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

Grupe, Dan W.; Nitschke, Jack B.

doi:10.1038/nrn3524

Cited by 2,007Anxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesMemory and Neural MechanismsNeural and Behavioral Psychology Studies

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

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Grupe, Dan W., Nitschke, Jack B.·2013·Nature Reviews Neuroscience

DOI 10.1038/nrn3524PMC PMC4276319

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Abstract

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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According to Grupe's uncertainty and anticipation model of anxiety (UAMA) theory, the overestimation of threat costs and probabilities causes exaggerated emotional and behavioral reactivity in anxious individuals.
“According to Grupe's “uncertainty and anticipation model of anxiety” (UAMA) theory (23), the overestimation of threat costs and probabilities causes exaggerated emotional and behavioral reactivity in anxious individuals”
From Anticipatory threat responses mediate the relationship between mindfulness and anxiety: A cross-sectional study (2022) · cites this paper as [23]
The UAMA section links elevated threat expectancies to greater behavioral reactivity and heightened anticipatory emotional responses; the section on inflated estimates also links biased cost and probability estimates to anticipatory distress. The source bounds these responses to uncertainty about potential threats, whereas the citing sentence presents the causal claim without that condition. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Limited habituation in mPFC biases information processing towards negative/threatening frameworks; individuals for whom this system is working more typically may be less susceptible to anxiety even if diagnosed with ASD.
“As noted by Grupe and Nitschke (2013), limited habituation in mPFC biases information processing towards negative/threatening frameworks; individuals for whom this system is working more typically may be less susceptible to anxiety even if they are diagnosed with ASD.”
From Sensory, emotional and cognitive contributions to anxiety in autism spectrum disorders (2017) · cites this paper as Grupe and Nitschke, 2013
The ‘Deficient safety learning’ section links altered vmPFC–amygdala function to fear generalization and notes possible benefits of preserved ACC/vmPFC regulatory function. The ‘Increased threat attention and hypervigilance’ section describes a bias toward interpreting uncertainty as threatening, but attributes it to indiscriminate amygdala activation, not limited mPFC habituation. Our copy does not establish the claimed habituation mechanism or address whether more typical function reduces anxiety susceptibility in people with ASD. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Disruptions to this network may lead to more vivid or visceral simulations of potential events and heighten a bias towards threat especially in uncertain situations.
“Disruptions to this network may then lead to “more vivid or visceral simulations of potential events” (p. 492) and heighten a bias towards threat especially in uncertain situations.”
From Sensory, emotional and cognitive contributions to anxiety in autism spectrum disorders (2017) · cites this paper as Grupe and Nitschke, 2013
In “Increased threat attention and hypervigilance” (page not provided), the paper says anxious individuals are biased to interpret uncertainty as threatening and describes a network linking threat attention to the valuation of future events. The cited copy does not contain the quoted phrase “more vivid or visceral simulations of potential events” or establish that network disruptions produce such simulations. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Medial orbitofrontal cortex and insula provide information about the subjective value of potential events, balancing an individual's feelings of probable risk separate from a reasoned consideration of risk.
“A seminal article on the neurobiology of IU (Grupe and Nitschke, 2013) suggests that medial orbitofrontal cortex and insula provide information about the subjective value of potential events, balancing an individual’s feelings of probable risk separate from a reasoned consideration of risk.”
From Sensory, emotional and cognitive contributions to anxiety in autism spectrum disorders (2017) · cites this paper as Grupe and Nitschke, 2013
In ‘Inflated estimates of threat cost and probability,’ the paper says orbitofrontal cortex activity reflects anticipated cost and represents the expected value of future states. In ‘Heightened reactivity to threat uncertainty,’ it proposes that the anterior insula contributes to subjective predictions of threat and describes a dissociation between feelings of threat and cognitive threat calculations. It does not say that the medial orbitofrontal cortex and insula jointly balance feelings of risk against reasoned risk assessment. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Both crises bring uncertainty, loss, and change, and induce grief, anxiety, and distress.
“Both crises bring uncertainty, loss, and change, and induce grief, anxiety, and distress.8”
From Psychological responses, mental health, and sense of agency for the dual challenges of climate change and the COVID-19 pandemic in young people in the UK: an online survey study (2022) · cites this paper as [8]
The paper’s ‘Uncertainty, unpredictability, and uncontrollability’ section links uncertainty to anxiety, and ‘Inflated estimates of threat cost and probability’ links uncertain negative outcomes to anticipatory distress (page numbers unavailable). It does not establish that the two crises involve loss and change or induce grief. (LLM, conf=0.86)
Experimental — accuracy not yet measured

