston, Nicholas L; Vytal, Katherine E; O'Connell, Katherine et al. (2017) Anxiety Patients Show Reduced Working Memory Related dlPFC Activation During Safety and Threat. Depress Anxiety 34:25-36
White, Stuart F; Geraci, Marilla; Lewis, Elizabeth et al. (2017) Prediction Error Representation in Individuals With Generalized Anxiety Disorder During Passive Avoidance. Am J Psychiatry 174:110-117
Cornwell, Brian R; Garrido, Marta I; Overstreet, Cassie et al. (2017) The Unpredictive Brain Under Threat: A Neurocomputational Account of Anxious Hypervigilance. Biol Psychiatry 82:447-454
Grillon, Christian; Robinson, Oliver J; Krimsky, Marissa et al. (2017) Anxiety-mediated facilitation of behavioral inhibition: Threat processing and defensive reactivity during a go/no-go task. Emotion 17:259-266
Balderston, Nicholas L; Hale, Elizabeth; Hsiung, Abigail et al. (2017) Threat of shock increases excitability and connectivity of the intraparietal sulcus. Elife 6:
Lago, Tiffany; Davis, Andrew; Grillon, Christian et al. (2017) Striatum on the anxiety map: Small detours into adolescence. Brain Res 1654:177-184

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