Uncertainty and stress: Why it causes diseases and how it is mastered by the brain

“From a theoretical perspective, the difference between attainable states and goal states can be formalized by the so-called ‘Kullback Leibler (KL) divergence’ (Kullback and Leibler, 1951).”

“How exactly these procedures are executed is one of the most fascinating questions in neuroscience (Friston, 2010).”

“The brain’s architecture is hierarchically organized (Felleman and Van, 1991).”

“All of these long-lasting effects of persistently activated stress reactions are called ‘allostatic load’ (McEwen, 1998).”

“It has been shown that both perceptual inference and learning can be described as a minimization of free energy or the suppression of prediction errors (Friston, 2005; Rao and Ballard, 1999).”

“In the short run, increased vigilance or anxiety in a hostile environment may be adaptive; however, when the danger passes and the behavioral state and the changes in neural circuitry become chronic, which get ‘stuck’, such maladaptation may require an external intervention to get it ‘unstuck’, as is the case for chro…”

“It has been shown that both perceptual inference and learning can be described as a minimization of free energy or the suppression of prediction errors (Friston, 2005; Rao and Ballard, 1999).”

“In this mode, LC projections to cortical areas lead to enhancement of only the few parts of the cortex involved in a specific task (Aston-Jones and Cohen, 2005; Berridge and Waterhouse, 2003).”

“, 1983) – particularly at branching sites of the blood vessel system (Malek et al., 1999).”

“Painful stimuli received by the CNS produce nociception (136).”

“Pathological anxiety is considered to result in part from a persistent prior belief about one ’ s own inability to manage error (Peters et al., 2017; Stephan et al., 2016).”

“Discussion: Towards a Translational Understanding of Psychosis A translational, that is to say, multi-conceptual, understanding of schizophrenia arises on the basis of the above, and this translational view can be integrated into the generally accepted vulnerability–stress model of psychiatry, which postulates that ac…”

“…creates confident behavior and motivates action, whereas decreasing precision subverts action through uncertainty (Friston et al., 2012; Clark, 2013a; Hohwy, 2013; Seth and Friston, 2016; Badcock et al., 2017; Parr and Friston, 2017; Peters et al., 2017; Clark et al., 2018; Palmer et al., 2019).”

“Disruption of HPA axis function has been associated with a variety of human diseases and disorders (Denhardt, 2018; Juster et al., 2016; Korte et al., 2005; Lupien et al., 2009; McEwen, 2000; McEwen, 2017; Peters et al., 2017; Shonkoff et al., 2009; Stavrou et al., 2017).”

“Finally, related to anxiety disorder symptoms and pathophysiology, stress has been conceptualized as amygdala-medi-atedincreasedallostaticloadresultingfromuncertaintyand(anticipated)lossofcontrolresultingfrominappropriateaction selection [125].”

“The findings of this study are consistent with the ‘selfish’ brain theory, which proposes that acute stress may serve an adaptive function when individuals are faced with uncertainty (Peters et al., 2017).”

“High-frequency brain waves produce a constricted feeling and increase time perception (Fredrickson and Joiner 2002; Yamada and Kawabe 2011; Peters et al. 2017) even for unconscious stimuli (Oei et al. 2012).”

“Stress arises when the brain is uncertain about the answer to that question (Peters et al., 2017).”

“Theoretical instantiations of the free energy principle such as predictive processing and active inference are increasingly utilized for understanding a range of psychiatric disorders, including Post Traumatic Stress Disorder (Linson and Friston, 2019), stress (Peters et al., 2017), eating disorders (Barca and Pezzulo…”

“This extended activation alters brain growth and architecture in regions, such as the PFC, amygdala, and hippocampus, which undermines stress regulation and coping (Peters et al., 2017).”

“If we focus our lens on the ACC, we appreciate the importance of the active inference and strategic prediction that takes place there as it engages in decisionmaking leading to the formation of a pre-motor template [116] (See Fig.”

“These issues have been discussed elsewhere from an active inference perspective (Ainley et al., 2016; Corcoran et al., 2020; Duquette, 2017; Fotopoulou and Tsakiris, 2017; Peters et al., 2017).”

“This is particularly true where stressed individuals lack control over the problem and make predictions based on their perceptions of the threat (Peters et al., 2017; Slovic et al., 1980).”

“In terms of linking linguistic and cognitive perspectives (Feldman & Friston, 2010; Hirsh et al., 2012; Hsu et al., 2005; Peters et al., 2017; T. Wu et al., 2020; Yu & Dayan, 2005), going forward, we need to develop a greater understanding of how cumulative exposure to longer term environmental…”

“In the light of FEP, then, circulating GC concentrations can probably be understood as the outputs of active state of the brain’s Markov blanket, reflecting directly whether the world is unfolding according to the brain’s expectations [12] (Figure 1A).”

“, positive school climate), students could rely on their personal resources to cope with events they may perceive as challenging or threatening (Peters and McEwen, 2015; Peters et al., 2017; Alsukah et al., 2020).”

“Peters et al. (2017) offer a related analysis of stress and allostatic load, with a special focus on how the representation of uncertainty (at a sub-personal, neuroendocrine level, in terms of precision), can be understood as slow fluctuations in setpoints as representations of uncertainty or…”

“Greco and Roger (2003) review evidence that “uncertainty constitutes a powerful stressor” (p. 1057), and Peters et al. (2017) call uncertainty the “essence of stress” (p. 164).”

