The Psychophysiology of Fear and Anxiety

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

The lab focuses on understanding several aspects of normal and pathological anxiety. Our research ranges from neuroimaging to understand brain mechanisms, psychophysiology to explore emotional reactivity, affective neuroscience to investigate cognitive processes, and psychopharmacology to screen new treatments. To study attentional problems caused by anxiety, we have developed a research program that explores the interaction between anxiety and working memory (WM). WM refers to the temporary storage and manipulation of information (e.g., remembering a phone number when dialing the number). WM not only helps keep in mind our current goals, but it also gives rise to the conscious experience of anxiety . In past studies, we have identified brain structures of a fronto-parietal control network that play important roles in the interaction between anxiety and WM. More recently, we implemented a pharmacological manipulation using a cognitive enhancer, methylphenidate, to investigate the impact of improving cognition on anxiety. We showed that methylphenidate increases overall WM performance and strengthened the engagement of the fronto-parietal control network while also reducing the default mode network deactivation. The facilitation of neural activation can be interpreted as an expansion of cognitive resources, which could foster both the representation and integration of anxiety-provoking stimuli as well as the top-down regulatory processes to protect against the detrimental effect of anxiety. This mechanism might establish an optimal balance between the fronto-parietal control network (cognitive processing) and default mode network (emotion regulation) recruitment. Cognitive control, the mind's ability to actively create an information picture that guide behavior, is a key factor in the maintenance of mental health. However, cognitive control is an effortful process that can be weakened by mental fatigue. In a recent study, we examined whether mental fatigue could confer vulnerability to anxiety disorders, increasing the risk for these conditions. We investigated the effect of mental fatigue on attention bias for threat. Attention bias for threat is the tendency to disproportionately attend to negative stimuli (e.g., fearful face) over neutral or positive stimuli (e.g., smiling face). Research on anxiety has long pointed out that this information processing bias confers elevated risk for anxiety and the development and maintenance of anxiety disorders. Mental fatigue was induced in volunteer subjects by protracted performance on various cognitive tasks. Attentional bias was evaluated with the dot-probe, a test that tests subjects attention towards fearful and neutral faces. Subjects reported increased subjective fatigue (feeling tired and less engaged in the task) following the mental fatigue induction procedure. Results showed that mental fatigue was associated with increased attentional bias for threat. Following mental fatigue, subjects paid more attention to fearful faces than to neutral faces. These results do not show that mental fatigue induces anxiety but shows that mental fatigue makes people more likely to attend to negative stimuli, which may facilitate the development of anxiety episodes and, potentially, anxiety disorders. This is an important finding with implications for mental health as mental fatigue is now a common phenomenon in everyday given that the nature of work has evolved from physical effort to mental effort. Epidemiology studies indicate that up to half the populations report feeling fatigue. In a recent survey, the 2-week period prevalence of fatigue in the US workforce was approximately 38%. In addition, numerous studies have shown an association between mental fatigue and anxiety. One of the labs objectives is to help discover new treatments. Psychiatric drug development is quite challenging, and many companies have abandoned the search for new therapies. Current treatment response rates for anxiety and trauma-based disorders rarely exceed 60% and no new agents for the treatment of these disorders have been approved by the Food and Drug Administration (FDA) or European authorities in the last decade. A considerable impediment to drug development is the long, arduous, and costly process through which a candidate drug moves from the discovery stage into an actual treatment. Currently, this process entails multiple steps, including screening candidate agents in animal models and moving to clinical trials in patients. A key problem to such approach is that most candidate anxiolytics with anti-anxiety effect in animal studies fail in clinical trials. We have argued that a new strategy is needed and, in a recent review, have proposed a new approach that may radically transform the pursuit of new anxiolytic treatments, via the use of human models of anxiety in healthy individuals. Specifically, we propose an additional screening step to help select candidate anxiolytics before launching clinical trials. This intermediate step moves the evidence for the potential anxiolytic property of candidate drugs from animals to humans, using experimental models of anxiety in healthy individuals. Anxiety-potentiated startle is a robust translational model of anxiety. The review of its face, construct, and predictive validity as well as its psychometric properties in humans establishes it as a promising tool for anxiolytic drug development. In conclusion, human models of anxiety may stir a faster, more efficient path for the development of clinically effective anxiolytics. Following this recommendation, we recently investigated in a human model a new compound that has shown anti-anxiety effects in animal model. Arginine vasopressin is a neuropeptide that modulates both physiological and emotional responses to threat. Until recently, drugs that target vasopressin receptors (V1a) in the human central nervous system were unavailable. The development of a novel V1a receptor antagonist, SRX246, enables the experimental validation of vasopressins role in the regulation of anxiety and fear in humans. Our study examined the effects of SRX246 in a proof-of-concept translational paradigm of fear (phasic response to imminent threat) and anxiety (prolonged response to unpredictable threat). Threat consisted of unpleasant electric shocks. As expected, we found that SRX246 decreased anxiety induced by an unpredictable threat. As anxiety to unpredictable threat is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as selective serotonin reuptake inhibitors and benzodiazepines, the V1a receptor is a promising novel treatment target. In recent year, the lab has increased research in computational psychiatry. Analysis of resting state fMRI data has gained prominence as a tool to infer functional connectivity (fc) in brain networks. Functional connectivity is defined as the similarity in neural activity of anatomically distinct brain regions. Surprisingly, one underlying assumption of most fc analyses is temporal stationarity, i.e., no phase difference between the signals considered. However, there is increasing evidence that challenges this assumption. There are several methods that capture the dynamic nature of the fc. Our lab has implemented a new technique based on dynamic time warping (DTW). This technique was found to be more efficient in assessing the separability of the SNc-cortical and VTA-cortical network compared to traditional methods. Finally, we have initiated an online Covid study (NCT04377100). The study has 2 aims. The first examines how anxiety caused by COVID-19 affects motivation and mental health. The objective of the second study is to identify neural and clinical predictors (pre-COVID) of individual differences in the response to the pandemics.