Trends in Cognitive Sciences
ReviewNeurocognitive mechanisms of anxiety: an integrative account
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.
Section snippets
Selective attention to threat
Patients suffering from anxiety disorders have been reported to show a bias in selective attention towards threat-related stimuli 11, 12. Similar findings have been observed for individuals with high levels of trait anxiety. Here, however, the results are less robust, and it has been suggested that a combination of high trait and high state anxiety might be required for threat-related attentional biases to be observed in non-clinical populations [13].
Several paradigms, including the emotional
Are there common neurocognitive mechanisms underlying the attentional, interpretative and associative processing of threat?
It has been argued that fear extinction results in the CS becoming, in effect, an emotionally ambiguous stimulus linked to representations of both threat (from acquisition) and safety (from extinction) [10]. In extinction recall, prefrontal inhibition of amygdala output is held to support activation of the latter representation over the former [21], providing a clear parallel to the proposed interaction of control mechanisms and threat evaluation mechanisms in attentional regulation of threat
Neuroimaging studies of fear conditioning
Human neuroimaging studies of fear conditioning have broadly confirmed findings from the basic neuroscience literature. Amygdala activity is observed during the acquisition of conditioned fear 31, 32, 33, 34, 35, with the magnitude of the amygdala response to the CS being strongest during the early stages of acquisition 31, 32, 33 and correlating positively with physiological measures of arousal, such as skin conductance responses (SCRs) [36]. Several studies have also reported enhanced
Neuroimaging studies of selective attention to threat
Several models have suggested that anxiety biases attention towards threat-related stimuli by augmenting the output from an amygdala-centered pre-attentive threat evaluation mechanism 12, 39. Within the neuroimaging literature, there has been a heated debate as to whether the amygdala does indeed show a pre-attentive response to threat-related stimuli. Studies using manipulations of spatial and object-based attention have reported amygdala activation to unattended threat-related stimuli 40, 41.
Neuroimaging studies of threat interpretation
Recently, several neuroimaging studies have examined the neural mechanisms underlying the interpretation of potentially threat-related stimuli. It has been shown that the amygdala response to neutral facial expressions, perceived by some as mildly negative, increases as a function of anxiety [50]. Expressions of surprise are also relatively ambiguous, signaling the occurrence of either a positive or a negative unexpected event, and sharing certain features with expressions of fear. The
Towards a central role for amygdala–prefrontal interactions in anxiety
Heightened acquisition and/or diminished extinction of learned fear, enhanced selective attention to threat, and negative biases in the interpretation of emotionally ambiguous stimuli have all been held to characterize anxiety and to potentially play a role in its maintenance and even possibly its etiology 6, 7, 12, 19, 21. Despite this, there has been little crosstalk between basic neuroscience studies of conditioned fear, and human cognitive studies of attentional and interpretative biases in
Concluding remarks
The findings reviewed here provide strong support for a common amygdala–prefrontal circuitry underlying selective attention to threat, interpretation of emotional stimuli, and acquisition and extinction of conditioned fear. Heightened amygdala activity and reduced prefrontal recruitment appear to bias the system towards threat-related responses. At a cognitive level, this is thought to reflect both increased activation of threat-related representations and a failure to use controlled processing
Acknowledgements
Thanks to Trevor Robbins and John Duncan for comments. This work was supported by a Career Development Award from the Medical Research Council, and conducted at the University of Cambridge Behavioural and Clinical Neuroscience Institute – cofunded by the Medical Research Council, and the Wellcome Trust – and at the Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK.
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