How do placebos work?

Saturday, August 4th, 2018

Using lab tools to activate the brain’s reward circuit in mice empowered the immune system to fight tumors:

Clues emerged in brain imaging experiments published a decade ago. Those analyses revealed that the same reward circuit activated by food, sex and social interactions (as well as gambling and addictive drugs) is also turned on in people who respond to placebos. Puzzling over those data, researchers in Israel turned the mind-body question into an easier-to-measure physiological one: Would activation of the reward circuit have any effect on the immune system?

It seemed fair to assume positive thoughts and emotions would alter the activity of neurons in the brain. “And neuronal activity is something we can manipulate,” says biologist Asya Rolls of Technion-Israel Institute of Technology, who was co-senior author of the current study.

In previous work her team stimulated the brains of mice with a relatively new technology called DREADD (designer receptors exclusively activated by designer drugs) that puts a molecular on-off switch on particular cells—in this case, neurons of the reward circuit. After activating a mouse’s reward system, the researchers analyzed immune cells in its spleen. The clearest effects showed up in monocytes—a group of white blood cells that chew up pathogens as part of the body’s non-specific immune defenses. Specifically, the team found that monocytes from brain-activated mice killed bacteria much more effectively than monocytes from untreated animals.

Seeing that the brain’s reward circuit could boost immune activity against pathogens, “our next thought was, what is a situation where the immune system fails?” says Tamar Ben-Shaanan, a biologist now at the University of California, San Francisco who published the bacterial experiments in 2016. Ben-Shaanan and Technion MD-PhD student Maya Schiller are co-lead authors on the new study.

The idea of looking into cancer came from study co-senior author Fahed Hakim, who directs the EMMS Nazareth Hospital and works as a pediatric pulmonologist and sleep specialist at Rambam Health Care Campus in Haifa, Israel. During a research stint at the University of Chicago, Hakim studied mouse models of cancer and published a 2014 study showing that fragmented sleep made the animals’ tumors grow faster. If bad sleep triggers tumor-promoting brain activity, Hakim says, it seemed reasonable to think that activating the reward pathway might produce the opposite effect—brain changes that slow cancer.

And that’s what the researchers found. In mice with implanted cancer cells, two weeks of daily reward circuit stimulation produced a powerful response—their tumors were 40 to 50 percent smaller than those in control mice that didn’t get the brain activation. Further experiments traced this effect to a specific group of immune cells made in the bone marrow called myeloid-derived suppressor cells (MDSCs). If left unhindered, MDSCs promote tumor growth by shutting down other immune cells that keep tumors in check. However, activating the brain’s reward system unleashes chemical signals that thwart this web of checks and balances in a manner that disables these pro-tumor MDSCs. That, in turn, allows typical anti-tumor immune responses to proceed.

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