Manipulating nerves to relieve pain without drugs

As an MIT-trained scientist, John Rogers has a lot of practice solving problems. Now a biomedical engineer and materials scientist at Northwestern University, Rogers studies soft materials that can be molded into wires, membranes, and tubes for different biological applications. 

While tackling everyday research challenges, Rogers noticed a major problem affecting society at large — poor pain management options — and wondered if his unique materials could provide a solution. “There’s an epidemic around opioids as painkillers due to their extreme addictive nature,” he said. “Our motivation is to develop alternatives that might be as effective and may actually offer advantages to more traditional pharmacological approaches.”

Pain is a shared symptom of a wide range of injuries and diseases, but drugs that dull pain can lead to tolerance and side effects. Opioid misuse and overdose rates are so high that the US Department of Health and Human Services declared the opioid crisis a public health emergency in 2017 (1). 

The severe shortcomings of standard pain medications have inspired researchers like Rogers to devise new ways to treat pain, including delivering thermal, electrical, or mechanical pulses that alter neural activity and pain signaling. Some researchers have developed devices that target a peripheral nerve to treat local pain, while others explore methods to modulate neurons in specific brain structures to manage more widespread sources of pain. By harnessing concepts from air conditioning to ultrasound, they hope to provide better solutions for both acute postoperative pain and chronic pain disorders. 

In the periphery 

Rogers set out to solve the problem of pain management after surgery. In a recent study in Science, he and his team reported a dissolvable cooling ribbon that wraps around a peripheral nerve for postoperative pain relief (2). The device’s icy grip produces a cooling sensation that slows down signaling between nerves to numb pain. “If you've ever been outside on a cold day without gloves on, you have experienced a kind of numbness in your fingertips,” Rogers said. “We're trying to exploit those same types of effects, but delivered into the depths of tissues at locations of peripheral nerves that are carrying pain signals from an injured site across the body.” 

Delivering a cooling effect to specific peripheral nerves is a significant engineering challenge. Traditional semiconductor-based technologies require bulky, rigid materials that can’t move with the soft tissues of the peripheral nervous system. A flexible device with microfluidic channels that could transport a cooling fluid to the nerve would be more compatible, but simply using a precooled liquid wouldn’t work. “It’s very difficult to keep the fluid cool as it moves through tissues before it arrives at the targeted location,” Rogers explained. “You end up cooling all sorts of parts of the body that you don't want to cool, and the amount of cooling power that you're left with at the position of the nerve is many times insufficient.”

 To solve this problem and produce the cooling effect directly at the site of the nerve, the researchers turned to an evaporative cooling mechanism similar to that of an air conditioner. In their strategy, perfluoropentane (a liquid with a low boiling point) snakes through the ribbon until it reaches a chamber at the site of the nerve. There, it meets nitrogen gas delivered through a separate microfluidic channel, causing the liquid to evaporate and absorb heat.

The cooling power can be increased or decreased by adjusting the flow rate of the liquid and gas, providing control over the level of relief. The device also includes a sensor that monitors temperature to alert a patient or doctor to excessive cooling, that could block motor signaling and cause permanent nerve damage.

The device is made from a dissolvable, biocompatible elastic polymer that breaks down over the course of several weeks. This timeline allows it to function for a standard postsurgical recovery period without an additional procedure to remove it. How fast or slow it degrades can be tuned by the composition and thickness of the materials used to construct it, and future generations of the device might include some sort of trigger to initiate the dissolution process.

The team tested their device in a rat model by applying it to the rat’s sciatic nerve, which runs down each leg. They found that when the device cooled the nerve environment to 10 degrees Celsius, a seven-fold greater force was required to cause the rat to retract its paw from a poke. They observed no effect on the opposite side of the body where the sciatic nerve was not cooled, demonstrating that the device disrupted peripheral nerve signaling only at the desired site.

“This is still early-stage research,” Rogers said. “We have some really convincing small animal model studies, but we need to expand the scope of those studies. We then need to move the technology into larger animals that are more at a human scale before we'll be able to think about trials in humans.” 

In its current state, the device requires the patient to be tethered to an external liquid handling system similar to an IV. While appropriate for postoperative recovery, the researchers would like to make this hardware portable like an insulin pump to treat chronic peripheral nerve pain. But adapting the technology for this application presents many more problems to solve. The researchers would need to find a way to shrink the pumping system, use a mobile power source, and recycle the fluid for the evaporative cooling mechanism. “Chronic pain is an incredible challenge and may be an opportunity also for engineered device-oriented approaches. And so we're trying to see what we can do along those lines as well into the future,” Rogers said. 

Devices that deliver electrical pulses rather than cooling to treat chronic peripheral nerve pain are already being used in humans. Electrical stimulation can “change the way the nerve conducts or the way the signal delivers to the spine or brain,” said Timothy Deer, an interventional pain specialist at the Spine and Nerve Centers of the Virginias who was not involved in Rogers’ study. 

To treat pain that’s local to a peripheral nerve, peripheral electrical stimulation devices can be surgically implanted in a minimally invasive procedure at the site of the pain using ultrasound to identify the nerve. How long the device stays in depends on the nature of the nerve pain and the fact that in some people, electrical stimulation of a peripheral nerve may reprogram the way the brain processes pain signals over time, allowing short-term treatment to have long-lasting effects. While researchers aren’t yet sure how this feedback mechanism unfolds in humans, animal studies have demonstrated changes in the activity of the prefrontal cortex and limbic system after stimulation of peripheral nerves (3). 

