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Neuroscience Breakthroughs Since Graduate School - Part 6: Stress

Updated: Mar 24

Stressed child

Recent studies have challenged core stress concepts taught in graduate classes. We cannot turn off our physiological reactions to stressors like a light switch. Furthermore, we shouldn't attempt to do so, as arousal can improve our performance. Kelly McGonigal compellingly presents evidence that major life changes will not shorten life expectancy if we reinterpret our activation as bravely facing challenges. In addition, our prosocial actions can protect us from the harmful effects of major life changes. Dr. Inna Khazan persuasively argues that a mindfulness approach to stress can enhance our cardiovascular and neuroendocrine responses to stressors.

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Challenges to Homeostasis

Claude Bernard, Walter Cannon, and Hans Selye were influential scientists who contributed significantly to the development and understanding of the concept of homeostasis, which refers to the ability of living organisms to maintain internal stability and balance in the face of changing external conditions.

Claude Bernard (1813-1878) was one of the first scientists to recognize the importance of maintaining a stable internal environment for the proper functioning of the body's cells and organs. He introduced the concept of the "milieu intérieur" (internal environment) and argued that the role of physiological processes is to maintain a constant internal environment, which is necessary for life. Bernard's work laid the foundation for the concept of homeostasis and emphasized the importance of the body's ability to regulate its internal conditions.

Claude Bernard

Walter Bradford Cannon (1871-1945) built upon Bernard's work and coined the term homeostasis to describe the dynamic equilibrium that living organisms maintain to ensure their survival. He identified several key physiological mechanisms responsible for maintaining homeostasis, such as the regulation of body temperature, blood sugar levels, and pH. Cannon also introduced the "fight or flight" response, which refers to the body's acute stress response and the physiological changes that occur to prepare an organism for action in the face of a threat.

Walter Cannon

János Hugo Bruno "Hans" Selye (1907-1982) is best known for his research on stress and its effects on the body. He developed the concept of the "general adaptation syndrome" (GAS), which describes the body's three-stage response to stress: alarm, resistance, and exhaustion. Selye's work contributed to our understanding of how the body strives to maintain homeostasis in the face of stressors and how chronic stress can lead to maladaptive responses, negatively affecting overall health.

Hans Selye

Together, the work of Claude Bernard, Walter Cannon, and Hans Selye has helped shape our understanding of homeostasis as a fundamental principle governing the function of living organisms. Their research has provided valuable insights into the complex regulatory systems that enable organisms to adapt and respond to their environments, ensuring their survival and well-being.

We will discuss powerful challenges to homeostasis, including cataclysmic events, early life stress/adversity, and childhood trauma.

Cataclysmic Events

Lazarus and Cohen (1977) described cataclysmic events as "sudden, unique, and powerful single life-events requiring major adaptive responses from population groups sharing the experience” (p. 91).

Intentional and unintentional, these events can impact local communities (e.g., mass shootings), geographic regions (e.g., earthquakes, fires, hurricanes, and tsunamis), and the entire planet (e.g., the COVID-19 pandemic. These catastrophes can produce death, dislocation, fear, grief, trauma, and Post-Traumatic Stress Disorder. Graphic © Syda Productions/

Masked medical staff

Many factors influence survivor response to these powerful stressful events, including perceived discrimination, resources, support, vulnerability to future harm, distance from the devastation, and media coverage. The stressfulness of an event is influenced by geographic proximity, its recency, and whether it was intended. Intentional events are more traumatic than natural disasters because the perpetrators targeted the victims and could do so again (Brannon et al., 2022).

Traumatic Stress and Post-Traumatic Stress Disorder (PTSD)

Traumatic stress is produced by a highly intense stressor that disrupts coping and endangers ourselves or others. Post-Traumatic Stress Disorder (PTSD) is a severe and long-lasting trauma and stressor-related disorder that often develops within three months of a traumatic event. DSM-5 (APA, 2013) divides its symptoms into four clusters: intrusion, avoidance, negative alterations in cognition and mood, and alterations in arousal and reactivity. Graphic © John Gomez/


The exposure can also be second-hand, such as witnessing domestic violence or learning about a family tragedy (Crider, 2004; Lamprecht & Sack, 2002). The lifetime prevalence of adult PTSD in the United States is about 6.8% (Kessler et al., 2005).

