Neuroimaging improves understanding of eating disorder
In a spacious hotel room not far from the beach in La Jolla, Calif., Kelsey Heenan gripped her fiancé’s hand. Heenan, a 20-year-old anorexic woman, couldn’t believe what she was hearing. Walter Kaye, director of the eating disorders program at the University of California, San Diego, was telling a handful of rapt patients and their family members what the latest brain imaging research suggested about their disorder.
It’s not your fault, he told them.
Heenan had always assumed that she was to blame for her illness. Kaye’s data told a different story. He handed out a pile of black-and-white brain scans — some showed the brains of healthy people, others were from people with anorexia nervosa. The scans didn’t look the same. “People were shocked,” Heenan says. But above all, she remembers, the group seemed to sigh in relief, breathing out years of buried guilt about the disorder. “It’s something in the way I was wired — it’s something I didn’t choose to do,” Heenan says. “It was pretty freeing to know that there could be something else going on.”
Years of psychological and behavioral research have helped scientists better understand some signs and triggers of anorexia. But that knowledge hasn’t straightened out the disorder’s tangled roots, or pointed scientists to a therapy that works for everyone. “Anorexia has a high death rate, it’s expensive to treat and people are chronically ill,” says Kaye.
Kaye’s program uses a therapy called family-based treatment, or FBT, to teach adolescents and their families how to manage anorexia. A year after therapy, about half of the patients treated with FBT recover. In the world of eating disorders, that’s success: FBT is considered one of the very best treatments doctors have. To many scientists, that just highlights how much about anorexia remains unknown.
Kaye and others are looking to the brain for answers. Using brain imaging tools and other methods to explore what’s going on in patients’ minds, researchers have scraped together clues that suggest anorexics are wired differently than healthy people. The mental brakes people use to curb impulsive instincts, for example, might get jammed in people with anorexia. Some studies suggest that just a taste of sugar can send parts of the brain barrelling into overdrive. Other brain areas appear numb to tastes — and even sensations such as pain. For people with anorexia, a sharp pang of hunger might register instead as a dull thud.
The mishmash of different brain imaging data is just beginning to highlight the neural roots of anorexia, Kaye says. But because starvation physically changes the brain, researchers can run into trouble teasing out whether glitchy brain wiring causes anorexia, or vice versa. Still, Kaye thinks understanding what’s going on in the brain may spark new treatment ideas. It may also help the eating disorder shake off some of its noxious stereotypes.
“One of the biggest problems is that people do not take this disease seriously,” says James Lock, an eating disorders researcher at Stanford University who cowrote the book on family-based treatment. “No one gets upset at a child who has cancer,” he says. “If the treatment is hard, parents still do it because they know they need to do it to make their child well.”
Pop culture often paints anorexics as willful young women who go on diets to be beautiful, he says. But, “you can’t just choose to be anorexic,” Lock adds. “The brain data may help counteract some of the mythology.”
Beyond dieting
A society that glamorizes thinness can encourage unhealthy eating behaviors in kids, scientists have shown. A 2011 study of Minnesota high school students reported that more than half of girls had dieted within the past year. Just under a sixth had used diet pills, vomiting, laxatives or diuretics.
But a true eating disorder goes well beyond an unhealthy diet. Anorexia involves malnutrition, excessive weight loss and often faulty thinking about one of the body’s most basic drives: hunger. The disorder is also rare. Less than 1 percent of girls develop anorexia. The disease crops up in boys too, but adolescent girls — especially in wealthy countries such as the U.S., Australia and Japan — are most likely to suffer from the illness.
As the disease progresses, people with anorexia become intensely afraid of getting fat and stick to extreme diets or exercise schedules to drop pounds. They also misjudge their own weight. Beyond these diagnostic hallmarks, patients’ symptoms can vary. Some refuse to eat, others binge and purge. Some live for years with the illness, others yo-yo between weight gain and loss. Though most anorexics gain back some weight within five years of becoming ill, anorexia is the deadliest of all mental disorders.
Though anorexia tends to run in families, scientists haven’t yet hammered out the suite of genes at play. Some individuals are particularly vulnerable to developing an eating disorder. In these people, stressful life changes, such as heading off to college, can tip the mental scales toward anorexia.
For decades, scientists have known that anorexic children behave a little differently. In school and sports, anorexic kids strive for perfection. Though Heenan, a former college basketball player, didn’t notice her symptoms creeping in until the end of high school, she remembers initiating strict practice regimens as a child. Starting in second grade, Heenan spent hours perfecting her jump shot, shooting the ball again and again until she had the technique exactly right — until her form was flawless.
