By Matt Wood

In the field of pediatric eating disorder studies, you might think that the one thing on which researchers could agree would be how to determine the appropriate body weight for a child. An exact determination of expected body weight for adolescents based on age, height and gender is critical for diagnosis and management of eating disorders such as anorexia nervosa and bulimia. Surprisingly, however, there are no clear guidelines regarding the appropriate method for calculating this weight in children with such disorders.

In a study published this week in Pediatrics, researchers from the University of Chicago, the Harvard School of Public Health and the University of Rochester Medical Center tackled this problem. “It may seem perfectly straightforward to an outsider to the field: How can we not have figured this out yet? And yet we haven’t,” said study author Daniel Le Grange, PhD, professor of psychiatry and Director of the Eating Disorders Program at the University of Chicago. He and his colleagues compared three common methods for calculating expected body weight of adolescents with eating disorders and found that one in particular, the body mass index (BMI) percentile method, is recommended for clinical and research purposes.

“There are no clear guidelines in the adolescent field,” said Le Grange. “We set out to do something that is relatively straightforward that hasn’t been done before, and that is look at some of the most frequently used methods of calculating weight in the pediatric and adolescent eating disorder populations, and see whether we can come up with a gold standard for clinical as well as for research purposes.”

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By Matt Wood

Each day people make decisions about how much effort they’re willing to put into various tasks. The decision about how much effort to invest in an activity is influenced by the reward for doing something and the probability of actually getting it. You might be willing to work hard at your job because the reward—a paycheck—is both valuable and fairly certain. But you might not be willing to try a complicated new recipe for dinner, even though it sounds delicious, because of the chance that it won’t turn out well.

Animal studies suggest that the neurotransmitter dopamine plays an important role in this type of decision-making, especially the decision to expend effort. In rats, dopamine levels influence tolerance for effort and probability costs. Rats with higher levels of dopamine are more willing to press levers and climb over barriers to reach better food, whereas those with lower levels will settle for food that’s less tasty but within easy reach.

Little is known about how dopamine affects effort-based decision-making processes in humans. But a new study published in The Journal of Neuroscience by Margaret Wardle, a post doctoral researcher in the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago, her mentor Harriet de Wit, Professor and Director of the Human Behavioral Pharmacology Laboratory, and colleagues at Vanderbilt University shows for the first time that people behave in much the same way. Their research, sponsored by the National Institute on Drug Abuse, not only sheds light on how dopamine influences decision-making in humans, but also points toward possible treatment for psychiatric disorders like depression.

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By Matt Wood

More than 1.25 million children in the United States, or one in every 58, suffered some kind of neglect or physical, emotional or sexual abuse in 2005-2006. Such maltreatment interferes with normal development and can lead to a host of psychological disorders and behavioral problems as they become adults, particularly aggression.

A new study by researchers from the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago takes that understanding a step further by examining the pattern of interaction between childhood maltreatment and “social information processing,” or the set of cognitive and emotional processes that control how people interpret social cues and determine the appropriate response. To help think about how social information processing works in everyday life, imagine if another driver cuts you off in traffic. Do you assume he did it on purpose, or just wasn’t paying attention? Do you get angry and honk your horn, or tap the brakes and let him pass?

Current research on the links between childhood maltreatment and aggression focuses mostly on how abuse or neglect affects the development of social information processing skills. Experiencing abuse or neglect during childhood is associated with increased deficits in the social information processing skills needed to handle potentially hostile situations like this, which in turn leads to higher levels of aggression in adolescence or adulthood. This is the “cycle of violence” that can lead children who were maltreated to become violent as adults.

The new study examines whether abuse or neglect actually amplifies the risk effects of biased social information processing on adult aggression. Pan Chen, a post-doctoral researcher and first author on the study, said, “Basically we expected to find evidence that biased social information processing is more likely to lead to aggressive behavior among people who were exposed to childhood maltreatment in comparison to those who were not.”

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Biology used to be the scientific discipline where data was at a premium, a rare resource painstakingly collected in the field or the laboratory. But today’s biologists are confronted with a flood of data, a fire-hose torrent of genetic and clinical information that only builds with the spread of fast sequencing and electronic medical records. But as these databases fill terabyte after terabyte of computer storage, the successful transformation of that data into practical information about human biology and disease has lagged behind. Genome-wide association studies (GWAS) have  explained only a small percentage of disease heritability, clinical records remain largely unstudied on a large scale, and the complications created by environmental influences and multi-gene disorders have frustrated scientists.

Into this impasse comes a new multi-institutional project based at the University of Chicago: the Silvio O. Conte Center, funded by a nearly $14 million combination of grants from the National Institute of Mental Health and the Chicago Biomedical Consortium. Led by Andrey Rzhetsky, professor of medicine and human genetics at the Medical Center, the collaboration of 15 scientists from 7 institutions will apply the power of advanced computation and data-mining to the growing tide of data collected about neuropsychiatric disorders. The trick will be to not just focus on one database, be it genetics or environmental factors or clinical outcomes, but all of them at once, creating a higher-resolution image of what goes awry in the brain to cause mental disease.

