Scientists identify brain’s brake that shuts off chronic pain
Finding from mouse study could lead to targeted treatments for chronic nerve pain
image:
A cluster of nerve cells (cyan, right) in the mouse brain (cyan, left) play a role in both pain relief and the generation of chronic pain. WashU Medicine researchers found that certain receptors on the surface of these cells can shut off chronic pain.
view moreCredit: Chao-Cheng Kuo
Deep at the base of the brain, a tiny cluster of nerve cells serves as the body’s natural pain reliever, dialing down pain signals traveling up the spinal cord. But nerve damage can flip this system into a hyperactive engine for chronic pain.
Now, researchers at Washington University School of Medicine in St. Louis have figured out why that switch flips, and how to shut it off. They identified, in mice, that certain receptors that reside on the surface of cells in the brain’s main alert and stress center act as biological brakes on pain. Previously known to influence stress in this region of the brain, these receptors also can turn off the pain engine to relieve chronic neuropathic pain following nerve injury.
The study, published Aug. 17 in Current Biology, opens new doors for developing therapies that specifically target this region of the brain, known as the locus coeruleus, to reduce chronic pain.
“Millions of adults live with chronic neuropathic pain caused by nerve damage,” said Jordan McCall, PhD, an associate professor in the Center for Clinical Pharmacology in the WashU Medicine Department of Anesthesiology and the study’s senior author. “The pain is difficult to treat, and traditional opioid medications bind to receptors throughout the entire body and brain, often leading to side effects, tolerance and addiction risk. Understanding how localized receptors in the locus coeruleus act as gatekeepers could lead to more targeted, effective pain therapies with fewer risks.”
A brake on pain
Neuropathic pain occurs when damaged nerve fibers send relentless, misfired signals to the brain, causing shooting, stabbing or burning sensations. The condition frequently stems from diabetes, viral infections or nerve compression, among other factors.
To understand how to stop these signals, McCall’s team, including co-first authors Chao-Cheng Kuo, PhD, a postdoctoral research associate, and Makenzie R. Norris, a former graduate student, focused on the locus coeruleus, a part of the brain that has been shown to play a role in pain regulation.
First, they confirmed that nerve injury turns this region into an active driver of pain. When they temporarily turned off locus coeruleus brain cells in mice, they observed reduced sensitivity to touch and heat among animals modeling neuropathic pain compared with healthy mice.
Next, they turned their attention to receptors on locus coeruleus brain cells that respond to opioids, and in particular, a type of opioid receptor known as mu. Mu opioid receptors are scattered throughout the brain and spinal cord. When the body’s naturally produced opioids or synthetic ones such as morphine and fentanyl land in the receptors’ pockets, pain throughout the nervous system lessens. Because the locus coeruleus is packed with these receptors, the researchers wondered if they play an important role in pain regulation.
They deleted the mu opioid receptors on only the locus coeruleus brain cells in mice with neuropathic pain. Without the receptors, the mice were even more sensitive to touch and heat compared with mice with mu opioid receptors still present in the locus coeruleus. Restoring the receptors to those same neurons reversed the hypersensitivity, effectively turning the pain off.
The result indicates that chronic pain may be impairing the ability of mu opioid receptors to tamp down the activity of brain cells in the locus coeruleus. Building on these findings, the researchers are exploring how to manipulate the locus coeruleus without affecting receptors across the rest of the nervous system. By designing therapies that specifically engage mu opioid receptors in this brain region, the researchers said they hope to pave the way for treatments that offer powerful relief for chronic neuropathic pain.
Kuo CC, Norris MR, Dunn SS, Becker LJ, Kim JR, Vazquez CR, Borges G, Thang LV, O’Brien JT, Parker KE, McCall JG. Mu opioid receptors gate the locus coeruleus pain generator. August 17, 2026. Current Biology.
This work was funded by the National Institutes of Health, grant numbers R01NS117899, R01NS135401, F31NS124301 and F31DA065440; the National Science Foundation, grant number DGE-2139839; the McDonnell Center for Systems Neuroscience; a Collaboration Support initiative for Translational Anesthesiology Research (COSTAR) award from the Department of Anesthesiology at Washington University School of Medicine; and the Rita Allen Foundation with added financial help from the Open Philanthropy Project. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH.