While the earliest model of PTSD focused on trauma during combat, subsequent research has shown that crime, domestic violence, natural disasters, sexual assault, and terrorism can precipitate PTSD symptoms. Since women are more likely than men to experience these stressful events, it should not be surprising that they are more often diagnosed with this disorder (Stein et al., 2000). Children and adolescent victims and witnesses of violence also share an elevated risk of PTSD (Silva et al., 2000).

A single traumatic event can reshape synapses and increase electrical activity in the amygdala 10 days later. The N-methyl-D-aspartate receptor (NMDA-R) protein, which plays a central role in long-term memory, mediates these changes (Yasmin et al., 2016). Amygdala graphic © Kateryna Kon/


Early Life Stress/Adversity (ELA)

Birnie and colleagues (2023) reported that early-life stress could disrupt reward circuitry, resulting in anhedonia or loss of pleasure and motivation. They discovered a corticotropin-releasing hormone (CRH)/gamma-aminobutyric acid (GABA) pathway from the basolateral amygdala to the nucleus accumbens in mice. Adverse experiences overactivated this pathway, disrupting reward-seeking behaviors. Silencing this pathway restored reward behaviors.

In humans, the amygdala's central nucleus activates the hypothalamus' paraventricular nucleus (PVN), increasing CRH release to the pituitary gland in response to stressful stimuli. Graphic from Behavioral Neuroscience (9th ed.) © Oxford University Press.

CRH release

Chronic, elevated CRH levels in the bloodstream may enhance learning classically conditioned fear responses, heighten arousal and attention to increase readiness to respond to a stressor, intensify the startle response, and reduce appetite and body weight, sexual behavior, and growth.

Childhood Trauma and PSTD

The overall one-year prevalence of childhood trauma is around 14% (SAMHSA, 2022). This number is likely an underestimation. Graphic © fasphotographic/

Depressed child

Intentional acts may produce more widespread distress than natural disasters because they threaten future and more devastating attacks. The impact of a catastrophic event depends on your distance from the event, the time interval since the event, and the perpetrators' perceived intentions (Brannon et al., 2022).

PTSD can permanently damage the systems that regulate our stress response, particularly the amygdala and hypothalamic-pituitary-adrenal (HPA) axis. Patients experience increased cortisol level fluctuation and persistent epinephrine, norepinephrine, testosterone, and thyroxin elevation (Taylor, 2006).

PTSD may promote medical illness through persistent immunosuppression (Kawamura et al., 2001). Military veterans diagnosed with PTSD are more likely to develop severe diseases following discharge than veterans without PTSD (Deykin et al., 2001). PTSD may also exacerbate pre-existing health problems. PTSD resulting from the September 11, 2001, World Trade Center attacks may have helped worsen asthmatic symptoms in New York residents (Fagan et al., 2003).

The Physiological Impact of Chronic Stress

Researchers have studied the deleterious effects of chronic stress on the microbiome and immune system. Consistent with Hans Selye's General Adaptation Syndrome, chronic stress can produce allostatic load, and exhaustion, resulting in depletion and death.

Allostasis is a concept that complements homeostasis, describing the adaptive processes the body uses to maintain stability or balance during times of stress or change. While homeostasis refers to maintaining relatively constant internal conditions, allostasis focuses on the body's ability to adapt and adjust to various stressors to maintain overall stability.

In the context of Hans Selye's General Adaptation Syndrome (GAS), allostasis plays a crucial role in the body's response to stress. GAS describes the body's three-stage response to stress: alarm, resistance, and exhaustion.

Alarm stage: This is the initial response to a stressor, where the body activates the "fight or flight" response, which Walter Cannon described. This involves the release of stress hormones such as adrenaline and cortisol, leading to increased heart rate, blood pressure, and other physiological changes that prepare the body to react to the threat. Allostasis is at work during this stage as the body adapts to the new stressor and deviates from its normal balance to deal with the immediate challenge.

Resistance stage: If the stressor persists, the body enters the resistance stage, attempting to adapt to the ongoing stress and maintain a new level of stability. Allostasis continues to play a role as the body adjusts its physiological processes to manage the stressor. This may include the continued release of stress hormones, adjustments in immune function, and alterations in metabolism.

Exhaustion stage: If the stressor continues for an extended period, the body's adaptive resources may become depleted, leading to the exhaustion stage. Allostasis may no longer be effective at this point, as the body's ability to adapt to the stressor is overwhelmed. This can result in a breakdown of physiological systems and an increased risk of illness and disease.

