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Focus: The Science of Stress

Introduction: the science of stress.

The term stress was widely popularized in its biological connotation in 1936 by Hans Selye, who defined it as “the non-specific response of the body to any demand for change” [ 1 ]. Stress was originally understood to be a collection of peripheral symptoms that accompany a variety of chronic illnesses affecting different parts of the body. However, since its conception, the term has taken on a broader meaning and encompasses the body’s response to any mental, emotional, or physical disturbance. It is now well accepted that stress is both a symptom and a major risk factor for anxiety, migraines, substance abuse, obesity, and heart disease [ 2 ]. In 2007, the American Psychological Association launched a Stress in America™ survey to document national levels of stress, assess mental and physical impacts, and correlate stress intensity to external factors, including the political climate and the state of the economy. The outcomes of subsequent surveys have established stress as a major contributor to the national mental health crisis that disproportionately impacts different groups across the country [ 3 ].

In a perspectives piece on the neuroscience of stress, Simisola Johnson discusses the evolution of the stress response and the role of the nervous system in eliciting neuroendocrine and behavioral responses that promote survival. However, as opposed to acute stress that can have beneficial effects, chronic stress can lead to severe impairments in circuits that regulate neuroendocrine signaling. For example, in addition to the direct biological consequences of SARS-CoV2 infection on the brain, chronic stress associated with the COVID-19 pandemic impacts similar neuronal signaling pathways in the CNS and PNS that hamper normal physiological function. In addition to impacting the brain, chronic stress also alters metabolism at the cellular level. Using a house sparrow model system, Beattie et al. combined chronic psychological stress and daily food restriction to test whether chronic stress decreases the animals’ ability to cope with acute stressors. The study measures a variety of parameters including levels of metabolites, total activity, and markers of the neuroendocrine stress response to assess overall stress responses. Both of these papers highlight the importance of studying the compounding effects of stress that are increasingly prevalent in a post-pandemic era.

Stress experienced by mothers during pregnancy can have deleterious effects on both the infant’s neuropsychiatric and behavioral health. Various studies have found associations between maternal prenatal distress and child developmental outcomes. Children exposed to prenatal stress are at increased risk for displaying disruptive behavioral problems, possessing lower motor function, and even developing neuropsychiatric illnesses at later stages. However, in a self-reported study examining the initiation and course of breastfeeding and room-sharing, Simons et al. found that there was no link between the quality of maternal caregiving and maternal prenatal distress. Although they found that levels of prenatal evening cortisol (a physiological marker of stress) at the end of pregnancy are positively correlated with their study parameters, a lack of homology with other stress markers urges future studies to examine alternative mechanisms. Davis et al. examine how increased reactive oxygen species in the embryonic brain generated due to prenatal stress affect the morphology and activity of neuronal cells during development and in mature brains. The authors found that treatment with antioxidant agents reversed the observed effects on neuronal cells but did not prevent behavioral impacts. The results of these studies emphasize a need to study intergenerational transmission of stress and its long-term effects.

The World Health Organization estimates that approximately 3.6% of the world’s population has experienced post-traumatic stress disorder (PTSD) [ 4 ]. Risk factors for developing PTSD include exposure to a traumatic life event, lack of social support, and a genetic predisposition. Liu et al. examined the relationship between personality type, social support, and prevalence of PTSD among Shidu Parents in China. They determined that those with social support and extroverted personalities were least likely to develop PTSD after losing a child. Nagy Youssef provides a perspectives piece on studying the transgenerational epigenetic inheritance of trauma. Conducting more studies on the inheritance of DNA methylation across generations can provide new insights into the impact of trauma and resilience across communities.

In this issue, the biological and social dynamics of stress are examined. Original research, reviews, and perspectives are presented on how stress affects development, metabolism, and various cellular and organ level processes of physiology. We hope this issue contributes to an emerging field and highlights the importance of an interdisciplinary approach to understanding the wide implications of stress.

