It’s All In Your Head: How Brain Circuitry Causes Placebo Effect

By Crystal Lindell

The placebo effect is very real. But how and why it happens has mostly remained a mystery. 

However, new research may shed light on what exactly is happening in our brains when just the expectation of pain relief is sufficient for people to feel better, even when the pill or treatment they’re taking has no therapeutic value.

The discovery may even lead to new treatment options. 

In studies on laboratory mice, researchers at the University of North Carolina School of Medicine discovered a pain control pathway that links the front of the brain, through the middle region of the brainstem, to the cerebellum in the back of the brain.

They then showed that certain parts of this pathway are activided in mice when they anticipate pain relief. 

“Our results do open the possibility of activating this pathway through other therapeutic means, such as drugs or neurostimulation methods to treat pain,” says lead researcher Greg Scherrer, PharmD, associate professor in the UNC Department of Cell Biology and Physiology, who conducted the study along with colleagues at Stanford, the Howard Hughes Medical Institute, and the Allen Institute for Brain Science. 

The research, recently published in the journal Nature, provides a new framework for investigating the brain pathways underlying other mind-body interactions beyond the ones involved in pain.

“We all know we need better ways to treat chronic pain, particularly treatments without harmful side effects and addictive properties,” Scherrer said. “We think our findings open the door to targeting this novel neural pain pathway to treat people in a different but potentially more effective way.”

How Scientists Studied Placebo Effect

The placebo effect is basically the brain’s way of trying to help us feel better. As such, just the expectation of pain relief is often enough to make our brains release hormones and natural chemicals that provide relief. Positive thinking and even prayer have been shown to provide similar benefits to patients, without the use of medication. 

The scientific community’s understanding of the placebo effect primarily came from human brain imaging studies, which showed increased activity in certain brain regions. However, those studies did not have enough precision to show what was actually happening in those brain regions. 

So Scherrer’s team designed a set of complex experiments to learn in more detail what was happening in the brain.

First, they created a method to generate in mice the expectation of pain relief. Then they used a series of experiments to study the anterior cingulate cortex (ACC) of their brains, which had previously been associated with the placebo effect. 

The experiments helped them see the intricate neurobiology of the placebo effect on the receptors, neurons, and synapses of the brain. When mice expected pain relief, it boosted signaling along the pain pathway.

“There is an extraordinary abundance of opioid receptors here, supporting a role in pain modulation,” Scherrer said. “When we inhibited activity in this pathway, we realized we were disrupting placebo analgesia and decreasing pain thresholds. And then, in the absence of placebo conditioning, when we activated this pathway, we caused pain relief.”

In a 2021 study, researchers had a similar breakthrough when studying the placebo effect. Researchers at Dartmouth University conducted an analysis of neuroimaging studies involving over 600 healthy people who participated in placebo studies. Their findings showed that placebo treatments reduced pain-related activity in multiple areas of the human brain.

Researchers Closer to Finding the Gene for Hypermobile EDS

By Crystal Lindell

We may be one step closer to discovering the specific gene mutations behind hypermobile Ehlers-Danlos syndrome (hEDS) — a connective tissue disorder that weakens collagen, muscles, ligaments and organs throughout the body, and makes joints highly flexible.

A research team at the Medical University of South Carolina has released the results of a genetic study of a family with high rates of hEDS. Five out of 11 family members met the clinical diagnostic criteria for hEDS and three were considered “probable.” 

Before we get too far into its conclusions though, it’s important to note that findings were released as a preprint in Research Square, which means they have not yet been peer-reviewed by a journal. As such, it’s in the early stages of release, and further scrutiny may result in changes to the conclusions.

That said, the researchers claim to have found what could be a variant linked to hEDS in the Kallikrein-15 gene, which is primarily expressed in the thyroid gland and other organs.

To check if this gene change actually causes hEDS, researchers used laboratory mice. After modifying the mice to have the same genetic variant, they found that the mice had similar connective tissue problems as seen in people with hEDS.

This supports the idea that the Kallikrein gene changes may play a role in causing hEDS.

But the research does not seem to show an all-encompassing hEDS gene. In a cohort of 197 hEDS patients, they found that less than a third (32.8%) had at least one KLK variant. Which means that over 60% of hEDS patients in the study did not have the variant.

As of now, hEDS is the only type of Ehlers-Danlos syndrome that does not have a known specific genetic marker, so finding one would be monumental. And even if this research doesn’t get us all the way there, it’s a huge step in the right direction.

Previous research has also associated hEDS to a genetic variant that causes a deficiency of folate, the natural form of Vitamin B9.

I should note here that I was diagnosed with hypermobile-EDS in 2018, so I have a lot of interest in the topic on a personal level. Since there is no genetic test currently available for hEDS, I was diagnosed via a physical assessment, along with my family’s medical history.

A lot of hEDS patients worry that if there ever is some sort of confirmed, definitive test like a genetic marker, they may not have the marker and would then “lose” their diagnosis.

Based on my personal experiences with medical professionals, I think that’s a legitimate fear. Doctors already seem unwilling to diagnose clear cases of hEDS for a variety of reasons, and this could just give them another excuse to continue doing that.

All I can really say is that if it happened to me, I would feel confident in knowing that my body is clearly not “normal” — so even if it’s not hEDS, there is something else impacting my health.

