A cruel consequence of advanced cancer is the deep apathy that many patients experience when losing interest in activities that previously appreciated. This symptom is part of a syndrome called caquexia, which affects approximately 80% of patients with advanced stage cancer, causing serious muscle wear and weight loss that leaves them with thin bones despite adequate nutrition.
This loss of motivation not only deepens the suffering of patients, but is isolated from their family and friends. Since patients have a hard time getting involved in demanding therapies that require effort and perseverance, it also generates tension in families and complicates treatment.
Doctors often assume that when patients with advanced stage cancer withdraw from life, it is an inevitable psychological response to physical deterioration. But what if apathy is not only a consequence of physical deterioration, but an integral part of the disease itself?
In a newly published investigation, it was discovered that cancer not only wears the body, but kidnaps a specific brain circuit that controls motivation. The findings, published in the Science magazine, challenge decades of assumptions and suggest that it could be possible to recover what many cancer patients describe as the most devastating loss: the will to live.
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To unravel the mystery of apathy in caquexia due to cancer, it was necessary to track the exact path that inflammation follows in the body and observe the interior of a living brain while the disease progresses, something impossible in people. However, neuroscientists have advanced technologies that make it possible in mice.
Modern neuroscience provides us with a powerful arsenal of tools to investigate how the disease alters brain activity in mice. Scientists can map complete brains at the cellular level, track neuronal activity during behavior and activate or disable precision neurons. We use these neuroscientific tools in a Murino model of cancer cocaxia to study the effects of the disease on the brain and motivation.
We identify a small brain region called the dessert area that acts as a brain inflammation detector. As a tumor grows, cytokines (molecules that trigger inflammation) release in the bloodstream. The dessertma area lacks the typical hematoencephalic barrier that prevents the entry of toxins, pathogens and other molecules to the body, which allows it to directly analyze the circulating inflammatory signals.
When the dessertma area detects an increase in inflammatory molecules, it triggers a neuronal waterfall in multiple brain regions, finally suppressing the release of dopamine in the center of brain motivation: the Accumbens nucleus. Although it is often misunderstood as a “chemical of pleasure”, dopamine is actually associated with impulse, or the willingness to strive to obtain rewards: inclines the internal cost of cost-benefit towards action.
The researchers directly observed this change through two quantitative tests designed with principles of behavioral economy to measure the effort. In the first, the mice repeatedly put their nose into a hole of food, requiring more and more pushing to obtain each food ball. In the second task, the mice repeatedly crossed a bridge between two water ports, each of which gradually emptied with the use, which forced them to change side to replace the supply, similar to collect berries until a bush is emptied.
As cancer progressed, mice were still looking for easy rewards, but quickly abandoned the tasks that required more effort. Meanwhile, we observed how dopamine levels decreased in real time, precisely reflecting the lower disposition of mice to work for rewards.
The findings suggest that cancer not only “exhausts” the brain in general, but sends specific inflammatory signals that the brain detects. The brain then responds rapidly reducing dopamine levels to reduce motivation. This coincides with what patients describe: “Everything feels too difficult.”
Mouse research gives light to possible innovative treatments against cancer
Perhaps the most exciting thing is that he found themselves were the various ways of recovering motivation in mice with cancer caquexia, even when cancer itself continued to progress.
First, by genetically deactivating neurons that detect inflammation in the dessert area or by directly stimulating neurons to release dopamine, we manage to restore normal motivation in mice.
Secondly, it was discovered that managing a drug that blocks a specific cytocin (which works similar to existing treatments for arthritis approved by FDA) was also effective. While the drug did not reversed physical wear, it did restored the disposition to work for rewards in the mice.
While these results are based on murine models, they suggest a possibility of treatment for people: acting on this specific circuit of inflammation and dopamine could improve the quality of life of cancer patients, even when the disease remains incurable.
The border between physical and psychological symptoms is an artificially drawn line. Cancer ignores this division, using inflammation to control the circuits that drive the will to act of the patient. But the findings suggest that these messages can be intercepted and the circuits restore.
The discovery has implications that go far beyond cancer. The inflammatory molecule that causes the loss of motivation in cancer is also involved in many other conditions, from autoimmune disorders such as rheumatoid arthritis to chronic infections and depression. This same brain circuit could explain the weakening apathy experienced by millions of people suffering from various chronic diseases.
The apathy caused by inflammation could have originally evolved as a protection mechanism. When the first humans faced acute infections, reducing motivation made sense: it retained energy and directed resources towards recovery. But what used to help people survive short diseases becomes harmful when inflammation persists chronically, as occurs in cancer and other diseases. Instead of favoring survival, prolonged apathy deepens suffering, worsening health results and quality of life. While translating these findings into therapies for people requires more research, our discovery reveals a promising objective for treatment. By intercepting inflammatory signals or modular brain circuits, researchers could restore the impulse of the patient. For patients and families who see how motivation vanishes, this possibility offers something powerful: the hope that, even as the disease progresses, we can recover our essence.
With information from The Conversation.
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