Human Stress Response Research Articles

Stress and the brain transcriptome: Identifying commonalities and clusters in standardized data from published experiments

Interpretation of transcriptomic experiments is hindered by many problems including false positives/negatives inherent to big-data methods and changes in gene nomenclature. To find the most consistent effect of stress on brain transcriptome, we retrieved data from 79 studies applying animal models and 3 human studies investigating post-traumatic stress disorder (PTSD). The analyzed data were obtained either with microarrays or RNA sequencing applied to samples collected from more than 1887 laboratory animals and from 121 human subjects.Based on the initial database containing a quarter million differential expression effect sizes representing transcripts in three species, we identified the most frequently reported genes in 223 stress-control comparisons. Additionally, the analysis considers sex, individual vulnerability and contribution of glucocorticoids. We also found an overlap between gene expression in PTSD patients and animals which indicates relevance of laboratory models for human stress response. Our analysis points to genes that, as far as we know, were not specifically tested for their role in stress response (Pllp, Arrdc2, Midn, Mfsd2a, Ccn1, Htra1, Csrnp1, Tenm4, Tnfrsf25, Sema3b, Fmo2, Adamts4, Gjb1, Errfi1, Fgf18, Galnt6, Slc25a42, Ifi30, Slc4a1, Cemip, Klf10, Tom1, Dcdc2c, Fancd2, Luzp2, Trpm1, Abcc12, Osbpl1a, Ptp4a2). Provided transcriptomic resource will be useful for guiding the new research.

The STRESS-NL database: A resource for human acute stress studies across the Netherlands

Stress initiates a cascade of (neuro)biological, physiological, and behavioral changes, allowing us to respond to a challenging environment. The human response to acute stress can be studied in detail in controlled settings, usually in a laboratory environment. To this end, many studies employ acute stress paradigms to probe stress-related outcomes in healthy and patient populations. Though valuable, these studies in themselves often have relatively limited sample sizes. We established a data-sharing and collaborative interdisciplinary initiative, the STRESS-NL database, which combines (neuro)biological, physiological, and behavioral data across many acute stress studies in order to accelerate our understanding of the human acute stress response in health and disease (www.stressdatabase.eu). Researchers in the stress field from 12 Dutch research groups of 6 Dutch universities created a database to achieve an accurate inventory of (neuro)biological, physiological, and behavioral data from laboratory-based human studies that used acute stress tests. Currently, the STRESS-NL database consists of information on 5529 individual participants (2281 females and 3348 males, age range 6–99 years, mean age 27.7 ± 16 years) stemming from 57 experiments described in 42 independent studies. Studies often did not use the same stress paradigm; outcomes were different and measured at different time points. All studies currently included in the database assessed cortisol levels before, during and after experimental stress, but cortisol measurement will not be a strict requirement for future study inclusion. Here, we report on the creation of the STRESS-NL database and infrastructure to illustrate the potential of accumulating and combining existing data to allow meta-analytical, proof-of-principle analyses. The STRESS-NL database creates a framework that enables human stress research to take new avenues in explorative and hypothesis-driven data analyses with high statistical power. Future steps could be to incorporate new studies beyond the borders of the Netherlands; or build similar databases for experimental stress studies in rodents. In our view, there are major scientific benefits in initiating and maintaining such international efforts.

The Effect of Stress on the Progression and Development of HIV/AIDS

There is substantial evidence to indicate that the biological human stress response, when activated frequently or during long periods of time, can cause physiological health problems, including immunosuppression, which is particularly dangerous among patients with AIDS and HIV. The secretion of stress hormones, such as glucocorticoids, leads to a decrease in CD4 white blood cells, and this can facilitate the progression of HIV to AIDS and also exacerbate the course of the disease. HIV/AIDS is often associated with elevated stress levels, as well as mental illnesses such as anxiety and depression. Mental illness can also affect disease progression through similar biological mechanisms, although there is a lack of definitive research in this area. Stress alleviation therapy should be considered an important part of the treatment of people living with HIV and AIDS. Research indicates that as well as preventing the negative effects of stress, stress reduction treatments may also alleviate the symptoms of antiretroviral therapy, both of which could vastly contribute to the quality of life and health of patients. In this paper, we examine the biological mechanisms through which stress can impact the immune system and review relevant research on stress, its impact on HIV, potential future research, the role of mental health in disease progression, and implications of these findings.

