Cognition from the Body-Brain Partnership: Exaptation of Memory.

Examination of cognition has historically been approached from language and introspection. However, human language-dependent definitions ignore the evolutionary roots of brain mechanisms and constrain their study in experimental animals. We promote an alternative view, namely that cognition, including memory, can be explained by exaptation and expansion of the circuits and algorithms serving bodily functions. Regulation and protection of metabolic and energetic processes require time-evolving brain computations enabling the organism to prepare for altered future states. Exaptation of such circuits was likely exploited for exploration of the organism's niche. We illustrate that exploration gives rise to a cognitive map, and in turn, environment-disengaged computation allows for mental travel into the past (memory) and the future (planning). Such brain-body interactions not only occur during waking but also persist during sleep. These exaptation steps are illustrated by the dual, endocrine-homeostatic and memory, contributions of the hippocampal system, particularly during hippocampal sharp-wave ripples.

Allostatic load in children: The cost of empathic concern.

Early-life adversity affects long-term health outcomes but there is considerable interindividual variability in susceptibility to environmental influences. We proposed that positive psychological characteristics that reflect engagement with context, such as being concerned about people or performance on tasks (i.e., empathic concern), could moderate the interindividual variation in sensitivity to the quality of the early environment. We studied 526 children of various Asian nationalities in Singapore (46.6% female, 13.4% below the poverty line) with longitudinal data on perinatal and childhood experiences, maternal report on empathic concern of the child, and a comprehensive set of physiological measures reflecting pediatric allostatic load assessed at 6 y of age. The perinatal and childhood experiences included adversities and positive experiences. We found that cumulative adverse childhood experience was positively associated with allostatic load of children at 6 y of age at higher levels of empathic concern but not significantly associated at lower levels of empathic concern. This finding reveals evidence for the importance of empathic concern as a psychological characteristic that moderates the developmental impact of environmental influences, serving as a source for vulnerability to adversities in children.

Distinctive Roles of Medial Prefrontal Cortex Subregions in Strategic Conformity to Social Hierarchy.

People often align their behaviors and decisions with others' expectations, especially those of higher social positions, when they are being observed. However, little attention has been paid to the neural mechanisms underlying increased conformity to the social hierarchy under social observation. Using a preference rating task, we investigated whether and how individual preferences for novel stimuli were influenced by others' preferences by manipulating others' social hierarchy and observational context. The behavioral results showed that human participants of both sexes were more likely to change their preferences to match those of a superior partner in a public than in a private context. fMRI data revealed distinct contributions of the subregions of the medial prefrontal cortex (mPFC) to increased conformity to social hierarchy under observation. Specifically, the ventral mPFC showed increased activity when participants' preferences aligned with those of superior partners, regardless of behavioral manifestation. The rostral mPFC showed increased activity when conforming to a superior partner and nonconforming to an inferior one, indicating goal-dependent valuation. The dorsal mPFC showed increased activity in private conditions with a superior partner but only in those with a higher tendency to conform. These findings support the hierarchical allostatic regulation model of the mPFC function for social valuation and suggest strategic conformity as a way to minimize metabolic costs.SIGNIFICANCE STATEMENT This study revealed distinct roles of subregions of the mPFC in increased conformity to individuals of different social ranks under observation. Specifically, the ventral mPFC showed increased activity when participants' preferences aligned with those of higher-ranking partners, whereas the rostral mPFC showed increased activity when conforming to a superior partner and nonconforming to an inferior partner, indicating goal-dependent valuation. The dorsal mPFC was more active in private conditions with a superior partner but only in those with a higher tendency to conform. These findings support the hierarchical allostatic regulation model of the mPFC function for social valuation and suggest strategic conformity as a way to minimize metabolic costs.

Defining the brain control of physiological stability.

The last few decades have seen major advances in neurobiology and uncovered novel genetic and cellular substrates involved in the control of physiological set points. In this Review, I discuss the limitations in the definition of homeostatic set points established by Walter B Canon and highlight evidence that two other physiological systems, namely rheostasis and allostasis provide distinct inputs to independently modify set-point levels. Using data collected over the past decade, the hypothalamic and genetic basis of regulated changes in set-point values by rheostatic mechanisms are described. Then, the role of higher-order brain regions, such as hippocampal circuits, for experience-dependent, allostatic induced changes in set-points are outlined. I propose that these systems provide a hierarchical organization of physiological stability that exists to maintain set-point values. The hierarchical organization of physiology has direct implications for basic and medical research, and clinical practice.

