Spinal cord stimulation may help diabetic neuropathy.

Spinal cord stimulation may help diabetic neuropathy
Spinal cord stimulation may help diabetic neuropathy


People with painful diabetic neuropathy may be able to get relief from high-frequency spinal cord stimulation, according to a preliminary study released today, February 28, 2023, that will be presented at the American Academy of Neurology’s 75th Annual Meeting being held in person in Boston and live online from April 22-27, 2023.

Diabetic neuropathy is nerve damage due to diabetes and can lead to pain and numbness, most often in the hands and feet. About 25% of the 37 million Americans with diabetes have painful diabetic neuropathy.

“Diabetic neuropathy often results in poor quality of life, depression, anxiety and impaired sleep, and the available medications can be ineffective for many people or have side effects that people can’t tolerate,” said study author Erika Petersen, MD, of the University of Arkansas in Little Rock. “These results are exciting because there is an urgent need for more effective therapies.”

The study involved 216 people who had painful diabetic neuropathy symptoms for at least one year that were not responding to medications. Half of the people received spinal cord stimulation plus regular medical treatment for six months. Half received only regular medical treatment. After six months, people had the option to switch to the other treatment. People were followed for a total of two years.

Spinal cord stimulation involves a device that is implanted under the skin. The device delivers electrical stimulation to the spinal cord to cut off pain signals to the brain.

After six months, the people who received stimulation reported 76% decrease in their average pain amount, while the people who did not receive stimulation had a 2% increase in their average amount of pain. In tests of their motor function, sensation and reflexes, improvements were seen in 62% of those receiving stimulation compared to 3% of those receiving medication only.

A total of 93% of those receiving medication only and eligible to cross over chose to receive the stimulation after six months, while none of those receiving the stimulation wanted to receive medication only.

After two years, people reported 80% improvement in their average pain amount, and 66% continued to have improvement in motor function, sensation and reflexes.

None of the participants had their devices removed because they were not effective. Eight people had infections related to the device. Three of those cleared up and five people, or 3%, had their devices removed due to infection, which Petersen said is within the range reported for people receiving spinal cord stimulation for other conditions.

Petersen also noted that the high-frequency stimulation appears to provide greater pain relief than low-frequency stimulation. High-frequency stimulation also does not create the “pins and needles” sensation that comes with low-frequency stimulation.

“This study demonstrates that high-frequency stimulation provides long-term pain relief with acceptable safety,” Petersen said. “The improvements in motor function, sensation and reflexes suggest that this therapy could have disease-modifying potential.”

Petersen said, “Confirmation of results through studies in larger groups of people could further strengthen our understanding of this spinal cord stimulation therapy for the treatment of painful diabetic neuropathy.”

Research paves the way to early diagnosis of diabetic neuropathy

Diabetics exert less force to hold an object than people with other diseases that affect the nervous system. Grip force is a key behavioral biomarker to detect incipient diabetic neuropathy

Grip force is a key behavioral biomarker to detect incipient diabetic neuropathy CREDIT Paulo Barbosa de Freitas Júnior

Research conducted at Cruzeiro do Sul University in São Paulo, Brazil, can contribute to earlier diagnosis of diabetic neuropathy, a disorder characterized by damage to peripheral nerves, with symptoms such as pain and paresthesia (pricking, burning and numbness), mainly in the legs and feet.

In the study, a group led by Professor Paulo Barbosa de Freitas Júnior measured grip force in diabetic patients while they were holding and handling objects. The results were compared with data for healthy subjects and patients with other neurological diseases, such as multiple sclerosis, Parkinson’s, and carpal tunnel syndrome (pain, numbness and tingling in the hand and arm caused by a pinched nerve in the wrist).

Freitas and his group tested volunteers to measure the grip force exerted by diabetics with and without a diagnosis of neuropathy, as well as healthy subjects, and developed a methodology that can be used to produce equipment for use in clinical practice. In future, the innovation should help physicians diagnose the disorder quickly and easily not long after the onset of initial symptoms of neuropathy in diabetics.

The analysis focused on grip force used to hold and manipulate objects, and on relative safety margin, i.e. grip force normalized by the coefficient of friction between skin in contact with the object and surface of the manipulated material. The central nervous system “calculates” the amount of force needed to hold an object, learning to do so better over time. “Every object has a contact surface with which our fingers create friction when we hold it. The smoother the surface, the more grip force needed to hold it. If it’s rough, we can use less grip force thanks to friction,” Freitas explained.

