Chronic Stress and Its Toll on Human Health

Abstract 

Chronic stress affects many pathways of the brain, leading to innumerable complications in human functioning. Various studies have found links between stress and the prefrontal-striatal circuit as well as the prefrontal amygdala pathway. The disruption of these mechanisms has been proven to prompt abnormal decision-making, anxiety, and depression. Changes to dendritic morphology, hypothalamus, hippocampus structure also occur during stress, leading to psychological disorders including schizophrenia and memory loss. Additionally, diseases such as obesity and cancer are aggravated and can even be brought on by chronic stress. Finally, prolonged stress can disrupt sleep patterns, eating habits, and optimistic views on life through the dysregulation of cortisol secretion. This article traces the vastly contrasting and widespread effects of chronic stress on health through evidence compiled from various experiments. The following discussion therefore points to stress as a significant subject for future research and treatment development. 

Keywords: chronic stress, anxiety, brain pathway, cortisol, disease, depression

Chronic Stress and Its Toll on Human Health 

Stress, specifically chronic stress, affects a large amount of the human population numerous national surveys conducted by the American Psychological Association (APA) indicate that over 50 percent of US citizens are chronically stressed (American Psychological Association, 2023). Simultaneously, a significant proportion of the American population struggle with a variety of health issues – ranging from mental health disorders such as depression of schizophrenia to potentially fatal diseases such as cancer. Indeed, chronic stress is an important factor in the development of many medical conditions (Russel & Lightman, 2019). Combined with copious studies establishing links between stress and various health concerns, this review makes the conclusion that chronic stress does, in fact, cause and aggravate both mental, physical, and cognitive diseases (Russel & Lightman, 2019).  

Psychological stress should first be separated into two categories of acute and chronic stress. Acute stress, being an essential part of homeostasis – the body’s self-regulating process by which organisms maintain stability – is beneficial to the human mind and body. Characterized by a rhythmic, pulsatile secretion of cortisol – a hormone released into the bloodstream – acute stress is often a part of the body’s natural fight or flight system. Cortisol levels rise quickly when exposed to acute stress, allowing the body to use its energy to handle the stressor, and return to baseline soon after. On the other hand, chronic stress often results in this system going awry. Non-pulsatile, irregular patterns of cortisol are seen in prolonged stress, which will be the main form of stress discussed in this article. When exposed to chronic stress, cortisol levels tend to increase for extended periods of time, therefore causing implications in other parts of the body. (Russel & Lightman, 2019). 

In each section of this review, multiple systems of the brain and body will be analyzed through evidence obtained through surveys, models, and scientific experiments. Chronic stress, through its disruption of various brain mechanisms, will be proved to result in a wide spectrum of severe and sometimes fatal physiological and cognitive impairments. This discussion urges the development of effective and safe treatment to combat chronic stress and relieve the millions struggling from it. 

Disrupted Brain Pathways and Structure

Prefrontal-Striatal Circuit 

Chronic, prolonged stress has been proven to disrupt the brain’s prefrontal-striatal circuit. This neural pathway is essential to the decision-making process; therefore, dysfunction of this circuit leads to abnormal decision-making. In one study establishing this connection, experimenters presented a choice of pure chocolate milk paired with a strong light as opposed to the choice of diluted chocolate milk paired with a dim light to groups of control and chronically stressed rats (Friedman, et al., 2017). This task provided the rats with the challenge of choosing high reward and high cost, or low benefit and low cost. It was found that the control group chose the low-reward, low-cost option more frequently, representing normal decision-making and therefore normal cost-benefit integration. Stressed rats, however, were more inclined to take the pure chocolate milk, regardless of the costs (Friedman, et al., 2017). 

