Medical Student Well-Being: An Essential Guide

© Springer Nature Switzerland AG 2019

Dana Zappetti and Jonathan D. Avery (eds.)Medical Student Well-Beinghttps://doi.org/10.1007/978-3-030-16558-1_1

1. The Physiology of Stress

Joséphine Cool¹   and Dana Zappetti²  

(1)

New York Presbyterian Hospital/Weill Cornell Medical College, New York, NY, USA

(2)

Weill Cornell Medical College, New York, NY, USA

Joséphine Cool

Email: [email protected]

Dana Zappetti (Corresponding author)

Email: [email protected]

Keywords

StressAllostasisAllostatic loadAllostatic load index

Allostasis: The Normal Stress Response and the Reason that Stress Exists

All human beings occasionally feel stress. Healthcare workers have jobs that are often demanding physically, mentally, and emotionally and can often be overwhelmed by stress. However, it is important to remember that the stress response exists for a reason. This chapter will review the normal physiologic stress response, examine how this stress response can become dysfunctional and lead to disease, and finally explore the ways that stress can be studied in human beings. This will be framed throughout the chapter with the concepts of allostasis, allostatic load, and allostatic load index.

To start, we will define some terms that will be referred back to throughout this chapter.

Stressor

Any actual or potential disturbance of an individual’s environment due to real or perceived noxious stimuli.

Stress mediators

Molecules that bind to receptor targets, act on specific neuronal populations, and have unique downstream effects, for example, catecholamines or cytokines.

Stress response

The activation of coordinated neurophysiological responses in the brain and periphery, through the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, to respond to the environmental demands caused by stressors. This enables us to adapt to a changing environment.

Stress is difficult to study because its effects on the body are widespread and not easily isolated. Allostasis is a way to conceptualize the reason that our body creates stress. In the original terms, an organism maintains physiological stability by changing the parameters of its internal milieu by matching them appropriately to environmental demands [1]. To translate into layman’s terms, allostasis indicates achieving stability through change. An example of allostasis in nature would be the accrual of body fat in bears in preparation for hibernation. Allostasis is different from homeostasis in the sense that after the stressor ebbs, there is not necessarily return to the same prestress set point; for example, the bear may not lose all of its hibernation fat when spring arrives.

A normal stress response occurs when the body recognizes a stressor, which can be real or perceived, and thereafter creates a state of heightened vigilance and arousal through the activation of coordinated neurophysiological responses in the brain and in the periphery. A crucial part of the normal stress response is that, after the stressor is removed, there is a recovery phase with return to either the same or a different baseline.

An effective stress response allows us to function in a world with normal development and efficient energy utilization, therefore allowing us to adapt to a changing environment.

We will first illustrate the concept of allostasis with the regulation of heart rate in response to a stressor.

Under normal circumstances, the heart rate is regulated by the autonomic nervous system, i.e., the parasympathetic nervous system (PNS) and the sympathetic nervous system (SNS), which acts on the sinoatrial (SA) node. Prior studies where both propranolol and atropine were administered, so-called double blockade studies, found that the resulting heart rate when the double blockade was present is higher than the normal resting heart rate in the absence of these medications. This implies that vagal dominance, or a basal parasympathetic vagal tone, exists on the SA node that is stronger than the tone exerted by the SNS [2], which allows for energy conservation.

In addition, the PNS has a fast on and off effect on the SA node, which leads to a high heart rate variability (HRV) or so-called beat-to-beat variability. The reason that the PNS affects the SA node faster than the SNS is secondary to the difference in speed of action of the neurotransmitters characterizing each branch of the ANS. As a reminder, the cardiac parasympathetic pathways start in the nucleus ambiguus of the medulla oblongata (dorsal motor nucleus of the vagus nerve), proceed through the cervical vagus nerves close to the common carotid artery, enter the chest through the mediastinum, and synapse with postganglionic cells on the epicardial surface or within the walls of the heart itself. These cells are close in proximity to the SA and AV nodes. The right vagus nerve predominantly acts on the SA node, and the left vagus nerve predominantly acts on the AV conduction tissue. When the vagus nerve is activated, it leads to release of acetylcholine which acts quickly on muscarinic receptors to decrease the activity of acetylyl cyclase and does not require secondary messengers like cyclic adenosine monophosphate (cAMP), allowing for beat-to-beat control. Indeed, the PNS acts on the order of milliseconds, which allows for the heart to be able to respond quickly to stressors when needed.

