杏吧原创

IF IT feels like you have been running on empty recently, you aren鈥檛 alone. Amid the turmoil of the past few years, a bone-weary sense of tiredness has become a familiar part of life for many.

Fatigue might be the most universal experience of the pandemic. It is one of the primary symptoms of both covid-19 and long covid, as well as the burnout and depression that have accompanied the stress of the past two-and-a-half years. Even , exhaustion brought on by video meetings, has聽become a recognised phenomenon.

One silver lining of all this is that it has brought fatigue, both in its everyday and more聽persistent forms, to the forefront of the聽scientific agenda. For decades, fatigue was dismissed as a fuzzy symptom with no clear biological origin.

Now, research is revealing that聽it is the result of an ongoing conversation between the body and the brain about how much cellular energy is available. A better understanding of the many pathways involved is bringing hope for tackling it. With chronic fatigue affecting nearly (a number that could now be an underestimate due to long covid), and 25 per cent of聽healthy people reporting regular struggles with fatigue, finding new avenues for聽relief has聽never been more important.

There are many different drains on our energy that can act as triggers of fatigue. Exhaustion can follow a bout of flu, a hard workout, a long day at the office or it can be due to a post viral syndrome such as long covid. While these causes of fatigue are very different, how they manifest in the brain is remarkably similar. The thing that varies is what saps the body鈥檚 energy and聽whether there are any barriers that stop it聽from being restored.

鈥淭he analogy I always give is if there鈥檚 a forest fire in front of you, it could have been [caused by] a careless smoker, it could have been a聽lightning strike or it could have been a firework. But the end result is this forest fire,鈥� says Michael VanElzakker, a neuroscientist at聽Tufts University in Massachusetts.

In the brain, there are four key areas that keep track of available cellular energy and work聽together to predict whether the outcome of聽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鈥檚 interoception network, which is in charge of monitoring the body鈥檚 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 two brain regions are the prefrontal cortex, which is important for self-control and future planning, and the striatum, part of the brain鈥檚 reward network, which signals the potential pay-off.

These four 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聽don鈥檛 add up, fatigue sets in.

This analysis is carried out by the , the output of which is motivation. While motivation is a loaded term, in a scientific context it isn鈥檛 about desire or willpower, it is about managing resources. 鈥淭he fact that you鈥檙e not willing to expend effort for a reward doesn鈥檛 mean that you鈥檙e lazy,鈥� says Andrew Miller, a psychiatrist at Emory University in Atlanta, Georgia. 鈥淚t聽means that your body is doing a certain calculus, and that calculus is that I don鈥檛 have the energy reserves to expend in order to go and do that activity.鈥�

杏吧原创s have seen this relationship between motivation and fatigue in healthy volunteers performing tedious memory and attention tasks. After concentrating for long periods, and they report feelings of fatigue. In the brain, this聽shows up as a decrease in activity and connectivity in that fatigue network. However, if at the end of the experiment people are offered a monetary bonus based on their scores, they become , and they subsequently perform better and show increased brain activity again. With money on the line, the brain deems the reward to be worth the effort again.

Problems with energy supply

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: people show an initial in parts of the fatigue network during a test of strength, but there is a聽decline in activity in the circuit as muscle strength runs out.

Usually, this is temporary. After resting, sleeping or eating, energy stores are replenished and you no longer feel fatigued. With chronic forms of fatigue, though, this doesn鈥檛 happen (see 鈥淲hen sleep doesn鈥檛 work鈥�). Research is beginning to reveal why, by focusing on problems in the production of energy in the cells, or the way the body delivers energy to where it is needed.

When you perform a challenging task, either mental or physical, your brain or muscles require more energy to work harder. Part of that extra energy comes from increased blood flow, which carries more oxygen to the active area, and part comes from tapping into the body鈥檚 glucose reserves.

There is evidence that in some cases of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), for reasons that aren鈥檛 known, the body switches from using glucose to a less efficient fuel source, such as . Other studies have shown that the cells in people with ME/CFS are unable to聽produce enough energy, both before and during a period of stress, which may explain why聽fatigue gets worse after physical or mental聽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.

