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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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“Being able to correctly interpret what will happen next (i.e., decrease the levels of uncertainty; Peters et al., 2017) by placing a longer attentional focus on the teacher compared to what happens around her can help the child feel less distressed by a potentially threatening situa-Table tion…”
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“When individuals feel threatened by physical changes, they may find themselves facing a lot of uncertainty, which can lead to stress [14].”
Moreno, A., & Coughlan, A. U. (2025) · Revista Mexicana de Opinión Pública · doi:10.22201/fcpys.24484911e.2025.38.90089 · Cited by 1
Dolberg, P., Lev, S., & Kagan, M. (2025) · Family Relations · doi:10.1111/fare.70025 · Cited by 1
Kim, D.-W., Lee, J., Lee, I.-H., & Lee, K.-J. (2025) · Annals of Occupational and Environmental Medicine · doi:10.35371/aoem.2025.37.e33 · Cited by 1
“18 In the 6th Work Environment Survey, psychological health issues were investigated in terms of depression, anxiety, and fatigue.”
InfluentialWhy is income volatility associated with poor health? Longitudinal evidence from the UK and France
Nettle, D., Chevallier, C., Pickett, K. E., Johnson, M., Johnson, E., & Melissa Bateson, B. (2025) · SSM - Population Health · doi:10.1016/j.ssmph.2025.101869 · Cited by 1
“Uncertainty generates psychological stress (Berker et al., 2016; Peters et al., 2017), which is closely linked to poor mental and physical health.”
Jolly, D., Puckett, J. A., SturtzSreetharan, C., Armstrong, S. E., Hope, D. A., Mocarski, R. A., Juster, R., & DuBois, L. Z. (2025) · American Journal of Biological Anthropology · doi:10.1002/ajpa.70183 · Cited by 1
“Others have found uncertainty affects health (Greco and Roger 2003; Peters et al. 2017).”
Su, H., Liu, D., Zhang, L., Zhou, Y., Wang, H., & Li, Q. (2026) · Psychology Health & Medicine · doi:10.1080/13548506.2025.2591010 · Cited by 1
Minelli, A. (2026) · Brain Behavior and Immunity Integrative · doi:10.1016/j.bbii.2026.100158 · Cited by 1
Causal thinking in physiology: A search for vertically organizing principles
Frasch, M. G. (2026) · The Journal of Physiology · doi:10.1113/jp290762 · Cited by 3
“The principles of prediction, inference, and action apply equally to a cell maintaining metabolic homeostasis and an organism navigating a complex environment.”
Pan, Y., Liu, Y., Tang, R., Chang, M., Li, Y., & You, X. (2026) · International Journal of Industrial Ergonomics · doi:10.1016/j.ergon.2026.104010 · Cited by 1
Chasen, M. R., Bhargava, R., & Goldberg, G. (2018) · Elsevier eBooks · doi:10.1016/b978-0-323-54829-8.00015-9 · Cited by 1
YUNCU, E. N., Yurcu, G., & Akıncı, Z. (2020) · Journal of Recreation and Tourism Research · doi:10.31771/jrtr.2020.59 · Cited by 1
“Stress can arise from the threatening and challenging conditions of the external environment, as well as the way an individual views the environment and interprets the information coming from the external environment (Ramasubramanian, 2017, p.309; Peters et al., 2017, p.165).”
BackgroundSurprise Acts as a Reducer of Outcome Value in Human Reinforcement Learning
Sumiya, M., & Katahira, K. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00852 · Cited by 1
“Some researchers using this theory have proposed that surprise affects the reward value of a decision outcome (Peters et al., 2017; Van de Cruys, 2017; Friston, 2018).”
BackgroundExposure to Negative Life Events and Parental Subjective Evaluations of Stress: A Meta-Analysis
Gauthier-Légaré, A., Tarabulsy, G. M., Ouellet, G., Gagné, L.-M., & Langlois, É. (2022) · Journal of Child and Family Studies · doi:10.1007/s10826-022-02299-w · Cited by 1
“Greater levels of stress are considered to be at the heart of numerous problems in adjustment if they are frequent or chronic (Fink, 2009; Peters et al., 2017) and during parenthood, stress is an important correlate and precursor of different aspects of parenting behaviors and, subsequently, child…”
BackgroundDevakumar, D., & Issa, R. (2022) · The Lancet · doi:10.1016/s0140-6736(22)00827-3 · Cited by 1
Productive teaming under uncertainty: when a human and a machine classify objects together
Rother, A., Notni, G., Hasse, A., Noack, B., Beyer, C., Reißmann, J., Zhang, C., Ragni, M., Arlinghaus, J. C., & Spiliopoulou, M. (2023) · IEEE Workshop on Advanced Robotics and its Social Impacts (ARSO) · doi:10.1109/arso56563.2023.10187430 · Cited by 1
“While it is tempting to capitalize upon the findings on the correlation between uncertainty and stress [22], we must keep in mind that an industrial setting offers more sources of stress than uncertainty.”
