12.4 Clinical Implications of Stress

Allostasis vs. allostatic (over)load

We now know that the stress response is a necessary, survival-promoting response that allows us to adapt to challenges. What happens, however, if this response is activated for too long or too often, as a result of repeated exposure to stressors, or lack of proper shut down?

Well, it’s very much the continuation of the beneficial, life-saving aspects of stress that become detrimental when they are prolonged or chronic (inverted-U nature of the response). Think about the acute effects of stress. For example, you are confronted with a stressor and your blood pressure increases because that is what’s needed in order to run away from the threat. But, if your blood pressure is increased constantly, that becomes your new set point and now you have hypertension. Hypertension is a disease that affects most organ systems in the body. In the long-term, it increases wear and tear on many systems and accelerates the aging process. Other bodily systems are similarly affected. The immune and reproductive systems are turned down leading to immune suppression and reproductive distress/dysfunction. In the digestive tract, you can develop ulcers and decreased nutrient absorption. If the excessive stress exposure came early on in life, it can result in stunted growth. In terms of metabolism, glucose thrown into the bloodstream helps the muscles in the short run (escaping the threat) but can lead to diabetes if chronic. Similarly, in the brain, prolonged or severe stress exposure can lead to regional changes in brain structure (dendritic hypo/hypertrophy, remodeling, circuit plasticity) that can alter brain function and lead to pathologies such as anxiety, depression, and PTSD.

Recall that allostasis refers to the processes that restore homeostasis and also allow us to adapt through change. Our body’s activation of the nervous, endocrine (and immune) systems during a stress response, for example, are allostatic mechanisms that allow us to adjust and increase our resilience in the face of stress. Allostatic (over)load, on the other hand, is the physiological cost of that adaptation to our body, i.e., the ‘wear and tear’ that accumulates after repeated or chronic stress exposure (see Figure 12.25).

Figure 12.25 Allostatic overload Allostatic load is the difference between new and old set points that arises due to a cumulative burden of adaptation to stress.

Types of allostatic (over)load include:

1. Frequent activation of allostatic systems: e.g., repeated hits from multiple stressors resulting in overexposure to stress hormones.
2. Lack of adaptation to a repeated stressor: e.g., not getting used to public speaking.
3. Failure to shut off stress response activation after the stressor has passed: i.e., the inability to efficiently shutoff the stress response resulting in overexposure to stress hormones.
4. Failure to adequately activate the stress response: e.g., an inability to mount the proper HPA activation.

These aren’t mutually exclusive. There can be combinations of these occurring at the same time.

Ultimately, continual or chronic stress exposure results in allostatic (over)load. Allostatic (over)load serves no useful function and can predispose individuals to stress-related disorders and pathology. Some of the clinical consequences are discussed below.

Mood disorders

Mood disorders are often accompanied by a distorted or inconsistent emotional state that persistently interferes with the ability to function. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) categorizes several disorders as part of mood disorders including major depressive disorder (MDD), bipolar disorder, and others. Many studies have implicated that both acute and chronic stress are related to the onset of MDD (McEwen, 2004). One potential mechanism connecting stress and mood disorders is dysregulation of the neurotransmitter serotonin. Serotonin is a crucial neurotransmitter for mood regulation in the brain (see Chapter 13 Emotion and Mood). Chronic stress is known to modulate neurotransmitters linked to mood disorders and their receptors. For instance, chronic stress reduces 5-HT1A autoreceptor sensitivity in the dorsal raphe nucleus—the brainstem nucleus where serotonergic cell bodies are located (Chaouloff et al., 1999). Although 5-HT1A receptors are not actively engaged in anti-depressant drug effects, the receptors are well-known for regulating the entire serotonergic system. Furthermore, an increase in stress hormones due to hyperactivity of the HPA axis has been shown to elevate expression of the gene encoding the serotonin reuptake transporter—a main target of major anti-depressant drugs, which inhibit the transporter’s ability to reuptake/remove serotonin from synapses (Tafet et al., 2001). It is notable that dysregulation of serotonin homeostasis during critical periods (in utero, childhood, adolescence) and adulthood via exposure to chronic stress and dysregulated HPA axis function may produce long-lasting changes in the brain and ultimately impact the development of (and affect treatments for) mood disorders including MDD.

