Neuroscientists discover brain circuitry of placebo effect for pain relief

The placebo effect is very real. This we've known for decades, as seen in real-life observations and the best double-blinded randomized 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.

Publishing 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

It is the human experience, in the face of pain, to want to feel better. As a result -- and in conjunction with millennia of evolution -- our brains can search for ways to help us feel better. It releases chemicals, which can be measured. Positive thinking and even prayer have been shown to benefit some patients. And the placebo effect -- feeling better even though there was no "real" treatment -- has been documented as a very real phenomenon for decades.

In clinical research, the placebo effect is often seen in what we call the "sham" treatment group. That is, individuals in this group receive a fake pill or intervention that is supposed to be inert; no one in the control group is supposed to see a benefit. 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. This is one of the reasons why clinical research of therapeutics is so difficult and demands as many volunteers as possible so scientists can parse the treatment benefit from the sham. One way to help scientists do this is to first understand what precisely is happening in the brain of someone experiencing the placebo effect.

Enter the Scherrer lab

The authors of the Nature paper knew that the scientific community's understanding of the biological underpinnings of pain relief through placebo analgesia -- when the positive expectation of pain relief is sufficient for patients to feel better -- 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 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.

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."

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From the first bite, our sense of taste helps pace our eating

When you eagerly dig into a long-awaited dinner, signals from your stomach to your brain keep you from eating so much you'll regret it -- or so it's been thought. That theory had never really been directly tested until a team of scientists at UC San Francisco recently took up the question.

The picture, it turns out, is a little different.

The team, led by Zachary Knight, PhD, a UCSF professor of physiology in the Kavli Institute for Fundamental Neuroscience, discovered that it's our sense of taste that pulls us back from the brink of food inhalation on a hungry day. Stimulated by the perception of flavor, a set of neurons -- a type of brain cell -- leaps to attention almost immediately to curtail our food intake.

"We've uncovered a logic the brainstem uses to control how fast and how much we eat, using two different kinds of signals, one coming from the mouth, and one coming much later from the gut," said Knight, who is also an investigator with the Howard Hughes Medical Institute and a member of the UCSF Weill Institute for Neurosciences. "This discovery gives us a new framework to understand how we control our eating."

The study, which appears Nov. 22, 2023 in Nature, could help reveal exactly how weight-loss drugs like Ozempic work, and how to make them more effective.

New views into the brainstem

Pavlov proposed over a century ago that the sight, smell and taste of food are important for regulating digestion. More recent studies in the 1970s and 1980s have also suggested that the taste of food may restrain how fast we eat, but it's been impossible to study the relevant brain activity during eating because the brain cells that control this process are located deep in the brainstem, making them hard to access or record in an animal that's awake.

Over the years, the idea had been forgotten, Knight said.

New techniques developed by lead author Truong Ly, PhD, a graduate student in Knight's lab, allowed for the first-ever imaging and recording of a brainstem structure critical for feeling full, called the nucleus of the solitary tract, or NTS, in an awake, active mouse. He used those techniques to look at two types of neurons that have been known for decades to have a role in food intake.

The team found that when they put food directly into the mouse's stomach, brain cells called PRLH (for prolactin-releasing hormone) were activated by nutrient signals sent from the GI tract, in line with traditional thinking and the results of prior studies.

However, when they allowed the mice to eat the food as they normally would, those signals from the gut didn't show up. Instead, the PRLH brain cells switched to a new activity pattern that was entirely controlled by signals from the mouth.

"It was a total surprise that these cells were activated by the perception of taste," said Ly. "It shows that there are other components of the appetite-control system that we should be thinking about."

While it may seem counterintuitive for our brains to slow eating when we're hungry, the brain is actually using the taste of food in two different ways at the same time. One part is saying, "This tastes good, eat more," and another part is watching how fast you're eating and saying, "Slow down or you're going to be sick."

"The balance between those is how fast you eat," said Knight.

The activity of the PRLH neurons seems to affect how palatable the mice found the food, Ly said. That meshes with our human experience that food is less appetizing once you've had your fill of it.

Brain cells that inspire weight-loss drugs

The PRLH-neuron-induced slowdown also makes sense in terms of timing. The taste of food triggers these neurons to switch their activity in seconds, from keeping tabs on the gut to responding to signals from the mouth.

Meanwhile, it takes many minutes for a different group of brain cells, called CGC neurons, to begin responding to signals from the stomach and intestines. These cells act over much slower time scales -- tens of minutes -- and can hold back hunger for a much longer period of time.

