RESEARCH New study gives the most detailed look yet at the neuroscience of placebo effects A large proportion of the benefit that a person gets from taking a real drug or receiving a treatment to alle-viate pain is due to an indi-vidual’s mindset, not to the drug itself. Understanding the neural mechanisms driv-ing this placebo effect has been a longstanding ques-tion. A meta-analysis pub-lished in Nature Communi-cations finds that placebo treatments to reduce pain, known as placebo analgesia, reduce pain-related activity in multiple areas of the brain. Previous studies of this kind have relied on small-scale studies, so until now, researchers did not know if the neural mechanisms un-derlying placebo effects ob-served to date would hold up across larger samples. This study represents the first large-scale mega-analysis, which looks at individual participants’ whole brain images. It enabled research-ers to look at parts of the brain that they did not have sufficient resolution to look at in the past. The analysis was comprised of 20 neuro-imaging studies with 600 healthy participants. The re-sults provide new insight on the size, localization, signifi-cance and heterogeneity of placebo effects on pain-re-lated brain activity. The research reflects the work of an international collaborative effort by the Placebo Neuroimaging Consortium, led by Tor Wa-ger, the Diana L. Taylor Distinguished Professor in Neuroscience at Dartmouth and Ulrike Bingel, a profes-sor at the Center for Trans-lational Neuro-and www.Cndoctor.ca Behavioral Sciences in the department of neurology at University Hospital Essen, for which Matthias Zun-hammer and Tamás Spisák at the University Hospital Essen, served as co-authors. The meta-analysis is the second with this sample and builds on the team’s earlier research using an established pain marker developed ear-lier by Wager’s lab. “Our findings demonstrate that the participants who showed the most pain reduc-tion with the placebo also showed the largest reductions in brain areas associated with pain construction,” explains co-author Wager, who is also the principal investigator of the Cognitive and Affective Neuroscience Lab at Dart-mouth. “We are still learning how the brain constructs pain experiences, but we know it’s a mix of brain areas that pro-cess input from the body and those involved in motivation and decision-making. Placebo treatment reduced activity in areas involved in early pain signaling from the body, as well as motivational circuits not tied specifically to pain.” Across the studies in the meta-analysis, participants had indicated that they felt less pain; however, the team wanted to find out if the brain responded to the placebo in a meaningful way. Is the pla-cebo changing the way a person constructs the experi-ence of pain or is it changing the way a person thinks about it after the fact? Is the person really feeling less pain? With the large sample, the researchers were able to con-fidently localize placebo ef-fects 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 lots of different nuclei, which act like processing stations for different kinds of sensory input. The results showed that parts of the thal-amus that are most impor-tant 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 experi-ences 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 findings revealed that placebo treatments reduce activity in the posterior insula, which is one of the areas that are involved in early construc-tion of the pain experience. This is the only site in the cortex that you can stimulate and invoke the sense of pain. The major ascending pain pathway goes from parts of the thalamus to the posterior insula. The results provide evidence that the placebo af-fects that pathway for how pain is constructed. Prior research has illus-trated that with placebo ef-fects, the prefrontal cortex is activated in anticipation of pain. The prefrontal cortex helps keep track of the con-text of the pain and maintain the belief that it exists. When the prefrontal cortex is acti-vated, there are pathways that trigger opioid release in the midbrain that can block pain and pathways that can modify pain signaling and construction. The team found that acti-vation of the prefrontal cor-tex is heterogeneous across studies, meaning that no particular areas in this region were activated consistently or strongly across the studies. These differences across studies are similar to what is found in other areas of self-regulation, where differ-ent types of thoughts and mindsets can have different effects. For example, other work in Wager’s laboratory has found that rethinking pain by using imagery and storytelling typically activates the prefrontal cortex, but mindful acceptance does not. Placebo effects likely involve a mix of these types of pro-cesses, depending on the specifics of how it is given and people’s predispositions. Understanding the neural systems that utilize and mod-erate placebo responses has important implications for clinical care and drug-devel-opment. The placebo re-sponses could be utilized in a context-, patient-, and dis-ease-specific manner. The placebo effect could also be leveraged alongside a drug, surgery, or other treatment, as it could potentially en-hance patient outcomes. Journal Reference: Mat-thias Zunhammer, Tamás Spisák, Tor D. Wager, Ulrike Bingel. Meta-analysis of neu-ral systems underlying pla-cebo analgesia from individ-ual participant fMRI data. Nature Communications, 2021; 12 (1) DOI: 10.1038/ s41467-021-21179-3 —Dartmouth College. Orig-inal by Amy D. Olson. Content may be edited for length. March/April 2021 Chiropractic and Naturopathic Doctor 7
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