• Selye H. The Stress of Life . New York: McGraw-Hill; 1956. [ Google Scholar ]
• What is stress? The American Institute of Stress . 2017. Retrieved March 22, 2022. Available from: https://www.stress.org/what-is-stress
• American Psychological Association . 2020. Stress in America™ 2020: A National Mental Health Crisis. American Psychological Association . Retrieved March 22, 2022. Available from: https://www.apa.org/news/press/releases/stress/2020/report-october
• World Health Organization . 2013. Who releases guidance on mental health care after trauma. World Health Organization . Retrieved March 23, 2022. Available from: https://www.who.int/news/item/06-08-2013-who-releases-guidance-on-mental-health-care-after-trauma#:~:text=Traumatic%20events%20and%20loss%20a%20common%20experience&text=An%20estimated%203.6%25%20of%20the,previous%20year%2C%20the%20study%20showed

Recent developments in stress and anxiety research

• Published: 01 September 2021
• Volume 128 , pages 1265–1267, ( 2021 )

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• Urs M. Nater 1 , 2  

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Stress and anxiety are virtually omnipresent in today´s society, pervading almost all aspects of our daily lives. While each and every one of us experiences “stress” and/or “anxiety” at least to some extent at times, the phenomena themselves are far from being completely understood. In stress research, scientists are particularly grappling with the conceptual issue of how to define stress, also with regard to delimiting stress from anxiety or negative affectivity in general. Interestingly, there is no unified theory of stress, despite many attempts at defining stress and its characteristics. Consequently, the available literature relies on a variety of different theoretical approaches, though the theories of Lazarus and Folkman ( 1984 ) or McEwen ( 1998 ) are relatively pervasive in the literature. One key issue in conceptualizing stress is that research has not always differentiated between the perception of a stimulus or a situation as a stressor and the subsequent biobehavioral response (often called the “stress response”). This is important, since, for example, psychological factors such as uncontrollability and social evaluation, i.e. factors that may influence how an individual perceives a potentially stressful stimulus or situation, have been identified as characteristics that elicit particularly powerful physiological stressful responses (Dickerson and Kemeny 2004 ). At the core of the physiological stress response is a complex physiological system, which is located in both the central nervous system (CNS) and the body´s periphery. The complexity of this system necessitates a multi-dimensional assessment approach involving variables that adequately reflect all relevant components. It is also important to consider that the experience of stress and its psychobiological correlates do not occur in a vacuum, but are being shaped by numerous contextual factors (e.g. societal and cultural context, work and leisure time, family and dyadic systems, environmental variables, physical fitness, nutritional status, etc.) and dispositional factors (e.g. genetics, personality, resilience, regulatory capacities, self-efficacy, etc.). Thus, a theoretical framework needs to incorporate these factors. In sum, as stress is considered a multi-faceted and inherently multi-dimensional construct, its conceptualization and operationalization needs to reflect this (Nater 2018 ).

