Scientific Overview
Stress and Stress Tolerance
HPA Axis
Circadian Rhythms
Immune System
Placebo Effect
Chronic Fatigue Syndrome
Chronic Pain
Psychiatric vs Organic Debate
Irritable Bowel Syndrome
Chronic Lyme Disease
Recovery from CFS

Stress and Stress Tolerance

The body's response to stress is similar no matter what the cause. The short-term reaction is the "fight-or-flight" response, consisting of activation of the sympathetic nervous system and the release of adrenaline. Longer-term stress activates the HPA axis, which causes cortisol to be released from the outer adrenal cortex. Cortisol has similar effects to adrenaline in the body, but remains in blood for a longer period of time. During normal homeostasis, the release of cortisol is ultimately controlled by the body clock, and is released in a circadian pattern with the highest levels shortly after waking in the morning and lowest levels around midnight. During periods of stress, neurons in the hypothalamus which control the amount of cortisol released increase their output, resulting in a higher overall circadian release of cortisol.

Stress also causes changes to thyroid hormone levels, via the hypothalamic-pituitary-thyroid axis. While mild stress results in a slight increase in thyroid hormones, acute or chronic stress causes a reduction in thyroid hormones.

Immune System / Neuroinflammation

Stress significantly influences the immune system, including suppressing the immune system and shifting the immune response away from the Th1 response that fights viral infections, and towards the Th2 response which is responsible for fighting bacterial infections (and which also causes allergic reactions). Both the main stress hormones — corsitol and adrenaline — are significant immune system modulators, as is the sympathetic nervous system.

Various cytokines (immune signalling molecules) such as TNF-alpha are increased during psychological stress. These are the same cytokines which are released during viral and bacterial infections and cancer, and they cause symptoms such as fatigue, pain, fever, depression, anxiety and other symptoms collectively termed "sickness behaviour". Studies on rats have found that cells in the brain cortex release TNF-alpha after 1 hour of restraint stress. A human study found that low perceived social support was associated with associated with high levels of CD8+CD57+ lymphocytes and TNF-alpha.

Recent research has shown that social stress results in neuroinflammation and microglial over-activation in the brain, in a similar process to that seen in neurodegenerative disorders. It is thought that neuroinflammation due to mental stress may play a large part in causing symptoms of anxiety and depression.

Chronic Stress

Long-term stress causes a number of changes within the central nervous system in order to maintain appropriate levels of cortisol. The paraventricular nucleus of the hypothalamus is the main brain region responsible for activating the HPA axis (and thus producing cortisol). However other regions of the brain feed into the hypothalamus and can either increase or decrease HPA axis activation, including the prefrontal cortex (which is responsible for long-term goals and planning) and the amygdala (which is responsible for emotions). There are also many negative feedback loops within the HPA axis, which decrease cortisol output in order to prevent excessive levels of cortisol over long periods of time.

Patients suffering from CFS, burnout and PTSD generally have an underactive HPA axis, and lower than normal levels of cortisol, as well as a less pronounced circadian rhythm of cortisol and other hormones. This appears to be due to negative feedback, as a result of long-term chronic stress.

As well as providing the body with energy and vitality, the HPA axis also modulates the immune system, autonomic nervous system and digestive system, so a reduced or dysfunctional HPA axis activation will result in abnormal immune system activation, increased inflammation and allergic reactions, IBS symptoms such as constipation and diarrhea, as well as a reduced tolerance to physical and mental stresses.

Unconscious Cost-benefit Analysis

What seems to happen is that the brain reduces its HPA axis activation when it appears that participating in further stressful activities may not be beneficial. This results in a reduced ability to handle stress (reduced "stress tolerance"), and in extreme cases results in illnesses such as CFS.

In fact research in animals has shown that the brain does a subconscious "cost-benefit analysis" in stressful situations to determine whether or not the costs of an activity outweigh the benefits. This happens in the dopaminergic systems of the brain, which are responsible for goal-directed behaviour, motivation and rewards. The dopamine system activates when a goal exceeds expectations, and also when an expected goal fails to materialise. The brain uses this information to determine whether it is worth expending energy on a task, resulting in fatigue if the cost outweighs the benefit.

Whether or not long-term stress results in burnout depends on whether the subconscious "cost benefit analysis" is positive, as well as factors such as the time since onset of the stress, the nature of the threat, the controllability of the stressor and other factors. Stressors that are necessary for survival will likely tip the scales strongly in favour of a robust stress response and high energy expenditure, whereas stresses that are not perceived as being beneficial to the organism will likely cause fatigue and burnout in the long-term.

In modern life where stresses are more abstract, the same dopaminergic systems in the brain activate when achieving job-related and similar goals. Studies show that whether or not a job results in burnout depends on factors such as job demands vs job resources, engagement/enjoyment and motivation. However, even in the case where the person enjoys the stressful activity, there still seems to be a point at which the body simply shuts down due to long-term overactivation of the stress system. This is seen in ultramarathon runners who suffer from overtraining syndrome, which appears to be identical to CFS.

For further information, see burnout.

External Links and references

Wikipedia entry on Stress

Miller, G. E., Chen, E., & Zhou, E. S. (2007). "If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans." Psychological bulletin, 133(1), 25.

Charmandari, E., Tsigos, C., & Chrousos, G. (2005). "Endocrinology of the stress response" 1. Annu. Rev. Physiol., 67, 259-284.

Demerouti, E., Bakker, A. B., Nachreiner, F., & Schaufeli, W. B. (2001). The job demands-resources model of burnout. Journal of Applied psychology, 86(3), 499.

Helmreich, D. L., & Tylee, D. (2011). Thyroid hormone regulation by stress and behavioral differences in adult male rats. Hormones and behavior, 60(3), 284-291.

Running on Empty

Marsland, A. L., Walsh, C., Lockwood, K., & John-Henderson, N. A. (2017). The effects of acute psychological stress on circulating and stimulated inflammatory markers: a systematic review and meta-analysis. Brain, behavior, and immunity.

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DISCLAIMER: is an educational resource for chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), burnout and related disorders, and is not giving medical advice. Seek advice from a medical practitioner before making any changes to your life, or if you experience worsening symptoms. CFS is a diagnosis of exclusion, so it is important to rule out other causes for illness.