Wynn Legon (left), the faculty director of the transcranial MR-guided focused ultrasound facilities at the Fralin Biomedical Research Institute, and Andrew Strohman, an M.D.-Ph.D. student at Virginia Tech, were among researchers reporting that application of low-intensity focused ultrasound to an area deep within the brain may potentially help people cope with chronic pain. The research was published in the Journal of Neuroscience. Photo by Clayton Metz for Virginia Tech.

Virginia Tech researchers at the Fralin Biomedical Research Institute at VTC report that applying low-intensity focused ultrasound to an area deep within the brain may point to new ways to help people cope with chronic pain.

In a study showing published in the Journal of Neuroscience, scientists demonstrated the effectiveness of using low-intensity focused ultrasound to modulate the activity in a critical region in the brain that processes and regulates pain signals. 

Researchers, including first author Andrew Strohman, a Virginia Tech M.D.+Ph.D student at the Fralin Biomedical Research Institute, found the application of low-intensity ultrasound to a structure known as the dorsal anterior cingulate cortex reduced pain, diminished bodily responses to pain, and decreased pain-related brain activity without the need for invasive procedures, researchers said.

“This study points to a non-invasive and effective way to modulate a critical region of the brain involved in pain processing, while eliminating many of the risks associated with surgeries,” said Wynn Legon, assistant professor at the Fralin Biomedical Research Institute and senior author of the study. “It provides a potential new means to modulate the brain activity in response to pain that may serve to better understand the mechanisms of chronic pain to provide a new, innovative therapeutic option that could change how we approach and treat pain in the future.”

In a study with 16 healthy volunteers, researchers focused ultrasound energy on the dorsal anterior cingulate cortex to see if it could change how people feel pain. To test whether it changed someone’s perception of pain, they applied brief heat to the skin and measured pain perception, heart rate variability, skin responses, and brain electrical signals.

Data were collected in three sessions on three separate days along with an imaging visit consisting of an anatomical computerized tomography (CT) and structural magnetic resonance imaging (MRI) to accurately and reliably target this hard-to-reach area in each individual.

The results showed that the ultrasound made people feel less pain, and it also altered how the brain and heart communicate. Overall, the heart did not respond as strongly to pain, and certain brain signals changed. 

“Chronic pain patients often experience cardiovascular issues, which may either be at the root of their chronic pain or play a role in contributing to it,” said Legon, who is also an assistant professor of the School of Neuroscience of the College of Science and in the VTC School of Medicine Department of Neurosurgery. “Understanding this intricate relationship is crucial, because it enhances our comprehension of pain mechanisms and suggests the importance of addressing both pain perception and cardiovascular health.”

The results suggest that using ultrasound applied to this specific region of the brain may help reduce pain and change how the body reacts to pain. 

More recently, in a study published in the journal PAIN on Feb. 5, the researchers found soundwaves from low-intensity focused ultrasound aimed at a brain region called the insula can also reduce the perception of pain and other effects.

“This study provides some of the first evidence we can change three major areas of activity, those being pain perception, brain activity, and cardiac activity,” Strohman said. “The next steps are to look at how these metrics relate to each other and explore how these findings can be applied to improve the lives of patients suffering from chronic pain.”

“While there has been tremendous progress in recent years in the use of high intensity focused ultrasound for creating small lesions in patients’ brain to treat disorders such as essential tremor and for tumor ablation, we are at the very beginning of exploration of the use of low intensity focused ultrasound to mildly modulate brain activity and affect perception and behavior,” said Michael Friedlander, executive director of the Fralin Biomedical Research Institute, who was not involved with the study. 

“The new work by Strohman and Legon and their pioneering team represents some of the most exciting new advances of this approach,” added Friedlander, who is also Virginia Tech’s vice president for health sciences and technology.  

“The fact that it is addressing one of the most debilitating diseases, chronic pain, represents a major step in this important emerging field of biomedical research and provides hope for better treatments that may avoid the untoward effects of many drugs used for treating pain,” Friedlander said. 

Research Assistant Brighton Payne, medical student Alexander In, and M.D.+Ph.D. student Katelyn Stebbins of the Legon lab at the Fralin Biomedical Research Institute contributed to the study.

A soft hydrogel fibre enables optogenetic pain inhibition during locomotion.  CREDIT Credit: Sabrina Urbina Villafranca

Scientists have a new tool to precisely illuminate the roots of nerve pain. 

