Tag: placebo effect

Categories : Neurology VaccinesTags :

The Brain Can Boost Vaccine Effectiveness, New Study Suggests

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Photo by National Cancer Institute

New research reveals that activating the brain’s reward system through positive anticipation strengthens the immune response and increases antibody production

Can positive anticipation that activates the brain’s reward system strengthen the body’s immune defences? A new study by Tel Aviv University, the Technion, and Tel Aviv Medical Center (Ichilov), published in the prestigious journal Nature Medicine, provides the first evidence in humans that brain activity associated with the expectation of reward has a measurable effect on the body’s response to a specific vaccine.

Training the Brain’s Reward SystemThe study was conducted through a collaboration between two research groups: the laboratory of Prof Talma Hendler, from the School of Psychological Sciences and the Gray Faculty of Medical and Health Sciences; and the laboratory of Prof Asya Rolls from The George S. Wise Faculty of Life Sciences,.

Eighty-five healthy volunteers participated in the experiment. Some underwent special brain training using fMRI neurofeedback technology – a method that enables individuals to learn, in real time, to regulate activity in specific brain regions through reinforcing learning. The aim of the brain training was to increase activity in a key region of the brain’s reward system including the Ventral Tegmental Area (VTA), which is responsible for dopamine release in the context of mental activity related to the expectation of positive outcomes and motivation to obtain rewards. Participants were instructed to modulate their brain activity using various mental strategies (eg, thoughts, feelings, memories) while monitoring positive feedback about the strategy that was successful in regulating their brain.

From Brain Activation to Antibodies

Immediately after completing the brain training, all participants received a hepatitis B vaccine. The researchers then tracked the immune response through a series of blood tests, measuring levels of specific antibodies produced following the vaccination.

The results showed that participants who succeeded in significantly increasing activity in the brain’s reward region also demonstrated a greater increase in antibody levels after vaccination. The association was specific to the VTA and was not observed in other brain regions used for control purposes (such as the hippocampus), nor in other reward-system areas linked to different reward-related experiences such as pleasure and satisfaction. In other words, the effect was both anatomically and mentally specific.

The Role of Positive Anticipation

Furthermore, an in-depth analysis of the mental strategies participants used during training of the VTA (and not other regions) revealed that those who focused on positive anticipation, such as belief in a good outcome, or the expectation of something positive about to happen, were able to maintain higher VTA brain activity over time, which was also associated with a better immune response. In other words, the researchers identified a link between reward-system brain activity, a mental state of positive anticipation, and the body’s response to an immune challenge.

According to the research team, this is not “positive thinking” in the popular sense or a New Age slogan, but a measurable neurobiological mechanism – related, among other things, to the well-known placebo effect in medicine (a therapeutic response beyond a specific medical intervention). “We show that mental states have a clear brain signature, and that this signature can influence physiological systems such as the immune system,” explain the researchers.

While the study does not propose a substitute for vaccines or medical treatment, it opens the door to new, noninvasive approaches that may one day strengthen immune responses, improve the effectiveness of medical treatments, and even contribute to fields such as immunotherapy and the treatment of chronic immune pathologies. The researchers note that the study’s findings underscore a broader message: the mind–body connection is not merely a theoretical concept, but a real biological process that can be measured, trained, and potentially harnessed to promote better health.

Implications for Medicine and Health

The research team adds that the findings highlight the potential inherent in integrating neuroscience, psychology, and medicine. “Our study shows that the brain is not only a system that responds to the body’s state of health, but also an active player that influences it,” say the researchers. “The ability to consciously activate brain mechanisms associated with positive anticipation opens a new avenue for research and future treatments – as a complement to existing medicine, not as a replacement. In the future, it may be possible to develop simple, noninvasive tools to help strengthen immune responses and enhance the effectiveness of medical treatments by relying on the brain’s natural capacity to influence the body. However, it is important to emphasise that activation of the reward system and its effect on immune response vary between individuals. Therefore, this approach cannot replace existing medical treatments, but may well serve as an additional supportive component.”

Source: Tel Aviv University

Categories : Pain ManagementTags :

Asymmetric Placebo Effect in Response to Spicy Food

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Positive expectations facilitate reward processing and negative expectations prime pain processing

Photo by Ryan Quintal on Unsplash

The expectations humans have of a pleasurable sensation asymmetrically shape neuronal responses and subjective experiences to hot sauce, according to a study published October 8th, in the open-access journal PLOS Biology by Yi Luo from East China Normal University, Kenneth Kishida from Wake Forest School of Medicine, US, and colleagues.

Expectations shape our perception, profoundly influencing how we interpret the world. Positive expectations about sensory stimuli can alleviate distress and reduce pain through what’s known as the placebo effect, while negative expectations may heighten anxiety and exacerbate pain. In the new study, Luo, Kishida, and colleagues investigated the impact of the hedonic aspect of expectations on subjective experiences.

