In findings published this week in Nature Medicine, researchers from the Technion-Israel Institute of Technology’s Faculty of Medicine demonstrate that the brain’s “reward system” transmits messages – via the peripheral nervous system – that positively affect the immune system. The findings suggest a potential mechanism of action of the placebo effect, and might one day lead to development of new drugs that utilize the brain’s potential to cure.

The effect of the mind on the immune system is well documented: mental stress can lead to poor physical condition, and a good mood can alleviate the sensation of pain. There is also the placebo effect, in which a sham treatment (a sugar pill, for example) can affect a person’s physical condition. Since this is a genuine effect, drug approval processes and trials always include a “placebo group” that makes it possible to determine the actual chemical and physiological effects of the test drug on patients. In many cases, the findings show that the drug being tested is no more effective than the placebo.

“Our findings indicate that activation of areas of the brain associated with positive expectations can affect how the body copes with diseases,” explains Assistant Professor Asya Rolls, one of the paper’s lead authors. “Placebo is a complex phenomenon in which the patient’s expectation of recovery affects his state of health. Expectation of improvement and arousal of positive emotions are reflected in the activity of neurons in the brain. So we decided to understand, at the molecular level, how areas of the brain associated with positive expectations affect the functioning of the immune system – the body’s main defense system. Understanding the mechanisms connecting the brain to the immune system could lead to significant medical applications that can potentially improve the prognosis of diseases.”

The research, carried out by doctoral student Tamar Ben-Shaanan, examined the effect of the “reward system” – a brain region triggered in anticipation of a positive experience, and stimulated during the placebo effect. Using innovative technology, the researchers triggered the reward system in the brains of mice and examined the behavior of the immune system following this intervention. They found that triggering the reward system stimulates the immune system, specifically, causing it to operate more effectively and eliminate bacteria more quickly. The intervention also caused the immune system to create a more robust immune memory against the bacteria to which it was exposed so that it will operate more effectively the next time it is exposed to the same bacteria.

“Our breakthrough was made possible thanks to two new technologies,” explains the paper’s other lead author, Assistant Professor Shai Shen-Orr. “One is DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technology, which enables precise activation of specific neurons, and the second is CyTOF (mass cytometry) technology, which enables high resolution characterization of hundreds of thousands of cells in the immune system. By coupling these two technologies, we were able to demonstrate the connection between the activation of specific neural circuits in the brain and the increased activity of cell populations in the immune system.”

The researchers focused their attention on the ventral tegmental area (VTA), a key component in the dopaminergic reward system, and the area associated mainly with expectation of a positive reward. This area is stimulated, for example, when we anticipate a good meal. “We found that stimulation of the VTA also stimulates the immune system’s anti-bacterial response – especially if that stimulation occurs before exposure to bacterial infection,” said Prof. Rolls.

The researchers also mapped a route important for the message to pass from the brain to the immune system. That route is the sympathetic nervous system, which is responsible for immediate response in emergency situations and stress, and a major mode of communication between the brain and the peripheral systems. According to Prof. Rolls, it is also possible that other pathways mediate this interaction between the brain’s reward system and the immune system, and that hormones could be involved in this process. “This is only the beginning,” she said. “It is important to remember that these experiments were done in mice, and that it will be some time until we can translate this to humans.”

“This study demonstrates that the immune system is not completely autonomous. We know that our mental and emotional state impacts our health but in order to be able to use this potential of the brain to cure in modern medicine, we need to understand how it works,” said Prof. Rolls. “Understanding that activation of the reward system in the brain triggers the immune system will allow us to optimize existing therapies against infections and boost the effectiveness of vaccines.”

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