Engineers at MIT have developed soft and implantable fibres that can deliver light to major nerves throughout the body. When these nerves are genetically manipulated to respond to light, the fibres can send pulses of light to the nerves to inhibit pain. The optical fibres are flexible and stretch with the body. 

The new fibres are meant as an experimental tool that can be used by scientists to explore the causes and potential treatments for peripheral nerve disorders in animal models. Peripheral nerve pain can occur when nerves outside the brain and spinal cord are damaged, resulting in tingling, numbness, and pain in affected limbs. Peripheral neuropathy is estimated to affect more than 20 million people in the United States. 

“Current devices used to study nerve disorders are made of stiff materials that constrain movement so that we can’t really study spinal cord injury and recovery if pain is involved,” says Siyuan Rao, assistant professor of biomedical engineering at the University of Massachusetts at Amherst, who carried out part of the work as a postdoc at MIT. “Our fibres can adapt to natural motion and do their work while not limiting the subject’s motion. That can give us more precise information.”

“Now, people have a tool to study the diseases related to the peripheral nervous system, in very dynamic, natural, and unconstrained conditions,” adds Xinyue Liu PhD ’22, an assistant professor at Michigan State University (MSU). 

Details of their team’s new fibres will be reported in a study appearing in Nature Methods. Rao’s and Liu’s MIT co-authors include Atharva Sahasrabudhe, a graduate student in chemistry; Xuanhe Zhao, professor of mechanical engineering and civil and environmental engineering; and Polina Anikeeva, professor of materials science and engineering, along with others at MSU, UMass-Amherst, Harvard Medical School, and the National Institutes of Health.

Beyond the brain

The new study grew out of the team’s desire to expand the use of optogenetics beyond the brain. Optogenetics is a technique by which nerves are genetically engineered to respond to light. Exposure to that light can either activate or inhibit the nerve, which can give scientists information about how the nerve works and interacts with its surroundings. 

Neuroscientists have applied optogenetics in animals to precisely trace the neural pathways underlying a range of brain disorders, including addiction, Parkinson’s disease, and mood and sleep disorders — information that has led to targeted therapies for these conditions. 

To date, optogenetics has been primarily employed in the brain, which lacks pain receptors, allowing for the relatively painless implantation of rigid devices. However, the rigid devices can still damage neural tissues. The MIT team wondered whether the technique could be expanded to nerves outside the brain. Just as with the brain and spinal cord, nerves in the peripheral system can experience a range of impairments, including sciatica, motor neuron disease, and general numbness and pain. 

Optogenetics could help neuroscientists identify specific causes of peripheral nerve conditions and test therapies to alleviate them. However, the main hurdle to implementing the technique beyond the brain is motion. Peripheral nerves experience constant pushing and pulling from the surrounding muscles and tissues. If rigid silicon devices were used peripherally, they would constrain an animal’s natural movement and potentially cause tissue damage.  

Crystals and light

The researchers looked to develop an alternative that could work and move with the body. Their new design is a soft, stretchable, transparent fibre made from hydrogel — a rubbery, biocompatible mix of polymers and water, the ratio of which they tuned to create tiny, nanoscale crystals of polymers scattered throughout a more Jell-O-like solution. 

The fibre embodies two layers — a core and an outer shell or “cladding.” The team mixed the solutions of each layer to generate a specific crystal arrangement. This arrangement gave each layer a specific, different refractive index, and together the layers kept any light travelling through the fiber from escaping or scattering away. 

The team tested the optical fibres in mice whose nerves were genetically modified to respond to blue light that would excite neural activity or yellow light that would inhibit their activity. They found that mice could run freely on a wheel even with the implanted fibre in place. After two months of wheel exercises, amounting to 30,000 cycles, the researchers found the fibre was still robust and resistant to fatigue, and could also transmit light efficiently to trigger muscle contraction. 

The team then turned on a yellow laser and ran it through the implanted fiber. Using standard laboratory procedures for assessing pain inhibition, they observed that the mice were much less sensitive to pain than rodents that were not stimulated with light. The fibers were able to significantly inhibit sciatic pain in those light-stimulated mice. 

The researchers see the fibers as a new tool that can help scientists identify the roots of pain and other peripheral nerve disorders.

“We are focusing on the fiber as a new neuroscience technology,” Liu says. “We hope to help dissect mechanisms underlying pain in the peripheral nervous system. With time, our technology may help identify novel mechanistic therapies for chronic pain and other debilitating conditions such as nerve degeneration or injury.”