In contrast, the cardiac sympathetic pathways start in the intermediolateral columns of the lower cervical and upper thoracic segments of the spinal cord, synapse in the stellate and middle cervical ganglia, then are distributed to the various chambers of the heart via an extensive epicardial plexus and finally penetrate the myocardium along the coronary vessels. The SNS leads to the release of norepinephrine that acts on a beta-adrenergic receptor and leads to an increase in adenylyl cyclase activity. Because the CNS acts through a secondary messenger, its effects are slower. The PNS dominance on the SA node allows for a faster response to a stressor.

To summarize, there is a parasympathetic basal tone that acts on the SA node through the action of the vagus nerve. When a stressor occurs, there are both activation of the SNS and inhibition of the PNS to allow for the heart rate (HR) to increase appropriately. The SNS and PNS are themselves under control of a central autonomic network located in the brain.

When a stressor occurs, for example, a decrease in blood pressure from blood loss, baroreceptors in the aortic arch and carotid sinuses send afferent signals to the central autonomic network in the brain. This leads to inhibition of the vagus nerve through GABAergic neurons and release of the PNS basal tone on the SA node and allows for an increase in heart rate and therefore cardiac output [2].

The central autonomic network is itself under regulation of several areas in the brain, which means that at the highest level the brain is the gatekeeper of the stress response. In a very simplified manner, just like there is tonic inhibition of the SA node by the PNS, in the brain, there is tonic inhibition of the amygdala by the prefrontal cortex [2]. Other brain regions included in this process are the premotor cortex, frontal lobe, hypothalamus, temporal lobe, and cingulate gyrus. The amygdala is continuously assessing the threats and regulates the perception of fear, but the prefrontal cortex tonically inhibits this to prevent the presence of a continuous stress response. Perception of a stressor leads to release of this tonic inhibition, which allows for activation of the stress response via the HPA axis and the ANS. As discussed above, this leads to removal of vagal inhibition on the SA node and therefore an increase in the HR. To bring this back to the concepts introduced earlier, in this scenario, allostasis means that there is an increase in the heart rate in response to a stressor, but also recovery of the HR after removal of the stressor (Fig. 1.1).

Figure 1.1

The autonomic system regulates the stress response

The Hypothalamic-Pituitary-Adrenal Axis

As mentioned earlier, the purpose of a normal stress response is to summon additional energy in response to stress. The brain and the central autonomic network ultimately regulate when the stress response is activated, usually in response to visceral and sensory stimuli that reach the brain through ascending brainstem pathways and limbic pathways. Once it is activated, the stress response proceeds via the HPA axis, which is a neuroendocrine system that is the major stress system in the body, leading to the production of cortisol by the adrenal gland.

In more detail, when the brain agrees that the body needs to respond to a stressor, the parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) are activated, which leads to the release of corticotropin-releasing hormone (CRH) and vasopressin. These hormones in turn act in the anterior pituitary via CRHR1 to process pro-opiomelanocortin (POMC) to corticotropin (ACTH), opioid, and melanocortin peptides. ACTH then acts on the adrenal cortex to secrete cortisol in humans. As a reminder, the adrenal gland is composed of the medulla and the cortex. The medulla secretes catecholamines (epinephrine and norepinephrine); the cortex is divided into three zones: the outermost zona glomerulosa, which secretes aldosterone; the middle zone fasciculata, which secretes glucocorticoids; and the zona reticularis, which secretes androgens such as dehydroepiandrosterone (DHEA).

Cortisol is a glucocorticoid that affects numerous tissues to mobilize or store energy [3]. It alters glucose and fat metabolism, bone metabolism, cardiovascular responsiveness, and the immune system. Cortisol mediates the stress response in a biphasic manner through immediate and delayed responses.

The Fast and Slow Paths of the Stress Response

The fast effect of cortisol, which acts within milliseconds, is characterized by the release of catecholamines and neuropeptides such as norepinephrine, serotonin, dopamine, and CRH that lead to increased vigilance, alertness, arousal, and attention. The mechanism of the rapid responses is poorly understood but is thought to involve the binding of cortisol to the mineralocorticoid receptor (MR) in the brain leading to conformational changes and reaggregation with other proteins such as heat-shock proteins [3].

The slow effect of cortisol starts within 1–2 hours after stressor exposure. It is initiated when cortisol binds to both MRs and glucocorticoid receptors (GRs) in the brain, which leads to changes in gene transcription and therefore expression of proteins that affect neuronal function. This allows for the reorganization of resources to mobilize them on a longer time scale. Changes in cell metabolism, structure, and synaptic transmission are mediated by the altered expression of 70–100 genes through the activation of MRs or GRs in the hippocampus.

