The largest analysis ever done on the neurobiology of placebo has just been published, and we are finally beginning to understand how it plays with our brains.

A good part of the effect produced by each pill or pain treatment depends on something that goes beyond the drug itself: it is something that today is usually called ‘placebo effect’, but that has accompanied mankind (and traditional medicines) for thousands of years. And yet our knowledge on the subject is, to be charitable, limited.

We have had decades of tiny studies in which no one could figure out whether or not the neural mechanisms that seemed to be activated by the placebo effect actually did so. Now, the international collaboration of the Placebo Neuroimaging Consortium has just published in ‘Nature Communications’ the first major meta-analysis on the subject. A study that allows us to see parts of the brain of which we previously had no resolution and to get closer to the neurobiological roots of placebo. Another historical ‘checkbox’ that could be about to be marked as ticked.

A puzzle called placebo

The meta-analysis has used 20 neuroimaging studies with detailed information from 600 participants and identified the size, location, importance and heterogeneity of the neural mechanisms involved in (pain relief).

“Our findings show that participants who demonstrated greater pain reduction with placebo also showed greater reductions in areas of the brain that we know are associated with pain,” explains Tor Wager, scientific coordinator of the Placebo Neuroimaging Consortium. It may seem like a truism, but this truism is where so many researchers have failed.

Instead, these researchers have found that placebo especially affected the main ascending pain pathway. This pathway runs from the thalamus to the posterior insula and is intimately related not only to the processing of bodily information that triggers pain, but to the early processing of that painful sensation. In other words, using a telephone parallelism, it affects not only mobile coverage, but the tone of the call itself.

The team also found that the placebo affects the functioning of the basal ganglia that act as a ‘bridge’ between different sensory and motivational regions. Thus, not only does the “brain” not hear the nociceptors’ call, it also feels no need to be interested in them. On the other hand, in the prefrontal cortex (in the higher processes that have to do with context or beliefs), the results were far from conclusive. The researchers see this as evidence that placebo is not just a mechanism, but a family of processes.

In other words, it is more complex than it might seem. Even more so. In fact, Wager continues, “we are still learning how the brain constructs pain experiences, but we know that it is a mixture of areas of the brain that process information from the body, areas involved in motivation and decision-making areas”.

What is interesting about this work is that it shows that placebo treatment “reduces activity in areas involved in early pain signaling, as well as in motivational circuits not specifically related to pain.” It opens a door to the echoes of pain in the brain. We just have to walk through it.

Image: Robina Weermeijer