Anxiety disorders

Anxiety disorders are often characterized by intense and excessive symptoms of anxiety and worry that last persistently. According to the DSM-5, there are multiple types of anxiety disorders, diagnosed based on potential causes and symptoms such as generalized anxiety disorders, social anxiety disorders, phobias, and panic disorders. One of the risk factors for anxiety disorders includes exposure to chronic stress. Chronic stress is well known to enhance amygdala-mediated fear. For example, a study by Rosekranz et al. revealed that chronic stress can activate neural excitability in the lateral amygdala circuitry (Rosenkranz et al., 2010). The amygdala circuitry is particularly important in the regulation of emotion, anxiety, and fear. Thus, heightened amygdala activation mediated by stress plays a role in the development of anxiety disorders.

Repeated and chronic exposure to stress may also result in hyperactivity of the HPA axis, which can contribute to anxiety. A subgroup of patients with anxiety disorders often displays hyperactivity of the HPA axis (Tafet and Nemeroff, 2020). Furthermore, anti-anxiety drugs, such as benzodiazepines, tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs), all modulate components of the HPA axis. For instance, some types of benzodiazepines have been shown to alleviate anxiety symptoms and reduce the activity of CRH neurons in the hypothalamus, indicating the potential impact of anti-anxiety drugs on HPA axis regulation.

Posttraumatic stress disorder (PTSD)

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop in a subset of individuals exposed to a traumatic event (e.g., severe car accident, combat, sexual assault, natural disaster). It is characterized by persistent reexperiencing of the trauma (e.g., intrusive memories and flashbacks), avoidance of stimuli associated with the trauma and numbing of general responsiveness (similar to symptoms of depression) (see Figure 12.26).

Figure 12.26 Core symptoms of PTSD

Women are twice as likely to have PTSD than men (Kessler, 1995). Immediately following exposure to severe trauma, most individuals will present with a collection of these symptoms (i.e., will display an acute stress response). Yet, in most people, these symptoms will resolve within months. Only 15-25% of individuals will continue to show persistent symptoms a year after the traumatic event and meet the diagnostic criteria for PTSD (Yehuda et al., 1998). Thus, PTSD represents a physiological failure to recover from an acute stress response that is almost universal.

Not surprisingly, patients with PTSD display HPA axis dysregulation, but paradoxically, they show lower overall cortisol levels, especially in the hours immediately after the trauma (Mason et al., 1986; Yehuda, 2002). Additionally, they have an abnormally high noradrenaline/cortisol ratio which suggests a loss of coordinated activity between HPA axis and ANS function. Cortisol administration shortly after trauma (in ER patients exhibiting low cortisol levels) has been successful as a preventative intervention for PTSD (Zohar et al., 2011). Non-pharmacological interventions in the form of cognitive behavioral therapy, sometimes coupled with virtual reality scenarios, have also proven successful in treating the symptoms of PTSD.

Cognitive and memory disorders

Stress can affect multiple aspects of cognition including attention, learning, and memory. Some major cognitive/memory disorders in humans are Alzheimer’s disease (AD), attention deficit disorder, and dementia. Each of these is affected by stress exposure. Stress exacerbates AD (Machado et al., 2014; Justice, 2018), there’s a high comorbidity rate of PTSD with attention deficit disorder (Cuffe et al., 1994; Adler et al., 2004), and chronic stress is associated with dementia (Peavy et al., 2012) and increased risk for dementia later in life (Johansson et al., 2010). Stress-sensitive brain regions like the hippocampus and PFC likely contribute to these phenotypes.

Interestingly, PTSD can be viewed as a memory disorder, and it is easy to understand many of the symptoms via this lens. In addition to the strong recall of the traumatic event, PTSD patients report problems with declarative memory (remembering facts), fragmentation of memory and dissociative amnesia (not being able to recall important personal information). A salient feature of PTSD is an aberrant consolidation of the traumatic memory event (aberrant fear learning). It may manifest as a lack of fear extinction (new safety cues are not associated with the old memory) or a generalization of the fear response. For example, if the event was the experiencing of a bomb blast, then the result could be a sensitivity to other loud noises (Parsons and Ressler, 2013; Shalev et al., 2017; Fenster et al., 2018).