"Together, these two sets of neurons create a feed-forward, feed-back loop," said Knight. "One is using taste to slow things down and anticipate what's coming. The other is using a gut signal to say, 'This is how much I really ate. Ok, I'm full now!'"

The CGC brain cells' response to stretch signals from the gut is to release GLP-1, the hormone mimicked by Ozempic, Wegovy and other new weight-loss drugs.

These drugs act on the same region of the brainstem that Ly's technology has finally allowed researchers to study. "Now we have a way of teasing apart what's happening in the brain that makes these drugs work," he said.

A deeper understanding of how signals from different parts of the body control appetite would open doors to designing weight-loss regimens designed for the individual ways people eat by optimizing how the signals from the two sets of brain cells interact, the researchers said.

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How artificial intelligence gave a paralyzed woman her voice back

Researchers at UC San Francisco and UC Berkeley have developed a brain-computer interface (BCI) that has enabled a woman with severe paralysis from a brainstem stroke to speak through a digital avatar.

It is the first time that either speech or facial expressions have been synthesized from brain signals. The system can also decode these signals into text at nearly 80 words per minute, a vast improvement over commercially available technology.

Edward Chang, MD, chair of neurological surgery at UCSF, who has worked on the technology, known as a brain computer interface, or BCI, for more than a decade, hopes this latest research breakthrough, appearing Aug. 23, 2023, in Nature, will lead to an FDA-approved system that enables speech from brain signals in the near future.

"Our goal is to restore a full, embodied way of communicating, which is really the most natural way for us to talk with others," said Chang, who is a member of the UCSF Weill Institute for Neuroscience and the Jeanne Robertson Distinguished Professor in Psychiatry. "These advancements bring us much closer to making this a real solution for patients."

Chang's team previously demonstrated it was possible to decode brain signals into text in a man who had also experienced a brainstem stroke many years earlier. The current study demonstrates something more ambitious: decoding brain signals into the richness of speech, along with the movements that animate a person's face during conversation.

Chang implanted a paper-thin rectangle of 253 electrodes onto the surface of the woman's brain over areas his team has discovered are critical for speech. The electrodes intercepted the brain signals that, if not for the stroke, would have gone to muscles in her, tongue, jaw and larynx, as well as her face. A cable, plugged into a port fixed to her head, connected the electrodes to a bank of computers.

For weeks, the participant worked with the team to train the system's artificial intelligence algorithms to recognize her unique brain signals for speech. This involved repeating different phrases from a 1,024-word conversational vocabulary over and over again, until the computer recognized the brain activity patterns associated with the sounds.

Rather than train the AI to recognize whole words, the researchers created a system that decodes words from phonemes. These are the sub-units of speech that form spoken words in the same way that letters form written words. "Hello," for example, contains four phonemes: "HH," "AH," "L" and "OW."

Using this approach, the computer only needed to learn 39 phonemes to decipher any word in English. This both enhanced the system's accuracy and made it three times faster.

"The accuracy, speed and vocabulary are crucial," said Sean Metzger, who developed the text decoder with Alex Silva, both graduate students in the joint Bioengineering Program at UC Berkeley and UCSF. "It's what gives a user the potential, in time, to communicate almost as fast as we do, and to have much more naturalistic and normal conversations."

To create the voice, the team devised an algorithm for synthesizing speech, which they personalized to sound like her voice before the injury, using a recording of her speaking at her wedding.

The team animated the avatar with the help of software that simulates and animates muscle movements of the face, developed by Speech Graphics, a company that makes AI-driven facial animation. The researchers created customized machine-learning processes that allowed the company's software to mesh with signals being sent from the woman's brain as she was trying to speak and convert them into the movements on the avatar's face, making the jaw open and close, the lips protrude and purse and the tongue go up and down, as well as the facial movements for happiness, sadness and surprise.

"We're making up for the connections between the brain and vocal tract that have been severed by the stroke," said Kaylo Littlejohn, a graduate student working with Chang and Gopala Anumanchipalli, PhD, a professor of electrical engineering and computer sciences at UC Berkeley. "When the subject first used this system to speak and move the avatar's face in tandem, I knew that this was going to be something that would have a real impact."

An important next step for the team is to create a wireless version that would not require the user to be physically connected to the BCI.

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Pair of studies uncover surprising new roles for spinal cord and brainstem in touch

The sense of touch is essential to almost everything we do, from routine tasks at home to navigating unfamiliar terrains that may conceal dangers. Scientists have long been interested in understanding exactly how the touch information we obtain with our hands and other parts of the body makes its way to the brain to create the sensations we feel.