Specifically, the researchers measured neurobehavioral responses to the taste of hot sauce among individuals with a wide range of taste preferences. In total, 47 participants completed the tasks while undergoing functional magnetic resonance imaging scanning. The researchers identified participants who liked versus those who strongly disliked spicy flavors and provided contextual cues about the spiciness of the sauce to be tasted. That way, they were able to dissociate the effects of positive and negative expectations from sensory stimuli (i.e., visual and taste stimuli), which were the same across all participants.

The results showed that positive expectations lead to modulations in the intensity of subjective experience. These modulations were accompanied by increased activity in brain regions previously linked to pleasure, information integration, and the placebo effect, including the anterior insula, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex. By contrast, negative expectations decreased hedonic experience and increased neural activity in the Neurological Pain Signature network.

Taken together, these findings demonstrate that hedonic aspects of one’s expectations asymmetrically shape how the brain processes sensory input and associated behavioral reports of one’s subjective experiences of intensity, pleasure, and pain. The results suggest a dissociable impact of hedonic information. While positive expectations facilitate higher-level information integration and reward processing, negative expectations prime lower-level processes related to pain and emotions. According to the authors, this study demonstrates the powerful role of hedonic expectations in shaping subjective reality and suggests potential avenues for consumer and therapeutic interventions targeting expectation-driven neural processes.

The authors add, “Our study highlights how hedonic expectations shape subjective experiences and neural responses, offering new insights into the mechanisms behind pain perception.”

Provided by PLOS

Categories : Neurology Pain ManagementTags :

Scientists Trace the Neural Pathway of the Placebo Effect

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Photo by Danilo Alvesd on Unsplash

The placebo effect is very real. This we’ve known for decades, as seen in real-life observations and the best double-blinded randomised clinical trials researchers have devised for many diseases and conditions, especially pain. And yet, how and why the placebo effect occurs has remained a mystery. Now, neuroscientists have discovered a key piece of the placebo effect puzzle, reporting it in Nature.

Researchers at the University of North Carolina School of Medicine – with colleagues from Stanford, the Howard Hughes Medical Institute, and the Allen Institute for Brain Science – discovered a pain control pathway that links the cingulate cortex in the front of the brain, through the pons region of the brainstem, to cerebellum in the back of the brain.

The researchers, led by Greg Scherrer, PharmD, PhD, associate professor in the UNC Department of Cell Biology and Physiology, the UNC Neuroscience Center, and the UNC Department of Pharmacology, then showed that certain neurons and synapses along this pathway are highly activated when mice expect pain relief and experience pain relief, even when there is no medication involved.

“That neurons in our cerebral cortex communicate with the pons and cerebellum to adjust pain thresholds based on our expectations is both completely unexpected, given our previous understanding of the pain circuitry, and incredibly exciting,” said Scherrer. “Our results do open the possibility of activating this pathway through other therapeutic means, such as drugs or neurostimulation methods to treat pain.”

Scherrer and colleagues said research provides a new framework for investigating the brain pathways underlying other mind-body interactions and placebo effects beyond the ones involved in pain.

The Placebo Paradox

In conjunction with millennia of evolution, our brains can search for ways to alleviate the sensation of pain, in some cases quantifiably as with released chemicals, and less quantifiably through positive thinking and even prayer which have some documented benefit. And then there is the placebo effect.

In clinical research, the placebo effect is often seen in the “sham” treatment group that receives a fake pill or intervention that is supposed to be inert; no benefit is expected. Except that the brain is so powerful and individuals so desire to feel better that some experience a marked improvement in their symptoms. Some placebo effects are so strong that individuals are convinced they received a real treatment meant to help them.

In fact, it’s thought that some individuals in the “actual” treatment group also derive benefit from the placebo effect, complicating experimental design and driving larger sample sizes. One way to help scientists account for this is to first understand what precisely is happening in the brain of someone experiencing the placebo effect.

Enter the Scherrer lab

The scientific community’s understanding of the biological underpinnings of pain relief through placebo analgesia came from human brain imaging studies, which showed activity in certain brain regions. Those imaging studies did not have enough precision to show what was actually happening in those brain regions. So Scherrer’s team designed a set of meticulous, complementary, and time-consuming experiments to learn in more detail, with single nerve cell precision, what was happening in those regions.

First, the researchers created an assay that generates in mice the expectation of pain relief and then very real placebo effect of pain relief. Then the researchers used a series of experimental methods to study the intricacies of the anterior cingulate cortex (ACC), which had been previously associated with the pain placebo effect. While mice were experiencing the effect, the scientists used genetic tagging of neurons in the ACC, imaging of calcium in neurons of freely behaving mice, single-cell RNA sequencing techniques, electrophysiological recordings, and optogenetics – the use of light and fluorescent-tagged genes to manipulate cells.

These experiments helped them see and study the intricate neurobiology of the placebo effect down to the brain circuits, neurons, and synapses throughout the brain.

