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Uncertainty and stress: Why it causes diseases and how it is mastered by the brain
Open accessAbstract
The term 'stress' - coined in 1936 - has many definitions, but until now has lacked a theoretical foundation. Here we present an information-theoretic approach - based on the 'free energy principle' - defining the essence of stress; namely, uncertainty. We address three questions: What is uncertainty? What does it do to us? What are our resources to master it? Mathematically speaking, uncertainty is entropy or 'expected surprise'. The 'free energy principle' rests upon the fact that self-organizing biological agents resist a tendency to disorder and must therefore minimize the entropy of their sensory states. Applied to our everyday life, this means that we feel uncertain, when we anticipate that outcomes will turn out to be something other than expected - and that we are unable to avoid surprise. As all cognitive systems strive to reduce their uncertainty about future outcomes, they face a critical constraint: Reducing uncertainty requires cerebral energy. The characteristic of the vertebrate brain to prioritize its own high energy is captured by the notion of the 'selfish brain'. Accordingly, in times of uncertainty, the selfish brain demands extra energy from the body. If, despite all this, the brain cannot reduce uncertainty, a persistent cerebral energy crisis may develop, burdening the individual by 'allostatic load' that contributes to systemic and brain malfunction (impaired memory, atherogenesis, diabetes and subsequent cardio- and cerebrovascular events). Based on the basic tenet that stress originates from uncertainty, we discuss the strategies our brain uses to avoid surprise and thereby resolve uncertainty.
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“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 [120]
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“While sustained vigilance represents the initial adaptive response under conditions of uncertainty [35,120], it can develop into hypervigilance, that is, increased attention to threatening or potentially threatening stimuli.”
From Impact of Media-Induced Uncertainty on Mental Health: Narrative-Based Perspective. (2025) · cites this paper as [120]
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“Some studies in neuroscience also support this claim by providing evidence that the human brain is hardwired to interpret uncertainty as a danger and respond to it with fear and stress [2,3].”
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“Uncertainty has been identified as a key factor in the perception of stress and its subsequent physiological manifestation (Peters et al., 2017).”
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Feng, H., & Zeng, Y. (2022) · Frontiers in Neurorobotics · doi:10.3389/fnbot.2022.1025338 · Cited by 10
“The brain’s Free Energy Principle (FEP) proposes that organisms are constantly maintaining the low-entropy state, and abnormal phenomena are the high-entropy state (Friston et al., 2006; Karl, 2012; Peters et al., 2017), such as body injury.”
BackgroundNegative affect and stress‐related brain metabolism in patients with metastatic breast cancer
Reis, J. C., Travado, L., Antoni, M. H., Oliveira, F. P. M., Almeida, S. D., Almeida, P. M. D., Heller, A. S., Sousa, B., & Costa, D. C. (2020) · Cancer · doi:10.1002/cncr.32902 · Cited by 11
“The current study focuses on ROIs known to be associated with: 1) major depression in patients without cancer,(24-29) 2) NA in patients with nonmetastatic cancer,(19) and 3) stress responses to environmental and contextual uncertainty.(16) We hypothesized that patients reporting greater NA would evidence less metaboli…”
MethodTranscriptomics of the depressed and PTSD brain
Zhang, J., Kaye, A. P., Wang, J., & Girgenti, M. J. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100408 · Cited by 11
Psychosocial stress affects the acquisition of cerebellar-dependent sensorimotor adaptation
Gheorghe, D. A., Panouillères, M., & Walsh, N. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.03.013 · Cited by 11
“, 2010) as learning is metabolically costly and resources need to be conserved (Peters et al., 2017).”
Hellem, E., & Bruusgaard, K. A. (2018) · Physiotherapy Theory and Practice · doi:10.1080/09593985.2018.1550829 · Cited by 10
Smith, R. S., Kirlić, N., Stewart, J. L., Touthang, J., Kuplicki, R., Khalsa, S. S., Paulus, M. P., T Investigators, & Aupperle, R. L. (2020) · PsyArXiv (OSF Preprints) · doi:10.31234/osf.io/t2dhn · Cited by 9
How does sensitivity influence early executive function? A critical review on hot and cool processes
Ramos, C., Pereira, A. F., Feher, A., & Baptista, J. (2023) · Infant Behavior and Development · doi:10.1016/j.infbeh.2023.101895 · Cited by 10
Moeck, E. K., Greenaway, K. H., Bianchi, V., Gross, J. J., Koval, P., & Kalokerinos, E. K. (2024) · Emotion · doi:10.1037/emo0001407 · Cited by 12
Breathwork for Chronic Stress and Mental Health: Does Choosing a Specific Technique Matter?