Many people find uncertainty disquieting or avoid it altogether in situations that are personally threatening.
“Although people differ in their tolerance of uncertainty and ambiguity, many find uncertainty disquieting or avoid it altogether in situations that are personally threatening 66 .”
From Predictors and consequences of intellectual humility (2022) · cites this paper as [66]
The amygdala shows heightened activation to uncertain or ambiguous cues in anxious individuals.
“The amygdala, a key region for threat processing, shows heightened activation to uncertain or ambiguous cues in anxious individuals (64).”
From Predictive coding and neurocomputational psychiatry: a mechanistic framework for understanding mental disorders (2026) · cites this paper as [64]
Anxiety is a future-oriented emotional state.
“Recent perspectives consider anxiety to be a future-oriented emotional state”
From Anticipatory threat responses mediate the relationship between mindfulness and anxiety: A cross-sectional study (2022) · cites this paper as [23]
Abnormal and excessive anticipatory responses to unpredictable threats play an important role in anxiety symptoms.
“Recent studies suggest that abnormal and excessive anticipatory responses to unpredictable threats play an important role in anxiety symptoms”
From Anticipatory threat responses mediate the relationship between mindfulness and anxiety: A cross-sectional study (2022) · cites this paper as [23]
Excessive reactivity to uncertainty plays a central role in anxiety.
“Excessive reactivity to uncertainty plays a central role in anxiety”
From Responding to uncertain threat: A potential mediator for the effect of mindfulness on anxiety (2021) · cites this paper as Grupe & Nitschke, 2013
Extreme responses to uncertainty play a critical role in pathological anxiety.
“it has been argued that extreme responses to uncertainty play a critical role in pathological anxiety (Grupe & Nitschke, 2013).”
From Responding to uncertain threat: A potential mediator for the effect of mindfulness on anxiety (2021) · cites this paper as Grupe & Nitschke, 2013
Individuals often believe these cognitions and behaviors are productive, thus sustaining cycles of use.
“Individuals often believe these cognitions and behaviors are productive, thus sustaining cycles of use [15].”
From Dispositional mindfulness, anticipation and abstinence symptoms related to hypnotic dependence among insomniac women who seek treatment: A cross-sectional study (2018) · cites this paper as [15]
Humans display sustained vigilance and defensive responses under conditions of uncertainty.
“Humans display sustained vigilance and defensive responses under conditions of uncertainty [31,32,85].”
From Impact of Media-Induced Uncertainty on Mental Health: Narrative-Based Perspective. (2025) · cites this paper as [31]
Hypervigilance has been singled out as one of five key processes involved in aberrant and excessive anticipatory responding to uncertainty.
“Hypervigilance has been singled out as 1 of 5 key processes involved in aberrant and excessive anticipatory responding to uncertainty [31].”
From Impact of Media-Induced Uncertainty on Mental Health: Narrative-Based Perspective. (2025) · cites this paper as [31]
Psychological and neural mechanisms through which uncertainty-inducing stressors elicit negative mental states, particularly anxiety, and may lead to psychopathology have been extensively described in the literature.
“Psychological and neural mechanisms through which uncertainty-inducing stressors elicit negative mental states, particularly anxiety, and may lead to psychopathology have been extensively described in the literature [31,35,36,57,119,120], and these models are broadly relevant in the present context.”
From Impact of Media-Induced Uncertainty on Mental Health: Narrative-Based Perspective. (2025) · cites this paper as [31]
Uncertainty is an important moderator of individual differences in sensitivity to threat cues, with individuals with anxiety disorders demonstrating enhanced reactivity to uncertain compared to certain threat cues.
“Within this line of work, uncertainty has emerged as an important moderator of this observed individual difference in sensitivity to threat cues, with individuals with anxiety disorders demonstrating enhanced reactivity to uncertain compared to certain threat cues (Bradford, Kaye, & Curtin, 2014a; Bradford, Magruder, Korhumel, & Curtin, 2014b; Grupe & Nitschke, 2013).”
From Cued for Risk: Evidence for an Incentive Sensitization Framework to Explain the Interplay between Stress and Anxiety, Substance Abuse, and Reward Uncertainty in Disordered Gambling Behavior (2019) · cites this paper as Grupe & Nitschke, 2013
When safety is in doubt, subcortical inhibition by the vmPFC is decreased and amygdala activity is enhanced.
“When safety is in doubt, subcortical inhibition by the vmPFC is decreased and amygdala activity is enhanced (Grupe and Nitschke, 2013).”
From Exposed to events that never happen: generalized unsafety, the default stress response, and prolonged autonomic activity (2017) · cites this paper as Grupe and Nitschke, 2013
Neuropsychiatric symptoms are caused by dysfunction in specific networks.
“There is increasing evidence that NPS are caused by dysfunction in specific networks (Dichter et al., 2014; Greicius, 2008; Grupe and Nitschke, 2013; Hamon and Blier, 2013; Menon, 2011; Price and Drevets, 2010; Price and Drevets, 2012; Tromp et al., 2012; Uhlhaas, 2013), with overlap between proposed networks and conditions.”
From Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits? (2015) · cites this paper as Grupe and Nitschke, 2013
The structures dysfunctional in apathy overlap with circuits that subsume behavioral and cognitive avoidance.
“In Grupe et al.’s schematic, this overlaps with circuits that subsume behavioral and cognitive avoidance (Grupe and Nitschke, 2013).”
From Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits? (2015) · cites this paper as Grupe and Nitschke, 2013
Specific circuit alterations underlie the link of Alzheimer's disease pathology with neuropsychiatric symptoms, with these associations being particularly compelling for agitation and apathy in specific circuits.
“Our review of the data on the biology of NPS in AD suggests specific circuit alterations underlying the link of AD pathology with NPS, with these associations being particularly compelling for agitation and apathy in specific circuits (Fig. 1 and Fig. 2) given intriguing overlap with relevant brain circuits (Grupe and Nitschke, 2013).”
From Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits? (2015) · cites this paper as Grupe and Nitschke, 2013
Agitation in Alzheimer's disease involves miscalculation of the magnitude of potential threats, accompanied by increased threat attention and vigilance, and/or heightened reactivity to threat uncertainty.
“Thus, agitation in AD involves miscalculation of the magnitude of potential threats, accompanied by increased threat attention and vigilance, and/or heightened reactivity to threat uncertainty (Grupe and Nitschke, 2013) (see their fig. 1a, 1b, and 1f).”
From Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits? (2015) · cites this paper as Grupe and Nitschke, 2013

