placebo-brain
 

Why Nothing Works

for Discover

Winner of the 2015 NASW Science in Society Award in the category of “Science Reporting.”

(For the full story, click here)

Sarah Lidstone has a long history with the medical world. A ballet dancer from the age of 3, she developed acute scoliosis and wore a back brace throughout much of her teens. “I spent a lot of my childhood in doctors’ offices,” she says with a wide, Cheshire grin. “I loved carrying my X-rays around when I was 10.” The brace gradually coaxed Lidstone’s body to straighten itself out, but her experience left her with an enduring fascination for medicine and a desire to ease suffering in others. In college she gravitated to brain science, and particularly to Parkinson’s disease, a crippling condition caused by chronically low dopamine levels in the brain. Dopamine, in addition to moderating mood, controls brain regions crucial to movement. Lidstone was fascinated by the brain’s dopamine systems and with these patients, who were trapped in bodies that wouldn’t respond properly.

After starting her doctorate work in neurology in 2003 at the University of British Columbia, Lidstone led a rather odd brain-imaging experiment. She brought 40 patients with mild Parkinson’s into the lab for a simple drug therapy and explained that some would get their usual dose of Parkinson’s medication, which boosts the brain’s dopamine levels. The others, she said, would get a placebo — an inactive pill that looked just like their usual drug. Then they would lie in a high-resolution positron emission tomography (PET) scanner for a grueling 90 minutes while the machine took pictures in 2-millimeter increments of their nucleus accumbens, a region deep in the brain that (among other things) controls reward and motivation.

When Lidstone’s patients emerged from the scanner, many of them moved easily, as one would expect after a dose of their medication. One older patient with a tall, stooped frame arrived in a wheelchair. He took the pill, sat through the scan, and then walked out past the wheelchair and up a flight of stairs to the debriefing room. There, Lidstone dropped a bomb on him: There was no drug. Everyone in the trial got the same thing — a simple placebo pill.

“When I told him he actually got a placebo, he laughed at me,” Lidstone says. “He was like, ‘Are you serious? I can’t believe I was able to do this on my own without my medication.’ ”

Whether he improved “on his own” is open to interpretation. Parkinson’s patients are especially susceptible to the placebo effect — a phenomenon by which a condition improves solely because the patient believes treatment has occurred. When Lidstone’s team analyzed the patients’ brain activity, the PET images showed dopamine flooding the synapses in the crucial motor control region of their brains, just as surely as from a dose of medication. It was the first time placebo responses in Parkinson’s disease had been definitively linked to a natural burst of dopamine.

“Perhaps it was because I’ve been a patient myself, I don’t know. I think the idea of patients being able to heal themselves is very powerful,” says Lidstone, a gregarious woman who still moves with the grace of a dancer. Some practitioners dismiss the placebo effect as irrelevant. Others blame it on neurosis. But scientists are increasingly recognizing the placebo response as an authentic neurochemical reaction in the brain. In the past decade, imaging studies have opened up the possibility that scientists will soon understand the mysterious phenomenon and even harness it in clinical practice — unleashing the power of, well, nothing. The new evidence has established that placebos trigger the brain’s “internal pharmacy” — in essence, a warehouse perpetually stocked to deliver active drugs to itself. In addition to improving Parkinson’s symptoms, that same inner pharmacy can affect conditions like pain, depression, irritable bowel syndrome, anxiety, schizophrenia and more. As the placebo effect emerges from a long history in the shadows, the new question is: How can we use this age-old brain trick to our advantage? or as long as medicine has existed, the placebo effect has been quietly playing a role in treatment.

Placebos were first formally demonstrated in 1784 by Benjamin Franklin, but it wasn’t until after World War II that they became the milepost against which all drugs would be measured. The change came about after a massive scandal surrounding the drug thalidomide, which in the 1950s was widely prescribed to pregnant women to alleviate morning sickness. The drug, untested in pregnant women, caused severe birth defects in thousands of infants, and the FDA scrambled to improve drug testing. The use of placebos, though it would not have prevented the thalidomide disaster, was one such improvement. Beginning in 1962, drug trials were required to include patients getting bogus treatment. Today, every drug must outperform a placebo before being sold in the U.S.

