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Biomarkers for assessing population and individual health and disease related to stress and adaptation
Abstract
Biomarkers are important in stress biology in relation to assessing individual and population health. They facilitate tapping meaningfully into the complex, non-linear interactions that affect the brain and multiple systems of the body and promote adaptation or, when dysregulated, they can accelerate disease processes. This has demanded a multifactorial approach to the choice of biomarkers. This is necessary in order to adequately describe and predict how an individual embedded in a particular social and physical environment, and with a unique genotype and set of lifetime experiences, will fare in terms of health and disease risk, as well as how that individual will respond to an intervention. Yet, at the same time, single biomarkers can have a predictive or diagnostic value when combined with carefully designed longitudinal assessment of behavior and disease related to stress. Moreover, the methods of brain imaging, themselves the reflection of the complexity of brain functional architecture, have provided new ways of diagnosing, and possibly differentiating, subtypes of depressive illness and anxiety disorders that are precipitated or exacerbated by stress. Furthermore, postmortem assessment of brain biomarkers provides important clues about individual vulnerability for suicide related to depression and this may lead to predictive biomarkers to better treat individuals with suicidal depression. Once biomarkers are available, approaches to prevention and treatment should take advantage of the emerging evidence that activating brain plasticity together with targeted behavioral interventions is a promising strategy.
... In the world that we live in today, the word 'stress' is familiar and well-known far beyond the community of health researchers. As a scientifi c construct, however, the concept of stress has been introduced into academic parlance by Hans Selye (1956) in mid 20 century -originally with reference to physical stimuli only (such as physical impact, extreme temperatures etc.) and later amended by way of including the internal, psychological stressors in John Mason's (1969) works (for review also see: McEwen, 2016). ...
... Stress involves a stressor and a stress response. Th ere is no universal defi nition of stress or stressors due to the fact that stressors can be acute (of brief duration) and chronic (more prolonged or incessant in duration), and because both negative and positive events can be stressful (Cohen, Murphy, & Prather, 2018;Epel et al., 2018;McEwen, 2016;McEwen, 2019). In the most general terms, stress can be described as a strain of some kind that puts demands on the individual's resources or abilities to address the situation or condition that causes stress. ...
... Stress exposure, perceived stress severity, and their effects on health. pouris, Turner-Cobb, Barnett, & Arnold, 2020;McEwen, 2016;Segerstrom & O'Connor, 2012;Shields et al., 2023). It can therefore be said that stress is an internal response to a stressor. ...
While stress is one of the central concepts in many contemporary theories of health, there is no universal definition of stress or stressors. Stress is usually understood as a subjective experience of tension, pressure, distress, fear or negative emotions that occurs as a result of a perceived threat to one’s mental or physical well-being and is accompanied by an evolved biological response that facilitates adaptive reaction. While stress is conceptualized as a taxing condition, it is not understood as uniformly harmful per se. In fact, stress response is often cited as an adaptive reaction. Moreover, not every incident of stress exposure results in a disease or has an undermining effect on health. Mere exposure to stress does not warrant the healthy organism’s falling ill. Yet stress has been shown to affect health both directly and indirectly, having impact on multiple chronic conditions. Stressors vary in their severity and their ability to leave their mark on health, and it is therefore important to develop reliable methods of measuring stress to better understand how stress affects health and instigates pathology. One of the difficulties of measuring the effects of stress is connected to the distinction between external stressors and their internal appraisal. More recently, stress researchers began to make a distinction between stress exposure (i.e., facing an objectively measurable stressor) and perceived stress severity (i.e., a subjective experience of stress resulting from individual’s facing a stressor). The latter has been shown to have a superior predictive ability in terms of negative health outcomes (both breadth and depth of observed effects) compared to the former. Measurement-wise, subjective stress also tends to yield more precise results, which makes it preferable as a stress-assessment tool. The present article is a literature review study that delves into this distinction and attempts to shed light onto its implications for measuring stress and its effects on health.
... In the world that we live in today, the word 'stress' is familiar and well-known far beyond the community of health researchers. As a scientifi c construct, however, the concept of stress has been introduced into academic parlance by Hans Selye (1956) in mid 20 century -originally with reference to physical stimuli only (such as physical impact, extreme temperatures etc.) and later amended by way of including the internal, psychological stressors in John Mason's (1969) works (for review also see: McEwen, 2016). ...
... Stress involves a stressor and a stress response. Th ere is no universal defi nition of stress or stressors due to the fact that stressors can be acute (of brief duration) and chronic (more prolonged or incessant in duration), and because both negative and positive events can be stressful (Cohen, Murphy, & Prather, 2018;Epel et al., 2018;McEwen, 2016;McEwen, 2019). In the most general terms, stress can be described as a strain of some kind that puts demands on the individual's resources or abilities to address the situation or condition that causes stress. ...
... Stress exposure, perceived stress severity, and their effects on health. pouris, Turner-Cobb, Barnett, & Arnold, 2020;McEwen, 2016;Segerstrom & O'Connor, 2012;Shields et al., 2023). It can therefore be said that stress is an internal response to a stressor. ...
While stress is one of the central concepts in many contemporary theories of health, there is no universal definition of stress or stressors. Stress is usually understood as a subjective experience of tension, pressure, distress, fear or negative emotions that occurs as a result of a perceived threat to one’s mental or physical well-being, and is accompanied by an evolved biological response that facilitates adaptive reaction. While stress is conceptualized as a taxing condition, it is not understood as uniformly harmful per se. In fact, stress response is often cited as an adaptive reaction. Moreover, not every incident of stress exposure results in a disease or has an undermining effect on health. Mere exposure to stress does not warrant the healthy organism’s falling ill. Yet stress has been shown to affect health both directly and indirectly, having impact on multiple chronic conditions. Stressors vary in their severity and their ability to leave their mark on health, and it is therefore important to develop reliable methods of measuring stress to better understand how stress affects health and instigates pathology. One of the difficulties of measuring the effects of stress is connected to the distinction between external stressors and their internal appraisal. More recently, stress researchers began to make a distinction between stress exposure (i.e., facing an objectively measurable stressor) and perceived stress severity (i.e., a subjective experience of stress resulting from individual’s facing a stressor). The latter has been shown to have a superior predictive ability in terms of negative health outcomes (both breadth and depth of observed effects) compared to the former. Measurement-wise, subjective stress also tends to yield more precise results, which makes it preferable as a stress-assessment tool. The present article is a literature review study that delves into this distinction and attempts to shed light onto its implications for measuring stress and its effects on health.
... Measurement of AL is commonly conducted using biomarkers of multiple physiological systems affected by stress [5][6][7], including the dysregulation of cardiovascular, autonomic, metabolic, and immune systems [1,6,8,9]. AL can be characterized by a composite or domain score to reflect the severity of physiological dysregulation collectively or in specific systems [10][11][12]. ...
... The components of the AL score encompassed the cardiovascular domain (low-density lipoprotein cholesterol: fasting LDL-cholesterol, high-density lipoprotein cholesterol: HDL-cholesterol, total cholesterol: TC, fasting glucose, fasting insulin, glycated hemoglobin: HbA1c); the autonomic domain (pulse rate, systolic blood pressure: SBP, diastolic blood pressure: DBP); the metabolic domain (insulin resistance: HOMA-IR, fasting triglycerides, waist circumference), and the immune domain (C-reactive protein: CRP, white blood cell counts: WBC) ( Table S1). The selection of these biomarkers was based on previous research [10][11][12]14,21,[47][48][49][50]. A 3-level score indicator (0: normal, 1: moderate, or 2: high) was assigned to each biomarker within each domain for each participant by either a clinically or empirically meaningful cut point or reliable evidence in the literature to indicate a threshold of disease risk . ...
... The risk indicator for each biomarker was then summed in each domain to form AL domain scores and finally aggregated for each respondent to create an AL composite score (range: 0-28). A higher AL score indicates a higher extent of dysregulation [10,14]. ...
Introduction: Berries are a rich source of antioxidant polyphenols and other nutrients that are associated with good health. Allostatic load (AL) is an aggregate measure of chronic stress-induced physiological dysregulations across cardiovascular, metabolic, autonomic, and immune systems; the extent of these dysregulations, collectively or in each system, can be characterized by a composite score or a domain score assessed by integrated biomarkers. It was hypothesized that the anti-inflammatory and other effects of berries lower AL. The association was determined between berry consumption and AL composite and domain scores in the 2003–2010 National Health and Nutrition Examination Survey (NHANES). Methods: Berry intake was measured using two 24 h dietary recalls collected from US adults in the 2003–2010 NHANES (n = 7684). The association with AL and its specific domains was examined using population weight-adjusted multivariable linear regression. Results: The mean AL composite scores for consumers of any berries (11.9), strawberries (11.6), and blueberries (11.6), respectively, were significantly lower than nonconsumers (12.3), after fully adjusting for sociodemographic, lifestyle, and dietary confounders. A significant dose-response relationship was determined between greater consumption of total berries, strawberries, and blueberries and lower mean AL composite scores (p-trend < 0.05, for all). Consistently, mean cardiovascular and metabolic domain scores remained significantly lower in the consumers of total berries (mean cardiovascular domain score: 4.73 versus 4.97 for nonconsumers; mean metabolic domain score: 2.97 versus 3.1), strawberries (4.73 versus 4.95; 2.99 versus 3.1), and blueberries (4.6 versus 4.95; 2.92 versus 3.11). Berry consumers also had significantly lower mean AL immune scores (1.52 versus 1.56) and lower mean AL autonomic scores (2.49 versus 2.57) than nonconsumers (initial sample: n = 15,620). Conclusions: The current study indicates that consumption of berries lowers the AL composite scores and potentially reduces stress-related disease risks in the US adult population.
... It is when the activation of these systems is recurring or not terminated that health is undermined through inefficiently managed or overactive responses to chronic stressors. These changes are assessed and an AL score is calculated using a battery of physiological indicators including neuroendocrine, metabolic, inflammatory, neurophysiological, cardiovascular, and anthropometric factors (Juster et al., 2010;McEwen, 2015). Over the long term, systemic dysregulation may manifest as clinical conditions such as hypertension, cardiovascular disease, diabetes, or obesity (Juster et al., 2010;McEwen, 1998McEwen, , 2012McEwen, , 2015, some of which may be disproportionately high among communicators (Lilly et al., 2016;Smith et al., 2019). ...
... These changes are assessed and an AL score is calculated using a battery of physiological indicators including neuroendocrine, metabolic, inflammatory, neurophysiological, cardiovascular, and anthropometric factors (Juster et al., 2010;McEwen, 2015). Over the long term, systemic dysregulation may manifest as clinical conditions such as hypertension, cardiovascular disease, diabetes, or obesity (Juster et al., 2010;McEwen, 1998McEwen, , 2012McEwen, , 2015, some of which may be disproportionately high among communicators (Lilly et al., 2016;Smith et al., 2019). ...
... Allostatic Load (AL), consistent with previous studies, was designed to summarise physiological dysregulation across multiple bodily systems by including the core subconstructs that support the AL metaconstruct (Juster et al., 2010;McEwen, 2015). Practicable indicators were selected based on their contributions to homeostatic functioning across multiple systems as demonstrated in the AL literature. ...
Gender and work are important social determinants of health, yet studies of health inequities related to the gendered and emotional intricacies of work are rare. Occupations high in emotional labour – a known job stressor – are associated with ill-health and typically dominated by women. Little is known about the mechanisms linking health with these emotional components of work. Using physiological and questionnaire data from Canadian police communicators, we adopt an embodied approach to understanding the relationship between gender norm conformity, emotional labour, and physiological dysregulation, or allostatic load. For high conformers, emotional labour leaves gendered traces in the flesh via increased allostatic load, suggesting that in this way, gendered structures in the workplace become embodied, influencing health through conformity to gender and emotion norms. Findings also reveal that dichotomous conceptions of gender may mask the impact of gendered structures, obscuring the consequences of gender for work-related stress.
... Another important domain of stress is an emerging difficulty with tolerance to normal stress (Devylder et al., 2013;Trotman et al., 2014). This stress sensitivity likely reflects changes in biological stress systems (Dean et al., 2016;McEwen, 2015;Myin--Germeys and van Os, 2007). A separate, but related, line of research implicates sleep abnormalities in psychosis development (Clarke et al., 2021;Zanini et al., 2013). ...
... More impaired tolerance is associated with worse positive and negative symptoms of psychosis (Devylder et al., 2013;Munoz-Samons et al., 2021), global functioning declines (Munoz-Samons et al., 2021), and worsening of positive symptoms over time (Devylder et al., 2013;Ristanovic et al., 2020). As noted, impaired tolerance to stress likely reflects an index of changes in biological and psychological stress systems (McEwen, 2015;Myin-Germeys and van Os, 2007;Pruessner et al., 2011) and is mechanistically involved in pathogenesis of psychosis via alterations in the hypothalamic-pituitary-adrenal (HPA) axis Devylder et al., 2013;Trotman et al., 2014) and in the hippocampus (Dean et al., 2016). This is consistent with the diathesis-stress model which posits that a constitutional vulnerability to psychosis interacts with environmental stress to ultimately drive illness onset (Pruessner et al., 2017;Walker et al., 2008). ...
... Further, emerging research suggests sleep disturbances are prevalent during the psychosis-risk period (Clarke et al., 2021;Hennig et al., 2020;, 2015Poe et al., 2017). Subjective and self-report measures of sleep indicate that individuals at CHR for psychosis present with reduced sleep quality as indicated by lower perceived quality, greater time required to fall asleep, shorter sleep duration, lower sleep efficiency, and related greater daytime dysfunction Zanini et al., 2013). ...
Stress and sleep have been implicated in the etiology of psychosis, and literature suggests they are closely related. Two distinct domains of stress associated with sleep dysfunction in the general population are responsivity to environmental stressors and stress sensitivity. However, to date, no research has examined relationships between these stress domains and sleep dysfunction in individuals at clinical high-risk (CHR) for psychosis. A total of 57 CHR (mean age = 18.89, SD = 1.82) and 61 healthy control (HC; mean age = 18.34, SD = 2.41) adolescents and young adults completed a measure of emerging stress intolerance. A subset of participants (CHR = 50, HC = 49) completed a measure indexing responsivity to family stressors - an integral context for this developmental stage overlapping with the psychosis-risk period. Sleep efficiency, continuity, and duration were objectively assessed by actigraphy (CHR = 38, HC = 36). Partial correlations with age and sex as covariates were conducted in both groups separately to examine relationships between stress and sleep. Results indicated that automatic maladaptive responsivity to family stressors was associated with disrupted sleep in the CHR but not HC group. Specifically, greater involuntary engagement was associated with poorer sleep efficiency (r = −.42) but not sleep continuity (r = 0.31) and duration (r = .-19). Interestingly, both adaptative and maladaptive voluntary responses to stressors (engagement and disengagement coping) were not associated with sleep. Finally, impaired stress tolerance was associated with sleep efficiency (r = −0.47), continuity (r = 0.37), and duration (r = −0.43). Taken together, findings provided important groundwork for understanding the role of the relationship between involuntary maladaptive responsivity to family stressors and stress sensitivity with sleep in psychosis etiology.
... 29,50,53,82,91 A system that is in adaptive stages of functioning is indicated on the left side of the inverted U and those with high load are indicated at the top of the inverted U and those in overload are indicated on the right side of the inverted U. Measures of allostatic load represents an individual's current health status and relative "biological balance." 29,52,82 Both the clinical composite and the brain age gap are measures of allostatic load. 2,52,59 The individuals with protective dispositional traits living above poverty had the lowest pain intensity and functional limitations and youngest brain age. ...
... 29,52,82 Both the clinical composite and the brain age gap are measures of allostatic load. 2,52,59 The individuals with protective dispositional traits living above poverty had the lowest pain intensity and functional limitations and youngest brain age. They represent the group with the most adaptive systems, Figure 4. ...
Introduction
Factors contributing to individual differences in knee osteoarthritis remain elusive. Dispositional traits and socioeconomic status are independent predictors of mental and physical health, although significant variability remains. Dispositional traits serve as the biological interface for life experiences.
Objectives
We investigate group differences based on dispositional traits and poverty status, specific to (1) pain intensity and functional limitations and (2) biological measures, a clinical composite and brain age.
Methods
Adults aged 45 to 85 years with knee pain associated with chronic musculoskeletal pain provided information on demographics, socioeconomic and psychosocial factors, pain, and physical function. Kellgren–Lawrence scores were determined from knee radiographs, the clinical composite from fasting blood draws, and brain age from MRI data.