Journal
Current Biology
Method of Research
Experimental study
Subject of Research
Animals
Article Title
Mu opioid receptors gate the locus coeruleus pain generator.
Article Publication Date
17-Aug-2026
Laser therapy offers weapon against deadly brain tumors
Large analysis of patient outcomes shows that extent of tumor ablation, treatment timing extends survival
WashU Medicine
For patients facing a diagnosis of glioblastoma — one of the most aggressive and devastating forms of brain cancer — the standard path forward has long meant an invasive open-skull surgery and a daunting prognosis.
Over the past decade and a half, neurosurgeons have incorporated another treatment approach: a minimally invasive laser treatment — currently offered to patients with recurrent, difficult-to-access, or inoperable brain tumors — that is safe and extends survival by months, a meaningful milestone for people with a terminal diagnosis. Now, an analysis of patient outcomes led by researchers at Washington University School of Medicine in St. Louis found potential ways to enhance these benefits, revealing that the extent of tumor removal by the procedure and the timing of treatment extend survival.
The analysis, published Aug. 17 in the Journal of Clinical Oncology, has the potential to improve clinical care for patients.
“Our goal is to both extend the survival of our brain tumor patients and improve the quality of their lives,” said the study’s principal investigator and lead author Eric C. Leuthardt, MD, the Shi Hui Huang Professor of Neurological Surgery at WashU Medicine and chief of the Division of Neurotechnology, who treats patients at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine. “This analysis identifies the factors that lead to the best outcomes. This critical new information will help us find opportunities for patients to benefit the most from this therapy.”
The analysis focused on 787 brain tumor patients who were included in a prospective multicenter study that tracked patients for up to five years after undergoing the minimally invasive laser procedure. WashU Medicine led the study at Siteman Cancer Center and 24 other locations across the U.S.
Factors extending brain cancer survival
Patients diagnosed with glioblastoma and other brain tumors typically undergo an invasive surgery that involves temporarily taking off part of the skull to remove the tumor, often followed by both chemotherapy and radiation.
For those with tumors that are difficult or impossible to remove with open surgery, doctors often treat the cancer with a less-invasive intervention known as laser interstitial thermal therapy, or LITT. Neurosurgeons drill a tiny hole in the skull and insert a robotically controlled laser probe guided by real-time MRI that helps doctors steer the probe through the brain to the tumor on a path that avoids healthy tissue damage. Once inside the tumor, the laser emits heat that kills the surrounding tumor cells. The surgical tool, NeuroBlate, was developed by Monteris Medical, a neurosurgical technology company that funded the study. NeuroBlate was cleared for marketing by the U.S. Food and Drug Administration in 2009.
The researchers aimed to use the largest collected cohort of patients receiving laser surgery for brain tumors that originate in the brain or spread from other parts of the body to understand the factors driving successful patient outcomes of the minimally invasive surgery. The study provides actionable data to help physicians determine which patients may benefit most from the minimally invasive procedure.
Among patients with inoperable or recurrent tumors, the researchers found that how much of the tumor is destroyed by the laser is an important factor in how long a patient survives, especially for those with newly diagnosed glioblastoma. Their analysis showed that glioblastoma patients who had at least 91% of their tumor cleared survived 2.1 years from diagnosis. Because survival with standard open surgical resection is approximately 1 1/2 years, this provides essential information for considering NeuroBlate as a tool that can also be used to treat these tumors up front.
“By combining BJC HealthCare’s premier infrastructure with WashU Medicine’s world-class expertise, patients with brain cancer gain access to the most advanced medical technology available.” Eric Leuthardt, MD, WashU Medicine
Beyond glioblastomas, the analysis delivered insights for treating brain metastases — cancers that have spread to the brain from other parts of the body — after prior radiation therapy. The data revealed a survival advantage for patients who received laser therapy when the tumors were still small. This insight re-evaluates the common practice of watchful waiting, in which clinicians may wait several imaging cycles to confirm tumor growth. Treating earlier, when the tumor is smaller, yields better outcomes than waiting for the tumor to grow.