While these devices represent a widely explored and viable approach, “in many cases, the electrical stimulation itself can be a source of pain, especially in that initial startup phase of stimulation,” Rogers said. “But there may be opportunities to combine the two. You might be able to use cooling to reduce the voltages to reach a threshold for electrical blocking of pain signals.”

The experience of pain at the onset of electrical stimulation depends on the device’s settings, Deer said. Many newer devices “work at different frequencies and different waveforms, so you don't feel tingling at all.” Once evidence of the efficacy of cooling has been established in humans, he agrees that the two stimuli could be combined. 

In clinical studies, 80% of people showed positive long-term responses to electrical peripheral nerve stimulation (4). Deer hopes that these devices can prevent the need for extended pain drug administration, which is expensive and can lead to liver and kidney damage, and provide a solution for people who have developed resistance to pain medication over time or are at risk of addiction. 

Pain in the brain

To expand targeting to treat more diffuse pain, other researchers move straight to the center, seeking noninvasive methods to apply stimuli to modulate neural activity in the brain. For example, transcranial magnetic stimulation uses an external electromagnetic coil to generate fluctuating magnetic fields that alter neuron firing. Similarly, transcranial direct current stimulation relies on electrodes applied to the scalp to produce electrical currents that affect neural signaling. While these techniques show promise for treating neurodegenerative and depressive disorders, they have limited spatial precision and can only penetrate a few centimeters into the brain (5). 

Now, researchers are exploring low-intensity transcranial focused ultrasound as a strategy for pain management. While its millimeter-scale resolution and strong depth penetration are beneficial for imaging, these features also allow ultrasound to specifically access deep brain structures involved in pain that have previously evaded noninvasive approaches. To identify regions of the brain that regulate different types of pain to target with ultrasound, researchers can measure brain activity using techniques such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG).  

“The mechanisms of how ultrasound works on a cellular, molecular level are being more and more understood every day,” said Wynn Legon, a neuroscientist at the Fralin Biomedical Research Institute at Virginia Tech Carilion. “It's somewhat counterintuitive that mechanical energy, which is what ultrasound is, affects the brain, which is essentially an electrochemical organ. Lots of work is now being done showing that a lot of these electrochemical receptors and channels are mechanically sensitive. And so this is how ultrasound likely exerts its influence on neuronal activity.”

In a recent study in Nature Communications, researchers at Carnegie Mellon University reported that by tuning a specific frequency parameter of the ultrasound waves, they could selectively stimulate either excitatory or inhibitory neurons in the somatosensory cortex (6). Excitatory neurons showed higher activity when this parameter was increased, motivating the team to further study the effects of ultrasound frequency on pain.  

In that study, the researchers used a mouse model of sickle cell disease, which can cause widespread pain due to clumping misshapen blood cells, lack of oxygen in the blood, and inflammation. When they applied low-frequency ultrasound to the somatosensory cortex, the mouse showed increased tolerance for a heat stimulus within minutes, indicating effective and rapid pain suppression. However, when they used a high frequency, the mouse retracted its paw more quickly, suggesting that the ultrasound treatment actually increased pain. “We found that ultrasound stimulation frequencies are very sensitive for pain sensation control,” said Bin He, a neuroengineer at Carnegie Mellon University. “So that means to consider clinical translation, this needs to be carefully studied and managed.”  

Legon is exploring the potential of ultrasound to relieve pain by targeting the insula, a brain structure implicated in chronic pain in conditions like fibromyalgia. He delivers a safe pain stimulus to human volunteers and evaluates the effects of ultrasound treatment on their brain activity (measured with fMRI and EEG) and self-reported pain scores. Preliminary, small-scale experiments revealed ultrasound parameters that suppressed neural firing in the insula and yielded modest decreases in perceived pain. After further testing, Legon plans to conduct a trial in fibromyalgia patients to assess the effects of ultrasound treatment on long-term pain metrics and quality of life. 

As far as using this technology for chronic pain treatment, there are many details to sort out, Legon said. “Just as it is with drugs — they have a certain lifespan before you need to take another one — we have the same issue in this noninvasive neuromodulation field,” he said. “How often do you have to dose? How much do you have to dose, and how long does it last? What is the best, most efficient, most efficacious way to deliver this intervention? It's an ongoing area of research.” 

For He, the goal is a wearable helmet that delivers ultrasound to the brain for on demand pain relief. “I wish eventually that such a helmet would be available in every household, just like people play video games or computer games,” he said. “And then if you feel pain, you put on the helmet, you push the button for 10 minutes, and then you treat to the pain for that day, or maybe after a series of treatment, the pain will be gone.”

References

1. U.S. Department of Health and Human Services. What is the U.S. Opioid Epidemic? At < https://www.hhs.gov/opioids/about-the-epidemic/index.html>. 
2. Reeder, J.T., et al. Soft, bioresorbable coolers for reversible conduction block of peripheral nerves. Science  377, 109-115 (2022). 
3. Deer, T.R. et al. A review of the bioelectronic implications of stimulation of the peripheral nervous system for chronic pain conditions. Bioelectron Med  6, 9 (2020). 
4. Deer, T. et al. Prospective, multicenter, randomized, double-blinded, partial crossover study to assess the safety and efficacy of the novel neuromodulation system in the treatment of patients with chronic pain of peripheral nerve origin. Neuromodulation  19, 91-100 (2016). 
5. Yu, K., Niu, X., & He, B. Neuromodulation management of chronic neuropathic pain in the central nervous system. Adv Funct Mater  30, 1908999 (2020).  
6. Yu, K., Niu, X., Krook-Magnuson, E., & He, B. Intrinsic functional neuron-type selectivity of transcranial focused ultrasound neuromodulation. Nat Commun  12, 2519 (2021).