Results
One hundred seventy-three individuals participated in the study. Of those, 117 had protective dispositional traits (81 above poverty/36 in poverty), and 56 had vulnerable dispositional traits (24 above poverty/32 in poverty). With sex, study site, Kellgren–Lawrence score, and age/or image quality as covariates, significant group differences were observed across clinical pain (P < 0.001), functional limitations (P ≤ 0.001), and brain age (P ≤ 0.002) measures. Although not significant, the clinical composite measure aligned with the other outcome measures and demonstrated the hormesis inverted U pattern.
Conclusions
Groups based on dispositional traits and socioeconomic status explain differing clinical outcomes. Consistent with the allostatic load and hormesis inverted U models, one group was in an adaptive health status, 2 groups were showing signs of developing load, and the fourth group showing signs of overload, at risk of worse health outcomes.
... By combining 10 biomarkers of neurophysiological and somatic variation available from the McArthur Studies of Successful Aging (see Table 1), in 1997, Seeman and colleagues developed the first composite estimate of individual allostatic load [10], with cortisol, norepinephrine, dehydroepiandrosterone sulfate (DHEAs), and epinephrine, viewed as primary biomarkers of allostatic response, and six secondary mediators reflecting detrimental stressor-related physiology (Table 1). This original index, along with other composites, has been shown to associate significantly with morbid and mortal outcomes across populations [10][11][12][15][16][17][18]. ...
... While frailty is directly measurable as physical declines, allostatic load is estimated based on neuroendocrine, metabolic, cardiovascular, and immune system biomarkers of stress-related damage and systemic responses [10][11][12][15][16][17][18]. Since first described, multiple variable composite estimates of allostatic load have been published, most showing significant associations with childhood stressors, lifestyle factors, lifelong stressor exposures, psychological health, and morbid and mortal outcomes across populations and age groups [10-12, 15-18, 26-28, 34, 41, 42]. ...
Background
Physiological dysregulation/allostatic load and the geriatric syndrome frailty increase with age. As a neurophysiological response system, allostasis supports survival by limiting stressor-related damage. Frailty reflects decreased strength, endurance, and physical abilities secondary to losses of muscle and bone with age. One suggestion, based on large cohort studies of person’s ages 70 + years, is that frailty contributes to allostatic load at older ages. However, small community-based research has not confirmed this specific association.
Methods
To further explore possible associations between allostatic load and frailty, we enrolled 211 residents of Greater Poland aged 55–91 years living in a small village (Nekla, N = 104) and an urban center and capital of Greater Poland (Poznan, N = 107). For each, we recorded age, self-reported sex, and residence and estimated a 10-biomarker allostatic load score (ALS) and an 8-biomarker frailty index. We anticipated the following: higher ALS and frailty among men and rural residents; for frailty but not ALS to be higher at older ages; significant associations of ALS with sex and place of residence, but not with age or frailty. The significance of observed associations was evaluated by t -tests and multivariate regression.
Results
ALS did not vary significantly between men and women nor between Nekla and Poznan residents overall. However, women showed significantly higher frailty than men. Nekla men showed significantly higher ALS but not frailty, while Nekla women showed nonsignificantly higher ALS and lower frailty than Poznan. In multivariate analyses, neither age, nor sex, nor residence was associated with ALS. Conversely, age, sex, and residence, but not ALS, are associated significantly with frailty. In Nekla, both age and sex, but in Poznan only age, are associated with ALS. Among women, both age and residence, but among men, neither associated with ALS. In no case did ALS associate significantly with frailty.
Conclusion
In this sample, lifestyle factors associated with residence, age, and sex influence stress-related physiology, less so in women, while ALS and frailty do not covary, suggesting their underlying promoters are distinct. Similar complex associations of physiological dysregulation with frailty, age, sex, and residence likely exist within many local settings. Knowledge of this variation likely will aid in supporting health and healthcare services among seniors.
... Since the formation of allostatic load in cases of EH is closely related to stress [31][32][33], we calculated ALI [13,[34][35][36][37][38][39] using the following biomarkers: SBP, DBP, BMI, blood levels of LDL, HDL, TG, glucose, glycated Hb, creatinine, urea, and immunoreactive insulin (IRI), applying quartile scoring. These data were compared with hemodynamic features of EH realization in patients with the presence/absence of an adequate nigh ime BP reduction. ...
... Since the formation of allostatic load in cases of EH is closely related to stress [31][32][33], we calculated ALI [13,[34][35][36][37][38][39] using the following biomarkers: SBP, DBP, BMI, blood levels of LDL, HDL, TG, glucose, glycated Hb, creatinine, urea, and immunoreactive insulin (IRI), applying quartile scoring. These data were compared with hemodynamic features of EH realization in patients with the presence/absence of an adequate nighttime BP reduction. ...
Changes in the activity of the renin–angiotensin–aldosterone system are responsible for a stable shift in the regulation of the cardiovascular system in essential hypertension (EH). They can be characterized as hemodynamic allostasis. The purpose of our study was to determine the role of hemodynamic parameters in allostatic load in patients with EH without metabolic syndrome. Twenty-four hours of ambulatory blood pressure monitoring was performed, followed by linear and non-linear rhythm analysis. Based on the daily index, patients with EH were divided into two groups: group 1—patients with no significant nighttime decrease in blood pressure (BP); group 2—patients who had a nocturnal decrease in BP. The control group included healthy persons aged 25 to 69 years. A linear analysis was used to determine the mean values of systolic and diastolic BP, heart rate (HR), time load of BP, circadian index, and structural point of BP. Non-linear analysis was applied to determine the mesor, amplitude, range of oscillations and % rhythm of BP and HR. The allostatic load index (ALI) was also calculated on the basis of the corresponding biomarkers. It was found that ALI was significantly higher in groups 1 and 2 in comparison with the control group. The hemodynamic mechanisms of this increase were different.
... Importantly, the NHB adults also had greater sociodemographic risk factors compared to their NHW peers (Tanner et al., 2021). Consistent with the allostatic load conceptualization, we hypothesized that greater socioenvironmental stress adds an additional physiological and neurobiological "load" to the biological burden of chronic pain contributing to higher allostatic load which was indicated by thinner temporal lobe brain structures (McEwen, 2015;McEwen, 1998;. Following our publication and aligning with our interpretation, a population-based study indicated that greater socioenvironmental risk based on an additive social determinants of health (SDOH) index was associated with greater osteoarthritis disease severity (Rethorn et al., 2022). ...
... A novel finding, bilateral temporal lobe differences were indicated in an additive fashion based on a combination of greater socioenvironmental risk and greater chronic pain stage. Results align with the hypothesized interpretation consistent with the allostatic load model, and physiological and neurobiological systems are adaptive to stress until the cumulative load exceeds functional capacity (McEwen, 2015(McEwen, , 1998. Hence, individuals with "combined loads" of high socioenvironmental risk and high chronic pain stage show greater neurobiological "load" as indicated by a pattern of thinner temporal lobe brain structures than their peers with lower levels of socioenvironmental risk and lower levels of chronic pain stage . ...
Introduction: Previous research indicates ethnic/race group differences in pain and neurodegenerative diseases. Accounting for socioenvironmental factors reduces ethnic/race group differences in clinical and experimental pain. In the current study sample, we previously reported that in individuals with knee pain, ethnic/race group differences were observed in bilateral temporal lobe thickness, areas of the brain associated with risk for Alzheimer's disease, and related dementias. The purpose of the study was to determine if socioenvironmental factors reduce or account for previously observed ethnic/race group differences and explore if a combined effect of socioenvironmental risk and chronic pain severity on temporal lobe cortices is evident.
Methods: Consistent with the prior study, the sample was consisted of 147 adults (95 women, 52 men), 45–85 years of age, who self‐identified as non‐Hispanic Black (n = 72) and non‐Hispanic White (n = 75), with knee pain with/at risk for osteoarthritis. Measures included demographics, health history, pain questionnaires, cognitive screening, body mass index, individual‐ and community‐level socioenvironmental factors (education, income, household size, marital and insurance status, and area deprivation index), and brain imaging. We computed a summative socioenvironmental risk index. Results: Regression analyses showed that with the inclusion of socioenvironmental factors, the model was significant (p < .001), and sociodemographic (ethnic/race) group differences were not significant (p = .118). Additionally, findings revealed an additive stress load pattern indicating thinner temporal lobe cortices with greater socioenvironmental risk and chronic pain severity (p = .048).
Implications: Although individual socioenvironmental factors were not independent predictors, when collectively combined in models, ethnic/race group differences in bilateral temporal lobe structures were not replicated. Further, combined socioenvironmental risk factors and higher chronic pain severity were associated with thinner bilateral temporal lobes.
... However, persistent and prolonged activation of the stress regulatory systems without adequate recovery and/or sufficient buffers can contribute toward higher allostatic load as indicated by stress system dysregulation (McEwen and Stellar, 1993;McEwen, 1998b). Associated with increased risk of morbidity and mortality (Freire et al., 2020;Guidi et al., 2021;McEwen and Seeman, 1999;Seeman et al., 2001), allostatic load can be assessed by brain structure, a clinical composite of stress system measures (metabolic, neuroendocrine, inflammatory, cardiovascular), and telomere length, Fig. 1 (McEwen, 2007(McEwen, , 2015Sibille et al., 2012a;Zalli et al., 2014;Bobba-Alves et al., 2023). ...
... We and others have previously reported findings on clinical composite measures of allostatic load and clinical pain (Sibille et al., , 2017bSlade et al., 2012). We have also reported relationships between clinical pain and telomere length, another measure of allostatic load (Sibille et al., 2012a(Sibille et al., , 2017aBobba-Alves et al., 2023;McEwen, 2015). When investigating allostatic load based on pain-related brain structure, we identified that higher chronic pain stage was associated with a thinner bilateral insula and DLPFC. ...
Chronic pain is a stressor that affects whole person functioning. Persistent and prolonged activation of the body's stress systems without adequate recovery can result in measurable physiological and neurobiological dysregulation recognized as allostatic load. We and others have shown chronic pain is associated with measures of allostatic load including clinical biomarker composites, telomere length, and brain structures. Less is known regarding how different measures of allostatic load align. The purpose of the study was to evaluate relationships among two measures of allostatic load: a clinical composite and pain-related brain structures, pain, function, and socioenvironmental measures. Participants were non-Hispanic black and non-Hispanic white community-dwelling adults between 45 and 85 years old with knee pain. Data were from a brain MRI, questionnaires specific to pain, physical and psychosocial function, and a blood draw. Individuals with all measures for the clinical composite were included in the analysis (n = 175). Indicating higher allostatic load, higher levels of the clinical composite were associated with thinner insula cortices with trends for thinner inferior temporal lobes and dorsolateral prefrontal cortices (DLPFC). Higher allostatic load as measured by the clinical composite was associated with greater knee osteoarthritis pathology, pain disability, and lower physical function. Lower allostatic load as indicated by thicker insula cortices was associated with higher income and education, and greater physical functioning. Thicker insula and DLPFC were associated with a lower chronic pain stage. Multiple linear regression models with pain and socioenvironmental measures as the predictors were significant for the clinical composite, insular, and inferior temporal lobes. We replicate our previously reported bilateral temporal lobe group difference pattern and show that individuals with high chronic pain stage and greater socioenvironmental risk have a higher allostatic load as measured by the clinical composite compared to those individuals with high chronic pain stage and greater socioenvironmental buffers. Although brain structure differences are shown in individuals with chronic pain, brain MRIs are not yet clinically applicable. Our findings suggest that a clinical composite measure of allostatic load may help identify individuals with chronic pain who have biological vulnerabilities which increase the risk for poor health outcomes.
... One is the use of biological markers related to stress, and the other is concerned with the application of clinimetric tools. Biomarkers include metabolic parameters (glucose, insulin, lipid profiles), indices of inflammation (interleukins, C-reactive protein, fibrinogen), sympathetic nervous system activity (urinary norepinephrine and epinephrine), hypothalamic-pituitary-adrenal axis components (cortisol, dehydroepiandrosterone), insulin-like growth factor 1 [16,17]. Cumulative indices encompassing both clinical (e.g., blood pressure, waist circumference) and laboratory parameters have also been developed [18]. ...
... This methodology relies on biomarkers that express a state of body systems, but does not provide information on the underlying individual causes. Substantial heterogeneity exists across studies as to type and number of parameters to be considered [8,[16][17][18]. This approach is not suitable for everyday practice. ...
The building of life stress, well expressed by the concept of allostatic load, plays an important part in all phases of endocrine illness. Allostatic load refers to the cumulative burden of both stressful life events and chronic stress. When environmental challenges exceed the individual ability to cope, allostatic overload ensues. Assessment of allostatic load/overload by clinical measurements including indices and rating scales, in addition to biomarkers, offers a characterization of the person's psychosocial environment that is missing from current formulations. Consideration of allostatic load in endocrinology may shed light on a number of clinical issues: interpretation of abnormal hormone values that lack explanations; coping with the various phases of illness; maladaptive illness behavior; response to treatment; presence of residual symptoms; health-damaging lifestyle habits. Addressing allostatic load calls for innovative models of endocrine outpatients with multidisciplinary organization of care, extended time for the interview, focus on rehabilitation. We provide an overview on the mechanisms of allostatic load, how it can be assessed, its potential role in endocrine disturbances, and how its consideration may lead to a needed innovation in patient care.
... Since the purpose of AL is to understand the burden of stress as it affects several body systems (McEwen, 2015), a set of biomarkers capturing function across multiple body systems (cardiovascular, metabolic, and immune biomarkers) were included in its calculation. ...
... The dried blood samples were then shipped to US Specialty Labs for measurement of triglycerides, HDL, LDL, hsCRP, and HbA1c. Because clinical guidelines and cut-offs are rarely population specific (Duong et al., 2017), thresholds of risk were determined by using quartiles and subsequently scoring individuals with markers in the most extreme quartile associated with risk (McEwen, 2015). To account for variation in biomarkers by sex, high-risk quartiles were created for male and female participants separately and scores were pooled as recommended by McLoughlin et al. (2020). ...
Objectives:
Biological normalcy provides a framework to assess tensions between clinical definitions of "normal," statistical norms, and normative beliefs. A prevailing cultural belief is obesity directly causes poor health, but research has demonstrated consequences of fat stigma. Previous research linked fat stigma and allostatic load (AL) in adults, but this has not been demonstrated in youth, and the role of obesity prevalence is unknown. This study assesses the relationship between fat stigma and AL among youth from counties varying by obesity prevalence.
Materials and methods:
Undergraduates from 38 counties across the US state of Indiana (n = 175) were recruited. Fat stigma was measured using the brief stigmatizing situations inventory (SSI). AL was calculated using eight biomarkers representing cardiovascular, metabolic, and immune function. Poisson regression assessed relationships of interest and adjusted for potential confounding. An interaction term and stratified analyses were used to assess moderation.
Results:
SSI was not statistically associated with obesity prevalence (RR = 0.96, p = 0.173) but did statistically significantly predict AL (RR = 1.019, p = 0.045) when adjusting for confounders. Obesity prevalence moderated the relationship between SSI and AL (RR = 0.993, p = 0.001).
Discussion:
Results suggest that fat stigma, regardless of body fat percentage, is associated with physiologic wear and tear on the late adolescent body, and that exposure to obesity during earlier adolescence moderates this relationship. Those most at risk for high AL reported high fat stigma and lived in counties with relatively low obesity prevalence during earlier adolescence, suggesting vulnerability to fat stigma may be heightened where obesity is less common.
... The literature [10][11][12] suggests that burnout contributes to reducing the number of skilled health manpower through NCD-associated mortalities via dysregulation of multiple physiological systems (allostatic load) in victims [13]. According to Sterling and Eyer [14], allostasis describes the mechanism by which physiological stability is achieved through changing processes of bodily systems following exposure to chronic stressors. The allostatic process provides that one of the mechanisms of healthy adaptation to chronic environmental demands is through variability of physiological systems [15]. ...
... The literature [26][27][28]33] states that chronic stress manifesting as burnout has significant physiological impact on the body of victims and that this is often negative due to its longer duration. Whenever the stress response is activated, physiological adjustments, must be made and over time these adjustments lead to accumulated wear and tear of physiological systems; an allostatic load [13][14][15][16][17] and that exposure to stress for longer duration, causes sub-clinical dysfunction of physiological systems of victims leading to chronic diseases [16,[26][27][28]. Other studies [9][10][11][12] have pointed to this allostatic load pathway as the plausible link between job-related burnout and NCDs among employees engaged in stressful job-settings. ...