“A great deal of data already exists, yet nobody is already looking at it the way we plan to do and we have very smart people on this team,” said Rzhetsky, who is also a senior fellow of the Computation Institute at the University of Chicago and Institute for Genomics and Systems Biology. “When you have multiple communities that partially study the same subject you can get a kind of three-dimensional picture of a phenomenon.”

Rzhetsky has previously demonstrated the promise of data-mining - the discovery of patterns and information in large pools of data - using clinical records and scientific literature. In a 2007 study, his team examined 1.5 million patient records and found significant overlap between mental disorders such as schizophrenia, bipolar disorder, and autism, suggesting a similar overlap of the genetic factors that cause these conditions. Two years later, Rzhetsky and colleagues applied text-mining computation to the scientific literature database PubMed, creating a network of genes and biological interactions associated with cerebellar conditions such as ataxia and degeneration.

Beyond demonstrating the potential of data-mining, those studies also shed light on the hazy borders separating different psychiatric disorders. While the overlaps could complicate psychiatric diagnosis in the clinic, they might also make the disorders susceptible to the multi-faceted approach proposed by the Conte Center.

“Most studies are done one disorder at a time, and that’s like studying the trunk or the hoof or the tail of an elephant; you might miss the big picture,” said Benjamin Lahey, Irving B. Harris Professor of epidemiology at the University of Chicago and a co-investigator at the Conte Center. “This project will enable us to look at things in a way that has never been done before, at a scale that dwarfs anything that’s ever been done.”

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A visit to any casino will quickly demonstrate how vices clump together. At any hour of the day or night, many of the customers sitting intently in front of a slot machine will also be smoking cigarettes or drinking a cocktail. Sadly, addictions to these pursuits also tend to go hand in hand, with higher rates of compulsive gambling observed in people addicted to drugs such as cocaine and alcohol. Furthermore, when people perform gambling-like tasks while their brain is scanned by an MRI machine, the games activate areas of the brain also stimulated by drugs of abuse - perhaps accounting for the addiction-like behavior of gamblers.

“If you’ve ever been to a casino, and you watch people using slot machines, you’ll surely have noticed the sense of compulsion to put the next coin in, even though you get no money back most of the time,” said Paul Vezina, professor of psychiatry and behavioral neuroscience at the University of Chicago.

But does one bad habit truly lead to the other? In a recent paper for the journal Behavioural Brain Research, a team from Vezina’s laboratory offers evidence that the unpredictability crucial to gambling’s appeal can cross over to enhance the effects of abused drugs. By adapting self-administration, a common tool used to model drug-taking in animal research, to partially replicate the random pay-off of a slot machine, graduate student Bryan Singer was able to test whether gambling-like behavior influences a rat’s subsequent response to the drug amphetamine. The result suggests that gambling may have properties similar to a “gateway drug,” as an activity that can increase the abusive potential of drugs.

First of all, how do you simulate the casino experience for a rat? Self-administration - where the animal presses a lever to receive a food or drug reward - is fairly similar to a slot machine to begin with. In a self-administration protocol, the researcher sets the number of lever presses required before the reward is given. A “fixed ratio” of 5 means that the rat would have to hit the lever five times before receiving a food pellet or rewarding hit of cocaine. But with a “variable ratio” setup, unpredictability is introduced into the process. If the variable ratio is set to an average of 5, anywhere from 1 to 10 presses might be required to produce reward, a figure that changes every time like the random number generator of a slot machine. So while the rat does not have anything at stake other than the physical work it takes to hit the lever, it never knows when it will hit the “jackpot.”

“One of the main differences is that for a slot machine there’s a good chance you’re going to lose money, but here there’s little negative aspect,” Singer said. “It’s like a very loose slot machine.”

In this experiment, Singer and co-author John Scott-Railton used the non-caloric sweetener saccharine as a reward - a sweet treat that rats will work to acquire without ever getting full or intoxicated. For 55 days, half of the rats worked for saccharine under fixed ratio conditions and half worked under the variable ratio setup. Then, after a two week break, each rat was given a small dose of amphetamine, and researchers measured their activity as the dosed rats ran around their cage.

Even though the rats in each group received the same amount of saccharine and did the same amount of work during their lever-pressing careers, those exposed to the random rules of the variable ratio exhibited a stronger response to amphetamine. The result suggests that unpredictable rewards may prime the same brain areas hijacked by drugs of abuse, producing a stronger behavioral response - known in the field as sensitization - even upon first exposure to a stimulant drug.

“What this paper is showing is that unpredictable conditions may cause sensitization,” Vezina said. “There are activities that may play just as important a gateway role as drugs, and gambling may be one of them.”

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How do you know an animal model of a disease is really working? Researchers can create diseases such as cancer in a rat or mouse, but a tumor in a rodent may not behave the same way as a tumor in a human being. The challenge is even more difficult when scientists try to model psychiatric conditions, which in humans rely upon interviews and nuanced diagnosis. It’s hard to get a rat to stay on a therapist’s couch, much less ask whether they are feeling depressed or anxious.