Considering grip force and safety margin, people with neurological disorders such as multiple sclerosis and Parkinson’s tend to use more force to grip objects than healthy people. The force needed to manipulate an object is moderately greater than the minimum force needed to hold it in the desired position. “In the case of people with neurological alterations, our hypothesis is that they grip objects more strongly as a conservative strategy,” Freitas said. “The nervous system detects a neurological deficiency and sends a command for the hand to use more force as it grips the objects. This process is entirely unconscious, of course.”

The test results showed that healthy volunteers used between 100% and 120% of the minimum force required to hold an object, whereas the force used by participants with neurological alterations was two and a half times to three times greater.

Freitas and his team then investigated the performance of diabetics, who typically suffer from neuropathy as the disease worsens. “There was no prior research on diabetics involving the type of experiment we used in our study,” he said.

The hypothesis was that diabetics would grip objects more tightly, as is the case with people who suffer from carpal tunnel syndrome, multiple sclerosis and Parkinson’s. “However, what we found was the opposite: diabetics used half as much force to hold an object as controls in the simplest task, which was the static test, in which the subject merely has to hold an object without manipulating it,” Freitas said.

An article published in the journal Human Movement Science reports the main findings of the study, which was funded by FAPESP via a Regular Research Grant and a scientific initiation scholarship.

Calculating grip force

Three types of test were conducted with 36 volunteers, including 24 diabetics divided into two groups: 12 who had developed neuropathy, and 12 who had neither been diagnosed with neuropathy nor displayed clinical signs of the disorder. The other 12 participants were healthy and formed the control group. Before testing began, the researchers measured each participant’s skin sensitivity, since the sense of touch is a key factor in conveying to the central nervous system the information required by the brain to calculate the force needed to hold and manipulate objects.

Volunteers were each asked to perform three tasks using the same type of object instrumented to measure force. In the static holding test, they had to hold the object with their dominant hand as if they were holding a glass of water. A beep sounded after ten seconds, and they were to unclasp their fingers slowly so as to release the object, while a researcher measured the friction between the fingers and the object. The second task consisted of picking up an object from a table, lifting it about 5 cm, holding it for 10 seconds, and putting it back on the table. In the third task, termed oscillation, the volunteers had to grasp the object, hold it in front of their navel, and move it about 20 cm up and down for 15 seconds.

In the second and third tasks, the results for diabetics and diabetics with neuropathy were similar to those for controls. The surprise came in the simplest task of all, which was static holding, as diabetics and diabetics with neuropathy used half the force applied by the controls.

The explanation is not exactly a loss of sensitivity in the fingers of diabetics, the researchers explained, but deficient tactile information sent from their fingertips to the central nervous system. There is not enough information of high quality for the brain to make the requisite calculations and the hand to use the right amount of force. “In addition, there are studies showing that certain areas of the spinal cord and cortex that receive and process this sensory information are smaller in diabetics than in healthy people,” Freitas said.

The study suggests diabetes does not only affect the periphery of the body, causing loss of sensitivity in the toes and fingers, for example, but also affects the central nervous system. “This happens early in diabetes. People tend to think these complications happen only after a certain age or when a person has had diabetes for some time, but actually patients have the problem before neuropathy is diagnosed,” Freitas said.

Novel device for rapid early diagnosis

Scientists do not fully understand what causes neuropathy in diabetics. One hypothesis has to do with neuron death or loss of function due to alterations in blood vessels and metabolism. “Because of metabolic alterations, blood doesn’t reach the nerve ends in the soles, palms, toes and fingers, leading to the death of neurons in these peripheral regions,” Freitas surmised. As the disease progresses, neurons in other regions closer to the torso, knees and so on, also suffer damage and may die.

Given this lack of knowledge, prevention is the best option, and the study discussed here will help in this regard, according to Freitas. “Our research provides a foundation on which a simple device could be developed for use in the doctor’s office with rapid results,” he said. Grip and load force can serve as behavioral biomarkers to detect neurological alterations even before the patient manifests clear symptoms of neuropathy. “The idea is to have a device that enables physicians to measure force in a straightforward test and see if the patient shows signs of incipient neurological alterations.”