Addiction, compulsive and impulse disorders

Addiction is a compulsive behavior or use of a substance characterized by an inability to control consumption and withdrawal symptoms when unable to access it (see Chapter 14 Psychopharmacology). Gambling and shopping are examples of behaviors that can lead to a non-substance addiction. Substance abuse is highly studied and provides the basis for what we know about stress and addiction. Stress is a prominent risk factor for developing a substance use disorder or relapsing (Schmid et al., 2009; Enoch, 2011; Duffing et al., 2014; Tschetter et al., 2022). Stress and substance use both activate the HPA axis and connected amygdala, while down-regulating activation of the hippocampus and the PFC, leading to impaired decision making and impulsivity. These similarities suggest that stress may influence and further aggravate the effects of many drugs of abuse and contribute to addiction. Therefore, reducing stress could aid in efforts to treat addictions or prevent susceptibility.

Stress and (neuro)immune function

We all know that exposure to pathogens leads to characteristic changes in physiology and behavior. When we’re sick, we feel tired and sleepy, lose motivation, withdraw socially, don’t feel as hungry or thirsty, might have a fever and our brains might feel foggy. Sometimes we might also feel more sensitive to pain or more anxious and depressed. This constellation of symptoms is called the sickness response, and it is remarkably similar to endophenotypes that characterize stress-related mood disorders like MDD, anxiety and PTSD (see Chapter 17 Neuroimmunology). This intriguing observation hinted at the idea that neuropsychiatric conditions like mood disorders had an immune component. That is, the immune system might be involved in regulating an organism’s motivational state. This idea led to intense interest in the role of the immune system in brain function and how it relates to stress.

As we know, stress can affect every cell and tissue in the body, hence it is no surprise that it has profound effects on immune system function. In general, following the inverted-U pattern, acute stress seems to enhance immune responses while chronic stress has a suppressive effect. However, both acute and chronic stress can generate anti-inflammatory and proinflammatory responses, leading to a more complex picture. In recent years, inflammation has garnered a negative reputation, but it is in fact a necessary and beneficial immune response after an acute stressor like an injury/infection: here the immune system attacks the invaders, clears the threat and helps to promote healing. Inflammation is deleterious, however, if it becomes prolonged. Studies have shown, for example, that chronic socio-environmental stressors (poverty, bereavement) are associated with increased expression of genes involved in inflammation and decreased expression of antiviral responses—the conserved transcriptional response to adversity. This transcriptional program is thought to promote a state of chronic, low-grade inflammation which can result in development of inflammation-related diseases.

Stress and microglia—the brain’s resident immune cells

The brain, largely isolated from cells of the immune system due to the presence of the blood-brain-barrier, was long thought to be an immune-privileged organ; however, it contains its own tissue-resident immune cells: microglia. In recent years, there has been intense interest in understanding the crucial role of microglia in brain development and function.

As the resident phagocytes, microglia actively scan their environment for disruptions in homeostasis. They are first responders to threat (e.g., infection with a virus, tissue damage), play a critical role in neurodevelopment and perform numerous functions in the maintenance of the healthy adult brain. For example, they use their phagocytic activity to remove debris, dead/dying neurons and other cells. They also lend trophic (growth) support to neurons, modify synaptic connections and plasticity, and modulate neuronal activity. Additionally, because they are immunocompetent cells, microglia produce and release anti- and proinflammatory mediators (cytokines and chemokines), some of which have roles in synaptic plasticity and memory function. Figure 12.27 diagrams some of these cellular functions which impact brain function and development.

Figure 12.27 Microglial functions Through several cellular functions, microglia regulate injury/illness response, healthy brain function and neurodevelopment.

Homeostatic or surveilling microglia exhibit a highly branched morphology with a small cell body and unique transcriptional signature. This phenotype is suppressed when disruptions to CNS homeostasis occur (for example, during infection or aging). At the same time, microglia undergo changes in morphology, transcription and proinflammatory mediator profile (a spectrum of different functional states grouped under the umbrella term ‘activation’) which at the extreme becomes a phenotype characteristic of neurodegeneration. One of these activation states, termed ‘primed’, is seen in microglia under neuroinflammatory conditions like stress and aging. Microglia can also proliferate, increasing their numbers in response to homeostatic disruptions. Below, we will discuss more specifically the role of microglia in stress-related pathology with a focus on mood and cognitive dysfunction/neurodegenerative disorders.