So psychiatrists interested in using an animal model to probe the underlying biology of a mental condition are forced to be careful, clever and realistic. For a new model of obsessive-compulsive disorder (OCD) published last week by a team of scientists from the University of Chicago, the validity of the model was based on both the symptoms they observed in their animals and how those symptoms were treated.

More than 2 million people in the United States have been diagnosed with OCD, a condition marked by severe anxiety, repetitive behaviors, and intrusive thoughts. Yet only one drug has been found to help alleviate these symptoms - fluoxetine, a serotonin reuptake inhibitor originally developed for the treatment of depression - and the drug is only effective in roughly half of all OCD patients. Finding and testing better treatments for OCD will require animal models of the disease.

“Treatment for these people is greatly needed, and there really are very few highly valid animal models of the disorder,” said Nancy Shanahan, a postdoctoral researcher and lead author of the study in the journal Biological Psychiatry. “Having one that seems to mimic the disorder so well, especially in terms of the time course of treatments that work in humans, is potentially very useful for researching novel therapeutics.”

That’s easier said than done. The compulsive hand-washing, switch-flicking, or counting habits of human OCD sufferers would seem to be impossible symptoms to replicate in a rat, but some characteristics such as perseveration (repetitive movements or actions) and movement in an open field (a marker of a rodent’s comfort or anxiety in a strange environment) have been used by scientists as proxies for the debilitating effects of OCD. Some groups have created these behaviors by deleting genes, but for the new OCD model the UChicago team started with the unusual side effect of a migraine medication.

When the drug sumatriptan is given to people with OCD, it amplifies their symptoms, producing more intrusive thoughts and rituals. Shanahan gave her mice a similar drug that, like sumatriptan, activates a sub-class of receptors for the neurotransmitter serotonin called 1b receptors. In response, the mice showed behaviors that could be interpreted as OCD-like. Instead of exploring the entirety of their cage, they stayed close to the walls (as seen in the paths above) - a marker of high anxiety. Another test called prepulse inhibition that tests the animals’ startle response (thought to measure the brain’s ability to filter out intrusive thoughts), also revealed OCD-like behavior after the serotonin 1b drug was given.

Yet it’s still subjective to say that a mouse that paces around the walls of its cage is suffering from the same underlying biological issues as a human whose anxiety keeps them from leaving the house. More evidence was needed to prove the model’s “predictive validity” - how closely it resembles the human disease.

“A model should be evaluated on its ability to predict, not based on how much it looks like OCD,” explained Stephanie Dulawa, assistant professor in the Department of Psychiatry and Behavioral Neuroscience and senior author of the study. “The best way to do that is to evaluate manipulations with known effects in OCD.”

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Students might sometimes think that their textbook appeared out of thin air, the accumulated knowledge of a field spontaneously forming into a heavy slab of facts and figures. But textbooks are like any other type of book, with flesh-and-blood authors who labor over the words within and make a million tiny decisions to shape the final product. If you try to include everything, the book will likely be too heavy for even the most determined or muscular students to carry. Cut too much out, and your definitive textbook might be scorned as incomplete and elementary.

In writing her new textbook, professor of neurobiology Peggy Mason helped find the happy middle by starting with a very specific audience in mind: the medical students that she has spent 15 years teaching at the Pritzker School of Medicine. Her completed product, simply named “Medical Neurobiology,” is the first designed with aspiring physicians in mind, teaching med students about the broad influence of the central nervous system. Picking a specific target audience helped Mason make the hard choices about what to include and what to leave out, she said - even if the final 660 pages is heavier than she intended.

“I think it’s actually the only textbook completely aimed at the medical students,” Mason said. “I did a few things because of that that no other textbook does.”

For starters, Mason chose not to interpret “medical neurobiology” as simply “neurology.” Only a small percentage of medical students will eventually choose to train as neurologists, but the other 97 percent also need to be familiar with the central nervous system, she said. Knowing the anatomy and function of the brain, spinal cord, and nerve pathways can help everyone from future neonatologists measuring infants’ reflexes to future pulmonologists treating asthma to future geriatricians looking for the warning signs of dementia or motor deficits.

Another important decision came to Mason after a dinner with four medical students who gave her insight into the overwhelming workload of an aspiring doctor.

“All of a sudden I just realized that the immensity of the knowledge base that they need to acquire in two years,” Mason said. “It made me think anew about what we were teaching them, and I decided that as entertaining as it may be for us to talk about the newest, greatest research, it’s a disservice to them. They don’t have the time; they need the body of information that they need clinically and not the extraneous stuff. So I tried to cut out as much as I could.”

Mason kept the page count down by restricting the coverage wherever possible to topics of clinical relevance, leaving out popular neuroscience textbook subjects such as the fundamentals of smell and leech swimming (a common model for the neurobiology of locomotion). Instead, she focused on the anatomical regions where patients are most likely to suffer lesions that cause symptoms, and the neurotransmitter imbalances that cause behavioral changes. Pop-out boxes describe the clinical manifestations physicians are likely to see, such as the pupil constriction and droopy eyelid of Horner syndrome, which indicates damage to a specific pathway from the brain to the eye.