Manipulating Stress Responses during Spaceflight Training with Virtual Stressors

Virtual reality (VR) provides the ability to simulate stressors to replicated real-world situations. It allows for the creation and validation of training, therapy, and stress countermeasures in a safe and controlled setting. However, there is still much unknown about the cognitive appraisal of stressors and underlying elements. More research is needed on the creation of stressors and to verify that stress levels can be effectively manipulated by the virtual environment. The objective of this study was to investigate and validate different VR stressor levels from existing emergency spaceflight procedures. Experts in spaceflight procedures and the human stress response helped design a VR spaceflight environment and emergency fire task procedure. A within-subject experiment evaluated three stressor levels. Forty healthy participants each completed three trials (low, medium, high stressor levels) in VR to locate and extinguish a fire on the International Space Station (VR-ISS). Since stress is a complex construct, physiological data (heart rate, heart rate variability, blood pressure, electrodermal activity) and self-assessment (workload, stress, anxiety) were collected for each stressor level. The results suggest that the environmental-based stressors can induce significantly different, distinguishable levels of stress in individuals.

The Association Between Salivary FGF2 and Physiological and Psychological Components of the Human Stress Response

Background Fibroblast Growth Factor 2 (FGF2) is a neurotrophic protein that has been implicated as a biomarker for anxiety and depressive disorders, which comprise a significant component of the global burden of disease. Research using rodents has indicated that FGF2 is part of the stress response, but whether this translates to humans has yet to be investigated. In this study, we aimed to explore the potential role of FGF2 in the human stress response by examining its association with physiological and psychological processes during and following the Trier Social Stress Test (TSST). Methods Participants in the active stress experiment (N = 87) underwent the TSST, provided saliva samples to obtain levels of cortisol and FGF2, and reported on post-event rumination related to the TSST task over the following week. Participants in the no-stress experiment (N = 25) provided saliva samples for measurement of FGF2 and cortisol across a corresponding time period. Results Salivary FGF2 levels changed after the TSST and were associated with the pattern of change in salivary cortisol. Cortisol responses in the active stress condition were blunted in females (relative to males), however, sex did not interact with any other effect. FGF2 reactivity (ie, the magnitude of change over time) was not correlated with cortisol reactivity. Lower FGF2 reactivity following the TSST, but not overall FGF2 levels, or cortisol, was associated with higher fear of negative evaluation, repetitive negative thinking and post-event processing, as well as repetitive negative thinking in the week following the TSST. Participants in the no-stress experiment showed a decrease in cortisol, yet no change in their FGF2 levels. Conclusion These findings suggest that FGF2 is involved in the human stress response and higher levels of FGF2 reactivity may be associated with protective cognitive processes following stress exposure.

Neuronal Excitatory State Is Linked to Stress Resilience

The aging human brain is a study in both the importance and limitations of human stress response factors. Individual neurons can maintain functionality for 80 or more years, testifying to the potency of their stress response pathways. However, failure of these pathways during aging drastically increases the risk of neurodegenerative diseases. The transcriptional repressor REST is induced in the brains of long-lived humans but is lost in neurodegenerative disease. Here, we explore one modality of REST’s protective effects: regulation of neuronal excitability. We show that excitatory capacity and stress response are inversely correlated in the human brain. We find that REST and its C. elegans orthologs repress neuronal excitation in response to stressful conditions. Further, exogenously suppressing neuronal excitation restores stress resistance to REST-deficient animals, while enhancing stress response in wildtype ones. Thus, regulation of neuronal activity is an important aspect of neuronal stress response and a potential therapeutic modality.

Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses

SummaryTrauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A “systemic storm” pattern with release of 1,061 markers, together with a pattern suggestive of the “massive consumption” of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses.