Inflammatory priming and mood disorders

Microglia can respond directly to key stress mediators, including glucocorticoids and the catecholamines epinephrine and norepinephrine. Although glucocorticoids are widely known for their immunosuppressive effects, they can also have a more permissive role. A number of studies have implicated glucocorticoids in stress-induced inflammatory priming—that is, a sensitization or heightened immune response in microglia to subsequent inflammatory stimuli—in stress-related brain regions like the hippocampus. In other words, glucocorticoid exposure can make microglia more susceptible to a second inflammatory stimulus, and this can then trigger an exaggerated or prolonged inflammatory response that can damage nearby neurons or other cells and negatively affect brain function.

Experiments have tested the causal role of glucocorticoids in this phenomenon. For example, exposure to tailshock stress in rats where glucocorticoids signaling was blocked (via application of GR antagonists or adrenalectomy, removal of the adrenal glands) blocked this type of exaggerated inflammatory response in hippocampal microglia when subsequently stimulated with a bacterial product. Other experiments using β-adrenergic receptor agonists or antagonists and repeated social defeat stress have shown that catecholamines are also implicated in stress-induced microglial priming in regions of the brain related to threat-appraisal. Additionally, they play a critical role in the mobilization and redistribution of specific types of inflammatory peripheral immune cells to the CNS (for review see Frank et al., 2019). This type of infiltration of peripheral immune cells into the brain, along with a greater overall local inflammatory microenvironment, lead to a full-blown state of neuroinflammation.

Inflammatory priming is thought to contribute to the development of a number of mood disorders and their related symptoms. For example, microglia that have been primed by repeated stress exposure release several molecules that can directly impact emotion-related behaviors. IL-1β is one such molecule. It is a cytokine released by microglia that both contributes directly to further HPA axis activation and also drives sickness behaviors, like decreases in motivation to obtain a reward. Loss of motivation for previously rewarding stimuli is a core symptom of depressive disorders. Another protein released by stress-primed microglia, PGE2, stimulates increases in social avoidance and greater anxiety responses to stress (for review see Wolf et al., 2017). How this vicious cycle of stress and microglia function contributes to mood disorders is an active field of research which may yield new ways to treat depression and anxiety in the future.

Stress, microglia and neurodegeneration

Neurodegeneration is the age-related, progressive damage to neuronal structures and function in the CNS. It can result in disruptions to cognitive performance and is seen in disorders like Alzheimer’s disease (AD) and other dementias. Notably, a life-long history of stress exposure is a risk factor for developing cognitive deficits, brain atrophy and AD (Gracia-Garcı ́a et al., 2015, Alkadhi, 2012) and psychosocial stress, in particular, is a risk factor for late-onset AD (LOAD). Chronic stress has also been shown to worsen neurodegeneration and cognitive impairments in rodent models of AD (Carroll et al., 2011; Srivareerat et al., 2009). As discussed previously, chronic stress can lead to neuroinflammation, one of the hallmarks of many neurodegenerative disorders including AD.

Microglia play a key role in the establishment and progression of neurodegenerative disorders. Microglial dysfunction is prominent in AD, for example, and several genetic risk factors associated with the disease are specifically or highly expressed by microglia (APOE and TREM2). It is worth noting that during normal aging, microglia lose some of their surveillance/homeostatic capacity and are thought to become more proinflammatory or reactive in general. Additionally, their phagocytic function is impacted.

During neurodegeneration, microglia react to age-related, accumulated debris/protein aggregates through their dedicated pathogen and damage-sensing receptors. They also adopt an ‘extreme’ activated, primed phenotype termed MGnD (neurodegenerative microglia) or DAM (disease-associated microglia) characterized by induction of genes associated with cellular damage and degeneration. This phenotype also includes higher expression of immune modulators that induce astrocyte activation and aid in recruitment of inflammatory and other specialized immune cells that further contribute to neuronal damage. Thus, chronic stress can exacerbate neurodegeneration by compromising microglial homeostatic support for neurons/synaptic function and sensitizing microglia towards a primed state which leads to neuroinflammation and neuronal dysfunction and death. Interestingly, regions like the frontal cortex and hippocampus which are particularly sensitive to the effects of stress are also amongst the first brain areas affected in AD.