Some of the 787 brain tumor patients included in the analysis received laser therapy at Barnes-Jewish Hospital, part of BJC HealthCare. For decades, WashU Medicine and Barnes-Jewish Hospital have pioneered laser neurosurgery. In 2010, Leuthardt performed the nation’s first laser interstitial thermal therapy for a brain metastasis at Barnes-Jewish Hospital following the FDA-clearance of the NeuroBlate surgical tool. This milestone was enabled by early investments from BJC HealthCare in intraoperative MRI capabilities, allowing surgeons to see tissue in real time and make more precise decisions during the operation.
“By combining BJC HealthCare’s premier infrastructure with WashU Medicine’s world-class expertise, patients with brain cancer gain access to the most advanced medical technology available,” said Leuthardt.
Boosting quality of life for brain cancer patients
Aside from extending lives, the study confirmed that the laser treatment impacts the patient experience. Traditional brain surgery requires partial, temporary skull removal and weeks of recovery. In contrast, the laser procedure requires only a single-stitch incision a few millimeters wide.
Consistent with other publications analyzing data from the clinical study, the researchers, including WashU Medicine physician-scientist Albert H. Kim, MD, PhD, the August A. Busch, Jr. Professor of Neurological Surgery and director of The Brain Tumor Center at Siteman Cancer Center, showed that the procedure is well-tolerated, maintains a patient’s day-to-day quality of life and limits the average hospital stay to just 32 hours. Patients recovered quickly and most avoided intensive care and readmission. The procedure also reduced the need for anti-seizure medication compared to before the surgery.
“We are shifting the entire framework of how we handle brain tumors,” said Leuthardt. “When patients are told they have months to live, having the option of a low-risk procedure that gets them back home to their families in just over a day is profoundly meaningful.”
Journal
Journal of Clinical Oncology
Method of Research
Data/statistical analysis
Subject of Research
People
Article Title
aser interstitial thermal therapy for brain tumors: a prospective multicenter analysis of 787 patients from the LAANTERN study.
Article Publication Date
17-Aug-2026
COI Statement
ECL Stock ownership: Neurolutions, Face to Face Biometrics, Caeli Vascular, Acera, Sora Neuroscience, Inner Cosmos, Aurenar, Petal Surgical, Inflexion Vascular, Cordance Medical, Silent Surgical. Consultant: Monteris Medical, E15, Neurolutions. Licensing from Intellectual Property: Neurolutions, Caeli Vascular, Inner Cosmos. Licensing/Product Development Agreements or Royalties for inventions/IP: Intellectual Ventures, Sora Neuroscience, Inner Cosmos, Neurolutions, Aurenar. Washington University owns equity in Neurolutions. GR is a member of the Monteris medical safety committee for the LAANTERN and REMASTer studies. AHK is a consultant for Monteris Medical and has received research grants from Stryker for a clinical outcomes study about a dural substitute. SBT has received research support from Azurity Pharmaceuticals. VC is a consultant for Monteris Medical and ClearPoint Neuro. DS is a consultant for Monteris Medical. BJW is a consultant for Monteris Medical, Novocure, Areva Pharmaceuticals, and has received clinical trial funding from GT Medical. AR has research funding from the NIH 5R03CA289645-02 this study does not overlap with this published work. CGH is a consultant for Stryker Corp., Synaptive Medical, Hemerion Therapeutics, Integra, and True Digital Surgery. PL is on the medical advisory board and is a consultant for Neuropace. MDS is a consultant for Monteris Medical and Zimmer Biomet ROSA.
Researchers reveal deeper workings of brain’s information hub
New study shows how the frontoparietal cortex manages information flow and directs responses
University of Iowa
image:
University of Iowa researchers have detailed the workings of the brain's information hub, called the frontoparietal cortex. The colored areas in this illustration show frontoparietal regions tracking uncertainty when participants encounter changes to associations they previously learned.
view moreCredit: Kai Hwang lab, University of Iowa
The human brain is constantly awash with information. Even during a routine activity such as driving, the brain sorts through and reacts to multiple sources of information: Remembering the route, recalling how to operate the vehicle, and adapting to sudden obstacles such as a street closure or changing traffic.
The frontoparietal cortex is the brain’s information hub, sorting through signals from across the brain, deciding what matters, and then coordinating what happens next.
In a new study, University of Iowa researchers demonstrate how the frontoparietal cortex handles uncertainty in decision-making and organizes and coordinates responses in the brain and body.
