Researcher: Fan Wang

On a mission to alleviate chronic pain

Anne Trafton |

About 50 million Americans suffer from chronic pain, which interferes with their daily life, social interactions, and ability to work. MIT Professor Fan Wang wants to develop new ways to help relieve that pain, by studying and potentially modifying the brain’s own pain control mechanisms.

Her recent work has identified an “off switch” for pain, located in the brain’s amygdala. She hopes that finding ways to control this switch could lead to new treatments for chronic pain.

“Chronic pain is a major societal issue,” Wang says. “By studying pain-suppression neurons in the brain’s central amygdala, I hope to create a new therapeutic approach for alleviating pain.”

Wang, who joined the MIT faculty in January 2021, is also the leader of a new initiative at the McGovern Institute for Brain Research that is studying drug addiction, with the goal of developing more effective treatments for addiction.

“Opioid prescription for chronic pain is a major contributor to the opioid epidemic. With the Covid pandemic, I think addiction and overdose are becoming worse. People are more anxious, and they seek drugs to alleviate such mental pain,” Wang says. “As scientists, it’s our duty to tackle this problem.”

Sensory circuits

Wang, who grew up in Beijing, describes herself as “a nerdy child” who loved books and math. In high school, she took part in science competitions, then went on to study biology at Tsinghua University. She arrived in the United States in 1993 to begin her PhD at Columbia University. There, she worked on tracing the connection patterns of olfactory receptor neurons in the lab of Richard Axel, who later won the Nobel Prize for his discoveries of odorant receptors and how the olfactory system is organized.

After finishing her PhD, Wang decided to switch gears. As a postdoc at the University of California at San Francisco and then Stanford University, she began studying how the brain perceives touch.

In 2003, Wang joined the faculty at Duke University School of Medicine. There, she began developing techniques to study the brain circuits that underlie the sense of touch, tracing circuits that carry sensory information from the whiskers of mice to the brain. She also studied how the brain integrates movements of touch organs with signals of sensory stimuli to generate perception (such as using stretching movements to sense elasticity).

As she pursued her sensory perception studies, Wang became interested in studying pain perception, but she felt she needed to develop new techniques to tackle it. While at Duke, she invented a technique called CANE (capturing activated neural ensembles), which can identify networks of neurons that are activated by a particular stimulus.

Using this approach in mice, she identified neurons that become active in response to pain, but so many neurons across the brain were activated that it didn’t offer much useful information. As a way to indirectly get at how the brain controls pain, she decided to use CANE to explore the effects of drugs used for general anesthesia. During general anesthesia, drugs render a patient unconscious, but Wang hypothesized that the drugs might also shut off pain perception.

“At that time, it was just a wild idea,” Wang recalls. “I thought there may be other mechanisms — that instead of just a loss of consciousness, anesthetics may do something to the brain that actually turns pain off.”

Support for the existence of an “off switch” for pain came from the observation that wounded soldiers on a battlefield can continue to fight, essentially blocking out pain despite their injuries.

In a study of mice treated with anesthesia drugs, Wang discovered that the brain does have this kind of switch, in an unexpected location: the amygdala, which is involved in regulating emotion. She showed that this cluster of neurons can turn off pain when activated, and when it is suppressed, mice become highly sensitive to ordinary gentle touch.

“There’s a baseline level of activity that makes the animals feel normal, and when you activate these neurons, they’ll feel less pain. When you silence them, they’ll feel more pain,” Wang says.

Turning off pain

That finding, which Wang reported in 2020, raised the possibility of somehow modulating that switch in humans to try to treat chronic pain. This is a long-term goal of Wang’s, but more work is required to achieve it, she says. Currently her lab is working on analyzing the RNA expression patterns of the neurons in the cluster she identified. They also are measuring the neurons’ electrical activity and how they interact with other neurons in the brain, in hopes of identifying circuits that could be targeted to tamp down the perception of pain.

One way of modulating these circuits could be to use deep brain stimulation, which involves implanting electrodes in certain areas of the brain. Focused ultrasound, which is still in early stages of development and does not require surgery, could be a less invasive alternative.

Another approach Wang is interested in exploring is pairing brain stimulation with a context such as looking at a smartphone app. This kind of pairing could help train the brain to shut off pain using the app, without the need for the original stimulation (deep brain stimulation or ultrasound).