Glucocorticoid effects on the brain: from adaptive developmental plasticity to allostatic overload.

Exposure to stress during early life may alter the developmental trajectory of an animal by a mechanism known as adaptive plasticity. For example, to enhance reproductive success in an adverse environment, it is known that animals accelerate their growth during development. However, these short-term fitness benefits are often associated with reduced longevity, a phenomenon known as the growth rate-lifespan trade-off. In humans, early life stress exposure compromises health later in life and increases disease susceptibility. Glucocorticoids (GCs) are major stress hormones implicated in these processes. This Review discusses the evidence for GC-mediated adaptive plasticity in development, leading to allostatic overload in later life. We focus on GC-induced effects on brain structure and function, including neurogenesis; highlight the need for longitudinal studies; and discuss approaches to identify molecular mechanisms mediating GC-induced alteration of the brain developmental trajectory leading to adult dysfunctions. Further understanding of how stress and GC exposure can alter developmental trajectories at the molecular and cellular level is of critical importance to reduce the burden of mental and physical ill health across the life course.

Allostatic load and cognitive recall among young adults: Racial, ethnic, and sex-specific variations.

INTRODUCTION: While factors such as age and education have been associated with persistent differences in functional cognitive decline, they do not fully explain observed variations particularly those between different racial/ethnic and sex groups. The aim of this study was to explore the association between allostatic load (AL) and cognition in a racially diverse cohort of young adults. METHODS: Utilizing Wave V of the National Longitudinal Study of Adolescent to Adult Health - a nationally representative, longitudinal survey of adults aged 34-44, this study utilized primary data from 10 immune, cardiovascular, and metabolic biomarkers to derive an AL Index. Cognition was previously recorded through word and number recall scores. Regression analysis evaluated the association between cognitive recall, AL, age, sex, and race/ethnicity. RESULTS: Regression results indicated statistically higher AL scores among Blacks (IRR = 1.09, CI = 1.01, 1.19) compared to Whites and lower AL score among females compared to males (IRR = 0.76, CI = 0.72, 0.81). At zero AL, Blacks (IRR = 1.2399, CI = 1.2398, 1.24) and Other races (IRR = 1.4523, CI = 1.452, 1.4525) had higher recall while Hispanics (IRR = 0.808, CI = 0.8079, 0.8081) had lower recall compared to Whites. Relative to males, females had higher number recall (IRR = 1.1976, CI = 1.1976, 1.1977). However, at higher, positive levels of AL, Blacks (IRR = 0.9554, CI = 0.9553, 0.9554), Other races (IRR = 0.9479, CI = 0.9479, 0.9479) and females (IRR = 0.9655, CI = 0.9655, 0.9655) had significantly lower number recall than Whites and males respectively. CONCLUSIONS: Race and sex differences were observed in recall at different levels of AL. Findings demonstrate the need for further exploration of cognition in young adults across diverse populations that includes examination of AL.

Migraine chronification as an allostatic disorder: a proof-of-concept study.

OBJECTIVE: The underpinning biologics of migraine chronification are not well understood. We aim to investigate the role of the cumulative burden of stress, namely the allostatic load, in migraine chronification. METHODS: This was a cross-sectional study. The allostatic load was measured with a composite multi-system score (BALI: Bologna Allostatic Load Index), evaluating 20 biomarkers representing four physiological systems: immune, metabolic, cardiovascular, and neuroendocrinological systems. BALI score was subdivided into high score and low score based on the distribution in controls. Migraine patients were included and subclassified into low-frequency episodic migraine group (low-EM group), high-frequency episodic migraine group (high-EM group), and chronic migraine group (CM group). RESULTS: The distribution of BALI high-score increased in parallel with headache attacks monthly frequency: 16% in low-EM group (n = 10), 24% in high-EM group (n = 12), and 40% in CM group (n = 21) (p = 0.017). In a multivariable analysis, the odds ratio of having a high-score BALI in CM patients (vs. low-EM patients) was 2.78 (95% CI 1.07-7.22; p = 0.036). Individual BALI biomarkers values which were significantly different among migraine subgroups included systolic blood pressure (p = 0.018), diastolic blood pressure (p < 0.001), and heart rate (p = 0.019). CONCLUSION: Our study substantiates this emerging concept of migraine chronification as an allostatic disorder.