Further optogenetic manipulation, a technique that uses light to modify the activity of neurons in behaving animals, revealed that chronic stress in rats causes changes in neural circuits including the one being discussed here, the prefrontal-striatal circuit. These changes include an altered spike in neurons of the medial prefrontal cortex, increased activity in striatal projection neurons, and a decrease in activity of fast-firing interneurons. The alterations listed above have serious implications on the decision-making process: They affect how neurons encode and process information related to cost-benefit integration, and they also influence the balance of excitation and inhibition toward excitation in the neural circuitry, misbalancing neuron currents (Friedman, et al., 2017). Abnormal cost-benefit integration is often a symptom of many mental and mood disorders, such as anxiety and depression. In fact, the increased activity in striosomes caused by chronic stress can even lead to changes in dopaminergic activity, leading to a reduction in overall striatal dopamine release (Friedman, et al., 2017). This finding demonstrates the effect of the disruptions of this circuit not only on abnormal decision-making involving irregular cost-benefit integration but also on major depressive disorder, showing how chronic stress’ changes to brain function impact the mind and day-to-day functioning. 

Prefrontal-Amygdala Pathway 

An additional brain circuit, among many others, altered by chronic stress, includes the prefrontal cortex to the amygdala pathway, which processes emotional stimuli and regulates emotional behaviors. Specifically, it has been found that communication between the dorsal medial prefrontal cortex and projection neurons located in the basolateral amygdala – which play a role in processes involved with emotions, reward, fear, and anxiety – becomes disrupted. Miscommunication between these two areas of the brain leads to a drastic shift in the E-I balance towards excitation, impairing cognitive function (Liu, et al., 2020). Researchers tested the effects of this on rats using two behavior assessments to measure anxiety levels. They found that stressed mice exhibited behavior indicating increased anxiety (Liu, et al., 2020). Using light stimulation, researchers also found that stress slowed the decay of NMDAR-meditated currents, a form of glutamate channels. This, in turn, proves that stress increases the glutamate release at these channels. Overall, the effects of the disruption of this brain pathway include an increase in excitation and an increase in glutamate release, both of which result in heightened anxiety (Liu, et al., 2020).

Additional research shows that medial prefrontal-cortex neurons projected to the basolateral amygdala are more resilient to stress than ones projected to different brain regions. BLA-projecting neurons can maintain their centric structure and dendric spine density despite chronic stress (Liu, et al., 2020). This conveys how variable the effects of chronic stress are.

The detrimental effects of chronic stress on the prefrontal to amygdala pathway are key to understanding the impact stress has on the mind and body as they have been proven to lead to anxiety and mood disorders such as depression. (Liu, et al., 2020)

Dendritic Morphology 

The impacts of chronic stress can be more granular than one might expect, for example, in its effect on dendrites, a part of the neuron which receives synaptic input from axons. To explore the exact changes in dendritic morphology caused by stress, researchers conducted an experiment consisting of two groups. Male rats were exposed to either three hours of daily restraint stress or left untouched. On the last day of this experiment, the rats were exterminated and their brains stained using a Golgi-Cox procedure, which allowed researchers to do a detailed examination of the changed morphology of the neurons (Cook & Wellman, 2004). Thorough analysis of the brains of the stressed and unstressed rats revealed a significant difference in the structure of dendrites between the two groups; the number as well as the length of apical dendrite branches – dendrites that emerge from the tip of the cell – were reduced by about 18 and 32%, leaving basilar dendrites – dendrites that emerge from the base of the cell – unaffected. Additionally, there was a 58% decrease of dendritic material lateral to the soma, the body of the neuron (Cook & Wellman, 2004).

The consequences of stress on dendritic morphology are now proven, but what impact does this have on day-to-day life and functioning? The retraction of dendrites as seen in the experiment above is known to reduce glutamatergic transmission, leading to medial prefrontal cortex dysfunction and altered connectivity with the amygdala. The dysfunction of this pathway has several impacts on human mental, physical, and cognitive health, as discussed in the previous section (Liu, et al., 2020). Equally important are the roles these stress-induced alterations– especially in the prefrontal cortex – play in the development of psychological disorders such as major depressive disorder and schizophrenia (Cook & Wellman, 2004). Even so, more research is needed to solidify the contribution of these dendritic morphological variations on these disorders.  

