Stress and the Brain: How Chronic Stress Changes the Brain

Stress is the body's response to strain or to a change in the environment (both external and internal). It leads to adaptation to the given situation, which we call a stressor. A problem arises when stress becomes long-term (chronic). 

In the human body, this activates the so-called HPA axis. This is the main hormonal system controlling the body's response to stress. It includes three structures: the hypothalamus, the pituitary gland, and the adrenal glands. The hypothalamus triggers the production of CRH (corticotropin-releasing hormone), which prompts the pituitary gland to release ACTH (adrenocorticotropic hormone), stimulating the adrenal glands to produce the stress hormone cortisol. Through a feedback loop, cortisol affects the human body as a whole, as well as the brain, where it retroactively suppresses the release of CRH and ACTH. Not only the adult brain but also the developing brain responds to stress with structural and functional changes.

Acute stress rapidly activates the HPA axis. Typically, adrenaline and cortisol levels rise to provide the organism with enough energy, increasing alertness and preparing it for "fight or flight." An example of an acute stressor is nervousness before public speaking. An acute stressor acts briefly, not for months. It activates the sympathetic nervous system and alters the distribution of white blood cells, which can improve the immune system's initial recognition of an antigen (pathological to the body) and lead to stronger antibody production. Regarding antibody production and vaccination, it is necessary to highlight an important concept mentioned by the WHO and professional organizations for the general public: immunization stress-related responses (e.g., dizziness, fainting, anxiety symptoms), which are not an allergy to the vaccine, but a reaction to the stress associated with vaccination.

In chronic stress, the HPA axis is activated long-term. In this case, cortisol levels remain permanently elevated, which can damage the hippocampus (the "seat of memory"), increase the reactivity of the amygdala (the "seat of emotions"), and weaken the prefrontal cortex (attention, decision-making). Chronic dysregulation translates into impaired immunity, sleep disorders, a higher risk of developing depression, and cardiometabolic diseases.

How does a patient suffering from chronic stress feel?

They experience long-term fatigue, sleep and sleep-onset disorders, and complain of worsening memory and mood. It has been proven that people facing chronic stress reduce the production of antibodies in their bodies in general, not just after vaccination. Chronic stress impairs wound healing.

How Chronic Stress Changes the Brain?

• Functionally: impaired attention, memory, and increased emotional reactivity.
• Structurally: a reduction in hippocampal volume due to chronic exposure to glucocorticoids. Decreased production of new neurons (neurogenesis) is reflected in learning and memory impairments. Changes in the prefrontal cortex lead to poorer working memory, planning, and impulse control. An enlarged amygdala, which becomes hyperactive, increases anxiety, fear, and emotional reactivity.Chronic stress can activate microglia and increase the production of pro-inflammatory cytokines in the brain, disrupting synaptic function and plasticity, thereby worsening memory and emotional difficulties.Chronic stress also contributes to aging overall, as well as to "brain aging" at its lowest, cellular level.The hippocampus is influenced not only by glucocorticoids and excitatory amino acids but also by several protein hormones: IGF-I (insulin-like growth factor I), insulin, growth hormone, ghrelin, and leptin. These hormones enter the brain through various transport mechanisms and influence neurogenesis (the creation of new neurons), synaptic plasticity, memory, and mood in the hippocampus.

How Protein Hormones Structurally and Functionally Affect the Hippocampus:

• IGF-I and insulin: The hippocampus possesses their receptors; circulating IGF-I mediates the effect of physical activity on increasing neurogenesis (neuron production) in the hippocampus.
• Growth hormone: Exprinted in the hippocampus, it increases during acute stress and in women under the influence of the hormone estradiol; it also enters the brain from the circulation in small amounts.
• Ghrelin: Promotes synapse formation and improves hippocampal memory.
• Leptin: Has antidepressant effects in the hippocampus, reduces the likelihood of seizures, and improves certain cognitive functions; its transport into the brain is affected by fasting, glucose, and insulin.

Physical activity stimulates growth hormone (GH) → increases circulating IGF-I, and a portion of this serum IGF-I can enter the brain, where it supports neurotrophic signaling, neurogenesis, and synaptic plasticity. A single bout of exercise can briefly increase circulating IGF-I. Regular training can lead to more permanent changes in the GH–IGF-I axis and brain plasticity. Regular exercise, especially rhythmic activities like dancing or walking, is also recommended for patients with cognitive impairment (various types of dementia). Thus, even natural movement like walking contributes to neuroplasticity and better memory.