Betsy Keller, an exercise scientist at Ithaca College in New York, thinks one explanation may involve the brainstem. Ordinarily, a message is sent from the muscles to the brainstem when more oxygen is needed. The聽brainstem relays that message to the heart and聽lungs through the autonomic nervous system, which raises heart rate, blood pressure and respiration to increase delivery of oxygen via the blood.

According to Keller, some cases of chronic fatigue could be explained by a problem in the聽brainstem that results in this message not being communicated properly. Without extra oxygen-rich blood flow, cells can鈥檛 produce enough energy, so they get fatigued faster and take longer to recover. 鈥淏ased on what we see clinically, and when you consider how the brainstem impacts blood flow and oxygen delivery to the muscles, they tend to align pretty well; the brainstem is not functioning [properly],鈥� she says.

Another possibility is that there is a problem with the blood itself. Recent studies have found that people with current covid-19 infections, and ME/CFS have higher than average levels of microscopic blood clots, which can block small blood vessels and impede oxygen delivery. One treatment that is聽being explored to alleviate this in people with long covid is , in which volunteers breathe pressurised oxygen-rich air while in a hyperbaric chamber. Early results suggest that the treatment.

Another explanation for chronic fatigue is inflammation, the body鈥檚 first line of defence against injury or infection. Inflammation involves the release of proteins called cytokines that help ready the rest of the immune system for action. Cytokine release is聽also stimulated by stress to prepare the body聽for potential injury in times of danger. Whatever the cause, one of the most notable side effects of all this activity is that it makes you feel lousy: tired, heavy and with a general feeling of 鈥減lease let me lie on this couch and never move again鈥�.

鈥淐ytokines are effective in inducing sleep or聽fatigue, and it鈥檚 adaptive,鈥� says Craig Heller, a聽neurobiologist at Stanford University in California. 鈥淚f you have an infection, you want to聽decrease the amount of energy you鈥檙e spending on unnecessary activities.鈥�

Brain imaging studies have shown that a surge in cytokines 鈥� such as when people are experimentally injected with an immune-stimulating substance or given cytokines as聽part of a treatment for viral infections 鈥� dampens brain activity in the striatum, leading to reduced incentive to move and a general feeling of malaise. Researchers think this is the result of a signal sent to the brain to conserve energy so that all available resources can be used to fight the infection.

鈥淎n activated immune system takes up a tremendous amount of energy,鈥� says Miller. 鈥淭he thought of spending any energy to do anything [else] is put into the calculus of what the immune system needs, and the answer that comes out is, 鈥楴o, don鈥檛 have the energy.鈥欌�夆��

In an ideal situation, the inflammation 鈥� and fatigue 鈥� resolve once the body has cleared the infection or the source of stress is removed. But if the inflammation becomes chronic, that聽malaise can set in for the long haul.

Miller鈥檚 work has shown that chronic inflammation is common in people with ME/CFS, and that it correlates both with and the fatigue that people report. Curiously, his work聽also suggests that some people with and changes to the fatigue network that are seen with both short-lived ailments and chronic fatigue.

It is unclear what triggers the persistent inflammation that can occur in depression. For聽many types of fatigue, though, one idea is聽an unresolved viral infection.

VanElzakker thinks that in some cases of聽chronic fatigue, and possibly long covid, the聽cause is an infection of the vagus nerve. Receptors for this nerve, which provides a direct link from the organs of the body to the brain鈥檚 insula, 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.

鈥淎n infection on or near the vagus nerve that is driving inflammatory signalling up the vagus nerve is one possibility for non-remitting symptoms,鈥� says VanElzakker. 鈥淲e know from autopsy studies that the vagus nerve can get directly infected [with various pathogens].鈥�

New treatments

Given the wide range of possible causes, it is good news that a renewed interest in fatigue research, in part inspired by long covid, is providing hope for new treatments. Some of聽these tackle the root causes of energy depletion while others focus on removing barriers to energy restoration or changing brain activity in some way.