Hippocampus and Hypothalamus 

The hypothalamus and hippocampus both play necessary roles in human living and function. The hypothalamus controls homeostasis, involved in primary functions such as body temperature, heart rate, and hunger. On the other hand, the hippocampus is central to memory and learning. Chronic stress can disrupt many of these processes. One study found the following after inducing three weeks of unpredictable stress in a group of rats. To start, stress was found to inhibit input to neurons involved in the HPA axis, discussed previously (Joëls, et al., 2004). These neurons are found in the hippocampus, and disrupt homeostasis, leading to disease. In addition, chronic stress amplifies glutamate transmission in the dentate gyrus, part of the hippocampus specifically pertained to the formation of new memories (Joëls, et al., 2004). The researchers also found a significant decrease of cell growth in the dentate gyrus, impairing the acquisition, storage, and retrieval of new information in the brain. Synaptic plasticity – the capability of the brain to adapt to its constantly changing environment – diminishes as well because of prolonged stress. Along with this, neurogenesis – neuronal formation – and apoptosis – the death of harmful cells, such as cancerous cells – are reduced in these regions. Final outcomes of unpredictable stress included changes in the GABA receptors and calcium channel subunit composition. These mechanisms are involved in a variety of functions: muscular contraction, hormone excretion, and gene expression. Changes in these brain areas therefore lead to an inhibition of the functions mentioned above (Joëls, et al., 2004). 

These reverberations in the hippocampus and hypothalamus all contribute to the decline of memory, and inability of the brain to encode, store, and retrieve information. In addition, a serotonin decrease was found in an area of the hippocampus called CA1, and when paired with increased glutamate transmission mentioned previously, can contribute to depression and anxiety, exhibiting the importance of these effects on daily life (Joëls, et al., 2004).

Stress-Related Diseases 

Obesity 

According to the CDC, almost 42 percent of Americans were obese between 2017 and 2020, which compared to the almost 50 percent of chronically stressed adults, is not at all surprising. The relation between chronic stress and obesity is concrete, through a decrease in fitness levels, an increase in appetite, and a change in hormone levels and signals (Centers for Disease Control and Prevention, 2024).

In a survey of over 12,000 participants, chronic stress proved to be related to a decrease in physical activity, leading to obvious weight gain (Ng & Jeffery, 2003). Additional survey studies produce patterns concerning an increase in appetite when stressed, specifically for foods higher in sugar, fat, and calories (Torres & Nowson, 2007). An increase in appetite can also originate from an increase in dopamine – a neurotransmitter associated with movement, motivation and most importantly, pleasure reward – induced by chronic stress (Dallman, 2010).

The biochemistry of the development of obesity is arguably most important when discussing chronic stress’ role. Primarily two hormones are used to regulate appetite: leptin and ghrelin. These hormones, being opposite of each other, work to prevent the body from unnecessarily large food intake in different ways. Ghrelin – a hormone signaling caloric need – communicates the body’s hunger to brain (Russel & Lightman, 2019). Leptin, on the other hand, – a hormone signaling fullness – informs the brain when the body is no longer in need of excess calories (Russel & Lightman, 2019). Chronic stress weakens the signals of these hormones, resulting in inaccurate messages of caloric need to the brain (Russel & Lightman, 2019). This prompts the body’s unawareness of satiation, leading to an increased food intake through no fault of one’s own.  

Obesity is one of the leading health concerns in the world – a serious risk factor in an abundance of causes of death, including heart disease, stroke, diabetes, and cancer (Ritchie & Roser, 2017). As already indicated, chronic stress can increase the likelihood of obesity, therefore, providing a source of treatment for stress could result in a beneficial treatment for obesity. 