But to really help important neurobiology topics take up permanent residence in the minds of medical students, Mason deployed an armory of inventive examples and metaphors to make the text both enjoyable to read and memorable.

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Last November, a barrier was broken in the prolific Bollywood film industry of India. A film called Dunno Y featured the first on-screen male-male kiss - a provocative scene in a country that only the year before repealed a law making homosexuality illegal. Many tagged the film as India’s version of Brokeback Mountain, a controversial and progressive step in depicting male-male romance in popular culture that reflected a growing social acceptance of homosexuality. But the full significance of those cultural changes in the South Asian country have yet to be studied, and will require perspectives from law, anthropology, medicine, and more.

Just such a discussion will take place this Saturday morning at the University of Chicago and on the internet in the roundtable event, “Sexual Identity, Health and Stigma in India: Traditional Statuses and Western Influences.” Organized by John Schneider, assistant professor of medicine and epidemiology at the University of Chicago Medical Center and director of Global Health Programs, the discussion will be available worldwide on a webcast broadcast by the UChicago Facebook page, the Global Health Initiative website, and here on ScienceLife (watch this space).

“What I tried to do is bring together scholars from a number of different disciplines to make this a truly interdisciplinary discussion,” Schneider said. “I want it to be like a Sunday morning news program - but smarter - where a topic area is chosen and everybody fires away with their background about it, leaving room for remote viewer input.”

The central topic of whether sexual identity in India is truly shifting can be addressed from any number of angles. There’s the legal status of homosexuality after the 2009 repeal of Section 377 of the Indian Penal Code by the High Court of Mumbai. Or the sexual and mental health consequences after centuries of stigmatization of men having sex with men, including the spread of HIV and other sexually transmitted diseases. Or the pop culture ripples, such as Dunno Y, that may reflect changing attitudes and sexual roles in Indian culture. All of which are set against the backdrop of a country rapidly modernizing and playing an increasingly powerful role in global economy and society.

“I think that India is going through tremendous social and cultural changes as it emerges from what would be, in old terms, a less-developed economy to now becoming something of an economic powerhouse,” said Niranjan Karnik, assistant professor of psychiatry and behavioral neuroscience and another participant in the event. “This has the potential to really change the dynamics of the society and change the way people see themselves and behaviors.”

The participants in the roundtable are all accomplished researchers and experts on India. The keynote speaker, Lawrence Cohen of the University of California, Berkeley, studies medical anthropology in the country, and has written on homosexuality, aging, and organ transplant markets. Philip Kumar and Sanjay Srivastava are researchers based in India studying sexuality and advising the government on health issues related to men who have sex with men. Schneider himself has an extensive project underway in Indian truck drivers, where he is using cell phones in building a network of men who have sex with men to study their behavior and identify potential peer outreach points.

“One of the issues we are looking at is what changes in sex position roles might be occurring over time in India,” Schneider said. “Is a Western identity rubbing off on India, or is it developing a new identity? My work will help address those questions because of the cell phone network data that triangulates often sensitive self-reported data,” Schneider said.

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The odds of acquiring a disease are often portrayed as a tug of war between two foes: genes and environment. The battle is not always evenly matched. A disease such as cystic fibrosis is entirely genetic - if a child inherits the mutated CFTR gene from both parents, no environment will prevent the condition. On the other hand, environment can trump genetics for many other diseases, such as the relationship between exposure to the toxic substance arsenic and the cancer mesothelioma. But in most places, the tug of war is a more balanced contest, with the genetic factors controlling risk competing with a range of environmental factors from diet and exercise to education and climate.

Scientists have traditionally kept score on these competitions using a measure called heritability, the percentage of a phenotype (a disease or characteristic) that is determined by genetic factors. One way to measure heritability is with twin studies, which assemble data from thousands of pairs of identical or fraternal twins as a natural experiment of whether genes or environment win out. But a new study from University of Chicago psychiatry researchers shows that the blanket term of “environment” does not have to mean things outside the body - it can also refer to the biological state inside the body.

For the paper, published last month in Behavioral Genetics, a team led by post-doc Terrie Vasilopoulos set out to test the relationship between two health conditions: hypertension and cognitive decline. Previous research examining this link established hypertension as a risk factor for the loss of cognitive ability late in life, producing decreases in performance similar to those seen in Alzheimer’s disease and other forms of dementia. Meanwhile, heritability research revealed that genetics play a large part in a person’s risk of cognitive decline in their golden years. So does the “internal environment” of hypertension - and whether it is treated - move the tug-of-war of heritability for cognitive issues toward genes or environment?

To test this hypothesis, the team used data from the Vietnam Era Twin Study of Aging - over 1,200 male-male twin pairs who served in the military between 1965 and 1975. With an age range between 51 and 60, the researchers looked at an important time in a man’s cognitive lifetime before the first signs of dementia typically set in, Vasilopoulos said.

“We really think we are capturing a very important developmental period with the guys that we’re studying, especially for cognitive phenotypes,” said Vasilopoulos, a researcher in the laboratory of Kristen Jacobson, assistant professor of psychiatry. “The groundwork for these bad things that are happening to you later in life are being laid when you’re much younger. By finding these mechanisms early in life, we can start to figure out better game plans of trying to protect people and help people make smarter choices when younger so we don’t see these bad effects when they’re older.”