Stress Response Pattern of Heart Rate Variability in Patients with Functional Somatic Syndromes.

Functional somatic syndromes (FSSs) represent a clinically important group of disorders that are often stress-related. Their autonomic pathophysiology, including reduced heart rate variability (HRV), has been reported. However, the response pattern to mental stress and recovery in FSSs remains unclear. Thus, we aimed to clarify the pattern of autonomic stress response and recovery to mental arithmetic stress in patients with FSS compared to that in healthy controls. This cross-sectional study included 79 patients with FSS who visited the Department of Psychosomatic Medicine at a university hospital in Japan and 39 healthy controls. Following a mood questionnaire and obtaining epidemiologic information, HRV was measured during three periods (5 min each): relaxation baseline resting, stress (mental arithmetic task), and post-stress recovery period. The HRV analysis included inter-beat interval, low frequency power, and high frequency power. Compared to healthy controls, patients with FSS exhibited significantly higher scores on the mood questionnaire, prolonged duration of illness, and decreased functionality in daily activities. While the healthy control group showed a pronounced stress response pattern with a significant decrease in vagal HRV and recovery, the FSS group showed a "flat" vagal stress response pattern, and the HRV in the FSS group was lower at relaxation baseline, remained low during the stress, and did not change post stress. Patients with severe FSS exhibit an altered stress response pattern. Our results could provide significant clues for the diagnosis and treatment of such patients, as well as useful insights into the relationship between stress and illness.

Dyadic contagion in cognitive function: A nationally-representative longitudinal study of older U.S. couples.

Later-life cognitive function is strongly influenced by one's environment. At this life stage, a partner's behaviors and attributes-including their own cognitive status-are a key environmental determinant. A recent "social allostasis" theory also yields specific predictions on patterns of mutual influence-or "contagion"-in cognitive function. Yet, no population representative studies have examined these coupled dynamics. Using recently developed fixed-effects cross-lagged panel modeling (FE-CLPM) methods and ten-year data from the Health and Retirement Study-nationally-representative of U.S. adults over 50-the current study filled this gap. Results supported dyadic cognitive contagion over the long- but not short-run. Short-term associations suggested intriguing "cognitive cycling" possibilities among both men and women that need further investigation. Overall, results supported a theoretical model of coupled "cognitive careers," and relational inducement of allostatic load. Especially among men, recurrent impulses also cumulatively induced substantial path-dependent cognitive improvements, supporting the added value of repeated over one-time interventions. Theoretical and substantive implications are discussed.

Evidence-based approach to mitigate cumulative stress in pediatric nurses through the development of respite rooms.

BACKGROUND: The cumulative stress toll on nurses increased during the COVID-19 pandemic. An evidence-based practice (EBP) project was conducted to understand what is known about the impacts of cumulative stress within nursing and if there are ways to mitigate stress during a nurse's shift. AIM/IMPLEMENTATION: A project team from three clinical units completed an extensive literature review and identified the need to promote detachment while supporting parasympathetic recovery. Based on this review, leaders from three pediatric clinical units (neonatal intensive care unit, cardiovascular intensive care unit, and acute pulmonary floor) implemented respite rooms. OUTCOMES: Follow-up outcomes showed a statistically significant stress reduction. For all shifts combined, the Wilcoxon Signed-Rank Test revealed that perceived stress scores from an 11-point Likert scale (0 = no stress and 10 = maximum perceived stress) were significantly lower in the post-respite room (Md = 3, n = 68) compared to in the pre-respite room (Md = 6, n = 68), Z = -7.059, p < .001, with a large effect size, r = .605. Nurses and other staff frequently utilized respite rooms during shifts. IMPLICATIONS FOR PRACTICE: Clinical inquiry and evidence-based practice processes can mitigate cumulative stress and support staff wellbeing. Respite rooms within the hospital can promote a healthy work environment among nurses and promote a self-care culture change. Evidence-based strategies to mitigate cumulative stress using respite rooms are a best practice to promote nurse wellbeing and mitigate cumulative stress.