Cancer and the Immune System 

The immune system is crucial in protecting the body from various diseases, including preventing the growth and spread of tumor cells. This system can be greatly disrupted by chronic stress causing cancer cells to form and spread rapidly through the body. In addition, numerous studies and research have linked a promotion in breast cancer, pancreatic cancer, and gastric cancer due to prolonged stress. 

The body’s immune system – an integral part of defending the body against infection and protecting its own cells – can be harmed by stress in a variety of ways. For one, they increase levels of inflammatory cytokines – molecules that regulate the immune system – which can lead to disease and weaken the system, diminishing its ability to effectively fight against cancer cells (Russel & Lightman, 2019). 

Regarding cancer itself, stress induces a specific microRNA called miR-337-3p to effectuate EMT in breast cancer – a cellular process activated during cancer progression facilitating tumor development. A study conducted by Du et al. also demonstrated the effects of chronic stress on breast tumors of female mice. A significant increase in metastasis – the spread of cancer cells from an original tumor – was found in the stressed group rather than the control group (Du, et al., 2020).

The metastasis of pancreatic cancer has also been found to be affected by stress. Researchers discovered that chronic exposure of pancreatic cancer cells to epinephrine – a hormone significantly increased by stress – dramatically escalated cell production and migration (Al-Wadai, Al-Wadei, Ullah, & Schuller, 2012). Additionally, in stress-exposed mice, tumor tissue in the pancreatic region was enlarged, compared to unstressed mice. 

Furthermore, chronic stress is correlated with the promotion of gastric cancer, also known as stomach cancer. A study conducted by Zhang and other researchers found a significant enlargement in the gastric tumors of chronically stressed mice (Zhang, et al., 2019). An increase in tumor weight and volume was also observed and like the previous study, the exposure of cells to epinephrine led to increased cancer metastasis. 

According to the American Cancer Society, cancer is the second-leading cause of death worldwide. This in mind, along with the immense contribution of prolonged stress to the progression of various forms of tumors, demonstrates the need for chronic stress treatment, to reduce the number of cancer deaths (American Cancer Society, 2020).

Other Harmful Effects of Chronic Stress 

Memory 

As discussed earlier, memory can be disrupted when damage to the hippocampus occurs. This damage is often a result of prolonged, chronic stress. A series of experiments focusing on hippocampal calbindin – a protein which binds to calcium to regulate calcium levels in cells – has found specific links between stress and memory loss, and the effects of stress-induced memory on the brain. 

Researchers first measured the effect of stress on the calbindin levels in hippocampal excitatory and inhibitory neurons – neurons that work together to create neural circuits – of rats. They found that calbindin levels peaked during about the ninth day of the experiment and found the effect of stress exposure to be considerably higher in the stressed group rather than the control group (Li, et al., 2017). Further use of markers to identify the location of specific proteins revealed that interneurons containing calbindin were significantly decreased in stressed mice, stipulating that stress diminishes levels of hippocampal excitatory and inhibitory neurons (Li, et al., 2017). To determine the role of this decrease in memory, the researchers conducted several hippocampal-dependent location tasks, which measure spatial memory specifically, and found that only stressed mice were not able to differentiate objects in the inaccurate location. It was also established that the stressed group performed significantly worse than the controls, which indicates spatial memory deficits (Li, et al., 2017). 

Memory, extremely important to the daily lives of both humans and animals, naturally declines as one ages. However, earlier memory loss creates prominent disturbances and unnecessary challenges, as does chronic stress. The several experiments above highlighting the link between memory loss and chronic stress are the first steps in the research needed to decrease these complications. 

Sleep 

The detrimental effects chronic stress has on sleep are no surprise, however most are unaware of its extent and basis. One study aims to help people understand this through conducting an experiment measuring the effect stress brought on by school has on teenager’s sleep efficiency – the percentage of time spent asleep while in bed. 