The men were divided into three groups: those with hypertension receiving treatment, those with untreated hypertension, and those without hypertension. On overall measures of cognitive ability, the three groups showed no differences in performance, suggesting that the researchers were indeed looking at an age before any noticeable decline begins. But when the heritability of different cognitive measures was examined, a relationship with hypertension and anti-hypertension medication emerged.

For two measures - episodic memory and visual-spatial ability - the heritability of how a person performed on the tests actually decreased in those with untreated hypertension, relative to the other two groups. That is, in men with high blood pressure not taking medication, the “internal environment” of the disease outweighed the influence of genetics on two early warning signs of cognitive problems.

“These are the two types of cognitive domains that are first affected by age-related cognitive decline,” Vasilopoulos said. “In Alzheimer’s disease or other types of neurodegeneration or just regular aging, those are the most affected or first affected. So we really think we are honing in on the mechanisms of why hypertension is bad for cognitive performance late in life.”

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Over the year-long discussion of health disparities in the MacLean Center for Clinical Medical Ethics seminar series, the health gaps presented between American whites and blacks have been predominantly a one-way street. On nearly every health measure - from infant mortality to diabetes to cardiovascular disease - higher rates are observed for African-Americans. But there’s one health gap where the racial positions are surprisingly flipped, said James Jackson of the University of Michigan in his visit to the series in early May. Over the course of a provocative talk, Jackson demonstrated how this strange reverse disparity in mental health could be hiding a model explaining the physical health gaps that continue to resist reduction efforts.

In a 2007 study, a survey project led by Jackson measured the lifetime prevalence of major depressive disorder in African-Americans, Caribbean blacks, and white Americans. An almost complete reversal from the normal health disparity was observed, with roughly 18% of whites diagnosed with major depression at some point in their lives, compared to only 10.4% of African-Americans. The data, though replicated several times, was initially greeted with skepticism by observers who were mostly familiar with biased data based on hospital admissions, Jackson said.

“When people noticed this, they really began to contort  the data,” said Jackson, a psychologist and director of the Institute for Social Research at the U. of M. “The argument was that there must be something wrong with the way it was assessed, because everybody knows that African-Americans have to have higher rates of psychiatric disorders than whites.”

But now that the reverse disparity has been verified in many different populations, Jackson has started to ask why these differences exist. His working theory hinges on two other observations: the delayed appearance of physical health disparities over the course of life, and cultural differences in the way people cope with stress. When well-known health disparities on measures such as diabetes or hypertension are broken down by age, there is not a consistent gap between blacks and whites, but a gap that emerges and rapidly grows in middle age (45-64 years old). Putting aside differences in infant mortality rates, some evidence actually suggests that black children are healthier than white children on many measures, Jackson said.

The growing gap in health measures over the life course is paralleled by another growing gap - in the frequency of poor health behaviors. In white populations, smoking rates peak in young adulthood and then decline, while the rate in black populations accelerates with age. The same pattern holds true for heavy alcohol use and drug use, Jackson said, while frequency of vigorous physical activity declines with age faster for black females than white females. Obesity is more complex - it is the only black-white difference observed early in life, at least for females - but this gap also widens over life course, regardless of socioeconomic status.

The core of Jackson’s theory was to cast those physically unhealthy behaviors not as mere vices, but as methods people use to self-medicate themselves against the stress of daily living.

“If you’re having a bad day…you know it. At the end of the day, your stomach is upset, you have a headache. There are palpable things that are present with regard to the stress reaction to the circumstances,” Jackson said. “But if you are growing a tumor for cancer, you don’t know it, until it reaches a certain stage.”

“If you know you’re having these stress-related kinds of problems, this awareness motivates you to action - you are motivated to do something about the physiological and psychological consequences of stressors in your life. And what do you want to do? People eat comfort food to reduce stress, the activity in the chronic stress response network,” Jackson said. “If I’m stressed, a Twinkie makes me feel better.”

Self-regulating stress can also go beyond junk food, Jackson said, to severe drug and alcohol use. All of these coping strategies may help dampen the stress response and protect mental health, but only at the cost of exacerbating physical health problems.

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In the 11 years since the blueprint of human life was decoded by the Human Genome Project, much of the focus has been on when those instructions fail. Scientists have used our newfound genetic knowledge to look for the roots of common and rare diseases, the gene or genes that can increase the risk of everything from heart disease to cancer to asthma. But setting the stage for future illness is not the purpose of genes, of course. By coding for the proteins that make up the body and brain, genes lay the foundation for everything we do, feel, and probably even think.

Like the study of disease, genetic studies of human behavior have mostly focused on the abnormal - the targets of psychiatry. Mental illnesses such as schizophrenia, depression, and drug addiction have been the subjects of genetic hunts, known as genome wide association studies, where the ill are compared to controls to reveal genes that might be involved in the a particular disorder. As with diseases in the rest of the body, psychiatric disorders have mostly resisted easy genetic explanations - only a small percentage of schizophrenia, for instance, has been traced to genetic causes.