Background:
Burnout syndrome is a psycho-social disorder which develops in an individual exposed to chronic stress on the job. Health workers in sub-Saharan Africa (SSA) are at increased risk of burnout due to job-related challenges. Burnout does not only affect the job performance of employees, but could result in dysregulation of multiple physiological systems (allostatic load) in victims and predispose them to non-communicable diseases (NCDs). This study examined the association between burnout and allostatic load among health workers engaged in human resourced-constrained hospitals in Accra, Ghana.
Method:
This study was a hospital-based cross-sectional study involving 1264 health workers (clinicians and non-clinicians) from three public hospitals in Accra, Ghana who were recruited using a proportionate stratified random sampling technique. The participants completed a questionnaire which collected general and burnout information. In addition, each participant's anthropometric; biochemical and hemodynamic indices were measured. The allostatic load in the participants was determined using eleven (11) biomarkers from the neuro-endocrine, cardiovascular, metabolic and anthropometric measures. The relationship between burnout and allostatic overload (high allostatic load) was determined at the bivariate and multivariable levels. The data analysis was done with the aid of Stata 15.0 at a 95% confidence level.
Results:
The prevalence of burnout was 20.57%, higher in non-clinicians than clinicians (26.74% vs 15.64, p < 0.001). Also, non-clinical participants had higher levels of emotional exhaustion and depersonalization than the clinical participants. Over a quarter (26.27%) of the participants had allostatic overload manifesting as high allostatic load. Furthermore, for a one unit increase in overall burnout, the odds of experiencing allostatic overload was increased by 17.59 times (AOR = 17.59, 95% CI: 11.7-26.4) as compared to those without burnout and similar findings were found for the individual components of burnout syndrome with high allostatic load.
Conclusion:
Burnout among health workers is associated with multi-system physiological dysregulation manifesting as high allostatic load; a major risk factor for NCDs. It is recommended that measures aimed at reducing burnout and allostatic overload such as structured psychological counseling and healthy lifestyle patterns are recommended for health workers engaged in stressful work settings to reduce their risk of NCDs.
... These studies are challenging to conduct. Finally, an analysis of the epigenomic landscape should be conducted holistically, incorporating several histone modifications and their clinical correlates [10,28,34]. This type of analysis is mainly seen in cardiac diseases treated pharmacologically, with the paucity of data focusing on surgical interventions in general or cardiac surgery in particular [12,23,25,34]. ...
... We hypothesized that histone 3 (H3) would be released predominantly during the acute period after cardiac surgery, similar to other DAMP (HSP-60) [21,22]. Considering the immunostimulatory effect of circulating histones, we hypothesized that the level of circulating histones would correlate with immune system activation (serum IL-6, peripheral monocyte MO activation in response to bacterial challenge) [1,16,24,26,28,43,46,49]. Furthermore, we theorized that patients' histone modification profiles would change from peri-operative pro-inflammatory to convalescent anti-inflammatory. ...
Background
Despite clinical relevance of immunological activation due to histone leakage into the serum following cardiac surgery, long-term data describing their longitudinal dynamic are lacking. Therefore, this study examines the serum levels of histone 3 (tH3) and its modifications (H3K4me3 and H3K27ac) alongside immune system activation during the acute and convalescence phases of cardiac surgery.
Methods
Blood samples from fifty-nine individuals were collected before non-emergent cardiac surgery (t pre-op ) and 24 h (t 24hr ), seven days (t 7d ), and three months (t 3m ) post-procedure to examine serum levels of tH3, H3K4me3, and H3K27ac. Serum heat shock protein-60 (HSP-60) was a surrogate of the cellular damage marker. Serum C-reactive protein (CRP) and interleukin 6 (IL-6) assessed smoldering inflammation. TNFα and IL-6 production by whole blood in response to lipopolysaccharide (LPS) evaluated immunological activation. Electronic medical records provided demographic, peri-operative, and clinical information. Paired longitudinal analyses were employed with data expressed as mean and standard deviation (X ± SD) or median and interquartile range (Me[IQ25; 75%].
Results
Compared to pre-operative levels (tH3 Pre-op = 1.6[0.33;2.4]), post-operative serum tH3 significantly ( p > 0.0001) increased after heart surgery (tH3 24hr = 2.2[0.3;28]), remained elevated at 7 days (tH3 7d = 2.4[0.37;5.3]), and at 3 months (tH3 3m = 2.0[0.31;2.9]). Serum H3K27ac was elevated at 24 h (H3K27ac 24hr = 0.66 ± 0.51; p = 0.025) and seven days (H3K27ac 7d = 0.94 ± 0.95; p = 0.032) as compared to baseline hours (H3K27ac Pre-op = 0.55 ± 0.54). Serum H3K4me3 was significantly diminished at three months (H3K4me3 Pre-op = 0.94 ± 0.54 vs. H3K27ac 3m = 0.59 ± 0.89; p = 0.008). tH3 correlated significantly with the duration of anesthesia ( r ² = 0.38). In contrast, HSP-60 normalized seven days after surgery. Peri-operative intake of acetaminophen, but no acetylsalicylic acid (ASA), acid, ketorolac or steroids, resulted in the significant depression of serum H3K4me3 at 24 h (H3K4me3 acetom- = 1.26[0.71; 3.21] vs H3K4me3 acetom+ = 0.54[0.07;1.01]; W[50] = 2.26; p = 0.021). CRP, but not IL-6, remained elevated at 3 months compared to pre-surgical levels and correlated with tH3 24hrs ( r ² = 0.43), tH3 7d ( r ² = 0.71; p < 0.05), H3K4me3 7d ( r ² = 0.53), and H3K27ac 7d ( r ² = 0.49). Production of TNFα by whole blood in response to LPS was associated with serum tH3 24hrs ( r 2 = 0.67). Diminished H3K4me3 24hrs, H3K27ac 24hrs , and H3K27ac 3m , accompanied the emergence of liver failure.
Conclusions
We demonstrated a prolonged elevation in serum histone 3 three months after cardiac surgery. Furthermore, histone 3 modifications had a discrete time evolution indicating differential immune activation.
... Many age-related diseases and disorders involve molecular mechanisms associated with stress [1][2][3][4]. Several recent reviews have attempted to systematize stressor types, different responses to stressors, and the connections of these to diseases and aging [1,5,6]. For the past several decades, the concept of "allostatic load"-i.e., the cumulative total of adaptations to stress that may be damaging to an individual-has proven useful in determining stress-related factors that predispose to disease and aging [7][8][9]. ...
Background: Our previous comparison of peripheral blood mononuclear cells (PBMCs) from long-term Transcendental Meditation® (TM®) practitioners and matched non-practitioner controls found 200 differentially expressed (DE) genes. Bioinformatics analyses of these DE genes suggested a reduced risk of diseases associated with stress and aging in the TM group. Here we assessed additional signs of reduced stress and aging. Methods: A sample of 15 of the 200 DE genes was studied using qPCR in PBMCs from 40-year TM practitioners (“Old TM”, n = 23) compared to a “Young Control” group (n = 19) and an “Old Control” group (n = 21) of non-meditators. In these three groups, plus a “Young TM”, 12-year practitioner group (n = 26), we also studied EEG-based parameters of cognitive function (the Brain Integration Scale (BIS), and latency of three components of the event-related potential (ERP)). Finally, using LC/MS/MS, we compared persistent levels of cortisol (F) and its inactive congener, cortisone (E), in hair. Results: qPCR analysis showed that 13 of the 15 genes were more highly expressed in Old Controls than in Young Controls. In the Old TM group, 7 of these 13 were lower than in Old Controls. Both TM groups had higher BIS scores than their age-matched controls. The Old TM group had shorter N2, P3a, and P3b latencies than the Old Control group, and latencies in the Old TM group were not longer than in the Young Control group. The Hair F/Hair E ratio was higher in the control subgroups than in their age-matched TM subgroups, and Hair F was higher in the Young Control and combined control groups than in the Young TM and combined TM groups. Conclusions: These results are consistent with reductions in biomarkers of chronic stress and biological age in long-term TM meditators. They are also consistent with results from the previous study suggesting that TM practice lowers energy consumption or leads to more efficient energy metabolism.
... Additional biomarkers (glucose levels, lipid profiles, interleukin-6 and heart rate variability) were subsequently recognised as being attributable to AL and included in the cumulative AL Index (Allostatic Load Index, ALI). [8][9][10] Several studies have highlighted that this index is the best predictor of mortality and decline in physical functioning 11 compared with individual biomarkers. 9 12-14 A biological perspective must be complemented by psychological measurements that allow for building a comprehensive understanding of allostatic load, overload and related clinical phenomena. ...
Introduction
The allostatic load (AL) is a framework for conceptualising the physiological multisystemic impact of prolonged exposure to stress and its related side effects on mental health.Stress due to AL can influence the development and outcomes of cardiovascular diseases. AL increases the risk of coronary and peripherical artery diseases. AL emerges from the detection of emotional dimensions related to the disease, low psychosocial functioning and high rates of psychopathological signs in patients with hypertension or coronary heart disease.
Method and analysis
The primary endpoint of the PLAY-UP protocol is the implementation of a multidimensional model underlying the clinical treatment of patients with cardiovascular disease through the integration of medical and psychological clinical variables.PLAY-UP is a cohort study that will last for 24 months. 200 participants will be recruited and divided into three groups: early disease, midterm disease and long disease. All patients will undergo a clinical evaluation based on the detection of biological, medical and psychological indicators and variables. The evaluation battery will comprise three types of measurements: medical, psychological and pharmacological treatments. Clinical and psychological measurements will be processed in an integrated manner through the combination of all variables examined, elaborating the Allostatic Load Index from a longitudinal time perspective. The Allostatic Load Index will be calculated by measuring the z-score.
Ethics and dissemination
Ethical Committee Approval was obtained from CEtRA Abruzzo Region (IT) (ID 0461499/23). The results of the present project will be published in peer-reviewed journals, disseminated electronically and in print, and presented as abstracts and/or personal communications during national and international conferences.
... Numerous studies have demonstrated associations between occupational stress and these conditions. Long-term exposure to occupational stress can cause dysregulation of the hypothalamic-pituitaryadrenal (HPA) axis, resulting in physiological changes including insulin resistance, disrupted circadian rhythms, increased inflammation and dysregulation of intestinal flora [42][43][44]. Furthermore, previous studies have associated occupational stress with unhealthy behaviors such as cigarette smoking [45], alcohol consumption [45,46], high-calorie dietary intake [47], and lower physical activity [48] -all of which contribute to metabolic issues and visceral fat accumulation, potentially increasing the risk of MASLD and chronic diseases that may lead to MASLD [49]. ...
Background
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prominent cause of chronic liver disease, and occupational stress may serve as a potential risk factor. This study aims to assess the association between occupational stress trajectories and incident MASLD among Chinese female nurses.
Methods
We conducted a prospective longitudinal study using data from the Nurse’ Health Cohort Study, involving 1,113 female nurses, free of MASLD at baseline (2018). Occupational stress was measured using the Chinese Nurse Job Stress Scale at four time points. Group-based trajectory modeling was used to identify distinct stress trajectories. Through doctors’ diagnoses, we assessed incident MASLD over a subsequent 6-year period from 2019 to 2024. Cox proportional hazards regression models evaluated the association of stress trajectories and MASLD risk, adjusting for demographics, work-related factors, and medical conditions.
Results
During follow-up, 256 nurses reported incident physician-diagnosed MASLD. Three occupational stress trajectories were identified: moderate decreasing (36.4%), moderate stable (55.9%), and moderate increasing (7.7%). Participants in the moderate increasing stress trajectory had a significantly higher risk of developing MASLD (adjusted HR: 3.14, 95% CI: 2.19–4.49, p < .001) compared to those in the moderate stable trajectory. This association between stress trajectory and MASLD risk was not modified by age or BMI (pinteraction>0.50).
Conclusions and relevance
The study concludes that increasing stress levels over time are associated with a higher incidence of MASLD. These findings underscore the importance of stress management interventions in reducing the risk of MASLD progression. Further research is needed to explore the underlying mechanisms and to develop targeted strategies for stress reduction in clinical settings.
... Allostatic load has been extensively investigated in human health, where it has been associated with increased risk for a range of diseases, from cardiovascular diseases to neurological disorders (for a review, see Guidi et al., 2021). Several studies have identified allostatic load through biological markers (McEwen, 2015;Seeman et al., 1997Seeman et al., , 2001, such as cortisol and resting systolic and diastolic blood pressure. While biomarkers focus on the physiological evidence of allostatic load, clinical studies have focused on its underlying experiential factors (e.g., significant hardship and distress). ...
Protecting populations contending with co‐occurring stressors requires a better understanding of how multiple early‐life stressors affect the fitness of natural systems. However, the complexity of such research has limited its advancement and prevented us from answering new questions. In human studies, cumulative risk models predict adult health risk based on early adversity exposure. We apply a similar framework in wild yellow‐bellied marmots (Marmota flaviventer). We tested cumulative adversity indices (CAIs) across different adversity types and time windows. All CAIs were associated with decreased pup survival and were well supported. Moderate and acute, but not standardized CAIs were associated with decreased lifespan, supporting the cumulative stress hypothesis and the endurance of early adversity. Multivariate models showed that differences in lifespan were driven by weaning date, precipitation, and maternal loss, but they performed poorly compared with CAI models. We highlight the development, utility, and insights of CAI approaches for ecology and conservation.
... 15 Chronically increased cortisol levels can raise blood glucose levels and potentiate insulin resistance, which shares the pathogenesis of GDM. 16,17 There is conflicting evidence in the literature regarding the relationship between psychological stress, like anxiety and depression, and GDM. Research suggests that anxiety and stress can play an important role in the development of GDM. ...
BACKGROUND: Gestational Diabetes Mellitus (GDM) is a common disorder among pregnant women, increasing their vulnerability to psychological stress compared to non-GDM pregnant women. Motherhood is already a significant life-changing and stressful condition. Developing diabetes during pregnancy elevates women's psychological stress levels, leading to pregnancy-related complications and poor neonatal outcomes. This study aims to explore and compare the psychological stress of GDM in pregnant women with non-GDM women.
METHODS: This cross-sectional comparative study investigated diabetes-related distress using the Depression, Anxiety Stress Scale-21 (DASS-21) and the Problem Areas in Diabetes Scale-5 (PAID-5) in purposively selected 75 pregnant women with GDM and compared them to 75 non-GDM women attending antenatal checkups at BIHS General Hospital, Dhaka.
RESULTS: The average age of the pregnant women was 27.71±5.10 (GDM mean= 29.48±4.57, non-GDM mean= 25.95±5.02). Pregnant women with GDM had more stress (57.3%), anxiety (46.7%), and depression (61.3%) compared to non-GDM women (p<.001). According to DASS-21, among all women with GDM, 25.3% had moderate stress, 22.7% mild depression, and 29.3% extreme-severe anxiety. According to the PAID-5 scale, more than half (63%) of the GDM women had diabetes-related emotional distress.
CONCLUSION: Women with GDM are more likely to have psychological distress compared with non-GDM pregnant women. Interventions are needed to improve access to diabetes and mental health care with appropriate tools, such as digital technology-based health interventions.
... 3 AO implies an overuse of stress systems in a dysregulated manner, 4 which leads to systemic inflammations 5,6 and worsening of physical and mental health. 3,5,6 AO has specific biological 7,8 and clinical signatures. 9 The first were analyzed via biological markers (e.g., resting systolic and diastolic blood pressure, body mass index, plasma C-reactive protein, and cortisol). ...
The present study aimed at evaluating the prevalence of allostatic overload (AO) among subjects with different medical diseases and explore whether medically ill patients with or without AO differ for specific clinical features (i.e., co-occurring mental or psychosomatic disorders). An observational cross-sectional study was carried out. Outpatients with a diagnosis of blood cancer, systemic sclerosis, or migraine received a clinical assessment which included the Mini International Neuropsychiatric Interview or the Structured Clinical Interview for DSM-5 and the Diagnostic Criteria for Psychosomatic Research-Revised Semi-Structured Interview (DCPR-R SSI). Four hundred and thirty-nine outpatients were enrolled. Among them, 39 (8.9%) had a diagnosis of blood cancer, 200 (45.5%) had a diagnosis of systemic sclerosis, and 200 (45.5%) had a diagnosis of migraine. A total of 104 (23.7%) patients had a DCPR-R diagnosis of AO. Patients with a diagnosis of blood cancer, migraine, or systemic sclerosis did not differ for DCPR-R AO prevalence (P = 0.082). Based on multiple regression analysis, medically ill patients with DCPR-R AO were more likely to satisfy the diagnosis of DCPR-R illness denial (odds ratio [OR] = 2.99, 95% confidence interval [CI] = 1.04 – 8.58), conversion symptoms (OR = 5.32, 95% CI = 1.16 – 24.38), or demoralization (OR = 2.57, 95% CI = 1.08 – 6.11) and a DSM-5 diagnosis of major depressive episode/disorder (OR = 1.90, 95% CI = 1.03 – 3.50), if compared to those without DCPR-R AO. DCPR-R AO is a clinically useful transdiagnostic feature potentially associated with other psychosomatic syndromes and mental disorders that may contribute to the disease burden and the poor global health conditions of medically ill patients.