Neuropathy is currently diagnosed by means of a painful invasive examination using a technique called electroneuromyography, in which an electric current is passed through small electrodes in the shape of needles inserted into the patient’s muscles and the reaction time is measured to assess nerve conduction velocity. Freitas proposes a procedure that can be used during a regular visit to the doctor. The patient would hold an object instrumented to measure grip force. “After 10 to 15 seconds of this test, the physician would have the result: the object was held with this or that level of force, and the value measured is below or above the level considered safe to the act of holding the object. It could evidence neurological alterations arising from diabetes,” he said.

The next steps envisaged by Freitas include developing the instrumented object for use in such testing, which could be simpler than the one used in research. To do so, he needs to determine the best combination between the object’s weight and surface smoothness or roughness, so as to evidence the difference between diabetics and nondiabetics. “We need various combinations of smoothness and roughness, as well as lighter and heavier weights, in order to measure the differences between the combinations, and choose the best for use in future tests,” he said. He is pursuing partnerships with hospitals and companies interested in participating in the development of a solution, as well as volunteers for forthcoming studies. He can be contacted at Paulo.deFreitas@cruzeirodosul.edu.br or defreitaspb@gmail.com.

Scientists find new cell type implicated in chronic nerve pain, inflammation

Spinal cord illustration of pro-inflammatory cells (red) and anti-inflammatory MRC1+ macrophages (blue). CREDIT Zylka Lab, UNC School of Medicine

 One of the hallmarks of chronic pain is inflammation, and scientists at the UNC School of Medicine have discovered that anti-inflammatory cells called MRC1+ macrophages are dysfunctional in an animal model of neuropathic pain. Returning these cells to their normal state could offer a route to treating debilitating pain caused by nerve damage or a malfunctioning nervous system.

The researchers, who published their work in Neuron, found that stimulating the expression of an anti-inflammatory protein called CD163 reduced signs of neuroinflammation in the spinal cord of mice with neuropathic pain.

“Macrophages are a type of immune cell that are found in the blood and in tissues throughout the body. We found a class of anti-inflammatory macrophages that normally help the body to resolve pain. But neuropathic pain appears to disable these macrophages and prevent them from doing their job,” said senior author Mark Zylka, PhD, director of the UNC Neuroscience Center and Kenan Distinguished Professor of Cell Biology and Physiology. “Fortunately they don’t appear to be permanently disabled, as we were able to coax them to ramp up their anti-inflammatory actions and reduce neuropathic pain. We suspect it will be possible to develop new treatments for pain by boosting the activities of these macrophages.”

Roughly one-fifth of the U.S. population has chronic pain, according to the Centers for Disease Control and Prevention. Often the underlying causes are elusive, and patients need pain alleviated so they can function in life. While opioids are great at treating pain in the short term, these drugs can have severe side effects when used for extended periods, such as addiction, respiratory depression, dizziness, nausea, and death due to overdose.

One reason why strong pain relievers work well but can have dramatic side effects has to do with a basic biological fact: pain involves a highly diverse set of cells and current treatments lack cell type specificity. So, any given medication may resolve adverse changes in some cells to alleviate pain, but the medication might exacerbate a particular function in other cells, leading to adverse side effects.

With an emerging technology called single-cell RNA-sequencing, scientists can now interrogate thousands of cells at once to see which cells are altered during chronic pain, and in which ways the cells change.

“Knowing which cells to target allows us to design very specific therapies. Targeted therapies in theory should have fewer adverse side-effects,” said Jesse Niehaus, graduate student in the Zylka lab and first author of the Neuron paper.

To figure out which cells were changing and in what ways, Zylka’s lab performed single-cell RNA-sequencing on the spinal cords of mice with neuropathic pain, a type of chronic pain caused by nerve damage. The spinal cord undergoes many long-term changes that contribute to neuropathic pain.

From those experiments, the researchers found a population of anti-inflammatory cells called MRC1+ macrophages that were dysfunctional.

“This was incredibly interesting because long-term inflammation in the spinal cord is commonly seen in animals with neuropathic pain,” Niehaus said.

With the identity of the cells revealed, Zylka’s lab delivered a gene therapy designed to stimulate the expression of an anti-inflammatory protein called CD163 in MRC1+ macrophages. With this approach, a single treatment reduced spinal cord inflammation and relieved pain-related behavior for up to a month.

“This discovery is quite exciting,” Zylka said, “As it immediately suggests multiple distinct ways to boost the function of these macrophages. Any one of these therapeutic approaches could provide a more precise way to treat neuropathic pain.”

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