A more useful, but also vastly more complicated, approach might be to study not the binary comparison of healthy vs. sick, but the whole spectrum of human behavior. For example, rather than just looking at those with extreme enough depression symptoms for a clinical diagnosis and those who don’t, scientists could look at genes in subjects who are rarely, mildly, or frequently affected by depression, as well as those on the extremes. Such analyses may get closer to the genes and brain structures that control human behavior, both in everyday life and when it breaks down.

These types of experiments have caught the imagination of Abraham Palmer, assistant professor of human genetics at the Medical Center. In collaboration with the laboratory of Harriet de Wit, professor of psychiatry, Palmer has started to look at the behavioral trait of impulsivity, which has been associated with attention deficit disorder and predisposition to drug abuse.

“We’re coming at it from a tradition that’s very psychology, drug abuse-based, but we’re really interested in asking questions that get at the broadest range possible of behaviors,” Palmer said. “These are continuous traits that everybody in the population will have some value for. We’re not talking about it exclusively from a disease perspective. These are healthy people coming in.”

Palmer used Donald Rumsfeld’s infamous quote about known knowns, known unknowns, and unknown unknowns, to illustrate how studies of genes and behavior have classically been limited by the tunnel vision of previous knowledge. If a particular gene is already known to play a role in a behavior, scientists can study how individual variants in that gene correspond to behavior. In one such project, Palmer was part of a team that looked at the D2 dopamine receptor - a neurotransmitter receptor linked with the response to drugs of abuse - and impulsive decision-making.

Volunteers came to the laboratory and performed a “stop task,” a common psychology test. The subject is trained to look for a “go signal” and start hitting a certain keyboard key as quickly as possible until the “stop signal” sounds. The delay between the go and stop signals is steadily decreased with each round, and the ability of the subject to stop on time is measured. Researchers then compared their D2 genotype to their behavioral score, and found a link between different D2 variants and more “impulsive” results on the stop task.

These results help researchers study possible genetic predisposition for drug abuse or addition. But Palmer said he wants to expand the search beyond genes that are already implicated in behaviors and beyond psychiatric conditions.

“We’ve mostly looked at candidate genes, genes where we had reason to think it might modulate a behavior,” Palmer said. “But the more interesting question, if you had a sufficiently large sample and enough power, is to say let’s go at this with a blank state, let’s look at all the polymorphisms in a genome and pull out novel things maybe in genes we had never thought to be related to these processes.”

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Despite what beer commercials tell you, not everyone responds to alcohol in the same way. For some people, an alcoholic drink is a party-starter, increasing energy and sociability. For others, a drink can be a party-ender, producing feelings of fatigue and sluggishness. In pharmacological terms, alcohol is a mixed stimulant/depressant, able to produce a wide range of behavioral effects. But does an individual’s place on this spectrum of alcohol response predict more than their night on the town? Can it say something about their future potential to binge drink, or abuse alcohol in other ways?

Classically, psychiatrists have linked an individual’s alcohol response to their potential for abuse through one simple word: tolerance. According to the low-level response theory,  reduced “intoxicating” effects of alcohol were associated with heavier drinking, as individuals have fewer internal cues warning them to stop. But the experiments that informed the low-level response theory focused on the depressant effects of alcohol, measuring predominantly sedation in test subjects. What about the positive and rewarding effects that inspire some people to drink in the first place?

“What is intoxication? It’s really bi-modal,” said Andrea King, professor of psychiatry and behavioral neuroscience at the Medical Center. “Some people can think intoxication is great - you’re drunk, it’s fun - while others think of it as something bad, that it’s a toxic reaction.”

King studied both of those alcohol responses in a 2002 study, giving heavy and light drinkers a disguised drink in a laboratory and asking the how it made them feel on a variety of measures. The study found that heavy drinkers were indeed more likely to report positive and rewarding effects of alcohol, even when they didn’t know it was alcohol they were drinking. From that small study, King and her team sought to both expand their subject pool and follow participants for years to see how their acute responses in the lab tests might predict their future drinking behavior.

The first data from that epic undertaking - a two-year followup of nearly 200 subjects aged 21 to 35 - was published yesterday in Archives of General Psychiatry. True to King’s hypothesis, an individual’s response to a mystery drink was predictive of how their drinking behavior evolved over the following two years, with both stimulant and sedative effects playing a role. While some subjects who were heavy drinkers at the time of the original experiments curtailed their binge drinking episodes, others demonstrated an “exacerbating” trajectory, binge drinking more frequently - up to half of the days in a month.

The path a subject followed could be foretold by their acute response to alcohol in the lab. Subjects with both higher sensitivity to the rewarding effects of alcohol and lower sensitivity to its depressant effects were found to have the most alcohol problems in the follow-up period. Those subjects drank more and more often, increased the frequency of binge drinking, suffered more alcohol-related consequences, and were more likely to qualify for a diagnosis of an alcohol-use disorder.

“The results change our thinking about how alcohol responses affect the development of an alcohol-use disorder,” King said. “It’s not just overall tolerance, but also sensitivity to alcohol’s euphoric effects that increases risk for excessive drinking.”

