How do sickness feelings arise in the brain?

Fever, reduced physical activity, loss of appetite, and fatigue: When we’re sick, the body sends a variety of signals from its “most remote parts” to—as far as we know—deeper regions of the brain. But how is this information processed in the brain to create a “general feeling of illness”? And what role do the upper, outer brain regions—such as the cortex—play in this process?

The insula is part of the outer cerebral cortex—a region where bodily and emotional information is processed.

Researchers at the European Laboratory for Molecular Biology in Heidelberg, in collaboration with scientists from the ESI, have now published their latest findings on these questions in the journal *Current Biology*.

The body’s own signaling molecules influence symptoms…

In the case of an infection, typical signs of inflammation, such as fever, occur. Such signals are a sure sign that the immune system is already working at full capacity, for example, to fend off pathogens.

The body’s own signaling molecules play an important role in this process. For example, prostaglandin E2 (PGE2) is significantly involved in regulating typical inflammatory symptoms. Among other things, this tissue hormone acts on the hypothalamus, where it influences the development of fever.

… and the perception of those symptoms

In their experiment, the scientists induced a kind of artificial disease state in mice by directly infusing PGE2 into the brain, thereby enabling them to specifically investigate the messenger substance’s effect on the brain by excluding other bodily signals.

 In this way, the researchers were then able to observe which brain regions were primarily involved in processing PGE2. Using an imaging technique that visualizes active brain regions, the researchers first confirmed the known involvement of the hypothalamus and brainstem. They then specifically measured the activity of individual neurons in the insula and the somatosensory cortex.

There, the researchers made a surprising discovery…

The insula is part of the outer cerebral cortex—a region where bodily and emotional information is processed. There, as part of their study, the researchers made a surprising discovery: Analysis of stimulus processing revealed that the disease characteristics in the insula are not processed in isolation from one another, but rather simultaneously. According to the researchers, this could indicate that the brain integrates the individual symptoms into a unified sense of illness. Based on their findings, they propose an expanded explanatory model for the processing of inflammatory responses in the brain.

Future prospects for pain management

In the future, this knowledge could, for example, become relevant for the further development of pain medications: Many active ingredients already target the mechanism of prostaglandin production and could thus potentially be improved even further.

And since the insula, among other things, stores patterns of past pain signals and can reactivate or reconstruct them in response to corresponding triggers, the study results might also one day contribute to a better understanding of phantom pain or so-called pain memory in chronic conditions. However, many further research steps are still needed to achieve clinical benefits in this area.

Click here for the paper