How Placebos Work with Pain

How Placebos Work with Pain

By Jim Windell

             Is it all in your mind if you take a placebo for pain and it works?

            How could a placebo actually help relieve pain? Is it in the placebo or in your mindset?

            Those were questions on the minds of researchers who wanted to better understand the way the brain reacts when placebos are taken. Their analysis was comprised of 20 neuroimaging studies with 600 healthy participants. The results of this meta-analysis provides new insight on the size, localization, significance and heterogeneity of placebo effects on pain-related brain activity.

           The research reflects the work of an international collaborative effort by the Placebo Neuroimaging Consortium, led by Tor Wager, the Diana L. Taylor Distinguished Professor in Neuroscience at Dartmouth, and Ulrike Bingel, a professor at the Center for Translational Neuro- and Behavioral Sciences in the department of neurology at University Hospital Essen, in Essen, Germany. Matthias Zunhammer and Tamás Spisák, both at the University Hospital Essen, served as co-authors. These researchers’ meta-analysis is the second with this sample and builds on the team's earlier research using an established pain marker developed earlier by Wager's lab at Dartmouth.

           This study, published in Nature Communications, represents the first large-scale mega-analysis, which looks at individual participants' whole brain images. This approach enabled the scientists to look at parts of the brain that they did not have sufficient resolution to look at in the past.

           Although participants had indicated that they felt less pain when taking the placebo, the researchers wanted to find out if the brain responded to the placebo in a meaningful way. Does a placebo change the way a person constructs the experience of pain? Is it altering the way a person thinks about the experience of pain after the fact? Indeed, is the person really feeling less pain?

           Based on studying this large sample, the team of researchers was able to confidently localize placebo effects to specific zones of the brain, including the thalamus and the basal ganglia. The thalamus serves as a gateway for sights and sounds and all kinds of sensory motor input. It has several different nuclei, which act like processing stations for different kinds of sensory input. The results showed that parts of the thalamus that are most important for pain sensation were most strongly affected by the placebo. In addition, parts of the somatosensory cortex that are integral to the early processing of painful experiences were also affected. The placebo effect also impacted the basal ganglia, which are important for motivation and connecting pain and other experiences to action.

           "The placebo can affect what you do with the pain and how it motivates you, which could be a larger part of what's happening here," says Wager, who is also the principal investigator of the Cognitive and Affective Neuroscience Lab at Dartmouth. "It's changing the circuitry that's important for motivation."

           "Our findings demonstrate that the participants who showed the most pain reduction with the placebo also showed the largest reductions in brain areas associated with pain construction," explains co-author Wager. He went on to say that they are still learning how the brain constructs pain experiences, but they know it is a mix of brain areas that process input from the body and those involved in motivation and decision-making. Placebo treatment seems to reduce activity in areas involved in early pain signaling from the body, as well as motivational circuits not tied specifically to pain.

           The researchers believe that by understanding the neural systems that utilize and moderate placebo responses that there will be important implications for clinical care and drug-development. It is possible that the placebo effect could be leveraged alongside a drug, surgery, or other treatment, to potentially enhance patient outcomes.

           To read the journal article, find it with this reference:

Matthias Zunhammer, Tamás Spisák, Tor D. Wager, & Ulrike Bingel. Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI dataNature Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-21179-3

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