University of Iowa researchers have detailed the workings of the brain's information hub, called the frontoparietal cortex. The colored areas in this illustration show frontoparietal regions tracking uncertainty when participants encounter changes to associations they previously learned. Image courtesy of Kai Hwang lab, University of Iowa.
Through a series of experiments combining computational modeling and brain imaging, the researchers showed that the frontoparietal cortex changes how it communicates with other brain regions depending on what information is needed at each stage of a decision.
The findings may guide future research into how this exchange of information is altered in neurological and psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia.
“Our study shows in more detail how the frontoparietal cortex operates — what kind of information it extracts from other systems and how it uses its connectivity pattern to integrate information that is coming in from different areas of the brain,” says Kai Hwang, associate professor in the Department of Psychological and Brain Sciences and the study’s corresponding author. “That's the main contribution.”
Neuroscientists have long known that the frontoparietal cortex plays central role in decision-making. Like an air traffic controller at a busy airport, it constantly monitors signals from other parts of the brain. But it isn’t simply a repository. Instead, it sifts through those signals, discarding some and focusing on others depending on the task at hand.
In a study published in 2025, Hwang’s team found that the frontoparietal cortex creates a running, high-level summary of information coming from other parts of the brain. It weighs incoming signals — some incomplete and others uncertain — distills them into a coherent picture, and then instructs other areas of the brain how to respond.
“It’s like where other areas of the brain don’t have all the information, so they send what they have to the frontoparietal cortex for guidance,” Hwang explains.
In this new study, the team built on its previous findings by exploring the frontoparietal cortex’s flexibility — how it changes its interactions with other areas of the brain depending on the problem or situation.
To do that, the researchers asked 38 participants, ages 18 to 35, to learn associations between combinations of colors, faces, and scenes with specific responses, such as pressing a button with the index or middle finger of either hand. The researchers then changed the pairings, forcing the participants to learn new associations and respond by pressing the correct button with the appropriate hand and finger.
The changed instructions created uncertainty, allowing the researchers to track how the frontoparietal cortex connected with other systems in the brain.
“If they always get it right, they know they’ve made the correct association, but once they start doing it wrong, they will have to guess, ‘Oh, did the context change, or did I not see the color clearly?’ That creates uncertainty,” Hwang says.
Using data from the experiments and functional MRI scans, Hwang’s team created a computational model that isolated distinct signals from different areas of the brain and showed how the frontoparietal cortex integrated them.
“Rather than simply becoming more active during difficult tasks, we observed how this network dynamically changes how it communicates with other brain regions depending on what information is needed at each stage of a decision,” Hwang says.
The findings could advance research into psychiatric disorders that impair the brain’s ability to adapt behavior to changing situations, such as speaking too loudly in a library or difficulty controlling impulses, as often occurs with ADHD.
“These are situations where people struggle with regulating their behavior. That, to me, is an integration problem. If that integration function is not working properly, then that could very likely mean they didn’t use the right context to regulate their behavior,” Hwang says.
Stephanie Leach, a sixth-year graduate student in Hwang’s lab, helped design the project, led the in-person experiments, and co-led the writing of the manuscript.
“Having the opportunity to conduct this research has been especially rewarding because it has allowed me to contribute to answering questions about the most fascinating, mysterious, and complex system we know—the human brain,” says Leach, who is the study’s first author.
The study, “Frontoparietal hub connectivity integrates information from multiple sources,” was published online July 6 in the Journal of Neuroscience.
Contributing authors include Jiefeng Jiang, who led the computational modeling, and Shannon Stokes, both in the Department of Psychological and Brain Sciences.
The National Institute of Mental Health and the Iowa Neuroscience Institute funded the research.
Journal
JNeurosci
Method of Research
Observational study
Subject of Research
People
Article Title
Frontoparietal hub connectivity integrates information from multiple sources
Flexible brain circuits can switch between different tasks
Neuroscientists have discovered circuits in the prefrontal cortex that can be repurposed to store different types of information.
Massachusetts Institute of Technology
As we move through everyday life, our brains engage in a huge variety of cognitive tasks. For example, during a grocery run, we might have to recall the items for a recipe, remember where the clerk said the flour was located, and count out money to pay.