For instance, Miller is attempting to address chronic fatigue in people with either ME/CFS or treatment-resistant depression using typically used to treat autoimmune conditions. Importantly, he says聽this won鈥檛 work for everyone with fatigue; it is only for the subset of people who have inflammation at the root of their exhaustion. Inflammation becomes the target, he says. 鈥淚t doesn鈥檛 matter that you have fatigue and lack of motivation in depression, PTSD, schizophrenia or ME/CFS. If you have inflammation, and it鈥檚 driving that symptom, the treatment is an anti-inflammatory strategy.鈥�

Other research is focused on treating the energy production problem. A of an experimental drug that aims to help cells increase oxygen uptake from the blood in people with ME/CFS launched at Brigham and Women鈥檚 Hospital in Boston earlier this year.

Miller is also investigating the use of drugs like the Parkinson鈥檚 medication L-DOPA to raise activity in the striatum to nudge the brain鈥檚 cost-benefit calculation towards action. Another group at the聽University of California, Los Angeles, is investigating whether targeting the , which influences the聽brain鈥檚 electrical activity, may help shift the聽energy/motivation calculation and relieve聽fatigue. These treatments are still experimental; only聽time will tell how effective they are, and聽for whom.

For people needing help with chronic fatigue聽now, a , or pacing, which involves continuously monitoring how they feel and聽resisting the urge to push through their fatigue. Similarly, cognitive behavioural therapy can help some people cope with the limitations of their condition.

These strategies can be particularly helpful for people who lived an active life before their diagnosis. Lisa Clock, a former collegiate athlete in Georgia who developed ME/CFS after a viral infection in her 20s, learned these lessons the hard way. When fatigue first started to affect her life, she tried to draw on her experiences as聽an athlete.

鈥淚 learned in sports that you push through pain, and you create endurance by working and pushing yourself in a strategic way,鈥� she says. 鈥淎nd every time I鈥檇 say, 鈥極K, I鈥檓 going to do that. I鈥檓 going to push through,鈥� I would end up flat on my back with swollen glands and [it was] hard to move. It worked completely in reverse to how it had always been for me.鈥�

Instead, to manage her symptoms, Clock has聽learned to pay attention to her energy levels and work in spurts when she feels better, often聽while lying down on the floor.

She is now being treated by Miller with drugs that target some of the possible causes of her fatigue. So far, she has tried L-DOPA, IV fluids with electrolytes and even ketamine, an experimental treatment for depression that boosts activity in the prefrontal cortex. Now she is on the immune-suppressing drug rapamycin to target inflammation. Some treatments work better than others, and she hasn鈥檛 found a cure yet, but she says she has to keep trying. 鈥淵ou get one life, and I don鈥檛 want to miss my own life, but it feels like a lot of times I am,鈥� she says. 鈥淚 have to keep trying. I don鈥檛 want to miss everything.鈥�

You should consult your doctor before starting medical treatment.

When sleep doesn鈥檛 work

Ordinarily, resting after exertion allows the body to replenish its energy stores within 24 hours. Sleep plays a key role in聽this.

Although sleepiness and fatigue often聽overlap, they depend on separate biological processes. Sleep is regulated by the circadian rhythm. This is the body鈥檚 24-hour cycle that is controlled by an area of the brain called the hypothalamus, which triggers the release of sleep-promoting hormones including melatonin and adenosine.

鈥淎denosine is released by cells when their energy supply is compromised,鈥� says Craig Heller, a neurobiologist at Stanford University in California. 鈥淥ne of聽the functions of sleep is to restore the聽energy reserves of the brain.鈥�

For this reason, sleep is the brain鈥檚 default response to fatigue. However, for聽reasons that aren鈥檛 fully understood, in many cases of chronic fatigue, sleep is聽unable to serve this replenishing role. In fact, a key symptom of ME/CFS is 鈥渘on-refreshing sleep鈥�, meaning people don鈥檛 feel re-energised if they take a nap or get a good night鈥檚 sleep.

Some studies suggest that disruption to the activity of the , preventing people from reaching the restorative, deeper stages of sleep. A聽handful of drugs are being investigated to tackle this, but research is in its early stages. While there are numerous drugs聽for insomnia on the market, unfortunately none target non-refreshing sleep.

For people who feel fatigued and don鈥檛聽have a chronic condition, the best thing you can do for your body is listen to聽it and rest when you need. Take a nap;聽say no to non-essential activities; eat a nutritious meal; go to bed early. And, talk to your doctor, because fatigue may be telling you something important about your body and brain.

Dana G. Smith is a science journalist based in Durham, North California