WITHDRAWN: Modeling analysis of the coping effect of dance piano accompaniment music on interpersonal pressure at work

Piano accompaniment is necessary for the creation and performance in music atmosphere and exhibits dance motion, passionate appeal, or qualities of the style. These are stated positively, and work rates were poor with no music, while removing the music is considered the longest in limited research to find the differences with reports that could derive from methodological problems. Performing a complete evaluation of music affects hormones, autonomous behavior, and human stress response with health deficiencies. Therefore, music classification analysis using the machine learning (MCA-ML) technique has been introduced to predict this qualitative method to explore dance, music as a rehabilitation process described in a stressful life event by persons involved and affected. A convolution neural network (CNN) approach is frequently employed to analyze various coping effects of different music pattern-based classification issues to attain high advantages. A musical perception approach based on cloud computing is introduced to efficiently allocate resources to analyze the music with cognitive systems efficiently. Empirical analysis revealed that the proposed architecture permits real-time access to the data and successfully supports several parallel applications with 97.81%performance.

Resting-state dynamic functional connectivity predicts the psychosocial stress response

Acute stress triggers a complex cascade of psychological, physiological, and neural responses, which show large and enduring individual differences. Although previous studies have examined the relationship between the stress response and dynamic features of the brain’s resting state, no study has used the brain’s dynamic activity in the resting state to predict individual differences in the psychosocial stress response. In the current study, resting-state scans of forty-eight healthy participants were collected, and then their individual acute stress responses during the Montreal Imaging Stress Test (MIST) paradigm were recorded. Results defined a connectivity state (CS) characterized by positive correlations across the whole brain during resting-state that could negatively predict participants’ feelings of social evaluative threat during stress tasks. Another CS characterized by negative correlations between the frontal-parietal network (FPN) and almost all other networks, except the dorsal attentional network (DAN), could predict participants’ subjective stress, feelings of uncontrollability, and feelings of social evaluative threat. However, no CS could predict participants’ salivary cortisol stress response. Overall, these results suggested that the brain state characterized as attentional regulation, linking self-control, and top-down regulation ability, could predict the psychosocial stress response. This study also developed an objective indicator for predicting human stress responses.

IMVEST, an immersive multimodal virtual environment stress test for humans that adjusts challenge to individual's performance

Laboratory stressors are essential tools to study the human stress response. However, despite considerable progress in the development of stress induction procedures in recent years, the field is still missing standardization and the methods employed frequently require considerable personnel resources. Virtual reality (VR) offers flexible solutions to these problems, but available VR stress-induction tests still contain important sources of variation that challenge data interpretation. One of the major drawbacks is that tasks based on motivated performance do not adapt to individual abilities. Here, we provide open access to, and present, a novel and standardized immersive multimodal virtual environment stress test (IMVEST) in which participants are simultaneously exposed to mental -arithmetic calculations- and environmental challenges, along with intense visual and auditory stimulation. It contains critical elements of stress elicitation – perceived threat to physical self, social-evaluative threat and negative feedback, uncontrollability and unpredictability – and adjusts mathematical challenge to individual's ongoing performance. It is accompanied by a control VR scenario offering a comparable but not stressful situation. We validate and characterize the stress response to IMVEST in one-hundred-and-eighteen participants. Both cortisol and a wide range of autonomic nervous system (ANS) markers – extracted from the electrocardiogram, electrodermal activity and respiration – are significantly affected. We also show that ANS features can be used to train a stress prediction machine learning model that strongly discriminates between stress and control conditions, and indicates which aspects of IMVEST affect specific ANS components.

The association of the 5-HTTLPR polymorphism and the response to different stressors in healthy males