... Allostatic load is a composite index representing the bodily wear and tear inflicted by chronic stress and adaptation to stress [3,4] that often includes physiological measurements such as blood pressure, body mass index (BMI), and waist-to-hip ratio as well as biomarkers of stress including cortisol and C-reactive protein [5][6][7]. Allostatic load is associated with higher rates of type 2 diabetes, obesity, cardiovascular disease, cancer and mortality [3,[8][9][10]. It is inversely related to income and education [11][12][13][14], but directly associated with neighborhood incomeand/or race-based segregation [11,12]. ...
Background
Social determinants of health (SDOH) and cumulative stress contribute to chronic disease development. The physiological response to repeated stressors typical of lower-income environments can be measured through allostatic load – a composite measure of cardiovascular, metabolic, and immune variables. Healthcare systems have employed patient navigation for social and medical needs to improve SDOH that has demonstrated limited impact on chronic disease outcomes. This study evaluates a novel community health worker navigation intervention developed using behavioral theories to improve access to social and medical services and provide social support for poverty stressed adults.
Methods
The Integrated Population Health Study (IPOP) study is a randomized, parallel two arm study evaluating community health worker navigation in addition to an existing integrated population health program (IPOP CHW) as compared to Usual Care (population health program only, IPOP) on allostatic load and chronic disease risk factors. IPOP CHW participants receive a 10-month navigation intervention.
Results
From 381 screened individuals, a total of 202 participants (age 58.15 ± 12.03 years, 74.75 % female, 79.21 % Black/African American, 17.33 % Hispanic) were enrolled and randomized to IPOP CHW (n = 100) or IPOP Only (n = 102).
Conclusion
This study will evaluate whether CHW navigation, using a structured intervention based on health behavior theories, can effectively guide poverty stressed individuals to address social and medical needs to improve allostatic load—a composite of cumulative stress and physiological responses. Healthcare systems, nonprofit organizations, and governmental entities are interested in addressing SDOH to improve health, thus developing evidence-based interventions could have broad clinical and policy implications.
... In this regard, there are various normal physiological biomarkers, which denote the healthy status of an individual, if present within the normal range. However, the presence of stress marker indicates the physiological uncomforting of the individual that might results due to operation of different energy consuming mechanisms within the body in the process of maintaining the homeostasis and thereby involves numerous biomarkers [6,7]. Moreover, the changes in the body due to stress involves various physiological and endocrine alterations, along with disturbances in the corresponding functional, biochemical, and metabolic systems and thereby, the alterations in the metabolic biomarkers such as the enzymes, metabolites, and hormones, etc., also result [8,9]. ...
The aim of the present study was to evaluate the fundamental physiological functional biomarkers analysis of biofield treated/blessed novel test formulation in Unpredictable Chronic Stress (UCS) male Sprague Dawley (SD) rats. The constituents of the test formulation were divided into two parts; one section was defined as the untreated test formulation, while the other part of each components and three group of animals received biofield energy healing/blessing treatment by Mr. Mahendra Kumar Trivedi, a famous biofield energy healer. Total Leucocyte Count (TLC) count was significantly (p≤0.001) improved by 75.62%, 64.20%, 44.03%, 82.53%, and 50.83% in the biofield energy treated test formulation to the untreated rats (G5), biofield energy treatment per se to the rats (G6) groups, 15 days pre-treatment of biofield energy treated test formulation (G7), 15 days pre-treatment of biofield energy treated test formulation to the biofield energy treatment per se to rats (G8), and untreated test formulation to the biofield energy treated rats (G9) respectively, as compared with the G2 group. Besides, lymphocytes count were significantly increased by 52.50% (p≤0.001), 47.02% (p≤0.001), 32.21%, 83.86% (p≤0.001), and 40.15% (p≤0.001) in the G5, G6, G7, G8, and G9 groups, correspondingly with reference to G2 group. In addition, monocyte counts were also significantly increased by 82.52% (p≤0.05), 65.06% (p≤0.05), 38.68%, and 17.03% in the G5, G6, G8, and G9 groups, respectively as compared with the G2 group. Biochemical analysis showed that glucose level was maintained in all the experimental test groups, while UCS significantly increased the level of glucose. Biochemical analysis showed that HDL level was significantly (p≤0.001) improved by 37.62%, 46.64%, and 36.27% in the G5, G7, and G9 groups, respectively as compared with the G2. However, total cholesterol was decreased by 14.86%, 30.32%, 44.29%, and 32.66% in the G5, G7, G8, and G9 groups, correspondingly with reference to G2. However, VLDL level was also significantly reduced by 14.91%, 30.70%, 44.30% (p≤0.01), and 32.89% in the G5, G7, G8, and G9 groups, respectively as compared with the G2. Hepatic and cardiac biomarkers analysis showed that ALP level was decreased by 27.97% and 13.37% in the G5 and G9 groups, respectively as compared with the G2. The level of SGOT was significantly (p≤0.01) decreased by 21.45%, 19.19%, and 19.81% in the G5, G7, and G9 groups, respectively as compared with the G2. On the other hand, SGPT level was also altered by 11.32% and 11.72% in the G5 and G6 groups, respectively with reference to G2 group. CK-MB level was significantly reduced by 16.32% and 37.01% (p≤0.01) in the G8 and G9 groups, respectively with reference to G2. Animal weight parameters like body weight, organ to body weight ratio, and feed intake data showed that the changes were non-significant and no toxic effect was observed after the experimental period. Overall, the data suggested a significant improvement of immune-related hematology parameters, CK-MB, SGOT, and lipid profile after biofield treatment and slowdown the disease progression rate and related symptoms in the preventive maintenance groups. Therefore, the data could be benefitted to build-up good body immune responses, enhance resistance towards diseases, and reduce allergies and lethargic conditions.
... Este desbalance afecta la fisiología sistémica neuroendocrina, autonómica, inmune y metabólica a través de distintos mediadores. (7) Varios estudios se han enfocado en identificar la carga alostática a través de marcadores biológicos (8,9,10) como el cortisol, la dihidroepiandrosterona (DHEA), la epinefrina, la norepinefrina, el colesterol, la hemoglobina glicosilada, la presión de sangre sistólica y diastólica, el índice de masa corporal, y la proporción de la cintura-cadera. Existe una relación compleja entre homeostasis, respuesta de estrés e inflamación, que incluye mecanismos celulares y extracelulares puestos en marcha por desviaciones extremas de las variables reguladas o por la intervención de un agente exterior. ...
Introducción:
La homeostasis es la propiedad fundamental de los sistemas biológicos de preservar el medio interno. La presión arterial, el pH, las concentraciones plasmáticas de sodio y glucosa son ejemplos de variables homeostáticos, donde el propósito de la regulación fisiológica es fijar cada parámetro interno en un punto de ajuste, detecta errores y los corrige con realimentación negativa. Los fisiólogos han evidenciado que muchos errores no son constantes sino adaptativos.
Objetivo:
Exponer los conceptos novedosos acerca de la influencia de un ambiente de estrés sobre nuestra fisiología y sus efectos deletéreos a largo plazo.
Métodos:
Se realizó una revisión bibliográfica, en el motor de búsqueda Google académico, los descriptores: homeostasis, alostasis y carga alostática.
Conclusiones:
Se expuso los conceptos novedosos acerca de la influencia de un ambiente de estrés sobre nuestra fisiología y sus efectos deletéreos a largo plazo. La alostasis es el precio que el cuerpo paga por verse obligado a adaptarse a situaciones psicosociales o físicas adversas. La obesidad, la diabetes, la insulinoresistencia, la hipertensión arterial, son variables alostáticas, no homeostáticas, no son parámetros constantes, sino adaptativos, el organismo cambiará su medio interno para enfrentar el desafío o perturbación que le llega desde el exterior. Pensar en muchas de estas patologías bajo un modelo alostático puede enriquecer los recursos conceptuales del médico y modificar el abordaje de enfermedades prevalentes.
... Additionally, CVDs cause a considerable burden on individual and public health. Therefore, biomedical and social science research has striven to understand and identify the principal physiological changes that could signal the onset of CVDs in individuals at the pre-symptom stage of the disease (Davillas et al., 2019;Dowd & Zajacova, 2007;McEwen, 2015;Mitchell & Aneshensel, 2017). Prevention and identification of the population at significant risk of CVDs have been a primary objective for social scientists, public health policy-makers, and epidemiologists (Davillas et al., 2017;Herd et al., 2007;Mitchell & Aneshensel, 2017). ...
•This study analyzed the total health inequality on risks of chronic inflammation.•We used Bayesian multiple and distributional regression models.•Between-group posterior distributions show a robust educational gradient in health.•Within-group posterior distributions show polarized risks for individuals.
... This situation probably leads to unhealthy ageing promoting chronic diseases [12,13]. Researchers are attempting to clarify the procedures implicated in the physiological and pre-pathological (pre-disease) states through the evaluation of correlations between the molecular markers, physiological systems and physical and cognitive efficiencies [14,15]. In this regard, ageing is modelled as an oncoming reduction of the integrity and level of functions between various organs [14]. ...
Background
Mustard gas as a chemical weapon has been used in wars and its long-term side effects are substantial in the human body. This study was aimed to apply an extension of allostatic load, known as synthetic biological health score (BHS), including the wear-and-tear of four physiological systems (endocrine, inflammatory, cardiovascular and metabolic systems) and two organs (liver and kidney) to estimate biological aging caused by sulfur mustard (SM) gas poisoning.
Methods
The plasma samples were prepared from two following groups of people; 1) 446 individuals exposed to SM gas in 1987. 2) 115 healthy members, at the same range of age and residence, as the non-exposed group. These people were chosen from the same patients’ families and have not had any exposure to SM or pulmonary dysfunction. To estimate BHS, 18 blood-derived biomarkers of the mentioned systems and organs were measured and the relative contribution of many social and body parameters across the age groups was explored.
Results
It was revealed, in BHS calculation, the cardiovascular system had the most effect. Also, in the SM group, BHS was significantly higher than in the control group. This feature has a positive correlation with physical parameter (BMI) and a negative correlation with social parameters (salary and educational levels).
Conclusion
The multisystem BHS could be useful in the evaluation of biological aging due to SM exposure. Social (education, good-paying job) and physical (BMI) parameters could influence BHS and the higher BHS indicates the progress of biological aging due to mustard gas.
... There are a wide range of approaches for stress management in people and animals, many of which rely on the rapid detection of damage that is largely caused by stress and is referred to as biomarkers (Griffiths and Moller, 2002). The stress markers indicate that the person is distressed and expends a lot of energy in order to maintain homeostasis (McEwen, 2015). Biomarker is considered as an indicator to evaluate pathologic and physiologic state of the body (Naylor, 2003). ...
COVID-19 epidemic had a significant impact on many aspects of people lives, when these people urged to quarantine and lockdown to prevent the virus from spreading which had a major effect on people’s mental health, depression and stress. Many internal and environmental causes contribute to this stress, which has a detrimental impact on the body’s homeostasis. As a result, stress may have an impact on the body’s ability to conflict pathogens using its energy. Many recent studies have revealed strong associations between human mental stress and secretion of hormones, prohormones and/or immunological substances, part of these studies have confirmed the correlation between stress and the salivary CgA level, also Secretory IgA (sIgA) plays an important role in immunity by binding the surface molecules of pathogenic microorganisms and preventing adhesion and colonization. The aim of this study is to measure salivary chromogranin A as a stress biomarker as well as Secretory IgA levels among COVID-19 patients. 84 samples were collected from adults who have been divided into two groups: COVID-19 group consists of 42 patients and COVID-19 free group which consists of 42 subjects. All subjects undergo PCR test to confirm their healthy status, collection of unstimulated saliva was done and laboratory investigations was carried out to measure the salivary chromogranin A and Salivary IgA levels by the use of chromogranin A kit (human CGA ELISA kit) by alshakirate establishment for medical supply and SIgA kit (IgA saliva ELISA) by LDN company. SPSS version 21 was used for statistical analysis. Salivary chromogranin A was substantially greater in the COVID-19 group than in the COVID-19 free group, whereas secretory IgA was lower in the COVID-19 group, according to the statistical analysis. In conclusion a significant negative association was found between salivary chromogranin A and secretory IgA (p = 0.001).so, when the concentration of salivary chromogranin A elevated in the COVID-19 group, the level of secretory IgA reduced.
... (2) The stress indicators show that the individual is disturbed and exerts a lot of energy to maintain homeostasis. (3) A biomarker is an indicator used to assess the pathologic and physiologic condition of the individual. (4) According to the FDA, an ideal biomarker should be easily tested, capable of distinguishing between different disorders, safe and harmless, and specific for certain pathological and physiological conditions. ...
Background: The COVID-19 virus outbreak had a massive effect on many parts of people's lives, as they were advised to quarantine and lockdown to prevent the virus from spreading, which had a big impact on people's mental health, anxiety, and stress. Many internal and external factors lead to stress. This negatively influences the body's homeostasis. As a result, stress may affect the body's capacity to use energy to defend against pathogens. Many recent investigations have found substantial links between human mental stress and the production of hormones, prohormones, and/or immunological chemicals. some of these researches have verified the link between stress and salivary cortisol levels. The aim of this study is to measure salivary cortisol as a stress biomarker as well as a total viable count of salivary bacterial microbiome among COVID-19 patients. Materials and methods: a sample of 84 adults patients was collected who were divided into two groups: the COVID-19 group consists of 42 patients and the COVID-19 free group which consists of 42 subjects. All subjects undergo a PCR test to confirm their health status. The collection of Un-stimulated saliva was done. Laboratory investigations were carried out to measure the total viable count of the salivary bacterial microbiome by culturing on Brain Heart Infusion Agar and to evaluate the salivary cortisol level using cortisol kit (Elecsys Cortisol II). Results: SPSS version 21 was used for statistical analysis. According to the statistical analysis, the salivary cortisol and total viable count of salivary bacterial microbiome values were substantially greater in the COVID-19 group than in the COVID-19 free group. Conclusion: A positive association was found between salivary cortisol and the total viable count of the salivary bacterial microbiome. So, when the concentration of salivary cortisol is elevated in the COVID-19 group, the level of the total viable count of the salivary bacterial microbiome is also elevated.
... Biomarkers are an important tool for understanding exposure and risk from the environment as well as providing early warnings or evidence of biological effect (Travis, 2013). Allostatic load (AL) is a biomarker-based measure of cumulative stress (McEwen, 2015) and has been used to explore associations between stress and processes leading to disease (Hansen et al., 2014). Evidence shows that biological measures of stress, based on AL, are associated with a number of individual factors such as age, gender, income and race. ...
Research suggests that individuals living in more disadvantaged neighbourhoods experience higher levels of stress but this has generally been based on self-reported stress. We used survey-based neighbourhood quality indicators and biomarker data from Understanding Society, linked to census and crime statistics to explore associations of allostatic load (AL), an objective biomarker-based measure of cumulative stress, with subjective and objective neighbourhood characteristics. Analyses of 6887 respondents living in England show greater AL among those living in more disadvantaged areas, with objective measure associations stronger than subjective. Neighbourhood inequalities in AL were lower among respondents with higher individual SEP. These results suggest that individual-level SEP mitigates against the impact of negative, particularly objective, neighbourhood characteristics. Policies to reduce health inequalities should consider both individual and neighbourhood circumstances.
... Prolonged and severe stress can induce mental health disorders such as anxiety, depression, and post-traumatic stress disorders [44]. Multiple biomarkers from different tissues have been identified including proteins, hormones, metabolites, miRNA, etc., as potent indicators of various biological processes and consequences induced by different types of stress and stressors [45][46][47][48]. Different peripheral biomarkers may be responsible for identical type of stress, either generally or specifically. ...