Brain Network Allostasis after Chronic Alcohol Drinking Is Characterized by Functional Dedifferentiation and Narrowing.

Alcohol use disorder (AUD) causes complex alterations in the brain that are poorly understood. The heterogeneity of drinking patterns and the high incidence of comorbid factors compromise mechanistic investigations in AUD patients. Here we used male Marchigian Sardinian alcohol-preferring (msP) rats, a well established animal model of chronic alcohol drinking, and a combination of longitudinal resting-state fMRI and manganese-enhanced MRI to provide objective measurements of brain connectivity and activity, respectively. We found that 1 month of chronic alcohol drinking changed the correlation between resting-state networks. The change was not homogeneous, resulting in the reorganization of pairwise interactions and a shift in the equilibrium of functional connections. We identified two fundamentally different forms of network reorganization. First is functional dedifferentiation, which is defined as a regional increase in neuronal activity and overall correlation, with a concomitant decrease in preferential connectivity between specific networks. Through this mechanism, occipital cortical areas lost their specific interaction with sensory-insular cortex, striatal, and sensorimotor networks. Second is functional narrowing, which is defined as an increase in neuronal activity and preferential connectivity between specific brain networks. Functional narrowing strengthened the interaction between striatal and prefrontocortical networks, involving the anterior insular, cingulate, orbitofrontal, prelimbic, and infralimbic cortices. Importantly, these two types of alterations persisted after alcohol discontinuation, suggesting that dedifferentiation and functional narrowing rendered persistent network states. Our results support the idea that chronic alcohol drinking, albeit at moderate intoxicating levels, induces an allostatic change in the brain functional connectivity that propagates into early abstinence.SIGNIFICANCE STATEMENT Excessive consumption of alcohol is positioned among the top five risk factors for disease and disability. Despite this priority, the transformations that the nervous system undergoes from an alcohol-naive state to a pathologic alcohol drinking are not well understood. In our study, we use an animal model with proven translational validity to study this transformation longitudinally. The results show that shortly after chronic alcohol consumption there is an increase in redundant activity shared by brain structures, and the specific communication shrinks to a set of pathways. This functional dedifferentiation and narrowing are not reversed immediately after alcohol withdrawal but persist during early abstinence. We causally link chronic alcohol drinking with an early and abstinence-persistent retuning of the functional equilibrium of the brain.

The impact of sociality and affective valence on brain activation: A meta-analysis.

Thirty years of neuroimaging reveal the set of brain regions consistently associated with pleasant and unpleasant affect in humans-or the neural reference space for valence. Yet some of humans' most potent affective states occur in the context of other humans. Prior work has yet to differentiate how the neural reference space for valence varies as a product of the sociality of affective stimuli. To address this question, we meta-analyzed across 614 social and non-social affective neuroimaging contrasts, summarizing the brain regions that are consistently activated for social and non-social affective information. We demonstrate that across the literature, social and non-social affective stimuli yield overlapping activations within regions associated with visceromotor control, including the amygdala, hypothalamus, anterior cingulate cortex and insula. However, we find that social processing differs from non-social affective processing in that it involves additional cortical activations in the medial prefrontal and posterior cingulum that have been associated with mentalizing and prediction. A Bayesian classifier was able to differentiate unpleasant from pleasant affect, but not social from non-social affective states. Moreover, it was not able to classify unpleasantness from pleasantness at the highest levels of sociality. These findings suggest that highly social scenarios may be equally salient to humans, regardless of their valence.

Resilience to Maltreatment in Early Adulthood Does Not Predict Low Allostatic Load at Midlife.

