The mystery of the silent "sixth sense"

Leviathan Press:

Unlike a normal person who is lost in the dark and cannot locate himself, a patient with "proprioception loss" cannot locate certain parts of his body (such as the nose) under the condition of closing his eyes (darkness). At the same time, he (she) cannot feel the slightest touch of the outside world on his (her) body. This is indeed very strange - the patient can control his (her) body and limbs, but his (her) external stimulation circuit is interrupted.

Please imagine the following scene: you try to walk for a while with your eyes closed. Generally speaking, although the route deviates, your basic direction and sense of space are still there. However, people with proprioception loss can hardly move forward and may even fall to the ground.

Strapped to a chair at the National Institutes of Health Clinical Center, the French woman is called Sana, 31 years old. She is petite and has curly brown hair. In front of her is a table surrounded by 12 infrared cameras that track her every move. The test is about to begin.

On the table was a cylinder with a silver plastic ball on top. Sana's task was to touch her nose first, then the plastic ball in front of her. It was simple, and she did it, first touching her nose, then the plastic ball.

Now comes the hard part.

The lab technician asked Sana to close her eyes, then placed her fingers on the plastic ball, then moved them back to Sana's nose, and finally let go and asked Sana to continue to close her eyes and do the action again.

As a result, the location of the plastic ball seemed to have suddenly disappeared from Sana's mind. She fumbled around, swinging her arms wildly from side to side. When she succeeded in catching the plastic ball, it seemed to be completely accidental. She even had difficulty locating the nose on her face, and several times she found it completely wrong.

“It felt like I was lost,” Sana told us through a translator. With her eyes closed, she had no idea where her body was in space.

You can also try this yourself to see if you can do it. Put a glass of water in front of you and touch the top a few times with your eyes open, then try to close your eyes and see if you can still find the position. There is a good chance that you can still do it.

When we close our eyes, our perception of the world and our sense of where our bodies are don’t disappear; there’s still an invisible imprint of our perception of the world and our sense of where our bodies are. This sense is called proprioception, and it’s an awareness of where our limbs are and where our bodies are in space. Like our other senses (vision, hearing, etc.), proprioception helps our brains navigate the world. Scientists sometimes call it our “sixth sense.”

Proprioception differs from the other senses in one crucial respect: it can never be turned off, except in rare cases. We know silence when we cover our ears, and we know darkness when we close our eyes.

Sana is one of very few people in the world whose proprioception shuts down. Another is her 36-year-old sister Sawson, who was also tested at the National Institutes of Health in August 2019. The results showed that she also couldn't locate her nose in the dark.

"At home," Thorson said, if the lights went out and she was standing, "I had trouble finding a chair to sit down." The feeling is hard to imagine and hard to describe. "It's like someone blindfolded you, turned you around a few times, and told you to walk in a certain direction. For the first few seconds, you can't tell east from west," with no sense of direction at all.

For privacy reasons, I cannot reveal the sisters' last names. They both share another quirk: They can't feel many things they touch. "Even if I touch the ball with my eyes open, I can't feel it," Thorson said.

Of all our senses, touch and proprioception are probably the least understood. But over the past decade, neuroscientists have made major breakthroughs in understanding how these two senses work. This could eventually lead to better pain relief and prosthetics for amputees. It could also help us gain a more complete understanding of what it means to be human and how our bodies experience the world.

Sana, Thorson, and other patients with similar symptoms are ideal subjects for scientists studying touch and proprioception. There is nothing wrong with their muscles or brains, but they are missing something tiny but significant: a molecule-sized receptor that acts like a portal through which physical forces enter the nervous system and rise to the level of consciousness. This receptor is called piezo2, and it was discovered only 10 years ago.

The sisters' missing molecule likely caused them to lose the "eyes" of their proprioceptive system and made their skin unable to recognize specific touch sensations.

Patients who lack piezo2 are extremely rare—only 18 have been confirmed so far by the NIH Clinical Center and their colleagues around the world. The first two cases were published in the New England Journal of Medicine in 2016. “These two cases are like the first blind and first deaf people confirmed,” says Alexander Chesler, a neuroscientist at the NIH Clinical Center who led the work of Sana, Thorson, and others. “Based on what we knew about the piezo2 molecule at the time, we thought these patients had no sense of touch.”