BackgroundTomes, C. D., Canetti, E. F. D., Schram, B. L., & Orr, R. M. (2023) · Healthcare · doi:10.3390/healthcare11192677 · Cited by 1
Neuropragmatism, Neuropsychoanalysis, Therapeutic Trends, and the Care Crisis
Solymosi, T. (2023) · European Journal of Pragmatism and American Philosophy · doi:10.4000/ejpap.3590 · Cited by 2
StrEx: Towards a Modulator of Stressful Experience in Virtual Reality Games
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“Adapting video games solely based on in-game performance may not be sufficient, as players have individual goals, personalities, skills, and emotional/cognitive competencies [6].”
BackgroundEarly life stress, literacy and dyslexia: an evolutionary perspective
Kershner, J. R. (2024) · Brain Structure and Function · doi:10.1007/s00429-024-02766-8 · Cited by 2
“And third, the release of NE throughout the brain modulates the disbursement of GABA and glutamate, the brain’s primary inhibitory and excitatory neurotransmitters (Peters et al. 2017).”
BackgroundGao, Y., Fan, M., Li, Y., Zhao, S., Chen, W., Zhang, D., & Zheng, X.-F. (2024) · Psychology Research and Behavior Management · doi:10.2147/prbm.s447426 · Cited by 2
“20 Grupe and Nitschke 18 found that participants tended to link uncertain expectations with aversive outcomes.”
BackgroundDemateis, M., Llull, D. M., & Castañeiras, C. E. (2024) · Revista de Psicopatología y Psicología Clínica · doi:10.5944/rppc.37453 · Cited by 3
Cocco, R., Sechi, S., Rizzo, M., Arrigo, F., Giannetto, C., Piccione, G. G., & Arfuso, F. (2024) · Animals · doi:10.3390/ani14162354 · Cited by 1
“On the one hand, the response activated following a stressful event is positive for the organism, as it can be adaptive, leading to beneficial modification to brain regions supporting learning [6]; on the other hand, it could be maladaptive, causing welfare impairments and psychopathologies [6,7].”
BackgroundInfluentialUnethical Conduct Under Uncertainty: A Fear-Based Perspective
Pustovit, S., Hetrick, A. L., & Darden, T. R. (2025) · Journal of risk and financial management · doi:10.3390/jrfm18020103 · Cited by 2
Temporal patterns in the complexity of child-directed song lyrics reflect their functions
Labendzki, P., Goupil, L., & Wass, S. V. (2025) · Communications Psychology · doi:10.1038/s44271-025-00219-4 · Cited by 1
“These two needs (predictability and complexity), which are fundamental and antagonist, are essential to enable learners to reduce their uncertaintybycreatingmodelsoftheirenvironmentinordertomakefuture predictions 20 – 23 , but also aid effective communication and cooperation 24 – 27 .”
Putting Everything Together: Integrated Models and Pathological Aspects of Symptom Perception
Köteles, F. (2021) · Springer eBooks · doi:10.1007/978-3-030-63201-4_7 · Cited by 1
Chien, J., Hung, I., Goh, J. O. S., Kuo, L., & Chang, W. (2022) · Human Brain Mapping · doi:10.1002/hbm.25963
“Indeed, uncertainty or risk is thought to be an aversive mental state in the brain (Peters et al., 2017) and social uncertainty particularly so (FeldmanHall & Shenhav, 2019; Merkin, 2006).”
BackgroundSela, S., Miehl, C., Huygelier, H., Oren‐Suissa, M., Gjorgjieva, J., & Gillebert, C. R. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15797 · Cited by 1
“This disruption of the continuity of the mentee ’ s work has made it hard to plan and execute research projects, negatively affecting motivation and increasing stress (Peters et al., 2017).”
Background
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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