The goal of the World Association for Stress Related and Anxiety Disorders (WASAD) is to promote and make available basic and clinical research on stress-related and anxiety disorders. Coinciding with WASAD’s 3rd International Congress held in September 2021 in Vienna, Austria, this journal publishes a Special Issue encompassing state-of-the art research in the field of stress and anxiety. This special issue collects answers to a number of important questions that need to be addressed in current and future research. Among the most relevant issues are (1) the multi-dimensional assessment that arises as a consequence of a multi-faceted consideration of stress and anxiety, with a particular focus on doing so under ecologically valid conditions. Skoluda et al. 2021 (in this issue) argue that hair as an important source of the stress hormone cortisol should not only be taken as a complementary stress biomarker by research staff, but that lay persons could be also trained to collect hair at the study participants’ homes, thus increasing the ecological validity of studies incorporating this important measure; (2) the incongruence between psychological and biological facets of stress and anxiety that has been observed both in laboratory and field research (Campbell and Ehlert 2012 ). Interestingly, there are behavioral constructs that do show relatively high congruence. As shown in the paper of Vatheuer et al. ( 2021 ), gaze behavior while exposed to an acute social stressor correlates with salivary cortisol, thus indicating common underlying mechanisms; (3) the complex dynamics of stress-related measures that may extend over shorter (seconds to minutes), medium (hours and diurnal/circadian fluctuations), and longer (months, seasonal) time periods. In particular, momentary assessment studies are highly qualified to examine short to medium term fluctuations and interactions. In their study employing such a design, Stoffel and colleagues (Stoffel et al. 2021 ) show ecologically valid evidence for direct attenuating effects of social interactions on psychobiological stress. Using an experimental approach, on the other hand, Denk et al. ( 2021 ) examined the phenomenon of physiological synchrony between study participants; they found both cortisol and alpha-amylase physiological synchrony in participants who were in the same group while being exposed to a stressor. Importantly, these processes also unfold over time in relation to other biological systems; al’Absi and colleagues showed in their study (al’Absi et al. 2021 ) the critical role of the endogenous opioid system and its relation to stress-related analgesia; (4) the influence of contextual and dispositional factors on the biological stress response in various target samples (e.g., humans, animals, minorities, children, employees, etc.) both under controlled laboratory conditions and in everyday life environments. In this issue, Sattler and colleagues show evidence that contextual information may only matter to a certain extent, as in their study (Sattler et al. 2021 ), the biological response to a gay-specific social stressor was equally pronounced as the one to a general social stressor in gay men. Genetic information is probably the most widely researched dispositional factor; Kuhn et al. show in their paper (Kuhn et al. 2021 ) that the low expression variant of the serotonin transporter gene serves as a risk factor for increased stress reactivity, thus clearly indicating the important role of dispositional factors in stress processing. An interesting factor combining both aspects of dispositional and contextual information is maternal care; Bentele et al. ( 2021 ) in their study are able to show that there was an effect of maternal care on the amylase stress response, while no such effect was observed for cortisol. In a similar vein, Keijser et al. ( 2021 ) showed in their gene-environment interaction study that the effects of FKBP5, a gene very closely related to HPA axis regulation, and early life stress on depressive symptoms among young adults was moderated by a positive parenting style; and (5) the role of stress and anxiety as transdiagnostic factors in mental disorders, be it as an etiological factor, a variable contributing to symptom maintenance, or as a consequence of the condition itself. Stress, e.g., as a common denominator for a broad variety of psychiatric diagnoses has been extensively discussed, and stress as an etiological factor holds specific significance in the context of transdiagnostic approaches to the conceptualization and treatment of mental disorders (Wilamowska et al. 2010 ). The HPA axis, specifically, is widely known to be dysregulated in various conditions. Fischer et al. ( 2021 ) discuss in their comprehensive review the role of this important stress system in the context of patients with post-traumatic disorder. Specifically focusing on the cortisol awakening response, Rausch and colleagues provide evidence for HPA axis dysregulation in patients diagnosed with borderline personality disorder (Rausch et al. 2021 ). As part of a longitudinal project on ADHD, Szep et al. ( 2021 ) investigated the possible impact of child and maternal ADHD symptoms on mothers’ perceived chronic stress and hair cortisol concentration; although there was no direct association, the findings underline the importance of taking stress-related assessments into consideration in ADHD studies. As the HPA axis is closely interacting with the immune system, Rhein et al. ( 2021 ) examined in their study the predicting role of the cytokine IL-6 on psychotherapy outcome in patients with PTSD, indicating that high reactivity of IL-6 to a stressor at the beginning of the therapy was associated with a negative therapy outcome. The review of Kyunghee Kim et al. ( 2021 ) also demonstrated the critical role of immune pathways in the molecular changes due to antidepressant treatment. As for the therapy, the important role of cognitive-behavioral therapy with its key elements to address both stress and anxiety reduction have been shown in two studies in this special issue, evidencing its successful application in obsessive–compulsive disorder (Ivarsson et al. 2021 ; Hollmann et al. 2021 ). Thus, both stress and anxiety are crucial transdiagnostic factors in various mental disorders, and future research needs elaborate further on their role in etiology, maintenance, and treatment.

In conclusion, a number of important questions are being asked in stress and anxiety research, as has become evident above. The Special Issue on “Recent developments in stress and anxiety research” attempts to answer at least some of the raised questions, and I want to invite you to inspect the individual papers briefly introduced above in more detail.

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Nater, U.M. Recent developments in stress and anxiety research. J Neural Transm 128 , 1265–1267 (2021). https://doi.org/10.1007/s00702-021-02410-3

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DOI : https://doi.org/10.1007/s00702-021-02410-3

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Stress and Health: A Review of Psychobiological Processes

Affiliations.

