Subsequent phases of the study will assess whether the technique offers long-term practical benefits to a larger group of chronic pain patients by fundamentally changing their modulatory systems so that they can reduce pain all the time without constantly and consciously trying to do so. If they can, then the technique would not merely provide shelter from the storm of pain; it would bring about climate change. Unpublished work found that repeated training over six weeks of subjects with chronic pain significantly reduced their pain.
“I believe the technique could make lasting changes because the brain is a machine designed to learn,” Dr. deCharms says. The brain is plastic: whenever you learn something, new neural connections form, and old, unused ones wither away (a process known as activity-dependent neuroplasticity). Thus, engaging a certain brain region can alter it. (Neuroimaging has shown, for example, that the part of the brains of London cabdrivers that deals in spatial relations is larger than usual. More strikingly, after merely three months of training, learning to juggle creates visible changes in parts of the brain involved with motor coordination.)
Many diseases of the central nervous system involve inappropriate levels of activation in particular brain regions that change the way they operate. Some regions experience less activity, and other regions become hyperactive. (For example, epilepsy involves abnormal hyperactivity of cells; stroke, Parkinson’s, and other diseases involve neurodegeneration.) In the case of chronic pain, new nerve cells, recruited for transmitting pain, create more pain pathways in the nervous system, while nerve cells that would normally inhibit or slow the signaling begin to decrease or function abnormally. Neuroimaging therapy may mitigate this harm by teaching people how to increase the efficacy of their healthy brain cells.
“It gives people a tool they didn’t know they had,” Dr. Mackey says. “Cognitive control over neuroplasticity.”
The technique may offer a particular advantage over drug therapy. It is difficult to design drugs to change a disease process in a specific region of the brain, because drugs work by targeting receptors, and most receptors, such as opiate receptors, are present in multiple systems throughout the brain and body (one reason such drugs almost always have side effects). Neuroimaging therapy, by contrast, is anatomically specific, allowing for the possibility of targeted neuroplasticity, much as a muscle can be isolated and trained.
Neuroimaging therapy “provides tangible evidence that people can change their own brains, which can be very empowering,” Dr. Mackey says. Much as people were once puzzled by Freud’s talking cure (how could describing problems solve them?), the idea of a “looking cure,” as it were, makes us wonder: How could one part of our brain control another, and why would looking at the process help to do so? Who, then, is the “me” controlling my brain? The technique seems to deepen—rather than resolve—the mind-body problem, widening the Cartesian divide by splitting the self into agent and object, mind and brain, ghost and machine.
“The decision-making parts of the brain are thought to be the prefrontal regions of the cortex,” Dr. Mackey says. But as for how those brain parts cause the change in the rACC—“Heck if I know! How do we get the brain to do anything? We can map out the anatomical circuits involved and the general functions of those circuits, but we can’t tell you the mechanism by which any cognitive decision—large or small—is translated into action.”
Neuroimaging therapy as a treatment for disease is one of those novel ideas that seems obvious in retrospect, but no one thought to try before. Although some researchers have experimented with teaching subjects to control their brain activation to create a “brain-computer interface,” the purpose of those experiments has been theoretical rather than therapeutic. In one such experiment, for example, subjects were taught to navigate a cursor through a maze on a screen using only their brains. Subjects completed a sequence of mental strategies. Each strategy activated a different part of the brain that automatically moved the cursor a different way. By observing how certain activations resulted in corresponding movements of the cursor, subjects were able to learn how to navigate the cursor through the maze.
Perhaps the best example of a “looking cure” is a novel treatment for phantom limb pain. The neurologist Vilayanur S. Ramachandran used a mirror box (a box with two mirrors in the center, one facing each way), in which patients put their actual limb in one side and their stump in the other. When patients move their actual limb, looking in one side of the mirror box, they appear to be moving both arms. Phantom limb pain typically involves the sensation that the phantom arm is stuck in an uncomfortable position. By straightening her existing arm in the mirror box, a patient can have the illusion of uncurling her phantom arm, and the cramping pain goes away. (More recently, scientists from the University of Manchester have had success using a computer-generated simulation to create a more realistic-looking illusion.)
Since patients know it is an illusion, why does the trick help? Through an unknown mechanism, the visual cortex communicates the image to the somatosensory cortex, which somehow decides to mimic the image in the mirror by making the phantom limb relax. Phantom limb pain is theorized to derive from the neural reorganization in the somatosensory cortex. Functional imaging has shown that repeated use of the mirror can reverse those changes and reduce pain. Although more extensive trials are needed, repeated training has shown long-term improvements in some patients.
TERRA INCOGNITA
One of the limitations of pain treatment today is that pain presents the same symptom regardless of how it is generated or what type of pain it is, yet different conditions require different treatment. Brain imaging might be used diagnostically for individual patients, to determine the nature of their pain. It might also spur the development of more targeted pain drugs.