This new theory, dubbed a “modified differentiator theory” in King’s paper, could be a game-changer for how substance abuse experts identify people at-risk for alcohol problems.  Those who respond very positively to an alcoholic drink might be warned early on that they are at elevated risk for drinking problems.

“If we know more about who’s going to become a problem drinker, we may be able to prevent future escalations and intervene earlier, before development of severe alcoholism,” King said. “The stimulant-type responder could learn that while such a response pattern may not be their fault, it could put them at risk for longer-term problems and consequences.”

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For some diseases, taking a census is easy. Most people who have cancer are diagnosed with the disease before they die and seek treatment, allowing for the collection of detailed national cancer statistics. But other diseases tend to hide in the shadows, undetected and under-counted due to infrequent diagnosis or an unwillingness of patients to seek treatment. Into this latter group falls the eating disorders: anorexia nervosa, bulimia nervosa, and other conditions. Because many of these patients try to avoid treatment, psychiatrists have long suspected the numbers are skewed because only a subset of people suffering from eating disorders find their way to their clinical practice.

“We only see the tip of the iceberg,” said Daniel Le Grange, professor of psychiatry and director of the University of Chicago Eating Disorders Program. “As clinicians and researchers, we’ve known that in the community there are thousands of people out there with eating disorder behaviors that we never see in our clinics.”

Hard data on the frequency of eating disorders in the broader community has been hard to come by. But a new survey study of over 10,000 adolescents, released last week in the Archives of General Psychiatry, confirmed that the iceberg of eating disorder prevalence among American teens is as broad below the surface as psychiatrists suspected. Almost 6 percent of those surveyed in the study met the criteria for one of the five eating disorders tested at some point in their lifetime, a number extrapolated by some media outlets to 500,000 teens in the United States.

But the total numbers were just one of the eyebrow-raising results of the research. Le Grange, a co-author on the study, sat down with ScienceLife and detailed the most significant findings of this long-awaited census, and discussed its implications for the nature of these diseases and the patients who are slipping through the field’s fingers.

1. The Myth of Rarity

Health care dollars are not infinite, and cynical as it may sound, diseases must compete for research funding and insurance reimbursements. So when conditions such as eating disorders are perceived as rare occurrences, the people who treat and study those conditions face an uphill struggle for attention and support. Thus, the under-reporting of eating disorder prevalence has held the field back from being considered as a priority concern in adolescents. The new numbers - lifetime prevalences of 0.3% for anorexia nervosa, 0.9% for bulimia nervosa, 1.6% for binge-eating disorder, and 3.3% for sub-threshold disorders - lift eating disorders into a higher tier of concern for teenage and adult health.

“The myth has been that eating disorders and especially anorexia nervosa are relatively rare disorders, and we constantly have to argue that they’re not, because that’s what it feels like when we sit in clinical practice and we are inundated by patients,” Le Grange said. “This is robust data to demonstrate that eating disorders are not rare.”

2. A Gender-Blind Illness

In the clinic, psychiatrists see far more girls with eating disorders than boys - a ratio of 9-to-1. But surprisingly, the community survey revealed roughly equal prevalence for anorexia nervosa in males and females, suggesting that boys are not less likely to suffer from the condition, but are much less likely to be diagnosed and treated. Le Grange said he suspects that physician bias may lead them to more quickly consider an eating disorder  when the patient is a she rather than a he.

“We are so convinced that anorexia nervosa is predominantly a female disorder that pediatricians and mental health professionals, when presented with a boy who’s lost weight, do not consider anorexia to be a legitimate  diagnosis,” he said. “When we do see boys in our clinic, they usually have had an extensive preliminary workup, as the clinicians don’t consider an eating disorder…until everything comes back negative.”

3. Effects Beyond Mealtime

Psychiatrists observe that eating disorders don’t typically occur in isolation, as patients often carry “co-morbid” psychiatric issues such as depression or anxiety. The community survey puts a number on this observation, finding that the majority of those that met the criteria of an eating disorder also met the criteria of at least one other psychiatric disorder. Perhaps most alarming was the very high occurrence of suicidal thoughts and attempts in adolescents with eating disorders - more than half of those with bulimia nervosa reported thinking about suicide, and more than a third reported attempts.

Also striking was that these associations were just as common for kids who exhibited “sub-threshold” eating disorders, those did not meet the full criteria for anorexia nervosa or bulimia nervosa. In the DSM-IV, the diagnostic bible of psychiatry, such patients would be lumped into the category of Eating Disorders Not Otherwise Specified (EDNOS). The health risks associated with these patients suggest that EDNOS should not be seen as any less severe an illness, Le Grange said.

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Here’s how genetic medicine was supposed to work. Once the basic menu of human genes was mapped by the Human Genome Project, scientists could turn their attention to gene variants associated with common diseases. These disease-associated variants had to be relatively common; according to the “common disease, common variant” theory, rare variants with negative effects would quickly be removed by natural selection. So hundreds of studies - called genome-wide association studies, or GWAS - were organized to compare common gene variants in people with and without a specific disease or trait. Once the gene variants associated with heart disease, diabetes, or psychiatric disorders were found, treatments to cure those diseases would follow.

