USU Team Researches Brain’s Response, Adaptation to Pain After Amputation

Photo By Thomas Balfour | Laxmi Iyer, postdoctoral fellow in the School of Medicine at the Uniformed Services University, is part of the team using electrophysiological measurements and histology studies to locate the brain region of mice dedicated to whiskers. (Photo credit: Tom Balfour, USU)  

BETHESDA, MD, UNITED STATES

04.11.2023

Story by Hadiyah Brendel 

Uniformed Services University

In the U.S, 185,000 people undergo amputations each year. Whether resulting from traumatic injury or a medical condition, limb loss requires recovery, rehabilitation, and lifestyle changes. Recovery also includes pain management. Current pain management treatments may involve medication, physical and occupation therapy, or other methods. A large part of selecting and implementing successful treatment involves understanding from where the pain originates. Yet, pinpointing where in the body the acute and chronic pain of amputees originates from poses challenges. Therefore, a greater understanding of the brain, and the pain signals it sends, is pivotal in the approach to successful pain management.

Dr. Emily Petrus, assistant professor of Anatomy, Physiology and Genetics at the Uniformed Services University’s (USU) F. Edward Hébert School of Medicine (SOM) is studying how the brain adapts after injury. The study explores the mechanisms involved with pain following a loss of nerve supply (denervation) and amputation.
“If we understand how some people just don’t have pain, we could try to figure out how to get that to happen for everybody,” says Petrus.

Petrus’ research aims to understand why some amputation patients experience beneficial recovery while others experience pain conditions. Part of understanding pain processes involves looking at the brain after an amputation. Brain plasticity, or the process by which the brain adapts after injury, occurs after most amputation events. For example, after the loss of a hand, areas of the brain responding to sensory input from the missing hand are recruited to respond to the intact hand instead.

By identifying the neural “drivers of plasticity,” Petrus says, the research team attempts to find what “particular groups of cells might underlie the adaptations that motivate the brain to change.”

Since there is no set pathway the brain follows in restructuring after injury, there is no way to predict how the brain will respond to amputation.

“When we look at the functional activity of the brain with fMRI [functional magnetic resonance imaging],” says Petrus, “people who have phantom limb pain and people who don’t have fairly similar brain activity patterns.” Because there are no clear indicators for how the patient will recover, there is also no broadly beneficial intervention to provide care once an issue arises.

For some patients, rerouting of the brain’s functions results in enhanced sensory input from other areas.

“For example,” explains Petrus, “a person who lost an arm might learn to paint with their feet. So that's not learning to use a prosthetic, but that's a recovery in a different way to adapt to the injury.”

For others, the rerouting of the brain can result in hypersensitivity, referred pain, or phantom limb pain. Hypersensitivity, or hyperalgesia, is a dramatic increase in sensitivity to pain. Referred pain is when pain felt in one area of the body is actually originating from a different area; this can exhibit as lower back pain experienced as hip pain. Phantom limb pain is when the brain receives pain signals from an area of the body that is no longer there.

Petrus examines brain responses using mouse model whisker nerve bundles. For a mouse, whiskers aid in daily sensory activities equivalent to a person’s hands. Additionally, the mouse’s brain region devoted to whiskers is large. This larger area assists the team in locating the region during fMRI scans, electrophysiological measurements, which measure the electrical activity of neurons, and histology studies, staining and sectioning tissue for examination beneath a microscope.

Petrus says the research examines the brain to “characterize at the gene expression level, at the synaptic level, the neuron level, the circuit level, and the behavior level,” what changes occur. From this gene-expression approach, Petrus endeavors to understand the differences between populations who respond well to amputations and those who do not.

“If there was some kind of marker we could use–to either predict how people react or try to characterize what is underlining the good or the bad adaptation–we could modulate those adaptations to enhance beneficial recovery, or to reduce maladaptive problems,” says Petrus.

While this model does not enable categorization of either referred or phantom limb pain, it does allow understanding of the brain’s response in a different way. Petrus and her team also characterize the activity of brain cells following amputation.

“This activity is what yields the fMRI signal observed in both humans and mice. The goal is to locate the mechanisms that the neurons in the brain use to adapt to injury.”

A mouse model can lead to a better understanding of how the human brain responds to pain, or activates an effective recovery strategy.

“In a human,” says Petrus, “when you study their response to injury, you don't have the mechanism, you just can look at what the brain is doing, what the person is doing. But when you are using a mouse model, you can get all the way down to genes, receptors, and synapses. So you can really understand the mechanism.”

According to Petrus, once the mechanism is found, there is potential for treatments that approach pain management or recruit beneficial adaptations at the source. The theory is, after locating the specific cells or mechanisms that underlie these adaptations, they could be modulated, or changed, to enhance recovery.

“For example, if you put a magnet [on that area of the brain] and you pulse current through the magnet, it will turn on or off different parts of the brain,” Petrus says. By modulating the brain’s response, you may be “turning that brain region off, [and] maybe that pain perception could go away.”

Petrus’ goal is to one day utilize the results of her research to help people with limb loss through their rehabilitation and recovery, explaining that “one of the main reasons that [she] wanted to come to USU was the ability to know, in the future, if we found something really interesting in the mouse, to try to collaborate with people who work with humans.”

She is now in collaboration with Tawnee Sparling, an assistant professor in the department of Physical Medicine and Rehabilitation at USU. Petrus and Sparling are working on a review that bridges the gap between clinical observation and intervention and findings from animal models of amputation.

“Having that clinical-basic interaction is really important because if it's in a mouse that doesn't mean it works in a human. Looking at mouse models and human amputees, where do they intersect? Where do they not make sense? And what are the avenues that are maybe interesting to explore between the two models?” says Petrus. Studying the brain’s response to amputation at USU is a unique opportunity, where basic researchers like Petrus are able to collaborate and connect with both clinicians and patients.

• Date Taken: 04.11.2023
• Date Posted: 04.14.2023 08:01
• Story ID: 442623
• Location: BETHESDA, MD, US