“It’s very rare for me to see a person with anorexia in my office who isn’t a straight-A student,” Lock says. Even at an early age, people who later develop the eating disorder tend to exert an almost superhuman ability to practice, focus or study. “They will work and work and work,” says Lock. “The problem is they don’t know when to stop.”
In fact, many scientists think anorexics’ brains might be wired for willpower, for good and ill. Using new imaging tools that let scientists watch as a person’s mental gears grind through different tasks, researchers are starting to pin down how anorexic brains work overtime.
Different wiring: Studies of the brains of people with anorexia have revealed a number of complex brain circuits that show changes in activity compared with healthy people. Medical RF, adapted by M. Atarod
Control signs
To glimpse the circuits that govern self-control, experimental neuropsychologist Samantha Brooks uses functional magnetic resonance imaging, or fMRI, a tool that measures and maps brain activity. Last year, she and colleagues scanned volunteers as they imagined eating high-calorie foods, such as chocolate cake and French fries, or using inedible objects such as clothespins piled on a plate. One result gave Brooks a jolt. A center of self-control in anorexics’ brains sprung to life when the volunteers thought about food — but only in the women who severely restricted their calories, her team reported March 2012 in PLOS ONE.
The control center, two golf ball–sized chunks of tissue called the dorsolateral prefrontal cortex, or DLPFC, helps stamp out primitive urges. “They put a brake on your impulsive behaviors,” says Brooks, now at the University of Cape Town in South Africa.
For Brooks, discovering the DLPFC data was like finding a tiny vein of gold in a heap of granite. The control center could be the nugget that reveals how anorexics clamp down on their appetites. So she and her colleagues devised an experiment to test anorexics’ DLPFC. Using a memory task known to engage the brain region, the researchers quizzed volunteers while showing them subliminal images. The quizzes tested working memory, the mental tool that lets people hold phone numbers in their heads while hunting for a pen and paper. Compared with healthy people, anorexics tended to get more answers right, Brooks’ team wrote June 2012 in Consciousness and Cognition. “The patients were really good,” Brooks says. “They hardly made any mistakes.”
A turbocharged working memory could help anorexics hold on to rules they set for themselves about food. “It’s like saying ‘I will only eat a salad at noon, I will only eat a salad at noon,’ over and over in your mind,” says Brooks. These mantras may become so ingrained that an anorexic person can’t escape them.
But looking at subliminal images of food distracted anorexics from the memory task. “Then they did just as well as the healthy people,” Brooks says. The results suggest that anorexic people might tap into their DLPFC control circuits when faced with food.
James Lock has also seen signs of self-control circuits gone awry in people with eating disorders. In 2011, he and colleagues scanned the brains of teenagers with different eating disorders while signaling them to push a button. While volunteers lay inside the fMRI machine, researchers flashed pictures of different letters on an interior screen. For every letter but “X,” Lock’s group told the teens to push a button. During the task, anorexic teens who obsessively cut calories tended to have more active visual circuits than healthy teens or those with bulimia, a disorder that compels people to binge and purge. The result isn’t easy to explain, says Lock. “Anorexics may just be more focused in on the task.”
Bulimics’ brains told a simpler story. When teens with bulimia saw the letter “X,” broad swaths of their brains danced with activity — more so than the healthy or calorie-cutting anorexic volunteers, Lock’s team reported in the American Journal of Psychiatry. For bulimics, controlling the impulse to push the button may take more brain power than for others, Lock says.
Though the data don’t reveal differences in self-control between anorexics and healthy people, Lock thinks that anorexics’ well-documented ability to swat away urges probably does have signatures in the brain. He notes that his study was small, and that the “healthy” people he used as a control group might have shared similarities with anorexics. “The people who tend to volunteer are generally pretty high performers,” he says. “The chances are good that my controls are a little bit more like anorexics than bulimics.”
Still, Lock’s results offered another flicker of proof that people with eating disorders might have glitches in their self-control circuits. A tight rein on urges could help steer anorexics toward illness, but the parts of their brain tuned into rewards, such as sugary snacks, may also be a little off track.
