Chronic pain rewires how the brain processes punishment, new research suggests

A study of adults with chronic inflammatory arthritis found that these individuals have heightened sensitivity to punishment (i.e., losses) compared to healthy controls. They also showed greater neural activity associated with punishment prediction errors in several brain regions. The research was published in Brain.

Chronic pain and fatigue are persistent conditions that often occur together and can significantly impair daily functioning. Chronic pain refers to long-lasting pain that continues for months or years beyond the normal healing period. Fatigue in this context goes beyond ordinary tiredness—it is a profound, ongoing exhaustion that rest does not fully relieve.

These symptoms can result from various medical issues, such as fibromyalgia, autoimmune diseases, or prolonged stress. Pain and fatigue often reinforce one another: pain can deplete energy, while fatigue can reduce pain tolerance. Both can interfere with sleep, creating a vicious cycle. Emotional effects such as depression and anxiety are common and may intensify the perception of both symptoms. People with chronic pain and fatigue often experience difficulties with concentration, physical activity, and maintaining social relationships.

Study author Flavia Mancini and her colleagues set out to explore whether individuals with chronic pain and fatigue show distinct patterns in how they make reward and loss decisions—and whether these differences correspond to specific patterns of brain activity.

The authors noted that reward and loss decision-making underlies much of everyday behavior, and that the ability to pursue benefits and avoid negative outcomes might be altered in the presence of chronic pain and fatigue.

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The study included 29 patients with chronic inflammatory arthritis and 28 healthy individuals as controls. The average age of the patient group was 54 years, and 27 of them were women. The average age of the control group was 52 years, with 18 women. Chronic inflammatory arthritis is a long-lasting autoimmune condition marked by persistent joint inflammation, pain, swelling, and stiffness, which can lead to joint damage and reduced mobility over time.

Participants underwent brain imaging using functional magnetic resonance imaging (fMRI) while completing a four-armed bandit decision-making task. In this task, they chose between four abstract boxes shown on a screen. Each choice had a changing and independent probability of resulting in a gain of £1, a loss of £1, both, or neither. These probabilities fluctuated gradually over time, requiring participants to continuously learn about rewards and losses separately. This setup allowed researchers to isolate reward and punishment learning.

Participants also gave blood samples, which were analyzed for inflammatory markers. In addition, they wore actigraphs—wrist-worn devices that measure movement—continuously for 5 to 7 days to monitor activity levels. They also recorded daily pain and fatigue ratings.

The results showed that participants with chronic pain were more sensitive to punishments—that is, to negative outcomes in the task. They also exhibited greater brain activity when outcomes deviated from their expectations about losses (i.e., punishment prediction errors). This increased activity was observed in the right posterior insular cortex, putamen, pallidum, and dorsolateral prefrontal cortex. Additional analyses showed that connectivity within the insula—specifically, its centrality in brain networks—was associated with how much pain and fatigue participants reported during the task.

The putamen and pallidum are involved in movement regulation and habit formation. The dorsolateral prefrontal cortex plays a key role in executive functions like working memory, decision-making, and cognitive control. The insula integrates bodily sensations with emotional and cognitive states. Its posterior portion, particularly the right posterior insular cortex, processes physical sensations such as pain, temperature, and internal body awareness.

“The findings of this exploratory study suggest that pain and fatigue in chronic pain relate to objective behavioural changes in loss-decision making, which can be mapped to a specific pattern of activity in brain circuits of motivation and decision-making,” the study authors concluded.

The study contributes to the scientific understanding of the neural underpinnings and psychological consequences of chronic pain. However, it should be noted that all the study participants with chronic pain suffered from inflammatory arthritis. Findings on individuals suffering from other conditions that result in chronic pain may differ.

The paper, “Enhanced behavioural and neural sensitivity to punishments in chronic pain and fatigue,” was authored by Flavia Mancini, Pranav Mahajan, Anna á V Guttesen, Jakub Onysk, Ingrid Scholtes, Nicholas Shenker, Michael Lee, and Ben Seymour.