The numbers here are not trivial. In some conditions, such as cancer, few patients respond to placebos; in others, such as pain and depression, more than 50 percent might. But despite the placebo effect’s clear influence on health, it was long consigned to a mysterious realm somewhere between psychology and pharmacology. The placebo effect “was regarded for many, many years as just a nuisance variable, something you had to take into account to find out about something else,” says Harvard University psychologist Irving Kirsch, who has studied placebos and clinical trial design for decades. “And very few people were at all interested in understanding it.”

Interest sparked with the discovery of endorphins — morphine-like molecules, often called opioids, that the body produces during exercise and that have painkilling or euphoric effects on the brain. It wasn’t long before researchers made the connection between opioids and placebos. In 1978, rheumatologist Jon Levine and neurologist Howard Fields, both at the University of California, San Francisco, did a simple experiment with people in pain after dental surgery. Telling patients it was something to ease their pain, Levine and Fields gave patients either a placebo injection or a dose of naloxone, which blocks the brain’s ability to soak up endorphins.

The patients who got naloxone were still miserable; their brains couldn’t use endorphins to temper their pain. In contrast, many who got a placebo felt their pain subside. The study elegantly showed that for pain, placebo effects were not some neurosis but the brain medicating itself. The paper was hailed as further proof of the need for placebo controls in drug trials. But Fabrizio Benedetti, an Italian neuroscientist, saw wider implications. In the 1990s, he further tested the relationship between opioids and the placebo effect. He was also curious whether a similar process could explain nocebo effects — a parallel phenomenon in which the brain is fooled into perceiving increased pain. He focused on the natural hormone cholecystokinin (CCK), which actually increases pain by counteracting opioids. In one experiment, Benedetti gave patients recovering from minor surgery a drug that he said would increase their pain. Really what he injected was saltwater, yet just as they’d been led to expect, they reported more pain. When Benedetti blocked the release of CCK in his patients, they felt immensely better.

Perhaps, Benedetti thought, CCK is to nocebos what opioids are to placebos: Whereas blocking opioids cancelled pain relief, blocking CCK actually supercharged it by allowing opioids to run wild in the brain. It was a fascinating idea, but still mostly inference, as Benedetti and others weren’t able to truly watch either the placebo or the nocebo process unfurl. Scientists needed a tool to allow them to witness the process in action.

Then came two papers that took placebo research into the age of brain imaging. In the first, published in Science in 2002, a team led by neuroscientist Predrag Petrovic at the Karolinska Institute in Stockholm strapped painful hot metal pads to nine subjects. They injected some subjects with a powerful opioid painkiller and others with a placebo and had them rate their pain. As expected, the placebo worked. But Petrovic was most interested in how the placebo effect played out in the brain. Subjects completed the experiment while in a PET scanner, allowing Petrovic to track their brain activity as they experienced both pain and pain relief. As hypothesized, the brain activity of those in the placebo group resembled those that got the drug, especially in a region called the anterior cingulate cortex, or ACC. This region in the middle of the brain is important in processing emotion, anticipating rewards and registering pain. Clearly, Petrovic’s findings showed, the ACC also responds to placebos.

Then psychologist Tor Wager, at the time a graduate student at the University of Michigan, took placebo imaging one step further. Raised in Christian Science, Wager had an enduring curiosity about mind-body connections. But he got the impression that that kind of work was considered “flaky” for a promising young scientist. “When I started grad school, there was this idea that there were certain areas that people should study,” says Wager, now at the University of Colorado at Boulder. The placebo effect was not one of them. “Placebo has a long history of being a word for an effect that can’t possibly be something real, by definition.”

But Wager longed to follow up Benedetti’s work looking at a tangible link between thought and bodily experience. So he set up a side project attempting to map the placebo effect as it was happening. In one experiment, he and colleagues had 24 subjects lie in an fMRI machine, an imaging device that tracks the blood flow and oxygen use that accompany brain activity.

While subjects were in the scanner, the researchers administered a series of electric shocks to their wrists, each time warning them (by showing them either a blue or a red cue on a screen) whether the next shock would be mild or intense. After each shock, subjects described their pain. After a round of shocks, the experimenter rubbed a skin cream on subjects’ wrists, telling some it was an experimental salve and others that it was a placebo cream. In reality it was all placebo cream. A third of subjects who got what they thought was the painkilling cream reported less pain, showing a clear placebo effect.

