When the hair rises on the back of your neck through a process called piloerection or something hurts so much your primitive response prompts you to run away, your body can completely block out pain to deal with the survival scenario at hand.
“Beautiful” is the word Luke Henderson, PhD, uses to describe this process, which is centered in a core region of the brainstem called the periaqueductal gray matter (PAG). The histology professor at the University of Sydney’s Brain and Mind Centre and his research colleagues have managed to map the PAG — and better understand its function. The results were published in Science.
And that’s just one recent discovery.
Multiple teams from institutions across the globe have delivered new research into the brainstem and how its concentrated circuitry may be leveraged for the Holy Grail of pain medicine: more effective nonaddictive treatments.
How Does One Map a Brainstem?
Henderson and his team used the power of 7 Tesla (7T) MRI — as well as a specific placebo design for participants — to map a deep area of the brainstem, the PAG, and the rostral ventromedial medulla.
The newly mapped region appears to be somatotopically organized, but crudely so. Leveraging analgesia response, researchers have found the PAG simply detects head pain or pain in the rest of the body — with no differentiation between the arm or leg, as can be found in other brain regions.
“You basically get a rostral activation when you do the face, and you get a caudal activation when you do the body,” said senior author Henderson, adding that the resulting map “makes sense because the idea of that map is to just drive a behavior, to drive a fight or a flee. It doesn’t tell you where [the pain] is. It doesn’t give you the perception that ‘it’s on my hand’ or ‘it’s on my leg.’ It’s not about perceiving it. It’s just about creating an automatic behavioral response.”
The findings’ potential is particularly geared toward treating head pain, such as migraine, Henderson said, because you wouldn’t want to block pain response to the entire lower body. The map could also unlock new neuromodulation opportunities and also guide cellular research for the development of targeted drugs.
“If you could design something that was nonaddictive and could actually target this area, then I think you would solve most pain,” Henderson said.
Using Placebo to Great Effect
Before asking 93 participants to remain extremely still for the 7T MRI scan, they were conditioned using a sham “lidocaine” application of petroleum jelly and exposed to varying intensities of heat stimuli to achieve a moderate pain level. The stimulus sites included the face, arm, and leg.
“You tell them you’re going to give them the same temperature on both, but you actually lower the temperature on the fake pain analgesic cream. So that’s the conditioning,” Henderson said.
Participants believed the sham cream works, and the responses were consistent during a second conditioning session. The researchers identified responders and nonresponders to the placebo analgesia for each stimulus site.
“And then you put them in the scanner, and you say, ‘Okay, I’m going to do exactly the same inside the scanner,’” Henderson explained. “But this time, instead of lowering the temperature on the pain-inhibiting cream, you just keep both temperatures the same.”
Matthew E. Fink, MD, chair of neurology at Weill Cornell Medical College in New York City (who was not involved with the study), said the placebo effect sizes were particularly compelling in themselves (d=0.55 for face, d=0.39 for arm, and d=0.67 for leg).
“An active drug works 50% of the time, and a placebo works 40% of the time. So that tells you immediately why it’s hard to find effective drugs approved for use to treat pain,” Fink said, adding that this study “gives us confirmation from neuroanatomy that the placebo effect for management of pain is a real effect.”
He called the new research “very difficult work,” noting how exceptionally still the participants themselves had to be for such a scan, even with the 7T MRI’s power.
“Preclinical work has been looking at the brainstem for a long time. It’s just human imaging hasn’t caught up,” Henderson said.
Until now.
“With the brainstem, everything is so tightly packed in, and if you move 2 mm to the left, you could be going from something that moves your tongue to something that moves your bowel,” Henderson explained.
By contrast, the scale in the cortex is in centimeters. The difference is important because image analyzation can happen much more quickly in the cortex. It’s bigger, and the software is more adept at matching up various-sized cortexes from different people. But the software “doesn’t do a very good job on the brainstem,” Henderson said.
For his brainstem work, Henderson got a little software help, but mostly it was manual tracing. He relished spending so much time with the brain region he has been fascinated by for 30 years.
“I just think it’s a genius part of the brainstem, and people in medicine think, ‘Oh, the PAG is just opiate analgesia,’ and it’s such a limited view of what the PAG does,” he said.
Using the New Unlocked Map
Other researchers are already poised to use Henderson’s map to further explore the potential for new pain treatments targeting the brain stem.