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Neuronal circuits for fear and anxiety
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Using Neuroscience to Help Understand Fear and Anxiety: A Two-System Framework
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Irritable bowel syndrome
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Anxiety and the Ecological Crisis: An Analysis of Eco-Anxiety and Climate Anxiety
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Fear of the unknown: One fear to rule them all?
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Frontal midline theta reflects anxiety and cognitive control: Meta-analytic evidence
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Eco-Anxiety and Environmental Education
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Intolerance of uncertainty as a framework for understanding anxiety in children and adolescents with autism spectrum disorders
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The interplay between sensory processing abnormalities, intolerance of uncertainty, anxiety and restricted and repetitive behaviours in autism spectrum disorder
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Computations of uncertainty mediate acute stress responses in humans
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Coexistence of Two Forms of LTP in ACC Provides a Synaptic Mechanism for the Interactions between Anxiety and Chronic Pain
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The human BNST: functional role in anxiety and addiction
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Rethinking Concepts and Categories for Understanding the Neurodevelopmental Effects of Childhood Adversity
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Anxiety and climate change: a validation of the Climate Anxiety Scale in a German-speaking quota sample and an investigation of psychological correlates
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Neural Mechanisms Underlying Anxiety–Chronic Pain Interactions
Zhuo, M. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.01.006 · Cited by 341 · see citing works
The Relationship Between Uncertainty and Affect
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The prefrontal cortex, pathological anxiety, and anxiety disorders
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Intolerance of uncertainty in emotional disorders: what uncertainties remain?
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Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits?
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The Social Regulation of Emotion: An Integrative, Cross-Disciplinary Model
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Aversive state processing in the posterior insular cortex
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Adaptive learning under expected and unexpected uncertainty
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Anxiety and depression: toward overlapping and distinctive features
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Towards a systems view of IBS
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Resolving uncertainty in a social world
FeldmanHall, O., & Shenhav, A. (2019) · Nature Human Behaviour · doi:10.1038/s41562-019-0590-x · Cited by 276 · see citing works
Sensory, emotional and cognitive contributions to anxiety in autism spectrum disorders
South, M., & Rodgers, J. (2017) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2017.00020 · Cited by 270 · see citing works
“As noted by Grupe and Nitschke (2013), limited habituation in mPFC biases information processing towards negative/threatening frameworks; individuals for whom this system is working more typically may be less susceptible to anxiety even if they are diagnosed with ASD.”
Background
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The neurobiology of irritable bowel syndrome
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The Pharmacological Action of Kaempferol in Central Nervous System Diseases: A Review
dos Santos, J. S., Cirino, J. P. G., Carvalho, P. D. O., & Ortega, M. M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.565700 · Cited by 258 · see citing works
Predictors and consequences of intellectual humility
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The Overlapping Neurobiology of Induced and Pathological Anxiety: A Meta-Analysis of Functional Neural Activation
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The default response to uncertainty and the importance of perceived safety in anxiety and stress: An evolution-theoretical perspective.
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Generalized unsafety theory of stress: unsafe environments and conditions, and the default stress response
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Bidirectional Control of Anxiety-Related Behaviors in Mice: Role of Inputs Arising from the Ventral Hippocampus to the Lateral Septum and Medial Prefrontal Cortex
