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Neural circuit basis of pathological anxiety

Nature Reviews Neuroscience volume 26, pages 5–22 (2025)Cite this article

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Abstract

Anxiety disorders are the most prevalent mental health conditions worldwide. Unfortunately, the understanding of the precise neurobiological mechanisms that underlie these disorders remains limited. Current diagnostic classifications, based on observable symptoms rather than underlying pathophysiology, do not capture the heterogeneity within and across anxiety disorders. Recent advances in functional neuroimaging have provided new insights into the neural circuits implicated in pathological anxiety, revealing dysfunctions that cut across traditional diagnostic boundaries. In this Review, we synthesize evidence that highlights abnormalities in neurobehavioural systems related to negative valence, positive valence, cognitive systems and social processes. We emphasize that pathological anxiety arises not only from heightened reactivity in acute threat (‘fear’) circuits but also from alterations in circuits that mediate distant (potential) and sustained threat, reward processing, cognitive control and social processing. We discuss how circuit vulnerabilities can lead to the emergence and maintenance of pathological anxiety. Once established, these neural abnormalities can be exacerbated by maladaptive behaviours that prevent extinction learning and perpetuate anxiety disorders. By delineating the specific neural mechanisms in each neurobiological system, we aim to contribute to a more comprehensive understanding of the neurobiology of anxiety disorders, potentially informing future research directions in this field.

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Fig. 1: Current conceptualizations for treatment of pathological anxiety.
Fig. 2: Brain circuitry of the RDoC domains and constructs that are relevant to pathological anxiety.
Fig. 3: Emergence of pathological anxiety.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) (grant numbers R01MH101496 (L.M.W.; NCT02220309), U01MH109985 (L.M.W., J.J., C.B.)). The authors acknowledge the editing services of J. Kilner, MS, MA (Pittsburgh).

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  1. These authors contributed equally: Teddy J. Akiki, Jenna Jubeir, Claire Bertrand.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Teddy J. Akiki, Jenna Jubeir, Claire Bertrand, Leonardo Tozzi & Leanne M. Williams

  2. National Center for PTSD, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Teddy J. Akiki

  3. Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Leanne M. Williams

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The authors contributed equally to all aspects of the article. T.J.A., J.J. and C.B. contributed equally.

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L.M.W. declares US Patent Applications 10/034,645 and 15/820,338: ‘Systems and methods for detecting complex networks in MRI image data’. T.J.A. serves on the scientific advisory board of and has stock options with Mindbloom, and receives payment for editorial work from Elsevier. L.T. is employed by Ceribell Inc. The remaining authors declare no competing interests.

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Glossary

Acute threat system

Neural circuitry involved in immediate responses to imminent danger or threat stimuli.

Appraisal

An evaluation of the emotion-relevant aspects of a stimulus or event.

Default mode network

A neural network that is active when an individual is not focused on the outside world and is thought to be involved in self-referential processing.

Dorsal attention network

A brain network involved in top-down, voluntary allocation of attention, including the intraparietal sulcus and frontal eye fields.

Emotional valence

The intrinsic attractiveness (positive valence) or aversiveness (negative valence) of an event, object or situation.

Fear extinction

The gradual decrease in fear response to a conditioned stimulus that occurs when the stimulus is repeatedly presented without the associated aversive outcome.

Generalization

The process by which a learned response to a specific stimulus is transferred to other similar stimuli.

Implicit learning

Learning that occurs without conscious awareness or intention, whether of rewards, patterns or other information.

Maladaptive

Behaviours or responses that are counterproductive or interfere with an individual’s ability to adjust to situations.

Natural kinds

Distinct categories that exist independently of human classification, with clear boundaries between them.

Normative anxiety

Adaptive responses to potentially threatening situations or ambiguous circumstances that do not disrupt a person’s ability to function.

Reward learning

The process by which the brain associates certain behaviours or stimuli with rewards, occurring either implicitly (without conscious awareness) or explicitly (with conscious awareness).

Reward prediction errors

The differences between the expected reward and the actual reward received.

Reward valuation

The process by which the brain assigns value to different rewards.

Salience network

A large-scale brain network involved in detecting and filtering salient stimuli, comprising the anterior insula and dorsal anterior cingulate cortex (dACC).

Units of analysis

The major entities that are being analysed in a study, which can include genetic, neurocircuit, behavioural and self-report assessments.

Ventral attention network

A brain network involved in bottom-up, stimulus-driven attentional control, including the temporoparietal junction (TPJ) and ventral frontal cortex.

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Akiki, T.J., Jubeir, J., Bertrand, C. et al. Neural circuit basis of pathological anxiety. Nat. Rev. Neurosci. 26, 5–22 (2025). https://doi.org/10.1038/s41583-024-00880-4

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