Looking to the Brain to Understand Chronic Pain

New brain studies presented at a recent neuroscience conference show why the experience of pain is more than just a physical sensation. Image credit: 5505292/123RF Stock Photo.

Pain might feel like it’s happening in the body—when nerves are triggered by potentially harmful threats in the environment, such as extreme heat or cold, we know right where we feel the sensation. But activation of the nerves that detect those threats is only the first step on the road to pain. In fact, the experience of pain arises from complex nervous system activity that reaches across the brain, involving many different regions and circuits.

One way to put it is that pain is a whole-brain experience. Viewed in this light, pain—chronic pain in particular—is more than just a physical sensation. By its nature, pain makes a person withdraw, by removing a foot from a sharp object, for example, or a hand from a hot stove. Pain has emotional qualities too. It is associated with negative feelings that make us avoid future pain at all costs and help us to lay low while an injury heals. This avoidance is known as the aversive aspect of pain. And of course people have many thoughts about their pain.

Researchers, doctors and patients have focused on the sensory quality of pain—on how intense the sensation of pain is. But scientists are increasingly using new technologies to probe how the complex experience of pain arises in the brain, in hopes that a better understanding will lead to effective treatments.

Several labs presented the fruits of these investigations last November at the 2017 annual meeting of the Society for Neuroscience in Washington, DC, the world’s largest neuroscience conference for scientists and physicians seeking to understand the brain and nervous system. Much of this work is unpublished, so it has not yet undergone strict review by other researchers. It does, however, give an early glimpse from the cutting edge of pain research.

What we perceive and how we behave in the face of pain
Unpublished research presented by Laura Tiemann, from Technical University of Munich in Germany, is teasing apart three different components of acute pain: the perception of pain, the behavioral response to pain, and the workings of the autonomic nervous system (which works outside of conscious awareness).

To do so, Tiemann measures electrical signals produced in the brain. She uses electroencephalography (EEG), a common and noninvasive technique that records the activity of huge groups of neurons by using electrodes placed on the scalp.

“The signals can only be detected if millions and millions of neurons are acting together,” she said.

Tiemann and senior investigator Markus Ploner evoked pain in 51 healthy human subjects by applying a laser to the hand. Subjects were asked to rate their pain on a scale of zero (no pain) to 100 (the worst pain tolerable) as an indicator of the perceptual component of pain. They also had to withdraw their hand from a button they were pressing as soon as they detected pain—a measure of behavioral reaction time. Finally, the researchers measured the skin conductance response (SCR), the tiny sweating reaction that occurs with pain. The SCR is part of the autonomic response, which keeps body systems in balance.

“If someone is attacking you and you need to run away, for example, blood flow to the muscles will increase in preparation—that’s the autonomic response,” Tiemann told RELIEF.

As expected, study participants’ pain ratings were higher, their reaction times faster, and their SCR stronger when the laser was more intense.

While the laser was causing pain, the researchers recorded the EEG signals. “There are four different brain patterns—classic pain responses you always see” when using this type of pain stimulus, Tiemann said. The patterns are characterized according to when they appear following the stimulus.

Previous work showed that the EEG signals correlate with how intense subjects rate their pain, and with their reaction time, “but these were only correlations. We wanted to know, are they mechanistically involved in translation” of something painful into the perceptual, behavioral, and autonomic aspects of pain. That is, are these patterns of electrical signals reflections of the brain activity itself that gives rise to those aspects of pain?

Tiemann used a method of analysis that had not previously been applied to EEG studies of pain. This allowed her to determine which specific EEG patterns represented which components of pain. It turned out that behavioral and autonomic responses were brought about by the earliest wave of activity Tiemann detected, whereas pain perception was brought about by later patterns of activity.

“These findings show how brain responses play differential roles in the translation of a painful stimulus into the different components of pain,” she said.

Together, the results showed that painful stimuli are represented by at least three components—the perceptual, behavioral and autonomic—that are served by different but complementary patterns of brain activity that arise independently.

Compromising the brain’s “brake” on chronic pain
Researchers from New York University Medical School in New York City showed that rats with experimental inflammatory pain found painful stimuli even more aversive—that is, they were more likely to avoid those stimuli—than healthy animals were.

Jing Wang, who presented the unpublished research in a talk at the meeting, measured how aversive animals found a painful stimulus with a test called conditioned place aversion. Here, healthy rats had access to two connected chambers for ten minutes, and initially spent about half the time in each chamber. After a so-called conditioning phase when they received a painful pinprick in one chamber, the animals then avoided that chamber during a ten-minute test period. That indicated the rats found pain aversive, Wang said.