BACKGROUND: Although childhood maltreatment is associated with a host of poor health and social outcomes in adulthood, many individuals manifest resilience. PURPOSE: We tested competing predictions about whether achieving positive psychosocial outcomes in young adulthood would be differentially predictive of allostatic load at midlife for those with and without a childhood history of maltreatment. METHODS: The sample included 808 individuals, 57% of whom had court-documented records of childhood abuse or neglect between 1967 and 1971, and demographically matched controls without those histories. Participants provided information on socioeconomic, mental health, and behavioral outcomes in interviews conducted between 1989 and 1995 (mean age = 29.2 years). Indicators of allostatic load were measured between 2003 and 2005 (mean age = 41.2 years). RESULTS: The relationship between positive life outcomes in young adulthood and allostatic load in middle adulthood varied depending on childhood maltreatment status (b = .16, 95% CI: .03; .28); for adults who did not experience childhood maltreatment, more positive life outcomes predicted lower allostatic load (b = -.12, 95% CI: -.23; -.01), whereas the relationship was not significant for adults with a childhood history of maltreatment (b = .04, 95% CI: -.06; .13). There were no differences in the results predicting allostatic load for African-American and White respondents. CONCLUSIONS: Childhood maltreatment may have enduring effects on physiological functioning that are manifest in elevated allostatic load scores in middle age. Alternatively, resilience to maltreatment-as manifest in positive functioning in socioeconomic and behavioral domains-may not be sufficiently stable over adulthood to buffer individuals from the physiological consequences of stressful environments.

We tested whether young adults who were succeeding in life according to conventional standards would have lower allostatic load at midlife, which reflects wear and tear on organs and tissues, resulting from chronic stress. We also tested whether any association between positive outcomes in young adulthood and allostatic load at midlife would differ depending on whether someone had a childhood history of maltreatment. That is, does being resilient to maltreatment in young adulthood predict good health in middle age? In a sample of 808 individuals, 57% of whom had court-documented records of childhood maltreatment, we found that success in young adulthood was associated with lower allostatic load at mid-life only for those without a history of maltreatment. Individuals with a childhood history of maltreatment had elevated allostatic load at midlife regardless of their success in young adulthood. Thus, although some individuals were resilient to maltreatment in young adulthood, this did not predict low allostatic load, at mid-life. The findings suggest that (1) childhood maltreatment may have enduring physiological effects or (2) individuals with childhood histories of maltreatment may have difficulty maintaining or building on the successes they establish early in life, such that their buffering effects on health are limited.

The renin-angiotensin system in COVID-19: Why ACE2 targeting by coronaviruses produces higher mortality in elderly hypertensive patients?

This renin-angiotensin system (RAS) interpretation is focused on differences in tissue dependence on RAS and on the topological hierarchy that allows mediators to act only on downstream tissues. Dependence of tissues on RAS: Tested by expectation maximization clustering of the RNA human tissue expression (https://biogps.org/). ACE and vasoconstrictive AT1R clustered with the prorenin receptor. ACE2 and dilatory MAS1 clustered with nine RAS-related genes, highly expressed in: Liver; Cardiac_Myocytes; Skeletal_Muscle; Uterus; Kidney; Lung; Small_Intestine; Smooth_Muscle. RAS and stress accumulation: While prorenin is active after binding to its receptor, binding of soluble renin increases its enzymatic activity several times. Increased renin secretion multiplies the overall capacity for producing Ang I, leading to hypertension and increased vascular resistance. Coronavirus infection and comorbidities: Cardiorespiratory failure during infection is linked to the previously altered RAS role in lungs and myocardium. Reduced vasodilation by ACE2 lead to vasoconstriction and suboptimal tissue perfusion patterns. Also see the video abstract here https://www.youtube.com/watch?v=Jf0Iped-Mws.

Cumulative physiological stress is associated with age-related changes to peripheral T lymphocyte subsets in healthy humans.