Sugar low
When an anorexic woman unexpectedly gets a taste of sugar (yellow) or misses out on it (blue), her brain’s reward circuitry shows more activity than a healthy-weight or obese woman’s. Anorexics’ reward-processing systems may be out of order. Credit: G. Frank et al/ Neuropsychopharmacology 2012
For many anorexics, food just doesn’t taste very good. A classic symptom of the disorder is anhedonia, or trouble experiencing pleasure. Parts of Heenan’s past reflect the symptom. When she was ill, she had trouble remembering favorite dishes from childhood, for example — a blank spot common to anorexics. “I think I enjoyed some things,” she says. Beyond frozen yogurt, she can’t really rattle off a list.
After Heenan started seriously restricting her calories in college, only one aspect of food made her feel satisfied. Skipping, rather than eating, meals felt good, she says. Some of Heenan’s symptoms may have stemmed from frays in her reward wiring, the brain circuitry connecting food to pleasure. In the past few years, researchers have found that the chemicals coursing through healthy people’s reward circuits aren’t quite the same in anorexics. And studies in rodents have linked chemical changes in reward circuitry to under- and overeating.
To find out whether under- and overweight people had altered brain chemistry, eating disorder researcher Guido Frank of the University of Colorado Denver studied anorexic, healthy-weight and obese women. He and his colleagues trained volunteers to link images, such as orange or purple shapes, with the taste of a sweet solution, slightly salty water or no liquid. Then, the researchers scanned the women’s brains while showing them the shapes and dispensing tiny squirts of flavors. But the team threw in a twist: Sometimes the flavors didn’t match up with the right images.
When anorexics got an unexpected hit of sugar, a surge of activity bloomed in their brains. Obese people had the opposite response: Their brains didn’t register the surprise. Healthy-weight women fit somewhere in the middle, Frank’s team reported August 2012, in Neuropsychopharmacology. While obese people might not be sensitive to sweets anymore, a little sugar rush goes a long way for anorexics. “It’s just too much stimulation for them,” Frank says.
One of the lively regions in anorexics’ brains was the ventral striatum, a lump of nerve cells that’s part of a person’s reward circuitry. The lump picks up signals from dopamine, a chemical that rushes in when most people see a sugary treat.
Frank says that it’s possible cutting calories could sculpt a person’s brain chemistry, but he thinks some young people are just more likely to become sugar-sensitive than others. Frank suspects anorexics’ dopamine-sensing equipment might be out of alignment to begin with. And he may be onto something. Recently, researchers in Kaye’s lab at UCSD showed that the same chemical that makes people perk up when a coworker brings in a box of doughnuts might actually trigger anxiety in anorexics.
Mixed signals
Usually a rush of dopamine triggers euphoria or a boost of energy, says Ursula Bailer, a psychiatrist and neuroimaging researcher at UCSD. Anorexics don’t seem to pick up those good feelings.
When Bailer and colleagues gave volunteers amphetamine, a drug known to trigger dopamine release, and then asked them to rate their feelings, healthy people stuck to a familiar script. The drug made them feel intensely happy, Bailer’s team described March 2012 in the International Journal of Eating Disorders. Researchers linked the volunteers’ happy feelings to a wave of dopamine flooding the brain, using an imaging technique to track the chemical’s levels.
But anorexics said something different. “People with anorexia didn’t feel euphoria — they got anxious,” Bailer says. And the more dopamine coursing through anorexics’ brains, the more anxious they felt. Anorexics’ reaction to the chemical could help explain why they steer clear of food — or at least foods that healthy people find tempting. “Anorexics don’t usually get anxious if you give them a plate of cucumbers,” Bailer says.
Beyond the anxiety finding, one other aspect of the study sticks out: Instead of examining sick patients, Bailer, Kaye and colleagues recruited women who had recovered from anorexia. By studying people whose brains are no longer starving, Kaye’s team hopes to sidestep the chicken-and-egg question of whether specific brain signatures predispose people to anorexia or whether anorexia carves those signatures in the brain.
Though Kaye says that there’s still a lot scientists don’t know about anorexia, he’s convinced it’s a disorder that starts in the brain. Compared with healthy children, anorexic children’s brains are getting different signals, he says. “Parents have to realize that it’s very hard for these kids to change.”
Kaye thinks imaging data can help families reframe their beliefs about anorexia, which might help them handle tough treatments. He thinks the data can also offer new insights into therapies tailored for anorexics’ specific traits.
Sensory underload
One trait Kaye has focused on is anorexics’ sense of awareness of their bodies. Peel back the outer lobes of the brain by the temples, and the bit that handles body awareness pops into view. These regions, little islands of tissue called the insula, are one of the first brain areas to register pain, taste and other sensations. When people hold their breath, for example, and feel the panicky claws of air hunger, “the insula lights up like crazy,” Kaye says.