Depression has become one of the severe mental disorders threatening global human health. In this study, we first used the proteomics approach to obtain the differentially expressed proteins in the liver between naive control and chronic social defeat stress (CSDS) induced depressed mice. We have identified the upregulation of iron binding protein transferrin (TF) in the liver, the peripheral blood, and the brain in CSDS-exposed mice. Furthermore, bioinformatics analysis of the Gene Expression Omnibus (GEO) database from various mouse models of depression revealed the significantly upregulated transcripts of TF and its receptor TfR1 in multiple brain regions in depressed mice. We also used the recombinant TF administration via the tail vein to detect its permeability through the blood-brain barrier (BBB). We demonstrated the permeability of peripheral TF into the brain through the BBB. Together, these results identified the elevated expression of TF and its receptor TfR1 in both peripheral liver and the central brain in CSDS-induced depressed mice, and peripheral administration of TF can be transported into the brain through the BBB. Therefore, our data provide a compelling information for understanding the potential role and mechanisms of the cross-talk between the liver and the brain in stress-induced depression.
... Этот индекс обладает высокой прогностической значимостью в отношении риска развития ряда патологических состояний и заболеваний: метаболического синдрома, диабета II типа, болезней системы кровообращения и сердечно-сосудистых событий [60]. Несмотря на отсутствие «золотого стандарта», набор переменных для расчёта индекса аллостатической нагрузки, по мнению B.S. McEwen, в обязательном порядке должен включать OCCUPATIONAL HEALTH параметры нейрофизиологических путей (гипоталамо-гипофизарно-надпочечниковой оси и вегетативной нервной системы), а также опосредованные биомаркеры -общепринятые факторы риска соматических расстройств, для которых хронический стресс может служить потенциальным триггером [61]. По данным D. Mauss с соавт., наиболее часто при расчёте ИАТ у работающих в условиях профессионального стресса в качестве первичных медиаторов исследователи использовали кортизол слюны или сыворотки крови, а в качестве опосредованных биомаркеров -артериальное давление, холестерин липопротеидов высокой плотности и глюкозу крови (см. ...
The review concentrates on generalizing results produced by contemporary studies on relations between chronic occupational stress and a wide range of biomarkers of homeostasis and functional state of the body. Bearing in mind diagnostic and predictive significance of neuroendocrine, neurophysiologic, immune and metabolic biomarkers of chronic occupational stress, we analyzed sixty two published papers that were best suitable for our goals. These works were selected from one hundred eighty seven information sources available in CyberLeninka, PubMed and Google Scholar databases. We considered key hormones and intermediates which impose certain limitation on the balance and directions of reactions by the sympathoadrenal system, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-gonadal axis and hypothalamic-pituitary-thyroid axis. We also examined several most significant indicators of the immune system functioning which described the ratio of pro- and anti-inflammatory processes occurring in the body under chronic exposure to psychoemotional occupational factors. We spotted out major methodical issues (a choice of a research object, absence of unified research procedures, interfering factors) which created certain difficulties in interpretation of results produced by testing biomarkers under chronic stress and in use of neuroendocrine and immune indicators in clinical practice. Poly-biomarker studies based on the concept of allostatic loads were shown to bring about new opportunities for preventive and prospect occupational stress management.
... As such, the need to understand the pathophysiological adjustments to maintain homeostatsis is critical. Also, understanding the allostatic load on a military diver will provide documentation of health and habituation to the stress (McEwen, 2015). ...
Introduction: Cold water exposure poses a unique physiological challenge to the human body. Normally, water submersion increases activation of parasympathetic tone to induce bradycardia in order to compensate for hemodynamic shifts and reduce oxygen consumption by peripheral tissues. However, elevated stress, such as that which may occur due to prolonged cold exposure, may shift the sympatho-vagal balance towards sympathetic activation which may potentially negate the dive reflex and impact thermoregulation.
Objective: To quantify the acute stress response during prolonged extreme cold water diving and to determine the influence of acute stress on thermoregulation.
Materials and Methods: Twenty-one (n = 21) subjects tasked with cold water dive training participated. Divers donned standard diving equipment and fully submerged to a depth of ≈20 feet, in a pool chilled to 4°C, for a 9-h training exercise. Pre- and post-training measures included: core and skin temperature; salivary alpha amylase (AA), cortisol (CORT), osteocalcin (OCN), testosterone (TEST) and dehydroepiandosterone (DHEA); body weight; blood glucose, lactate, and ketones.
Results: Core, skin, and extremity temperature decreased (p < 0.001) over the 9-h dive; however, core temperature was maintained above the clinical threshold for hypothermia and was not correlated to body size (p = 0.595). There was a significant increase in AA (p < 0.001) and OCN (p = 0.021) and a significant decrease in TEST (p = 0.003) over the duration of the dive. An indirect correlation between changes in cortisol concentrations and changes in foot temperature (ρ = -0.5,p = 0.042) were observed. There was a significant positive correlation between baseline OCN and change in hand temperature (ρ = 0.66, p = 0.044) and significant indirect correlation between changes in OCN concentrations and changes in hand temperature (ρ = -0.59, p = 0.043).
Conclusion: These data suggest that long-duration, cold water diving initiates a stress response—as measurable by salivary stress biomarkers—and that peripheral skin temperature decreases over the course of these dives. Cumulatively, these data suggest that there is a relationship between the acute stress response and peripheral thermoregulation.
... 34 Repeated cycles of activation and inactivation of allostasis over time or the inability to adequately cope with stress can alter a person's diurnal cortisol rhythm and trigger hormone dysfunction called glucocorticoid resistance. 5,35 If these stresses are not adequately resolved or become chronic, changes in physiological (e.g., diurnal cortisol rhythm or inflammatory functions) or behavioral factors (e.g., physical activity, harmful use of cigarettes and alcohol, or eating patterns) due to stress can occur, which are known to negatively impact physical and psychological health. 36 Several studies have reported that major or minor stress has a negative effect on sleep, which is known to cause insomnia or worsen insomnia symptoms. ...
Objective:
Among various causes of insomnia, stress is the most common and representative cause. Insomnia is also known to negatively affect the quality of life (QoL). The objective of this study was to explore the effect of stress on QoL and the mediating role of insomnia symptoms in the relationship between stress and QoL.
Methods:
In this study, the mediating effect of insomnia symptoms on the relationship between stress and QoL was analyzed by enrolling 3,714 participants from the Ansung and Ansan cohorts of the Korea Association Resource project from 2001 to 2004. These cohort participants were asked about how much they felt stressed during their everyday life. Insomnia symptoms were evaluated by asking participants whether they had trouble sleeping such as difficulty in falling asleep, disrupted sleep, and early morning awakening due to the lack of a validated questionnaire for this cohort. QoL was evaluated using the World Health Organization QoL Scale Brief Version.
Results:
In total, stress was positively associated with insomnia symptoms, which in turn predicted QoL. The same result could be derived from subgroup analysis according to sex, and it was confirmed that insomnia symptoms acted as a mediating factor more significantly in female than in male.
Conclusion:
In this study, insomnia symptoms were confirmed to act as a significant mediating factor between stress and QoL, suggesting that insomnia symptoms should be actively identified and controlled to alleviate the negative effect of stress on QoL in clinical practice.
... For example, Präg and Richards (2019) drew on nurse-collected information in the context of a large and representative British survey to assess associations of social mobility with well-being. For their measure of well-being, they used allostatic load, a measure of the "wear and tear" that the body experiences over the life course (McEwen 2015). This measure is unaffected by any sort of reporting bias, as it is based on nurse-collected information (such as body mass index (BMI)) and a blood sample. ...
Social theory has long predicted that social mobility, in particular downward social mobility, is detrimental to the well-being of individuals. Dissociative and “falling from grace” theories suggest that mobility is stressful due to the weakening of social ties, feelings of alienation, and loss of status. In light of these theories, it is a puzzle that the majority of quantitative studies in this area have shown null results. Our approach to resolve the puzzle is two-fold. First, we argue for a broader conception of the mobility process than is often used and thus focus on intragenerational occupational class mobility rather than restricting ourselves to the more commonly studied intergenerational mobility. Second, we argue that self-reported measures may be biased by habituation (or “entrenched deprivation”). Using nurse-collected health and biomarker data from the UK Household Longitudinal Study (2010–2012, N = 4,123), we derive a measure of allostatic load as an objective gauge of physiological “wear and tear” and compare patterns of mobility effects with self-reports of health using diagonal reference models. Our findings indicate a strong class gradient in both allostatic load and self-rated health, and that both first and current job matter for current well-being outcomes. However, in terms of the effects of mobility itself, we find that intragenerational social mobility is consequential for allostatic load, but not for self-rated health. Downward mobility is detrimental and upward mobility beneficial for well-being as assessed by allostatic load. Thus, these findings do not support the idea of generalized stress from dissociation, but they do support the “falling from grace” hypothesis of negative downward mobility effects. Our findings have a further implication, namely that the differences in mobility effects between the objective and subjective outcome infer the presence of entrenched deprivation. Null results in studies of self-rated outcomes may therefore be a methodological artifact, rather than an outright rejection of decades-old social theory.
Introduction. Currently, biomarkers (BMs) of chronic stress and their integral indicators are successfully used in prenosological diagnostics and prediction of progressing of chronic diseases and assessing impacts exerted on health by various environmental factors, including occupational ones. Materials and methods. We used male workers employed at a metal processing enterprise as an example to examine influence exerted by duration of work under harmful conditions on BM trend and integral indicators of their adaptive conjugacy. The examined workers were aged between 24 and 65 years and their work records varied from 1 to 47 years. The analyzed indicators included the number of significant correlations, the weight of the correlation graph (CG), and correlation adaptation coefficient (CAC). Statistical analysis was performed using the Statistica 10.0 software package. Results. We determined the average level of 16 individual BMs and 5 integral indicators of neuroendocrine, immunoinflammatory and metabolic processes and functional activity of the cardiovascular system in different age groups of subjects (< 10 years; 10–19 years; 20–29 years; ≥ 30). As a result, we established record-dependent elevated levels of cortisol, C-reactive protein and pro-inflammatory cytokines, cholesterol atherogenicity coefficient, blood pressure, body mass index and waist circumference. The highest values of the latter, above the reference limits, were determined in workers with work records ≥ 30 years. The risk group with the greatest adaptive tension consisted of workers with work records of 20–29 years. The lowest values of G and CCA, identified in workers who had to experience harmful working conditions for ≥ 30 years, could indicate a breakdown of adaptation mechanisms and the body’s transition to a state of allostasis. Limitations. The study included only male blue-collar workers. Conclusions. Poly-biomarker approach, including correlation adaptometry, is a preferable tool for population assessment of impacts exerted by duration of contacts with harmful occupational factors as opposed to determining levels of individual BMs.
Although dysregulated stress biology is becoming increasingly recognized as a key driver of lifelong disparities in chronic disease, we presently have no validated biomarkers of toxic stress physiology; no biological, behavioral, or cognitive treatments specifically focused on normalizing toxic stress processes; and no agreed-upon guidelines for treating stress in the clinic or evaluating the efficacy of interventions that seek to reduce toxic stress and improve human functioning. We address these critical issues by (a) systematically describing key systems and mechanisms that are dysregulated by stress; (b) summarizing indicators, biomarkers, and instruments for assessing stress response systems; and (c) highlighting therapeutic approaches that can be used to normalize stress-related biopsychosocial functioning. We also present a novel multidisciplinary Stress Phenotyping Framework that can bring stress researchers and clinicians one step closer to realizing the goal of using precision medicine-based approaches to prevent and treat stress-associated health problems.
Various internal and external factors negatively affect the homeostatic balance of the individual at the whole-body level and cause a state of stress. Stress affects the state of comfort and causes changes in energy consumption mechanisms to combat its effects. Individuals may be immunocompromised, susceptible to pathogens. Stress biomarkers play an important role in the prognosis of stress-related diseases and disorders, and therapy. In addition, different components have been identified as potent mediators of cardiovascular, central nervous system, hepatic, and nephrological disorders, which can also be used to evaluate these conditions precisely, but with strict validation and specificity. Considerable scientific progress has been made in the quantization and application of these biomarkers. This review describes current advances in biomarker identification, their prognostic and therapeutic value. Articles review were carried out using the scooping review method by identifying research publications that match the theme through an online search system. The result of this review is that 31 stress-related biomarkers have an important role in the prognosis of stress-related diseases and disorders, and have been identified as potent mediators of cardiovascular, central nervous system, hepatic, and nephrological disorders. From this review, it can be concluded that chronic stress can cause pathological responses in the body due to disruption of body homeostasis in the long term, resulting in changes in the value of physiological biomarkers of the body. The specific biomarkers that are affected then can be used as diagnostic or prognostic biomarkers.
Objective
Structural forms of stigma and discrimination are associated with adverse health outcomes across numerous stigmatized groups, including lesbian, gay, and bisexual (LGB) individuals. Yet, the biological consequences of structural stigma among LGB populations are understudied. To begin to address this gap, we assessed associations between indicators of structural stigma (i.e., state-level policies) targeting LGB individuals and allostatic load (AL) indices representing physiological dysregulations.
Methods
Pooled data from the continuous 2001-2014 National Health and Nutritional Examination Survey were analyzed (LGB: n = 864; heterosexual: n = 20,310). Ten state-level LGB-related policies (e.g., employment non-discrimination protections, same-sex marriage) were used to operationalize structural stigma. A sex-specific AL index representing 11 immune, metabolic, and cardiovascular biomarkers was estimated. Multi-level models were used to examine associations between structural stigma and AL, net of 9 individual-level characteristics (e.g., education, race/ethnicity, age, and health behaviors).
Results
Sexual minority men living in states with low levels of structural stigma experienced significantly lower AL (β = -.45, p = .02) compared to sexual minority men living in states with high structural stigma (i.e., fewer protective policies). There was no significant association between structural stigma and AL among sexual minority women.
Conclusions
By demonstrating direct associations between structural stigma and indices of physiological dysregulation, our findings provide a mechanistic understanding of how the social environment can “get under the skin and skull” for sexual minority men in the United States. Future research should explore whether these mechanisms generalize to other marginalized groups exposed to structural stigma.
Assessing the allostatic load of workers in the context of COVID-19 is of vital importance to elucidate the physiological responses to social and work stress. This is an integrative review of the literature including seven established steps: 1) identification of the topic and the guiding question; 2) definition of MeSH terms and search equations; 3) search in databases following defined criteria; 4) data collection according to inclusion criteria; 5) evaluation of the studies included in the integrative review; 6) discussion of results; and 7) presentation of the review/synthesis of knowledge. Seventeen studies were included, of which 15 were cross-sectional observational studies and two were longitudinal studies. Heterogeneity in the measurement of allostatic load was the common denominator of the studies. Allostatic load is mentioned in all of them as a parameter of measurement, but they measured it differently; therefore, the relationship between burnout, work environment, and allostatic load, although positive in most studies, was highly variable. In conclusion, it is necessary to conduct studies that combine both biological markers and clinimetric tests, trying to standardize the battery of tests of allostatic load, so that the correlation with work stress is significant and reliable. Similarly, allostatic load requires a systemic and interdisciplinary approach, since this condition puts chronic stress on all organs and physiological compensation mechanisms. Therefore, the allostatic load invites to a comprehensive care of people, considering the work, social, psychological, and biological domains. Keywords | occupational stress; allostasis; professional burnout. RESUMEN | Valorar la carga alostática de los trabajadores en el contexto de la Covid-19 es de vital importancia para dilucidar las respuestas fisiológicas al estrés social y laboral. Esta es una revisión integrativa de la literatura, de siete pasos establecidos: 1) identificación del tema y de la pregunta orientadora; 2) definición de términos MeSH y ecuaciones de búsqueda; 3) búsqueda en bases de datos siguiendo criterios definidos; 4) recopilación de datos acorde a criterios de inclusión; 5) evaluación de los estudios incluidos en la revisión integradora; 6) discusión de resultados; 7) presentación de la revisión/síntesis de conocimientos. Se incluyeron 17 estudios, de los cuales 15 fueron estudios observacionales transversales y dos estudios longitudinales. La heterogeneidad en la medición de la carga alostática fue el común denominador de los estudios. En todos se menciona la carga alostática como parámetro de medición. Sin embargo, todos la midieron de formas diferentes, por lo que la relación entre desgaste ocupacional y carga alostática, aunque positiva en la mayoría de los estudios, fue muy variable. Se concluye que es necesario realizar estudios que combinen tanto los marcadores biológicos como las pruebas clinimétricas, tratando de estandarizar la batería de exámenes de la carga alostática, para que la correlación con estrés laboral sea significativa y confiable. De igual forma, la carga alostática requiere un abordaje sistémico e interdisciplinario, dado que se ponen en tensión crónica todos los órganos y mecanismos de compensación fisiológicos. Por lo tanto, la carga alostática hace una invitación a un cuidado integral de las personas, desde los ámbitos laboral, social, psicológico y biológico. Palabras clave | estrés laboral; alostasis; agotamiento profesional.