Siebieszuk, A., Płoński, A. F., & Baranowski, M. (2025) · Medical Sciences · doi:10.3390/medsci13030127 · Cited by 12
“Key factors affecting mental health include uncertainty and the anticipation of future stress, intensified by constant access to distressing global news [28,29].”
Reis, J. C., Travado, L., & Antoni, M. H. (2025) · International Journal of Clinical and Health Psychology · doi:10.1016/j.ijchp.2025.100615 · Cited by 10
“Stress appraisals and coping processes are mediated by a network of brain regions involved in evaluating environmental threats and orchestrating physiological and behavioral adaptations (McEwen, 2012, 2017a; Peters et al., 2017).”
Metabolic psychiatry targeting metabolic dysregulation in mental health
Sethi, S., Berk, M., Andreazza, A. C., Mujica-Parodi, L. R., Campbell, I. H., Campbell, H., Longhitano, C., Rasgon, N., Volek, J. S., Calkin, C., et al. (2026) · Nature Mental Health · doi:10.1038/s44220-026-00609-5 · Cited by 13
Naess, C. R., & Kolnes, L.-J. (2022) · Journal of Eating Disorders · doi:10.1186/s40337-022-00675-x · Cited by 9
“The regulation of the affected systems may become impaired [78] and specific breathing patterns can be generated when problematic feelings and thoughts are repressed over time, blocking both awareness and expression.”
BackgroundShanahan, L., Johnson‐Ferguson, L., Loher, M., Steinhoff, A., Bechtiger, L., Murray, A. L., Hepp, U., Ribeaud, D., & Eisner, M. (2023) · Adversity and Resilience Science · doi:10.1007/s42844-023-00096-y · Cited by 10
Early Chronic Stress Induced Changes within the Locus Coeruleus in Sporadic Alzheimer’s Disease
Minné, D., Marnewick, J. L., & Engel-Hills, P. C. (2023) · Current Alzheimer Research · doi:10.2174/1567205020666230811092956 · Cited by 10
Volta, M. F. C. D., Vallone, F., & Zurlo, M. C. (2024) · Healthcare · doi:10.3390/healthcare12070752 · Cited by 10
“…the detrimental effects of prolonged feelings of uncertainty and stressful experiences not only in the short-term but also in the long-term [57,58], and research on less-lasting medical emergencies (e.g., H1N1 and SARS) has already warned that the psychological impact of experiences of…”
BackgroundStress-related consequences of the coronavirus disease 2019 pandemic on symptoms of Crohn’s disease
Goodday, S., Travis, S. P. L., Walsh, A., & Friend, S. H. (2021) · European Journal of Gastroenterology & Hepatology · doi:10.1097/meg.0000000000002081 · Cited by 9
Gronewold, J., & Engels, M. (2022) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2022.729621 · Cited by 9
“As a response to the dysregulation, subclinical functional deficits occur, finally resulting in clinical system damage manifested as (cerebro-) vascular disease (Peters et al., 2017).”
BackgroundPiloting the Update: The Use of Therapeutic Relationship for Change – A Free Energy Account
Hauke, G., & Lohr, C. (2022) · Frontiers in Psychology · doi:10.3389/fpsyg.2022.842488 · Cited by 9
Hussain, J. S., Sundaraj, K., & Subramaniam, I. D. (2020) · PLoS ONE · doi:10.1371/journal.pone.0228089 · Cited by 9
“Various psychological effects, such as those of thinking about an upcoming assignment or a future meeting, might induce stress [10].”
BackgroundGlobal Adversities, the Media, and Mental Health
Kesner, L., & Horáček, J. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.809239 · Cited by 9
“Indeed, in current theorising, stress itself is regarded as a form of uncertainty (35).”
