Study Probes Why Some Don’t Experience Placebo Effect

Differences in the physical architecture of the brain may explain why some people with multiple sclerosis (MS), but not others, experience a placebo effect, according to a new study.

The results suggest that MS itself may make some individuals unable to experience the benefits of a placebo.

“Our findings revealed significant structural brain differences between those MS patients who experienced a placebo response and those who did not,” the researchers wrote. “These findings advance our understanding of both the neurobiology of placebo responses and how the neuropathological changes in MS might impact the propensity to experience them.”

The study, “Cortical morphology predicts placebo response in multiple sclerosis,” was published in Scientific Reports.

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The placebo effect is a well-documented scientific phenomenon in which a person can experience benefits from a treatment that is known to be ineffective (e.g., sugar pills instead of real medicine). Although the placebo effect has been recorded innumerable times, the biological processes that cause this effect remain unclear.

Here, a team of scientists in Canada conducted an analysis of data from a clinical trial that tested a surgical procedure called venoplasty in people with MS. The idea was that increasing blood flow to certain parts of the brain might benefit MS patients. But results from large clinical trials have clearly shown this procedure does not objectively benefit MS patients, and the hypothesis is now widely considered disproven.

Nonetheless, in the trial, many participants — both those given venoplasty, and individuals who received a sham procedure — reported a substantial improvement in quality of life that lasted several months after the intervention.

Since the patients had undergone regular brain imaging as part of the trial, “this presented a unique opportunity to examine brain correlates of placebo responses in an MS clinical trial,” the researchers wrote.

The analysis included 43 “responders,” who reported a benefit after venoplasty or sham intervention, and 45 “non-responders” who did not report a noteworthy improvement in life quality. The two groups were demographically similar — about two-thirds female, with an average age in the mid-50s — and most measures of brain health were comparable between the groups.

However, some differences were noted. First, compared with non-responders, the responders had significantly more inflammatory lesions in their brains. Additionally, among non-responders, patients with more lesions tended to also have a thinner cortex (the outermost layer of the brain), particularly in certain regions of the brain associated with regulating movement and processing sensory input. However, this association was not seen among responders.

Further analyses indicated differences between the groups in terms of brain architecture. Generally, non-responders had less interconnection among brain regions than did responders, resulting in more “segregated” brain patterns.

Notably, the brain architecture seen in responders was more similar to what is normally seen in non-MS brains, suggesting the changes seen in non-responders are likely a result of MS itself. Indeed, the researchers noted that prior studies have shown similar changes in MS, with the brain becoming more segregated and compartmentalized.

Taken together, “the evidence points to a pathological shift towards more segregated and regular [brain] networks in MS,” the researchers concluded.

“Our findings suggest that the MS patients who experience these shifts [in brain networks] may also lose their capacity to experience placebo effects,” they added.

Based on these findings, the researchers speculated that a brain with more connections between disparate parts, where information is shared among many brain regions, may aid in the development of the placebo effect. The team stressed this study is limited by its relatively small size and the fact that the analysis was done on data from a prior trial. So, more research is needed to validate these observations and to determine their implications outside of MS.