Now more than ever, health-care systems and public health agencies are focused on improving health-care quality and outcomes among disparity populations and other individuals from medically underserved groups. As part of this, multilevel approaches are being developed through transdisciplinary research programs that seek to understand and address determinants of disease risk and outcomes within and between multiple domains and levels of influence. The goal of this chapter is to provide an overview of multilevel determinants of cancer health disparities, describe key issues in measuring these factors and translating these discoveries into evidence-based interventions, and identify opportunities for future directions in multilevel research to enhance cancer health equity.
Introduction:
The concept of allostatic load encompasses the cumulative effects of both ordinary daily life events as well as major challenges, and also includes related health-damaging behavior. Allostatic overload ensues when environmental challenges exceed the individual's ability to cope. Identification of allostatic load is carried out through the use of biomarkers and clinimetric criteria. Studies are increasingly reported on allostatic load in younger populations, yet a systematic review is missing.
Objective:
The aim of the present systematic review was to summarize the current knowledge on allostatic load/overload among children and adolescents.
Methods:
PubMed, PsycINFO, Web of Science, and the Cochrane Library were searched from inception to April 2023. A manual search of the literature was also performed. We considered only studies in which allostatic load or overload were adequately described and assessed in either clinical or non-clinical populations younger than 18 years.
Results:
A total of 38 original investigations were included in this systematic review. Studies reported an association between allostatic load and sociodemographic characteristics (e.g., poverty, ethnicity, perceived discrimination, adverse childhood experiences) and environmental factors, as well as consequences of allostatic load on both physical and mental health among children and adolescents.
Conclusions:
The findings indicate that greater allostatic load is associated with poorer health outcomes in both clinical and non-clinical pediatric populations, with possible enduring effects. The results support the clinical utility of the transdiagnostic identification of allostatic load and overload in children and adolescents across a variety of settings, with a number of potential clinical implications.
Chronic kidney disease (CKD) affects over 10% of the world population with increasing prevalence in middle age. The risk for CKD is dependent on the number of functioning nephrons through the life cycle and 50% of nephrons are lost through normal aging, revealing their vulnerability to internal and external stressors. Factors responsible for CKD remain poorly understood with limited availability of biomarkers or effective therapy to slow progression. This review draws on the disciplines of evolutionary medicine and bioenergetics to account for the heterogeneous nephron injury that characterizes progressive CKD following acute kidney injury with incomplete recovery. The evolution of symbiosis in eukaryotes led to the efficiencies of oxidative phosphorylation and the rise of metazoa. Adaptations to ancestral environments are the products of natural selection that have shaped the mammalian nephron with its vulnerabilities to ischemic, hypoxic, and toxic injury. Reproductive fitness rather than longevity has served as the driver of evolution, constrained by available energy and its allocation to homeostatic responses through the life cycle. Metabolic plasticity has evolved in parallel with robustness necessary to preserve complex developmental programs, and adaptations that optimize survival through reproductive years can become maladaptive with aging, reflecting antagonistic pleiotropy. Consequently, environmental stresses promote tradeoffs and mismatches that result in cell fate decisions that ultimately lead to nephron loss. Elucidation of the bioenergetic adaptations by the nephron to ancestral and contemporary environments may lead to the development of new biomarkers of kidney disease and new therapies to reduce the global burden of progressive CKD.
Poor resilience is the result of prolonged chronically stressful experiences that ultimately lead to widespread biological and behavioral impairments throughout the whole being due in large part to a dysregulated stress response system, and the lack of effective emotion–regulation coping strategies and personal and social resources. This chapter reviews the progressively corrosive neurophysiological, immune, and molecular impairments and lack of neural and behavioral flexibility caused by emotional distress that predispose the individual to cancer or a chronic illness.KeywordsPoor resilienceAllostatic loadAllostatic overloadNursingCancer care
Psychological stress is the individual’s neurophysiological and behavioral response to internal and external environmental stressors. Because resilient processes are triggered by diverse stressor events, this chapter covers the differential forms of stress on the human organism as a function of their duration, intensity and frequency. Good, tolerable, and potentially threatening forms of stress are highlighted. Given the research and clinical trend toward developing measurable cumulative indexes that capture the effects of stress throughout the whole being, measurable terms of allostasis, allostatic load, and allostatic overload are also described as well as their potential applicability in cancer care.KeywordsPsychological stressAllostasisAllostatic load/overloadNursing careCancer careCumulative measure of allostatic load
Depressive and anxiety disorders account for some of the most important causes of nonfatal health loss worldwide and are currently treated through pharmacological interventions with several undesired side effects. In the past decade, increasing evidence has shown that the consumption of certain probiotic strains might exert health benefits beyond the gastrointestinal tract. These probiotics capable of improving psychiatric conditions upon ingestion in the adequate amounts were named psychobiotics and represent a promising complementary approach to improve the life quality of those undergoing mental distress. This chapter presents the most recent data supporting the therapeutic effect of psychobiotics as well as some of the potential mechanisms involved.
The recent Food and Drug Administration and European Medicine Agency regulatory approval of intranasal (S)-Ketamine for the treatment-resistant depression in adults and its quick introduction in everyday psychiatric practice might be considered as a second revolution in the field of neuropsychopharmacology after the first one, which started over 50 years ago with the discovery of the monoaminergic antidepressants. This chapter will present the critical antidepressant features of Ketamine, including its putative mechanisms of action and other Ketamine-like glutamatergic drugs in development for the treatment of chronic stress-related psychiatric disorders. First, a detailed picture of NMDA-dependent and independent glutamatergic mechanisms mediating Ketamine effects will be given. The following section will be dedicated to an in-depth description of cellular and molecular mechanisms which have been suggested to underlie the fast antidepressant properties of Ketamine. Alternative investigational therapeutic uses of Ketamine (besides as an antidepressant) will then be presented, followed by the description of other glutamatergic drugs which received significant attention for their potential antidepressant effects. The following part will be dedicated to limitations related to Ketamine use. Finally, we will share our insights and provide recommendations on the future perspectives in the prevention and early management of chronic stress and stress-related disorders, focusing on glutamate-based aspects of proposed interventions.
Adverse Childhood Experiences (ACEs) are stressful and/or traumatic experiences associated with an increased lifetime risk of negative health outcomes. The Allostatic Load (AL) is a measure of multisystem dysregulation, resulted by chronic stress. We systematically reviewed the English language literature on the association between ACEs and AL to identify the clinical risk profile, with the exclusion of reviews and preclinical studies. Searches covered the publication period up to the 1st of February 2022 and identified 25 studies in which ACEs such as maltreatment, abuse, poverty, psychological abuse, and discrimination were investigated in the context of AL. The selected studies used different sets of AL biomarkers resulting in substantial heterogenicity of calculating the AL index. Overall, we found that ACEs are associated with elevated AL and poorer health outcomes in adulthood. Furthermore, health risk behaviors, social support, and coping resources either moderate or mediate this association. These findings suggest that targeting individuals at risk and starting interventions early might reduce AL and its deleterious health consequences.
During the latter half of the twentieth century, an explosion of research elucidated a growing number of causes of disease and contributors to health. Biopsychosocial models that accounted for the wide range of factors influencing health began to replace outmoded and overly simplified biomedical models of disease causation. More recently, models of lifecourse health development (LCHD) have synthesized research from biological, behavioral and social science disciplines, defined health development as a dynamic process that begins before conception and continues throughout the lifespan, and paved the way for the creation of novel strategies aimed at optimization of individual and population health trajectories. As rapid advances in epigenetics and biological systems research continue to inform and refine LCHD models, our healthcare delivery system has struggled to keep pace, and the gulf between knowledge and practice has widened. This paper attempts to chart the evolution of the LCHD framework, and illustrate its potential to transform how the MCH system addresses social, psychological, biological, and genetic influences on health, eliminates health disparities, reduces chronic illness, and contains healthcare costs. The LCHD approach can serve to highlight the foundational importance of MCH, moving it from the margins of national debate to the forefront of healthcare reform efforts. The paper concludes with suggestions for innovations that could accelerate the translation of health development principles into MCH practice.
To identify molecular mechanisms underlying the prospective health advantages associated with psychological well-being, we analyzed leukocyte basal gene expression profiles in 80 healthy adults who were assessed for hedonic and eudaimonic well-being, as well as potentially confounded negative psychological and behavioral factors. Hedonic and eudaimonic well-being showed similar affective correlates but highly divergent transcriptome profiles. Peripheral blood mononuclear cells from people with high levels of hedonic well-being showed up-regulated expression of a stress-related conserved transcriptional response to adversity (CTRA) involving increased expression of proinflammatory genes and decreased expression of genes involved in antibody synthesis and type I IFN response. In contrast, high levels of eudaimonic well-being were associated with CTRA down-regulation. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity in structuring the observed differences in gene expression associated with eudaimonic well-being (reduced NF-κB and AP-1 signaling and increased IRF and STAT signaling). Transcript origin analysis identified monocytes, plasmacytoid dendritic cells, and B lymphocytes as primary cellular mediators of these dynamics. The finding that hedonic and eudaimonic well-being engage distinct gene regulatory programs despite their similar effects on total well-being and depressive symptoms implies that the human genome may be more sensitive to qualitative variations in well-being than are our conscious affective experiences.
The primary objectives of this article are (a) to put forth an explicit operational formulation of positive human health that goes beyond prevailing "absence of illness" criteria; (b) to clarify that positive human health does not derive from extant medical considerations, which are not about wellness, but necessarily require a base in philosophical accounts of the "goods" in life; (c) to provoke a change of emphasis from strong tendencies to construe human health as exclusively about the mind or the body toward an integrated and positive spiral of mind-body influences; (d) to delineate possible physiological substrates of human flourishing and offer future directions for understanding the biology of positive health; and (e) to discuss implications of positive health for diverse scientific agendas (e.g., stress, class and health, work and family life) and for practice in health fields (e.g., training, health examinations, psychotherapy, and wellness intervention programs).
Importance
Currently, fewer than 40% of patients treated for major depressive disorder achieve remission with initial treatment. Identification of a biological marker that might improve these odds could have significant health and economic impact.Objective
To identify a candidate neuroimaging “treatment-specific biomarker” that predicts differential outcome to either medication or psychotherapy.Design
Brain glucose metabolism was measured with positron emission tomography prior to treatment randomization to either escitalopram oxalate or cognitive behavior therapy for 12 weeks. Patients who did not remit on completion of their phase 1 treatment were offered enrollment in phase 2 comprising an additional 12 weeks of treatment with combination escitalopram and cognitive behavior therapy.Setting
Mood and anxiety disorders research program at an academic medical center.Participants
Men and women aged 18 to 60 years with currently untreated major depressive disorder.Intervention
Randomized assignment to 12 weeks of treatment with either escitalopram oxalate (10-20 mg/d) or 16 sessions of manual-based cognitive behavior therapy.Main Outcome and Measure
Remission, defined as a 17-item Hamilton Depression Rating Scale score of 7 or less at both weeks 10 and 12, as assessed by raters blinded to treatment.Results
Positive and negative predictors of remission were identified with a 2-way analysis of variance treatment (escitalopram or cognitive behavior therapy) × outcome (remission or nonresponse) interaction. Of 65 protocol completers, 38 patients with clear outcomes and usable positron emission tomography scans were included in the primary analysis: 12 remitters to cognitive behavior therapy, 11 remitters to escitalopram, 9 nonresponders to cognitive behavior therapy, and 6 nonresponders to escitalopram. Six limbic and cortical regions were identified, with the right anterior insula showing the most robust discriminant properties across groups (effect size = 1.43). Insula hypometabolism (relative to whole-brain mean) was associated with remission to cognitive behavior therapy and poor response to escitalopram, while insula hypermetabolism was associated with remission to escitalopram and poor response to cognitive behavior therapy.Conclusions and Relevance
If verified with prospective testing, the insula metabolism-based treatment-specific biomarker defined in this study provides the first objective marker, to our knowledge, to guide initial treatment selection for depression.Trial Registration
Registered at clinicaltrials.gov (NCT00367341)
Excessive glucocorticoid exposure during chronic stress causes synapse loss and learning impairment. Under normal physiological conditions, glucocorticoid activity oscillates in synchrony with the circadian rhythm. Whether and how endogenous glucocorticoid oscillations modulate synaptic plasticity and learning is unknown. Here we show that circadian glucocorticoid peaks promote postsynaptic dendritic spine formation in the mouse cortex after motor skill learning, whereas troughs are required for stabilizing newly formed spines that are important for long-term memory retention. Conversely, chronic and excessive exposure to glucocorticoids eliminates learning-associated new spines and disrupts previously acquired memories. Furthermore, we show that glucocorticoids promote rapid spine formation through a non-transcriptional mechanism by means of the LIM kinase-cofilin pathway and increase spine elimination through transcriptional mechanisms involving mineralocorticoid receptor activation. Together, these findings indicate that tightly regulated circadian glucocorticoid oscillations are important for learning-dependent synaptic formation and maintenance. They also delineate a new signaling mechanism underlying these effects.
In response to queries about whether brain imaging technology has reached the point where it is useful for making a clinical diagnosis and for helping to guide treatment selection, the American Psychiatric Association (APA) has recently written a position paper on the Clinical Application of Brain Imaging in Psychiatry. The following perspective piece is based on our contribution to this APA position paper, which specifically emphasized the application of neuroimaging in mood disorders. We present an introductory overview of the challenges faced by researchers in developing valid and reliable biomarkers for psychiatric disorders, followed by a synopsis of the extant neuroimaging findings in mood disorders, and an evidence-based review of the current research on brain imaging biomarkers in adult mood disorders. Although there are a number of promising results, by the standards proposed below, we argue that there are currently no brain imaging biomarkers that are clinically useful for establishing diagnosis or predicting treatment outcome in mood disorders.Molecular Psychiatry advance online publication, 2 April 2013; doi:10.1038/mp.2013.25.
Context: Current behavioral measures poorly predict treatment outcome in social anxiety disorder (SAD). To our knowledge, this is the first study to examine neuroimaging-based treatment prediction in SAD.
Objective: To measure brain activation in patients with SAD as a biomarker to predict subsequent response to cognitive behavioral therapy (CBT).
Design: Functional magnetic resonance imaging (fMRI) data were collected prior to CBT intervention. Changes in clinical status were regressed on brain responses and tested for selectivity for social stimuli.
Setting: Patients were treated with protocol-based CBT at anxiety disorder programs at Boston University or Massachusetts General Hospital and underwent neuroimaging data collection at Massachusetts Institute of Technology.
Patients: Thirty-nine medication-free patients meeting DSM-IV criteria for the generalized subtype of SAD.
Interventions: Brain responses to angry vs neutral faces or emotional vs neutral scenes were examined with fMRI prior to initiation of CBT.
Main Outcome Measures: Whole-brain regression analyses with differential fMRI responses for angry vs neutral faces and changes in Liebowitz Social Anxiety Scale score as the treatment outcome measure.
Results: Pretreatment responses significantly predicted subsequent treatment outcome of patients selectively for social stimuli and particularly in regions of higher-order visual cortex. Combining the brain measures with information on clinical severity accounted for more than 40% of the variance in treatment response and substantially exceeded predictions based on clinical measures at baseline. Prediction success was unaffected by testing for potential confounding factors such as depression severity at baseline.
Conclusions: The results suggest that brain imaging can provide biomarkers that substantially improve predictions for the success of cognitive behavioral interventions and more generally suggest that such biomarkers may offer evidence-based, personalized medicine approaches for optimally selecting among treatment options for a patient.
We examined relationships between neighborhood poverty and allostatic load in a low- to moderate-income multiracial urban community. We tested the hypothesis that neighborhood poverty is associated with allostatic load, controlling for household poverty. We also examined the hypotheses that this association was mediated by psychosocial stress and health-related behaviors.
We conducted multilevel analyses using cross-sectional data from a probability sample survey in Detroit, Michigan (n = 919) and the 2000 US Census. The outcome measure was allostatic load. Independent variables included neighborhood and household poverty, psychosocial stress, and health-related behaviors. Covariates included neighborhood and individual demographic characteristics.