Irene Tracey—who directs Oxford University’s brain imaging center in England and is a rising star in the field—believes that brain imaging could also be useful in medical malpractice and disability court cases to document the reality of the pain of a plaintiff. These cases are currently hampered by the lack of an objective measure of pain, leaving juries at a loss how to distinguish between honest plaintiffs and malingerers.
The Gothic kingdom of Oxford seemed gloomy in the late November afternoon as I made my way to Dr. Tracey’s office. But inside, everything began to seem brighter. Her cheeks flushed as she discussed the future of her research. “In five to ten years,” she said definitively, “we will be able to put someone in a scanner and say, ‘Your pain comes 10 percent from hypervigilance [paying too much attention to the pain], 20 percent from catastrophizing [excessive worry], 20 percent from peripheral input [from the original injury or disease], and 50 percent from brain circuit dysfunction.’ We can already scan people and tell them far more about their pain than they can tell us,” she concluded crisply.
Beneath her pale blouse, with its pattern of tiny flowers, the swell of her third child was just visible. I pictured the fetus’s brain cells dividing into neural networks in a design that would one day be known. One day, too, would my pain be known because imaging would identify each of the elements of which it is composed? Would the mystery of pain, then, finally be unveiled?
Three years later I write to Dr. Tracey, asking her to update me on her work. Since so much time had elapsed, I expect her to tell me that we are much closer to achieving her vision of using brain imaging to identify different kinds of pain. But instead she is much more circumspect. “In five to ten years, we might be able to put someone in a scanner and say, ‘Your pain comes from a combination of hypervigilance . . .’ ” she writes.
I object that the conditional makes the prediction meaningless (after all, anything “might” happen . . . aliens might bring us pain-scanning technology), to no avail. She also writes that the idea of assigning an actual percentage to the different kinds of pain in a sufferer’s mind sounds “amateur” because “all these factors are interactive, you see . . .”
I recall how Ari (the Israeli artist wh
o suffered from migraines and fibromyalgia) had asked me if I believed there would be a cure for chronic pain. “Oh yes,” I’d said. There had been an inspiring update to the crushing study on chronic pain shrinking the gray matter of the brain. A German research group found that when patients who had suffered from chronic hip pain got a total hip replacement, their gray matter regenerated, suggesting that the shrinkage that had been observed did not stem from neuronal loss, which is irreversible, but merely from a change in the size of cells. So, perhaps the damage of all chronic pain syndromes could be reversed. Perhaps, too, one day, chronic pain would be controlled just as acute pain can be controlled through anesthesia, and anyway, no one would develop chronic pain in the future, because pain would be treated at its onset. I launched into my pet analogy of TB and how pain clinics would all fold up shop like the sanatoriums. As I talked, I had an image of the consumptives packing their suitcases on the magic mountain, the directors discussing whether to turn it into a museum.
“One day . . .” Ari drawled, “in the next millennium?”
I hesitated.
“Let me put it this way,” he said. “If you were a venture capitalist, would you invest in a company whose mission was to find a cure for chronic pain?”
I recalled the catch in my optimistic analogy: the lag time—the half century between the discovery of the tuberculosis bacterium and the discovery of antibiotics. And pain is not a simple bacterium, visible under a microscope, but a complex aspect of consciousness. The tools to look at the brain have only just been invented, and the brain itself is still mainly terra incognita—more like the ancient maps of faraway lands than like Google Earth. Would the discoveries of pain-related genes lead to the development of effective drugs soon? For how many years will the critical breakthrough about pain remain five to ten years hence?
“Not if I wanted to get rich quickly,” I conceded.
“How’s your pain?” he asked.
I never knew how to respond to that question. Okay. Better than it used to be. Bearable, almost never unbearable. But still there—always. Since my arthritic condition is degenerative, presumably it has degenerated further over the years, but I do not have more pain now—I have less—and for that I am grateful and thrilled. It’s so hard to know the best attitude to assume! On the one hand, I want to be satisfied with the progress I’ve made: to accept the balance of pain that remains and close the pages of my pain diary forever. On the other hand, to fully accept it feels as if I am settling for a pained life. I want to keep a candle in the window of my mind for my pathography to have something besides a philosophical ending.
In the three years I’ve been married, though, I’ve been surprised to discover that my wishes have changed. On my first birthday after our wedding, I wished to have a child and realized that I wanted that more than I wanted not to have pain, and that if the Wish Fairy would grant only one wish, I’d choose the child. (Of course, if my pain worsened, that could change, I hastened to let the Wish Fairy know, lest she think I had forgotten how compelling pain can be.)
The next birthday I wished for a baby again. But on my last birthday, I had a new wish: that the twins with whom—through the miracle of medical science—we were about to be twice blest would be healthy, that their new bodies would be gifted with the pain-protective gene variant and spared the pain-sensitivity gene variant, and that their lives would not be blighted by persistent pain.