(www.nejm.org/doi/full/10.1056/NEJMoa1602812)

Patients with this condition have difficulty controlling their bodies, especially when their vision is blocked. In addition, the symptoms of this rare genetic disease are often misdiagnosed or go undiagnosed for years.

Through the study of these cases, neuroscientists have been able to explore the basic functions of the touch and proprioception systems and understand the brain's unparalleled adaptability.

Small molecules, big power

Carsten Bönnemann is a detective who investigates neurological mysteries. When children present with neurological symptoms that are difficult to diagnose, he swoops in to solve these cold cases. “We’re looking for something that has no explanation,” says the pediatric neuroscientist at the National Institute of Neurological Disorders and Stroke.

In 2015, Borneman traveled to Calgary, Canada, for a case involving an 18-year-old woman with a strange condition. She could walk—she learned to walk around age 7—but only by looking at her feet. If she closed her eyes while standing, she would fall to the ground. It was as if her sight had the power to turn on a secret switch, and when the switch was turned on, she could control the part of her body she was looking at. Once she lost her sight, her body was out of control.

"As I was examining her, I realized she had no proprioception," Porneman said. With her eyes closed, she couldn't feel the doctor gently move her fingers. But the loss of sensation wasn't limited to her finger joints. She couldn't feel her elbows, shoulders, hips, any joints in her body move.

Although proprioception is not part of our conscious mind, it still serves a vital function. “If you’re going to move in a coordinated way, you have to know where your body is at all times,” says Adam Hartman, a neuroscientist who studies proprioception at the Howard Hughes Medical Institute. “You can look at your limbs, but then you’re not looking at anything else.” Proprioception allows our eyes to focus on things outside our bodies.

To find out what was causing this symptom, Borneman’s team sequenced the woman’s entire genome and found a mutation in a gene responsible for a touch receptor called piezo2, which was still new to science in 2015.

Scientists had long known that specialized nerves play a role in how we perceive the outside world. If nerves are the wires that carry information from the outside world to our brains, then these receptors are the switches—the first gears in our biological machinery—where electrical signals are generated.

The landmark discovery of piezo2 came at the Scripps Research Institute, where researchers had been stimulating cells with tiny glass probes for years. (When a piezo receptor is stimulated, it releases a small electric current. Piezo means "pressure" in Greek.) The researchers found two types of receptors: piezo1 and piezo2. When cells containing these two receptors are stretched, the receptors open, allowing external ions to enter the cell and release an electrical impulse.

Piezo1 is linked to our body's built-in blood pressure monitoring system and other internal systems that rely on pressure sensing. Further research showed that piezo2 is a molecule that is important for both touch and proprioception, a gateway through which mechanical forces can travel to our consciousness.

(www.ncbi.nlm.nih.gov/pubmed/27797339)

In 2015, scientists were just beginning to study the effects of piezo2 in mice, let alone people. Poneman had to do his own research, returning to the National Institutes of Health Clinical Center in Bethesda, Maryland. Poneman emailed Chesler, who was working on mice that had had their piezo2 gene snipped out through gene editing. Poneman described the Canadian case and another case, an 8-year-old girl in San Diego, who had both been confirmed to have a mutation in the piezo2 gene.

“That email made me jump out of my chair and run to Pawneman’s office,” Chesler said. “I didn’t even have a chance to ask the mouse to describe its life or its experience. I didn’t even have a chance to ask any questions.”

Mystery of human sense of touch, solved

Like Borneman's first patient, Sana and Thorson were born with a genetic mutation that disables piezo2. This has left them with lifelong proprioception, tactile and motor impairments. Both women can only walk a little on their own, and can only use electric wheelchairs to get around like normal people. However, neither of them has special care and lives alone. Sana is a clinical psychologist, and Thorson is the director of a camp for disabled children.

They simply haven’t experienced life with proprioception, and have trouble even describing the senses they’re missing. “I don’t even have a good comparison because I’ve always been this way,” Sana said.

Of the few cases of proprioception loss documented in medical history, the most famous is that of Ian Waterman. The British man's neurons responsible for touch and proprioception were disabled by an infection. As a result, he had no sensation or proprioception from the neck down, although he could still move. It was a "prison without limbs," neuroscientist Jonathan Cole wrote in Waterman's medical records.

