Neurocognitive mechanisms of anxiety: an integrative account

Anxiety can be hugely disruptive to everyday life. Anxious individuals show increased attentional capture by potential signs of danger, and interpret expressions, comments and events in a negative manner. These cognitive biases have been widely explored in human anxiety research. By contrast, animal models have focused upon the mechanisms underlying acquisition and extinction of conditioned fear, guiding exposure-based therapies for anxiety disorders. Recent neuroimaging studies of conditioned fear, attention to threat and interpretation of emotionally ambiguous stimuli indicate common amygdala–prefrontal circuitry underlying these processes, and suggest that the balance of activity within this circuitry is altered in anxiety, creating a bias towards threat-related responses. This provides a focus for future translational research, and targeted pharmacological and cognitive interventions.

Introduction

It has been argued that fear mechanisms evolved to enable us to shift our focus from the task at hand at the first suggestion of potential danger; for example, interrupting foraging at the glimpse of a potential predator behind a tree. However, in a short evolutionary timescale our world has changed dramatically. The mass media brings news of natural disasters, potential pandemics, terrorist atrocities and violent crime straight into our homes. Perhaps it is not surprising that nearly one in four of us will experience a clinical level of anxiety within our lifetimes [1]. Previously, it might have been adaptive to attend to any potential source of danger and to interpret each ambiguous event as threat-related, but this is no longer the case. Arguably, a more interesting question is why only some individuals experience the excessive fear, worry and disruption to everyday function that characterizes clinical anxiety. This article focuses on the neurocognitive mechanisms implicated in anxiety; the literature on the genetics and neurochemistry of anxiety having been reviewed elsewhere 2, 3.

Fear is viewed as a biologically adaptive physiological and behavioral response to the actual or anticipated occurrence of an explicit threatening stimulus. Anxiety crucially involves uncertainty as to the expectancy of threat [4], is triggered by less explicit or more generalized cues [5], and is characterized by a more diffuse state of distress, with symptoms of hyperarousal and worry. The human cognitive anxiety literature has provided compelling evidence that anxious individuals show increased attentional capture by cues signaling danger and are more likely to interpret emotionally ambiguous stimuli in a threat-related manner. It has been suggested that these cognitive biases are implicated in the maintenance, and possibly even the etiology, of anxiety 6, 7. The neural substrate of these processes, however, is not easily amenable to investigation with animal models. This contrasts with associative fear mechanisms, where basic neuroscience studies of Pavlovian fear conditioning (see Glossary) have extensively investigated the neural mechanisms mediating the acquisition and extinction of learned or conditioned fear. Although research into factors influencing extinction has been influential in informing exposure therapy for anxiety disorders, there has been little integration of this work with the literature on attentional and interpretative biases in anxiety.

Several recent findings have highlighted the possible interaction of associative and attentional processes in determining the response to threat-related stimuli, while also suggesting conceptual links between associative and interpretative processes 8, 9, 10. Crucially, the advent of neuroimaging has provided a route for examining the neural substrate of these processes in humans. Thus, we can investigate whether the neurocognitive mechanisms underlying attention to, and interpretation of, potentially threat-related stimuli are related to those identified by the animal literature as underlying conditioned fear. The emergence of affective cognitive neuroscience has seen a surge in neuroimaging studies in this area. Findings from these studies support the contention that amydala-prefrontal circuitry is centrally involved in enabling both representations of stimulus emotional salience and top-down control mechanisms to influence associative, attentional and interpretative processes. Initial evidence suggests disruption of this circuitry in anxiety, with deficient recruitment of prefrontal control mechanisms and amygdaloid hyper-responsivity to threat potentially leading to alterations in associative, attentional and interpretative processes that sustain a threat-related processing bias in anxious individuals.