When Wager analyzed subjects’ brain activity, he found that the people who reported the greatest relief after receiving a placebo also showed the strongest reduction in activity in the ACC, the thalamus and the insula, all evolutionarily primitive brain structures that respond to physical pain. Suddenly, it was clear that when a patient improved on placebo, it wasn’t just some delusion, or an effort to please a person in a lab coat. It was a measurable brain event and reflected an actual reduction in the experience of pain. Even more interestingly, Wager and his colleagues saw that when their subjects were anticipating pain relief, activity spiked in the more evolutionarily advanced prefrontal cortex, a region in the front of the brain that is central

to generating expectations, and in a section of the midbrain that is key to the release of opioids. The more a subject’s prefrontal cortex ramped up with anticipated pain relief, the more activity Wager’s group saw in the midbrain. Wager’s findings implied that the physiological stream of events involved in placebo responses might be the reverse of what happens during the experience of pain. Normally, pain signals begin somewhere in the body and work their way to the thalamus, deep in the brain, and then to the prefrontal cortex, producing conscious perception of pain. By contrast, Wager’s work, published in Science in 2004, suggested that the placebo effect starts in the more advanced parts of the brain related to expectations and works its way backward toward more primitive areas that release opioids. It’s as though the brain goes out of its way to ensure reality matches expectations.

Like many in the field of placebo research, neurologist Luana Colloca has a practiced calmness about her. Her bedside manner is a sort of bashful nerdiness punctuated by sudden mischievous smiles. That manner, coupled with a level gaze and warm eyes behind glasses that slip down her nose, inspires both comfort and confidence.

Perhaps that is how she persuaded me one cold, clear January day to strap a painful electrode to my left hand for half an hour. Colloca’s laboratory is tucked into a small corner of the sprawling National Institutes of Health complex in Bethesda, Md. Her lab is tidy, containing her electric chair, in which I will be shocked, and a few odd little instruments, like a bike helmet that blows air on your face to make you anxious. Soon an assistant is sticking sensors below my eye, on my chest and on my hand to measure my reactions — sweating, flinching, heartbeat. But it’s the electrodes on the back of my hand that have my attention. That’s where Colloca will repeatedly zap me, sometimes mildly and sometimes not so mildly. A computer screen, she explains, will warn me which shock I am to receive — a green screen for a mild zip and a red one for a blast I’ve ranked on a pain scale as six out of 10. I’ll then rate the pain of each shock as I go.

Alone in the room, I quickly learn to hate the red screen. It’s not technically torture, but it really hurts — my foot twitches with each shock — and I find myself fretfully counting seconds between the red screen and the jolt. We go three rounds of 18 shocks each. In the third round, I notice that the diminished “green” shock has gotten slightly worse, mounting from a 1 to a 2 on my pain scale. I worry momentarily that I’ve somehow short-circuited my hand. Finally, the session is done and Colloca returns. As before, she wears a long lab coat and a deadpan expression. She starts by telling me that I have a decent tolerance to pain, which is deeply gratifying. But a sheet of paper in her hand says the “red” shock represented about 101 milliamps — not even enough to power a light bulb. Less gratifying. Colloca’s results also show that for the first two rounds of shocks, the difference between what I rated as light and strong pain was about 40 milliamps.

Then Colloca points to the results of the third round and says something truly startling. For that one, she fired every shock at full blast. Yet the shocks that came after a green screen felt far less painful — barely a 2 on my pain scale. Colloca flashes a mischievous smile. Essentially, in the first two rounds of shocks my brain tied “less pain” with “green screen.” So in the third, when a green screen was paired with harder shocks, my brain released opioids rapid-fire to dampen the increased pain. A high tolerance to pain, but it seems I’m kind of gullible. Colloca smiles at this. She says not to think of myself as gullible, but rather as a good learner. In two rounds of shocks, my brain learned to activate complex pathways — starting in my prefrontal cortex and trickling through to more primitive parts — every time I saw a green screen.