The experience of stress is related to individual wellbeing and vulnerability to psychopathology. Therefore, understanding the determinants of individual differences in stress reactivity is of great concern from a clinical perspective. The functional promotor polymorphism of the serotonin transporter gene (5-HTTLPR/rs25531) is such a factor, which has been linked to the acute stress response as well as the adverse effect of life stressors. In the present study, we compared the impact of two different stress induction protocols (Maastricht Acute Stress Test and ScanSTRESS) and the respective control conditions on affective ratings, salivary cortisol levels and cognitive performance. To this end, 156 healthy young males were tested and genotyped for the 5-HTTLPR/rs25531 polymorphism. While combined physiological and psychological stress in the MAST led to a greater cortisol increase compared to control conditions as well as the psychosocial ScanSTRESS, subjective stress ratings were highest in the ScanSTRESS condition. Stress induction in general affected working memory capacity but not response inhibition. Subjective stress was also influenced by 5-HTTLPR/rs25531 genotype with the high expression group showing lower stress ratings than lower expression groups. In line with previous research, we identified the low expression variant of the serotonin transporter gene as a risk factor for increased stress reactivity. While some dimensions of the human stress response may be stressor specific, cognitive outcomes such as working memory performance are influenced by stress in general. Different pathways of stress processing and possible underlying mechanisms are discussed.

Chronobiology of transient global amnesia

IntroductionThe etiology of transient global amnesia (TGA) is still a matter of debate. Based, among others, on the observation of a close temporal relation between certain events and subsequent TGA episodes, recent proposals discuss the relevance of stress-associated processes impacting on hippocampal functioning. Circadian, infra- and ultradian rhythmicity has been found to play a relevant role in the multifactorial pathomechanisms of various disorders but has not been thoroughly studied in TGA.MethodsData of patients with a final diagnosis of TGA were collected in Mannheim, Germany (06/1999–01/2018, n = 404), and in the Kansai district, Japan (04/2006–03/2018, n = 261). Chronological patterns of TGA occurrence were determined.ResultsSignificant circadian rhythmicity of TGA occurrence with bimodal peaks (mid-morning, late afternoon) was found for the entire population (p = 0.002) and for either sub-cohort (Mannheim: p = 0.003, Kansai: p = 0.007). This finding was confirmed for either sex (women: p = 0.004, men: p = 0.004) and different age groups (< 65 years: p = 0.0009, ≥ 65 years: p = 0.003). There was no variation according to day of the week, month or season, but the proportion of patients with a weekday episode was significantly higher in the Mannheim cohort (p = 0.002).DiscussionWe identified a robust circadian rhythm in TGA occurrence which remarkably applied to either of the two study sites located on different continents and which was independent of sex and age. In light of abundant evidence of circadian rhythmicity of both, components of the human stress response system and memory, chronobiological analyses may provide an opportunity to further uncover the mechanisms underlying TGA.

Chronic social defeat stress mouse model: Current view on its behavioral deficits and modifications.

Stress is the main cause of mood disorders such as depression and posttraumatic stress disorder. Individuals respond to stress differently, as some develop depressive symptoms, whereas others successfully cope with adversity, but it remains unclear what makes some particularly vulnerable to stress. The chronic social defeat stress (CSDS) mouse model, an ethologically valid rodent model that exhibits long-term physiological and behavioral phenotypes similar to depression and anxiety, can imitate individual differences in stress responses in humans. In this review, we not only summarize various behavioral deficits of the CSDS mouse model that were reported since its establishment but also concentrate on modified CSDS mouse models that have been developed in recent years, aiming at providing useful information for future research and application of this model. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

AP Collagen Peptides Prevent Cortisol-Induced Decrease of Collagen Type I in Human Dermal Fibroblasts.

Cortisol is an endogenous glucocorticoid (GC) and primary stress hormone that regulates a wide range of stress responses in humans. The adverse effects of cortisol on the skin have been extensively documented but the underlying mechanism of cortisol-induced signaling is still unclear. In the present study, we investigate the effect of cortisol on collagen type I expression and the effect of AP collagen peptides, collagen tripeptide-rich hydrolysates containing 3% glycine-proline- hydroxyproline (Gly-Pro-Hyp, GPH) from the fish skin, on the cortisol-mediated inhibition of collagen type I and the cortisol-induced signaling that regulates collagen type I production in human dermal fibroblasts (HDFs). We determine that cortisol downregulates the expression of collagen type I. AP collagen peptides or GC receptor (GR) inhibitors recover the cortisol-mediated inhibition of collagen type I and GR activation. AP collagen peptides or GR inhibitors also prevent the cortisol-dependent inhibition of transforming growth factor (TGF)-β signaling. AP collagen peptides or GR inhibitors are effective in the prevention of collagen type I inhibition mediated by cortisol in senescent HDFs and reconstituted human skin models. Taken together, GR signaling might be responsible for the cortisol-mediated inhibition of TGF-β. AP collagen peptides act as GR-mediated signaling blockers, preventing the cortisol-dependent inhibition of collagen type I. Therefore, AP collagen peptides have the potential to improve skin health.