However, MRs and GRs have different cellular and behavioral effects. MRs, which in the brain lack specificity for aldosterone, are implicated in the appraisal process and are mainly involved in the fast effect at the onset of the stress response. MRs are located in the hippocampus, the amygdala paraventricular nucleus (PVN), and the locus coeruleus and therefore help with the cognitive, emotional, and neuroendocrine processing of stressful events. GRs have a tenfold higher threshold of activation than MRs and are ubiquitous in the brain but mainly located in the hippocampus and parvocellular nucleus. They are more involved in the slow effect of the stress response via changes in gene transcription and are also essential in the termination of the stress response via negative feedback regulation. GRs also help prepare for future stressors by promoting memory storage. Research in rats [4, 5] has shown that early adverse life events or chronic stress in adulthood led to a decrease in the number of functioning GRs in the hippocampus, presumably leading to deficient memory storage of stressors and termination of the stress response.

Although MRs and GRs seem to mediate many of the effects of the stress response, further research [6] has also shown that there may be other membrane-associated receptors such as G-protein-coupled receptors that are also involved.

Changes in Stressor Type Can Lead to Changes in Mediator

Different types of stress can activate varied areas of the brain. For example, physical stressors such as blood loss, trauma, or cold lead to preferential activation of the brainstem and hypothalamic regions. Psychological stressors such as social embarrassment or deadlines lead to preferential activation of the amygdala and prefrontal cortex (for emotion and decision-making) and hippocampus (for memory). Similarly, the duration of a stressor can affect which mediator is used in the stress response. Stress mediators include but are not limited to catecholamines, dopamine, serotonin, CRH, urocortins, vasopressin, orexin, dynorphin, corticosteroids, neurosteroids, insulin, ghrelin, and leptin. These different mediators act preferentially on different areas of the brain and can lead to varied end effects. For example, norepinephrine can act on the locus coeruleus to shift the processing of information from focused to general scanning; dopamine released from the prefrontal cortex allows for better risk assessment; and CRH of course leads to the activation of ACTH in the anterior pituitary but is also released in the amygdala, hippocampus, and locus coeruleus to enhance memory consolidation [4].

Allostatic Load: When the Stress Response Becomes Pathological

As described above, allostasis is a way to conceptualize the normal physiologic stress response that includes a period of activity followed by a period of recovery.

Allostatic load describes the wear and tear of the body from stress and inefficient allostasis [7]. This wear and tear can include genetic load, life experiences such as major life events or trauma, and health habits and determines the resilience to stress. In contrast to allostasis, in allostatic load, there is no normal return to baseline after removal of the stressor. Based on the model set in place by McEwen, there are four main ways in which allostatic states deviate from healthy responses. The first is in the setting of repeated hits. If one gets repeated hits of the same stressor in short periods of time, there is not enough time to habituate to the recurrence of the same stressor. The second manner, which is an extension of the first, is through lack of adaptation. Not only is one unable to habituate to repeated stressors, but with each hit, one is less efficient and less capable of responding appropriately to the stressor. The third way in which allostatic load can develop is when there is a prolonged response to a stressor without recovery after the stressor is removed. And finally, the fourth way in which allostatic load can occur is through the development of an inadequate response, i.e., that the normal physiologic stress response is not elicited at all (Fig. 1.2).

Figure. 1.2

Development of allostatic load [7]

Allostatic load therefore means that there is either an inadequate stress response or an inadequate recovery to the stress response.

When a stressor occurs, primary mediators , such as stress hormones and their antagonists, pro- and anti-inflammatory cytokines (IL6, TNF-alpha), etc., exert primary effects on cellular processes by changing the activity of enzymes, receptors, ion channels, and genes. In a normal allostatic response, these primary effects ebb once the stress response ends. However, when these primary effects are allowed to proceed unfettered without recovery, they lead to secondary outcomes , or detrimental changes in metabolic, cardiovascular, and immune functions to subclinical levels. This can include increase in insulin resistance, cholesterol, blood pressure, CRP, etc. When the stress response proceeds even further, these secondary outcomes lead to tertiary outcomes, i.e., disease and death, indicating allostatic overload .

Bringing this back to the example of tachycardia described previously, if there is no brake on the brain’s perception of fear and threat, then the stress response can proceed unfettered via the HPA axis and the ANS. This leads to continuous removal of vagal inhibition on the SA node, constantly elevated heart rate, and no recovery after removal of the stressor.