Scientists for the Placebo Neuroimaging Consortium have undertaken a systematic meta-analysis of human neuroimaging studies to generate new insights into how placebo treatments for pain reduction—placebo analgesia—reduce pain-related activity in multiple areas of the brain. The team claims their research, which involved analyzing experimental functional magnetic resonance imaging (fMRI) data from 600 patients involved in 20 neuroimaging studies, represents the first large-scale mega-analysis that looked at individual participants’ whole brain images. The results will help researchers better understand the size, localization, significance and heterogeneity of placebo effects on pain-related brain activity, and could have implications for clinical care and drug development.

“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 Tor Wager, PhD, the Diana L. Taylor Distinguished Professor in Neuroscience at Dartmouth College, who is also the principal investigator of the Cognitive and Affective Neuroscience Lab at Dartmouth. “We are still learning how the brain constructs pain experiences, but we know it’s a mix of brain areas that process 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.”

Wager is co-corresponding author of the team’s paper, which is published in Nature Communications, and titled, “Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data.” Co-corresponding author is Ulrike Bingel, MD, PhD, a professor at the Center for Translational Neuro- and Behavioral Sciences in the department of neurology at University Hospital Essen. Co-authors included Matthias Zunhammer, and Tamás Spisák at the University Hospital Essen.

A large proportion of the benefit that a person gets from taking a drug can reflect their mindset, not just the activity of the drug itself, the researchers wrote. “Placebo effects contribute substantially to treatment outcomes in both medical research and clinical practice.” Understanding the neural mechanisms driving this placebo effect has thus been a longstanding question, and is important both for optimizing clinical care, but also for drug development.

Placebo analgesia is the most well studied type of placebo effect, and a growing number of neuroimaging studies have looked at how placebo analgesia affects different areas of the brain, the team continued. However, these studies have been small, and the results have varied substantially. Its not been known if the neural mechanisms underlying placebo effects observed to date would hold up across larger samples. “ … the lack of large-sample assessments hampers the detection of small to moderate effects, and makes it difficult to identify precisely which structures are consistently altered by placebo treatment,” Wager, Bingel and colleagues continued.

Their newly reported study represents the first large-scale mega-analysis, comprised of 20 neuroimaging studies of experimental placebo analgesia, involving 600 healthy participants, and looking at individual participants’ whole brain images. It enabled researchers to investigate parts of the brain that they did not have sufficient resolution to look at in the past. The meta-analysis is the second with this sample and builds on the team’s earlier research using an established pain marker developed by Wager’s lab.

This new analysis has provided insights into the size, localization, significance and heterogeneity of placebo effects on pain-related brain activity. “Our results provide a reliable, aggregated view of the size, localization, significance, and heterogeneity of placebo-effects on pain-induced brain activity,” the investigators wrote.

Across the studies included, 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. Does the placebo change the way a person constructs the experience of pain, or is it changing the way a person thinks about it after the fact? Is the person really feeling less pain?

fMRI activity during pain is reduced in the areas shown in blue. Many of these are involved in constructing the experience of pain, including the feeling of suffering, and motivating actions to avoid it. Activity is increased in the areas shown in red and yellow. These are broadly involved in the control of cognition and memory. The involvement of these areas varied across studies, suggesting that different types of placebo effects involved different brain mechanisms. [M.Zunhammer et al.]

With the large sample, the researchers were 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 lots of 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,” said Wager. “It’s changing the circuitry that’s important for motivation.”

The findings revealed that placebo treatments reduce activity in the posterior insula, which is one of the areas that are involved in early construction 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 affects that pathway for how pain is constructed.

Prior research had illustrated that with placebo effects, the prefrontal cortex is activated in anticipation of pain. The prefrontal cortex helps keep track of the context of the pain and maintain the belief that it exists. When the prefrontal cortex is activated, there are pathways that trigger opioid release in the midbrain that can block pain and pathways that can modify pain signaling and construction.

The results also suggested that activation of the prefrontal cortex is heterogeneous across studies, such that no particular areas in this region were activated consistently or strongly across the studies. These differences across studies are similar to what has been found in other areas of self-regulation, where different 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 processes, depending on the specifics of how it is given and people’s predispositions.

“The present results corroborated previous findings of increases in frontal-parietal regions and reductions in the insula,” the investigators summarized. “In addition, they revealed new effects systematically missed in previous smaller-scale analyses, including reductions in the habenula, specific parts of the thalamus (particularly VPL, a nociceptive nucleus), and the cerebellum, promising new targets in explaining placebo analgesia.”

Bingel explained, “Our results suggest that placebo effects are not restricted solely to either sensory/nociceptive or cognitive/affective processes, but likely involves a combination of mechanisms that may differ depending on the placebo paradigm and other individual factors. The study’s findings will also contribute to future research in the development of brain biomarkers that predict an individual’s responsiveness to placebo and help distinguish placebo from analgesic drug responses, which is a key goal of the new collaborative research center, Treatment Expectation.”

The authors further concluded, “In this systematic meta-analysis of individual participant data, we show that placebo treatments induce small, yet robust, inhibitory effects in large parts of the brain … Our results suggest, that placebo is neither restricted to sensory/nociceptive nor to selective cognitive/affective processes but likely involves a combination of mechanisms that may differ depending on the paradigm and other individual factors.”

Understanding the neural systems that utilize and moderate placebo responses has important implications for clinical care and drug-development. The placebo responses could be utilized in a context-, patient-, and disease-specific manner, the scientists stated, while “Fostering the therapeutic processes underlying placebo effects in clinical settings promises to boost the efficacy (and tolerability) of analgesic drug treatments.” The placebo effect could be leveraged alongside a drug, surgery, or other treatment, as it could potentially enhance patient outcomes. “Likewise, controlling and homogenizing placebo responses during drug development can enhance the assay sensitivity in clinical trials,” the team noted. “Finally, biomarkers based on the types of brain alterations we identify here, and reported in other studies, may help to dissect placebo from analgesic drug responses in pre-clinical trials.”