About 50 million Americans suffer from chronic pain, which interferes with their daily lives, social interactions and ability to work. Professor Fan Wang of MIT wants to develop new ways to help alleviate this pain, by studying and potentially modifying the pain control mechanisms of the brain.
His recent work has identified a pain “off switch” located in the amygdala of the brain. She hopes that finding ways to control this change could lead to new treatments for chronic pain.
“Chronic pain is a major societal problem,” says Wang. “By studying pain suppressing neurons in the central amygdala of the brain, I hope to create a novel therapeutic approach to pain relief.”
Wang, who joined the MIT faculty in January 2021, is also leading a new initiative at the McGovern Institute for Brain Research that studies addiction, with the goal of developing more effective addiction treatments.
“Prescribing opioids for chronic pain is a major contributor to the opioid epidemic. With the Covid pandemic, I think addictions and overdoses are getting worse. People are more anxious and looking for drugs to relieve such mental pain,” Wang says. “As scientists, it is our duty to tackle this problem.”
Wang, who grew up in Beijing, describes herself as “a nerdy kid” who loved books and math. In high school, she competed in science competitions, then continued to study biology at Tsinghua University. She came to the United States in 1993 to begin her doctorate at Columbia University. There she worked tracing the connection patterns of olfactory receptor neurons in the lab of Richard Axel, who went on to win the Nobel Prize for his discoveries on olfactory receptors and the organization of the olfactory system.
After completing her doctorate, Wang decided to switch gears. As a post-doctoral researcher at the University of California, San Francisco and then at Stanford University, she began to study how the brain perceives touch.
In 2003, Wang joined the faculty of Duke University School of Medicine. There she began developing techniques to study the brain circuitry that underlies the sense of touch, tracing the circuits that carry sensory information from mouse whiskers to the brain. She has also studied how the brain integrates movements of tactile organs with signals from sensory stimuli to generate perception (such as using stretching movements to detect elasticity).
As she continued her studies in sensory perception, Wang became interested in studying pain perception, but felt she needed to develop new techniques to deal with it. While at Duke, she invented a technique called CANE (capture of activated neural ensembles), which can identify neural networks 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 provide much useful information. In order to indirectly understand 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 speculated that the drugs could also shut off pain perception.
“At that time, it was just a crazy idea,” Wang recalls. “I thought there might be other mechanisms – that instead of just losing consciousness, the anesthetics might be doing something to the brain that turns off the pain.”
Support for the existence of a “kill switch” for pain came from the observation that wounded soldiers on a battlefield can continue to fight, essentially blocking out the pain despite their injuries.
In a study of mice treated with anesthetic drugs, Wang discovered that the brain has this type of switch, in an unexpected place: the amygdala, which is involved in regulating emotions. She showed that this group of neurons can disable pain when activated, and when suppressed, mice become highly sensitive to ordinary soft touch.
“There’s a baseline level of activity that makes animals feel normal, and when you activate those neurons, they feel less pain. When you silence them, they will feel more pain,” Wang says.
Turn off the pain
This finding, reported by Wang in 2020, raised the possibility of somehow modulating this change in humans to try and treat chronic pain. This is a long-term goal for Wang, but more work needs to be done to achieve it, she said. Currently, her lab is working on analyzing the RNA expression patterns of neurons in the group she identified. They are also measuring the electrical activity of neurons and how they interact with other neurons in the brain, in hopes of identifying circuits that could be targeted to dampen pain perception.
One way to modulate 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 its infancy and does not require surgery, could be a less invasive alternative.
Another approach Wang wants to explore is to associate brain stimulation with a context such as viewing a smartphone app. This type of pairing could help train the brain to stop 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 might just need to re-enable it with context,” says Wang. “After a while, you would probably need to be restimulated or reconditioned, but at least you have a longer window where you don’t have to go to the hospital for stimulation, and you just need ‘use a context.’
Wang, who was drawn to MIT in part because it focuses on fostering cross-disciplinary collaborations, now works with several other members of the McGovern Institute who are taking different angles to try to understand how the brain generates energy. craving that occurs in drug addiction, including opiate addiction.
“We are going to focus on understanding this craving: how it is created in the brain and how can we somehow erase this 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 regain control,” she says.