BACKGROUND: Progressive age-associated change in frequencies and functional capacities of immune cells is known as immunosenescence. Despite data linking chronic environmental, physiological, and psychosocial stressors with accelerated aging, how stress contributes to immunosenesence is not well characterized. OBJECTIVE: To help delineate the contribution of cumulative physiological stress on immunosensence we assessed relationships between a composite measurement of cumulative physiological stress, reflecting the functioning of the hypothalamic-pituitary-adrenal axis, sympathetic nervous system, cardiovascular system, and metabolic processes, and lymphocyte changes typically affiliated with aging in a cohort of healthy volunteers ranging from 18 to 66 y. RESULTS: Physiological stress load positively correlated with subject age in the study cohort and was significantly higher in adults 50-66 y compared to adults 18-33 y and 34-49 y. Using physiological stress load, we identified a significant age-dependent association between stress load and frequencies of circulating regulatory T lymphocytes (Tregs). Frequencies were higher in younger participants, but only in participants exhibiting low physiological stress load. As stress load increased, frequencies of Tregs decreased in young participants but were unchanged with increasing stress load in middle and older age individuals. Follow-up analysis of stress load components indicated lower circulating DHEA-S and higher urinary norepinephrine as the primary contributors to the effects of total stress load on Tregs. In addition, we identified age-independent inverse associations between stress load and frequencies of naïve Tregs and naïve CD4 T cells and positive associations between stress load and frequencies of memory Tregs and memory CD4 T cells. These associations were primarily driven by stress load components waist circumference, systolic and diastolic blood pressure, CRP, and HbA1c. In summary, our study results suggest that, in younger people, physiological stress load may diminish regulatory T cell frequencies to levels seen in older persons. Furthermore, independent of age, stress load may contribute to contraction of the naïve Treg pool and accumulation of memory Treg cells. CLINICAL TRIAL: Registered on ClincialTrials.gov (Identifier: NCT02367287).

Race and ethnic variation in college students' allostatic regulation of racism-related stress.

Racism-related stress is thought to contribute to widespread race/ethnic health inequities via negative emotion and allostatic stress process up-regulation. Although prior studies document race-related stress and health correlations, due to methodological and technical limitations, they have been unable to directly test the stress-reactivity hypothesis in situ. Guided by theories of constructed emotion and allostasis, we developed a protocol using wearable sensors and daily surveys that allowed us to operationalize and time-couple self-reported racism-related experiences, negative emotions, and an independent biosignal of emotional arousal. We used data from 100 diverse young adults at a predominantly White college campus to assess racism-related stress reactivity using electrodermal activity (EDA), a biosignal of sympathetic nervous system activity. We find that racism-related experiences predict both increased negative emotion risk and heightened EDA, consistent with the proposed allostatic model of health and disease. Specific patterns varied across race/ethnic groups. For example, discrimination and rumination were associated with negative emotion for African American students, but only interpersonal discrimination predicted increased arousal via EDA. The pattern of results was more general for Latinx students, for whom interpersonal discrimination, vicarious racism exposure, and rumination significantly modulated arousal. As with Latinx students, African students were particularly responsive to vicarious racism while 1.5 generation Black students were generally not responsive to racism-related experiences. Overall, these findings provide support for allostasis-based theories of mental and physical health via a naturalistic assessment of the emotional and sympathetic nervous system responding to real-life social experiences.

Gambling Associated Risk-taking Behaviors Correlate with Emotional Regulation and the Iowa Gambling Task but not Wisconsin Card Sorting.

It is not known why some novice gamblers eventually develop Gambling Disorder while most do not. This study tested predictions from two competing models of Gambling Disorder etiology: the Pathways Model of Problem and Pathological Gambling (Blaszczynski & Nower, 2002) and the Allostatic Model of addictions (Koob & Schulkin, 2019) applied to Gambling Disorder. Participants were drawn from introductory psychology courses and screened as non-gamblers (N = 91). They completed computerized versions of the Iowa Gambling Task (IGT-2), Wisconsin Sorting Task (WCST-64), and a Difficulties with Emotional Regulation Scale (DERS). Risk-taking tendencies were observed by having participants play a typical electronic slots game for up to 15 min. Higher betting on the slots game was correlated with the frequency of Deck A selections on the IGT-2 and lower total DERS scores. There were no significant correlations involving slots betting and the WCST-64. Greater risk-taking on the slots game was correlated with more frequent wins, partial losses that were disguised as wins, bonus game features, and the largest nominal amount won on a single spin. However, there were no significant correlations between betting behaviors and the 'payback percentage', defined as total winnings as a proportion of total wagers made throughout the session. Post-game ratings were positively correlated with frequency of reinforcing outcomes. These findings suggest that novice gamblers' likelihood of further gambling participation may be elevated by high sensitivity to immediate rewards and low difficulty self-regulating negative emotions. These findings are consistent with the Allostatic Model; they are not consistent with Pathways Model.

Toward the unity of pathological and exertional fatigue: A predictive processing model.