While Waterman was clearly aware of his nerve damage, Sana and Thorson had no idea what was wrong with them until they were tested about a year ago. That test came back positive for a mutation in the piezo2 gene, and Borneman and Chesler were studying the function of piezo2 in the human body, so Sana and Thorson were drawn into the research of the two neuroscientists. So far, the researchers have found 12 cases of piezo2 receptor failure.

Touch is a very complex sense because it comes in various forms, each relying on a slightly different system of nerves and receptors.

Just thinking about the things we can feel can bring on a sense of awe. “If one of us walked up behind you and ruffled your hair, you’d know it right away,” Chesler says. “It’s one of the most amazing biological mechanisms.”

The sensory information we receive through our bodies is in many ways more diverse than that received through our eyes, ears, and mouth.

For example, the sensations of cold and heat involve different nerves and use different receptors than the sensation of light touch. (Some of these we have only recently discovered.) Pain, itch, and pressure also involve different nerves and receptors. And some tactile sensations depend on context. Think about this: The longer you wear a T-shirt, the less you are aware of the sensation of it lightly touching your body; wearing the same T-shirt after getting a sunburn may suddenly make you feel unbearably painful.

(www.ncbi.nlm.nih.gov/pmc/articles/PMC4843893/)

Without piezo2, Sana and Thorson can’t sense light touches, especially on their hands and fingers. Thorson told me that she would reach into her purse and “think I had something in my hand, and I’d pull it out, and there was nothing.” She couldn’t sense objects, and she didn’t know where her hands were. So if she wasn’t looking at her purse, it would probably have been like a black hole.

However, the sisters can feel cold and heat, as well as pressure and pain, and, remarkably, they can also feel sharpness.

Thorson's hobby is sharpshooting ("to relieve stress"), and she has a rectangular object with a sharp edge attached to the trigger of her weapon so that when her finger touches the sharp edge, she can feel it and pull the trigger.

That tingling sensation must be entering the nervous system through receptors other than piezo2. “We don’t understand at a molecular level what is activating the neurons when you feel the tingling,” Chesler said.

It’s amazing that in 2019, how the intense pain of stepping on a Lego brick enters our nervous system is still a question.

Patients with Piezo2 deficiency can feel that stinging pain, but they cannot experience another type of pain, called tactile allodynia, in which light touch that is normally pleasurable becomes painful. (In the lab, researchers produce this tactile allodynia by rubbing the skin with capsaicin, the spicy chemical in chili peppers.)

Another mystery: Patients who lack piezo2 can feel the touch of hairy skin, such as on their arms, but oddly, they can't seem to feel the movement of individual hairs. "We don't know why that is," says Chesler. That is to say: neuroscience has not yet fully figured out how sensations are created in the body.

It is these findings that have many practical applications, namely new ways to treat pain. Scientists hope to next identify the various receptors that give the body physical sensations, and then either learn to enhance them or shut them down when they cause pain.

"This is the dream of every pain researcher," said Chesler. "The methods we use to study pain are still quite crude. Can we get away from these relatively low-level methods and understand the problem of pain from a more systematic perspective in the future?" The upgrade of the way of understanding is of great significance. For example, if you don't know the receptors related to tingling pain, you certainly can't design a drug to shut down this receptor.

The mystery of proprioception

The sense of touch is complex, but proprioception may be even more complex than touch. However, in the process of studying proprioception, researchers may also make discoveries and applications far beyond the scope of the human body.

Deep inside all muscles in the body are fibers called muscle spindles. These fibers and nerve bundles register muscle extension. Yes, you'll find piezo2 on the nerve endings of the fasciculus calyx. When this muscle stretches, other muscles contract, and piezo2 then transmits all of this information to the spinal cord to determine the position of the limb.

Every muscle in our body releases this information all the time. It's amazing. Somehow the nervous system processes a lot of data without conscious involvement. What if the processing of this information required conscious involvement? You would definitely go crazy from information overload.

Think about sitting up straight. To sit up straight, all the muscles in your back have to send the right messages to keep all the bones in your spine aligned. Those who lack piezo2 can't do that. They sit with scoliosis because their back muscles don't send the message to the brain to keep all the bones in their spine aligned. (I've heard that many of these patients were born with malpositioned fetuses in the womb or with misaligned hips - a fundamental problem caused by lack of proprioception.)