Allostasis highlights the dynamic nature of the body's response to stress and underscores the importance of adaptability in maintaining stability. However, prolonged or chronic stress can lead to allostatic load, which describes the cumulative wear and tear on the body due to repeated or excessive adaptation to stressors. This can negatively affect overall health, increasing the risk of various physical and mental health conditions. Graphic adapted from Biostrap.

General Adaptation Syndrome

Stress and the Microbiome

The human body primarily comprises single-celled organisms, which outnumber our human cells 1.3-to-1 (Sender et al., 2016). Viruses vastly outnumber bacteria and could sharply increase the microbe-to-human cell ratio (Saey, 2016). The microbiome is a collection of microorganisms (including bacteria, viruses, fungi, and other microscopic organisms) that live in and on our bodies. Most human bacteria are located in our gut. Graphic © Kateryna Kon/


Research using rodents suggests that the 40 trillion bacteria in our microbiome may influence brain development, neurotransmitter synthesis, emotions, pain thresholds, and response to stressors. In rodents, shifts in the microbiome's ecology can produce more exploratory or cautious behavior. Illustration 168610495 © Burgstedt |


The relationship between the brain and gut biome appears to be bidirectional. While the brain and gut microbiome probably communicate using several pathways, the 100 million enteric system neurons that regulate the GI tract may be a crucial nexus. Mild stress can reduce the number of beneficial bacteria.

Chronic stress can significantly impact the human microbiome. The gut microbiome, in particular, plays a crucial role in many aspects of our health, including digestion, immune function, and even mental health.

Chronic stress can affect the human microbiome in several ways:

Altered composition: Chronic stress has been shown to cause alterations in the composition of the gut microbiota, leading to imbalances between beneficial and potentially harmful microorganisms. This dysbiosis can disrupt the normal functioning of the gut microbiome and contribute to various health issues, including inflammatory bowel diseases, obesity, and immune dysregulation.

Increased permeability: Chronic stress can lead to increased gut permeability, often called "leaky gut." This occurs when the tight junctions between the cells lining the gut weaken, allowing bacteria, toxins, and undigested food particles to pass into the bloodstream. This increased permeability can lead to inflammation and exacerbate immune-related conditions.

Weakened immune function: A significant proportion of the immune system is located in the gut, and the gut microbiome plays a vital role in modulating immune responses. Chronic stress can impair immune function, making it harder for the body to control potentially harmful microorganisms and increasing the risk of infection and inflammation.

Impact on mental health: The gut microbiome communicates with the brain through the gut-brain axis, a complex network involving the nervous system, hormones, and immune signaling. Chronic stress can disrupt this communication, contributing to anxiety, depression, and other mental health disorders. Conversely, alterations in the gut microbiome can also influence stress responses, creating a bidirectional relationship between stress and the gut microbiome. Disorders like anxiety and depression may be associated with abnormal microbiota (Carpenter, 2012).

Lifestyle factors: Chronic stress can lead to unhealthy lifestyle choices, such as poor diet, lack of exercise, and insufficient sleep, which can negatively impact the gut microbiome. For example, a diet high in processed foods and low in fiber can lead to a less diverse gut microbiota, which has been associated with various health problems.

In summary, chronic stress can significantly affect the human microbiome, particularly in the gut, leading to imbalances in microbial composition, increased gut permeability, weakened immune function, and impacts on mental health. Maintaining a healthy microbiome through a balanced diet, regular exercise, and stress management techniques can help promote overall health and well-being.

Stress and the Immune System

Although brief stress does not suppress immunity and may strengthen it (Dhabhar, 2018), chronic stress can reduce immunocompetence.

Klopack and colleagues (2022) reported an archival study involving responses from over 5,700 US adults 50 and older about stress from discrimination, their jobs, life events, and traumatic experiences. They cross-referenced responses with immune cell counts from their blood. Higher stress levels were associated with accelerated immune aging, as measured by CD4+ and CD8+ cells. T lymphocytes (T cells) are white blood cells and crucial components of the immune system. CD4+ and CD8+ T cells play essential roles in adaptive immunity, which is a highly specific and long-lasting defense against pathogens and foreign substances. Also known as helper T cells, CD4+ T cells primarily assist in the immune response by coordinating and regulating the activities of other immune cells. They are crucial for activating and directing B cells to produce antibodies, stimulating cytotoxic T cells to kill infected cells, and recruiting other immune cells, like macrophages and neutrophils, to the site of infection.

