The Psychophysiology of Fear and Anxiety

该实验室的一个重点项目是更好地理解焦虑如何影响行为。焦虑会引发一连串的生理反应，使机体做好应对潜在威胁的准备。焦虑也使人更加谨慎和高度警惕。这些都是正常的适应性反应，增加了生存的机会。然而，过度焦虑是很常见的，而且会干扰我们的日常生活。更好地了解焦虑对行为和认知过程的影响可能有助于开发针对特定症状的更好的治疗方法。

A key project of the lab is to better understand how anxiety affects behavior. Anxiety triggers a cascade of physiological responses that prepares the organism to deal with a potential threat. Anxiety also makes people more cautious and hypervigilant. These are normal and adaptive reactions that increase the chance of survival. However, excessive anxiety is common and debilitating as it interferes with our daily life. A better understanding of the effect of anxiety on behavior and cognitive processes may help develop better treatments that target specific symptoms. In past years, we have shown that anxiety can make people faster to act, but also more cautious when a response needs to be stopped. Anxiety speeds up time (Sarigiannidis et al 2019), facilitates the detection of threat, and narrows attention (Lago et al 2019), but it also distracts from ongoing activity (Lago et al 2019). In fact, individuals with anxiety disorders frequently complain that they cannot concentrate: their anxious thoughts interfere with tasks at hand. Using functional magnetic resonance imaging (fMRI) to measure brain activity, we have reported that people who feel threatened exhibit increased activation and connectivity (brain areas talking with each other) in a rear region called the parietal cortex. This suggests that heightened parietal activity could account for the excess vigilance commonly experienced by people with anxiety disorders. This raises the possibility that reducing parietal activation may reduce hypervigilance. In order to study attentional problems due to anxiety, we have explored the effect of anxiety on 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 In a series of studies during the last few years, we have shown that in controls, anxiety induced experimentally by threat of shock can be reduced when participants are involved in a difficult WM task. This is probably because thinking about the task prevents attention to process (i.e., distract from) threat information, an effect due to increased activation of the dorsolateral prefrontal cortex (dlPFC), a key region that supports WM. This hypothesis is consistent with the observation that individuals with anxiety disorders show poor engagement of the dlPFC during such a task. The clinical implication of these findings is that improving WM via facilitation of the dlPFC may reduce anxiety. Traditionally, research aimed at reducing anxiety has focused on the fear circuit, especially targeting the amygdala and bed nucleus of the stria terminalis. But this work has not readily translated into improved treatments for patients. Our recent studies on vigilance and WM suggest therefore important practical and theoretical implications for explaining key cognitive symptoms of anxiety such as lack of concentration and distractibility. alternative routes of treatment by targeting structures that help control attention (i.e., working memory) and vigilance and play a role in the regulation of anxiety, such as the dlPFC and the parietal cortex. We recently tested in two studies the hypothesis that non-invasive neurostimulation of these structures using transcranial magnetic stimulation (TMS) may reduce anxiety. In the first study, we tested the effect of high-frequency repetitive TMS (rTMS) on the right dlPFC (Balderston et al 2019). High frequency rTMS is believed to increase brain excitability, potentially boosting dlPFC activation, while low-frequency rTMS is believed to reduced brain excitability. The study measured anxiety in healthy subjects before and after a session of rTMS neurostimulation. Anxiety was induced by the anticipation of unpleasant shock to the wrist. Counter to our hypothesis, results showed an increase in anxiety following active but not sham (placebo) rTMS. While these results were negative, they confirm that the right dlPFC is involved in anxiety, laying the groundwork for further exploration into the cortical mechanisms modulating anxiety. Indeed, our hypothesis depended on the assumption that high-frequency rTMS would increase right dlPFC activity. It is possible that other rTMS frequency and/or neurostimulation of the left dlPFC would be anxiolytic. The second study focused on rTMS of the parietal cortex and was more successful in reducing anxiety (Balderston et al 2020). The placebo-controlled trial involved controls who were anticipating shock. The startle reflex, a physiological measure of anxious arousal, was used as an index of anxiety. Low-frequency rTMS targeted a part of the parietal cortex called the intraparietal sulcus (IPS) in order to reduce its excitability. Results showed that when rTMS was being directed to the IPS, as opposed to another brain structure, there was a measurable reduction in the startle response, suggesting reduced anxious physiological arousal. These preliminary results are encouraging. TMS has been FDA-approved for depression since 2008 but has not been as successfully applied in anxiety disorders. It is possible that the parietal cortex plays a causal role in a state of elevated anxiety that regulates physiological arousal. Using rTMS to reduce excitability in the IPS can reduce physiological arousal associated with fear and anxiety during threat. All our studies were stopped in March 2020 because of the pandemic. We quickly obtained approval from the NIH Investigational Review Board to conduct an online study (NCT04377100). The study has 2 aims. The first examines how anxiety caused by COVID-19 affects motivation and mental health. Motivation is operationally defined as the amount of effort people invest in performing a challenging task. The objective of the second study is to identify neural and clinical predictors (pre-COVID) of individual differences in the response to the pandemics. To accomplish this 2nd goal, we are recruiting for the online study people we tested during the last several years. We will take advantage of the fact that we have brain imaging data as well as various measure of mental health and cognitive and emotional functioning in these subjects to identify individual differences in response to COVID-19.