The Placebo Effect: It’s All in the Head and Here’s the Proof

A new study at Israel’s Technion shows how arousal of the brain’s reward center stimulates the immune system to fight more effectively.

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Two years ago, American biologist Bruce Lipton, the author of “The Biology of Belief,” visited Israel. In his lectures, he used ornate words and endless examples to repeat the message drummed into every Israeli conscript’s head from the first day of boot camp: “It’s all in your head.” Or, in the civilian version: “Think positively and all will be well.”

In a TV report during his visit, Lipton said it’s classic science – the brain shapes the chemistry of a cell’s content and applies this to 50 trillion cells. The connection Lipton was talking about is known as the placebo effect. It remains one of the biggest scientific mysteries. Its presence is unquestioned but the puzzle over which biological processes turn a dummy pill into significantly better health remains unsolved.

Researchers at the Technion technology institute in Haifa have found a possible mechanism for the placebo effect. In a study just published in the journal Nature Medicine, they propose a physiological model that shows how anticipation of an improvement or cure is transmitted through the brain’s reward system to the immune system in its action against hostile bacteria.

It’s very difficult to bring into the laboratory an effect perceived to be mainly psychological. But the result of such an attempt can be fascinating.

The study was conducted in the lab of Prof. Asya Rolls from the Technion’s faculty of medicine, together with Prof. Shai Shen-Orr. The research was led by Ph.D. candidate Tamar Ben-Shaanan.

The twilight zone between modern medicine and what is derisively called New Age science is an arena of tussles and arguments that many researchers prefer to avoid. But the placebo effect arouses special interest. This is a phenomenon with a rich history, having served health practitioners for thousands of years, from Indian shamans to Jewish dybbuk exorcists.

Since the mid-20th century, with the development of the drug industry and the application of scientific standards for medicines' approval, the use of placebos has diminished and their standing has been shaken. In a 1954 article in The Lancet, it was argued that placebos are only effective in ignorant or “retarded” patients.

But placebos didn’t go away. Subsequent articles described research using them in situations such as infections and pain in psychiatry, neurology, cardiology and surgery. They also have a role in experiments with new drugs.

In 1955, researcher Henry Beecher published an article in the Journal of the American Medical Association called “The Powerful Placebo.” He claimed, based on an analysis of numerous studies, that one-third of the population responds to placebos. That estimate hasn’t changed much over time, but today it’s believed that different people react differently to placebos, and that the method isn't effective against all maladies.

In the 2011 book “13 Things That Don’t Make Sense,” British-American scientist Michael Brooks called the placebo effect one of the unsolved questions in science, along with others such as what the universe is made of and whether there’s life on Mars. Brooks believed that the assumption that it was possible to tease out the placebo effect from the chemistry of the tested drug was mistaken. And, as he put it, it seemed the whole glorious structure of drug tests that was built on the use of placebos would have to be torn down.

He noted that the National Institutes of Health declared research into the placebo effect an urgent need. A group of doctors standing around one’s bed offering words of encouragement is enough to trigger the effect, he wrote. Studies have shown that white lab coats and stethoscopes can induce surprising placebo effects. The power of the placebo lies in the misleading message it gives, he added.

Intense deception

Ostensibly, this has a simple explanation. The drug’s chemistry acts in concert with substances released by the brain. Brooks wrote that despite the great impact of placebos, their use is controversial in the medical community. Some see it as unethical, even dangerous, as deception of the patient. But the intensity of this deception was too powerful to ignore.

There are different theories on how placebos work, but basic research into the effect is still in its infancy. “It’s a phenomenon accompanied by a sense of a missed medical potential that depends on our psychology, on our anticipation of a cure,” says Rolls, the Technion professor.

Her field of research is neuro-immunology, dealing with links between the brain and the immune system. “Up to now it was difficult to deal with this scientifically and understand what was really going on there, mainly due to technical limitations,” she says.

“Today we can activate neurons remotely while closely observing them. That opens the door for beginning to understand how the placebo effect works.”

She and immunologist Shen-Orr study the conversion of psychology to biological processes. “Defined regions in the brain, including those associated with positive emotions, can activate various physiological mechanisms. In our study we examined one mechanism, the immune system,” Rolls says.

“Modern science can define brain regions that are involved in different functions. Thus it was proved that a patient’s anticipation of an improvement activates the reward system, which provides positive reinforcement, but it wasn’t known if activating this region can affect the process of healing.”

It was a calculated risk to look for a link between the placebo effect and the immune system, since placebos work in a wide array of diseases for which a cure, especially without drugs, requires the body’s defense systems.

The researchers tried subjecting the process to imaging and documentation using mice. In the first phase they injected genetically engineered viruses into the relevant brain areas. The viruses induced several brain responses.

“This allowed us to activate and control certain neurons and to image a state of anticipation of healing in the brain,” Rolls says. These neurons activated a network of other neurons, some of which included the sympathetic nervous system, which is responsible for fight-or-flight responses in emergency situations.

As Rolls puts it, “This is the system that dilates pupils and speeds up the heart rate under stressful conditions. It’s not surprising, therefore, that this is the highway over which the brain sends alert messages to the immune system, ahead of a bacterial infection or even in cases of a tumor.”

After the researchers activated the brain’s reward system they tagged bacteria with a fluorescent tag. When they followed the immune system’s activity after activating the reward system they found a faster and more effective destruction of bacteria by white blood cells, in comparison to a control group where this system had not been activated, Rolls says.

This was also examined in a dish in the lab, where immune system cells were challenged by bacteria after activation of the reward system, in comparison to normal immune cells. The results were significantly different.

“Under the influence of brain activation of the reward system, immune cells destroyed twice as many bacteria,” Rolls says. “The researchers found that the sympathetic nervous system is an essential mediator in creating this effect and that disconnecting it blocked the effect.”

Immunological memory

The researchers focused on the ventral tegmental area, a key part of the brain’s dopamine reward system. “This is where anticipation of a positive reward takes place,” Rolls says.

“It’s aroused, for example, before a good meal. Stimulating this region, we found, spurs the antibacterial activity of the immune system, particularly if the stimulation occurs before exposure to the bacterial infection.”

Until recently, such an experiment would have seemed a fantasy. According to Shen-Orr, it has become possible due to two new technologies. One allows the activation of specific neurons while the other enables the high-resolution characterization of hundreds of thousands of cells in the immune system.

“By linking these two technologies we managed to prove a circumstantial link between the activation of specific neuronal circuits in the brain and the enhancement of the activity of immune cell populations,” Shen-Orr says.

This is the first scientific study to experimentally demonstrate, in an animal model, a link between the dopaminergic activity of the brain and the antibacterial action of the immune system. Rolls explains that the link between the reward and immune systems is reasonable given that the brain sees the bigger picture of the body and its environment so that it can prioritize actions and direct the immune system.

“Moreover, such a link can have an evolutionary advantage. The reward system is activated in situations such as a good meal or during sex, which expose us to bacteria and infections,” Roll says.

“Furthermore, if we enjoy these activities, it’s likely that we’ll repeat them in the future. The body has a vested interest in creating a strong immunological memory of these bacteria in order to defeat them next time.”

Still, the placebo effect is far from being completely understood. Rolls emphasizes that these experiments are a first step, examining only one possible pathway.

The brain’s reward system is activated in many ways by different emotional situations, and it’s unclear if an experimental activation reflects exactly what happens in our bodies every time someone plants a soothing idea in our head suggesting that we’re on our way to full recovery.

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