The Potential Impact of Selected Bacterial Strains on the Stress Response.

Introduction: The composition of the microbiome is subject to a variety of factors, such as eating behavior and the history of medical treatment. The interest in the impact of the microbiome on the stress response is mainly explained by the lack of development of new effective treatments for stress-related diseases. This scoping review aims to present the current state of research regarding the impact of bacterial strains in the gut on the stress response in humans in order to not only highlight these impacts but to also suggest potential intervention options. Methods: We included full-text articles on studies that: (a) were consistent with our research question; and (b) included the variable stress either using biomedical parameters such as cortisol or by examining the subjective stress level. Information from selected studies was synthesized from study designs and the main findings. Results: Seven studies were included, although they were heterogenous. The results of these studies do not allow a general statement about the effects of the selected bacterial strains on the stress response of the subjects and their precise pathways of action. However, one of the works gives evidence that the consumption of probiotics leads to a decrease in blood pressure and others show that stress-induced symptoms (including abdominal pain and headache) in healthy subjects could be reduced. Conclusion: Due to different intake period and composition of the bacterial strains administered to the subjects, the studies presented here can only provide a limited meaningful judgement. As these studies included healthy participants between the ages of 18 and 60 years, a generalization to clinical populations is also not recommended. In order to confirm current effects and implement manipulation of the microbiome as a treatment method for clinical cases, future studies would benefit from examining the effects of the intestinal microbiome on the stress response in a clinical setting.

Detection of acute stress by smooth muscle electromyography: A translational study on rat and human

AimsNon-invasive and simultaneous recording of gastrointestinal (GI) activity during stress induction is still an unexplored field. In our previous investigation, the stress-induced alteration of the gastrointestinal tract was explored in rats. Our aims were to expand our previous rat experiment and to induce stress response in rats (Study 1) and humans (Study 2) to detect the GI tract activity, heart rate and body temperature. Materials and methodsIn the preclinical sample, acute stress was induced by immobilization in Sprague-Dawley rats (N = 10). Acute stress response was generated by the Trier Social Stress Test among healthy volunteers (N = 16). Detection of acute stress was measured by using smooth muscle electromyography, which recorded the myoelectric waves of the gastrointestinal tract (stomach, ileum and colon) simultaneously with heart rate and body temperature in rats and humans. Key findingsThe myoelectric waves of the stomach, the cecum and the ileum increased during immobilization in rats, rising in parallel with heart rate and the dermal temperature of the abdominal surface. The same alterations were found during the stress period among humans, except in the case of the colon, where no change was detected. SignificanceThe crucial role of the GI tract in stress response was revealed by translating the outcome of basic research into human results. The similar GI alterations during stress in rats and humans underpin the robustness of our findings. In summary, our preliminary translational-based study can serve as an appropriate basis for further human studies.

Evolutionary Significance of the Neuroendocrine Stress Axis on Vertebrate Immunity and the Influence of the Microbiome on Early-Life Stress Regulation and Health Outcomes

Stress is broadly defined as the non-specific biological response to changes in homeostatic demands and is mediated by the evolutionarily conserved neuroendocrine networks of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Activation of these networks results in transient release of glucocorticoids (cortisol) and catecholamines (epinephrine) into circulation, as well as activation of sympathetic fibers innervating end organs. These interventions thus regulate numerous physiological processes, including energy metabolism, cardiovascular physiology, and immunity, thereby adapting to cope with the perceived stressors. The developmental trajectory of the stress-axis is influenced by a number of factors, including the gut microbiome, which is the community of microbes that colonizes the gastrointestinal tract immediately following birth. The gut microbiome communicates with the brain through the production of metabolites and microbially derived signals, which are essential to human stress response network development. Ecological perturbations to the gut microbiome during early life may result in the alteration of signals implicated in developmental programming during this critical window, predisposing individuals to numerous diseases later in life. The vulnerability of stress response networks to maladaptive development has been exemplified through animal models determining a causal role for gut microbial ecosystems in HPA axis activity, stress reactivity, and brain development. In this review, we explore the evolutionary significance of the stress-axis system for health maintenance and review recent findings that connect early-life microbiome disturbances to alterations in the development of stress response networks.