“Maybe you don’t need to constantly stimulate the brain. You may just need to reactivate it with a context,” Wang says. “After a while you would probably need to be restimulated, or reconditioned, but at least you have a longer window where you don’t need to go to the hospital for stimulation, and you just need to use a context.”

Wang, who was drawn to MIT in part by its focus on fostering interdisciplinary collaborations, is now working with several other McGovern Institute members who are taking different angles to try to figure out how the brain generates the state of craving that occurs in drug addiction, including opioid addiction.

“We’re going to focus on trying to understand this craving state: how it’s created in the brain and how can we sort of erase that trace in the brain, or at least control it. And then you can neuromodulate it in real time, for example, and give people a chance to get back their control,” she says.

The craving state

by Jennifer Michalowski |

This story originally appeared in the Winter 2022 issue of BrainScan.

***

For people struggling with substance use disorders — and there are about 35 million of them worldwide — treatment options are limited. Even among those who seek help, relapse is common. In the United States, an epidemic of opioid addiction has been declared a public health emergency.

A 2019 survey found that 1.6 million people nationwide had an opioid use disorder, and the crisis has surged since the start of the COVID-19 pandemic. The Centers for Disease Control and Prevention estimates that more than 100,000 people died of drug overdose between April 2020 and April 2021 — nearly 30 percent more overdose deaths than occurred during the same period the previous year.

In the United States, an epidemic of opioid addiction has been declared a public health emergency.

A deeper understanding of what addiction does to the brain and body is urgently needed to pave the way to interventions that reliably release affected individuals from its grip. At the McGovern Institute, researchers are turning their attention to addiction’s driving force: the deep, recurring craving that makes people prioritize drug use over all other wants and needs.

McGovern Institute co-founder, Lore Harp McGovern.

“When you are in that state, then it seems nothing else matters,” says McGovern Investigator Fan Wang. “At that moment, you can discard everything: your relationship, your house, your job, everything. You only want the drug.”

With a new addiction initiative catalyzed by generous gifts from Institute co-founder Lore Harp McGovern and others, McGovern scientists with diverse expertise have come together to begin clarifying the neurobiology that underlies the craving state. They plan to dissect the neural transformations associated with craving at every level — from the drug-induced chemical changes that alter neuronal connections and activity to how these modifications impact signaling brain-wide. Ultimately, the McGovern team hopes not just to understand the craving state, but to find a way to relieve it — for good.

“If we can understand the craving state and correct it, or at least relieve a little bit of the pressure,” explains Wang, who will help lead the addiction initiative, “then maybe we can at least give people a chance to use their top-down control to not take the drug.”

The craving cycle

For individuals suffering from substance use disorders, craving fuels a cyclical pattern of escalating drug use. Following the euphoria induced by a drug like heroin or cocaine, depression sets in, accompanied by a drug craving motivated by the desire to relieve that suffering. And as addiction progresses, the peaks and valleys of this cycle dip lower: the pleasant feelings evoked by the drug become weaker, while the negative effects a person experiences in its absence worsen. The craving remains, and increasing use of the drug are required to relieve it.

By the time addiction sets in, the brain has been altered in ways that go beyond a drug’s immediate effects on neural signaling.

These insidious changes leave individuals susceptible to craving — and the vulnerable state endures. Long after the physical effects of withdrawal have subsided, people with substance use disorders can find their craving returns, triggered by exposure to a small amount of the drug, physical or social cues associated with previous drug use, or stress. So researchers will need to determine not only how different parts of the brain interact with one another during craving and how individual cells and the molecules within them are affected by the craving state — but also how things change as addiction develops and progresses.

Circuits, chemistry and connectivity

One clear starting point is the circuitry the brain uses to control motivation. Thanks in part to decades of research in the lab of McGovern Investigator Ann Graybiel, neuroscientists know a great deal about how these circuits learn which actions lead to pleasure and which lead to pain, and how they use that information to establish habits and evaluate the costs and benefits of complex decisions.

Graybiel’s work has shown that drugs of abuse strongly activate dopamine-responsive neurons in a part of the brain called the striatum, whose signals promote habit formation. By increasing the amount of dopamine that neurons release, these drugs motivate users to prioritize repeated drug use over other kinds of rewards, and to choose the drug in spite of pain or other negative effects. Her group continues to investigate the naturally occurring molecules that control these circuits, as well as how they are hijacked by drugs of abuse.