Yet, key aspects of touch -- including how the spinal cord and brainstem are involved in receiving, processing, and transmitting signals -- have remained poorly understood.

Now, a pair of papers by scientists at Harvard Medical School reveal critical new insights into how the spinal cord and brainstem contribute to the sense of touch.

Specifically, the research shows that the spinal cord and the brainstem, previously thought to be mere relay centers for touch information, are actively involved in processing touch signals as they travel to higher-order brain regions.

One study, published Nov. 4 in Cell, shows that specialized neurons in the spinal cord form a complex network that processes light touch -- think the brush of a hand or a peck on the cheek -- and sends this information to the brainstem.

In another study, published Nov. 23 in Nature, researchers established that direct and indirect touch pathways work together, converging in the brainstem to shape how touch is processed.

"These studies focus the spotlight on the spinal cord and the brainstem as sites where touch information is integrated and processed to convey different types of touch. We hadn't fully appreciated before how these areas contribute to the brain's representation of vibration, pressure, and other features of tactile stimuli," said David Ginty, the Edward R. and Anne G. Lefler Professor of Neurobiology in the Blavatnik Institute at HMS and the senior author on both papers.

Although the studies were conducted in mice, mechanisms for touch are largely conserved across species, including humans, which means the basics of touch processing could be useful for scientists studying human conditions such as neuropathic pain characterized by touch dysfunction.

"This detailed understanding of tactile sensation -- that is, feeling the world through contact with the skin -- may have profound implications for understanding how disease, disorder, and injury can affect our ability to interact with the environment around us," said James Gnadt, program director at the National Institute of Neurological Disorders and Stroke (NINDS), which provided part of the funding for the studies.

Overlooked and underappreciated

The historical view of touch is that sensory neurons in the skin encounter a touch stimulus such as pressure or vibration and send this information in the form of electrical impulses that travel directly from the skin to the brainstem. There, other neurons relay touch information to the brain's primary somatosensory cortex -- the highest level of the touch hierarchy -- where it is processed into sensation.

However, Ginty and his team wondered if and how the spinal cord and brainstem are involved in processing touch information. These areas occupy the lowest level of the touch hierarchy, and combine to form a more indirect touch pathway into the brain.

"People in the field thought that the diversity and richness of touch came just from sensory neurons in the skin, but that thinking bypasses the spinal cord and brainstem," said Josef Turecek, a postdoctoral fellow in the Ginty lab and the first author on the Nature paper.

Many neuroscientists are not familiar with spinal cord neurons, called postsynaptic dorsal column (PSDC) neurons, that project from the spinal cord into the brainstem -- and textbooks tend to leave PSDC neurons out of diagrams depicting the details of touch, Turecek explained.

For Ginty, the way that the spinal cord and brainstem have been overlooked in touch brings to mind early research on the visual system. Initially, scientists studying vision thought that all processing occurred in the visual cortex of the brain. However, it turned out that the retina, which receives visual information long before it reaches the cortex, is heavily involved in processing this information.

"Analogous to research on the visual system, these two papers address how touch information coming from the skin is processed in the spinal cord and brainstem before it moves up the touch hierarchy to more complex brain regions," Ginty said.

Connecting the dots

In the Cell paper, the researchers used a technique they developed to simultaneously record the activity of many different neurons in the spinal cord as mice experienced various types of touch. They discovered that over 90 percent of neurons in the dorsal horn -- the sensory processing area of the spinal cord -- responded to light touch.

"This was surprising because classically it was thought that dorsal horn neurons in the superficial layers of the spinal cord respond mostly to temperature and painful stimuli. We hadn't appreciated how light-touch information is distributed in the spinal cord," said Anda Chirila, a research fellow in the Ginty lab and the co-lead author on the paper with graduate student Genelle Rankin.

Moreover, these responses to light touch varied considerably across genetically different populations of neurons in the dorsal horn, which were found to form a highly interconnected and complex neural network. This variation in responses, in turn, gave rise to a diversity of touch information carried from the dorsal horn to the brainstem by PSDC neurons. In fact, when the researchers silenced various dorsal horn neurons, they saw a reduction in the diversity of light-touch information conveyed by PSDC neurons.

"We think this information on how touch is encoded in the spinal cord, which is the first site in the touch hierarchy, is important for understanding fundamental aspects of touch processing," Chirila said.

In their other study, published in Nature, scientists focused on the next step in the touch hierarchy: the brainstem. They explored the relationship between the direct pathway from sensory neurons in the skin to the brainstem and the indirect pathway that sends touch information through the spinal cord, as described in the Cell paper.