Increase in Beta Power Reflects Attentional Top-Down Modulation After Psychosocial Stress Induction.

Selective attention depends on goal-directed and stimulus-driven modulatory factors, each relayed by different brain rhythms. Under certain circumstances, stress-related states can change the balance between goal-directed and stimulus-driven factors. However, the neuronal mechanisms underlying these changes remain unclear. In this study, we explored how psychosocial stress can modulate brain rhythms during an attentional task and a task-free period. We recorded the EEG and ECG activity of 42 healthy participants subjected to either the Trier Social Stress Test (TSST), a controlled procedure to induce stress, or a comparable control protocol (same physical and cognitive effort but without the stress component), flanked by an attentional task, a 90 s of task-free period and a state of anxiety questionnaire. We observed that psychosocial stress induced an increase in heart rate (HR), self-reported anxiety, and alpha power synchronization. Also, psychosocial stress evoked a relative beta power increase during correct trials of the attentional task, which correlates positively with anxiety and heart rate increase, and inversely with attentional accuracy. These results suggest that psychosocial stress affects performance by redirecting attentional resources toward internal threat-related thoughts. An increment of endogenous top-down modulation reflected an increased beta-band activity that may serve as a compensatory mechanism to redirect attentional resources toward the ongoing task. The data obtained here may contribute to designing new ways of clinical management of the human stress response in the future and could help to minimize the damaging effects of persistent stressful experiences.

A Systemic Storm in Critically Injured Humans Revealed by Longitudinal Multi-Omics

Trauma is a leading cause of death and morbidity worldwide. The lack of a comprehensive characterization of the human response to severe injury limits progress in this field. Here, we analyzed a longitudinal, multi-omic dataset comprised of clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome and proteome data from severely injured humans. A “Systemic Storm” pattern with release of 1061 markers together with a pattern suggestive of the “Massive Consumption” of 892 circulating markers were identified in the hyper-acute phase post-trauma. This was followed by resolution and non-resolution signatures represented by 56 and 172 biomarkers, respectively. Data integration yielded two human injury response endotypes, which aligned with clinical trajectory. Prehospital allogeneic thawed plasma rescued only endotype 2 patients with traumatic brain injury (30d mortality: 30.3% vs. 75%, p=0.0015). These novel response patterns re-define the paradigm and the datasets provide a resource for the study of critical illness, trauma and human stress response.

Children's altruism following acute stress: The role of autonomic nervous system activity and social support.

Altruistic behavior after stress exposure may have important health and psychological benefits, in addition to broader societal consequences. However, so far experimental research on altruism following acute stress has been limited to adult populations. The current study utilized an experimental design to investigate how altruistic donation behavior among children may be influenced by (a) exposure to an acute social stressor, the Trier Social Stress Test modified for use with children (TSST-M), (b) individual differences in stress physiology, and (c) social support from a parent. The sample consisted of 180 children (54.9% male, 45.1% female; mean age=9.92years, SD=0.56years) randomly assigned to one of three conditions involving the TSST-M: (a) prepare for the TSST-M alone, (b) prepare for the TSST-M with a parent, and (c) no-stress control group. Results revealed that children made larger donations post-stressor if they were alone before the acute stressor, if they had moderate cardiac autonomic balance, reflecting both parasympathetic and sympathetic influence, and if they were older. Children who prepared for the TSST-M with social support from a parent made comparable donations as children in the no-stress control group, in accord with stress buffering models. Increased altruism following acute stress among children suggests that a comprehensive understanding of the human stress response needs to incorporate "tend-and-befriend" behavior-the tendency for humans to show increased altruistic behavior during times of distress.