Distribution of opioid receptors targeted by morphine (shown in blue) in two regions in the dorsal striatum and nucleus accumbens of the mouse brain. Image: Ann Graybiel

In Fan Wang’s lab, work investigating the neural circuits that mediate the perception of physical pain has led her team to question the role of emotional pain in craving. As they investigated the source of pain sensations in the brain, they identified neurons in an emotion-regulating center called the central amygdala that appear to suppress physical pain in animals. Now, Wang wants to know whether it might be possible to modulate neurons involved in emotional pain to ameliorate the negative state that provokes drug craving.

These animal studies will be key to identifying the cellular and molecular changes that set the brain up for recurring cravings. And as McGovern scientists begin to investigate what happens in the brains of rodents that have been trained to self-administer addictive drugs like fentanyl or cocaine, they expect to encounter tremendous complexity.

McGovern Associate Investigator Polina Anikeeva, whose lab has pioneered new technologies that will help the team investigate the full spectrum of changes that underlie craving, says it will be important to consider impacts on the brain’s chemistry, firing patterns, and connectivity. To that end, multifunctional research probes developed in her lab will be critical to monitoring and manipulating neural circuits in animal models.

Imaging technology developed by investigator Ed Boyden will also enable nanoscale protein visualization brain-wide. An important goal will be to identify a neural signature of the craving state. With such a signal, researchers can begin to explore how to shut off that craving — possibly by directly modulating neural signaling.

Targeted treatments

“One of the reasons to study craving is because it’s a natural treatment point,” says McGovern Associate Investigator Alan Jasanoff. “And the dominant kind of approaches that people in our team think about are approaches that relate to neural circuits — to the specific connections between brain regions and how those could be changed.” The hope, he explains, is that it might be possible to identify a brain region whose activity is disrupted during the craving state, then use clinical brain stimulation methods to restore normal signaling — within that region, as well as in other connected parts of the brain.

To identify the right targets for such a treatment, it will be crucial to understand how the biology uncovered in laboratory animals reflects what’s happens in people with substance use disorders. Functional imaging in John Gabrieli’s lab can help bridge the gap between clinical and animal research by revealing patterns of brain activity associated with the craving state in both humans and rodents. A new technique developed in Jasanoff’s lab makes it possible to focus on the activity between specific regions of an animal’s brain. “By doing that, we hope to build up integrated models of how information passes around the brain in craving states, and of course also in control states where we’re not experiencing craving,” he explains.

In delving into the biology of the craving state, McGovern scientists are embarking on largely unexplored territory — and they do so with both optimism and urgency. “It’s hard to not appreciate just the size of the problem, and just how devastating addiction is,” says Anikeeva. “At this point, it just seems almost irresponsible to not work on it, especially when we do have the tools and we are interested in the general brain regions that are important for that problem. I would say that there’s almost a civic duty.”

How general anesthesia reduces pain

by Sabbi Lall |

General anesthesia is medication that suppresses pain and renders patients unconscious during surgery, but whether pain suppression is simply a side effect of loss of consciousness has been unclear. Fan Wang and colleagues have now identified the circuits linked to pain suppression under anesthesia in mouse models, showing that this effect is separable from the unconscious state itself.

“Existing literature suggests that the brain may contain a switch that can turn off pain perception,” explains Fan Wang, a professor at Duke University and lead author of the study. “I had always wanted to find this switch, and it occurred to me that general anesthetics may activate this switch to produce analgesia.”

Wang, who will join the McGovern Institute in January 2021, set out to test this idea with her student, Thuy Hua, and postdoc, Bin Chen.

Pain suppressor

Loss of pain, or analgesia, is an important property of anesthetics that helps to make surgical and invasive medical procedures humane and bearable. In spite of their long use in the medical world, there is still very little understanding of how anesthetics work. It has generally been assumed that a side effect of loss of consciousness is analgesia, but several recent observations have brought this idea into question, and suggest that changes in consciousness might be separable from pain suppression.