Also known as cytotoxic T cells or killer T cells, CD8+ T cells are responsible for directly killing infected or abnormal cells, such as virus-infected cells or cancer cells. Graphic © Juan Gaertner/

T cells

Positive Perspectives on Stress

Although challenge is an inescapable and often energizing part of living, stress does not have to produce illness and premature death. In this section, we will discuss the effect of reframing the stress response as courage, the protective effects of prosocial behavior, hardiness, and the benefits of a mindfulness perspective.

Reframe the Stress Response as Courage

Cannon (1942) studied voodoo deaths in shamanistic cultures and published speculation about how beliefs can produce lethal cascades of system failure in the American Anthropologist. Graphic © Fer Gregory/

Voodoo doll

Keller et al. (2012) conducted a regression analysis of the 1998 National Health Interview Survey and prospective National Death Index data from 28,753 adults. Both elevated levels of reported stress and the perception that stress negatively impacted health independently and jointly predicted poor physical and psychological health outcomes. While neither variable independently predicted premature death, those who reported high levels of stress and the perception that stress impacts health experienced a 43% greater risk of early death.

Check out Kelly McGonigal's TED Talk How to Make Stress Your Friend. McGonigal proposes that we train clients to reframe sympathetic activation as evidence of our courage to rise to a challenge instead of the body injuring itself.

Kelly McGonigal

Prosocial Behavior Buffers Stress Effects

A prospective study of 846 adults by Poulin et al. (2013) showed that providing tangible assistance to friends or family members in the previous year buffered the effects of stress on mortality over 5 years. In contrast, stress predicted mortality for participants who did not help others. Graphic © Ljupco Smokovski/

Young man helping an older man

Follow-up data from the longitudinal National Survey of Midlife Development in the U.S. (MIDUS II) of 1054 middle-aged adults found that women who perceived that they supported others in positive social relationships had lower IL-6 levels, which is a marker for inflammation (Jiang et al., 2021). Elevated IL-6 levels are linked to an increased risk for serious diseases.

Hardiness: Thriving in the Face of Adversity

Some individuals do not experience illness or psychological distress when exposed to adverse life events and hassles. Although they may experience brief distress, they generally recover (Lehrer, 2021). Researchers use the concept of hardiness to explain these outliers (Maddi, 2017; Maddi et al., 2017; Pitts et al., 2016; Stoppelbein et al., 2017). Graphic © lassedesignen/


The hardiness concept emerged from a 12-year study of manager stress responses at the Illinois Bell Company (Maddi, 1987). Halfway through the study, their parent company's reorganization eliminated half their employees within a year. Two-thirds of the managers experienced severe stress reactions (e.g., heart attacks, depression, and suicide), and one-third thrived. The investigators concluded that the hardy managers were protected by attitudes of commitment (strong involvement), control (internal locus of control), and challenge (learning from experience and accepting change).

Hardiness involves biological (McVicar et al., 2014; Parkash et al., 2017) and social factors (Kuzman & Konopak, 2016). Longitudinal studies suggest that infants' autonomic and emotional reactivity predicts later emotional reactivity (Berry et al., 2012; Wagner et al., 2017). Less reactive infants may become more resilient. In addition, cohesiveness and social support (actual and perceived) may buffer hardy individuals against stressors. Graphic © Nina Buday/


Dr. Inna Khazan's Mindfulness Perspective

Brooks (2014) showed that attempts to calm oneself before stressful performances failed to reduce physiological arousal and were unnecessary. In several studies, arousal was associated with better math, public speaking, and singing performance. We do not need to calm ourselves; we need to reframe our arousal as excitement instead of anxiety.

Mindfulness involves "paying attention in a particular way: on purpose, in the present moment, and nonjudgmentally" (Kabat-Zinn, 1994). Mindfulness teaches clients to focus on their immediate feelings, cognitions, and sensations in an accepting and nonjudgmental way.

Mindfulness Mother and Child

Clients learn to distinguish between what they can and cannot change and to change the things they can (Khazan, 2013). The key to escaping quicksand is not to struggle.


