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.
“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]
Section 1.2 describes neural pathways linking uncertainty to stress responses, and section 1.3 links unresolved uncertainty to depressed mood and increased depression risk. The cited passages do not specifically establish anxiety as the negative mental state elicited by these stressors, so that emphasized part of the claim is not supported by this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSustained vigilance represents the initial adaptive response under conditions of uncertainty, but it can develop into hypervigilance.
“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]
Section 3.1 says that arousal, including increased vigilance, is the first response to a stressful challenge and that uncertainty prompts a switch from normal vigilance to hypervigilance. It does not describe sustained vigilance as the initial adaptive response; it describes the switch to hypervigilance as immediate. Section 4.1 discusses hypervigilance being sustained when uncertainty remains unresolved. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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- 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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