But ten years later, that simple process hasn’t quite worked as well as hoped. GWAS has revealed some 400 gene variants responsible for traits and diseases. But for many of the largest medical targets, the GWAS results have fallen far short, finding variants that only explain a small fraction of the disease. For a highly heritable disease such as schizophrenia, which afflicts both members of an identical twin pair 60 percent of the time, this is a mystery. The gap between GWAS and twin studies inspired an influential 2008 Nature news story with a headline worthy of the Hardy Boys: The Case of the Missing Heritability.

One place where scientists are looking for their lost heritability has to do less with the content of a gene variant than how often it appears in a person’s genome. Copy number variants, or CNVs, are errors of replication in the genetic code where stretches of DNA are deleted or duplicated, leaving behind zero copies of a genetic region, or two copies, or even more. These copy errors are more common than traditional gene mutation (100 to 10,000 times more frequent), and some CNVs can have dramatic consequences.

“These are very frequent events,” said Elliot Gershon, professor of psychiatry and human genetics. “They are important causes of disease and they turn out to be important causes of neuropsychiatric diseases.”

Schizophrenia is one disease where several CNV associations have been found in recent years, including the latest, published last week in Nature. Gershon, whose laboratory has studied the genetics of schizophrenia and bipolar disorder, contributed “interpretation of data” to the new study and said that it adds more weight to the argument that rare copy errors, not only common variants, can be important drivers of common diseases.

“The importance of a finding like this is that rare mutations were not thought to be generally a cause of common disease,” Gershon said. “But this is another rare variant that can cause schizophrenia.”

The new CNV, a duplication found on chromosome 7, was found in 29 of 8,290 schizophrenic patients tested in the study, compared to only 2 of 7,431 controls. It’s notable, Gershon said, for being a duplication rather than a deletion - instead of eliminating genes, it appears to increase the transcription of one specific gene, called VIPR2. This gene also implicates a previously unrecognized target for potential schizophrenia therapy, the vasoactive intestinal peptide system, previously associated with brain functions such as circadian rhythms and secretion of the hormone prolactin (involved in lactation and some sexual behaviors).

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Tablets of olanzopine, an atypical antipsychotic drug (from Wikimedia Commons)

If you watch enough football games, you might come away with the impression that today’s most profitable drugs are for erectile dysfunction, cholesterol, and allergies. But far less public attention is paid to one of the most expensive classes of drugs : the antipsychotics, drugs designed to treat certain mental disorders. From 1995 to 2006, the number of doctor visits where antipsychotics were prescribed or continued tripled from 6.2 million to 16.7 million, reflecting a nearly $10 billion chunk of the industry. What’s more, the majority of those prescriptions and dollars result from off-label uses of the drugs to treat illnesses where the clinical evidence of their effectiveness and safety is not crystal clear.

Those astonishing figures come from a new study by University of Chicago and Stanford University researchers, published earlier this month in Pharmacoepidemiology and Drug Safety. In the paper, a team led by G. Caleb Alexander, assistant professor of medicine at the University of Chicago Medical Center, used physician survey data to determine the trends and costs of antipsychotic use from 1995 to 2008. The results portray a corner of the pharmaceutical industry that has evolved at a much faster pace than regulatory agencies and the best scientific evidence can keep up with.

The history of antipsychotic medications stretches back more than 50 years to the first wave of agents, now called the “typical” antipsychotics. These drugs, with names such as haloperidol and chlorpromazine (more commonly known as Thorazine), were originally developed to treat the psychotic symptoms of schizophrenia. The typical antipsychotics led the field until the mid-1990’s, when a new class of “atypical” antipsychotics with a slightly different mechanism began to appear on the market for the treatment of schizophrenia, boasting of fewer motor side effects than the older drugs.

Despite the higher cost of atypical agents - typically 5 to 10 times that of the generic, typical agents - they quickly overtook their predecessors despite unconvincing evidence that they were safer or more effective. Though the atypical agents largely avoided the short-term dyskinesia seen with older antipsychotics, longer-term studies found effects upon weight gain and other metabolic conditions, leading to diabetes in some cases. Furthermore, when directly compared against the typical agents for treatment of symptoms such as mania in bipolar syndrome, atypical drugs were no more effective than the cheaper, older medications.

Alexander’s study shows the magnitude of that turnover: in 1995, 84 percent of antipsychotics used were from the typical group; in 2008, just 7 percent were typical therapies. Furthermore, the shift wasn’t simply a one-for-one replacement. From 2002 to 2006, the overall use of antipsychotics soared, with atypical agents leading the expansion into new uses of the drugs. Ironically, there was a return to using typical agents to treat schizophrenia over the 1995-2008 period studied, while atypical antipsychotics became popular for the treatment of bipolar disorder, depression, and other disorders that were beyond the scope of the original FDA approval.

“We saw remarkable changes over time,” Alexander said. “We know from other prescription drugs that uses change or evolve over time, and one reason is clinical innovation, but there’s also substantial over-use and over-adoption of therapies beyond the evidence base.”

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