Kaye and colleagues have shown that the insulas of people with anorexia seem to be somewhat dulled to sensations. In a recent study, his team strapped heat-delivering gadgets to volunteers’ arms and cranked the devices to painfully hot temperatures while measuring insula activity via fMRI.
Compared with healthy volunteers, bits of recovered anorexics’ insulas dimmed when the researchers turned up the heat. But when researchers simply warned that pain was coming, other parts of the brain region flared brightly, Kaye’s team reported in January in the International Journal of Eating Disorders. For people who have had anorexia, actually feeling pain didn’t seem as bad as anticipating it. “They don’t seem to be sensing things correctly,” says Kaye.
If anorexics can’t detect sensations like pain properly, they may also have trouble picking up other signals from the body, such as hunger. Typically when people get hungry, their insulas rev up to let them know. And in healthy hungry people, a taste of sugar really gets the insula excited. For anorexics, this hunger-sensing part of the brain seems numb. Parts of the insula barely perked up when recovered anorexic volunteers tasted sugar, Kaye’s team showed this June in the American Journal of Psychiatry. The findings “may help us understand why people can starve themselves and not get hungry,” Kaye says.
Though the brain region that tells people they’re hungry might have trouble detecting sweet signals, some reward circuits seem to overreact to the same cues. Combined with a tendency to swap happiness for anxiety, and a mental vise grip on behavior, anorexics might have just enough snags in their brain wiring to tip them toward disease.
Now, Kaye’s group hopes to tap neuroimaging data for new treatment ideas. One day, he thinks doctors might be able to help anorexics “train” their insulas using biofeedback. With real-time brain scanning, patients could watch as their insulas struggle to pick up sugar signals, and then practice strengthening the response. More effective treatment options could potentially spare anorexics the relapses many patients suffer.
Heenan says she’s one of the lucky ones. Four years have passed since she first saw the anorexic brain images at UCSD. In the months following her treatment, Heenan and her family worked together to rebuild her relationship with food. At first, her fiancé picked out all her meals, but step by step, Heenan earned autonomy over her diet. Today, Heenan, a coordinator for Minneapolis’ public schools, is married and has a new puppy. “Life can be good,” she says. “Life can be fun. I want other people to know the freedom that I do.”
Searching for treatments
The bowl of pasta sitting in front of Kelsey Heenan didn’t look especially scary.
Spaghetti, chopped asparagus and chunks of chicken glistened in an olive oil sauce. Usually, such savory fare might make a person’s mouth water. But when Heenan’s fiancé served her a portion, she started sobbing. “You can’t do this to me,” she told him. “I thought you loved me!”
Heenan was confronting her “fear foods” at the Eating Disorders Center for Treatment and Research at UCSD. Therapists in her treatment program, Intensive Multi-Family Therapy, spend five days teaching anorexic patients and families about the disorder and how to encourage healthy eating. “There’s no blame,” says Christina Wierenga, a clinical neuropsychologist at UCSD. “The focus is just on having the parent refeed the child.” Therapists lay out healthy meals and portion sizes for teens, bolster parents’ self-confidence and hammer home the dangers of not eating. Heenan compares the experience to boot camp. But by the end of her time at the center, she says, “I was starting to see glimpses of what life could be like as a healthy person.”
Treatment options for anorexia include a broad mix of behavioral and medication-based therapies. Most don’t work very well, and many lack the support of evidence-based trials. Hospitalizing patients can boost short-term weight gain, “but when people go home they lose all the weight again,” says Stanford University’s James Lock, one of the architects of family-based treatment. That treatment is currently considered the most effective therapy for adolescent anorexics.
In a 2010 clinical trial, half of teens who underwent FBT maintained a normal weight a year after therapy. In contrast, only a fifth of teens treated with adolescent-focused individual therapy, which aims to help kids cope with emotions without using starvation, hit the healthy weight goal.
Few good options exist for adult anorexics, a group notorious for dropping out of therapy. New work hints that cognitive remediation therapy, or CRT, which uses cognitive exercises to change anorexics’ behaviors, has potential. After two months of CRT, only 13 percent of patients abandoned treatment, and most regained some weight, Lock and colleagues reported in the April International Journal of Eating Disorders. Researchers still need to find out, however, if CRT helps patients keep weight on long-term.
(Source: sciencenews.org)
![The Search for the Best Depression Treatment
Brain scans, blood samples, and other diagnostic tests could one day direct doctors to the best treatments for depression patients and uncover the biological basis of the condition.