"Brainstem neurons get both direct and indirect input, and we were really curious about what aspects of touch each pathway brings to the brainstem," Turecek said.

To parse this question, the researchers alternately silenced each pathway and recorded the response of neurons in mouse brainstems. The experiments showed that the direct pathway is important for communicating high-frequency vibration, while the indirect pathway is needed to encode the intensity of pressure on the skin.

"The idea is that these two pathways converge in the brainstem with neurons that can encode both vibration and intensity, so you can shape responses of those neurons based on how much direct and indirect input you have," Turecek explained. In other words, if brainstem neurons have more direct than indirect input, they communicate more vibration than intensity, and vice versa.

Additionally, the team discovered that both pathways can convey touch information from the same small area of skin, with information on intensity detouring through the spinal cord before joining information on vibration that travels directly to the brainstem. In this way, the direct and indirect pathways work together, enabling the brainstem to form a spatial representation of different types of touch stimuli from the same area.

Finally on the map

Up until now, "most people have viewed the brainstem as a relay station for touch, and they haven't even had the spinal cord on the map at all," Ginty said. For him, the new studies "demonstrate that there's a tremendous amount of information processing occurring in the spinal cord and brainstem -- and this processing is critical for how the brain represents the tactile world."

Such processing, he added, likely contributes to the complexity and diversity of the touch information that the brainstem sends to the somatosensory cortex.

Next, Ginty and team plan to repeat the experiments in mice that are awake and behaving, to test the findings under more natural conditions. They also want to expand the experiments to include more types of real-world touch stimuli, such as texture and movement.

The researchers are also interested in how information from the brain -- for example, about an animal's level of stress, hunger, or exhaustion -- affects how touch information is processed in the spinal cord and brainstem. Given that touch mechanisms appear to be conserved across species, such information may be especially relevant for human conditions such as autism spectrum disorders or neuropathic pain, in which neural dysfunction causes hypersensitivity to light touch.

"With these studies we've laid the fundamental building blocks for how these circuits work and what their importance is," Rankin said. "Now we have the tools to dissect these circuits to understand how they're functioning normally, and what's changing when something goes wrong."

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Novel brainstem circuit gives rise to the rhythms of vocalization

The vocal sounds of humans -- laughing, crying, and the babbling of babies -- have the same rhythmic quality as the sounds made by many mammals, songbirds, and even some species of fish. Researchers at UC San Francisco have discovered that a small cluster of neurons in the brain stem not only regulates tempo but also coordinates vocalization with breathing.

"Just to laugh or shout, the body has to coordinate about 100 different muscles in a rhythmic pattern within a single breath," said Kevin Yackle, MD, PhD, a Sandler Faculty Fellow and senior author of the study published online Jan. 7, 2022, in Neuron. "We discovered the neurons that, when switched on, give us this unconscious ability."

It's been widely understood that many animals, including humans, have innate control of breathing -- you don't have to use your brain to do it. Yackle and his team suspected that the same control exists for innate vocalizations.

To confirm the existence of this brain circuit, Yackle and his team studied the sounds made by baby mice when they were separated from their mothers. The babies' cries had a recognizable pattern associated with specific muscle movements. The researchers then determined which cells in the brain stem were responsible for this rhythm, which turned out to be a previously unknown circuit that appears to control the breath and coordinate the muscles needed to produce the vocal sounds.

Identifying this system will enable scientists to ask new questions about how we speak and why some people have trouble doing it.

A New Perspective on Speech Pathologies

"It could be that when we're learning to speak, we're learning to either bypass this system or to directly control it," Yackle said. "Altered wiring in this pattern-generating system could cause speech pathologies."

Yackle and his team are intrigued by studies suggesting that early in their lives, children with autism innately produce different kinds of sounds than other children do. Some children with autism are either unable to speak or have difficulty producing and understanding the tones and rhythms of speech.

Yackle and his team are intrigued by studies suggesting that early in their lives, children with autism innately produce different kinds of sounds than other children do. Some children with autism are either unable to speak or have difficulty producing and understanding the tones and rhythms of speech.

Such speech pathologies are often viewed as an inability to learn how to talk, said Yackle. He is flipping that perspective on its head, asking whether the speech problems are less about learning and more about the brain circuit controlling speech.

"A child may be hearing and learning language, but if the system that allows them to vocalize is different in some way, they just may not be able to coordinate the breath and movements to make the sounds," he said. "If we know how that system is different, it might change how we'd teach some people to speak."

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