Dr. Khazan proposes that we reframe "threats" as "challenges." This avoids the "futile effort to control the uncontrollable" (Khazan, 2019, p. 217). Reframing improves performance and produces a healthier cardiovascular response to stressors, increasing cardiac performance while reducing peripheral resistance (Jamieson et al., 2010).

The Yerkes-Dodson curve graphs the relationship between stressors and performance. Reframing can reduce perceived pressure and energize performance.

The left side of the inverted U-curve depicts an underload where an individual is insufficiently challenged and bored. This phenomenon of low motivation and performance has been termed rust out and reminds us that we require stressors for motivation and creativity (O'Dowd, 1987). The middle region that ends with peak performance corresponds to eustress. An optimal level of challenge promotes focus, motivation, and creativity. The right side of the curve represents the worsening effects of excessive pressure, overload, and burn-out with anxiety, panic, and anger. Graphic © Olivier Le Moal/

Reinterpreting physiological activation as adaptive increases the dehydroepiandrosterone (DHEA) to cortisol ratio (Morgan et al., 2004). This is beneficial for several reasons. DHEA and cortisol are steroid hormones produced by the adrenal glands but have different bodily functions.

Balancing effects: DHEA and cortisol have opposing effects on the body. While cortisol is a catabolic hormone that breaks down tissues, increases inflammation, and suppresses the immune system, DHEA is anabolic, promoting tissue growth, repair, and a healthy immune response. A higher DHEA-to-cortisol ratio signifies that the body is more balanced, with adequate resources for growth and repair.

Stress response: Cortisol is a stress hormone that increases in response to physical, emotional, or psychological stressors. Chronic stress can lead to persistently elevated cortisol levels, negatively impacting health by promoting inflammation, impairing immune function, and increasing the risk of chronic diseases. A higher DHEA-to-cortisol ratio suggests that the body can better cope with stress and maintain a healthier stress response.

Aging and cognitive function: DHEA levels decline with age, and lower levels have been associated with cognitive decline, mood disorders, and other age-related health issues. A higher DHEA-to-cortisol ratio may indicate better overall cognitive function and reduced risk of age-related diseases.

Cardiovascular health: A higher DHEA-to-cortisol ratio has been linked to better cardiovascular health. Elevated cortisol levels can contribute to high blood pressure, arterial stiffness, and other risk factors for heart disease, while DHEA has been shown to have cardioprotective effects.


We do not need to purposefully change our physiological response to stress. We do not need to calm down in order to do our best. All we need to do is interpret the sensations of activation in a more helpful way (Khazan, 2019, p. 217).


Take a five-question exam on Quiz Maker to test your mastery.


amygdala: a limbic system structure that plays a crucial role in learning about the consequences of our actions and creating declarative memories for events with emotional significance.

B lymphocytes: the immune cells central to humoral immunity that rapidly produce antibodies that counter bacteria in the blood, neutralize toxins, and prevent reinfection by viruses.

cataclysmic event: a sudden, large-scale, and often destructive natural or man-made occurrence that results in significant changes to the environment, ecosystems, and human societies.

childhood trauma: experiencing harm or threat of harm to oneself or others.

corticotropin-releasing hormone (CRH): hormone released by the hypothalamus that triggers ACTH release by the pituitary gland.

cortisol: a catabolic steroid hormone that catabolic hormone that breaks down tissues, increases inflammation, and suppresses the immune system.

cytotoxic T (Tc) cells: immune cells that release toxins to destroy specific virally infected cells.

dehydroepiandrosterone (DHEA): a steroid hormone that promotes tissue growth, repair, and healthy immune response.

hardiness: the ability to thrive under stressful conditions.

lymphocytes: white blood cells, including T cells, B cells, and natural killer (Nk) cells, that play a crucial role in immune defenses. microbiome: the collection of microorganisms that reside in the human body.

pituitary gland: the endocrine gland found at the base of the skull that is divided into the anterior pituitary, which secretes the tropic hormones adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and growth hormone (GH), and the posterior pituitary that releases oxytocin and vasopressin produced by the hypothalamus. post-traumatic stress disorder (PTSD): a severe and long-lasting trauma and stressor-related disorder that often develops within three months of a traumatic event and may include re-experiencing a traumatic event, avoidance of stimuli associated with the trauma, numbing of responsiveness, and hyperarousal. social support: received (support provided) and perceived support (expected support) from individuals and organizations. traumatic stress: stress produced by a highly intense stressor that disrupts coping and endangers ourselves or others.


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