An artistic representation of the interaction between the NaV1.7 sodium ion channel and collapsin response mediator protein 2 (CRMP2). The researchers identified a unique regulatory sequence in NaV1.7 that is required for NaV1.7 function. They found that this peptide disrupted the interaction with CRMP2 and reduced excitability in sensory neurons. The researchers then showed that this peptide relieved pain in animal models, demonstrating that this interaction can be targeted to ameliorate chronic pain. CREDIT Samantha Perez-Miller and Rajesh Khanna (New York University)

Researchers at NYU College of Dentistry’s Pain Research Center have developed a gene therapy that treats chronic pain by indirectly regulating a specific sodium ion channel, according to a new study published in the Proceedings of the National Academy of Sciences (PNAS).

The innovative therapy, tested in cells and animals, is made possible by the discovery of the precise region where a regulatory protein binds to the NaV1.7 sodium ion channel to control its activity.

“Our study represents a major step forward in understanding the underlying biology of the NaV1.7 sodium ion channel, which can be harnessed to provide relief from chronic pain,” said Rajesh Khanna, director of the NYU Pain Research Center and professor of molecular pathobiology at NYU Dentistry.

Chronic pain is a significant public health issue that affects roughly a third of the U.S. population. Scientists are eager to develop pain medications that are more effective and safer alternatives to opioids.

Sodium ion channels play a key role in the generation and transmission of pain, as they are critical for nerve cells, or neurons, communicating with each other. One particular sodium ion channel called NaV1.7 emerged as a promising target for treating pain following the discovery of its importance in people with rare, genetic pain disorders. In some families, a mutation in the gene that encodes for NaV1.7 allows large amounts of sodium to enter cells, causing intense chronic pain. In other families, mutations that block NaV1.7 result in a complete lack of pain.

Scientists have been trying for years to develop pain treatments to selectively block NaV1.7—with little success. Khanna has taken a different approach: rather than blocking NaV1.7, his goal is to indirectly regulate it using a protein called CRMP2.

“CRMP2 ‘talks’ to the sodium ion channel and modulates its activity, allowing more or less sodium into the channel. If you block the conversation between Nav1.7 and CRMP2 by inhibiting the interaction between the two, we can dial down how much sodium comes in. This quiets down the neuron and pain is mitigated,” said Khanna, the PNAS study’s senior author.

Khanna’s lab previously developed a small molecule that indirectly regulates Nav1.7 expression through targeting CRMP2. The compound has been successful in controlling pain in cells and animal models, and studies are continuing towards its use in humans. But despite the compound’s success, a key question remained: why does CRMP2 only communicate with the NaV1.7 sodium ion channel, and not the eight other sodium ion channels in the same family?

In their PNAS study, the researchers pinpointed a specific region within NaV1.7 where the CRMP2 protein binds to the sodium ion channel in order to regulate its activity. They learned that this region is specific to NaV1.7, as CRMP2 did not readily bind to other sodium ion channels.

“This got us really excited, because if we took out that particular piece of the NaV1.7 channel, the regulation by CRMP2 was lost,” said Khanna.

To limit the communication between CRMP2 and NaV1.7, the researchers created a peptide from the channel that corresponds to the region where CRMP2 binds to NaV1.7. They inserted the peptide into an adeno-associated virus in order to deliver it to neurons and inhibit NaV1.7. Using viruses to transport genetic material to cells is a leading approach in gene therapy, and has led to successful treatments for blood disorders, eye diseases, and other rare conditions.

The engineered virus was given to mice experiencing pain, including sensitivity to touch, heat, or cold, as well as peripheral neuropathy that results from chemotherapy. After a week to 10 days, the researchers’ assessed the animals and found that their pain was reversed.

“We found a way to take an engineered virus—containing a small piece of genetic material from a protein that all of us have—and infect neurons to effectively treat pain,” said Khanna. “We are at the precipice of a major moment in gene therapy, and this new application in chronic pain is only the latest example.”

The researchers replicated their findings inhibiting NaV1.7 function across multiple species, including rodents and the cells of primates and humans. While more studies are needed, this is a promising sign that their approach will translate into a treatment for humans.

“There is a significant need for new pain treatments, including for cancer patients with chemotherapy-induced neuropathy. Our long-term goal is to develop a gene therapy that patients could receive to better treat these painful conditions and improve their quality of life,” said Khanna.