Scientists have long theorized that the brain contains modules, or clusters of neurons, that perform the same computation across many different types of tasks. This type of modularity could help explain why our brains are able to take on so many functions, with little difficulty.
In a new study of mice, MIT neuroscientists have found the first evidence for the existence of these flexible modules. They identified neurons in the prefrontal cortex that can be used to store either a sensory input or an action plan in working memory.
“We found that the brain doesn’t dedicate a separate group of neurons for every type of information. Instead, it uses the same populations of neurons to perform the same computation on different kinds of information, which means the same subset of neurons can hold both an action and a sensory stimulus in working memory,” says Yuma Osako, an MIT postdoc and the lead author of the new study.
The discovery supports the theory that reusable circuits allow the brain to mix and match components to generate a rich variety of behavior, the researchers say.
Mriganka Sur, the Newton Professor of Neuroscience at MIT’s Picower Institute for Learning and Memory, and Timothy Buschman PhD ’08, a professor at the Princeton Neuroscience Institute, are the senior authors of the paper, which appears today in Nature Neuroscience. MIT graduate student Greggory Heller and postdoc Sofie Ahrlund-Richter are also authors of the study.
Cognitive building blocks
Dating back to his time as a graduate student at MIT, Buschman has been interested in understanding how the brain is able to perform so many different kinds of behavior.
“One of the solutions that’s always been proposed has been this idea of compositionality — that you can take pieces of cognition that perform part of a task and reuse them in another task,” he says.
In a study published last year, Buschman’s lab at Princeton showed that when animals perform a task such as categorizing objects based on their shape or color, they assemble neural circuits that perform different pieces of the task. Just like “cognitive Legos,” these building blocks can be flexibly combined to generate new behaviors.
Osako, who joined Sur’s lab several years ago, was also interested in studying cognitive flexibility. He and Sur teamed up with Buschman to explore a related question: whether individual neural circuits can be repurposed to perform different functions.
“Our everyday life requires us to temporarily hold many different kinds of information. One big question is how the brain can represent an unlimited variability of information using only a finite number of neurons,” Osako says.
To get at that question, the researchers trained mice on a task in which they have to determine whether two sensory stimuli (high or low pitched tones) are the same, and respond accordingly.
The researchers recorded electrical impulses from the brain while the mice performed this task, focusing on the prefrontal cortex, which is involved in executive functions such as planning and decision-making, and the parietal cortex, which processes sensory information and plans movement.
After measuring electrical activity from thousands of neurons, the researchers performed computational analyses that allowed them to identify groups of neurons that encode specific pieces of information.
They focused on two time periods — the time between the first and second tone, when the animals are holding a memory of the first tone, and the time between the second tone and the point where they have to decide on an action. During that second period, the animals are holding their decision and action plan in their working memory.
Within the parietal cortex, the researchers found that neurons appeared to exclusively store memory of the tone. But in the prefrontal cortex, they identified a cluster of neurons that could switch between the two types of memory. During the first period, they stored a memory of the first tone, but during the second, they were responsible for remembering the plan of action.
Re-using these clusters for different purposes allows the animals to flexibly store different types of information, the researchers say.
“When mice do tasks that test whether memory computations can be reused, the answer is they are. There are subspaces of functional activity in the prefrontal cortex that can be the substrate of mixing and matching toward flexible cognition,” Sur says.
Computational flexibility
The new findings offer support for the idea that the same computational circuits can be used for different purposes, Buschman says.
“The main result from this study is that there’s a circuit in the brain that maintains items in working memory, and you can put either sensory or motor information into it, and flexibly reuse it depending on what your current task is,” he says. “This means you do not have to build an entire new circuit for holding information in mind every time you want to learn a new task.”
The researchers now plan to study whether inhibiting these modules during different parts of the task affects the animals’ behavior, which could offer additional evidence that the flexible modules they identified participate in a variety of functions.
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The research was funded by the National Institutes of Health, a MURI Grant, the Picower Institute Innovation Fund, the Japan Society for the Promotion of Science Overseas Research Fellowships, and the Uehara Memorial Foundation Postdoctoral Fellowship.
Journal
Nature Neuroscience
Article Title
Reusable modular architecture enables flexible cognitive operations in the mouse brain and artificial recurrent networks
Article Publication Date
17-Aug-2026