Fatigue is a common experience in both health and disease. Yet, pathological (i.e., prolonged or chronic) and transient (i.e., exertional) fatigue symptoms are traditionally considered distinct, compounding a separation between interested research fields within the study of fatigue. Within the clinical neurosciences, nascent frameworks position pathological fatigue as a product of inference derived through hierarchical predictive processing. The metacognitive theory of dyshomeostasis (Stephan et al., 2016) states that pathological fatigue emerges from the metacognitive mechanism in which the detection of persistent mismatches between prior interoceptive predictions and ascending sensory evidence (i.e., prediction error) signals low evidence for internal generative models, which undermine an agent's feeling of mastery over the body and is thus experienced phenomenologically as fatigue. Although acute, transient subjective symptoms of exertional fatigue have also been associated with increasing interoceptive prediction error, the dynamic computations that underlie its development have not been clearly defined. Here, drawing on the metacognitive theory of dyshomeostasis, we extend this account to offer an explicit description of the development of fatigue during extended periods of (physical) exertion. Accordingly, it is proposed that a loss of certainty or confidence in control predictions in response to persistent detection of prediction error features as a common foundation for the conscious experience of both pathological and nonpathological fatigue.

Multiple stressors, allostasis and metabolic scaling in developing zebrafish.

Deoxygenation and warming affect adult fish physiology in all aquatic ecosystems, but how these stressors impact the energetics of sensitive developing stages is largely unknown. Addressing this knowledge gap, we investigated chronic and acute effects of two stressors (high temperature and hypoxia) in yolk-sac larval (48-168 hpf) zebrafish (Danio rerio) energy budgets measuring, oxygen consumption rate, growth rate (absolute and specific), % net conversion efficiency, net cost of growth and scaling relationships. Embryos and larvae were raised under four chronic treatments: (1) control (28°C and PO2 21 kPa, T28O21), (2) high temperature (31°C and PO2 21 kPa, T31O21), (3) hypoxia (28°C and PO2 11 kPa, T28TO11) and (4) high temperature and hypoxia (31°C and PO2 11 kPa, T31O11). From each chronic treatment, larvae were acutely exposed to the same combinations of stressors for 1 h in a respirometer. At hatching, larvae from chronic high temperature (T31O21 and T31O11) treatments were larger (higher dry mass and standard length) than controls (T28O21 and T28O11), but by the end of the yolk-sac stage, increased metabolic demands diverted energy away from growth, increasing net cost of growth and lowering % net conversion efficiency. Control metabolic scaling relationships were significant and differed from 0.75, but metabolic levels were lower in acute hypoxia and high temperature/hypoxia. Thus, high temperature dominated larval energetics, acting synergistically with hypoxia to increase cumulative energetic costs and making allostasis difficult compared with older stages.

The Clinical Science of Euthymia: A Conceptual Map.

Euthymia is a trans-diagnostic construct characterized by lack of mood disturbances; presence of positive affect; balance of psychological well-being dimensions, flexibility, consistency, and resistance to stress. The aim of this critical review is to draw a conceptual map of euthymia. Relationships with other constructs, continuum between euthymia and dysthymia with discomfort as an intermediate area, associations with lifestyle, clinimetric assessment, role of psychotherapeutic interventions, establishment of therapeutic targets, and neurobiological mechanisms are discussed. The model is based on the bipolar nature of well-being dimensions. Euthymia means using allostasis optimally and maintaining a healthy balance that promotes positive aspects of brain and body health through health-promoting behaviors. It may provide a framework for a renewed definition of recovery, for measuring treatment outcome and for targeting interventions, including the sequential administration of therapeutic components. Clinical assessment requires a clinimetric approach encompassing a broad range of aspects, such as allostatic load and lifestyle behaviors, all interacting with each other and contributing to the euthymia/dysthymia balance. Clinimetric indices for assessing euthymia (the Clinical Interview for Euthymia and the Euthymia Scale) and related constructs (the Clinical Interview for Dysthymia and the Semi-Structured Interview for the Diagnostic Criteria for Psychosomatic Research) are presented here. Well-Being Therapy, a psychotherapeutic strategy specifically aimed at pursuing euthymia, relies on self-observation of well-being episodes using a structured diary as a distinct therapeutic ingredient. The clinical science of euthymia may unravel innovative approaches to assessment and treatment of psychiatric and medical disorders, according to a unitary conceptual framework.