Without the essential input provided by proprioception, Sana and Thorson had to concentrate hard to avoid getting disoriented. Sana said that sometimes, just having her hair floating in front of her eyes could cause her to lose her sense of where her body was. A similar situation would occur if someone got too close to her face, blocking her peripheral vision. This meant that if she wanted to kiss someone, she had to concentrate extremely hard.

How the brain integrates all these sources of proprioceptive information so effortlessly remains a considerable mystery.

“What’s amazing is how flexible the brain is in processing this information,” says Adam Hantman, a neuroscientist who studies proprioception at the Howard Hughes Medical Institute. “You can ask me to reach for this cup and say, ‘Do it in a way you haven’t done before,’ and I can, without any prior practice, turn my hands upside down, put them behind my back and reach for the cup. I’ve never done this before in my life, and now I can do it without any practice.”

In addition, there are many elegant "complications" in this research that have not yet been thoroughly studied by scientists.

Scientists generally think of touch and proprioception as separate systems. “But the two senses overlap to some extent,” says Joriene De Nooij, a neuroscientist at Columbia University who studies proprioception. Sensors in our skin help us keep track of the position of our limbs. “When you walk, all these pressure receptors in your feet activate with every step,” she says. This sends information to the brain about the body’s position.

There are lots and lots of inputs coming into our sensory systems that give us feedback and tell the brain what the body is doing. "Understanding how the brain works — what algorithms it uses to build these models and use them — can help us build better machines," Hantmann said.

Crucially, the researchers could use this to build better prosthetics that are directly controlled by the patient’s nervous system. “Right now, these machines are very capable of taking signals from the brain and driving the prosthesis to move,” he said, “but we haven’t yet been able to get sensory feedback back from the prosthesis, that is, we haven’t been able to close the loop and do the whole thing perfectly.”

The brain does another thing that involves proprioception and that researchers are very interested in understanding: How does it compensate for information loss, as happened in Sana and Thorson's case?

The most important thing the brain can do

Muscle bundles and other nerve endings explain how proprioception works in the body, but even stranger is how this sense manifests in our minds.

I've been thinking about what happens when I close my eyes and reach for something. There's a glass on the table in front of me, and I can reach it even with my eyes closed. I'm trying to focus on the position of the glass in space and to dissect this thought: What am I experiencing at this moment?

It's a bit like describing a daydream. You know the glass is there and it seems real, but it doesn't have any form. "That's consciousness," said Ardem Patapoutian, a neuroscience researcher at the Scripps Research Institute whose lab first discovered the piezo receptors. He said there is a physical aspect of consciousness that is determined and shaped in part by proprioception.

In describing this story, I came to think of the brain's process of creating consciousness as a wizard or magician mixing a potion. The wizard takes sensory input from our bodies, such as touch, temperature, and joint sensations, mixes it with our thoughts, emotions, memories, and predictions about the world, and then throws it into the crucible to produce consciousness. From these discrete parts emerges a complete sense of self that is greater than the sum of its parts.

However, even if one component is missing, the resulting "consciousness" potion does not necessarily fail. Sana and Thorson both lack information from the piezo2 receptors, but their brains still use other components to make up for the lack of information. Their consciousness is no different from that of other people.

Chesler believes that the sisters' brains were still able to generate images of their bodies. They just had to use other inputs, such as vision, or other sensations, such as heat, cold, or pain.

Just as blind people often have keen hearing, Sana and Thorson use their other senses to compensate for their lack of proprioception. Sana said that when she reached for the cylinder on the table with her eyes closed, she tried to feel the temperature change nearby. She remembered that it felt cold when she touched the ball, so she wanted to find the place with the lower temperature.

“How do their brains construct a body image when they don’t have the proprioceptive information we take for granted? That’s one of the most important questions about proprioception,” Chesler said. “I hope my lab will really start to address that in the next few years.”

But you don’t have to try hard to prove that the human mind is certainly incredibly resilient.

“You get used to your body,” Thorson said, “and you learn how to deal with the different materials you’re given.”

By Brian Resnick

Translated by Qiao Qi

Proofreading/Rabbit's Light Footsteps

Original article/www.vox.com/the-highlight/2019/11/22/20920762/proprioception-sixth-sense

This article is based on the Creative Commons Agreement (BY-NC) and is published by Qiao Qi on Leviathan

The article only reflects the author's views and does not necessarily represent the position of Leviathan