Connection with Metabolism and Environmental Factors

• Metabolic factors (glucose metabolism regulation, obesity, a high-fat diet) affect hippocampal function and volume. In people with mild cognitive impairment and in animal models, connections are shown between glucose metabolism disorders, diet, and memory decline. Diabetes is one of the risk factors for dementia. The combination of a high-fat diet and chronic stress can lead to a shrinkage of neuronal dendrites in the hippocampal region.
• Every individual perceives a certain level of stress and responds to it differently. This involves not only inter-individual differences but also our previous life experiences with stressful situations. Early life experiences especially influence how an individual reacts to new situations. To some extent, certain genetic differences also play a role.Just as it is known that an increase in mediator levels (e.g., catecholamines) increases heart rate and blood pressure during acute stress, the same mediators cause chronic pathophysiological changes in the cardiovascular system over the years, contributing to atherosclerosis, and consequently to strokes and myocardial infarctions. 
• In addition to glucocorticoids like cortisol, the body produces other substances that affect immunity during stress: pro-inflammatory cytokines.The main role in controlling the neuroendocrine, autonomic (sympathetic and parasympathetic), and immune systems is, of course, played by the brain. 

Chronic stress changes brain function. 

One common stressor in our population is sleep deprivation, along with the associated weight gain and obesity.Shortening night sleep to just 4 hours increases blood pressure, decreases parasympathetic tone, raises evening cortisol and insulin levels, and promotes increased appetite—likely by increasing ghrelin, the appetite-stimulating hormone, along with reduced leptin levels. Sleep deprivation is precisely one of the stressors that raise levels of pro-inflammatory cytokines. In psychomotor vigilance tests, performance drops even when night sleep is shortened to 6 hours.A significant portion of the acquired information about the impact of stress on the structure of the human brain comes from animal studies conducted so far. Functional imaging methods in individuals exposed to common stressors suggest permanent changes in neuronal activity that correspond to increased cortisol levels.

Structural Brain Changes and the Impact of Stress

Structural changes: 

In recurrent depression and certain anxiety disorders, a reduction in the volume of the hippocampus and prefrontal cortex is observed; the amygdala may be enlarged in some phases of the illness. 

PTSD (post-traumatic stress disorder) and borderline personality disorder also show hippocampal atrophy, suggesting a common process of chronic imbalance in adaptive systems.The level of stress hormones, especially cortisol, reflects emotions and psychological disorganization. This means a disruption of thinking, speech, emotions, and behavior, manifesting as difficulty maintaining a flow of thought and altered social interactions. It is these changes in the regulation of cortisol and other mediators that contribute to psychiatric and systemic diseases (such as diabetes).

Chronic stress, fatigue, and idiopathic pain disorders—chronic fatigue syndrome (CFS), fibromyalgia, and irritable bowel syndrome (IBS)—often overlap and are linked to the disruption of the body's regulatory systems. This includes hormonal changes, inflammatory markers, and changes in brain activity, which together increase pain perception, fatigue, and psychological symptoms.

The main symptoms in these patients are:

• Persistent or recurrent fatigue disproportionate to exertion.
• Widespread pain in muscles and joints (fibromyalgia).
• Digestive disorders: abdominal pain, bloating, irregular stools (IBS).
• Sleep disorders, impaired memory, and concentration.
• Worsening of symptoms under stress or after physical exertion.
• The syndromes overlap: CFS, fibromyalgia, IBS, and symptoms of PTSD or burnout frequently co-occur.
• Hormonal and inflammatory changes: In CFS, low levels of aldosterone and cortisol in the urine, increased pro-inflammatory cytokines, and changes in other hormones (DHEA, serotonergic system) are reported.
• Brain activation: In chronic pain and IBS, the activation of areas processing pain and emotions (brainstem, insula, amygdala, hippocampus, cingulate cortex) changes.
• Neurochemistry: Reduced dopaminergic activity in the nucleus accumbens and increased NMDA-mediated activity may contribute to pain sensitization.
• Placebo and cognition: Expectations and cognitive processes significantly influence pain perception (placebo/nocebo effect).
• Complex etiology: There is no single defect of the HPA axis; the disorder is rather a broader disruption of the organism's entire balance network.

Stress and Cognitive Control of Food Intake

• Stress and lack of sleep often trigger the consumption of "comfort food"—dishes frequently associated with childhood or home that bring a sense of comfort, safety, or nostalgia.
• The hippocampus helps limit uncontrolled food intake; its damage leads to increased intake and weight gain.
• Obese individuals show less activation of the posterior hippocampus after a satiating meal than lean individuals, suggesting weakened satiety control.
• Vagus-induced gastric distension increases activation of the anterior hippocampus, which correlates with emotional eating.
• Other brain regions (orbitofrontal cortex, striatum, anterior cerebellum) are involved in the desire for rewarding stimuli, resembling craving mechanisms in addictions.

In light of the above, it may now be clear to a layperson that stepping out of this vicious cycle is not easy: stress, lack of sleep, increased and uncontrollable appetite, and an insufficient feeling of fullness resulting in obesity with all its risks.

Is there any difference in the response to stress between men and women?