BackgroundInvestigating the effect of continuous and partial reinforcement in conceptual fear generalization
Mitra, S., & Asthana, M. K. (2024) · Scientific Reports · doi:10.1038/s41598-024-71575-0 · Cited by 7
“Consistent with previous findings, we found that fear generalization is directly related to the uncertainty of the UCS occurrence 57,58 and covaries with the reinforcement rate during the acquisition phase.”
ResultWhen health care workers became patients with COVID‐19: A qualitative study
Du, L., Liu, Q., Chen, Q., Wang, X. Q., Fang, S., Chen, P., Chen, J., Zhang, Z., Liu, Z., Yang, B. X., et al. (2021) · International Journal of Nursing Practice · doi:10.1111/ijn.13034 · Cited by 8
Gharbo, R. S. (2020) · Physical Medicine and Rehabilitation Clinics of North America · doi:10.1016/j.pmr.2020.07.003 · Cited by 9
Kang, S. H., Kim, S., Park, E., & Jang, S. (2021) · International Journal for Equity in Health · doi:10.1186/s12939-021-01531-1 · Cited by 8
Split-Second Unlearning: Developing a Theory of Psychophysiological Dis-ease
Hudson, M., & Johnson, M. I. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.716535 · Cited by 10
Salamanca‐Balen, N., Qiu, M., & Merluzzi, T. V. (2021) · Psychology and Health · doi:10.1080/08870446.2021.2020273 · Cited by 8
Corbett, B. F., Urban, K. R., Luz, S., Yan, J. H., Arner, J., & Bhatnagar, S. (2022) · Biology of Sex Differences · doi:10.1186/s13293-022-00460-0 · Cited by 8
“Habituation to stress is considered adaptive, because it allows humans and animals to filter out irrelevant stimuli and focus selectively on important stimuli [8].”
BackgroundEmerson, A., & Costley, D. (2023) · Education Sciences · doi:10.3390/educsci13060575 · Cited by 11
Huppert, J. D., Fradkin, I., & Cahill, S. P. (2020) · Oxford University Press eBooks · doi:10.1093/oso/9780190881511.003.0010 · Cited by 8
Scarola, S. J., & Bardi, M. (2020) · Developmental Psychobiology · doi:10.1002/dev.22007 · Cited by 8
Dopamine, uncertainty, and fear generalization
Zweifel, L. S. (2019) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2019.01.003 · Cited by 8
Allostasis, interoception, and the free energy principle: feeling our way forward.
Corcoran, A. W., & Hohwy, J. (2017) · doi:10.31234/osf.io/zbqnx · Cited by 12
Graham, K., Stuart, G. P., & McAdie, T. M. (2023) · Journal of College Student Retention Research Theory & Practice · doi:10.1177/15210251231196523 · Cited by 8
“Uncertainty stress, de fi ned as expended energy exerted in order to avoid anticipated and unpleasant surprises (Peters et al., 2017), is associated with intolerance of uncertainty (Demirtas & Yildiz, 2019), and positively correlated with traditional undergraduate students ’ mental disorders (Wu et…”
Metadata
- Authors
- Peters, A., McEwen, B. S., & Friston, K.
- Affiliations
- University of Lübeck (DE)
- Rockefeller University (US)
- Wellcome Centre for Human Neuroimaging (GB)
- Corresponding author
- Peters, Achim
- Venue
- Progress in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 156
- Pages
- 164-188
- ISSN
- 0301-0082 (ISSN-L)
- OpenAlex
- W2618517468
- Cited by
- 652
- References
- 216
- Citations by year
- 2026: 53 · 2025: 65 · 2024: 82 · 2023: 90 · 2022: 97 · 2021: 103 · 2020: 74 · 2019: 48 · 2018: 32 · 2017: 8
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Progress in Neurobiology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Embodied and Extended Cognition
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- uncertainty, stress, free energy principle, information theory, entropy (information theory), surprise, brain energy metabolism, allostasis, allostatic load
- MeSH terms
- Animals, Brain, Diabetes Mellitus, Humans, Memory Disorders, Stress, Psychological, Uncertainty, Atherosclerosis
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