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Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective

Key Points

  • Anxiety can be thought of as a future-oriented emotional state that is characterized by anticipatory cognitive, behavioural and affective changes in response to uncertainty about potential threat. Although it often serves an adaptive role, extreme anxiety that is disproportionate to the actual presence or likelihood of threat can cause distress and suffering for individuals with clinical anxiety disorders.

  • We propose a new model, called the 'uncertainty and anticipation model of anxiety' (UAMA), which emphasizes five processes explaining why uncertainty about future threat is so disruptive in anxiety. These five processes are inflated estimates of threat cost and probability, increased threat attention and hypervigilance, deficient safety learning, behavioural and cognitive avoidance and heightened reactivity to threat uncertainty. The neural circuitry for each of the five UAMA processes promotes an adaptive role in responding to and reducing uncertainty about threat.

  • However, alterations in that neural circuitry result in maladaptive responses to uncertainty in pathological anxiety.

  • The key brain regions implicated in maladaptive responses to uncertainty in anxiety include the amygdala, bed nucleus of the stria terminalis, ventromedial prefrontal cortex, orbitofrontal cortex, dorsomedial and dorsolateral prefrontal cortex and anterior insula.

  • The anterior mid-cingulate cortex, which is heavily interconnected with each of these brain regions, shows consistent functional and structural abnormalities in clinical anxiety. We propose a central role for this region in contributing to an array of maladaptive responses to uncertainty.

  • In focusing the experimental and theoretical literatures through the common lens of uncertainty, this perspective provides a unifying theme that binds together many diverse features of clinical anxiety and thus provides a conceptual framework for advancing future research on the neurobiology of anxiety disorders.


Uncertainty about a possible future threat disrupts our ability to avoid it or to mitigate its negative impact and thus results in anxiety. Here, we focus the broad literature on the neurobiology of anxiety through the lens of uncertainty. We identify five processes that are essential for adaptive anticipatory responses to future threat uncertainty and propose that alterations in the neural instantiation of these processes result in maladaptive responses to uncertainty in pathological anxiety. This framework has the potential to advance the classification, diagnosis and treatment of clinical anxiety.

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Figure 1: Neural regions and circuitry implicated in the UAMA.
Figure 2: Altered anticipatory processes in response to threat uncertainty in anxiety.


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The authors wish to thank L. Abramson, R. Davidson, N. Kalin, J. Curtin and members of the Curtin laboratory for feedback on previous versions of this manuscript. This work was supported by the National Science Foundation (Graduate Research Fellowship to D.W.G.) and the US National Institute of Mental Health (R01-MH74847, K02-MH082130 to J.B.N.).

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Corresponding authors

Correspondence to Dan W. Grupe or Jack B. Nitschke.

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The authors declare no competing financial interests.

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The suite of anticipatory affective, cognitive and behavioural changes in response to uncertainty about a potential future threat.

Ventromedial prefrontal cortex

(vmPFC). It encompasses the medial orbitofrontal cortex, posterior frontopolar cortex, subgenual anterior cingulate cortex (ACC) and inferior pregenual ACC, including Brodmann areas 11, 14 and 25, and portions of 10, 24 and 32.

Orbitofrontal cortex

(OFC). Medial and lateral aspects of the orbital surface of the prefrontal cortex, including Brodmann areas 11, 13 and 14, and ventral portions of 10 and 47/12.

Fear-potentiated startle

The enhanced response to a startling stimulus observed in negative arousing states, such as fear or anxiety.


A state of increased attention to a perceived threat in one's environment.

Fear conditioning

The process by which a neutral conditioned stimulus (CS+) becomes associated with an aversive, unconditioned stimulus (US) through repeated contingent presentations of the CS+ and US, resulting in fear expression following presentation of the CS+ alone.

Prediction error

The difference between predicted and actual outcomes, which results in a neural signal that leads to increasingly accurate future predictions.

Rostral cingulate cortex

Encompasses the anterior cingulate cortex and anterior mid-cingulate cortex, including Brodmann areas 24, 25, 32 and 33.


The propensity of a stimulus to form associations with other stimuli in the environment; associability increases following surprising or unpredicted outcomes.

Conditional discrimination tasks

A variant of fear-conditioning paradigms that allows for the independent investigation of safety learning and the inhibition of fear responses in the presence of learned safe cues.

Fear extinction

An active learning process in which a conditioned stimulus (CS+) is repeatedly presented in the absence of a contingent unconditioned stimulus (US), leading to a new association between the CS+ and safety that competes with the original association between the CS+ and US.

Diffusion tensor imaging

An MRI technique that assays the diffusion properties of water molecules, providing insight into the microstructural properties of white matter.

Uncinate fasciculus

The primary white matter tract connecting ventral portions of the prefrontal cortex and anterior cingulate cortex with medial temporal lobe structures, including the amygdala.

Exposure therapy

A therapeutic technique in which individuals are presented with feared objects, situations or memories in a safe setting, thus causing a reduction of fearful associations.

Cognitive behavioural therapy

A diverse collection of therapies in which there is an emphasis on the correction or restructuring of inaccurate beliefs and maladaptive behaviours.


A widely used class of GABA receptor agonists for the treatment of anxiety disorders.


The perception of sensory events occurring within one's body.


A partial agonist of the NMDA glutamate receptor that has been shown to enhance learning.

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Grupe, D., Nitschke, J. Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat Rev Neurosci 14, 488–501 (2013).

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