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Recent research conducted by Washington University School of Medicine in St. Louis challenges traditional viewpoints regarding the fatigue and lack of motivation experienced by cancer patients in the later stages of their illness. Previously seen as unavoidable byproducts of deteriorating health and significant weight loss, these symptoms are now understood to originate from specific neurons in the brain that respond to inflammation.
In a study published on April 11 in Science, the researchers established a direct correlation between inflammation associated with cancer and the motivational decline observed in patients. By investigating mice suffering from cancer-related cachexia—a condition marked by severe muscle wasting and weight reduction—they identified a novel pathway in the brain that detects inflammation. This pathway was found to inhibit dopamine, a neurotransmitter crucial for motivation, leading to apathy and reduced initiative.
Intriguingly, the research team found that blocking this pathway restored motivation in the mice, even as the cancer progressed and weight loss continued. This discovery illustrates that apathy can be addressed independently from the primary disease.
Adam Kepecs, PhD, a professor of neuroscience and psychiatry at WashU Medicine, emphasized the significance of their findings. “We’ve uncovered a direct brain mechanism through which inflammation drives apathy in cancer, and we were able to restore normal motivation in mice with cachexia, despite ongoing inflammation as cancer progressed,” he stated.
About 70% of individuals with advanced cancer are affected by cachexia, which not only entails physical decline but also leads to severe fatigue and a significant drop in motivation, thereby impacting the overall quality of life of patients.
To discern whether these psychological challenges arise from physical degradation or distinct biological mechanisms, Kepecs and his colleagues, including Marco Pignatelli, MD, and Tobias Janowitz, MD, PhD, utilized a well-established mouse model of cancer cachexia. Their research was unique in its focus on behavioral symptoms, a subject that had not garnered extensive attention prior to this study, and it involved mapping the associated brain regions.
The researchers discovered that a specific region in the brainstem, responsible for regulating essential functions like respiration and heart rate, also acts as an inflammatory sensor. This brain structure particularly reacts to elevated levels of interleukin-6 (IL-6), a molecule commonly found in cancer cachexia. An increase in IL-6 leads to neuron activity in the brainstem that sends signals suppressing dopamine release in the nucleus accumbens, which is crucial for motivation and reward, ultimately causing a decrease in the mice’s motivation.
To determine whether modifying this inflammation response could alleviate apathy, the team employed two strategies: increasing dopamine levels and inhibiting inflammation-sensing neurons in the brainstem. Both strategies successfully diminished apathy in the affected mice. Furthermore, administering an IL-6 antibody, akin to an existing FDA-approved treatment for rheumatoid arthritis, also rejuvenated the mice’s motivation, suggesting a pathway for potential therapeutic interventions for the psychological challenges linked to advanced cancer.
“What’s remarkable is that motivation was restored even in late-stage disease,” Pignatelli noted. “It suggests we may be able to improve quality of life by targeting the brain circuit.”
In the context of acute illnesses such as infections, the inflammation-induced drop in motivation might be beneficial, allowing the body to conserve energy for fighting diseases. However, in chronic conditions like cachexia, ongoing apathy can lead to detrimental effects, including a reduced appetite and diminished social engagement, further compromising health and quality of life. Given that IL-6 is elevated in numerous other health conditions, and given the central role of these brain regions in regulating motivation, this circuit may also be implicated in apathy across various chronic illnesses.
“This gives us a new way to understand apathy in advanced cancer,” stated Kepecs. “It’s not merely a consequence of physical decline but a direct reaction to inflammation in the brain. This opens up opportunities to target the underlying biological mechanisms to enhance motivation and improve the quality of life, even when the cancer is no longer treatable.”
The research received funding from various organizations, including the National Institute of Child Health and Human Development of the National Institutes of Health (NIH), Deutsche Forschungsgemeinschaft, LaCaixa, the Mark Foundation for Cancer Research, the Simons Foundation, and several NIH grants. This funding underlines the collaborative effort to enhance understanding and treatment of the psychological impacts associated with cancer.
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