“Thus, consolidation of the internal model of the world is promoted at optimal (low normal) glucocorticoid concentrations, which indicate the absence of uncertainty or stress; in contrast, the reformation of the internal model of the world is promoted at excess glucocorticoid concentrations, which favor LTD (Peters et…”

“Prior research has established that across species, the default response to uncertainty is anxiety and stress (Brosschot et al., 2016; Freeston and Komes, 2023; Hirsh et al., 2012; Peters et al., 2017), even in the absence of potentially threatening outcomes (Morriss et al., 2022).”

“Although it is largely acknowledged that brain networks orchestrate the 74 overall stress response and adaptability (Hermans et al., 2014), it remains unclear what cir-75 cuit guides it (Peters et al., 2017).”

“The hierarchical Bayesian control systems perspective on living organisms allows for a clear definition of ‘stress’ (Peters et al., 2017).”

“…of precision; ranging from autism through to schizophrenia; from tremor through to Parkinson's disease; from obsessive ‐ compulsive disorder through to post ‐ traumatic stress disorder; from depression through to chronic stress; from fatigue through to functional medical symptoms (65, 97, 119–130).”

“In parallel, the increase in free energy would increase the generative model’s uncertainty signaling allostatic overload (Peters et al., 2017).”

“Our framework is inspired by Karl Friston’s Free Energy Principle (67, 68) and its application to stress (69).”

“Since its application to brain function [51, 52, 53, 31], the variational Free Energy Principle (FEP) has been extended into an explanatory framework for living systems at all scales [32, 54, 55, 56, 57], along with an extensive scope of related clinical studies (e.g. [58, 59, 191, 60]).”

“For instance, false proprioceptive inference has been implicated in motor movement disorders (Edwards et al., 2012), whereas false exteroceptive inference, in psychosis (Adams et al., 2013; Powers et al., 2017).”

“Indeed, ground-breaking research in the nematode Caenorhabditis elegans has identified stress-related noncoding RNAs as an epigenetic mechanism capable of moving adaptive brain changes to the germline (Posner et al., 2016).”

“Stress-induced glucocorticoid signaling overlaps with the mesocorticolimbic dopaminergic pathway to bias decision-making of goal-directed behaviors in both humans and animals (Gourley et al., 2012; Peters et al., 2017; Soares et al., 2013).”

“Since one of the characteristics of major incidents is a high level of uncertainty, 2 3 and the essence of stress has been suggested to consist of uncertainty, 25 this finding is not surprising.”

“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.”

“Second, within the scope of the transactional theory of stress, affective forms of coping have traditionally been considered effective in terms of avoiding losses (e.g., reducing allostatic load by redirecting attention away from the stressor; Peters et al., 2017), but not in terms of achieving gains (Lazarus & Folkma…”

“The theoretical motivation for the current study borrows from enactive and embodied treatments that can be seen in the light of interoceptive inference [32, 33, 34, 35, 36].”

“Notably, emerging research suggests that, in the context of biological outcomes, physical and non-physical influences cannot be disentangled [16].”

“This is an example of a functional diaschisis (Carrera and Tononi 2014; Fornito et al. 2015; Price et al. 2001), in which altering one part of a network has implications for all other parts.”

“In the early implementation stage, a higher IU was associated with a context- and valence-independent decrease of neural activity within l-ACC, an area assumed to subtend the behavioral and cognitive avoidance of exposure to uncertainty [6], and the continuous assessment of environmental uncertainty levels [68].”

“Uncertainty over access to food and water activate allostasis, redirecting internal energy allotments to food- and water-seeking activity (see Peters et al. 2017).”

“This is combined with a body of neurobiological literature on the neuronal substrate of the brain’s stress and prediction networks [49].”

“As energy is required to change information that is already neurologically encoded [51], less energy may be required for people to make reference to their existing internal world models than is required for reasoning about new information.”

“developing such disorders (Peters et al., 2017), and it can also make us less capable of coping with risky decision-making (Soares et al.”

“During stress, our body tries to regain its homeostasis and stability, which have become disrupted [3].”

“…Quadt et al., 2018; R. Smith et al., 2020), including depression (Arnaldo et al., 2022; Badcock et al., 2017; Barrett et al., 2016; Seth & Friston, 2016; Stephan et al., 2016) and anxiety-related disorders (J. E. Clark et al., 2018; Gerrans & Murray, 2020; Linson et al., 2020; Peters et al., 2017).”

“To reduce perceived uncertainty and stress, obtaining information plays an important role (Peters et al., 2017).”

“Uncertainty stress management should be emphasized, including attention, learning and habituation of uncertainty stress cognition; it is critical to maintain hope, and resolve information problems (Peters et al., 2017).”

“In addition, co-occurring factors, such as stigma, access to education and living in the context of structural poverty and a fragile health system have an impact on the mental health of PLWH [8].”

“These neuroenergetic alterations promote visceral fat accumulation (the wide-waisted phenotype), subcutaneous fat loss, and atherogenesis with subsequent cardiovascular events [28,31].”

“There is evidence that social isolation and disconnection can induce major health problems (Peters et al., 2017).”

“…stress can reduce the capacity for deliberative decision making and increase the reliance on rules in a variety of contexts (Porcelli & Delgado, 2009; Schwabe et al., 2012; Starcke & Brand, 2012; see also, Janis & Mann, 1977; Kassam et al., 2009; Peters et al., 2017; Porcelli & Delgado, 2017).”

“This cooperation introduced two new relationships to the theory: first, how cerebral information processing – in which information-theoretic free energy is minimised – relates to brain energy metabolism – in which thermodynamic free energy is optimised (Peters et al., 2017); and second, how”

“Meanwhile, the conceptual reducibility of active inference to the need to minimise uncertainty or stress readily lends itself to clinical applications [185].”