Theodore Price, PhD, a neuroscientist at the University of Texas at Dallas, just wrapped up two studies of human donor tissue analyzing the dorsal root ganglion, ventral horn, and spinal dorsal. The preprints are awaiting group publication with other work by members of the National Institutes of Health’s PRECISION Human Pain consortium. He said Henderson’s work positions his team to do similar cellular and molecular analyses if they secure human brainstem donor tissue.
Henderson’s Science paper demonstrates which “columns of cells within the PAG are probably the most important for some aspect of placebo analgesia, which we knew was neuroanatomically housed in the PAG in some way, but now we have more anatomical information about it,” Price said. “And although it wasn’t a main aim of the paper, it gives really good clues on which parts of the PAG are also likely to be involved in just endogenous opioid-induced analgesia and exogenous-induced opioid analgesia.”
“There have been questions for a long time whether those work in exactly the same way,” Price continued. “And the paper suggests to me that maybe they don’t. So I think that ultimately what we need to do is to profile these cells in more detail.”
Asking a Mouse, ‘How Do You Feel?’
Meanwhile, a team from the University of Pennsylvania, Scripps Research, and the University of Pittsburgh recently leveraged artificial intelligence (AI) learning for a rodent model to identify a cell type called Y1 receptor neurons in the brainstem’s lateral parabrachial nucleus (PBN). These receptor neurons encode chronic pain and appear to play a key role in survival-based analgesia, according to their recent Nature paper.
“People have cured the behavioral response to pain in rodents for 20 years with different approaches,” said Nicholas Betley, PhD, associate professor of biology at the University of Pennsylvania in Philadelphia and senior author. “The problem is, researchers can’t ask a mouse ‘how do you feel?’”
AI-driven techniques and increasingly tiny implantable devices are pushing rodent pain research to new possibilities, Betley said.
“We’re at kind of like a novel nexus here, where we’re combining new strategies to essentially ask the animal if they’re in pain. So in our paper, we used neurophysiological signatures, but we also combined that with computational behavioral decoding — taking large datasets of behaviors of animals that are in pain, that are not in pain — and running it through AI to see how the animal is behaving to predict the pain.”
Interestingly, the receptors Betley’s team studied are distributed in cells in a mosaic fashion and only present in 20% of PBN neurons. Betley said this suggests the receptors could serve as a tunable pain target.
“All of these neurons respond to pain, and I think it’s a threshold thing,” he said. “If you can dampen down the 20% response in each of the populations, then you’re reducing or filtering out the threshold at which you experience pain.”
A challenge, he acknowledged, is that the receptors do other things in other parts of the body — including the gut — so drug development to target the brainstem receptors would be challenging.
The next step, he said, is to “identify molecules that can get to these neurons and suppress their activity or reduce their activity.” There are “a couple” of good candidates that were identified as a result of his Nature paper, which also sequenced in situ 1200 genes in the Y1 neurons.
“Maybe we can’t shut off the Y1 neurons that are a critical bottleneck, but maybe we can shut off one of the regions downstream that is equally important in the transmission of pain,” Betley said. “Because what’s happening is these neurons are getting pain information, they’re sending it to somebody else, who’s sending it to somebody else, and eventually the mail comes home and you feel pain.”
What It All Means Going Forward
More effective pain treatments being the goal, Henderson suggested whatever may come will require precision.
For example, “You could potentially stimulate the PAG with focused ultrasound, but I think everyone’s too scared,” he said. That’s because “if you stimulated the cortex and something went wrong and it lesions it, depending on the area of cortex, it’s probably going to have potentially minimal effects. Whereas if you lesion the brainstem, you could kill them.”
Fink thinks neurosurgeons may see potential in the PAG and Henderson’s map. He noted that the PAG is adjacent to the trigeminal nucleus, which mediates pain for an excruciating facial condition called trigeminal neuralgia.
“Patients who get it tell me it’s the worst pain they’ve ever had in their lives. Women who get it say it’s worse than childbirth,” said Fink. “I found the placebo impact much more interesting because we know there’s structures in the brainstem already that mediate any kind of pain that emanates from your head and your face and that’s mediated through the trigeminal nucleus. We’ve known that for a long time, and we have a lot of treatments for that.”
But Fink thinks it’s a prime target.
“Theoretically, our neurosurgeons could put an electrode in this particular area of the brain, and it might turn out to be a way to help to treat some of these chronic long-term pain problems,” Fink said. “I’m sure that could be done. I have no doubt it could be done.”
