Updated: Nov 5
New Scientist (10 September 2022) reports that "research is revealing that fatigue is the result of an ongoing conversation between the body and the brain about how much cellular energy is available. Chronic fatigue [is] affecting nearly 1 percent of the global population and 25 percent of healthy people reporting regular struggles with fatigue while the [various] causes of fatigue are very different, how they manifest in the brain is remarkably similar. New Scientist (10 September 2022) reports that "research is revealing that fatigue is the result of an ongoing conversation between the body and the brain about how much cellular energy is available.New Scientist (10 September 2022) reports that "research is revealing that fatigue is the result of an ongoing conversation between the body and the brain about how much cellular energy is available.
The thing that varies is what saps the body's energy and whether there are any barriers that stop it from being restored. In the brain, there are 4 key areas that keep track of available cellular energy and work together to predict whether the outcome of performing a task will be worth the investment needed to act. Two of these regions, the insula and the anterior cingulate cortex, are part of the brain's interoception network, which is in charge of monitoring the body's internal state. Their job is to keep track of energy levels and how hard the body and brain are working, and to flag if there is a mismatch. The other 2 brain regions are the prefrontal cortex, which is important for self-control and future planning, and the striatum, part of the brain's reward network, which signals the potential pay-off. These 4 regions perform a cost-benefit analysis to determine how much energy is available and whether an action is, biologically speaking, worth the effort.
When cellular energy levels are low, the benefit must be higher to outweigh the energy cost. If the sums don't add up, fatigue sets in. This analysis is carried out by the fatigue network, the output of which is motivation. While motivation is a loaded term, in a scientific context it isn't about desire or willpower, it is about managing resources. Even with incentives, though, after an extended period of concentration, our cellular energy stores become depleted, metabolic by-products begin to build up and performance starts to decline. The same is true for physical effort. Usually this is temporary. After resting, sleeping or eating, energy stores are replenished. With chronic forms of fatigue, though, this doesn't happen.
Research [is] focusing on problems in the production of energy in the cells, or the way the body delivers energy to where it is needed. In some cases of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) the body switches from using glucose to a less efficient fuel source, such as fats or amino acids. Other studies have shown that the cells in people with MEE/CFS are unable to produce enough energy, both before and during a period of stress, which may explain why fatigue gets worse after physical or mental exertion. It is possible that this happens because cells are unable to get sufficient oxygen and glucose from the blood to make energy in the cells. Or it could be that the flow of blood around the body is disrupted. One explanation may involve the brainstem.
Ordinarily, a message is sent from the muscles to the brainstem when more oxygen is needed. The brainstem relays that message to heart and lungs through the autonomic nervous system, which raises heart rate, blood pressure and respiration to increase delivery of oxygen via the blood. Some cases of chronic fatigue could be explained by a problem in the brainstem that results in this message not being communicated properly. Another possibility is that there is a problem with the blood itself. People with current covid-19 infections, long covid and ME/CFS have higher than average levels of microscopic blood clots, which can block small blood vessels and impede oxygen delivery. One treatment is hyperbaric oxygen therapy. Early results suggest that the treatment reduces fatigue, pain and brain fog. Another explanation for chronic fatigue is inflammation [which] involves the release of proteins called cytokines that help ready the rest of the immune system for action. Cytokine release is also stimulated by stress to prepare the body for potential injury in times of danger it makes you feel lousy. Studies have shown that surge in cytokines dampens brain activity in the striatum, leading to reduced incentive to move and general feeling of malaise, the result of a signal sent to the brain to conserve energy so that all available resources can be used to fight the infection. An activated immune system takes up a tremendous amount of energy. If the inflammation becomes chronic, that malaise can set in for the long haul. Inflammation is common in people with ME/CFS and it correlates both with disrupted activity in the striatum and the fatigue that people report.
For many types of fatigue, one idea is an unresolved viral infection. The cause [may] be an infection of the vagus nerve. Receptors for this nerve are particularly prevalent in places where pathogens enter the body, like the lungs, the oesophagus and the gut. If the vagus nerve becomes inflamed, the insula receives a constant message that there is an infection in the body and energy needs to be conserved. If you have inflammation, the treatment is an anti-inflammatory strategy, [other treatments] aim to help cells increase oxygen uptake from the blood [also using] Parkinson's medication L-DOPA to raise activity in the striatum to nudge the brain's cost-benefit calculation towards action [and] using transcranial magnetic stimulation, which influences the brain's electrical activity. For people needing help with chronic fatigue now, a common treatment option is energy management, or pacing, which involves continuously monitoring how they feel and resisting the urge to push through their fatigue. Similarly, cognitive behavioural therapy can help some people cope with the limitations of their condition.