• 1 School of Psychology, University of Leeds, Leeds LS2 9JT, United Kingdom; email: [email protected].
• 2 Department of Psychological Science, School of Social Ecology, University of California, Irvine, California 92697, USA; email: [email protected].
• 3 Division of Primary Care, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom; email: [email protected].
• PMID: 32886587
• DOI: 10.1146/annurev-psych-062520-122331

The cumulative science linking stress to negative health outcomes is vast. Stress can affect health directly, through autonomic and neuroendocrine responses, but also indirectly, through changes in health behaviors. In this review, we present a brief overview of ( a ) why we should be interested in stress in the context of health; ( b ) the stress response and allostatic load; ( c ) some of the key biological mechanisms through which stress impacts health, such as by influencing hypothalamic-pituitary-adrenal axis regulation and cortisol dynamics, the autonomic nervous system, and gene expression; and ( d ) evidence of the clinical relevance of stress, exemplified through the risk of infectious diseases. The studies reviewed in this article confirm that stress has an impact on multiple biological systems. Future work ought to consider further the importance of early-life adversity and continue to explore how different biological systems interact in the context of stress and health processes.

Keywords: HPA axis; allostatic load; autonomic nervous system; cortisol; genomics.

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• Autonomic Nervous System / metabolism
• Hydrocortisone / metabolism
• Hypothalamo-Hypophyseal System / metabolism
• Pituitary-Adrenal System / metabolism
• Stress, Psychological / metabolism*
• Hydrocortisone

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• Review Article
• Published: 27 June 2019

The human stress response

• Georgina Russell 1 &
• Stafford Lightman   ORCID: orcid.org/0000-0002-8546-9646 1  

Nature Reviews Endocrinology volume  15 ,  pages 525–534 ( 2019 ) Cite this article

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• Adrenal cortex hormones
• Circadian rhythms
• Multihormonal system disorders
• Stress signalling

The human stress response has evolved to maintain homeostasis under conditions of real or perceived stress. This objective is achieved through autoregulatory neural and hormonal systems in close association with central and peripheral clocks. The hypothalamic–pituitary–adrenal axis is a key regulatory pathway in the maintenance of these homeostatic processes. The end product of this pathway — cortisol — is secreted in a pulsatile pattern, with changes in pulse amplitude creating a circadian pattern. During acute stress, cortisol levels rise and pulsatility is maintained. Although the initial rise in cortisol follows a large surge in adrenocorticotropic hormone levels, if long-term inflammatory stress occurs, adrenocorticotropic hormone levels return to near basal levels while cortisol levels remain raised as a result of increased adrenal sensitivity. In chronic stress, hypothalamic activation of the pituitary changes from corticotropin-releasing hormone-dominant to arginine vasopressin-dominant, and cortisol levels remain raised due at least in part to decreased cortisol metabolism. Acute elevations in cortisol levels are beneficial to promoting survival of the fittest as part of the fight-or-flight response. However, chronic exposure to stress results in reversal of the beneficial effects, with long-term cortisol exposure becoming maladaptive, which can lead to a broad range of problems including the metabolic syndrome, obesity, cancer, mental health disorders, cardiovascular disease and increased susceptibility to infections. Neuroimmunoendocrine modulation in disease states and glucocorticoid-based therapeutics are also discussed.

The hypothalamic–pituitary–adrenal (HPA) axis is a key system that synchronizes the stress response with circadian regulatory processes.

Regulation of the HPA axis is very dynamic with both ultradian and circadian oscillations.

Short-term and longer-term stress result in different regulatory mechanisms involving hypothalamic, pituitary and adrenal activity, as well as cortisol metabolism.

Chronic elevation and nonphysiological patterns of cortisol result in poor cognitive, metabolic and immune function.

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Cues that entrain or synchronize the body’s 24-h cycle

Biological rhythms that occur with a frequency of <24 h.

A biochemical oscillator with phases synchronized with solar time.

Neural pathways involving at least one relay.

The microcirculation that allows transport of hypothalamic hormones to the pituitary gland.

The threshold power of (solar) electromagnetic radiation needed to exert an effect.

Repetitive body movements that serve no biological function.

Behaviours engaged for a specific functional purpose.

Any biological process that displays an oscillation of approximately 24 h.

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Russell, G., Lightman, S. The human stress response. Nat Rev Endocrinol 15 , 525–534 (2019). https://doi.org/10.1038/s41574-019-0228-0

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DOI : https://doi.org/10.1038/s41574-019-0228-0

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