When you break your foot, the pain is mostly confined to your foot. When you get the flu or another systemic infection, your entire being aches: Lethargy creeps into your limbs, your appetite vanishes, your temperature jags between scorching and chilled to the bone, and you just want to pull the covers over your head.
This kind of overpowering mind-body malaise is known as “sickness syndrome,” and it’s considered a distinct physiological and emotional state. Scientists believe sickness syndrome helps the body prepare to fight infections, but they don’t fully understand what is happening in the brain when this storm cloud descends.
Read more: “How to Unlearn a Disease”
Recently, a team from across Europe decided to model sickness syndrome by injecting mice with a compound known as prostaglandin E2, or PGE2, which floods the cerebrospinal fluid when the immune system is challenged and is associated with the progression of an inflammatory illness. The researchers mapped resulting changes in the behavior and in the brains of mice.
When the team of scientists injected the mice with PGE2, the rodents ran fevers, began moving slowly, ate less, and squinted their eyes, a sign of discomfort. But they came back to life before their fevers peaked, which suggests the fever itself was not responsible for their sluggish and low-appetite behavior. Something else was—but what something else?
The researchers noticed that the injection activated the mice’s body-monitoring network, including the brainstem, the hypothalamus, and the insular cortex, brain regions responsible for managing internal bodily states. They also recorded electrical activity in hundreds of neurons at once in two primary areas of the cortex: The insular cortex, the hub of checking in on the body’s status, and the primary somatosensory cortex, which mostly handles touch and other bodily sensations.
When they analyzed the patterns they recorded in the neurons, they found that the insular cortex did a better job of predicting sickness than the somatosensory cortex. The finding suggests the brain’s insular cortex keeps a big-picture sense of “I’m sick,” not just a bunch of separate readings of how tired or feverish or achy you are. The team published their results recently in Current Biology.
I spoke with study author Gretel Kamm of King’s College London about what it means to call sickness a whole-brain state and what the findings might tell us about the placebo effect and chronic illness.
What does it mean to say that sickness is a whole brain state?
The idea is that when we are sick, many things in our physiology change. We feel awful, we have headaches, body aches, we lose our appetite, we develop a fever. We know that the brain plays an important role in that response, but there are many debates about what that specific role is.
It could be that different parts of the brain are involved: one part controlling fever, another part controlling appetite, another part controlling pain. But there also might be part of the brain in which all that information is centralized, which generates a universal sense of being unwell.
Or it could be that all these processes are working in parallel: It’s not only that you have fever, feel awful, lack appetite, it's that you feel something different, which is to be sick. We have evidence that suggests this may be what is happening.
What kind of sickness does this apply to?
It’s inflammatory sickness, which can happen either with bacterial or viral infections. But our model is artificial. We don’t use bacteria. We don’t use any viruses. We simply use a compound called prostaglandin E2 that is produced in large amounts when we have viral or bacterial infections in the lungs or other organs. That’s one of the ways the brain knows that an infection is happening.
Your study focused primarily on how this proxy for infection affects the neocortex. What role does the neocortex play during sickness?
It’s still unclear. We have evidence that suggests a part of the neocortex known as the insular cortex, on one hand, can generate memories of infections, at least in animal models. It’s also a part of the brain that can help us to associate certain environments with certain immune responses. For example, if you arrive at a place you have been before, it might change how your immune system works.
There’s also more and more evidence in humans that this part of the cortex plays an important role in what is known as interoception, or an awareness of your internal state, how your body’s doing, if you’re sick or hungry or thirsty. One of the most important things the insular cortex has to do is to keep us alive, so that’s why we decided to try to see what’s going on there.
Does engagement of the whole brain during sickness help the body recover faster and better?
Honestly, I don’t have a good answer. There’s more and more evidence that information related to even simple states, like being thirsty, can be found in almost every single part of the brain. Also, with this sickness model, we see that many parts of the brains of mice seem to be activated. But exactly what role the different parts play, or why it’s important for so many parts of the brain to get engaged, there is no good answer as far as I know. There are some hypotheses.
What are those hypotheses?
That, for example, when you are sick or thirsty, there are many things that need to be aligned for the brain to help us to survive. We need to stop doing what we are doing. If we are thirsty, we need to refocus on finding water. Maybe we are doing something that allows too much water to escape through evaporation, so we need to stop doing whatever that is.
The same thing happens with sickness. You refocus, you want to go to bed, you don’t feel like interacting with your friends. Your body temperature changes. The whole body, your motivation, your physiology changes. The whole brain needs to be informed just because you cannot have part of the brain that’s doing one thing and part of the brain that’s trying to do another. Everything needs to be coordinated. So that’s one possibility. Perhaps information is flowing from the neocortex to the rest of the brain so that all of the objectives are aligned and we don’t lose focus.
Do your findings tell us anything about the placebo effect?
I never worked with humans, so the direct translation of anything we’ve done so far into humans is pure speculation. But in humans, when we have expectations of something, there is a possibility of a placebo or a nocebo effect. If you are expecting to be sick, if a part of your brain tells you you’re sick, that might influence how you feel.
How might your findings eventually help us design better treatments for humans?
This is basic research, but it points to the idea that this particular part of the brain, the insular cortex, might generate a feeling of being unwell. In the future this might be important if you want to find areas to target with medication.
If you want to say, “Okay, what type of receptors or what type of chemicals are being released by the brain in this area that are generating this representation of being unwell.” Because there may be some pathological conditions in which the brain might think you are sick when you are not. And that might be because the chemistry in that part of the brain is twisted. Maybe it has released too much or too little of certain modulators.
If there are cases in which people feel unwell, but there is no infection, it’s possible that one of the parts of the brain is not working properly, the insular cortex. Maybe in vulnerable individuals, who feel chronically unwell, the insular cortex is misfiring. Again, this is speculation. We need a lot more information to actually know what is going on. But it might inform research in humans or in patients who are suffering from chronic fatigue or many other diseases that are connected with this chronic feeling of being sick.
Just be very clear, this is not medical research. There is nothing specific that can be applied to humans at this stage. It’s very basic. It’s another piece of the puzzle pointing to a brain area that might be relevant to a feeling of being unwell in the context of peripheral inflammation or infections, for instance. But future research will tell. 
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