Women are more sensitive to the consequences of chronic stress and have a higher incidence of depression and anxiety disorders than men; the differences stem from interactions among sex hormones, the HPA axis, the immune system, and brain circuits responding to stress.Neurology is not the only field where we observe that women are affected by autoimmune diseases—such as multiple sclerosis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, etc.—several times more frequently than men. In addition to these autoimmune diseases, there is a higher incidence of migraines (and headaches and spinal pain in general) in women.Mechanisms and why they differ

• Gonadal hormones (estrogen, testosterone) modulate neurotransmitters, plasticity, and inflammatory responses; estrogen can increase or alter stress sensitivity depending on the context and developmental stage.
• CRF (corticotropin-releasing factor) and the locus coeruleus display sex-specific responses, affecting alertness, anxiety, and adaptation to repeated stress.
• HPA axis: Dysregulation is more frequently observed in women (e.g., changes in cortisol reactivity), increasing the risk of long-term neuropsychiatric consequences.
• Brain networks and strategies: Men and women may achieve similar performance in tasks but engage different circuits and strategies; this has implications for targeted interventions and rehabilitation.

For this reason, it is necessary to consider biological sex as a variable in medicine, i.e., differing responses to medications and psychotherapeutic approaches. In women, it is crucial to address chronic stress, sleep, and social support early on, as long-term dysregulation increases the risk of depression and cognitive problems. Research in this direction continues, and we need more studies that include women.It is worth noting that differences in brain processing are often not about gender identity or sexual orientation, but about the level and type of stress experienced, including discrimination and available social support. 

Studies addressing stress processing specifically affecting the LGBTQ+ community involve smaller test populations and do not yet yield definitive results due to differing research methodologies. Sexual minorities and transgender individuals often show different physiological and brain responses to stress. Most evidence shows that these differences are largely a consequence of minority stress (repeated discrimination, stigma, internalized negativity), which alters the HPA axis, cardiovascular reactivity, and emotional-processing brain circuits; in transgender individuals, a flattened daily cortisol profile is also frequently observed alongside high exposure to stigma. As I have mentioned, this issue requires a sufficient amount of high-quality data, which we can only obtain through well-executed studies on a large enough population sample.

Conclusion

Chronic stress changes both the brain and the body: it permanently elevates stress hormone levels, weakens areas responsible for memory and emotional regulation (e.g., the hippocampus and prefrontal cortex), increases pain sensitivity, and promotes inflammatory processes. These changes manifest as fatigue, sleep disturbances, impaired memory, irritability, and a higher risk of depression or cardiometabolic diseases. The good news is that the brain shows signs of neuroplasticity from birth practically until the end of life—many negative impacts can be mitigated or reversed through targeted lifestyle steps and treatment.What to do right now (practical steps)

• Ensure regular sleep: Go to bed and wake up at approximately the same time; reduce watching TV, computer, laptop, tablet, and mobile phone screens in the evening, and avoid drinking stimulating beverages containing caffeine or energy drinks.
• Incorporate regular movement: 30 minutes of moderate activity (brisk walking, cycling) most days of the week; start gradually. Set rational and achievable goals.
• Work with stress: Simple breathing exercises, short relaxation techniques, or 10–20 minutes of mindfulness daily. Mindfulness means consciously perceiving the present moment without judgment—your thoughts, feelings, bodily sensations, and surroundings. It improves attention and reduces stress levels. You can imagine it as returning to the time when you were a young child, curiously observing your surroundings and absorbing the sensations around you in the present moment, without analyzing.
• Strengthen social bonds: Regular contact with friends and family, group activities.
• Diet and habits: A balanced diet, limiting alcohol, and avoiding smoking; reducing the consumption of highly processed foods.
• Manage your energy: Divide tasks, take breaks, and avoid overloading yourself.

When to seek professional help

• If stress significantly restricts daily functioning, sleep, or relationships.
• In case of persistent symptoms of depression, anxiety, significant memory impairment, or suicidal thoughts.
• When physical symptoms (pain, fatigue, digestion) persist despite basic measures—a general practitioner, psychologist, or specialist will help with diagnosis and treatment.

What can help in treatment (overview of options)

• Psychotherapy (e.g., cognitive-behavioral therapy, trauma-focused therapy) to learn coping strategies.
• Physical rehabilitation and exercise guided by a professional to return to activity without overloading.
• Medical care: In some cases, medications are useful for short-term symptom management; always discuss choice and dosage with a doctor.
• Community programs and support groups that combine movement, social contact, and meaningful activity.

Chronic stress is not just "in your head"—it changes both the brain and the body. We cannot avoid some forms of stress. However, there are specific steps you can take to better manage stress and maintain a degree of control over it. The basic steps mentioned above reduce the risk of long-term consequences and improve quality of life. If you feel exhausted and experience physical or psychological difficulties, contact a professional.

MUDr. Petra Mištríková, MBA