When someone is diagnosed with depression, patient and doctor often begin a long trial-and-error process of testing different treatments. Sometimes they work, sometimes they don’t, so patients may try several options before finding the best one. But in the future, a brain scan, blood test, or some combination could help guide doctors to the best drugs, or lead them to suggest talk therapy.
Recently, Emory University researcher Helen Mayberg reported that a PET scan, a commonly used imaging method, can reveal whether a patient will respond better to an antidepressant or cognitive behavioral therapy. And in May, Medscape reported that David Mischoulon of Massachusetts General Hospital presented findings that the amount of a particular protein in the blood of depression patients could indicate whether a patient would do better by adding a form of folic acid to his or her treatment.
A key goal of such research is to distinguish between causes of depression. “The presence of certain biomarkers might give us a clue whether [a particular patient’s] depression is truly biologically driven, or whether it is depression like sadness over an event,” says Mischoulon. “If we can identify people who have these biological bases, it might suggest these patients might do better with medications, as opposed to psychotherapies or meditation.”
According to the World Health Organization, depression is the leading cause of disability globally. Many people do not seek or do not have access to treatment, and among those who do, fewer than 40 percent of depression patients improve with the first type of treatment they try. The problem is not that treatments like antidepressants and cognitive behavioral therapy don’t work, it’s that no one treatment works for every patient. Researchers from many disciplines, from neuroscience to genomics, are studying this complex disorder, which likely represents many different conditions with unique origins and treatments. Large clinical trials to predict a patient’s response to therapy or drugs based on brain or body biomarkers could improve treatment for future patients and perhaps uncover a clearer understanding of depression’s origins.
“You see now a number of big studies on predictive biomarkers,” says Mayberg, who has pioneered pacemaker-like implants as a treatment for severe cases of depression. She’s also involved in a large study of patients who will be treated with antidepressants or cognitive behavioral therapy based on brain scans. “It’s going to be interesting over the next year or two to see how this plays out,” she says. One question will be whether researchers will be able to identify markers that are both unambiguous but also practical to test. Brain scans may be the best place to start, she says, because they focus on the origin of the condition, but once good biomarkers are identified via brain scan, surrogates found in the blood may provide a simpler and more affordable option.
One challenge for researchers is that depression is probably a conglomeration of many diseases, says Madhukar Trivedi, a University of Texas Southwestern researcher heading a large trial that is trying to distinguish patients who respond better to one type of antidepressant compared to another. “There are a lot of subtypes in depression, so any given marker, whether genetic, protein, imaging, or EEG, ends up accounting for only a small percentage of variance for any group of patients,” says Trivedi.
If these researchers are successful, they could dramatically change how depression is treated and perhaps diagnosed. Doctors in the United States use the Diagnostic and Statistical Manual of Mental Disorders, or DSM, to diagnose depression. The diagnoses are largely based on the collection of symptoms presented or described by patients. In May, the head of the National Institute of Mental Health, Thomas Insel, announced that his institution would focus its research in areas other than the categories presented by the DSM. “Patients with mental disorders deserve better,” he said.
Bruce Cuthbert is heading the NIMH’s project to establish new ways of studying mental illness and potentially to improve future versions of the DSM by more precisely identifying the brain abnormalities in various diseases, including depression. The idea behind the project is to map out the genetic, circuit, and cognitive aspects of mental illness and to focus on individual features of disorders instead of clinical diagnoses. It could provide the information necessary to improve the DSM so that it is based on neuroscience and not just collections of symptoms. “In the future, we might define the disorders differently, or we might not. But this project will provide a framework to look at neural systems and how they operate and how that contributes to disease,” says Cuthbert.
Perhaps more immediately, the NIMH project could help researchers tune clinical trials of drugs to the right patients by focusing on discrete symptoms. For example, anhedonia, the inability to feel pleasure or seek pleasure, is a major symptom of depression, but it is also found in other patients, such as those with schizophrenia. By recruiting patients with measurable anhedonia, drug developers may be more likely to succeed in clinical trials than if they focused only on depression patients, says Cuthbert.
The NIMH project could also help to identify biomarkers of depression. “It could give us a structure to look at the pathology through different markers of the disease,” says Trivedi. “The goal is fantastic, but the proof is going to come in doing it.”](http://40.media.tumblr.com/2cee06d8ba637a69d1ed2f2d29d4c882/tumblr_mr0drrDP3b1rog5d1o1_500.jpg)