Using the amount of sleep attained during holidays as a baseline, researchers found that school attendance drastically reduced time spent in bed by about 90 minutes and total sleep time by about an hour. A significant change in percent of sleep efficiency was not observed (Astill, Verhoeven, Vijzelaar, & Van Someran, 2013). Moreover, the researchers compared these levels of stress brought on by simply school attendance to stress levels during important exams – a time of increased pressure and anxiety. To no surprise, examination further decreased time spent in bed by about 17 minutes and reduced sleep efficiency by about 1.5% – seemingly insignificant values, however, when accumulated for years can be injurious to one’s health (Astill, Verhoeven, Vijzelaar, & Van Someran, 2013).

The basis of these effects on sleep is just as, if not more, important to consider in the discussion of chronic stress. As discussed previously, chronic stress elevates cortisol levels during its daily cycle – its circadian rhythm. Regarding sleep, cortisol levels are specifically increased during the lowest points of this daily rhythm, called the nadir. Over time, constant exposure of these elevated levels can lead to sleep deprivation, causing a variety of health problems (Russel & Lightman, 2019). Sleep deprivation additionally interferes with daily life, leading to problems at school, work, and even simple tasks such as driving. 

Sleep itself is obviously extremely necessary and beneficial to human functioning, but combined with its additional needs, it should not be disregarded. Because of the harmful effects chronic stress has on human’s daily sleep patterns, the importance of finding solutions and treatment becomes increasingly vital.   

Positive Outlook 

As evidenced thus far, chronic stress has unmistakable effects on one’s health and well-being, fostering implications in mood and everyday life. One such complication includes the consequence of chronic stress on human’s outlook of the world.  

An effective experiment administered hydrocortisone – cortisol in a medication form – to otherwise healthy men in two methods, pulsatile or non-pulsatile, and later assigned them to several facial recognition tasks. As reviewed in earlier discussion, a pulsatile pattern of cortisol secretion is seen in acute stress, and is beneficial to the body, while continuous or non-pulsatile secretion is seen in chronic stress. Subjects given hydrocortisone in a pulsatile pattern were more likely to accurately recognize positive faces than negative, while those administered the medication in a non-pulsatile pattern recognized positive faces more accurately, but to a much weaker extent (Kalafatakis, et al., 2018). Pulsatile secretion also led to a bias towards happy rather than fearful facial expression while non-pulsatile secretion resulted in a bias towards neither (Kalafatakis, et al., 2018).

In summary, a pulsatile pattern of cortisol secretion, as seen in acute stress, contributes to a more optimistic view on emotional faces, which can ultimately give rise to a more positive outlook on life. In contrast, a non-pulsatile secretion of cortisol, as seen in chronic stress, has a considerably diminished effect on a person’s optimistic outlook, leading to mental health disorders such as depression. 

Future Directions of Chronic Stress Research and Treatment

As demonstrated through this review of the literature, the effects of chronic stress are more extensive than is assumed by most. Chronic stress has been proven to play a role in the disruption of two major brain pathways – the prefrontal striatal circuit and the prefrontal to amygdala pathway – as well as in the onset and development of serious diseases such obesity and cancer. Additionally, stress disrupts daily functioning, through its implications in memory, sleep, and positive outlook. 

Chronic stress has the potential to disrupt brain function affects fundamentally all areas of the human body. Because of this, and all other evidence discussed pointing to this conclusion, it is increasingly vital that greater research is conducted to facilitate the development of more effective and safe treatment. Finding effective treatment for this condition is more difficult than most others as not many medications exist which mimic the specific bursts of rising and falling cortisol levels seen in adaptive, acute stress without producing a large amount of harmful side effects. However, according to Yale Medicine, stress management techniques such as exercise, adequate sleep intake, and a healthy diet can be used to prevent the acute stress response from becoming maladaptive (Yale Medicine , 2007). Chronic stress’ dangerous nature as well as its commonality makes it a significant subject for further research and effort to produce treatment. This is critical not only to provide comfort for the millions struggling mentally but also physically, due to stress’ widespread effects on the body

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