Neighborhood poverty was positively associated with allostatic load (P < .05), independent of household poverty and controlling for potential confounders. Relationships between neighborhood poverty were mediated by self-reported neighborhood environment stress but not by health-related behaviors.
Neighborhood poverty is associated with wear and tear on physiological systems, and this relationship is mediated through psychosocial stress. These relationships are evident after accounting for household poverty levels. Efforts to promote health equity should focus on neighborhood poverty, associated stressful environmental conditions, and household poverty.
Suicidal behaviors are frequent in mood disorders patients but only a subset of them ever complete suicide. Understanding predisposing factors for suicidal behaviors in high risk populations is of major importance for the prevention and treatment of suicidal behaviors. The objective of this project was to investigate gene expression changes associated with suicide in brains of mood disorder patients by microarrays (Affymetrix HG-U133 Plus2.0) in the dorsolateral prefrontal cortex (DLPFC: 6 Non-suicides, 15 suicides), the anterior cingulate cortex (ACC: 6NS, 9S) and the nucleus accumbens (NAcc: 8NS, 13S). ANCOVA was used to control for age, gender, pH and RNA degradation, with P ≤ 0.01 and fold change ± 1.25 as criteria for significance. Pathway analysis revealed serotonergic signaling alterations in the DLPFC and glucocorticoid signaling alterations in the ACC and NAcc. The gene with the lowest p-value in the DLPFC was the 5-HT2A gene, previously associated both with suicide and mood disorders. In the ACC 6 metallothionein genes were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H, MT1X, MT2A) and three were down-regulated in the NAcc (MT1F, MT1G, MT1H). Differential expression of selected genes was confirmed by qPCR, we confirmed the 5-HT2A alterations and the global down-regulation of members of the metallothionein subfamilies MT 1 and 2 in suicide completers. MTs 1 and 2 are neuro-protective following stress and glucocorticoid stimulations, suggesting that in suicide victims neuroprotective response to stress and cortisol may be diminished. Our results thus suggest that suicide-specific expression changes in mood disorders involve both glucocorticoids regulated metallothioneins and serotonergic signaling in different regions of the brain.
Experiential factors shape the neural circuits underlying social and emotional behavior from the prenatal period to the end of life. These factors include both incidental influences, such as early adversity, and intentional influences that can be produced in humans through specific interventions designed to promote prosocial behavior and well-being. Here we review important extant evidence in animal models and humans. Although the precise mechanisms of plasticity are still not fully understood, moderate to severe stress appears to increase the growth of several sectors of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. Structural and functional changes in the brain have been observed with cognitive therapy and certain forms of meditation and lead to the suggestion that well-being and other prosocial characteristics might be enhanced through training.
There is increasing interest in discovering mechanisms that mediate the effects of childhood stress on late-life disease morbidity and mortality. Previous studies have suggested one potential mechanism linking stress to cellular aging, disease and mortality in humans: telomere erosion. We examined telomere erosion in relation to children's exposure to violence, a salient early-life stressor, which has known long-term consequences for well-being and is a major public-health and social-welfare problem. In the first prospective-longitudinal study with repeated telomere measurements in children while they experienced stress, we tested the hypothesis that childhood violence exposure would accelerate telomere erosion from age 5 to age 10 years. Violence was assessed as exposure to maternal domestic violence, frequent bullying victimization and physical maltreatment by an adult. Participants were 236 children (49% females; 42% with one or more violence exposures) recruited from the Environmental-Risk Longitudinal Twin Study, a nationally representative 1994-1995 birth cohort. Each child's mean relative telomere length was measured simultaneously in baseline and follow-up DNA samples, using the quantitative PCR method for T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Compared with their counterparts, the children who experienced two or more kinds of violence exposure showed significantly more telomere erosion between age-5 baseline and age-10 follow-up measurements, even after adjusting for sex, socioeconomic status and body mass index (B=-0.052, s.e.=0.021, P=0.015). This finding provides support for a mechanism linking cumulative childhood stress to telomere maintenance, observed already at a young age, with potential impact for life-long health.Molecular Psychiatry advance online publication, 24 April 2012; doi:10.1038/mp.2012.32.
Neural circuits display a heightened sensitivity to external stimuli during well-established windows in early postnatal life. After the end of these critical periods, brain plasticity dramatically wanes. The visual system is one of the paradigmatic models for studying experience-dependent plasticity. Here we show that food restriction can be used as a strategy to restore plasticity in the adult visual cortex of rats. A short period of food restriction in adulthood is able both to reinstate ocular dominance plasticity and promote recovery from amblyopia. These effects are accompanied by a reduction of intracortical inhibition without modulation of brain-derived neurotrophic factor expression or extracellular matrix structure. Our results suggest that food restriction could be investigated as a potential way of modulating plasticity.
Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety- and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders.
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits.
In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5-10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163.
118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7-38·4]) than in the placebo group (24·3 points [19·9-28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial seizure (one [<1%] vs 0).
In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit.
Public French National Programme for Clinical Research.
Adult brain plasticity, although possible, remains more restricted in scope than during development. Here, we address conditions under which circuit rewiring may be facilitated in the mature brain. At a cellular and molecular level, adult plasticity is actively limited. Some of these "brakes" are structural, such as perineuronal nets or myelin, which inhibit neurite outgrowth. Others are functional, acting directly upon excitatory-inhibitory balance within local circuits. Plasticity in adulthood can be induced either by lifting these brakes through invasive interventions or by exploiting endogenous permissive factors, such as neuromodulators. Using the amblyopic visual system as a model, we discuss genetic, pharmacological, and environmental removal of brakes to enable recovery of vision in adult rodents. Although these mechanisms remain largely uncharted in the human, we consider how they may provide a biological foundation for the remarkable increase in plasticity after action video game play by amblyopic subjects.
The brain is the key organ of stress processes. It determines what individuals will experience as stressful, it orchestrates how individuals will cope with stressful experiences, and it changes both functionally and structurally as a result of stressful experiences. Within the brain, a distributed, dynamic, and plastic neural circuitry coordinates, monitors, and calibrates behavioral and physiological stress response systems to meet the demands imposed by particular stressors. These allodynamic processes can be adaptive in the short term (allostasis) and maladaptive in the long term (allostatic load). Critically, these processes involve bidirectional signaling between the brain and body. Consequently, allostasis and allostatic load can jointly affect vulnerability to brain-dependent and stress-related mental and physical health conditions. This review focuses on the role of brain plasticity in adaptation to, and pathophysiology resulting from, stressful experiences. It also considers interventions to prevent and treat chronic and prevalent health conditions via allodynamic brain mechanisms.
The purpose of this study was to evaluate the effectiveness of integrative health (IH) coaching on psychosocial factors, behavior change, and glycemic control in patients with type 2 diabetes.
Fifty-six patients with type 2 diabetes were randomized to either 6 months of IH coaching or usual care (control group). Coaching was conducted by telephone for fourteen 30-minute sessions. Patients were guided in creating an individualized vision of health, and goals were self-chosen to align with personal values. The coaching agenda, discussion topics, and goals were those of the patient, not the provider. Preintervention and postintervention assessments measured medication adherence, exercise frequency, patient engagement, psychosocial variables, and A1C.
Perceived barriers to medication adherence decreased, while patient activation, perceived social support, and benefit finding all increased in the IH coaching group compared with those in the control group. Improvements in the coaching group alone were also observed for self-reported adherence, exercise frequency, stress, and perceived health status. Coaching participants with elevated baseline A1C (>/=7%) significantly reduced their A1C.
A coaching intervention focused on patients' values and sense of purpose may provide added benefit to traditional diabetes education programs. Fundamentals of IH coaching may be applied by diabetes educators to improve patient self-efficacy, accountability, and clinical outcomes.
Posttraumatic stress disorder (PTSD) is a psychiatric condition that is directly precipitated by an event that threatens a person's life or physical integrity and that invokes a response of fear, helplessness, or horror. In recent years it has become clear that only a proportion of those exposed to fear-producing events develop or sustain PTSD. Thus, it seems that an important challenge is to elucidate aberrations in the normal fear response that might precipitate trauma-related psychiatric disorder. This paper summarizes the findings from recent studies that examined the acute and longer term biological response to traumatic stress in people appearing to the emergency room immediately following trauma exposure. In the aggregate, these studies have demonstrated increased heart rate and lower cortisol levels at the time of the traumatic event in those who have PTSD at a follow-up time compared to those who do not. In contrast, certain features associated with PTSD, such as intrusive symptoms and exaggerated startle responses, are only manifest weeks after the trauma. The findings suggest that the development of PTSD may be facilitated by an atypical biological response in the immediate aftermath of a traumatic event, which in turn leads to a maladaptive psychological state.
Objective: To determine whether depressed patients demonstrate hypothalamic-pituitary-adrenal (HPA) axis activation during the late afternoon and evening, a time when the HPA axis is usually quiescent in normal subjects. Methods: We administered metyrapone, an 11-βhydroxylase inhibitor of cortisol synthesis, to normal controls and depressed patients between 4 and 10 PM. Metyrapone blockade of cortisol secretion would amplify any HPA axis secretion. Results: In 10 normal control subjects, administration of metyrapone lowered plasma cortisol levels to a mean of 36 nmol/L. No rebound corticotropin or β-endorphin secretion was seen in these normal controls between 4 and 10PM, supporting the existence of a period of minimal endogenous corticotropin releasing factor drive. Compared with a group of placebo-treated depressed patients (n=10), metyrapone-treated depressed subjects (n=17) had significantly decreased plasma cortisol concentrations. However, in contrast to normal controls treated with metyrapone, metyrapone-treated depressed patients demonstrated rebound corticotroph secretion, particularly between 7:30 and 10PM( P =.036 for patients vs normal controls for β-endorphin secretion from 4:30 to 10PM). Conclusion: These data support the hypothesis of increased corticotropin releasing factor drive in the evening in depressed subjects and are in agreement with the longstanding observation of "early escape" from dexamethasone suppression between 4 and 11 PM in depressed patients.
The prefrontal cortex (PFC) is involved in working memory and self-regulatory and goal-directed behaviors and displays remarkable structural and functional plasticity over the life course. Neural circuitry, molecular profiles, and neurochemistry can be changed by experiences, which influence behavior as well as neuroendocrine and autonomic function. Such effects have a particular impact during infancy and in adolescence. Behavioral stress affects both the structure and function of PFC, though such effects are not necessarily permanent, as young animals show remarkable neuronal resilience if the stress is discontinued. During aging, neurons within the PFC become less resilient to stress. There are also sex differences in the PFC response to stressors. While such stress and sex hormone-related alterations occur in regions mediating the highest levels of cognitive function and self-regulatory control, the fact that they are not necessarily permanent has implications for future behavior-based therapies that harness neural plasticity for recovery.
The present study tested the hypothesis that some subjects may not readily show habituation of adrenocortical stress responses to repeated psychological stress. Twenty healthy male subjects were each exposed five times to the same, brief psychosocial stressor (public speaking and mental arithmetic in front of an audience) with one stress session per day. Salivary cortisol levels were assessed as an index of adrenocortical stress responses. For the total group, cortisol levels were significantly elevated on each of the 5 days. The mean response decreased from day 1 to day 2; however, no further attenuation could be observed on the remaining days. Cluster analysis revealed two groups of subjects who showed completely different response kinetics. In the first group (N = 13), termed "low responders," cortisol levels were elevated on day 1 only. Day 2 to 5 cortisol levels were unaltered. In contrast, subjects in the second group ("high responders") displayed large increases to each of the five experimental treatments. This group had no significant response decrement from day 1 to day 2 to 4 and only a marginal response difference between day 1 and day 5. Discriminant analysis revealed that a combination of five personality scales plus the scores on a symptoms checklist significantly discriminated between high and low responders. With this discriminant function, all 20 subjects were correctly classified to the two groups. These results are discussed with a focus on the possible impact of adrenocortical response types on health and disease.
Obesity is a prevalent global-health problem associated with substantial morbidity, impairment and economic burden. Because most readily available forms of treatment are ineffective in the long term, it is essential to advance knowledge of obesity prevention by identifying potentially modifiable risk factors. Findings from experimental studies in non-human primates suggest that adverse childhood experiences may influence obesity risk. However, observations from human studies showed heterogeneous results. To address these inconsistencies, we performed Medline, PsycInfo and Embase searches till 1 August 2012 for articles examining the association between childhood maltreatment and obesity. We then conducted a meta-analysis of the identified studies and explored the effects of various possible sources of bias. A meta-analysis of 41 studies (190 285 participants) revealed that childhood maltreatment was associated with elevated risk of developing obesity over the life-course (odds ratio=1.36; 95% confidence interval=1.26-1.47). Results were not explained by publication bias or undue influence of individual studies. Overall, results were not significantly affected by the measures or definitions used for maltreatment or obesity, nor by confounding by childhood or adult socioeconomic status, current smoking, alcohol intake or physical activity. However, the association was not statistically significant in studies of children and adolescents, focusing on emotional neglect, or adjusting for current depression. Furthermore, the association was stronger in samples including more women and whites, but was not influenced by study quality. Child maltreatment is a potentially modifiable risk factor for obesity. Future research should clarify the mechanisms through which child maltreatment affects obesity risk and explore methods to remediate this effect.Molecular Psychiatry advance online publication, 21 May 2013; doi:10.1038/mp.2013.54.
"This new edition of Social Determinants of Health takes account of the most recent research in the field, and includes additional chapters on ethnicity and health, sexual behaviours, the elderly, housing, and neighbourhoods. It is written by acknowledged experts in each field, using non-technical language to make the book accessible to students and those with no previous expertise in epidemiology. This volume provides the evidence behind the WHO initiatives on the social determinants of health, known as The Solid Facts handbook.". "Social Determinants of Health is the most comprehensive, ground-breaking, and authoritative survey of research findings in this field, and is a must for everyone interested in the wellbeing of modern societies. Public health professionals, health promotion specialists, and anyone working in the many fields of public policy will engage with the issues raised in this book."--BOOK JACKET.
In the ageing process, neural areas¹,² and cognitive processes³,⁴ do not degrade uniformly. Executive control processes and the prefrontal and frontal brain regions that support them show large and disproportionate changes with age. Studies of adult animals indicate that metabolic⁵ and neurochemical⁶ functions improve with aerobic fitness. We therefore investigated whether greater aerobic fitness in adults would result in selective improvements in executive control processes, such as planning, scheduling, inhibition and working memory. Over a period of six months, we studied 124 previously sedentary adults, 60 to 75 years old, who were randomly assigned to either aerobic (walking) or anaerobic (stretching and toning) exercise. We found that those who received aerobic training showed substantial improvements in performance on tasks requiring executive control compared with anaerobically trained subjects.
A stark warning about the societal costs of stress comes from links
between shortened telomeres, chronic stress and disease, say Elizabeth
H. Blackburn and Elissa S. Epel.
In this review, we propose a broader view of the role of the fibroblast growth factor (FGF) family in modulating brain function. We suggest that some of the FGF ligands together with the FGF receptors are altered in individuals with affective disorder and modulate emotionality in animal models. Thus, we propose that members of the FGF family may be genetic predisposing factors for anxiety, depression, or substance abuse; that they play a key organizing role during early development but continue to play a central role in neuroplasticity in adulthood; and that they work not only over extended time frames, but also via rapid signaling mechanisms, allowing them to exert an "on-line" influence on behavior. Therefore, the FGF family appears to be a prototype of "switch genes" that are endowed with organizational and modulatory properties across the lifespan, and that may represent molecular candidates as biomarkers and treatment targets for affective and addictive disorders.
The theoretical constructs of allostasis and allostatic load (AL) have contributed to our understanding of how constantly changing social and environmental factors impact physiological functioning and shape health and aging disparities, particularly along socioeconomic, gendered, racial, and ethnic lines. AL represents the cumulative dysregulation of biological systems with prolonged or poorly regulated allostatic responses. Nearly two decades of empirical research has focused on operationalizing the AL construct for examining the antecedents and health outcomes accompanying multisystem biological dysregulation. The purpose of this systematic review is to examine the empirical literature that quantifies the AL construct; the review also evaluates the social, environmental, and genetic antecedents of AL as well as its predictive utility for a variety of health outcomes. A total of 58 articles published between 1997 and 2012 were retrieved, analyzed, and synthesized. The results revealed considerable heterogeneity in the operationalization of AL and the measurement of AL biomarkers, making interpretations and comparisons across studies challenging. There is, however, empirical substantiation for the relationships between AL and socioeconomic status, social relationships, workplace, lifestyle, race/ethnicity, gender, stress exposure, and genetic factors. The literature also demonstrated associations between AL and physical and mental health and all-cause mortality. Targeting the antecedents of AL during key developmental periods is essential for improving public health. Priorities for future research include conducting prospective longitudinal studies, examining a broad range of antecedent allostatic challenges, and collecting reliable measures of multisystem dysregulation explicitly designed to assess AL, at multiple time points, in population-representative samples.