A key clue that analgesia is separable from general anesthesia comes from the accounts of patients that regain consciousness during surgery. After surgery, these patients can recount conversations between staff or events that occurred in the operating room, despite not feeling any pain. In addition, some general anesthetics, such as ketamine, can be deployed at low concentrations for pain suppression without loss of consciousness.

Following up on these leads, Wang and colleagues set out to uncover which neural circuits might be involved in suppressing pain during exposure to general anesthetics. Using CANE, a procedure developed by Wang that can detect which neurons activate in response to an event, Wang discovered a new population of GABAergic neurons activated by general anesthetic in the mouse central amygdala.

These neurons become activated in response to different anesthetics, including ketamine, dexmedetomidine, and isoflurane. Using optogenetics to manipulate the activity state of these neurons, Wang and her lab found that they led to marked changes in behavioral responses to painful stimuli.

“The first time we used optogenetics to turn on these cells, a mouse that was in the middle of taking care of an injury simply stopped and started walked around with no sign of pain,” Wang explains.

Specifically, activating these cells blocks pain in multiple models and tests, whereas inhibiting these neurons rendered mice aversive to gentle touch — suggesting that they are involved in a newly uncovered central pain circuit.

The study has implications for both anesthesia and pain. It shows that general anesthetics have complex, multi-faceted effects and that the brain may contain a central pain suppression system.

“We want to figure out how diverse general anesthetics activate these neurons,” explains Wang. “That way we can find compounds that can specifically activate these pain-suppressing neurons without sedation. We’re now also testing whether placebo analgesia works by activating these same central neurons.”

The study also has implications for addiction as it may point to an alternative system for central pain suppression that could be a target of drugs that do not have the devastating side effects of opioids.

Fan Wang joins the McGovern Institute

by Sabbi Lall |

The McGovern Institute is pleased to announce that Fan Wang, currently a Professor at Duke University, will be joining its team of investigators in 2021. Wang is well-known for her work on sensory perception, pain, and behavior. She takes a broad, and very practical approach to these questions, knowing that sensory perception has broad implications for biomedicine when it comes to pain management, addiction, anesthesia, and hypersensitivity.

“McGovern is a dream place for doing innovative and transformative neuroscience.” – Fan Wang

“I am so thrilled that Fan is coming to the McGovern Institute,” says Robert Desimone, director of the institute and the Doris and Don Berkey Professor of Neuroscience at MIT. “I’ve followed her work for a number of years, and she is making inroads into questions that are relevant to a number of societal problems, such as how we can turn off the perception of chronic pain.”

Wang brings with her a range of techniques developed in her lab, including CANE, which precisely highlights neurons that become activated in response to a stimulus. CANE is highlighting new neuronal subtypes in long-studied brain regions such as the amygdala, and recently elucidated previously undefined neurons in the lateral parabrachial nucleus involved in pain processing.

“I am so excited to join the McGovern Institute,” says Wang. “It is a dream place for doing innovative and transformative neuroscience. McGovern researchers are known for using the most cutting-edge, multi-disciplinary technologies to understand how the brain works. I can’t wait to join the team.”

Wang earned her PhD in 1998 with Richard Axel at Columbia University, subsequently conducting postdoctoral research at Stanford University with Mark Tessier-Lavigne. Wang joined Duke University as a Professor in the Department of Neurobiology in 2003, and was later appointed the Morris N. Broad Distinguished Professor of Neurobiology at Duke University School of Medicine. Wang will join the McGovern Institute as an investigator in January 2021.

Fan Wang

Sensing the World

Why do we feel pain? What causes us to have intense cravings? How do we manage move so effortlessly through the world?

Fan Wang’s research focuses on the neural circuits governing the bidirectional interactions between the brain and body. She is specifically interested in the circuits that control the sensory and emotional aspects of pain and addiction, as well as the sensory and motor circuits that work together to execute behaviors such as eating, drinking, and moving. She has explored how anesthesia suppresses pain, how brain circuits generate rhythmic behaviors, how the brain coordinates speaking and breathing, and how drugs of abuse influence brain circuits that drive addiction. Wang’s lab deploys a range of techniques to gain traction in these studies, including genetic and viral methods, in vivo electrophysiology, in vivo imaging, and behavioral and autonomic response tracking. Her research has profound implications for real-world problems, including chronic pain and addiction.