The scientists found that when mice expected pain relief, the rostral anterior cingulate cortex neurons projected their signals to the pontine nucleus, which had no previously established function in pain or pain relief. And they found that expectation of pain relief boosted signals along this 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 realised 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.

Lastly, the scientists found that Purkinje cells – a distinct class of large branch-like cells of the cerebellum – showed activity patterns similar to those of the ACC neurons during pain relief expectation. Scherrer and first author Chong Chen, MD, PhD, a postdoctoral research associate in the Scherrer lab, said that this is cellular-level evidence for the cerebellum’s role in cognitive pain modulation.

“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.”

Source: University of North Carolina Health Care

Categories : Mental HealthTags :

Even When Informed, Participants Found Placebos Reduced Anxiety

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Even when participants knew they had placebos, their COVID anxiety reduced

Photo from Pixabay CCO

A study out of Michigan State University found that non-deceptive placebos, or placebos given with people fully knowing they are placebos, effectively manage stress – even when the placebos are administered remotely. 

Researchers recruited participants experiencing prolonged stress from the COVID pandemic for a two-week randomised controlled trial. Half of the participants were randomly assigned to a non-deceptive placebo group and the other half to the control group that took no pills. The participants interacted with a researcher online through four virtual sessions on Zoom. Those in the non-deceptive placebo group received information on the placebo effect and were sent placebo pills in the mail along with instructions on taking the pills. 

The study, which appears in Applied Psychology: Health and Well-Being, found that the non-deceptive group showed a significant decrease in stress, anxiety and depression in just two weeks compared to the no-treatment control group. Participants also reported that the non-deceptive placebos were easy to use, not burdensome and appropriate for the situation.

“Exposure to long-term stress can impair a person’s ability to manage emotions and cause significant mental health problems, so we’re excited to see that an intervention that takes minimal effort can still lead to significant benefits,” said Jason Moser, co-author of the study and professor in MSU’s Department of Psychology. “This minimal burden makes non-deceptive placebos an attractive intervention for those with significant stress, anxiety and depression.”

The researchers are particularly hopeful in the ability to remotely administer the non-deceptive placebos by health care providers.

“This ability to administer non-deceptive placebos remotely increases scalability potential dramatically,” said Darwin Guevarra, co-author of the study and postdoctoral scholar at the University of California, San Francisco, “Remotely administered non-deceptive placebos have the potential to help individuals struggling with mental health concerns who otherwise would not have access to traditional mental health services.”

Source: Michigan State University

Categories : Mental HealthTags :

Ketamine’s Effect on Depression is Essentially Placebo Effect

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Photo by Bruce Christianson on Unsplash

Over the years, studies have demonstrated the psychoactive drug ketamine’s effect on depression, providing profound and fast relief to many people. But these studies have a critical flaw: participants usually can tell whether they have been given ketamine or a placebo. Even in blinded trials in which participants are not told which they received, ketamine’s oftentimes trippy effects are a dead giveaway.

In a new study published in Nature Mental Health, Stanford Medicine researchers devised a clever workaround to hide the psychedelic, or dissociative, properties of the anesthetic first developed in 1962. They recruited 40 participants with moderate to severe depression who were also scheduled for routine surgery, then administered a single infusion of ketamine (0.5 mg kg−1) or placebo (saline) during usual anaesthesia.

All researchers and clinicians involved in the trial also were blinded to which treatment patients received. The treatments were revealed two weeks later.

The researchers were amazed to find that both groups experienced the large improvement in depression symptoms usually seen with ketamine.

“I was very surprised to see this result, especially having talked to some of those patients who said ‘My life is changed, I’ve never felt this way before,’ but they were in the placebo group,” said Boris Heifets, MD, PhD, assistant professor of anaesthesiology, perioperative and pain medicine, and senior author.

Just one day after treatment, both the ketamine and placebo groups’ scores on the Montgomery-Åsberg depression rating scale (MADRS) dropped, on average, by half. Their scores stayed roughly the same throughout the two-week follow-up.

“To put that into perspective, that brings them down to a category of mild depression from what had been debilitating levels of depression,” said Theresa Lii, MD, a postdoctoral scholar in the Heifets lab and lead author of the study.

What does it all mean?

The researchers concede that their study, having taken an unexpected turn, raises more questions than it answers.

“Now all the interpretations happen,” said Alan Schatzberg, MD, a co-author of the study. “It’s like looking at a Picasso painting.”

The researchers determined that it was unlikely the surgeries and general anaesthesia account for the improvements because studies have found that depression generally does not change after surgery; sometimes, it worsens.

A more likely interpretation, the researchers said, is that participants’ positive expectations may play a key role in ketamine’s effectiveness.

At their last follow-up visit, participants were asked to guess which intervention they had received. About a quarter said they didn’t know. Of those who ventured a guess, more than 60% guessed ketamine.

Their guesses did not correlate with their treatment – confirmation of effective blinding – but rather with how much better they felt.

Source: Stanford Medicine