A UNIVERSE OF HURT
I hope functional imaging will progress in my lifetime enough to have clinical input,” comments John Keltner, who spent several years working with Irene Tracey in her center before deciding to begin new training as a psychiatrist. He points out that CT scanning and MRI technology were revolutionary technologies, with huge immediate clinical impact, because they created the first anatomically accurate pictures of the inside of a body. How much more revolutionary it seemed when, in the late 1980s, functional imaging produced the first 3-D movies of the working brain. But the films were and remain largely indecipherable. Researchers puzzle over the images like Columbus staring at the gray shoreline, thinking, India?
“We don’t understand virtually anything about the human brain,” Dr. Keltner says soberly. “Pain, sleep, memory, thinking, adding two and two—we don’t understand any of that stuff. When I started doing functional imaging research on pain twenty years ago, I thought it would soon lead to a meaningful diagnostic tool. Now I hope that in the next forty years I will help come up with a test that will be able to answer a simple clinical question about a patient’s pain, such as, Should we focus on treating your toe or your emotional state? That’s such a basic question, and right now there isn’t a single diagnostic test that can answer it.
“Brain function turns out to be so complicated. It would be a lot easier if there were a part of the brain associated with pain and only pain, but so far we haven’t been able to find a single unique marker that would allow us to definitively identify a pain state. If you show me a brain scan and say, Is this person in pain or thinking about running from a tiger? I wouldn’t be able to tell you.” A brain scan of a person in a state of repose would look different, of course, but pain and fear are both salient experiences with strong activation in common brain regions.
“We had to start recognizing that the fundamental pillars of human experience—pain, fear, anxiety, sadness, joy—involve the whole brain, with dozens of areas switching on and off. And many of those parts also light up in scans that have nothing to do with pain. Of the countless possible brain states, perhaps only ten thousand happen if a person is in pain. But nobody has come up with a rich and complicated enough model to analyze the complexity of the distributed patterns of neural networks and deduce any underlying rules. The daunting aspect is that it’s a bit like chess. Chess is eight spaces by eight spaces and you have thirty-two pieces, yet by the third move of any game, there are a thousand possibilities.” But instead of thirty-two pieces, the brain has a hundred billion neurons that can form an unknown number of neural networks.
“The pictures are so complicated,” he says for the fourth time. “If we change one parameter in an experiment—say, change a visual cue from blue to red or change from color to sound—we’d expect to see corresponding changes in the auditory and visual sections of the brain. But instead we see changes in a dozen areas.
“I’m not discouraged,” he adds, sounding like a hiker who has realized that he can’t figure out where he is on a map, but is reminding himself that he likes hiking and should trudge on. “We’re literally grappling with the fundamental aspects of human beings. We naively believed that pain is simple—it hurts or it doesn’t hurt—so there should be a single brain state we could see every time someone is in pain. But what we’ve stumbled into is the discovery that there’s a relative universe of hurt—that hurting is an immense, rich, and varied human experience, associated with an unknown number of possible brain states. From a scientific position, we’re overwhelmed at how large that universe is. We’re still at the stage where each step forward makes us realize how far we have to go . . .”
“We’re getting there faster than we thought possible,” Sean Mackey responds. He and his Stanford colleagues recently made a significant encroachment in an experiment in which they were able to distinguish, with approximately 85 percent accuracy, brain scans of volunteers given a painfully hot stimulus from those given a non-painfully hot stimulus or no stimulus. A further step, he points out, would be to ask volunteers to simply imagine being given a thermal stimulus and to see if he could distinguish those scans from the scans of volunteers who actually had the heat stimulus (in other experiments, imagined pain has been shown to engage similar brain regions as physical pain).
Although Dr. Mackey believes that this kind of simple, acute pain probably has very little to do with the experience of chronic pain, he also feels that “we are rapidly moving to a point where we may be able to detect the subjective experience of pain and to find a separate signature for it that all
ows us to distinguish it from other affective states, such as depression or anxiety.” He points to the amazing acceleration of certain kinds of technology, such as machine learning techniques and pattern classifiers—complex software algorithms that can be fed a set of known examples (scans of people experiencing thermal pain, or not) and then used to classify new, uncategorized scans.
He feels it is important, however, to understand that this technology is a long way from being able to recognize—let alone provide insight into—the state of chronic pain. He has great concerns about how this kind of technology will be used, because he thinks it is “ripe for abuse by the legal community and insurance companies to try to disprove that somebody is having chronic pain and deny care.” He has already seen a lawsuit that relied on claims about using scanning to detect pain. The suit involved a worker who developed chronic pain after his arm was injured by molten tar. The worker’s lawyer claimed that a cognitive neuropsychologist had validated the man’s chronic pain by scanning his brain. The expert had, in fact, scanned the man doing various activities, such as squeezing a ball, with both his injured and his uninjured arm. Because the two brain scans were different and the scan of the injured side showed more brain activity, the expert inferred that the scans proved the patient had more pain on the injured side.
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