Parfitt, G. M., Nguyen, R., Bang, J. Y., Aqrabawi, A. J., Tran, M. M., Seo, D. K., Richards, B. A., & Kim, J. C. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.56 · Cited by 229 · see citing works
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Expectancies as core features of mental disorders
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More than just noise: Inter-individual differences in fear acquisition, extinction and return of fear in humans - Biological, experiential, temperamental factors, and methodological pitfalls
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Stress-induced plasticity and functioning of ventral tegmental dopamine neurons
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The role of oxidative stress in anxiety disorder: cause or consequence?
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Towards a model of uncertainty distress in the context of Coronavirus (COVID-19)
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Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer’s disease: a systematic review of symptom-general and –specific lesion patterns
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Intolerance of uncertainty: Neural and psychophysiological correlates of the perception of uncertainty as threatening
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Anxious brain networks: A coordinate-based activation likelihood estimation meta-analysis of resting-state functional connectivity studies in anxiety
Xu, J., Van Dam, N. T., Feng, C., Luo, Y., Ai, H., Gu, R., & Xu, P. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.11.005 · Cited by 212 · see citing works
Functional heterogeneity in the bed nucleus of the stria terminalis
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Modeling Trait Anxiety: From Computational Processes to Personality
Raymond, J. G., Steele, J. D., & Seriès, P. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00001 · Cited by 203 · see citing works
How Financial Constraints Influence Consumer Behavior: An Integrative Framework
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Bearing worlds: learning to live-with climate change
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Emotional modulation of interval timing and time perception
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Are extremes of consumption in eating disorders related to an altered balance between reward and inhibition?
Wierenga, C. E., Ely, A., Bischoff-Grethe, A., Bailer, U. F., Simmons, A. N., & Kaye, W. H. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00410 · Cited by 195 · see citing works
Enhanced Risk Aversion, But Not Loss Aversion, in Unmedicated Pathological Anxiety
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Amygdala–Prefrontal Cortex Functional Connectivity During Threat-Induced Anxiety and Goal Distraction
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Putting the “mental” back in “mental disorders”: a perspective from research on fear and anxiety
Taschereau-Dumouchel, V., Michel, M., Lau, H.-K. C., Hofmann, S., & LeDoux, J. E. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01395-5 · Cited by 138 · see citing works
A review on human reinstatement studies: an overview and methodological challengesPreprint
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Fear balance is maintained by bodily feedback to the insular cortex in mice
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Novelty-facilitated extinction: Providing a novel outcome in place of an expected threat diminishes recovery of defensive responses
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Authors: Grupe, D. W., & Nitschke, J. B.
Affiliations: University of Wisconsin–Madison (US)
Corresponding author: Nitschke, Jack B.
Venue: Nature Reviews Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2013-06-20
Volume: 14
Issue: 7
Pages: 488-501
ISSN: 1471-003X (ISSN-L)
1471-0048
DOI: 10.1038/nrn3524
PMC: PMC4276319
OpenAlex: W2004873925
Semantic Scholar: 76c65983fa7dc2ad5afb5128da8f60ef082964b2
Cited by: 2,007
References: 223
Citations by year: 2026: 243 · 2025: 207 · 2024: 199 · 2023: 174 · 2022: 232 · 2021: 255 · 2020: 159 · 2019: 127 · 2018: 101 · 2017: 106 · 2016: 107 · 2015: 56 · 2014: 37 · 2013: 3
FWCI: 11.25
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Neuroscience (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (5k02mh082130-05)
National Institute of Mental Health (K02‑MH082130, R01MH074847, R01-MH74847)
Topics: Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords: anxiety, uncertainty, anticipation, threat anticipation, neurobiology of anxiety, anticipatory responses, anxiety treatment
MeSH terms: Adaptation, Psychological, Anxiety, Attention, Brain, Decision Making, Humans, Neurobiology, Uncertainty

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

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