Some patients diagnosed with hEDS may actually be suffering from something else -- so a genetic test might help them to get the right diagnosis and treatment. I know that probably sounds naively optimistic to many patients. The more likely result is doctors telling patients nothing is wrong with them, and then sending them on their way to suffer.  

On the other hand, I think hEDS is so under-diagnosed, that having a definitive test for it would result in many, many more people finally getting an hEDS diagnosis.

Discovering the exact gene responsible for hEDS could also result in better treatments going forward. As of now, most doctors tell hEDS patients that there’s no cure, so all they can really do is treat the symptoms as they arise and avoid activities that could make their condition worse.  

This is purely wishful thinking, but perhaps in the future researchers will someday discover a way to actually strengthen our collagen and connective tissue, which could have countless benefits for patients suffering from the pain and other common hEDS symptoms.

Advancements like that still feel a long way off though, so until they happen, helping people get an hEDS diagnosis through a genetic test would be progress for millions of patients.

New Society Launched to Advance Pain Research

By Gregory Carbonetti, Guest Columnist

“I live with layers of chronic pain,” writes Dr. Richard Hovey, a professor of dentistry at McGill University. Diagnosed with psoriatic arthritis and enduring lower back pain from a bicycling accident, Hovey also faces painful chemotherapy for advanced metastasized prostate cancer.

“The combination of these pain-inducing events presented significant life-changing challenges to retaining my sense of personhood,” Hovey wrote in a personal essay in the Journal of Patient Experience.

Many Americans may relate. Chronic pain is more prevalent in the U.S. than diabetes, coronary heart disease, stroke and cancer combined. It costs our economy some $635 billion a year in direct treatments and lost productivity.

These problems are exacerbated by the ongoing opioid epidemic, which claimed approximately 450,000 lives over the last two decades and stigmatized people who take prescription pain medication. The nation, and the world, lacks efficient and safe pharmaceutical treatments for pain.  

Thus, one might think a scientific and professional society comprising scientists, clinicians, healthcare providers and policymakers exists, working to reduce the burden of pain. There was such a group, the American Pain Society, but it filed for bankruptcy in 2019. This absence was rectified only this past December with the inaugural meeting of the United States Association for the Study of Pain (USASP).

The circumstances leading to the formation of this new organization underlie the importance of pain research in the United States, which scientific societies play a fundamental role in. They foster interdisciplinary collaboration among members; attract young investigators through early-career grants; work to increase policy impact and address social issues; and promote members’ personal and research integrity.

Scientific societies bring together diverse perspectives and translate knowledge into directives for action. The death of the old pain society and the birth of a new one illustrates the importance of transparency for societies of every discipline.

The now-defunct American Pain Society did some good work. It provided clinical guidelines for pain treatments, increased funding for research, and advocated for multidisciplinary care. But it became a victim of toxic philanthropy, tarnished by its connection to opioid manufacturers such as Purdue Pharma, which settled criminal and civil charges last year by agreeing to pay $8.3 billion for its role in the opioid crisis.

Purdue and other opioid manufacturers accounted for nearly $1 million of the American Pain Society’s $6.5 million in contributions between 2012 and 2017, according to a U.S. Senate committee report, and covered over 5% of the society’s expenses during those years.  

The American Pain Society wasn’t the only professional society accepting donations from opioid manufacturers. The Academy of Integrative Pain Management, which accepted approximately $1.3 million between 2012 and 2017, also dissolved in 2019 due to financial problems. While its focus was different, both societies shared members, and its loss was another setback.

For many pain researchers, clinicians and advocates, the American Pain Society’s demise meant losing important support for their work. These professionals soon had difficulty meeting with pain management leaders and experts in other sub-specialties and disciplines.

More Transparency Needed

Many members were stunned by what had transpired, unaware of the American Pain Society’s dependence on opioid manufacturers. According to the Pacific Standard, when the society’s contributions from opioid manufacturers began to dwindle, leaders never directly told members that fewer industry donations were contributing to their financial problems. 

The dissolution of the American Pain Society created a vacuum, and strategies to organize the USASP began. Forming the new society included a GoFundMe campaign to purchase the old society’s Journal of Pain through auction.

While membership in the USASP is similar to the American Pain Society, its leaders stress that they have learned valuable lessons, making the new constitution and expectations of leadership more transparent and talking with members about the role industry will hold. The USASP is committed to “values-based” decision-making.  

Creating a new society will not instantly end either the chronic pain crisis or the opioid crisis. Nor will it absolve certain players of their past errors. Nonetheless, this history should push other scientific societies to strive toward full transparency and remain in service to those they seek to help.

Dr. Hovey wrote of the transformation “that occurs as patients become people again and are awakened by the multitude of challenges that [lie] ahead of them.”

The formation of the United States Association for the Study of Pain is a significant moment for chronic pain research and for sufferers like Dr. Hovey. The work of rebuilding vital infrastructure for understanding and managing chronic pain, the invisible epidemic, begins anew.

Gregory Carbonetti, PhD, is a Civic Science Fellow at the Alan Alda Center for Communicating Science, working to more meaningfully connect science and research with diverse communities and our shared civic life.

This column is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.