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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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“For instance, disasters in the whole society can increase an individual’s risk perception and worsen mental health (Li and Lyu 2021; Peters, McEwen, and Friston 2017; Zhang, Xin, and Li 2021).”
Tomes, C. D., Schram, B. L., Canetti, E. F. D., & Orr, R. M. (2025) · PLoS ONE · doi:10.1371/journal.pone.0317124 · Cited by 4
Instability in the environment and children’s in-school self-regulatory behaviors
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Cardiovascular Responses to Stress Utilizing Anticipatory Singing Tasks
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Anxiety-related circuitry in affective neuroscience
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“sential glucocorticoid, has many significant functions in the natural processes of the body, involved in regulating metabolism, immune response, and general homeostasis [70].”
BackgroundThe Price of Predictability: Estimating Inconsistency Premiums in Social Interactions
Gerten, J., Zürn, M., & Topolinski, S. (2021) · Personality and Social Psychology Bulletin · doi:10.1177/0146167221998533 · Cited by 4
“…is experienced as aversive (e.g., Heine et al., 2006; Proulx et al., 2012; Schubert et al., 2017; Topolinski & Strack, 2015) and increases stress and physiological arousal (e.g., de Berker et al., 2016; Herry et al., 2007; Jackson et al., 2015; Mendes et al., 2007; Peters et al., 2017).”
BackgroundTekanan Psikologis Mahasiswa Saat Pembelajaran Jarak Jauh Selama Pandemi COVID-19
Kristiyani, T. (2021) · SMART Seminar on Architecture Research and Technology · doi:10.21460/smart.v5i1.151 · Cited by 4
Spatiotemporal Signatures of Surprise Captured by Magnetoencephalography
Mousavi, Z., Kiani, M. M., & Aghajan, H. K. (2022) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2022.865453 · Cited by 4
“In the context of predictive coding, the brain tries to avoid surprise to prevent stress, which can in long-term lead to heart disease, depression, and type 2 diabetes (Peters et al., 2017).”
BackgroundCoping with COVID-19 using contact tracing mobile apps
Li, C., Li, H., & Fu, S. (2023) · Industrial Management & Data Systems · doi:10.1108/imds-05-2022-0293 · Cited by 4
Providing trauma-informed care to patients who identify as LGBTQAI
Guelbert, C. (2023) · Nursing · doi:10.1097/01.nurse.0000920440.68593.aa · Cited by 4
Mignonac, K., Boujendar, S., & Bergon, G. (2023) · Group & Organization Management · doi:10.1177/10596011231208232 · Cited by 4
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“A longer forecast period has the potential to assist in addressing this challenge and reduce stress caused by future uncertainty [39].”
BackgroundInternal Strengths for Adverse Life Events
Zhao, J., Chapman, E., & Houghton, S. J. (2024) · Behavioral Sciences · doi:10.3390/bs14080665 · Cited by 4
“Uncertainty may bring which has been found to be negatively associated with mental health [52].”
BackgroundInfants’ neural sensitivity to social interactions varies by income and infant‐directed speech
Lopera‐Perez, D. C., Nayak, S., Stangier, G., Tuladhar, C. T., John, A. M. S., Grieve, P. G., & Tarullo, A. R. (2022) · Developmental Psychobiology · doi:10.1002/dev.22265 · Cited by 3
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“…/ exit / GHQ-12 / labor market / locked-in / logistic regression / self-rated health / work environment Introduction There is evidence that lack of control and uncertainty increase stress reactions (Ganster & Rosen 2013; Peters et al. 2017) and risks for illness (Nixon et al. 2011).”
BackgroundFaghankhani, M., Sodagari, F., Shokrani, M., Baradaran, H. R., Adabi, A., Zabihi, M., Adeli, A. M., Fathimakvand, M., Golalipour, E., Aghdasi, S., et al. (2021) · The Canadian Journal of Psychiatry · doi:10.1177/07067437211004881 · Cited by 4
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“Furthermore, stress changes the sensory gain via increased alpha2 noradrenergic receptor activation [64], which could make patients perceive tinnitus louder.”
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“The data are in line with theories about habituation that explain the brain’s need to conserve energy (Peters et al., 2017).”
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“…may foster a cognitive bias toward threat perception, impair the accurate sensing of bodily states, elevate anxiety, increase allostatic load, and contribute to mental health disorders (Paulus and Stein 2006, Hakamata et al. 2010, Sterling 2014, Peters et al. 2017, Van den Bergh et al. 2017).”
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“…Mechanistically, stress re-sults in locus coeruleus activation, 150 releasing noradrenaline, which may modulate alpha-2 adrenergic receptors in the auditory cortex 150,151 and the cochlear nucleus, 151 altering the sensory gain 152 and consequently causing louder tinnitus perception under stress.”
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“…exercise … ) and the uncertain environment (e.g., pollution, climate change, economic and social pressure … ) influence dementia progression by acting as systemic stressors on the body and converging on brain functions through the regulation of neuroendocrine systems (for reviews see 7 – 11 ).”
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“[9] Social skills correlate with reduced stress experiences.”
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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