This study aims to provide evidence concerning the effects of experiencing multiple forms of victimization (poly-victimization) on self-esteem and post-traumatic stress symptoms in Spanish adolescents. A total of 722 adolescents were recruited from seven secondary schools in Catalonia, Spain. The Rosenberg Self-Esteem Scale, the Youth Self Report and the Juvenile Victimization Questionnaire were employed to assess self-esteem, post-traumatic stress symptoms and victimization, respectively. Participants were divided into three groups (non-victim, victim and poly-victim groups) according to the total number of different kinds of victimization experienced. Results showed that 88.4 % of adolescents had been exposed to at least one kind of victimization. Poly-victimization was associated with a higher number of post-traumatic stress symptoms in both boys and girls. Also, self-liking was significantly lower in the poly-victim group, whereas self-competence was equivalent across the three victimization groups. Girls were approximately twice as likely to report child maltreatment (OR = 1.92) and sexual victimization (OR = 2.41) as boys. In conclusion, the present study adds evidence on the importance of taking account of the full burden of victimizations suffered when studying victimization correlates. Also, it highlights the importance of prevention policies to focus particularly on preserving adolescents' sense of social worth.
Background:
The surveillance and effector functions of the immune system are critically dependent on the appropriate distribution of immune cells in the body. An acute or short-term stress response induces a rapid and significant redistribution of immune cells among different body compartments. Stress-induced leukocyte redistribution may be a fundamental survival response that directs leukocyte subpopulations to specific target organs during stress, and significantly enhances the speed, efficacy and regulation of an immune response. Immune responses are generally enhanced in compartments (e.g., skin) that are enriched with leukocytes, and suppressed in compartments that are depleted of leukocytes during/following stress. The experiments described here were designed to elucidate the: (1) Time-course, trajectory, and subpopulation-specificity of stress-induced mobilization and trafficking of blood leukocytes. (2) Individual and combined actions of the principal stress hormones, norepinephrine (NE), epinephrine (EPI), and corticosterone (CORT), in mediating mobilization or trafficking of specific leukocyte subpopulations. (3) Effects of stress/stress hormones on adhesion molecule, L-selectin (CD62L), expression by each subpopulation to assess its adhesion/functional/maturation status.
Methods:
Male Sprague Dawley rats were stressed (short-term restraint, 2-120 min), or adrenalectomized and injected with vehicle (VEH), NE, EPI, CORT, or their combinations, and blood was collected for measurement of hormones and flow cytometric quantification of leukocyte subpopulations.
Results:
Acute stress induced an early increase/mobilization of neutrophils, lymphocytes, helper T cells (Th), cytolytic T cells (CTL), and B cells into the blood, followed by a decrease/trafficking of all cell types out of the blood, except neutrophil numbers that continued to increase. CD62L expression was increased on neutrophils, decreased on Th, CTL, and natural killer (NK) cells, and showed a biphasic decrease on monocytes & B cells, suggesting that CD62L is involved in mediating the redistribution effects of stress. Additionally, we observed significant differences in the direction, magnitude, and subpopulation specificity of the effects of each hormone: NE increased leukocyte numbers, most notably CD62L⁻/⁺ neutrophils and CD62L⁻ B cells. EPI increased monocyte and neutrophil numbers, most notably CD62L⁻/⁺ neutrophils and CD62L⁻ monocytes, but decreased lymphocyte numbers with CD62L⁻/⁺ CTL and CD62L⁺ B cells being especially sensitive. CORT decreased monocyte, lymphocyte, Th, CTL, and B cell numbers with CD62L⁻ and CD62L⁺ cells being equally affected. Thus, naïve (CD62L⁺) vs. memory (CD62L⁻) T cells, classical (CD62L⁺) vs. non-classical (CD62L⁻) monocytes, and similarly distinct functional subsets of other leukocyte populations are differentially mobilized into the blood and trafficked to tissues by stress hormones.
Conclusion:
Stress hormones orchestrate a large-scale redistribution of immune cells in the body. NE and EPI mobilize immune cells into the bloodstream, and EPI and CORT induce traffic out of the blood possibly to tissue surveillance pathways, lymphoid tissues, and sites of ongoing or de novo immune activation. Immune cell subpopulations appear to show differential sensitivities and redistribution responses to each hormone depending on the type of leukocyte (neutrophil, monocyte or lymphocyte) and its maturation/functional characteristics (e.g., non-classical/resident or classical/inflammatory monocyte, naïve or central/effector memory T cell). Thus, stress hormones could be administered simultaneously or sequentially to induce specific leukocyte subpopulations to be mobilized into the blood, or to traffic from blood to tissues. Stress- or stress hormone-mediated changes in immune cell distribution could be clinically harnessed to: (1) Direct leukocytes to sites of vaccination, wound healing, infection, or cancer and thereby enhance protective immunity. (2) Reduce leukocyte traffic to sites of inflammatory/autoimmune reactions. (3) Sequester immune cells in relatively protected compartments to minimize exposure to cytotoxic treatments like radiation or localized chemotherapy. (4) Measure biological resistance/sensitivity to stress hormones in vivo. In keeping with the guidelines for Richter Award manuscripts, in addition to original data we also present a model and synthesis of findings in the context of the literature on the effects of short-term stress on immune cell distribution and function.
A single episode of acute immobilization stress has previously been shown to trigger a delayed onset of anxiety-like behavior and spinogenesis in the basolateral amygdala (BLA) of rats. Spurred on by a seemingly paradoxical observation in which even a modest increase in corticosterone (CORT), caused by a single vehicle injection before stress, could dampen the delayed effects of stress, we hypothesized a protective role for glucocorticoids against stress.
We tested this hypothesis by analyzing how manipulations in CORT levels modulate delayed increase in anxiety-like behavior of rats on the elevated plus-maze 10 days after acute stress. We also investigated the cellular correlates of different levels of anxiety under different CORT conditions by quantifying spine density on Golgi-stained BLA principal neurons.
CORT in drinking water for 12 hours preceding acute stress prevented delayed increase in anxiety rather than exacerbating it. Conversely, vehicle injection failed to prevent the anxiogenic effect of stress in bilaterally adrenalectomized rats. However, when CORT was restored in adrenalectomized rats by injection, the delayed anxiogenic effect of stress was once again blocked. Finally, high and low anxiety states were accompanied by high and low levels of BLA spine density.
Our findings suggest that the presence of elevated levels of CORT at the time of acute stress confers protection against the delayed enhancing effect of stress on BLA synaptic connectivity and anxiety-like behavior. These observations are consistent with clinical reports on the protective effects of glucocorticoids against the development of posttraumatic symptoms triggered by traumatic stress.
The present study investigated the association between self-esteem and free cortisol stress responses with regard to experimentally induced success or failure. 52 subjects (29 women and 23 men, mean age 22.9±2.8 years) were exposed to a computer-generated mental stressor consisting of arithmetic tasks to be calculated under time pressure. For one half of the subjects, the computer produced tasks which were easy to solve (success condition), the other half was confronted with a significantly higher level of difficulty ( failure condition). Testing was performed in groups of ten subjects at a time in the same room. After each of three sets of arithmetic tasks, individuals had to report their outcome in front of the group.Results indicate that test difficulty had a profound impact on the performance of the subjects. More important, subjects performance covaried with his/her self-esteem, i.e. persons scoring high in self-esteem achieved better results in the mental arithmetics than their counterparts in the same condition. Moreover, there was a significant negative correlation between the free cortisol response to this stress task and self-esteem in the failure condition (r=−47, p=0.01), however not in the success condition (r=−0.26; p=0.20).These results suggest that self-esteem is affecting the endocrine stress response. Furthermore, they indicate that the impact of this personality characteristic on the human cortisol stress response is also situation dependent. Inclusion of success and failure conditions turned out to be a crucial factor for revealing the role of self-esteem in endocrine stress responses. Future study designs should therefore include those variables, or assess subjective perception of success and failure, when investigating the role of personality differences in stress responses.
Epigenetics and epigenomic medicine encompass a new science of brain and behavior that are already providing unique insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. Epigenetic mechanisms include DNA methylation, histone modifications, nucleosome repositioning, higher order chromatin remodeling, non-coding RNAs, and RNA and DNA editing. RNA is centrally involved in directing these processes, implying that the transcriptional state of the cell is the primary determinant of epigenetic memory. This transcriptional state can be modified not only by internal and external cues affecting gene expression and post-transcriptional processing, but also by RNA and DNA editing through activity-dependent intracellular transport and modulation of RNAs and RNA regulatory supercomplexes, and through trans-neuronal and systemic trafficking of functional RNA subclasses. These integrated processes promote dynamic reorganization of nuclear architecture and the genomic landscape to modulate functional gene and neural networks with complex temporal and spatial trajectories. Epigenetics represents the long sought after molecular interface mediating gene–environmental interactions during critical periods throughout the lifecycle. The discipline of environmental epigenomics has begun to identify combinatorial profiles of environmental stressors modulating the latency, initiation and progression of specific neurological disorders, and more selective disease biomarkers and graded molecular responses to emerging therapeutic interventions. Pharmacoepigenomic therapies will promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cell fate decisions, targeted tissue remodeling and restoration of neural network integrity, plasticity and connectivity.
Free cortisol measured in saliva has been shown to have the same diurnal rhythm as serum cortisol, one that typically declines rapidly throughout the waking day. A recent study showed that over 15% of a sample of community individuals who were monitored over two days did not show the typical diurnal rhythm. The present study specifically tested the hypothesis that there is significant between-subject variation (individual differences) in diurnal rhythms using multi-level, random regression models. Analyses of participants from four studies were conducted; studies varied in terms of the number of saliva samples taken per day, the number of days studied, and participants' demographic and health status. Significant individual differences of diurnal cycle in each of the four samples were found. In at least 10% of each sample no significant diurnal cycles was detected; however, the overall mean level of cortisol of those with flat cycles differed among the samples. These results suggest that some people do not have the expected diurnal rhythm of cortisol secretion. It is not clear what the determinants of this finding are or if there are any health consequences of having a flat cycle.
Glucocorticoids are a family of hormones that coordinate diverse physiological processes in responding to stress. Prolonged glucocorticoid exposure over weeks has been linked to dendritic atrophy and spine loss in fixed tissue studies of adult brains, but it is unclear how glucocorticoids may affect the dynamic processes of dendritic spine formation and elimination in vivo. Furthermore, relatively few studies have examined the effects of stress and glucocorticoids on spines during the postnatal and adolescent period, which is characterized by rapid synaptogenesis followed by protracted synaptic pruning. To determine whether and to what extent glucocorticoids regulate dendritic spine development and plasticity, we used transcranial two-photon microscopy to track the formation and elimination of dendritic spines in vivo after treatment with glucocorticoids in developing and adult mice. Corticosterone, the principal murine glucocorticoid, had potent dose-dependent effects on dendritic spine dynamics, increasing spine turnover within several hours in the developing barrel cortex. The adult barrel cortex exhibited diminished baseline spine turnover rates, but these rates were also enhanced by corticosterone. Similar changes occurred in multiple cortical areas, suggesting a generalized effect. However, reducing endogenous glucocorticoid activity by dexamethasone suppression or corticosteroid receptor antagonists caused a substantial reduction in spine turnover rates, and the former was reversed by corticosterone replacement. Notably, we found that chronic glucocorticoid excess led to an abnormal loss of stable spines that were established early in life. Together, these findings establish a critical role for glucocorticoids in the development and maintenance of dendritic spines in the living cortex.
How do adverse childhood experiences get 'under the skin' and influence health outcomes through the life-course? Research reviewed here suggests that adverse childhood experiences are associated with changes in biological systems responsible for maintaining physiological stability through environmental changes, or allostasis. Children exposed to maltreatment showed smaller volume of the prefrontal cortex, greater activation of the HPA axis, and elevation in inflammation levels compared to non-maltreated children. Adults with a history of childhood maltreatment showed smaller volume of the prefrontal cortex and hippocampus, greater activation of the HPA axis, and elevation in inflammation levels compared to non-maltreated individuals. Despite the clear limitations in making longitudinal claims from cross-sectional studies, work so far suggests that adverse childhood experiences are associated with enduring changes in the nervous, endocrine, and immune systems. These changes are already observable in childhood years and remain apparent in adult life. Adverse childhood experiences induce significant biological changes in children (biological embedding), modifying the maturation and the operating balance of allostatic systems. Their chronic activation can lead to progressive wear and tear, or allostatic load and overload, and, thus, can exert long-term effects on biological aging and health.
High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100-140 mg) or placebo within 6 h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. In parallel, a comparative study of morphological arborization in dentate gyrus and its modulating molecules was performed in stress-exposed animals treated with high-dose hydrocortisone. Steroid-treated stressed animals displayed significantly increased dendritic growth and spine density, with increased levels of brain-derived neurotrophic factor (BDNF) and obtunded postsynaptic density-95 (PSD-95) levels. The animal study provided insights into the potential mechanism of this intervention, as it identified relevant morphological and biochemical associations to the clinical observations. Thus, evidence from clinical and animal studies suggests that there is a "window of opportunity" in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD.
The hippocampus is a malleable brain region that responds to external agents such as hormones and stressors. Investigations that began in our laboratories with the Golgi technique and an appreciation of hippocampal neuroanatomy at the light and electron microscopic levels have led us down a path that has uncovered unexpected structural plasticity in the adult brain along with unanticipated cellular and molecular mechanisms of this plasticity and of hormone mediation of these effects. This chapter reviews the history of discoveries in our two laboratories involving the actions of estradiol and stress hormones on neuronal structure and function and then discusses the insight to hormone-brain interactions that this has engendered. These discoveries have led us to a new view of brain structural plasticity and the role and mechanism of steroid hormone action involving both genomic and non-genomic pathways. This new view is consistent with the predictions of Cajal in his book "The Structure of Ammon's horn", 1892.
Mesio-temporal lobe epilepsy (MTLE), the most common drug-resistant epilepsy syndrome, is characterized by the recurrence of spontaneous focal seizures after a latent period that follows, in most patients, an initial insult during early childhood. Many of the mechanisms that have been associated with the pathophysiology of MTLE are known to be regulated by brain-derived neurotrophic factor (BDNF) in the healthy brain and an excess of this neurotrophin could therefore play a critical role in MTLE development. However, such a function remains controversial as other studies revealed that BDNF could, on the contrary, exert protective effects regarding epilepsy development. In the present study, we further addressed the role of increased BDNF/TrkB signaling on the progressive development of hippocampal seizures in the mouse model of MTLE obtained by intrahippocampal injection of kainate. We show that hippocampal seizures progressively developed in the injected hippocampus during the first two weeks following kainate treatment, within the same time-frame as a long-lasting and significant increase of BDNF expression in dentate granule cells. To determine whether such a BDNF increase could influence hippocampal epileptogenesis via its TrkB receptors, we examined the consequences of (i) increased or (ii) decreased TrkB signaling on epileptogenesis, in transgenic mice overexpressing the (i) TrkB full-length or (ii) truncated TrkB-T1 receptors of BDNF. Epileptogenesis was significantly facilitated in mice with increased TrkB signaling but delayed in mutants with reduced TrkB signaling. In contrast, TrkB signaling did not influence granule cell dispersion, an important feature of this mouse model which is also observed in most MTLE patients. These results suggest that an increase in TrkB signaling, mediated by a long-lasting BDNF overexpression in the hippocampus, promotes epileptogenesis in MTLE.
This study examined the direct and interactive effects of stress reactivity and family adversity on socioemotional and cognitive development in three hundred and thirty-eight 5- to 6-year-old children. Neurobiological stress reactivity was measured as respiratory sinus arrhythmia and salivary cortisol responses to social, cognitive, sensory, and emotional challenges. Adaptation was assessed using child, parent, and teacher reports of externalizing symptoms, prosocial behaviors, school engagement, and academic competence. Results revealed significant interactions between reactivity and adversity. High stress reactivity was associated with more maladaptive outcomes in the context of high adversity but with better adaption in the context of low adversity. The findings corroborate a reconceptualization of stress reactivity as biological sensitivity to context by showing that high reactivity can both hinder and promote adaptive functioning.