Next, a different group of rats received an injection of an inflammatory substance into one paw (a commonly used animal model of chronic inflammatory pain) and then underwent conditioning with a painful pinprick to the uninjured paw. Here, “the rats avoided the painful chamber even more than those without injury, demonstrating generalized pain aversion,” Wang said.

To explain these findings, Wang looked to the prefrontal cortex (PFC), an important brain area that provides a brake on both the physical and emotional components of pain. That brake is compromised by chronic pain, Wang showed.

The researchers recorded the electrical activity of neurons in the PFC in healthy live animals while giving them a painful poke to the paw. About a third of the neurons responded to the poke. But after inflammatory injury, a poke to the opposite, uninjured paw elicited responses from only 20 percent of PFC neurons, showing they were less responsive under chronic pain conditions. Wang said that chronic pain also reduced the normal resting firing rate and electrical excitability of individual neurons, and their ability to respond to acute pain stimuli such as a poke.

In his presentation, Wang told the audience that chronic pain reduces nerve cell activity within the PFC, “but we can turn up the gain on the PFC with optogenetics,” meaning that they could experimentally boost activity of the neurons. He was describing technology that allows scientists to control the electrical excitability of genetically engineered neurons by shining light on them (see a related RELIEF feature to learn more about optogenetics.)

In this case, the researchers stimulated PFC neurons with just enough light to make the cells more electrically excitable. “The neurons increased their firing rate and response to acute pain,” Wang said.

The researchers then used the conditioned place aversion test to see if activating the neurons in the PFC relieved pain’s aversive quality in the rats. They used light to stimulate the PFC during a conditioning phase in one chamber. The animals preferred to stay in the chamber in which they received PFC stimulation, indicating that activating the cells relieved not only the sensation of pain but also its aversiveness, Wang said.

The finding that stimulating the PFC improved pain aversion led Wang to speculate that low-intensity brain stimulation might relieve acute and chronic pain—an idea that has some evidence behind it.

“Maybe one day in the future we could use tDCS [transcranial direct current stimulation] in humans to stimulate PFC activity,” he said. Here Wang was referring to a noninvasive brain stimulation technique used in people to treat depression and Parkinson’s disease.

Update: Green light is a go in people
An even simpler pain treatment could be within easy reach. Researchers led by Mohab Ibrahim at the University of Arizona in Tucson presented an update on their work using a readily available green light to relieve pain (see RELIEF related news story).

The group had previously shown that rats exposed to ambient green light for eight hours per day for five days had increased pain tolerance, as the animals were able to keep a paw on a hot surface longer than rats that did not receive such treatment.

The researchers had also confirmed that this pain-relieving effect of green light depended on the visual system. They showed this by outfitting the rats with tiny contact lenses that stopped light from entering the eyes, which prevented the beneficial effect on pain. Animals with green contact lenses, which pass light only in the green wavelength, also showed reduced pain, confirming the role of the visual system.

At the meeting, the researchers reported that patients with either migraine or fibromyalgia lowered their pain rating from about an average of seven (out of ten) before treatment with green light to about a three after light exposure. Subjects used the lights daily for ten weeks, with benefits emerging after about three weeks.

“They showed about a 60 to 70 percent improvement,” Ibrahim said of these patients.

The patients were exposed to green light from a light-emitting diode (LED) strip—similar to those used for party and kitchen lighting—for an hour to two hours each evening at their home. Control subjects received white light strips to use at home. Each week, the study participants filled out five different surveys to report their pain, quality of life and daily activity, which revealed the beneficial effect of green light.

“You need to be in a dark room with no light pollution, no screens,” Ibrahim said. “But as long as your eyes are open, you can read, meditate, or just relax.”

Though the study has yet to be published and is small, with only seven test and four control subjects reported so far, another ten are still undergoing testing. But the results are clear, Ibrahim told RELIEF.

“The patients that got the green light improved, while white light had no effect.” Most of the study subjects opted to keep the green light at the end of the ten weeks.

The researchers will test the treatment in patients with other types of chronic pain. “It’s possible that only certain types of pain will respond to this,” Ibrahim said.

People with migraine often have photophobia, or painful sensitivity to light. While bright white lights have been used to treat depression, the therapeutic benefits of colored, low-level light of the sort used in Ibrahim’s study are new.

How green light works to relieve pain remains unknown. But researchers speculate that the light somehow signals to brain areas through light-sensitive neural pathways in the visual system (neural pathways are connections between neurons that allow electrical signals to be sent from one area of the brain to another). In this case, these pathways are associated not with visual images but with the circadian rhythm (the day-night cycle), which depends on light passing through the eyes.

Read additional reports from the meeting:

The Leading Edge of Personalized Pain Medicine: Tuning the Channel

The Role of Diet in Chronic Pain: You Are What You Eat?

Speaking Up for Science

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.